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PHARMACOLOGY - MBBS 2nd PROF ANSWERS

Topics: General Pharmacology, ANS, Autacoids, PNS

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

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VERY SHORT QUESTIONS (3 MARKS EACH)

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Oral drug → GI tract → Portal vein → Liver → Systemic circulation
                ↓                      ↓
          Gut wall metabolism    Hepatic metabolism
                        (First Pass Effect)

• Reduces bioavailability of drug (e.g., GTN, morphine, propranolol - oral bioavailability very low)
• Requires higher oral dose than parenteral dose
• Can be bypassed by sublingual, rectal, transdermal, or IV routes
• Prodrugs are activated by first pass (e.g., enalapril → enalaprilat)

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PRODRUG (inactive) → Metabolism → ACTIVE DRUG (pharmacologically active)

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         TD₅₀
TI = ─────────
         ED₅₀

• High TI → Wide safety margin → Safer drug (e.g., penicillin, TI = very high)
• Low TI → Narrow safety margin → Dangerous (e.g., digoxin, warfarin, lithium, phenytoin)

• Drugs with low TI require therapeutic drug monitoring (TDM)
• Guides dose selection and route of administration
• Helps compare safety of drugs in same class
• Useful in determining loading and maintenance doses

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• Early detection of ADRs
• Assess risk-benefit ratio
• Improve patient safety
• Provide regulatory information

Spontaneous reporting (Yellow Card, PVPI India)
     ↓
Prescription event monitoring
     ↓
Case-control / Cohort studies
     ↓
Signal detection and regulatory action

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Drug crosses placenta → Acts on fetal tissues → Structural/functional defects
(Critical period: weeks 3-8 of gestation - organogenesis)

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1. Glaucoma - Miotic; causes contraction of ciliary muscle and sphincter pupillae → opens trabecular meshwork → reduces IOP (used as 1-4% eye drops)
2. Xerostomia - Stimulates salivary secretion in Sjogren's syndrome and post-radiation xerostomia (oral tablets 5mg)
3. To reverse mydriasis - After ophthalmoscopic examination using atropine

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Autoantibodies → Destroy nicotinic ACh receptors (NMJ) → Reduced ACh-receptor interaction
→ Muscle weakness and fatigue

Neostigmine (Anticholinesterase)
     ↓
Inhibits Acetylcholinesterase enzyme
     ↓
Prevents breakdown of ACh at NMJ
     ↓
Increased ACh concentration in synaptic cleft
     ↓
Stimulates remaining nicotinic receptors
     ↓
Improved neuromuscular transmission → Muscle strength restored

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Organophosphate + AChE → OP-AChE complex (initially reversible)
                                    ↓ (if not treated - "aging" occurs)
                          Irreversible OP-AChE complex

Pralidoxime (nucleophile) + OP-AChE complex
          ↓ (before aging)
Pralidoxime-OP compound + Regenerated FREE AChE
          ↓
Restored cholinesterase activity → Resolution of nicotinic symptoms

• Must be given EARLY (before "aging" of OP-AChE complex - within 24-48 hrs for most OPs)
• Effective for nicotinic (neuromuscular) symptoms - muscle paralysis
• Does NOT cross BBB well → does not help central symptoms much
• Always given WITH atropine (which handles muscarinic and CNS symptoms)
• Dose: Pralidoxime 1-2g IV slowly

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Triggering agents (Succinylcholine, volatile anesthetics)
     ↓
Mutation in ryanodine receptor (RYR1) on sarcoplasmic reticulum
     ↓
Massive uncontrolled Ca²⁺ release from SR
     ↓
Sustained muscle contraction → Heat generation → High fever (>40°C)
     ↓
Rhabdomyolysis, hyperkalemia, metabolic acidosis, cardiac arrest

Dantrolene → Blocks Ryanodine receptor (RYR1)
          → Prevents Ca²⁺ release from SR
          → Stops uncontrolled muscle contraction
          → Temperature normalizes

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1. Does not release histamine → safer in asthmatics and allergic patients
2. No ganglionic blockade → less hypotension
3. More potent → smaller dose needed

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Antigen + IgE on mast cells/basophils
     ↓
Massive histamine, leukotrienes, prostaglandins release
     ↓
Vasodilation, increased capillary permeability, bronchospasm
     ↓
Hypotension + Urticaria + Bronchospasm = Anaphylaxis

α₁ stimulation → Vasoconstriction → Raises BP, reduces edema
β₁ stimulation → ↑HR and contractility → Combats hypotension
β₂ stimulation → Bronchodilation → Relieves bronchospasm
β effect → Inhibits mast cell degranulation → Stops mediator release

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Adrenaline (α₁ agonist)
     ↓
Vasoconstriction at injection site
     ↓
Reduces systemic absorption of lignocaine
     ↓
Prolonged local anesthetic action (duration ↑ from 45-60 min to 2-3 hrs)
Reduced systemic toxicity of lignocaine
Reduced bleeding at operative site
Lower dose of LA needed

• Ring block (digits, penis, pinna) - risk of gangrene
• Patients on MAO inhibitors
• Thyrotoxicosis, severe hypertension

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Dobutamine (Synthetic catecholamine)
     ↓
Predominantly β₁ agonist (also weak β₂ and α₁)
     ↓
↑ Heart rate + ↑ Contractility (positive inotrope and chronotrope)
     ↓
↑ Cardiac output
     ↓
↑ Tissue perfusion → Correction of shock

• Less tachycardia (relatively)
• No dopaminergic receptor stimulation
• Less vasoconstriction → reduces afterload (beneficial)
• Does not raise pulmonary capillary wedge pressure as much

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Enlarged prostate → Dynamic (smooth muscle contraction α₁) + Static (enlarged gland) component
     ↓ 
Bladder outlet obstruction → Hesitancy, poor flow, frequency, retention

α₁A receptors present in:
• Prostate smooth muscle (predominant)
• Bladder neck
• Urethra
     ↓
Selective α₁A blockade
     ↓
Relaxation of prostate smooth muscle + Bladder neck
     ↓
Relief of dynamic obstruction
     ↓
Improved urine flow, reduced symptoms (IPSS score ↓)

• Tamsulosin: selective for α₁A > α₁B → less systemic hypotension, no first-dose effect
• Silodosin: more selective for α₁A → minimal cardiovascular effects

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Prazosin (α₁ blocker)
     ↓
First dose → Sudden blockade of α₁ receptors
     ↓
Marked vasodilation (arteriolar + venous)
     ↓
Severe postural hypotension, dizziness, syncope
     ↓
Especially on standing (within 1-3 hrs of first dose)

1. Start with very low dose (0.5 mg) at bedtime
2. Patient should be lying down when first dose is taken
3. Avoid concomitant diuretics or antihypertensives initially
4. Gradually titrate dose upwards
5. Adequate hydration before starting therapy

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β Blockers (e.g., Propranolol, Atenolol)
     ↓
β₁ blockade in heart → ↓HR + ↓Contractility → ↓Cardiac output → ↓BP

β₁ blockade in JGA (Kidney) → ↓Renin release
     ↓
↓Angiotensin II → ↓Aldosterone → ↓Na⁺/water retention → ↓Blood volume → ↓BP

Central action (Propranolol crosses BBB) → ↓Sympathetic outflow → ↓BP

Reset baroreceptors → Maintained at lower BP level

• First-line in young patients with high cardiac output hypertension
• Hypertension with angina, tachyarrhythmia, post-MI
• Cardioselective (atenolol, metoprolol) preferred in diabetics/asthmatics

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• Lignocaine 2.5% + Prilocaine 2.5% (in oil-in-water emulsion cream)
• The eutectic mixture has melting point of 18°C (both individual compounds melt at ~37°C)
• At room temperature, it forms an oily liquid → allows penetration through intact skin

EMLA cream applied to intact skin under occlusive dressing
     ↓
Drug penetrates through epidermis
     ↓
Blocks Na⁺ channels in dermal nerve endings
     ↓
Surface anesthesia achieved (depth ~5mm after 60-90 min)

1. Venipuncture and IV cannulation (especially in children)
2. Superficial skin procedures (shave biopsy, laser treatment)
3. Split-skin grafting
4. Removal of molluscum contagiosum
5. Circumcision (neonatal)

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PROPHYLAXIS OF MIGRAINE
(Used when ≥2 attacks/month, or prolonged/severe attacks)
         ↓
┌─────────────────┬──────────────────┬─────────────────┐
│   Beta Blockers │  Antidepressants │   Anticonvulsants│
│  Propranolol    │  Amitriptyline   │   Valproate     │
│  Metoprolol     │  Venlafaxine     │   Topiramate    │
└─────────────────┴──────────────────┴─────────────────┘
         ↓                 ↓                  ↓
Also: Flunarizine (Ca²⁺ blocker), Cyproheptadine (5-HT + H₁ blocker),
      Pizotifen (5-HT antagonist), Candesartan (ARB)

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Ergotamine (Ergot alkaloid - partial agonist)
     ↓
5-HT₁B/D agonist (like triptans) → Cranial vasoconstriction
α-adrenergic agonist → Vasoconstriction of cranial vessels
     ↓
Reverses intracranial vasodilation of migraine
     ↓
Reduces release of vasoactive neuropeptides
     ↓
Relief of migraine headache

• Nausea, vomiting (major side effect - 5-HT₃ stimulation in gut)
• Ergotism with overuse (peripheral vasospasm, gangrene)
• Contraindicated in: Pregnancy, CAD, hypertension, peripheral vascular disease
• Mostly replaced by Triptans (better tolerated)

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Platelet activation → Thromboxane A₂ (TXA₂) synthesis via COX-1
     ↓
TXA₂ → Platelet aggregation + Vasoconstriction → Thrombus formation → MI

Low-dose Aspirin (75-150 mg/day)
     ↓
Irreversible acetylation of COX-1 in platelets
     ↓
↓ TXA₂ synthesis (platelets cannot synthesize new COX - no nucleus)
     ↓
↓ Platelet aggregation
     ↓
Prevention of coronary artery thrombus
     ↓
Prophylaxis of MI and stroke

• High dose also inhibits vascular endothelial PGI₂ (prostacyclin) which is anti-aggregatory
• Low dose selectively inhibits platelet COX-1 >> vascular COX-1
• Endothelial cells can synthesize new COX; platelets cannot (anucleate)

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Normal dose: Paracetamol → Glucuronide/Sulfate conjugates (safe)
                                    ↓ minor
                             NAPQI (toxic metabolite via CYP2E1)
                                    ↓
                    Detoxified by Glutathione (GSH) → Safe mercapturic acid

OVERDOSE: GSH depleted → NAPQI accumulates
     ↓
Binds covalently to hepatocyte proteins → Hepatocellular necrosis

NAC → Precursor of Glutathione (provides cysteine for GSH synthesis)
    → Direct reducing agent (reduces NAPQI)
    → Provides sulfate for safe conjugation
     ↓
Replenishes GSH → Detoxifies NAPQI → Prevents hepatic necrosis

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Methotrexate (folic acid analogue)
     ↓
Inhibits Dihydrofolate reductase (DHFR)
     ↓
↓ Tetrahydrofolate → ↓ Purine and pyrimidine synthesis
     ↓
↓ Proliferation of rapidly dividing cells (lymphocytes, synoviocytes)
Also: ↑ Adenosine release → Anti-inflammatory
Also: Inhibits methylation reactions
     ↓
↓ Inflammation + ↓ Synovial proliferation + ↓ Joint damage

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↑ Uric acid production or ↓ Excretion
     ↓
Hyperuricemia → Monosodium urate crystal deposition in joints
     ↓
Acute gouty arthritis + Tophi formation + Uric acid nephropathy

Allopurinol (purine analogue - structural analogue of hypoxanthine)
     ↓
Competitive inhibitor of Xanthine Oxidase (XO)
     ↓
Xanthine → [XO blocked] → Cannot form Uric acid
Hypoxanthine → [XO blocked] → Cannot form Xanthine
     ↓
↓ Uric acid synthesis
Xanthine + Hypoxanthine accumulate (more soluble → easily excreted)
     ↓
↓ Serum uric acid → Prevention of gout attacks and tophi

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SHORT QUESTIONS (5 MARKS EACH)

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1. 100% bioavailability - No first-pass metabolism, no absorption barriers
2. Rapid onset of action - Drug reaches systemic circulation immediately
3. Precise blood level control - Accurate dosing
4. Large volumes can be administered (fluids, blood products)
5. Suitable for irritant drugs - Rapidly diluted in blood (e.g., anticancer drugs)
6. Unconscious/vomiting patients - Only viable route
7. Continuous infusion possible - Steady plasma levels maintained
8. Immediate effect in emergencies - Epinephrine in anaphylaxis, antiarrhythmics

1. Irreversibility - Once injected, cannot be withdrawn (unlike oral - emesis/charcoal)
2. Risk of infection - Septicemia, thrombophlebitis, endocarditis
3. Air embolism risk
4. Requires trained personnel and sterile technique
5. Rapid high blood levels → Toxicity (cardiac arrest with IV potassium bolus)
6. Expensive, painful, inconvenient
7. IV drug abuse potential
8. Incompatibility issues (cannot mix all drugs in same infusion)

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1. Faster absorption than oral/SC
2. Suitable for oily preparations and depot formulations (slow release over weeks)
   e.g., Depo-Provera, fluphenazine decanoate (depot antipsychotic)
3. No first-pass metabolism
4. Suitable for moderately irritant drugs (less pain than SC for irritants)
5. Can be given when oral route unavailable (vomiting, unconscious)
6. Large volumes (up to 5mL per site)

1. Painful - Injection pain, hematoma formation
2. Tissue damage - Fibrosis, sterile abscess (especially with irritant drugs)
3. Sciatic nerve injury possible (if wrong site - buttock injection)
4. Not suitable for anticoagulated patients (risk of hematoma)
5. Absorption erratic in shock/poor perfusion (vasoconstricted muscle)
6. Requires trained personnel
7. Cannot be self-administered easily

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1. BYPASSES FIRST-PASS METABOLISM completely
   (Venous drainage: sublingual veins → superior vena cava → directly to heart)
2. Rapid onset - Highly vascular mucosa → quick absorption
   e.g., GTN (onset 1-2 min for angina relief)
3. Convenient, self-administered
4. Drug can be removed/spat if adverse effects occur
5. No GI degradation (useful for peptides)
6. Suitable when patient is vomiting

1. Limited drug quantity (small surface area)
2. Not suitable for all drugs (must be lipid soluble, non-irritant)
3. Cannot eat, drink, or smoke while drug under tongue
4. Bitter taste may be unpleasant
5. Salivation may wash drug down
6. Short duration (repeated dosing needed for some drugs)

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1. Direct delivery to site of action (lungs) → Rapid onset
2. Lower doses needed → Fewer systemic side effects
   e.g., inhaled corticosteroids vs oral steroids
3. Large surface area for absorption (70-80 m² alveolar surface)
4. High blood flow → Fast systemic absorption if needed (anesthetics)
5. Avoids first-pass metabolism
6. Titratable dose (especially volatile anesthetics)
7. Convenient for respiratory diseases (asthma, COPD)

1. Requires patient cooperation and correct technique
2. Particle size critical (1-5 μm for alveolar deposition)
3. Local side effects - Oral candidiasis (inhaled steroids), cough, irritation
4. Not all drugs available in inhalable form
5. Expensive devices (MDI, DPI, nebulizers)
6. Environmental pollution (volatile anesthetics)
7. Drug quantity deposited variable (technique-dependent)
8. CNS depression with anesthetic vapors (narrow therapeutic window)

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1. Sustained, controlled drug delivery → Steady plasma levels
2. Bypasses first-pass metabolism
3. Non-invasive, painless, convenient (once daily/weekly application)
4. Avoids GI degradation and GI side effects
5. Easy to terminate - Remove patch
6. Improves patient compliance
7. Suitable for drugs with short half-life requiring frequent dosing

1. Only lipophilic, low molecular weight, low-dose drugs can be delivered
2. Slow onset - Not for acute conditions (GTN patch not for acute angina)
3. Local skin reactions - Erythema, contact dermatitis, itching
4. Limited drug load
5. Expensive
6. Heat (fever, hot bath) increases absorption unpredictably → toxicity
7. Reservoir patches - Damage → Dose dumping

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CLASSIFICATION OF NOVEL DRUG DELIVERY SYSTEMS
              ↓
┌─────────────┬──────────────┬───────────────┬────────────────┐
│ Liposomes   │ Nanoparticles│ Osmotic pumps │  Microspheres  │
└─────────────┴──────────────┴───────────────┴────────────────┘

• Phospholipid bilayer vesicles containing drug
• Targeted drug delivery (e.g., liposomal doxorubicin - Doxil)
• Reduced toxicity, prolonged action

• 1-1000 nm particles
• Can cross BBB, targeted delivery
• e.g., nab-paclitaxel (Abraxane) for cancer

• Osmotic pressure drives drug out at constant rate
• e.g., Adalat OROS (nifedipine), Glucotrol XL
• Zero-order release kinetics

• e.g., Norplant (levonorgestrel) - 5-year contraception
• Buprenorphine implant for opioid dependence

• Microencapsulated drug for prolonged release
• e.g., Long-acting octreotide LAR

• Antibody-drug conjugates (ADC) - e.g., Trastuzumab emtansine (T-DM1)
• pH-sensitive systems (colon targeting)
• Magnetic nanoparticles

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Bioavailability (F) = Fraction of administered drug dose that reaches 
                      systemic circulation in unchanged (active) form
                      
         AUC oral
F = ──────────────── × 100%
         AUC IV

• Extensive hepatic/gut wall metabolism → ↓ bioavailability
• e.g., GTN (oral BA <5%), propranolol (25-30%), morphine (25%)

• Lipid solubility → Good absorption
• Molecular size → Large molecules poorly absorbed
• Ionization state (pKa and GI pH) → Unionized form absorbed better

• Particle size (smaller → faster dissolution)
• Excipients, binders
• Coating type (enteric vs plain)
• Generic vs branded differences

• GI motility: ↑motility → ↓absorption time (less bioavailability)
• Food: Fatty food increases absorption of fat-soluble drugs
• GI pH: Affects ionization
• Gut flora: Metabolize some drugs

• P-glycoprotein efflux pump (reduces absorption)
• CYP3A4 in gut wall (metabolizes before entering blood)
• Chelation with antacids (tetracycline + Ca²⁺/Mg²⁺ → ↓ BA)
• Grapefruit juice inhibits gut CYP3A4 → ↑ BA of felodipine, simvastatin

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Drugs in plasma exist in two forms:
[Free Drug] ⇌ [Drug-Protein Complex]
(pharmacologically active)    (inactive, reservoir)

• Albumin (most important - binds acidic drugs: NSAIDs, warfarin, diazepam)
• α₁-acid glycoprotein (binds basic drugs: lidocaine, propranolol, quinidine)
• Specific globulins (sex hormone binding globulin, cortisol-binding globulin)

• Only free drug is pharmacologically active, distributes to tissues, gets metabolized and excreted
• High protein binding → prolonged duration of action

Drug A (high binding, e.g., warfarin 99% bound)
+ Drug B (displaces A from albumin, e.g., aspirin)
     ↓
↑ Free warfarin → Enhanced anticoagulation → Bleeding risk

• High protein binding → Low Vd (drug stays in plasma)
• Low protein binding → High Vd (wide tissue distribution)

• Hypoalbuminemia (malnutrition, liver disease, nephrotic syndrome) → ↑ free drug → Toxicity
• e.g., Phenytoin: check free phenytoin levels in hypoalbuminemia

• Uremia: accumulation of endogenous compounds → displacement of drugs from albumin

• Only free drug filtered by kidney → protein binding affects renal clearance

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PHASE 1 REACTIONS
        ↓
OXIDATION (most common) | REDUCTION | HYDROLYSIS

• Microsomal oxidation (CYP450 system - SER of liver):
  • Aromatic hydroxylation (benzene → phenol)
  • Aliphatic hydroxylation
  • N-dealkylation, O-dealkylation, S-dealkylation
  • N-oxidation, S-oxidation
  • Deamination
• Non-microsomal oxidation:
  • Alcohol dehydrogenase (ethanol → acetaldehyde)
  • MAO (catecholamines, tyramine)
  • Xanthine oxidase (hypoxanthine → uric acid)

• Azo reduction (prontosil → sulfanilamide)
• Nitro reduction (chloramphenicol)
• Carbonyl reduction (ketones → alcohols)

• Ester hydrolysis (aspirin → salicylic acid + acetic acid)
• Amide hydrolysis (lignocaine, procainamide)
• Peptide bond hydrolysis

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Drug/Phase 1 metabolite + Endogenous molecule → Conjugate (inactive, highly polar, excreted)

• Genetic polymorphism: Fast vs slow acetylators
• Slow acetylators: ↑ risk of INH-neuropathy, SLE with procainamide, hydralazine-induced lupus
• Fast acetylators: Reduced drug efficacy of INH, higher NAPQI from INH

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Inducer → Binds to nuclear receptor (PXR, CAR)
        → ↑ Transcription of CYP genes
        → ↑ CYP enzyme synthesis
        → Increased rate of drug metabolism

• Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbitone, Smoking

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1. Competitive inhibition - Reversible, competes for same enzyme
2. Non-competitive - Binds allosteric site
3. Mechanism-based (suicide) inhibition - Irreversible (e.g., MAO inhibitors, erythromycin)

• Disulfiram, Erythromycin/clarithromycin, Valproate, Isoniazid, Ciprofloxacin, Enzyme inhibited by ketoconazole/fluconazole, SSRIs/fluoxetine

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Plasma half-life (t½) = Time required for plasma concentration of a drug
                         to fall to exactly half of its original value

              0.693 × Vd
t½ = ──────────────────────
               Clearance

• For a drug following first-order kinetics, t½ is constant regardless of dose
• After 4-5 half-lives: Drug almost completely eliminated (~97%)
• After 4-5 half-lives of repeated dosing: Steady-state achieved

• Short t½ → More frequent dosing (e.g., penicillin G t½ = 30 min → 6 hourly)
• Long t½ → Once daily/weekly dosing (e.g., amiodarone t½ = 40-55 days)

• Takes 4-5 × t½ to reach steady state
• Relevant for loading dose decisions

• Longer t½ → Prolonged action, slower offset

• Important when switching drugs
• e.g., Fluoxetine (t½ = 4-6 days) → 5 weeks washout before starting MAOI

• Drugs with long t½ + short dosing interval → Accumulation → Toxicity

• Reduced clearance → ↑ t½ → Drug accumulation → Dose reduction needed

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Rate of elimination is proportional to the concentration of drug present
dC/dt = -k × C

- Constant FRACTION eliminated per unit time (e.g., 50% per hour regardless of concentration)
- Constant t½ (independent of initial concentration)
- Linear relationship: Plot of log concentration vs time = straight line
- Most drugs follow first-order kinetics
- Plasma concentration vs time = exponential curve (straight line on semi-log plot)

Log Concentration
     |  \
     |   \  (straight line = first-order)
     |    \
     |     \
     └─────────── Time

Zero-order: Constant AMOUNT eliminated/time (e.g., alcohol - 10 mL/hr)
t½ not constant; Increases with ↑ dose → Nonlinear accumulation
Examples: Alcohol, high-dose phenytoin, aspirin (high dose)

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FACTORS PROLONGING DRUG ACTION
              ↓
┌──────────────────────────────────────────────────────┐
│ 1. Slow/Sustained Release Formulations               │
│    SR tablets, depot injections, transdermal patches │
│    e.g., Morphine SR (MSContin), nifedipine OROS     │
│                                                      │
│ 2. Plasma Protein Binding                            │
│    High protein binding = reservoir effect            │
│    e.g., Warfarin 99%, diazepam 99%                  │
│                                                      │
│ 3. Enterohepatic Circulation                         │
│    Drug excreted in bile → reabsorbed from gut       │
│    e.g., Chloramphenicol, morphine, estrogens, OCP   │
│                                                      │
│ 4. Slow/Decreased Metabolism                         │
│    Liver disease, enzyme inhibitors, genetic slow    │
│    metabolizers, drug competition for CYP enzymes    │
│                                                      │
│ 5. Poor Renal Excretion                              │
│    Renal failure, altered urinary pH                  │
│    Acidic urine → acidic drug reabsorbed             │
│                                                      │
│ 6. Redistribution Avoided                            │
│    (Low Vd, no redistribution from active sites)     │
│    Vasoconstriction with adrenaline prolongs LA      │
│                                                      │
│ 7. Prodrug Activation (if slow activation)           │
│ 8. Accumulation in tissues (high Vd drugs)           │
└──────────────────────────────────────────────────────┘

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• Neonates: Immature hepatic enzymes (↓glucuronidation → chloramphenicol grey baby syndrome), immature kidney
• Elderly: ↓ renal function, ↓ hepatic blood flow, altered body composition (↑fat, ↓albumin), altered receptor sensitivity

• Obese patients: Increased Vd for lipophilic drugs (e.g., benzodiazepines)
• Dose based on ideal body weight vs total body weight

• Women: Higher % body fat → ↑ Vd for fat-soluble drugs
• Hormonal influences on drug metabolism (CYP3A4 activity influenced by sex hormones)
• Pregnancy: Altered protein binding, ↑ renal clearance, ↑ gastric emptying time

• CYP2D6 polymorphism (codeine toxicity, poor vs ultra-rapid metabolizers)
• NAT2 polymorphism (INH - fast vs slow acetylators)
• G6PD deficiency (hemolysis with oxidant drugs)

• Hepatic disease: ↓ drug metabolism, ↓ albumin
• Renal disease: ↓ drug excretion, accumulation
• Cardiac failure: ↓ hepatic and renal blood flow
• Thyroid disease: ↑metabolism in hyperthyroid state

• IV > IM > SC > oral for speed
• Circadian rhythms: Aspirin absorption varies; cortisol highest at 8 AM
• Food interactions: Fatty food ↑ absorption of fat-soluble drugs

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Extracellular (ligand binding site)
          │
7 Transmembrane domains (serpentine receptor)
          │
Intracellular (coupled to G protein: α, β, γ subunits)

Agonist + GPCR → Activates G protein
                       ↓
              Gα exchanges GDP for GTP
                       ↓
          Gα-GTP dissociates → activates effector
                       ↓
   ↑/↓ Second messenger (cAMP, IP₃, DAG, Ca²⁺)
                       ↓
           Cellular response

• Muscarinic (M2 = Gi), Adrenergic (β1 = Gs, α1 = Gq, α2 = Gi), Dopamine (D1 = Gs, D2 = Gi), Opioid receptors

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Lipophilic drug → Crosses plasma membrane → Binds cytoplasmic/nuclear receptor
                                              ↓
                                   Hormone-receptor complex formed
                                              ↓
                                   Translocates to nucleus (if cytoplasmic)
                                              ↓
                                   Binds to Hormone Response Element (HRE) on DNA
                                              ↓
                                   ↑/↓ Gene transcription → mRNA synthesis
                                              ↓
                                   New protein synthesis (hours to days)
                                              ↓
                                   Cellular response (delayed onset)

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Ligand binds to receptor subunit
          ↓
Conformational change → Channel opens
          ↓
Rapid ion flux (Na⁺, K⁺, Cl⁻, Ca²⁺)
          ↓
Change in membrane potential
          ↓
Cellular response (milliseconds)

• Benzodiazepines: Positive allosteric modulator of GABA-A
• Succinylcholine: Depolarizing NMJ blocker at nAChR
• Ondansetron: 5-HT₃ antagonist

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Ligand (peptide hormone, growth factor)
          ↓
Binds extracellular domain of receptor
          ↓
Receptor dimerization → Autophosphorylation of intracellular tyrosine kinase domain
          ↓
Phosphorylated receptor recruits signaling proteins (Ras, PI3K, MAPK pathway)
          ↓
Gene expression changes → Cell growth, differentiation, metabolism

• Trastuzumab (Herceptin): Monoclonal antibody blocks HER2 RTK in breast cancer
• Imatinib (Gleevec): BCR-ABL tyrosine kinase inhibitor in CML
• Sildenafil: Inhibits PDE5 → ↑cGMP (downstream of guanylyl cyclase)

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DRUG SYNERGISM
      ↓
┌─────────────────┬──────────────────────────────────┐
│  SUMMATION      │  POTENTIATION (SUPRA-ADDITIVE)   │
│  (Additive)     │                                  │
│  Effect = A + B │  Effect >> A + B                 │
└─────────────────┴──────────────────────────────────┘

• Same mechanism → Simply additive effects
• Example: Two NSAIDs given together (additive analgesia + additive GI toxicity)
• Alcohol + Benzodiazepines (CNS depression additive)

• Different mechanisms but combined effect far greater
• Example 1: Cotrimoxazole (Trimethoprim + Sulfamethoxazole)
  • Trimethoprim blocks DHFR; Sulfonamide blocks DHPS (two steps in folate synthesis)
  • Combined effect 100x more potent than either alone - SYNERGISM
• Example 2: Levodopa + Carbidopa
  • Carbidopa inhibits peripheral decarboxylase → More levodopa reaches brain
  • Reduced peripheral side effects; lower dose of levodopa
• Example 3: β-lactam + Aminoglycoside in serious infections

---

DRUG ANTAGONISM
      ↓
┌──────────────┬──────────────┬──────────────┬──────────────┐
│ Pharmacologi-│  Chemical    │ Physiological│ Pharmaco-    │
│ cal Antagon- │  Antagonism  │ Antagonism   │ kinetic      │
│ ism          │              │              │ Antagonism   │
└──────────────┴──────────────┴──────────────┴──────────────┘

• Competitive (Reversible): Antagonist competes with agonist for same receptor; can be overcome by ↑ agonist
  • Example: Atropine vs. ACh (at muscarinic receptors); Naloxone vs. Morphine (opioid receptors)
• Non-competitive (Irreversible): Antagonist binds receptor irreversibly; ↑ agonist cannot overcome
  • Example: Phenoxybenzamine (α-blocker) vs. Adrenaline

• Direct chemical interaction between two agents
• Example: Protamine sulfate + Heparin (protamine is positively charged, heparin negatively charged → ionic binding → neutralization)
• DMSA/Dimercaprol + Heavy metals (chelation)

• Two drugs act on different receptors but produce opposing effects
• Example: Histamine (bronchoconstriction) vs. Adrenaline (bronchodilation)
• Glucagon vs. Insulin (opposite effects on blood glucose)

• One drug alters absorption, distribution, or metabolism of another
• Example: Rifampicin (enzyme inducer) reduces warfarin levels

---

Poor metabolizers (7-10% Caucasians) → ↑ drug levels → Toxicity
Ultra-rapid metabolizers → ↓ drug levels → Therapeutic failure
Affected drugs: Codeine, Tramadol, Antidepressants (fluoxetine), Metoprolol
Example: Codeine → Morphine (via CYP2D6)
         Poor metabolizer → No conversion → No analgesia
         Ultra-rapid → Excessive morphine → Toxicity/death

Slow acetylators (50% Indians, 60% Caucasians) vs Fast acetylators (Asians)
Affected drugs: Isoniazid (INH), Hydralazine, Procainamide, Dapsone, Sulfonamides
Slow acetylators: ↑ INH levels → Peripheral neuropathy
                 ↑ Hydralazine/Procainamide → Drug-induced lupus
Fast acetylators: ↓ INH levels → Reduced efficacy of TB treatment

Deficiency of G6PD → ↓ NADPH → ↓ Reduced glutathione → Cannot neutralize oxidants
Drugs triggering hemolysis: Primaquine, Dapsone, Nitrofurantoin, Chloroquine
Common in Mediterranean, African, Asian populations

Succinylcholine normally metabolized by plasma ChE in 5-10 min
Atypical pseudocholinesterase → Cannot metabolize succinylcholine
→ Prolonged muscle paralysis (Scoline apnea) 
→ Patient needs mechanical ventilation until drug wears off (2-3 hours)

Low TPMT → Cannot methylate thiopurines (azathioprine, 6-MP)
→ Accumulation of active metabolites → Severe myelosuppression

---

---

Neostigmine (Quaternary ammonium carbamate)
     ↓
1. Inhibits Acetylcholinesterase (reversible carbamylation)
   → Prevents breakdown of ACh
   → ↑ ACh concentration at all cholinergic synapses
     ↓
2. Direct nicotinic receptor agonist action (weak)
   (Especially at NMJ)

↑ ACh effect:
• Muscarinic: Miosis, bradycardia, ↑ GI motility, ↑ secretions, bronchoconstriction
• Nicotinic (NMJ): ↑ Neuromuscular transmission → Muscle contraction
• CNS: No (does not cross BBB)

1. Myasthenia gravis - Symptomatic treatment (15 mg oral QID; 0.5-1 mg SC/IM)
2. Reversal of non-depolarizing NMB - Post-operatively (with glycopyrrolate/atropine)
3. Paralytic ileus - Restores GI motility (0.5 mg SC)
4. Urinary retention (post-operative) - Stimulates detrusor
5. Cobra bite - Anticurare effect (temporary)

• Muscarinic effects: Nausea, vomiting, diarrhea, excessive salivation, bronchospasm, bradycardia, urinary urgency, miosis, sweating
• Nicotinic effects (overdose): Muscle fasciculations, cramps, weakness (cholinergic crisis at NMJ)
• Cholinergic crisis: Can mimic myasthenic crisis → Edrophonium test to differentiate

---

SLUDGE (Muscarinic) + Nicotinic + CNS effects
Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis
+ Miosis (pin-point pupils)
+ Bronchospasm, Bradycardia
+ Nicotinic: Muscle fasciculations, paralysis, tachycardia
+ CNS: Anxiety, seizures, coma, respiratory depression

SUSPECTED OP POISONING
         ↓
REMOVE FROM EXPOSURE
• Remove clothes, wash skin with soap and water
• If ingested → Gastric lavage (within 4 hours)
         ↓
ASSESS AIRWAY, BREATHING, CIRCULATION
• Establish IV access, O₂, suction secretions
         ↓
SPECIFIC ANTIDOTES (given simultaneously)

1. ATROPINE (Drug of choice for muscarinic symptoms)
   • Dose: 2-4 mg IV bolus, repeat every 5-10 min
   • End point: Drying of secretions, HR >80, clear chest
   • Large doses may be needed (10-100 mg in severe cases)
   • Does NOT help nicotinic or CNS effects much
         ↓
2. PRALIDOXIME (PAM - 2-PAM) - Oxime (for nicotinic symptoms)
   • Dose: 1-2 g IV over 15-30 min, then 200-400 mg/hr infusion
   • Given EARLY (before "aging" of OP-AChE complex within 24-48 hrs)
   • Regenerates AChE → Reverses nicotinic effects (muscle paralysis)
   • Also reduces atropine requirements
         ↓
3. BENZODIAZEPINES (for seizures)
   • Diazepam 5-10 mg IV for seizures/anxiety
         ↓
SUPPORTIVE CARE
• Mechanical ventilation if respiratory failure
• Monitor plasma ChE activity (guide to treatment)
• ICU monitoring

---

THERAPEUTIC USES OF ANTICHOLINESTERASES

1. MYASTHENIA GRAVIS
   Neostigmine (15 mg oral), Pyridostigmine (60 mg oral - preferred)
   Edrophonium (diagnostic - Tensilon test)

2. GLAUCOMA
   Physostigmine 0.25-0.5% eye drops (now less used)
   Echothiophate (irreversible) - chronic open-angle glaucoma

3. ALZHEIMER'S DEMENTIA
   Donepezil (5-10 mg OD), Rivastigmine (1.5-6 mg BD), Galantamine

4. REVERSAL OF NEUROMUSCULAR BLOCKADE (non-depolarizing)
   Neostigmine (2.5-5 mg IV) + Atropine/Glycopyrrolate
   Post-operatively to reverse vecuronium, rocuronium, pancuronium

5. POSTOPERATIVE ILEUS AND URINARY RETENTION
   Neostigmine 0.5 mg SC/IM

6. ATROPINE POISONING (Anticholinergic toxicity)
   Physostigmine (crosses BBB) - 0.5-2 mg IV slowly
   (Used for central anticholinergic features - delirium, hallucinations)

7. COBRA (ELAPID) SNAKE BITE
   Neostigmine - temporary anticurare effect

8. NERVE AGENT PRETREATMENT
   Pyridostigmine - protects AChE from irreversible OP binding
   (Used prophylactically in military for nerve agent exposure)

---

"Blind as a bat" - Mydriasis, blurred vision
"Dry as a bone" - Dry skin, dry mouth, anhidrosis
"Red as a beet" - Flushing (vasodilation)
"Hot as a hare" - Fever (loss of sweating)
"Mad as a hatter" - Delirium, hallucinations, confusion
"Full as a flask" - Urinary retention
"Fast as a flea" - Tachycardia

ATROPINE/BELLADONNA POISONING
          ↓
SUPPORTIVE MEASURES
• ABC - Airway, Breathing, Circulation
• IV access, monitor ECG, O₂
• Gastric lavage + Activated charcoal (if recent oral ingestion)
• Cooling measures for hyperthermia (tepid sponging, fans)
• Catheterize bladder (urinary retention)
• Dark, quiet room (photophobia)
          ↓
SPECIFIC ANTIDOTE
Physostigmine 1-2 mg IV slowly (0.5 mg/min)
• Crosses BBB → Reverses CENTRAL anticholinergic effects
• (Delirium, hallucinations, tachycardia, urinary retention)
• Repeat if needed; monitor for cholinergic excess
• Can use Neostigmine for PERIPHERAL symptoms only
          ↓
SYMPTOMATIC
• Diazepam for seizures/agitation
• Cold compress for fever
• Beta blockers for severe tachyarrhythmia (propranolol cautiously)

---

---

Pancuronium (structural analogue of ACh)
     ↓
Competitive antagonist at Nicotinic NMJ receptors (NM subtype)
     ↓
Competes with ACh for α-subunits of nAChR at motor end plate
     ↓
Prevents depolarization of end plate → No muscle contraction
     ↓
Paralysis: Small muscles first (eyes, face) → Limbs → Trunk → Respiratory muscles
Recovery in reverse order (respiratory first)

Eyes → Face → Throat → Limbs → Trunk → Intercostals → DIAPHRAGM
(Small rapidly contracting muscles first → large slow muscles last)

1. Endotracheal intubation and surgical relaxation
2. Facilitate mechanical ventilation (ICU)
3. Prevention of reflex muscle contractions during surgery

• Tachycardia (vagolytic effect - blocks M2 receptors at SA node)
• Mild hypertension (sympathetic stimulation; no histamine release)
• No histamine release (advantage over d-TC)
• Prolonged blockade in liver disease (hepatic metabolism), renal disease (renal excretion)
• Hyperkalemia in burns, denervation - AVOIDED (like all NMBs)

---

Succinylcholine (= Suxamethonium) - two ACh molecules joined end to end
     ↓
Binds to nAChR at NMJ (like ACh)
     ↓
Causes PERSISTENT depolarization of end plate
     ↓
Phase I block (Depolarization block):
• Initial fasciculations (brief visible muscle twitches)
• Then flaccid paralysis (receptor desensitization)
     ↓
NOT broken down by AChE
Broken down by Plasma Cholinesterase (Pseudocholinesterase) → Short duration (5-10 min)

1. Rapid Sequence Intubation (RSI) - Fast onset (60-90 sec), short duration → Ideal for emergency intubation, "cannot intubate" scenario
2. Endoscopy/short procedures
3. Electroconvulsive therapy (ECT) - to prevent fractures

1. Fasciculations - painful (give small dose of d-TC first to prevent - "defasciculating dose")
2. Muscle pains (post-operative myalgia)
3. Hyperkalemia (K⁺ efflux from depolarized muscle) - DANGEROUS in burns, renal failure, spinal cord injury (avoid)
4. Malignant Hyperthermia (in susceptible individuals with volatile anesthetics)
5. Prolonged paralysis (Scoline apnea) in pseudocholinesterase deficiency
6. Increased IOP (intraocular pressure) - avoid in open-eye injury
7. Increased intragastric pressure (aspiration risk)
8. Bradycardia (after repeated doses - muscarinic stimulation)
9. Phase II block (dual block) - with large/repeated doses; resembles non-depolarizing block

---

Adrenaline acts on all adrenergic receptors: α₁, α₂, β₁, β₂, β₃

α₁ effects: Vasoconstriction (skin, mucosa, viscera), pupil dilation (radial muscle)
α₂ effects: ↓ Presynaptic NE release (autoreceptor), ↓ Insulin, platelet aggregation
β₁ effects: ↑HR (chronotropy), ↑Contractility (inotropy), ↑AV conduction, ↑Renin
β₂ effects: Bronchodilation, vasodilation (skeletal muscle), ↓ Histamine release, tocolysis, ↑ Glycogenolysis
β₃ effects: Lipolysis in adipose tissue

Overall BP effect:
- IV bolus: Initial ↑ BP (α₁ dominant) then ↑ due to β₁ (cardiac)
- Low dose: β₂ effect lowers DBP; SBP maintained/raised by β₁

1. Anaphylactic shock - DRUG OF CHOICE (0.5 mg IM 1:1000)
2. Cardiac arrest - IV 1mg (1:10,000) - enhances coronary and cerebral perfusion
3. Bronchospasm - Subcutaneous (now replaced by salbutamol)
4. With local anesthetics - Prolongs duration, reduces toxicity
5. Topical hemostasis - Nasal bleeding (1:1000 on gauze)
6. Open-angle glaucoma - Dipivefrin (prodrug) → reduces aqueous production
7. Croup - Nebulized racemic epinephrine

• Hypertension, tachycardia, palpitations
• Arrhythmias (ventricular fibrillation especially with halothane anesthesia)
• Cerebrovascular accident (from severe hypertension)
• Anxiety, tremor, headache
• Hyperglycemia
• Tissue necrosis at injection site (vasoconstriction)

---

Dopamine is an endogenous catecholamine; DOSE-DEPENDENT receptor activation:

LOW DOSE (1-5 μg/kg/min):
D₁ receptors (renal, mesenteric, coronary, cerebral vessels)
→ Vasodilation → ↑ Renal blood flow → ↑ GFR → ↑ Urine output
Also D₂ (inhibitory, presynaptic)

MEDIUM DOSE (5-10 μg/kg/min):
β₁ receptors (heart)
→ ↑ HR, ↑ Contractility → ↑ Cardiac output
(+ D₁ effects maintained)

HIGH DOSE (>10 μg/kg/min):
α₁ receptors (predominant)
→ Vasoconstriction → ↑ SVR → ↑ BP (may ↓ renal blood flow)

                        DOPAMINE DOSE
                             ↓
    ┌────────────────────────┼──────────────────────────┐
    ▼                        ▼                          ▼
LOW (1-5 μg/kg/min)   MEDIUM (5-10 μg/kg/min)    HIGH (>10 μg/kg/min)
D₁ + D₂ receptors      β₁ receptors (+D₁)          α₁ receptors dominant
↓                            ↓                          ↓
Renal/mesenteric         ↑ Cardiac output           Vasoconstriction
vasodilation             ↑ HR, ↑ Contractility       ↑ BP
↑ Renal BF, ↑ GFR       BP maintained              ↓ Renal BF (can worsen renal failure)
↑ Urine output
USES:                    USES:                       USES:
Oliguria, oliguric       Cardiogenic shock,          Severe septic shock,
renal failure            heart failure               distributive shock (with caution)

1. Cardiogenic shock (medium dose - positive inotrope)
2. Septic shock (high dose with vasopressors)
3. Oliguric renal failure (low dose - improve renal perfusion)
4. Acute heart failure/low output state

• Nausea, vomiting
• Tachycardia, arrhythmias
• Angina, hypertension (high dose)
• Tissue necrosis with extravasation → Use central venous line; antidote phentolamine local infiltration
• Peripheral ischemia (high dose)

---

ALPHA BLOCKERS
      ↓
Non-selective (α₁+α₂): Phentolamine (reversible), Phenoxybenzamine (irreversible)
Selective α₁: Prazosin, Terazosin, Doxazosin
Selective α₁A: Tamsulosin, Silodosin (uro-selective)
Selective α₂: Yohimbine

1. Hypertension (Prazosin, Doxazosin) - especially with BPH
2. BPH (Tamsulosin, Silodosin, Terazosin, Alfuzosin)
3. Pheochromocytoma (Phenoxybenzamine - irreversible, pre-op; Phentolamine - during surgery)
4. Raynaud's disease (Prazosin)
5. Peripheral vascular disease (Phentolamine)
6. PTSD (Prazosin - reduces nightmares via α₁ blockade in CNS)
7. Drug-induced hypertensive crisis (Phentolamine IV - cocaine, tyramine with MAOI)
8. Urinary retention (Tamsulosin, α₁A selective)

• First-dose hypotension (postural hypotension, syncope - especially Prazosin)
• Reflex tachycardia
• Nasal stuffiness (vasodilation of nasal mucosa)
• Fluid retention (compensatory)
• Retrograde ejaculation (Tamsulosin - α₁A in vas deferens)
• Intraoperative floppy iris syndrome (IFIS) - Tamsulosin in cataract surgery

---

NON-SELECTIVE (β₁+β₂): Propranolol, Timolol, Nadolol, Sotalol
CARDIOSELECTIVE (β₁): Atenolol, Metoprolol, Bisoprolol, Nebivolol, Esmolol
WITH INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA): Pindolol, Acebutolol
WITH α-BLOCKING ACTIVITY: Labetalol, Carvedilol

1. Hypertension - First line, especially young patients with high output HTN
2. Angina - Reduces O₂ demand (↓HR, ↓contractility)
3. Cardiac arrhythmias - AF, flutter, SVT (slows AV conduction)
4. Heart failure - (Carvedilol, Metoprolol, Bisoprolol - reduce mortality)
5. Post-MI - Reduces reinfarction, sudden death
6. Hyperthyroidism/Thyroid storm - Controls symptoms (Propranolol also inhibits T4→T3)
7. Migraine prophylaxis (Propranolol)
8. Anxiety/Situational phobia (Propranolol - controls palpitations, tremor)
9. Glaucoma (Timolol eye drops - reduces aqueous humor production)
10. Pheochromocytoma - Only AFTER alpha blockade
11. Esophageal varices - Portal hypertension (Propranolol - non-selective)
12. Essential tremor (Propranolol)

• Bronchospasm (β₂ blockade - contraindicated in asthma)
• Bradycardia, Heart block (β₁)
• Masking hypoglycemia (β₂)
• Cold extremities (Raynaud's worsened)
• Fatigue, lethargy, depression (CNS - propranolol)
• Impotence
• ↑ Triglycerides, ↓ HDL (metabolic effects)
• Rebound angina if stopped abruptly (up-regulation of receptors)

---

As LOCAL ANESTHETIC:
Lignocaine (weak base, pKa 7.9)
     ↓
Enters nerve in unionized form → Inside nerve, ionized form blocks
     ↓
Blocks Voltage-gated Na⁺ channels (preferentially in "open" and "inactivated" state)
     ↓
Prevents Na⁺ influx → No depolarization → No action potential → Nerve block
(Use-dependent/frequency-dependent block - more effective at higher firing rates)

As ANTIARRHYTHMIC:
Shortens action potential duration (APD) and effective refractory period (ERP) in ventricular tissue
Raises ventricular fibrillation threshold
No effect on normal SA node/atrial tissue

1. Infiltration anesthesia
2. Nerve block (e.g., dental, brachial plexus)
3. Epidural and spinal anesthesia
4. Topical anesthesia (viscous lignocaine for oropharynx, EMLA)

1. Ventricular tachycardia (VT)
2. Ventricular fibrillation (post-DC cardioversion)
3. Premature ventricular complexes (PVCs) - especially post-MI
4. Digitalis-induced ventricular arrhythmias

• Dizziness, tinnitus, perioral numbness
• Slurred speech, confusion
• Seizures (major toxic sign)
• Respiratory arrest (severe toxicity)

• Myocardial depression (high doses)
• Bradycardia, hypotension
• Cardiovascular collapse (rare but serious)

• Rare with amide class (more common with esters like procaine)
• Preservative methylparaben can cause allergy

---

1st GENERATION (sedating): Diphenhydramine, Chlorpheniramine, Promethazine, Cyclizine, Cinnarizine
2nd GENERATION (non-sedating): Loratadine, Cetirizine, Fexofenadine, Levocetirizine, Desloratadine

1. Allergic conditions - Urticaria, hay fever (allergic rhinitis), contact dermatitis, drug allergies
2. Anaphylaxis - Adjunct to adrenaline (not substitute!)
3. Pruritus - Atopic dermatitis, insect bites
4. Common cold - Symptomatic relief of rhinorrhea (1st gen better due to anticholinergic drying)
5. Motion sickness - Dimenhydrinate, Meclizine, Cinnarizine (also H₁ blockers)
6. Nausea and vomiting - Promethazine, Cyclizine (anti-emetic via CTZ H₁ blockade)
7. Pre-anesthetic medication - Promethazine (sedation, anti-emetic)
8. Insomnia - Diphenhydramine (OTC sleep aids)
9. Parkinsonism - Diphenhydramine (anticholinergic action)

• CNS sedation (main disadvantage - impairs driving, cognitive function)
• Anticholinergic: Dry mouth, blurred vision, constipation, urinary retention, tachycardia
• Paradoxical CNS excitation in children (promethazine - avoid <2 years; fatal)
• Impaired coordination
• Epigastric distress

• Non-sedating (advantage) - minimal CNS effects
• Headache, dry mouth (minimal)
• QT prolongation at high doses (cetirizine less so)
• Terfenadine and Astemizole (withdrawn) - severe cardiac arrhythmia (Torsades de pointes) when combined with ketoconazole/erythromycin

---

---

Sumatriptan (Selective 5-HT₁B/₁D agonist)
     ↓
5-HT₁B on cranial vessel walls → Vasoconstriction of dilated meningeal/cranial vessels
5-HT₁D on trigeminal nerve terminals → ↓ Release of vasoactive neuropeptides (CGRP, substance P)
     ↓
Reverses neurogenic inflammation of meningeal vessels
     ↓
Aborts migraine headache

1. Acute migraine attack - Drug of choice for moderate-to-severe migraine (oral 50-100 mg; SC 6 mg; nasal spray 20 mg)
2. Cluster headaches - SC sumatriptan is DOC (100 mg oral or 6 mg SC)

• Chest tightness/pressure (coronary vasospasm - most important; feeling of chest/throat constriction)
• Tingling, warmth, heaviness in limbs, neck, jaw (serotonin-like sensations)
• Nausea, dizziness
• Flushing
• Rebound headache with overuse (medication overuse headache >10 days/month)

• CAD, ischemic heart disease, Prinzmetal's angina
• Uncontrolled hypertension
• Stroke/TIA
• Not to be used with ergotamine (within 24 hours)
• Severe hepatic impairment

---

Aspirin (Acetylsalicylic acid)
     ↓
Irreversible acetylation of Serine residue (Ser 530) in active site of COX-1 and COX-2
     ↓
↓ Prostaglandin (PGE₂, PGI₂) synthesis → Analgesia, Antipyresis, Anti-inflammation
↓ TXA₂ in platelets → Anti-platelet effect
(Platelets lack nucleus → Cannot synthesize new COX → Permanent effect for platelet lifetime 7-10 days)

1. Analgesic - Mild to moderate pain (headache, myalgia, dental pain) - 300-600 mg
2. Antipyretic - Fever (not used in children <12 years - Reye's syndrome risk)
3. Anti-inflammatory - Rheumatoid arthritis, osteoarthritis
4. Anti-platelet (Low dose 75-150 mg):
   • Prophylaxis of MI (secondary prevention)
   • Acute MI (loading dose 300 mg)
   • Unstable angina
   • TIA/Stroke prevention
   • Post-coronary angioplasty/stent
5. Kawasaki disease - High dose anti-inflammatory + Low dose antiplatelet
6. Pre-eclampsia prophylaxis (75 mg/day in high risk)
7. Rheumatic fever - High dose

1. GI: Nausea, vomiting, GI bleeding, peptic ulcer (inhibits mucosal PGE₂)
2. Reye's syndrome - Hepatic encephalopathy in children with viral illness (avoid <12 years)
3. Aspirin-induced asthma - Especially in nasal polyp patients (shunts AA to leukotrienes)
4. Salicylism - Tinnitus, deafness, vertigo, headache (chronic high dose)
5. Bleeding - Prolonged BT, surgical bleeding
6. Metabolic effects - Respiratory alkalosis → Metabolic acidosis (overdose)
7. Uricosuric paradox - Low dose: ↓ uric acid excretion (↑ uric acid); High dose: Uricosuric
8. Hypersensitivity - Urticaria, angioedema, anaphylaxis

---

METHOTREXATE (Anchor drug - first choice)
Dose: 7.5-25 mg once weekly + Folic acid
Mechanism: DHFR inhibition → ↓ Purine synthesis, ↑ Adenosine
ADRs: Hepatotoxicity, Myelosuppression, Pneumonitis, Mucositis, Teratogenicity

SULFASALAZINE
Mechanism: Inhibits prostaglandins, cytokines, neutrophil migration
ADRs: GI disturbance, hepatotoxicity, reversible oligospermia

HYDROXYCHLOROQUINE (Plaquenil)
Mechanism: ↓ Antigen presentation (raises lysosomal pH), immunomodulation
ADRs: Retinopathy (deposits in retina - baseline and annual eye exam), GI
Safest DMARD in pregnancy

LEFLUNOMIDE
Mechanism: Inhibits DHODH → ↓ Pyrimidine synthesis → ↓ T cell proliferation
ADRs: Hepatotoxicity, teratogenicity, hypertension, alopecia

TNF-α INHIBITORS:
• Methotrexate + TNF inhibitor = Gold standard combination
• Infliximab (chimeric mAb), Etanercept (TNF receptor fusion protein)
• Adalimumab (human mAb), Golimumab, Certolizumab
• ADRs: Reactivation of TB (screen before use!), infection, demyelination

IL-1 INHIBITOR:
• Anakinra (IL-1 receptor antagonist)

IL-6 INHIBITOR:
• Tocilizumab (anti-IL-6 receptor mAb)

T CELL CO-STIMULATION BLOCKER:
• Abatacept (CTLA4-Ig fusion protein)

B CELL DEPLETER:
• Rituximab (anti-CD20 mAb)

JAK INHIBITORS:
• Tofacitinib, Baricitinib, Upadacitinib
• Inhibit JAK1/JAK3 → ↓ Cytokine signaling
• ADRs: Thrombosis, infection, malignancy

Early RA → MTX (± HCQ ± Sulfasalazine)
If inadequate response (3-6 months) → Add biologic DMARD (TNF inhibitor preferred)
If inadequate response → Switch biologic or use JAK inhibitor
All patients: Monitor CBC, LFT, RFT regularly

---

---

• Definitions first
• Flowcharts and diagrams where relevant
• Tables for comparisons
• Mechanism → Uses → ADRs structure for drug questions
• References from KDT and Shanbhag

---

PHARMACOLOGY ANSWERS

Topics: CNS, Gastrointestinal System, Hormones

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

---

TOPIC: CNS — SHORT NOTES (5 MARKS)

---

Phenytoin (Diphenylhydantoin)
     ↓
Blocks Voltage-gated Na⁺ channels in "use-dependent" manner
(Preferentially blocks sustained high-frequency firing of neurons)
     ↓
Stabilizes neuronal membrane at inactivated state
     ↓
Prevents spread of epileptic discharge from focus
     ↓
Also: Blocks Ca²⁺ channels, reduces Ca²⁺-dependent neurotransmitter release

1. Tonic-clonic seizures (Grand mal) - first or second line
2. Partial (focal) seizures
3. Status epilepticus (IV fosphenytoin preferred over IV phenytoin)
4. Cardiac arrhythmias (digitalis-induced VT/VF) - Class Ib antiarrhythmic
5. Trigeminal neuralgia (second line after carbamazepine)

• Nystagmus (first sign of toxicity)
• Diplopia, ataxia, slurred speech
• Confusion, encephalopathy (high levels)
• Cardiac arrhythmias (rapid IV administration)

• Gingival hyperplasia (due to ↓ collagen breakdown; especially in children; 20% incidence)
• Hirsutism (cosmetically troublesome especially in women)
• Coarsening of facial features
• Megaloblastic anemia (↓ folate absorption and ↑ folate utilization)
• Osteomalacia (↑ CYP450 induction → ↑ Vitamin D metabolism → ↓ Calcium)
• Peripheral neuropathy (chronic use)
• Lymphadenopathy (rare)
• Cognitive impairment, cerebellar atrophy

• Maculopapular rash, SJS/TEN
• Hepatotoxicity
• DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

• Fetal hydantoin syndrome: Cleft palate, cardiac defects, growth retardation, microcephaly
• Neonatal hemorrhage (↓ Vit K-dependent clotting factors)

• Zero-order kinetics at therapeutic doses (saturation kinetics) → Small dose increase → Disproportionate ↑ in levels → Toxicity
• Highly protein bound (90%), enzyme inducer (CYP2C9, CYP3A4)
• Therapeutic range: 10-20 mg/L

---

Multiple mechanisms:

1. Blocks Voltage-gated Na⁺ channels
   → ↓ Sustained high-frequency neuronal firing (like phenytoin)

2. Enhances GABA-ergic transmission
   → Inhibits GABA transaminase (↓ GABA breakdown)
   → Inhibits succinic semialdehyde dehydrogenase
   → ↑ GABA levels in brain

3. Blocks T-type Ca²⁺ channels in thalamus
   → Suppresses absence seizures (like ethosuximide)

4. Reduces glutamate-mediated excitation

1. Broad-spectrum AED - effective in ALL types of epilepsy
2. Tonic-clonic (grand mal) seizures
3. Absence seizures (petit mal) - especially if mixed with GTC
4. Juvenile myoclonic epilepsy (JME) - Drug of Choice
5. Myoclonic seizures
6. Partial seizures
7. Migraine prophylaxis (proven effective)
8. Bipolar disorder (mood stabilizer) - acute mania and prophylaxis
9. Trigeminal neuralgia (second line)

• GI symptoms - Nausea, vomiting, diarrhea (most common; take with food; enteric-coated reduces this)
• Weight gain (common)
• Tremor (dose-related; can be treated with propranolol)
• Hair loss (alopecia - may become curly on regrowth)
• Hepatotoxicity (potentially FATAL idiosyncratic; especially in children <2 years on polytherapy - black box warning)
• Pancreatitis (rare but serious)
• Thrombocytopenia (dose-related)
• Teratogenicity - MOST teratogenic AED:
  • Neural tube defects (spina bifida - 1-2%) - folic acid supplementation mandatory
  • Valproate embryopathy (facial defects, cardiac, limb)
  • Neurocognitive impairment in exposed children (↓ IQ)
  • AVOID in pregnancy if possible; if essential, use lowest dose + folic acid 5 mg/day
• Hyperammonemia (may occur even with normal LFTs)
• Polycystic ovarian syndrome (chronic use in women)
• Sedation (mild)

---

Ethosuximide
     ↓
Selectively blocks T-type (Low-voltage activated) Ca²⁺ channels
     ↓
T-type channels present in THALAMIC NEURONS
     ↓
Thalamic pacemaker activity (3 Hz spike-wave oscillations) suppressed
     ↓
Prevents generation and spread of absence seizure discharges

1. Absence (Petit mal) seizures - DRUG OF CHOICE when absence occurs ALONE (without GTC)
2. Atypical absence seizures (less responsive)
3. NOT effective in GTC, partial, or myoclonic seizures

• GI: Nausea, vomiting, epigastric discomfort (most common; take with food)
• CNS: Drowsiness, headache, hiccups (characteristic)
• Behavioral changes: Mood changes, euphoria, aggressiveness in children
• Blood dyscrasias: Leukopenia, aplastic anemia (rare but serious; CBC monitoring)
• Lupus-like syndrome (rare)
• Urticaria, skin rash

---

Carbamazepine (Iminostilbene - structurally related to TCAs)
     ↓
Blocks Voltage-gated Na⁺ channels (use-dependent)
     ↓
Preferentially stabilizes inactivated state of Na⁺ channel
     ↓
↓ Sustained repetitive firing of neurons
     ↓
Suppresses spread of epileptic discharge
Also: ↓ Glutamate release, modulates GABA receptors

1. Partial (focal) seizures - DRUG OF CHOICE
2. Generalized tonic-clonic seizures - first line
3. Trigeminal neuralgia - DRUG OF CHOICE (reduces paroxysmal pain)
4. Glossopharyngeal neuralgia
5. Bipolar disorder - mood stabilizer (mania and prophylaxis; alternative to lithium)
6. Central diabetes insipidus (↑ ADH release and sensitizes collecting duct)
7. Alcohol withdrawal (second line)
8. Restless leg syndrome

• Diplopia, ataxia, vertigo (especially with dose increase)
• Drowsiness, cognitive impairment
• Nausea, vomiting

• Aplastic anemia (rare but serious - CBC monitoring)
• Agranulocytosis (serious)
• SJS/TEN - especially in HLA-B*1502 (Han Chinese, South Asians - screen before use)
• Hepatotoxicity

• Hyponatremia (SIADH-like effect) - especially elderly
• Teratogenicity: Neural tube defects (spina bifida), minor anomalies
• Enzyme inducer (auto-induces own metabolism → t½ shortens with chronic use)

• ↓ OCP efficacy, ↓ Warfarin, ↓ Phenytoin, ↓ Valproate levels

---

INHALATIONAL ANESTHETICS
          ↓
┌─────────────────┬───────────────────────────────────────┐
│   GASES         │         VOLATILE LIQUIDS              │
│  Nitrous Oxide  │  Halothane, Isoflurane, Sevoflurane,  │
│  (N₂O)          │  Desflurane, Enflurane                │
└─────────────────┴───────────────────────────────────────┘

Potentiates GABA-A receptors (↑ Cl⁻ influx → inhibition)
Inhibits NMDA receptors (glutamate)
→ Global CNS depression in dose-dependent manner
→ Loss of consciousness, analgesia, amnesia

• MAC = concentration of anesthetic in alveoli producing immobility in 50% of patients
• Lower MAC = More potent
• N₂O: MAC = 104% (not potent enough alone)
• Halothane: MAC = 0.75% (very potent)
• Isoflurane: MAC = 1.15%
• Sevoflurane: MAC = 2.0%

---

IV GENERAL ANESTHETICS
          ↓
┌────────────────┬────────────────┬──────────────┬────────────┐
│ BARBITURATES   │ BENZODIAZEPINES│ PHENCYCLIDINE│  OTHERS    │
│ Thiopentone Na │ Midazolam,     │  Ketamine    │ Propofol   │
│                │ Diazepam       │              │ Etomidate  │
└────────────────┴────────────────┴──────────────┴────────────┘

• Barbiturates/Propofol/Benzodiazepines: Potentiate GABA-A → ↑ Cl⁻ → Hyperpolarization
• Ketamine: NMDA receptor antagonist (dissociative anesthesia)
• Etomidate: GABA-A potentiation, minimal cardiovascular effects

---

Thiopentone Sodium (Thiopental)
     ↓
Potentiates GABA-A receptor (allosteric modulator)
     ↓
At CLINICAL doses: ↑ Duration of Cl⁻ channel opening
At HIGH doses: Directly opens Cl⁻ channel (like barbiturates)
     ↓
↑ Cl⁻ influx → Hyperpolarization → CNS depression
     ↓
Loss of consciousness in ONE arm-brain circulation time (~10-15 sec)

Fast onset (10-15 sec) due to high lipid solubility → Rapid distribution to brain
     ↓
Brief action (5-10 min) - NOT due to metabolism but due to REDISTRIBUTION
(Drug redistributes from brain → Skeletal muscle → Fat)
     ↓
Metabolism: Liver (slow) - oxypentobarbital
     ↓
CUMULATIVE effect with repeated doses (redistributed drug returns to blood)

1. Induction of general anesthesia (3-5 mg/kg IV)
2. Status epilepticus (refractory) - IV bolus
3. Cerebral protection (reduces CMRO₂ and ICP) - head injury
4. Basal anesthesia / supplemental anesthesia

• Respiratory depression (apnea with rapid injection - have airway support ready)
• Cardiovascular depression (hypotension, especially in hypovolemia)
• Laryngospasm (especially on stimulation during light plane)
• Bronchospasm (contraindicated in asthma)
• Tissue necrosis if extravasation occurs (highly alkaline pH 11) → Treat with local procaine/hyaluronidase
• Arterial injection → Arterial spasm, gangrene (if accidentally injected in artery)
• Hangover/Drowsiness (due to redistribution from fat back)
• Porphyria (absolute contraindication - precipitates acute porphyric crisis)
• No analgesia (anti-analgesic at sub-anesthetic doses)

---

Propofol (2,6-di-isopropylphenol)
     ↓
Potentiates GABA-A receptor (↑ duration of Cl⁻ channel opening)
Also: Inhibits NMDA receptor
     ↓
Rapid CNS depression
     ↓
Loss of consciousness in 15-45 sec
     ↓
Short acting due to rapid redistribution AND hepatic + extrahepatic metabolism
(Context-sensitive half-life favorable even with prolonged infusion)

1. Induction of anesthesia (1.5-2.5 mg/kg IV) - Most preferred IV induction agent today
2. Maintenance of anesthesia (TIVA - Total Intravenous Anesthesia) - 4-12 mg/kg/hr infusion
3. Sedation in ICU (mechanically ventilated patients) - allows rapid wakening
4. Day-case/ambulatory surgery (ideal - rapid complete recovery, minimal hangover)
5. Procedural sedation (endoscopy, bronchoscopy, minor procedures)
6. Anti-emetic effect (sub-anesthetic doses; reduces PONV) - unique advantage
7. Refractory status epilepticus (anticonvulsant)
8. Refractory ICP management (reduces CMRO₂)

• Pain on injection (most common complaint - 28-90%; inject in large vein, pretreat with lignocaine)
• Cardiovascular depression - Hypotension (vasodilation + ↓ contractility), bradycardia
• Respiratory depression - Apnea with induction dose
• Propofol Infusion Syndrome (PRIS) - Rare but FATAL: Metabolic acidosis, rhabdomyolysis, renal failure, cardiac failure (with high-dose prolonged infusion in critically ill; >4 mg/kg/hr for >48 hrs)
• Hyperlipidemia (formulated in lipid emulsion - soybean/egg lecithin - 10% lipid)
• Bacterial contamination risk (supports microbial growth; use within 6 hours of opening)
• No analgesic property
• Green urine (benign, due to phenol metabolites)
• Contraindicated in egg/soybean allergy (caution)

---

Ketamine
     ↓
Non-competitive NMDA (N-Methyl-D-Aspartate) receptor antagonist
     ↓
Blocks glutamate-activated Ca²⁺/Na⁺ channels (open channel block)
     ↓
DISSOCIATIVE ANESTHESIA:
• Profound analgesia
• Amnesia
• Cataleptic state (eyes open with nystagmus)
• Cardiovascular STIMULATION (unique)
• Consciousness partially maintained (emergence reactions)
Also: Stimulates sympathetic nervous system → ↑ NE release

1. Induction of anesthesia in hemodynamically compromised patients (shock, trauma, hypovolemia) - cardiovascular stimulation is beneficial
2. Ketamine-based analgesia for procedural pain - burns dressings, fracture reduction, EM procedures
3. Children - IM route for non-cooperative/uncooperative children (4-6 mg/kg IM)
4. Field/battlefield anesthesia - no requirement of O₂ or IV access mandatory
5. Bronchial asthma patients - bronchodilator (sympathomimetic), can be used cautiously
6. Short surgical procedures in children (circumcision, orthopedic manipulation)
7. Refractory depression (sub-anesthetic IV ketamine - rapid antidepressant effect; esketamine nasal spray approved)
8. Refractory status epilepticus (anti-NMDA mechanism)
9. Refractory pain (chronic pain, CRPS) - adjunct

• Emergence reactions - Vivid dreams, hallucinations, delirium, psychosis on waking (15-30%; reduced by premedication with benzodiazepine - diazepam or midazolam)
• ↑ ICP (contraindicated in head injury, intracranial hypertension)
• ↑ IOP - Avoid in open eye injury, glaucoma
• ↑ Salivation (antisialagogue premedication with glycopyrrolate required)
• Tachycardia, Hypertension (cardiovascular stimulation - avoid in HTN, CAD, thyrotoxicosis)
• Nausea, vomiting
• Laryngeal reflexes preserved (aspiration risk still present)
• Muscle hypertonia/tremors

---

<50 mg/dL: Euphoria, disinhibition
50-150 mg/dL: Incoordination, slurred speech, ataxia
150-250 mg/dL: Confusion, stupor, nystagmus
>250 mg/dL: Coma, respiratory depression
>400 mg/dL: Death

ACUTE ALCOHOL INTOXICATION
          ↓
ASSESS: Airway, Breathing, Circulation (ABC)
• Lateral position (prevent aspiration of vomitus)
• Protect airway, O₂ if needed
          ↓
ESTABLISH IV ACCESS
• Blood glucose monitoring (hypoglycemia common)
• If hypoglycemia: Dextrose 25-50 mL of 50% IV
          ↓
THIAMINE 100 mg IV BEFORE glucose
(To prevent Wernicke's encephalopathy precipitated by glucose)
          ↓
FLUIDS
• IV normal saline (hydration, alcohol is a diuretic)
• Correct electrolytes (hypokalemia, hypomagnesemia)
          ↓
NO SPECIFIC ANTIDOTE FOR ALCOHOL
• Hemodialysis - in severe poisoning with very high BAL (>400 mg/dL) or with methanol
• Gastric lavage - only if very recent ingestion and patient cooperative
          ↓
MONITOR:
• GCS, vital signs, blood glucose hourly
• Blood alcohol level
• ECG (arrhythmias possible)
          ↓
SUPPORTIVE:
• Treat aspiration pneumonia if occurs
• Thiamine supplements
• Benzodiazepines if severe agitation (not routine)

---

Dopamine does not cross BBB → Levodopa (precursor) crosses BBB via L-DOPA transporter
     ↓
In brain (striatum, substantia nigra):
Dopa decarboxylase → Dopamine (replenishes depleted dopamine in PD)
     ↓
Stimulates D₁ and D₂ receptors in striatum
     ↓
↓ ACh relative excess → ↓ Tremor, rigidity, bradykinesia

• Reduces all cardinal features of PD: Tremor, Rigidity, Bradykinesia, Postural instability
• Most effective drug for bradykinesia and rigidity (best response)
• Less effective for tremor (anticholinergics better for tremor alone)

• Nausea and vomiting (stimulates D₂ in CTZ; most common early; give with domperidone)
• Postural hypotension (↓ peripheral vascular resistance via dopaminergic receptors)
• Cardiac arrhythmias (tachycardia, premature beats)

• Dyskinesias (involuntary choreoathetotic movements - most troublesome long-term effect)
• On-Off phenomenon - Fluctuations between "on" (drug working well) and "off" (motor freezing) states; unpredictable with long-term use
• End-of-dose deterioration (wearing off) - effect wears off before next dose
• Psychiatric effects: Hallucinations, delusions, paranoia, confusion, vivid dreams (dopaminergic stimulation of mesolimbic/mesocortical system)

• Browning of urine (melanin-like pigment from dopamine oxidation)

• Pyridoxine (Vit B6) - increases peripheral metabolism of L-DOPA → ↓ brain levels (if given without dopa decarboxylase inhibitor)
• MAO inhibitors - hypertensive crisis (avoid within 2 weeks)
• Antipsychotics - oppose dopaminergic effect (avoid)

---

DOPAMINERGIC AGONISTS IN PD
          ↓
ERGOT DERIVATIVES (older)    NON-ERGOT (preferred now)
Bromocriptine (D₂)           Pramipexole (D₂, D₃ > D₄)
Pergolide                    Ropinirole (D₂, D₃)
Cabergoline                  Rotigotine (transdermal patch)
                             Apomorphine (D₁+D₂; SC injection for acute "off" episodes)

1. Direct D₂ receptor stimulation - do not require enzymatic conversion
2. Longer duration of action → Less "wearing off" and "on-off" fluctuations
3. Less dyskinesias (smoother receptor stimulation)
4. Do not compete with dietary amino acids for absorption (unlike L-DOPA)
5. Can be used when L-DOPA response wanes

1. Early PD (young patients <60 years): Monotherapy to delay introduction of L-DOPA and reduce dyskinesias
2. Add-on to L-DOPA: When L-DOPA response fluctuates ("on-off" phenomenon)
3. Reduce dose of L-DOPA needed (L-DOPA sparing effect)

• Nausea, vomiting (less than L-DOPA)
• Postural hypotension
• Impulse control disorders (gambling, hypersexuality, compulsive eating) - especially pramipexole/ropinirole
• Somnolence ("sleep attacks" - sudden daytime sleep → caution when driving)
• Hallucinations/psychosis (more than L-DOPA)
• Ergot-derived: Fibrosis (retroperitoneal, pleural, valvular heart disease) - reason for switching to non-ergots

---

In striatum/basal ganglia, dopamine is predominantly metabolized by MAO-B
(MAO-A metabolizes NE and 5-HT preferentially in periphery)
     ↓
MAO-B inhibition → ↓ Degradation of dopamine in brain
     ↓
↑ Synaptic dopamine levels
     ↓
Enhanced dopaminergic transmission in striatum → Symptomatic improvement in PD

1. Early PD monotherapy (selegiline/rasagiline) - possible neuroprotective effect (theoretical - reduces free radicals from MAO-B metabolism)
2. Add-on to L-DOPA - reduces "wearing off" fluctuations, L-DOPA sparing effect
3. Reduces "off" time in fluctuating patients

• Insomnia (selegiline - amphetamine metabolite)
• At high doses (>10 mg selegiline): Lose MAO-B selectivity → MAO-A also inhibited → Cheese reaction (tyramine) possible
• Drug interactions: Serotonin syndrome with SSRIs/pethidine (avoid combination)
• Nausea, dizziness

---

Catechol-O-Methyltransferase (COMT) metabolizes L-DOPA in the gut, liver, and periphery
(Converts L-DOPA to 3-O-methyldopa - inactive)
Also metabolizes dopamine in the brain
     ↓
COMT inhibition → ↓ Peripheral metabolism of L-DOPA
     ↓
More L-DOPA reaches brain (↑ bioavailability, prolonged plasma t½)
↓ Fluctuations ("wearing off" reduced)
↓ L-DOPA dose required by ~30%

1. Add-on to L-DOPA/carbidopa in PD with "wearing off" fluctuations
2. Allows dose reduction of L-DOPA
3. NOT used as monotherapy

• Dyskinesias (due to ↑ effective L-DOPA dose - dose of L-DOPA should be reduced by ~20-30%)
• Diarrhea (specific to COMT inhibitors; may be severe enough to stop drug)
• Nausea, urine discoloration (orange-brown - harmless)
• Tolcapone: Hepatotoxicity (fatal cases reported; LFT monitoring every 2 weeks for 1 year)

---

Morphine → μ, κ, δ opioid receptors (Gi-coupled)
     ↓
↓ cAMP, ↑ K⁺ efflux (hyperpolarization), ↓ Ca²⁺ influx
     ↓
↓ Neuronal excitability and neurotransmitter release
     ↓
ANALGESIA (supraspinal + spinal + peripheral)
CNS: Sedation, Euphoria, Respiratory depression, Nausea
GIT: ↓ Motility (constipation), ↓ Secretions
CVS: Histamine release → Vasodilation
Endocrine: ↑ ADH, ↑ Prolactin, ↑ GH

1. Severe acute pain - Post-operative, trauma, burns, MI (morphine is DOC for pain in AMI - reduces anxiety + relieves pain)
2. Cancer pain (WHO analgesic ladder - Step 3; oral morphine preferred)
3. Acute pulmonary edema / Acute LVF - IV morphine (reduces preload via venodilation + allays dyspnea/anxiety)
4. Cough suppressant (codeine preferred, but morphine used in terminal illness)
5. Acute diarrhea (codeine/loperamide preferred; morphine historically)
6. Pre-anesthetic medication (not routine now)

1. Head injury / ↑ ICP - CO₂ retention → cerebral vasodilation → ↑ ICP further; also pupils - diagnostically unreliable
2. Bronchial asthma - Histamine release → Bronchoconstriction; also respiratory depression
3. Hepatic failure - Reduced metabolism → Accumulation → Coma
4. Undiagnosed acute abdomen - Masks symptoms, delays diagnosis
5. Hypothyroidism - Enhanced sensitivity, prolonged effect
6. Adrenocortical insufficiency (Addison's disease) - Enhanced sensitivity
7. MAOI therapy (serotonin syndrome, hypertensive crisis - especially pethidine)
8. Premature infants - Immature blood-brain barrier, respiratory depression
9. Concurrent alcohol/CNS depressants - Enhanced CNS depression

• Respiratory depression (most serious - CO₂ retention, apnea)
• Nausea and vomiting (stimulates CTZ D₂ receptors, vestibular stimulation)
• Constipation (↓ GI motility, ↑ sphincter tone) - does NOT develop tolerance to this
• Sedation and cognitive impairment
• Miosis (pin-point pupils - diagnostic of opioid OD)
• Hypotension (histamine release + vasodilation)
• Urinary retention (↑ sphincter tone)
• Biliary colic (Oddi's sphincter spasm - ↑ biliary pressure)
• Dependence and addiction (physical and psychological)
• Tolerance develops to analgesia, euphoria, sedation, respiratory depression but NOT to constipation and miosis
• Pruritus (histamine release; especially with spinal/epidural morphine)

---

Pethidine vs Morphine:
• Duration shorter (2-4 hrs vs 4-6 hrs)
• More anticholinergic effects (tachycardia - not bradycardia like morphine)
• Less constipation, less biliary spasm
• DOES NOT cause miosis (anticholinergic counteracts)
• Active toxic metabolite: NORPETHIDINE (accumulates in renal failure → seizures)
• NOT for chronic pain / cancer pain (norpethidine accumulation)
• Has local anesthetic property
• More CNS excitatory effects

1. Acute pain - post-operative, obstetric pain (commonly used in labor; crosses placenta but shorter duration)
2. Biliary/Renal colic - Less biliary spasm than morphine (but still causes some)
3. Pre-anesthetic medication (with atropine - historically)
4. Shivering - Post-operative and post-anesthetic shivering (DOC is pethidine 25 mg IV - activates κ receptors)
5. NOT recommended for cancer pain (norpethidine toxicity)

• Norpethidine toxicity (in renal failure or overdose): Tremors, myoclonus, SEIZURES (neurotoxic - not reversed by naloxone, may worsen with naloxone)
• CNS excitation (instead of sedation in high doses - unique)
• Tachycardia (anticholinergic, unlike morphine)
• Respiratory depression (less than morphine at equianalgesic doses)
• Serotonin syndrome with MAO inhibitors (ABSOLUTE CONTRAINDICATION) - hyperpyrexia, rigidity, coma, death
• Nausea, vomiting, constipation (less than morphine)
• Dependence potential
• Hypotension (histamine release)

---

TRIAD:
1. Pin-point pupils (miosis)
2. Respiratory depression (bradypnea, apnea)
3. Coma (reduced consciousness)
+ Hypotension, bradycardia, cyanosis, hypothermia

ACUTE MORPHINE POISONING
          ↓
IMMEDIATE: AIRWAY, BREATHING, CIRCULATION
• Position patient (lateral) to prevent aspiration
• Oxygen via face mask / bag-valve-mask ventilation
• Intubate and mechanically ventilate if required
• IV access, monitoring (ECG, SpO₂, BP)
          ↓
GASTRIC LAVAGE (if oral ingestion, within 2 hours)
+ Activated charcoal 50g (if within 1 hour and airway protected)
          ↓
SPECIFIC ANTIDOTE: NALOXONE (Narcane)
• Pure competitive opioid receptor antagonist (μ, κ, δ)
• Dose: 0.4-2 mg IV/IM/SC, repeat every 2-3 min if no response
  Up to 10 mg total (if no response, reconsider diagnosis)
• Onset: 1-2 min IV
• Duration: 30-60 min (SHORTER than morphine t½)
          ↓
WATCH FOR RELAPSE
• Naloxone wears off before morphine → Re-sedation/respiratory depression
• NALOXONE INFUSION: 2/3 of initial effective dose per hour IV
• Duration of monitoring: At least 4-6 hours after last naloxone dose
          ↓
CAUTION WITH NALOXONE:
• In opioid-dependent patients → Precipitates ACUTE WITHDRAWAL
  (Agitation, vomiting, tachycardia, hypertension - not life-threatening but distressing)
• Use with caution - titrate dose to restore breathing, not full reversal
• Naltrexone: Long-acting oral opioid antagonist (not for acute overdose)
          ↓
SUPPORTIVE:
• Maintain temperature, treat hypotension with fluids
• Pulmonary edema: O₂, furosemide, positive pressure ventilation

---

Methanol (CH₃OH)
     ↓ Alcohol dehydrogenase (ADH)
Formaldehyde (HCHO) - highly toxic
     ↓ Aldehyde dehydrogenase
Formic acid (HCOOH) - toxic
     ↓
Inhibits cytochrome oxidase (mitochondrial) → Histotoxic hypoxia
     ↓
• SEVERE METABOLIC ACIDOSIS (high anion gap)
• RETINAL TOXICITY → Retinal edema → Blindness (formic acid damages retinal ganglion cells)
• CNS depression

METHANOL POISONING
          ↓
GENERAL MEASURES
• ABC, IV access, O₂
• Gastric lavage + Activated charcoal (early ingestion, <1 hr)
• Correct metabolic acidosis: NaHCO₃ IV (maintain pH >7.3)
          ↓
SPECIFIC ANTIDOTES (COMPETE FOR ALCOHOL DEHYDROGENASE)

1. ETHANOL (IV or oral) - traditional antidote
   • Ethanol has 10-20x higher affinity for ADH than methanol
   • Competitively inhibits ADH → Prevents methanol → Formaldehyde/Formate conversion
   • Methanol excreted unchanged by lungs and kidneys
   • Maintain blood ethanol level: 100-150 mg/dL
   • Target endpoint: Methanol level <20 mg/dL

2. FOMEPIZOLE (4-Methylpyrazole) - PREFERRED in developed countries
   • Competitive ADH inhibitor (>500x more potent than ethanol)
   • Dose: 15 mg/kg IV loading, then 10 mg/kg every 12 hrs
   • Advantages: No CNS depression/sedation like ethanol, no hypoglycemia,
     no monitoring of blood alcohol levels needed
   • Disadvantage: EXPENSIVE; given IV only
          ↓
3. FOLINIC ACID (Leucovorin) or FOLIC ACID
   • Enhances metabolism of formate to CO₂ + H₂O (folate-dependent pathway)
   • Reduces retinal and CNS toxicity
          ↓
4. HEMODIALYSIS
   • Indicated if: Methanol level >50 mg/dL, severe metabolic acidosis,
     visual disturbance, renal failure
   • Removes methanol and formate rapidly
   • Continue ethanol/fomepizole during hemodialysis (also dialyzed off)

---

Chlorpromazine - blocks multiple receptors:

PRIMARY MECHANISM:
D₂ receptor blockade (mesolimbic/mesocortical dopamine pathways)
     ↓
↓ Dopaminergic transmission → Antipsychotic effect

ALSO BLOCKS:
H₁ receptors → Sedation, weight gain
α₁ receptors → Hypotension, reflex tachycardia
M₁ (muscarinic) receptors → Anticholinergic effects (dry mouth, blurred vision)
5-HT₂ receptors (some)

D₂ blockade in:
Mesolimbic → Antipsychotic (therapeutic) ✓
Mesocortical → Worsens negative symptoms, cognitive impairment ✗
Nigrostriatal → EPS (extrapyramidal side effects) ✗
Tuberoinfundibular → ↑ Prolactin (hyperprolactinemia) ✗

1. Schizophrenia (positive symptoms - hallucinations, delusions, thought disorder)
2. Mania (acute - rapidly controls agitation)
3. Anti-emetic - CTZ D₂ blockade (post-operative vomiting, chemotherapy-induced N&V)
4. Hiccup (intractable hiccup - IV/oral)
5. Pre-anesthetic medication (sedation, anti-emetic, potentiates anesthetics)
6. Tetanus (reduces rigidity/spasm with sedation)
7. Delirium tremens (alcohol withdrawal delirium)
8. Psychomotor agitation in dementia, delirium

• Acute dystonias (within hours-days: torticollis, oculogyric crisis, opisthotonus)
• Drug-induced Parkinsonism (days-weeks: bradykinesia, tremor, rigidity)
• Akathisia (restlessness, weeks: cannot sit still - most distressing)
• Tardive Dyskinesia (months-years: irreversible choreoathetotic movements of face, tongue, limbs - most serious long-term)

• Dry mouth, blurred vision, constipation, urinary retention, tachycardia

• Postural hypotension, reflex tachycardia

• Sedation, weight gain

• Galactorrhea, amenorrhea, gynecomastia, sexual dysfunction

• Neuroleptic Malignant Syndrome (NMS) - Rare, life-threatening: Hyperthermia, rigidity, altered consciousness, autonomic instability; Treat: Stop drug, Dantrolene, Bromocriptine
• Jaundice (cholestatic)
• Agranulocytosis
• Photosensitivity, skin pigmentation
• QT prolongation
• Lowered seizure threshold

---

Fluoxetine (Prozac)
     ↓
Selectively inhibits Serotonin Transporter (SERT) - presynaptic
     ↓
↓ Reuptake of 5-HT from synapse back into presynaptic terminal
     ↓
↑ Synaptic serotonin concentration
     ↓
Sustained 5-HT₁A, 5-HT₂ receptor stimulation
     ↓
Antidepressant effect (delayed 2-4 weeks - due to receptor downregulation and neuroplasticity)
Also: Neurogenesis in hippocampus (BDNF ↑)

• Longest t½ of SSRIs: Fluoxetine 1-4 days; Active metabolite Norfluoxetine 4-16 days
• Once daily dosing
• 5-6 weeks washout before MAO inhibitors
• CYP2D6 and CYP3A4 inhibitor → Multiple drug interactions

1. Major Depressive Disorder (MDD) - First-line antidepressant
2. OCD (Obsessive Compulsive Disorder) - effective, higher doses needed
3. Bulimia nervosa - Only antidepressant approved for bulimia (60 mg/day)
4. Panic disorder
5. Social anxiety disorder
6. PMDD (Premenstrual dysphoric disorder)
7. PTSD (Post-traumatic stress disorder)

• GI: Nausea, diarrhea (most common early effects - related to ↑ 5-HT in gut)
• Sexual dysfunction - Reduced libido, anorgasmia, delayed ejaculation (very common, 30-40%)
• Insomnia, restlessness, anxiety (activating drug - give in morning)
• Headache
• Weight changes (initial weight loss, long-term possible gain)
• Serotonin syndrome (with MAO inhibitors, triptans, tramadol, lithium) - Hyperthermia, confusion, tremor, diarrhea, clonus → POTENTIALLY FATAL; MANDATORY washout period 14 days (5-6 weeks for fluoxetine) before/after MAOIs
• SIADH/Hyponatremia (especially elderly)
• QT prolongation (minor; more with citalopram/escitalopram)
• Bleeding risk (serotonin needed for platelet aggregation; ↑ risk with NSAIDs/warfarin)
• Withdrawal syndrome (minimal with fluoxetine due to long t½ - advantage)
• Teratogenicity concerns: Neonatal adaptation syndrome (3rd trimester)

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Diazepam → Binds BENZODIAZEPINE BINDING SITE on GABA-A receptor
               (located on γ subunit, between α and γ subunits)
     ↓
Positive allosteric modulator of GABA-A
     ↓
↑ FREQUENCY of Cl⁻ channel opening (in presence of GABA)
(Barbiturates ↑ DURATION; Benzodiazepines ↑ FREQUENCY)
     ↓
↑ Cl⁻ influx → Hyperpolarization of neuron → CNS inhibition
     ↓
Anxiolytic, Sedative, Hypnotic, Anticonvulsant, Muscle relaxant, Amnestic effects

• Long-acting (t½ 20-100 hrs + active metabolites nordazepam, desmethyldiazepam up to 200 hrs)
• Active metabolite: Desmethyldiazepam (also active)
• Onset: Rapid oral/IV

1. Anxiety disorders - GAD (short-term), panic disorder
2. Status epilepticus - IV diazepam (5-10 mg IV, first-line)
3. Insomnia (short-term)
4. Muscle spasms - skeletal muscle relaxant (central action; spasticity in MS, tetanus, cerebral palsy)
5. Alcohol withdrawal - Prevents/treats delirium tremens, withdrawal seizures (DRUG OF CHOICE for alcohol withdrawal)
6. Pre-anesthetic medication and procedural sedation
7. Vertigo (acute)
8. Febrile seizures (rectal diazepam)
9. Local anesthetic toxicity (IV for seizures)

• CNS Depression: Sedation, drowsiness, impaired cognition, anterograde amnesia
• Ataxia, incoordination (especially in elderly - fall risk)
• Paradoxical reactions (increased agitation in elderly and children)
• Tolerance (to hypnotic and anxiolytic effects; NOT to anticonvulsant effect)
• Dependence and Withdrawal syndrome:
  • Physical dependence with chronic use
  • Withdrawal: Anxiety, insomnia, tremors, seizures (taper slowly)
• Respiratory depression (especially IV + opioids/alcohol)
• Neonatal depression if used in late pregnancy ("floppy infant syndrome")
• Memory impairment (anterograde amnesia - exploited in procedures)

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Z compounds (e.g., Zolpidem)
     ↓
Bind to BENZODIAZEPINE SITE on GABA-A receptor
(Same site as BZDs but different binding affinity)
     ↓
BUT: Selective binding to α₁ subunit-containing GABA-A receptors
(BZDs bind α₁, α₂, α₃, α₅)
     ↓
α₁ → Sedation, hypnosis, anterograde amnesia (only these effects)
(NOT α₂ → less anxiolytic; NOT α₃ → less muscle relaxant; NOT α₅ → less amnestic effects)
     ↓
More SELECTIVE sedative-hypnotic; Less anxiolytic, less muscle relaxant

1. Insomnia - Short-term treatment (sleep onset insomnia - zolpidem, zaleplon; sleep maintenance - zopiclone, eszopiclone)
2. Zaleplon - ultra-short acting (t½ = 1 hr); can be taken in middle of night

• Less tolerance and dependence
• Less morning hangover (shorter t½ for zolpidem/zaleplon)
• Less anxiolytic/muscle relaxant (less side effects in daytime)
• Better sleep architecture (less REM suppression)

• Anterograde amnesia (sleep-walking, sleep-eating, sleep-driving - complex sleep behaviors; unique concern with zolpidem)
• Residual sedation (next-day grogginess - especially extended-release)
• Dependence (less than BZDs but can occur with chronic use)
• Dizziness, headache
• Rebound insomnia on stopping
• Metallic taste (zopiclone characteristic)

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TOPIC: CNS — 3 MARKS

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Glycopyrrolate (Quaternary ammonium anticholinergic)
     ↓
ADVANTAGES AS PREANESTHETIC:

1. ANTISIALAGOGUE - Most potent among anticholinergics
   ↓ Salivation and secretions → Prevents airway complications
   Facilitates intubation and inhalational anesthesia

2. PREVENTS BRADYCARDIA - Blocks M₂ (vagal) at SA node
   (Bradycardia caused by succinylcholine, halothane, traction on viscera)

3. REDUCES GASTRIC ACIDITY - Useful in at-risk patients (reduces aspiration pneumonitis risk)

4. NO CNS PENETRATION (quaternary - does NOT cross BBB)
   → No sedation, no confusion, no anti-emetic effect
   → PREFERRED OVER ATROPINE (atropine crosses BBB → CNS effects)

5. LONGER DURATION than atropine

6. USED WITH NEOSTIGMINE for reversal of NMB
   (Blocks muscarinic side effects of neostigmine without CNS effects)

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COMBINATION: N₂O + HALOTHANE
          ↓
N₂O (Nitrous Oxide) alone:
• MAC = 104% → Cannot produce surgical anesthesia alone (incomplete anesthetic)
• EXCELLENT ANALGESIC
• Fast onset and offset
• Minimal cardiovascular/respiratory depression

HALOTHANE alone:
• Potent (MAC = 0.75%) - can produce full surgical anesthesia
• But high dose → Significant cardiovascular depression (↓ CO, hypotension)
• Arrhythmias, dose-dependent toxicity

COMBINATION RATIONALE (Balanced Anesthesia):
• N₂O provides analgesia + reduces halothane requirement
• Halothane provides unconsciousness, muscle relaxation
• ↓ Halothane dose needed (by 50-60%) → ↓ Halothane toxicity
• ↓ Cardiovascular depression
• Better and faster induction, smoother anesthesia
• N₂O also has "Second Gas Effect" - enhances uptake of halothane

= Mutual benefit: Each drug compensates for the other's weakness
= Principle of BALANCED ANESTHESIA

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MECHANISM OF METHANOL TOXICITY:
Methanol → (Alcohol Dehydrogenase = ADH) → Formaldehyde → Formic acid
                   ↓ [BLOCK THIS STEP]

RATIONALE OF ETHANOL:
Ethanol has 10-20x HIGHER AFFINITY for Alcohol Dehydrogenase than Methanol
     ↓
COMPETITIVE SUBSTRATE for ADH
     ↓
ADH preferentially metabolizes ETHANOL instead of METHANOL
     ↓
Methanol is NOT converted to toxic formaldehyde/formate
     ↓
Methanol is excreted UNCHANGED via lungs (exhaled) and kidneys
     ↓
Prevents accumulation of toxic metabolites
     ↓
Prevents metabolic acidosis and retinal toxicity (blindness)

TARGET: Maintain blood ethanol level 100-150 mg/dL
DOSE: 0.6 g/kg loading → 0.1 g/kg/hr maintenance
Note: Fomepizole now preferred (no sedation, hypoglycemia side effects)

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Flumazenil = Specific competitive antagonist at the BENZODIAZEPINE binding site on GABA-A receptor
             → Reverses all effects of benzodiazepines and Z drugs
             → Short-acting (t½ = 1-2 hours) - SHORTER than most BZDs

1. Reversal of BZ-induced sedation (post-procedural - endoscopy, colonoscopy, minor surgery)
2. Benzodiazepine overdose (diagnostic and therapeutic)
3. Reversal of BZ-induced respiratory depression in ICU
4. Diagnosis - if coma is of unknown origin and BZ overdose is suspected

• Short t½ (1-2 hrs) < most BZDs → Re-sedation can occur → Repeat doses/infusion may be needed
• In BZ-dependent patients → Precipitates acute withdrawal including seizures (use cautiously, titrate)
• Does NOT reverse barbiturates, opioids, or alcohol
• Dose: 0.2 mg IV, repeat every 1 min up to 1 mg total

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DRUG-INDUCED PARKINSONISM:
Caused by: Antipsychotics (D₂ blockers), Metoclopramide, Reserpine
Mechanism: D₂ receptors in nigrostriatal pathway are BLOCKED (not degenerated)
               ↓
The dopamine-producing neurons are INTACT and functional
But D₂ receptors are occupied/blocked by the antipsychotic drug
               ↓
Levodopa → Dopamine (synthesized normally)
But Dopamine CANNOT ACT because receptors are blocked
→ Levodopa is INEFFECTIVE (receptor blocked, cannot displace antipsychotic at clinical doses)

1. STOP or REDUCE the causative drug (if possible)
   → Symptoms often resolve in weeks to months

2. If antipsychotic cannot be stopped:
   Switch to ATYPICAL ANTIPSYCHOTIC (lower EPS risk)
   e.g., Quetiapine, Clozapine (least EPS)

3. ANTICHOLINERGICS:
   Trihexyphenidyl (Benzhexol) 2-5 mg TDS
   Biperiden
   → Restore dopamine-ACh balance by reducing ACh
   → Most effective for drug-induced parkinsonism

4. Amantadine (weak DA agonist, NMDA blocker) - alternative

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LEVODOPA alone (without Carbidopa):
95% of oral levodopa converted to dopamine OUTSIDE brain (gut, liver, peripheral tissues)
by Dopa decarboxylase (AAAD - Aromatic Amino Acid Decarboxylase)
→ Only 1-2% enters brain
→ High dose needed → High peripheral dopamine → Severe peripheral side effects

CARBIDOPA = Peripheral AAAD (Dopa Decarboxylase) Inhibitor
            (Does NOT cross BBB → No effect on central conversion)

↓ Peripheral conversion → More L-DOPA survives to cross BBB
→ 5-10x more L-DOPA reaches brain
→ Dose of L-DOPA can be REDUCED by 75-80%

↓ Peripheral dopamine formation
→ ↓ Nausea and vomiting (less CTZ stimulation)
→ ↓ Postural hypotension (less vascular dopamine)
→ ↓ Cardiac arrhythmias

Pyridoxine (Vit B6) enhances peripheral AAAD activity
→ Increases L-DOPA destruction peripherally
→ WITH CARBIDOPA: Peripheral AAAD is already blocked
→ Pyridoxine-containing foods/supplements CAN be taken safely

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1. SAFER in overdose (SSRIs) vs. fatal cardiac toxicity with TCAs
2. Fewer anticholinergic side effects - SSRIs lack antimuscarinic activity → No dry mouth, urinary retention, constipation, blurred vision

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Naloxone (Narcan) = Pure competitive OPIOID RECEPTOR ANTAGONIST
Blocks μ, κ, δ receptors with high affinity; NO intrinsic agonist activity
     ↓
Reverses ALL effects of opioid agonists: Analgesia, sedation, respiratory depression, miosis
t½ = 30-60 min (SHORTER than most opioids → re-sedation possible)

1. Opioid overdose/poisoning (reversal of respiratory depression, coma, miosis) - DRUG OF CHOICE; 0.4-2 mg IV
2. Post-operative opioid reversal (reverses residual respiratory depression after opioid-based anesthesia)
3. Neonatal opioid depression (mother received opioid in labor; 0.01 mg/kg IV/IM/SC/endotracheal)
4. Diagnosis of opioid dependence (precipitates acute withdrawal in dependent patients)
5. Naloxone challenge test before initiating naltrexone therapy
6. Reversal of pruritus/nausea from epidural opioids (low dose)
7. Combination products: Suboxone (buprenorphine + naloxone) for opioid dependence treatment - naloxone prevents IV abuse

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Fentanyl = Synthetic strong opioid analgesic; Phenylpiperidine derivative
PRIMARY μ OPIOID RECEPTOR AGONIST
100x more potent than morphine
Highly lipid soluble → Rapid onset (1-2 min IV), Short duration (30-45 min IV)
Large Vd, extensively metabolized by CYP3A4 in liver

1. Intraoperative analgesia - Most widely used opioid in anesthesia (2-50 μg/kg IV)
2. Epidural and spinal analgesia (labor, post-operative)
3. Transdermal patch (Duragesic) - Chronic cancer pain and severe chronic non-cancer pain; changed every 72 hrs
4. Buccal/Transmucosal fentanyl - Breakthrough cancer pain (rapid onset)
5. ICU sedation/analgesia - Continuous IV infusion
6. TIVA (Total Intravenous Anesthesia) - Combined with propofol
7. Neuroanesthesia (minimal effects on ICP compared to morphine)
8. Cardiac surgery - High-dose fentanyl anesthesia (cardiovascular stability)

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ACUTE LVF / PULMONARY EDEMA:
↑ Left ventricular filling pressure
     ↓
Fluid transudation into alveoli
     ↓
Severe dyspnea, anxiety, frothy sputum

MORPHINE (IV 2-4 mg) RATIONALE:
          ↓
1. VENODILATION (↓ PRELOAD):
   Morphine → Releases histamine + Reduces sympathetic tone → Peripheral venodilation
   → ↓ Venous return to heart → ↓ Preload → ↓ LV filling pressure
   → ↓ Pulmonary congestion

2. ARTERIAL DILATION (↓ AFTERLOAD):
   ↓ Peripheral vascular resistance → ↓ Afterload → Easier LV ejection

3. ANXIOLYSIS:
   Reduces severe anxiety and sympathetic overdrive
   → ↓ Catecholamine surge → ↓ Tachycardia → ↓ O₂ demand

4. DYSPNEA RELIEF:
   Reduces sensation of breathlessness centrally (μ receptor in respiratory center)
   Acts on limbic system → Reduces fear/panic response to dyspnea

RESULT: ↓ Preload + ↓ Afterload + ↓ Anxiety + ↓ O₂ demand
→ Improved cardiac performance and symptom relief

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TOPIC: GASTROINTESTINAL SYSTEM — 3 MARKS

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ANTACIDS USED ALONE:

Aluminium Hydroxide alone:
• Advantage: Non-systemic, long-acting
• DISADVANTAGE: CONSTIPATION (Al³⁺ reduces bowel motility)
               Phosphate binding → Phosphate depletion with chronic use

Magnesium Trisilicate alone:
• Advantage: Good neutralizing capacity
• DISADVANTAGE: DIARRHEA (Mg²⁺ osmotic laxative effect + ↑ GI motility)
               Renal failure risk if absorbed Mg²⁺ (avoid in renal disease)

RATIONALE OF COMBINATION:
          ↓
OPPOSING GI MOTILITY EFFECTS CANCEL EACH OTHER:
Al³⁺ (constipating) + Mg²⁺ (laxative) = NORMAL BOWEL HABITS
          ↓
Combination also:
• Provides sustained neutralization (Mg works fast, Al works slow)
• Better patient tolerance and compliance
• Preparations: Gelusil, Digene, Mucaine (with oxetacaine)

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1. No extrapyramidal side effects (no CNS penetration - no nigrostriatal D₂ blockade)
2. No sedation
3. No CNS side effects (depression, anxiety) - acts only on CTZ (which is outside BBB) and gut

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H. PYLORI ERADICATION REGIMENS

Standard First-Line: PPI-based Triple Therapy (14 days preferred)

REGIMEN 1: CLASSIC TRIPLE THERAPY (7-14 days)
PPI (omeprazole 20 mg BD / pantoprazole 40 mg BD)
+ Amoxicillin 1g BD
+ Clarithromycin 500 mg BD
Eradication rate: ~70-85%

REGIMEN 2: BISMUTH QUADRUPLE THERAPY (10-14 days)
(Used in clarithromycin-resistant areas, 2nd line)
PPI BD
+ Bismuth subcitrate 120 mg QID
+ Metronidazole 400 mg TDS
+ Tetracycline 500 mg QID

REGIMEN 3: SEQUENTIAL THERAPY (10 days)
Days 1-5: PPI + Amoxicillin
Days 6-10: PPI + Clarithromycin + Tinidazole/Metronidazole

REGIMEN 4: CONCOMITANT THERAPY
PPI + Amoxicillin + Clarithromycin + Metronidazole (all 4 together x 10-14 days)
High eradication rates even with resistance

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LOPERAMIDE (Opium derivative/synthetic opioid)
     ↓
1. PERIPHERAL μ-OPIOID RECEPTOR AGONIST in gut
   (Does NOT cross BBB significantly → No CNS effects, no analgesia, no addiction potential)
          ↓
2. ↓ GI MOTILITY:
   Binds μ receptors in myenteric and submucosal plexus
   → Hyperpolarization of neurons
   → ↓ Peristaltic activity → ↑ Transit time
   → More water and electrolyte absorption from gut lumen
          ↓
3. ↑ ANAL SPHINCTER TONE
   → Reduces fecal urgency and incontinence
          ↓
4. ↓ INTESTINAL SECRETION:
   Reduces secretory stimuli, ↑ absorption of water and electrolytes

RESULT: ↓ Stool frequency, ↑ stool consistency, ↓ fluid loss

Dose: 4 mg initially, 2 mg after each loose stool; max 16 mg/day

USES:
• Acute non-specific diarrhea
• Traveler's diarrhea
• Chronic diarrhea (IBS, short bowel syndrome)
• Ileostomy/colostomy - reduce output

NOT for: Inflammatory bowel disease with infection/high fever (risk of toxic megacolon)

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ORS (Oral Rehydration Solution)
WHO Formula: Na⁺ 75 mEq/L, Cl⁻ 65 mEq/L, K⁺ 20 mEq/L, Citrate 10 mEq/L, Glucose 75 mEq/L
Osmolarity: 245 mOsm/L (Reduced osmolarity ORS)

1. Heat stroke/Heat exhaustion - rehydration after excessive sweating with electrolyte loss
2. Vomiting - Mild to moderate dehydration from persistent vomiting (sip slowly)
3. Excessive exercise/Sports - Electrolyte replacement after intense physical activity (better than plain water)
4. Hypernatremic dehydration - Correction of hypernatremia (hypotonic fluid slowly)
5. Burns - Initial fluid resuscitation (oral phase, minor burns)
6. Malnutrition with dehydration - WHO rehydration in malnourished children
7. Cholera - Continued use after initial IV correction
8. Pre/Post-operative oral hydration (fast-track ERAS protocols)

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TOPIC: GI SYSTEM — 5 MARKS

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Omeprazole (prodrug - weak base; pKa ~4.0)
     ↓
Oral enteric-coated formulation → Absorbed in small intestine (bypasses stomach acid)
     ↓
Enters blood → Accumulates in ACID MILIEU of parietal cell CANALICULUS
     ↓
Acidic environment converts omeprazole to SULFENAMIDE (active form)
     ↓
Sulfenamide covalently binds to (H⁺/K⁺-ATPase) - PROTON PUMP
(Irreversible inhibition via disulfide bond at Cys 813 and Cys 892)
     ↓
Proton pump CANNOT secrete H⁺ into gastric lumen
     ↓
PROFOUND, PROLONGED acid suppression
(Even though t½ = 1 hour, effect lasts 24-36 hrs due to irreversible pump inhibition)
New acid secretion only resumes when NEW proton pumps are synthesized (~18-24 hrs)

1. Peptic ulcer disease - Duodenal and gastric ulcers (heals faster than H₂ blockers)
2. H. pylori eradication - Component of all triple/quadruple regimens
3. GERD - Cornerstone of treatment (erosive esophagitis, NERD)
4. Zollinger-Ellison syndrome (Gastrinoma) - High-dose omeprazole (high gastrin → excess acid)
5. NSAID-induced ulcer prophylaxis (in patients who must continue NSAIDs)
6. Upper GI bleeding - IV pantoprazole infusion post-endoscopy
7. Stress ulcer prophylaxis (ICU patients)
8. Dyspepsia - functional and organic

• Headache, diarrhea, nausea, abdominal pain (generally well tolerated)

• Hypomagnesemia (↓ intestinal Mg²⁺ absorption; can cause hypokalemia, hypocalcemia)
• Vitamin B12 deficiency (requires acid for release from food-bound form)
• Iron deficiency (Fe²⁺ requires acid for absorption)
• C. difficile infection (altered gut microbiome)
• Community-acquired pneumonia (altered gastric bacteria)
• Bone fractures (↓ Ca²⁺ absorption; hip fractures with chronic high-dose use)
• Hyponatremia (SIADH-like)
• Gastric carcinoid tumors (chronic hypergastrinemia → enterochromaffin-like cell hyperplasia; mainly with very long-term use at high doses)

• Reduces clopidogrel activation (CYP2C19 competition) → ↓ antiplatelet effect (use pantoprazole/rabeprazole instead)
• ↑ Methotrexate levels (reduced renal elimination)
• Reduced ketoconazole/itraconazole absorption

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Ondansetron (Setron class)
     ↓
Competitive SELECTIVE 5-HT₃ RECEPTOR ANTAGONIST
5-HT₃ = Ligand-gated ion channel (Na⁺/K⁺) - excitatory

5-HT₃ receptors located in:
1. PERIPHERY - Vagal afferents (splanchnic/abdominal visceral nerves)
2. CTZ (Chemoreceptor Trigger Zone - area postrema, outside BBB)
3. Solitary tract nucleus (vomiting center)
          ↓
Chemotherapy / Radiotherapy / Uremia
→ ↑ 5-HT release from GI enterochromaffin cells
→ Stimulates 5-HT₃ on vagal afferents → Signals to CTZ → VOMITING
          ↓
ONDANSETRON blocks 5-HT₃:
• At peripheral vagal afferents → ↓ Afferent signals from gut
• At CTZ and NTS → ↓ Central emetic signals
     ↓
PREVENTS NAUSEA AND VOMITING
(Especially chemotherapy-induced, post-operative, post-radiotherapy)

1. Chemotherapy-Induced Nausea and Vomiting (CINV) - First-line (especially highly emetogenic chemo like cisplatin)
2. Post-Operative Nausea and Vomiting (PONV) - Most effective drug
3. Radiotherapy-induced vomiting
4. Pregnancy nausea/vomiting (hyperemesis gravidarum - off-label)
5. Alcohol withdrawal - reduces craving (off-label)
6. Renal failure / uremia - nausea
7. Pruritus associated with neuraxial opioids (antagonizes spinal 5-HT₃)

• Headache (most common - 15-20%)
• Constipation (5-HT₃ in GI normally increases motility; blocking it reduces motility)
• QT prolongation (dose-dependent; avoid in patients with long QT, hypokalemia, hypomagnesemia)
• Dizziness, fatigue
• Transaminase elevation (mild, transient)
• Serotonin syndrome (rare, with high doses + other serotonergic drugs)
• Flushing, injection site reactions (IV)

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LACTULOSE
     ↓
Reaches colon intact (not absorbed in small intestine)
     ↓
Colonic bacteria ferment lactulose to:
SHORT-CHAIN FATTY ACIDS (acetic acid, lactic acid, formic acid)
+ CO₂, H₂, CH₄ (gases)
     ↓
↑ Osmotic pressure in colon (acidic, hyperosmotic)
→ Water retention in lumen → Softens stool → Defecation
Also: ↑ Bowel motility

Acidification of colonic lumen (pH ↓)
     ↓
NH₃ (ammonia, lipid soluble, diffuses into blood) → NH₄⁺ (ammonium ion, ionized, TRAPPED in lumen)
     ↓
↓ Ammonia absorption from colon → ↓ Blood ammonia
Also: Cathartic effect removes ammonia-producing bacteria and substrates
Also: Alters gut microbiome - reduces urease-producing bacteria
     ↓
↓ Hepatic encephalopathy symptoms

1. Constipation - Chronic constipation in adults and elderly (15-30 mL BD/TDS)
2. Hepatic Encephalopathy - Most important use; prevents and treats acute HE (30-50 mL QID until 2-3 soft stools/day)
3. Portal-systemic encephalopathy (chronic maintenance)
4. Safe in pregnancy and elderly (non-absorbed)

• Flatulence and bloating (gas production by bacteria; most common complaint)
• Nausea (sweet taste)
• Diarrhea (dose-related; excessive use → electrolyte imbalance)
• Abdominal cramps
• Hypokalemia (with excessive loose stools)
• Not to use in galactosemia or lactase deficiency

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ORS = Glucose-electrolyte solution exploiting Na⁺-Glucose cotransport (SGLT1) mechanism
      for oral rehydration in dehydrating conditions

GLUCOSE-SODIUM COTRANSPORT MECHANISM:
In diarrhea: Na⁺ and water secretion is increased; absorption impaired
But: Na⁺-Glucose cotransporter (SGLT1) on enterocytes remains FUNCTIONAL
     even in diarrheal states (including cholera)
          ↓
Each glucose molecule carries 1 Na⁺ into enterocyte
     ↓
Osmotic gradient draws WATER into the cell along with Na⁺
(For each 1 glucose + 1 Na⁺ → 1 molecule H₂O absorbed)
     ↓
Net fluid absorption despite ongoing secretion

Component         Amount (per L)
Na⁺               75 mEq
Cl⁻               65 mEq
K⁺                20 mEq
Citrate           10 mEq (was bicarbonate earlier)
Glucose           75 mEq (13.5 g)
Total osmolarity: 245 mOsm/L

• Less vomiting, less stool output, less need for IV fluids vs older high-osmolarity ORS

1. Acute diarrhea with mild-moderate dehydration (cholera, rotavirus, bacterial diarrhea)
2. Diarrhea in ALL age groups (children, adults, elderly)
3. Adjunct to IV rehydration in moderate-severe cases
4. Non-diarrheal fluid loss (see Q7 above)

• Plan A: No dehydration → ORS at home
• Plan B: Some dehydration → 75 mL/kg ORS over 4 hours at clinic
• Plan C: Severe dehydration → IV Ringer's Lactate immediately

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TOPIC: HORMONES — 3 MARKS

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• Q10: Advantages of Inhalational steroids over systemic steroids in bronchial asthma
• Q11: Rationale of using Sodium cromoglycate in treatment of asthma
• Q12: Name 3 mucolytic drugs
• Q13: Name 3 drugs used in dry cough

• Q12: Salbutamol - mechanism, therapeutic uses & adverse effects
• Q13: Inhalational corticosteroids
• Q14: Theophylline - mechanism, therapeutic uses & adverse effects
• Q15: Management of Status Asthmaticus

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RESPIRATORY SYSTEM — PHARMACOLOGY ANSWERS

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

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3 MARKS QUESTIONS

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ADVANTAGES SUMMARY:
Inhalational steroids:
     ↓
High local concentration at bronchial mucosa
     ↓
↓ Mucosal inflammation, ↓ Airway hyperresponsiveness,
↓ Mucus secretion, ↓ Edema, ↑ β₂ receptor density
     ↓
Effective prophylaxis/maintenance
     ↓
WITHOUT systemic Cushingoid side effects

• Oral candidiasis (Candida growth in oropharynx - prevent by rinsing mouth after use)
• Hoarseness/dysphonia (steroid effect on laryngeal muscles)
• Both prevented by using a spacer device

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ASTHMA PATHOPHYSIOLOGY:
Allergen → IgE sensitization → IgE binds to mast cell surface receptors
     ↓
Re-exposure to allergen → Cross-linking of IgE-receptor complexes
     ↓
Mast cell degranulation → Release of:
• Histamine (Early phase - bronchoconstriction)
• Leukotrienes (LTC₄, LTD₄) - Late phase, prolonged
• Prostaglandins (PGD₂)
• Platelet Activating Factor (PAF)
     ↓
Bronchoconstriction + Airway inflammation + Hyperresponsiveness

SODIUM CROMOGLYCATE MECHANISM:
     ↓
1. MAST CELL STABILIZER
   Blocks Cl⁻ channels → Prevents Ca²⁺ influx into mast cells
   → ↓ Mast cell degranulation
   → ↓ Release of all mediators (histamine, leukotrienes, PAF)
          ↓
2. Also inhibits sensory nerve C-fibre activation
   (Reduces neurogenic inflammation component)
          ↓
3. Inhibits late-phase asthmatic reaction
   (The prolonged inflammation 6-12 hrs after allergen)

• Prevents BOTH early AND late phase bronchoconstriction
• Effective for exercise-induced asthma (use 15-20 min before exercise)
• Effective for allergic/extrinsic asthma (allergen-triggered)
• PURELY PROPHYLACTIC - no bronchodilator activity; must be used regularly
• Very safe - minimal systemic absorption (inhaled powder/solution)

1. Prophylaxis of mild persistent allergic asthma (especially children - very safe)
2. Exercise-induced bronchospasm prevention
3. Allergic rhinitis (nasal spray)
4. Vernal conjunctivitis (eye drops)

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5 MARKS QUESTIONS

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Salbutamol (Selective β₂ agonist)
     ↓
Binds β₂ adrenergic receptors on bronchial smooth muscle
     ↓
β₂ receptor → Gs protein → Adenylyl cyclase activated
     ↓
↑ cAMP (from ATP)
     ↓
cAMP activates Protein Kinase A (PKA)
     ↓
PKA phosphorylates:
• Myosin Light Chain Kinase (MLCK) → Inactivates MLCK
• K⁺ channels → Opens → Membrane hyperpolarization
• Reduces intracellular Ca²⁺ (sequestration into SR + ↓ entry)
     ↓
↓ Actin-Myosin cross-bridge formation
     ↓
BRONCHIAL SMOOTH MUSCLE RELAXATION → BRONCHODILATION

Additional β₂ effects:
• ↓ Mast cell mediator release (stabilization)
• ↑ Mucociliary clearance
• ↑ Alveolar fluid clearance
• Uterine relaxation (tocolysis at high doses)

• Inhaled (MDI/DPI/Nebulizer): Onset 5 min, Peak 15-30 min, Duration 4-6 hours
• Oral: Onset 30 min, Duration 4-6 hrs (more side effects)
• IV: For acute severe asthma/tocolysis

1. Acute bronchospasm / Acute asthma attack - DRUG OF CHOICE for acute relief (rescue inhaler); 2-4 puffs of MDI (100 μg/puff) or nebulization 2.5-5 mg
2. Bronchial asthma - Reliever therapy (PRN use for symptoms)
3. COPD - Acute relief of bronchospasm
4. Exercise-induced bronchospasm - 2 puffs 15 min before exercise
5. Status asthmaticus - Repeated nebulization every 20 min (3 doses in 1st hour), or continuous nebulization

• Tachycardia, palpitations (especially with oral/IV; less with inhaled)
• Tremor (skeletal muscle β₂ stimulation - most common side effect of inhaled salbutamol)
• Hypokalemia (β₂ → K⁺ shifts into cells; dangerous with high doses + diuretics; monitor K⁺ in status asthmaticus)

• Hyperglycemia (glycogenolysis via β₂ in liver)
• Lactic acidosis (high dose IV - rare)

• Throat irritation, cough (with dry powder inhalers)

• Tolerance to bronchodilator effect with overuse (downregulation of β₂ receptors)
• Overuse of SABA (>2 canisters/month) → Marker of poorly controlled asthma → Increased asthma mortality risk

• Non-selective β blockers (propranolol) → ANTAGONIZE bronchodilation (dangerous in asthmatics)
• MAO inhibitors → Potentiate cardiovascular effects
• Theophylline + Salbutamol → ↑ Hypokalemia risk

---

INHALATIONAL CORTICOSTEROIDS
          ↓
┌─────────────┬──────────────┬─────────────┬──────────────┐
│Beclomethasone│  Budesonide  │ Fluticasone │  Ciclesonide │
│(BDP)         │  (BUD)       │ propionate  │ (prodrug)    │
│100-400 μg/day│200-800 μg/day│100-500 μg/dy│80-320 μg/day │
└─────────────┴──────────────┴─────────────┴──────────────┘
Also: Mometasone, Flunisolide

ICS (Lipophilic - crosses cell membrane)
     ↓
Binds Glucocorticoid Receptor (GR) in cytoplasm
     ↓
Drug-GR complex translocates to nucleus
     ↓
Binds Glucocorticoid Response Elements (GRE) on DNA

TRANSACTIVATION (Anti-inflammatory genes ↑):
• ↑ Annexin-1 (Lipocortin) → Inhibits Phospholipase A₂
  → ↓ Arachidonic acid → ↓ ALL prostaglandins + Leukotrienes
• ↑ β₂ receptor synthesis (upregulates β₂ receptors → enhances β₂ agonist response)
• ↑ Anti-inflammatory mediators (IL-10, IL-12)

TRANSREPRESSION (Pro-inflammatory genes ↓):
• ↓ NF-κB activity → ↓ Pro-inflammatory cytokines (IL-1, IL-4, IL-5, IL-6, TNF-α)
• ↓ COX-2 expression
• ↓ iNOS → ↓ Nitric oxide (inflammation marker)

NET EFFECT ON AIRWAY:
↓ Airway inflammation (eosinophilic inflammation)
↓ Mucosal edema and swelling
↓ Mucus hypersecretion
↓ Airway hyperresponsiveness
↑ β₂ receptor density (synergy with SABAs)

1. Mild persistent asthma - First-line controller (Step 2): Low-dose ICS alone
2. Moderate persistent asthma (Step 3): Medium-dose ICS or Low-dose ICS + LABA (Salmeterol/Formoterol)
3. Severe persistent asthma (Step 4-5): High-dose ICS + LABA ± add-on therapy
4. COPD - ICS + LABA combination in moderate-severe COPD with frequent exacerbations
5. Allergic rhinitis - Nasal ICS (Fluticasone, Mometasone nasal sprays) - First-line
6. Eosinophilic bronchitis
7. Combined preparations: Seretide (Fluticasone + Salmeterol), Symbicort (Budesonide + Formoterol)

• Oral candidiasis (Candida albicans - oropharyngeal thrush; most common; Rx: Use spacer, rinse mouth after use; treat with clotrimazole troches)
• Dysphonia/Hoarseness (steroid myopathy of laryngeal muscles; adductor weakness; usually reversible)
• Cough, throat irritation (more with MDI - use spacer or DPI)

• HPA axis suppression (minimal with standard doses; significant with >800 μg/day BDP equivalent for prolonged periods)
• Growth retardation in children (controversial; usually temporary; high-dose ICS; monitor height)
• Osteoporosis (long-term high dose)
• Cataract/Glaucoma (long-term high dose; less than systemic)
• Easy bruising (skin atrophy)
• Adrenal insufficiency (very high doses)

Use SPACER DEVICE (valved holding chamber):
→ Larger particles deposit in spacer (not mouth)
→ More drug reaches lungs
→ ↓ Oropharyngeal deposition → ↓ Candidiasis, dysphonia

RINSE MOUTH AND GARGLE after each use
→ Removes deposited drug → ↓ Candidiasis

---

THEOPHYLLINE - Multiple mechanisms:

PRIMARY MECHANISM:
Inhibits Phosphodiesterase (PDE) enzyme (non-selective - PDE3, PDE4)
     ↓
↓ Breakdown of cAMP (and cGMP)
     ↓
↑ cAMP in bronchial smooth muscle → PKA activation → Bronchodilation
↑ cAMP in mast cells → ↓ Mediator release
↑ cAMP in diaphragm → ↑ Diaphragmatic contractility

ADDITIONAL MECHANISMS:
1. Adenosine receptor antagonism (A₁, A₂ receptors)
   → Adenosine causes bronchoconstriction + mast cell activation
   → Blocking adenosine → Bronchodilation + Anti-inflammatory
   (Also explains cardiac stimulation, diuresis, CNS stimulation)

2. Histone deacetylase (HDAC) activation at low doses
   → Anti-inflammatory (enhances steroid sensitivity - "Low-dose Theophylline")

3. Direct muscle relaxation of bronchial smooth muscle

4. ↑ Diaphragmatic contractility and ↓ respiratory muscle fatigue
   (Important in COPD with respiratory failure)

5. Mild anti-inflammatory (at low doses, independent of PDE inhibition)

• Oral bioavailability: Good (immediate and SR preparations)
• Therapeutic range: 10-20 mg/L (narrow therapeutic window)
• Metabolism: Hepatic (CYP1A2, CYP3A4) - subject to enzyme induction/inhibition
• t½: 8-9 hours (variable; affected by age, disease, smoking, drugs)
• Significant drug interactions (narrow TI)

1. Bronchial Asthma - Add-on therapy (Step 3-4); less preferred now due to narrow TI
2. COPD - Maintenance bronchodilation; particularly useful for improving respiratory muscle function
3. Status Asthmaticus - IV Aminophylline (theophylline + ethylenediamine; more water-soluble) infusion if β₂ agonists + steroids inadequate
4. Apnea of prematurity - Methylxanthines stimulate respiratory center (caffeine preferred now)
5. Cardiac failure with Cheyne-Stokes respiration (historically; less used now)

PLASMA LEVEL        ADVERSE EFFECTS
< 10 mg/L         : Minimal (subtherapeutic)
10-20 mg/L        : Therapeutic (mild nausea, headache, diuresis)
20-30 mg/L        : Nausea, vomiting, diarrhea, INSOMNIA, tachycardia
                    Irritability, tremor, anxiety
> 30 mg/L         : SERIOUS TOXICITY:
                    Seizures (convulsions - can be severe/fatal)
                    Cardiac arrhythmias (VT, AF, VF)
                    Hypotension
> 40 mg/L         : Death

• Nausea, vomiting, epigastric discomfort (PDE inhibition in GI)
• Headache, insomnia, restlessness
• Tachycardia, palpitations
• Diuresis (mild)

• Seizures (most serious CNS effect)
• Cardiac arrhythmias (SVT, VT, VF)
• Hypotension

↑ Theophylline levels (toxicity risk):
Erythromycin, Clarithromycin (CYP1A2 inhibitors)
Ciprofloxacin (CYP1A2 inhibitor) ← IMPORTANT CLINICAL INTERACTION
Cimetidine, Fluconazole, Verapamil, Allopurinol
Oral contraceptives

↓ Theophylline levels (reduced efficacy):
Rifampicin, Phenytoin, Carbamazepine, Phenobarbitone (enzyme inducers)
Smoking (↑ CYP1A2 activity → ↑ metabolism)

---

Status Asthmaticus = Severe acute asthma attack that does NOT respond to
                     standard initial bronchodilator therapy
                     (β₂ agonists + systemic steroids within 1-2 hours)
= Life-threatening medical emergency

SEVERE/LIFE-THREATENING FEATURES:
• Can't complete sentences in one breath
• RR > 25/min, HR > 110/min
• PEFR 33-50% of predicted (Moderate-Severe)
• PEFR <33% predicted (Life-threatening)
• SpO₂ < 92%, PaO₂ < 8 kPa
• Silent chest (no wheeze = very severe obstruction)
• Cyanosis, bradycardia, exhaustion, confusion
• PaCO₂ normal or rising (exhaustion sign - CO₂ should be low in asthma)
• Pneumothorax (surgical emergency)

STATUS ASTHMATICUS
        ↓
IMMEDIATE ASSESSMENT: ABCDE
• Pulse oximetry, IV access, ECG monitoring
• ABG (if SpO₂ < 92% or severe)
• Chest X-ray (rule out pneumothorax, pneumonia)
        ↓
STEP 1: OXYGEN
• High flow O₂ (40-60%) via face mask
• Target SpO₂: 94-98%
• NEVER withhold O₂ in asthma (unlike COPD - drive concern)
        ↓
STEP 2: SHORT-ACTING β₂ AGONISTS (SABA) - CORNERSTONE
• Salbutamol 2.5-5 mg via nebulizer (O₂-driven nebulizer)
• Repeat every 20 min for first hour (3 doses)
• CONTINUOUS nebulization in severe cases
• IV Salbutamol (250 μg slow IV over 10 min) - if poor inhaler technique
        ↓
STEP 3: IPRATROPIUM BROMIDE (Add-on bronchodilator)
• 0.5 mg nebulized, add to salbutamol nebulization
• Every 4-6 hours
• Anticholinergic (M3 blockade) → Bronchodilation (additive to β₂)
• Most benefit in first 24 hours
        ↓
STEP 4: SYSTEMIC CORTICOSTEROIDS (Anti-inflammatory - ESSENTIAL)
• Hydrocortisone 100-200 mg IV STAT (then QID)
• OR Prednisolone 40-60 mg oral (if can swallow)
• Onset: 4-6 hours (not immediate)
• Continue for 5-7 days oral prednisolone after discharge
        ↓
STEP 5: MAGNESIUM SULPHATE (if poor response to SABA)
• 2g IV over 20 min (single dose)
• Mechanism: Mg²⁺ inhibits Ca²⁺-mediated smooth muscle contraction
• Benefit in life-threatening asthma not responding to step 1-4
        ↓
STEP 6: IV AMINOPHYLLINE (if still not responding)
• Loading dose: 5 mg/kg IV over 20-30 min (if not already on theophylline)
• Maintenance: 0.5-0.9 mg/kg/hr infusion
• Monitor plasma level (target 10-20 mg/L)
• ECG monitoring (arrhythmia risk)
• Less preferred now due to toxicity and limited benefit over β₂+steroids
        ↓
STEP 7: IV β₂ AGONIST (severe cases not responding to nebulized)
• IV Salbutamol infusion 5-20 μg/min
• Monitor K⁺, blood glucose, ECG
        ↓
STEP 8: HELIOX (optional)
• 79% Helium + 21% O₂ mixture
• Less dense than air → ↓ Resistance to airflow → Improved ventilation
• Buys time; limited availability
        ↓
STEP 9: INTUBATION AND MECHANICAL VENTILATION
Indications (ICU):
• Respiratory arrest or near-arrest
• Deteriorating consciousness/confusion
• Exhaustion - rising PaCO₂ despite treatment
• Silent chest + hypoxia not responding
Strategy: Low tidal volume (permissive hypercapnia), prolonged expiratory phase

• PEFR after each nebulization
• ABG every 1-2 hours (severe cases)
• Continuous SpO₂, ECG
• Serum K⁺ (hypokalemia from β₂ + steroids)
• Blood glucose

• PEFR > 75% predicted
• SpO₂ > 94% on room air
• Symptoms improved
• Stable for 1 hour after last nebulization
+ Discharge with:
  - Reliever (SABA MDI with spacer)
  - ICS (start/continue)
  - Prednisolone course (5-7 days)
  - Written Asthma Action Plan
  - GP/Outpatient review in 2 days

---

MISCELLANEOUS TOPICS — PHARMACOLOGY ANSWERS

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

---

3 MARKS QUESTIONS

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---

OTC Drugs = Over-The-Counter Drugs
= Drugs that can be purchased WITHOUT a prescription from a licensed physician
= Available directly from a pharmacist/retail store
= Considered SAFE for self-medication when used as directed

• Low toxicity, wide therapeutic index
• Condition self-diagnosable by patient
• Instructions for use are clear and understandable
• No dependence or abuse potential
• Not teratogenic

• Reduces burden on healthcare system
• Empowers patient self-care
• Cost-effective
• Risk: Self-medication errors, masking serious conditions, drug interactions

---

P Drug = Personal Drug
= The drug that a physician chooses as their FIRST CHOICE drug
  for a given condition, based on:
  1. Efficacy
  2. Safety
  3. Suitability (patient factors)
  4. Cost

STEP 1: Define the diagnosis (indication)
     ↓
STEP 2: Specify the therapeutic objective
     ↓
STEP 3: Identify treatment options
(drug class → specific drug within class)
     ↓
STEP 4: Compare options using CRITERIA:
    E - Efficacy (proven clinical effectiveness)
    S - Safety (ADR profile, contraindications)
    S - Suitability (patient factors, age, pregnancy, comorbidities)
    C - Cost (affordability, availability)
     ↓
STEP 5: Choose YOUR P-drug
     ↓
STEP 6: Write prescription
     ↓
STEP 7: Give information, instructions, warnings
     ↓
STEP 8: Monitor/stop treatment

• For uncomplicated UTI → P drug: Nitrofurantoin or Cotrimoxazole (locally sensitive, affordable, safe, effective)
• For essential hypertension → P drug: Amlodipine (once daily, safe, affordable)

• Promotes RATIONAL DRUG USE
• Reduces irrational polypharmacy
• Improves prescribing confidence and consistency
• Core concept in pharmacotherapy teaching (WHO rational prescribing curriculum)
• Physician's P-drug may differ from another's based on clinical experience and local drug resistance patterns

---

PHARMACOVIGILANCE SYSTEM
          ↓
Spontaneous Reporting (Yellow Card - UK; MedWatch - USA; ADR Monitoring - India)
          ↓
Signal Detection (unusual pattern of ADRs from multiple reports)
          ↓
Signal Evaluation and Risk Assessment
          ↓
Regulatory Action (Labeling change / Withdrawal / Restricted use)

---

PHASES OF CLINICAL TRIALS:

Phase 1: Healthy volunteers (20-100); Safety, pharmacokinetics, MTD; First in human
Phase 2: Patients with disease (100-300); Efficacy, dose-finding, short-term safety
Phase 3: Large patient groups (1000-3000+); Efficacy vs standard; Randomized, double-blind, multicenter
                          ↓
                   DRUG APPROVAL (Regulatory)
                          ↓
Phase 4: Post-marketing surveillance (thousands to millions)

• Conducted AFTER drug approval and marketing
• Studies drug in REAL-WORLD conditions (general population, including elderly, children, special groups excluded from Phase 3)
• Detects RARE ADRs (incidence <1:1000 - too rare to detect in Phase 3)
• Long-term safety and efficacy data
• New indications (off-label use study)
• Drug-drug interactions in real prescribing
• Pharmacoeconomic studies
• Pharmacovigilance is the ongoing component of Phase 4

• Rofecoxib (Vioxx) - Cardiovascular events detected post-marketing → Withdrawn
• Cisapride - Cardiac arrhythmias → Withdrawn
• Thalidomide teratogenicity - Detected post-marketing

---

ELAPIDS (Cobra, Krait): NEUROTOXIC
→ Block NMJ (postsynaptic - cobra; presynaptic - krait)
→ Ptosis, descending paralysis, respiratory failure
→ Minimal local effects

VIPERS (Russell's Viper, Saw-scaled Viper): HEMOTOXIC + CYTOTOXIC
→ Coagulopathy (DIC), hemorrhage, thrombocytopenia
→ Severe local tissue necrosis, swelling
→ Renal failure (Russel's viper)

SNAKE BITE
     ↓
FIRST AID (Pre-hospital):
• Immobilize bitten limb (below heart level)
• Remove jewelry, tight clothing from bitten area
• DO NOT cut-and-suck, tourniquet, or ice
• Reassure (most bites are dry bites - no venom)
• Transport rapidly to hospital
     ↓
HOSPITAL - ASSESS:
• Type of snake if possible
• Signs of envenomation (systemic features)
• 20-minute Whole Blood Clotting Test (20-WBCT): 
  Put 2 mL blood in glass tube, leave 20 min
  If blood does NOT clot → Coagulopathy → Viper envenomation
• Check for neurotoxic features (ptosis, diplopia)
• Monitor vitals, urine output
     ↓
SPECIFIC TREATMENT: ANTI-SNAKE VENOM (ASV) - DRUG OF CHOICE

INDICATIONS for ASV:
• Neurotoxicity (ptosis, paralysis)
• Coagulopathy (non-clotting blood in 20-WBCT)
• Hemoglobinuria/Myoglobinuria
• Active bleeding
• Shock
• Local swelling beyond half the bitten limb

ASV DOSE:
• 10 vials (50 mL) IV over 30-60 min initially
• Repeat 6-hourly if features persist (up to 50 vials)
• Polyvalent ASV covers all 4 common Indian snakes

PREMEDICATION before ASV:
• Adrenaline 0.25 mg SC (prophylaxis against anaphylaxis)
• Promethazine 25 mg IM
• Hydrocortisone 200 mg IV
     ↓
FOR NEUROTOXICITY (Cobra):
• Neostigmine 0.5-2.5 mg IV + Glycopyrrolate 0.6 mg IV
  (Anticurare effect - useful for POST-SYNAPTIC neurotoxins - cobra)
• Mechanical ventilation if respiratory failure
     ↓
SUPPORTIVE CARE:
• IV fluids (maintain urine output >50 mL/hr)
• Fresh Frozen Plasma (FFP) for coagulopathy
• Dialysis for renal failure
• Tetanus prophylaxis
• Antibiotics (secondary infection)
• Surgical debridement of necrotic tissue

---

Scorpion venom (Mesobuthus tamulus - Indian red scorpion)
     ↓
Venom = Neurotoxin (voltage-gated Na⁺ channel activator)
     ↓
Prolonged Na⁺ channel opening → Sustained nerve firing
     ↓
MASSIVE AUTONOMIC STORM:
Initial: Cholinergic surge → Bradycardia, hypotension, salivation, vomiting, sweating
Then: Adrenergic surge → Tachycardia, hypertension, pulmonary edema, cardiac dysfunction
     ↓
CARDIOVASCULAR TOXICITY (Myocarditis, Pulmonary edema)
= Main cause of death

SCORPION STING
     ↓
FIRST AID:
• Cold compress/ice to sting site (reduces pain)
• Immobilize, reassure
• Analgesics (paracetamol/ibuprofen for pain)
     ↓
ASSESS:
• Grade 1: Local pain only → No systemic features → Observe
• Grade 2: Systemic features (autonomic storm, cardiovascular)
     ↓
DRUG OF CHOICE: PRAZOSIN (α₁ blocker)
     ↓
PRAZOSIN RATIONALE:
• Counters adrenergic surge (hypertension, coronary spasm)
• Reduces afterload → ↓ Pulmonary edema
• Reduces peripheral vasoconstriction
• Dose: 250-500 μg oral every 3-6 hours (children: 250 μg)
• Continue until autonomic storm subsides
     ↓
ANTI-SCORPION VENOM (ASV):
• Available in India (Maharashtra); IV slow infusion
• Best given early; neutralizes circulating venom
• Effective within 1-2 hours of sting
     ↓
FOR PULMONARY EDEMA:
• O₂, furosemide
• Prazosin (reduces afterload)
• Dobutamine (if cardiogenic shock with poor contractility)
• AVOID: Atropine (worsens hypertension), Hydrocortisone
     ↓
SUPPORTIVE:
• IV access, monitoring (ECG, SpO₂, BP)
• Hydration
• ICU if Grade 2 (cardiovascular features)
• Tetanus prophylaxis
• Analgesics for pain

---

NUTRACEUTICALS = NUTRITION + PHARMACEUTICALS
= Food or food-derived products that provide HEALTH BENEFITS
  beyond basic nutrition, including prevention and treatment of disease
= Term coined by Stephen DeFelice (1989)
= Products in the BORDERLINE between foods and drugs

• Drugs = treat disease; Nutraceuticals = prevent or support health
• Nutraceuticals do not require clinical trial evidence to same standard as drugs
• Cannot claim to "cure" diseases on label (only "structure/function" claims)

---

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ANTISEPTIC = Applied to LIVING TISSUE (skin, wounds, mucous membranes)
             to prevent infection by killing/inhibiting microorganisms
             (safe enough for body surfaces)

DISINFECTANT = Applied to INANIMATE SURFACES/OBJECTS (instruments, floors, walls)
               More potent, may be toxic to living tissue

---

1. Nutritional Rickets/Osteomalacia - Cholecalciferol D₃ 60,000 IU/week × 6-8 weeks, then maintenance
2. Renal Osteodystrophy - Calcitriol (bypasses diseased kidney)
3. Hypoparathyroidism - Calcitriol + Calcium supplementation
4. Osteoporosis - D₃ + Calcium as adjunct to bisphosphonates
5. Psoriasis - Topical Calcipotriol (Vitamin D₃ analogue)
6. Prevention of falls in elderly - Vitamin D supplementation

---

Retinol (Vitamin A₁) → Active forms: Retinal (vision), Retinoic acid (gene regulation)
Beta-carotene (Pro-vitamin A) → Converted to retinol in body
Isotretinoin, Tretinoin, Acitretin = Synthetic retinoids

• Night blindness (Nyctalopia) - Earliest sign; treated with Vitamin A 1,00,000-2,00,000 IU oral
• Xerophthalmia (dry eyes, Bitot's spots, corneal xerosis) - Leading preventable cause of blindness; Vitamin A supplements
• Keratomalacia (corneal softening and melting) - Emergency; High-dose Vitamin A
• Measles - WHO recommends Vitamin A 2,00,000 IU in children with measles (reduces morbidity and mortality)
• Protein-energy malnutrition - Vitamin A deficiency coexists

• Acne vulgaris (severe, cystic, nodular) - Oral Isotretinoin (13-cis-retinoic acid); DOC for severe acne
• Psoriasis - Acitretin (oral retinoid); Tazarotene (topical)
• Topical Tretinoin (All-trans retinoic acid) - Acne, Photo-aging, Fine wrinkles, Melasma (Retin-A cream)
• Ichthyosis (hyperkeratotic skin disorders) - Acitretin
• Lichen planus - Etretinate/Acitretin (severe cases)

• Acute Promyelocytic Leukemia (APL/M3 AML) - All-trans Retinoic Acid (ATRA/Tretinoin) + Arsenic trioxide → Induces differentiation of malignant promyelocytes; CURATIVE in many cases
• Prevention of recurrence of head and neck cancers (retinoids as chemopreventive agents)

• National Vitamin A Supplementation Programme (India) - 6 monthly doses of Vitamin A (1,00,000 IU at 9 months; 2,00,000 IU at 18, 24, 30, 36, 42, 48, 54, 60 months) to prevent deficiency and reduce child mortality

• Photosensitivity (Erythropoietic Protoporphyria) - Beta-carotene reduces photosensitivity

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5 MARKS QUESTIONS

---

Psoriasis = Chronic, immune-mediated inflammatory skin disease
characterized by well-demarcated, erythematous, silvery scaly plaques
(hyperproliferation of keratinocytes - turnover 4 days instead of 28 days)
Pathogenesis: T-cell mediated → IL-17, IL-23, TNF-α → Keratinocyte hyperproliferation

ASSESS SEVERITY FIRST:
• BSA (Body Surface Area) involved
• PASI score (Psoriasis Area and Severity Index)
• Quality of life (DLQI)

Mild: <10% BSA / PASI <10
Moderate: 10-30% BSA / PASI 10-20
Severe: >30% BSA / PASI >20

Narrow-Band UVB (NB-UVB):
• Most commonly used phototherapy
• 311 nm UV light → ↑ T cell apoptosis, ↑ Vit D₃, ↓ IL-2, IL-12
• 3x/week for 15-30 sessions
• Safe in pregnancy, children

PUVA (Psoralen + UVA):
• Psoralen (Methoxsalen) oral/topical → Absorbs UVA
• Forms DNA cross-links → ↓ Keratinocyte proliferation
• More effective than NB-UVB but ↑ skin cancer risk with long-term use

METHOTREXATE (First-line systemic):
• 7.5-25 mg once weekly + Folic acid
• Mechanism: DHFR inhibition → ↓ Lymphocyte and keratinocyte proliferation
• Monitoring: LFT, CBC, RFT
• ADRs: Hepatotoxicity, myelosuppression, pneumonitis, teratogenicity
• Liver biopsy after cumulative dose of 1.5g

CYCLOSPORINE:
• 2.5-5 mg/kg/day
• Calcineurin inhibitor → ↓ IL-2, ↓ T cell activation
• Fast onset (2-4 weeks)
• Short-term use (< 2 years due to nephrotoxicity, hypertension)

ACITRETIN (Retinoid):
• Oral retinoid; normalizes keratinocyte differentiation
• Less effective alone; synergistic with NB-UVB
• ADRs: Teratogenicity (continue contraception 3 years after stopping), dryness, hyperlipidemia
• Preferred in pustular psoriasis and erythrodermic psoriasis

APREMILAST (PDE4 inhibitor):
• Newer oral agent; ↑ cAMP → ↓ TNF-α, IL-17, IL-23
• Moderate psoriasis; fewer monitoring requirements

TNF-α INHIBITORS:
• Adalimumab, Etanercept, Infliximab
• Screen for TB before starting

IL-12/23 INHIBITOR:
• Ustekinumab (anti-p40 subunit; blocks both IL-12 and IL-23)

IL-17 INHIBITORS (Most effective for psoriasis):
• Secukinumab (anti-IL-17A) - Fastest and most effective
• Ixekizumab

IL-23 INHIBITORS:
• Guselkumab, Risankizumab, Tildrakizumab

• Scalp psoriasis: Coal tar shampoo + Calcipotriol + Topical steroids (betamethasone scalp application)
• Nail psoriasis: Calcipotriol, intralesional steroids, systemic agents
• Psoriatic Arthritis: MTX + NSAIDs + Anti-TNF biologics

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4 KEY FACTORS:
1. ↑ Sebum production (androgens stimulate sebaceous glands)
2. Follicular hyperkeratosis (plugging of pilosebaceous unit)
3. Propionibacterium acnes (Cutibacterium acnes) colonization
4. Inflammation (innate and adaptive immune response)

Grade 1 (Mild): Comedones (blackheads/whiteheads) only
Grade 2 (Moderate): Papules and pustules (inflammatory)
Grade 3 (Moderately Severe): Papulopustular + Nodules
Grade 4 (Severe/Nodulocystic): Nodules, cysts, risk of scarring

TOPICAL RETINOIDS (First-line for comedones):
• Tretinoin (All-trans retinoic acid) 0.025-0.1% cream/gel
• Adapalene 0.1% gel (more stable, less irritating - preferred)
• Tazarotene 0.05-0.1% gel (most potent retinoid)
Mechanism: Normalizes follicular epithelial desquamation → Prevents comedone formation

TOPICAL KERATOLYTICS:
• Salicylic acid 2% → Comedolytic
• Benzoyl Peroxide (BPO) 2.5-5% → Antibacterial (releases O₂ → kills P.acnes), comedolytic, anti-inflammatory

TOPICAL ANTIBIOTICS:
• Clindamycin 1% gel (most used)
• Erythromycin 2% (resistance increasing)
→ Combined ALWAYS with Benzoyl Peroxide (prevents resistance)
(Clindamycin + BPO = Clindac-BPO; Duac gel)

AZELAIC ACID 15-20%:
• Antibacterial + Reduces pigmentation (good for post-acne marks)
• Anti-inflammatory + Normalizes keratinization

ORAL ANTIBIOTICS (moderate-severe or topical failure):
• Doxycycline 100 mg OD (preferred - once daily, less resistance than tetracycline)
• Tetracycline 500 mg BD (cheap but twice daily, food interaction)
• Minocycline 100 mg OD
Duration: Minimum 6-8 weeks; Combine with Topical Retinoid
→ Topical BPO to prevent antibiotic resistance

ORAL ISOTRETINOIN (13-cis-retinoic acid) - DRUG OF CHOICE:
• Acts on ALL 4 pathogenic factors:
  ↓ Sebum production (80-90% reduction) - PRIMARY mechanism
  ↓ Follicular keratinization
  ↓ P.acnes count (indirectly)
  ↓ Inflammation

• Dose: 0.5-1 mg/kg/day × 4-6 months
  (Cumulative dose = 120-150 mg/kg total for remission)
• CURE RATE: 80-85% long-term remission (ONLY drug that alters natural history of acne)

ADVERSE EFFECTS of Isotretinoin:
• TERATOGENICITY (Category X) - Most important
  Must use 2 effective contraceptives 1 month before, during, 1 month after
  iPLEDGE program (USA)
• Cheilitis (dry cracked lips) - MOST COMMON, nearly universal
• Dry skin, dry eyes (use emollients)
• Elevated liver enzymes and triglycerides (monitor LFT, lipids)
• Depression/suicidal ideation (controversial association)
• Arthralgias, myalgias
• Photosensitivity
• Avoid blood donation during and 1 month after (teratogenicity risk to recipient)

• Combined OCP (Ethinyl estradiol + Cyproterone acetate - Diane-35)
  Cyproterone = Anti-androgen → ↓ Sebum
• Spironolactone (anti-androgen) 50-100 mg/day (off-label in women)
• Indicated: Acne flare with menstrual cycle, PCOS-associated acne

• After isotretinoin course: Topical retinoid (adapalene) maintenance
• Sunscreen mandatory
• Non-comedogenic moisturizers

---

Scabies = Infestation by Sarcoptes scabiei var. hominis
          (Human itch mite - obligate parasite)
          ↓
Female mite burrows into stratum corneum → Lays eggs → Intense pruritus
Transmitted by: Prolonged skin-to-skin contact (NOT casual contact)
Incubation: 3-6 weeks (primary); 1-3 days (re-infestation)

• Intense pruritus (worse at night - characteristic)
• Burrows (pathognomonic) - thin S-shaped or wavy lines in web spaces
• Sites: Web spaces of fingers, wrists, genitals, axillae, umbilicus, buttocks
• NOT face/scalp in adults (but infants - YES, including palms/soles)
• Secondary bacterial infection (impetigo) common from scratching

CONFIRMED/SUSPECTED SCABIES
          ↓
GENERAL PRINCIPLES:
• Treat ALL household contacts and sexual partners simultaneously
  (Even if asymptomatic - prevent re-infestation)
• Wash all clothing, bedding in HOT water (>60°C) or bag for 72 hrs
• Trimming nails (reduces reservoir under nails)
          ↓
TOPICAL SCABICIDE: DRUG OF CHOICE

1. PERMETHRIN 5% CREAM (DOC - First-line):
   • Synthetic pyrethroid
   • Mechanism: Opens voltage-gated Na⁺ channels → Sustained depolarization
     → Neurotoxic to mite (paralysis and death)
   • Application: Apply from NECK TO TOES (entire body; include under nails, web spaces)
     Leave on for 8-12 HOURS (overnight), then wash off
   • One application usually sufficient; repeat after 7 days
   • Safe in pregnancy, lactation, infants >2 months
   • Cure rate: >90%

2. BENZYL BENZOATE 25% LOTION (Alternative; cheaper):
   • Apply head to toe; leave 24 hours; wash off
   • Repeat after 24 hrs (2 applications total)
   • Dilute to 12.5% in infants, 6.25% in neonates
   • ADRs: Skin irritation, burning

3. GAMMA BENZENE HEXACHLORIDE (LINDANE / Gamma-HCH) 1%:
   • Mechanism: GABA-A antagonist → Neurological toxicity to mite
   • Apply thin layer, leave 8-12 hrs, wash off
   • ADRs: CNS toxicity (seizures) if absorbed excessively
   • AVOID in children <2 years, pregnant/lactating women, seizure disorder
   • Second-line

4. SULFUR OINTMENT (6-10%):
   • Safe in neonates and pregnant women
   • Apply nightly × 3 nights; leave 24 hours each time
   • Cheap, widely available, safe
   • Messy, unpleasant smell

5. CROTAMITON 10% (Eurax):
   • Apply × 2 consecutive nights; less effective
   • Also anti-pruritic (additional benefit)
          ↓
ORAL TREATMENT: IVERMECTIN (DOC for Crusted/Norwegian Scabies)

IVERMECTIN:
• Mechanism: Potentiates GABA → ↑ Cl⁻ influx → Paralysis of mite
• Dose: 200 μg/kg single oral dose; repeat after 2 weeks
• Preferred for:
  - Crusted (Norwegian) scabies (extensive, hyperkeratotic; seen in immunocompromised)
  - Institutional outbreaks (easier administration, all contacts)
  - Failure of topical treatment
  - Patient unable to apply topical correctly
• Combined with topical permethrin in crusted scabies
          ↓
SYMPTOMATIC TREATMENT:
• Antihistamines (Cetirizine, Chlorpheniramine) - For pruritus
  (Pruritus persists for 4-6 weeks even after successful treatment - due to allergic reaction to dead mite remains)
• Topical Calamine lotion - Soothing, anti-pruritic
• Topical/Oral antibiotics (if secondary bacterial infection/impetigo)
          ↓
SPECIAL SITUATIONS:
• Crusted/Norwegian Scabies: Oral Ivermectin + Topical Permethrin 5% (combined)
  Salicylic acid/urea cream to remove hyperkeratotic scale first
• Infants: Permethrin 5% (≥2 months); Sulfur 6% (neonates)
• Pregnancy: Permethrin 5% (safest), Sulfur ointment
• Immunocompromised: Ivermectin + Topical scabicide (combination)
          ↓
FOLLOW-UP:
• Review at 4 weeks
• Pruritus persisting >4 weeks after adequate treatment = Residual hypersensitivity
  (Not treatment failure; treat with antihistamines)
• If new burrows appearing after 2 weeks = Treatment failure or re-infestation
  → Repeat treatment; check contacts were treated

---

HORMONES — COMPLETE PHARMACOLOGY ANSWERS

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

---

3 MARKS QUESTIONS

---

---

---

---

---

---

LONG-TERM CORTICOSTEROID SIDE EFFECTS
(Exogenous Cushing's Syndrome)
          ↓
┌─────────────────────────────────────────────────────────┐
│ METABOLIC                                               │
│ • Hyperglycemia / Steroid-induced Diabetes Mellitus     │
│ • Hypertriglyceridemia, hypercholesterolemia            │
│ • Central obesity (moon face, buffalo hump, truncal)    │
│ • Weight gain                                           │
│                                                         │
│ MUSCULOSKELETAL                                         │
│ • OSTEOPOROSIS → Vertebral/hip fractures (most serious) │
│   (↓ Ca²⁺ absorption, ↑ Ca²⁺ excretion, ↓ osteoblasts) │
│ • Avascular necrosis of femoral head                    │
│ • Proximal myopathy (weakness of proximal muscles)      │
│ • Growth retardation in children                        │
│                                                         │
│ ENDOCRINE                                               │
│ • HPA axis suppression → Adrenal insufficiency          │
│   (if stopped abruptly → Addisonian crisis)             │
│ • Cushingoid features (striae, easy bruising)           │
│                                                         │
│ OPHTHALMIC                                              │
│ • Posterior subcapsular CATARACT                        │
│ • Glaucoma (↑ IOP)                                      │
│                                                         │
│ IMMUNOSUPPRESSION                                       │
│ • Opportunistic infections (TB reactivation, fungal)    │
│ • Delayed wound healing                                 │
│ • Masking of infections                                 │
│                                                         │
│ CNS                                                     │
│ • Psychiatric effects (euphoria, psychosis, depression) │
│ • Insomnia                                              │
│                                                         │
│ CVS/RENAL                                               │
│ • Hypertension (↑ Na⁺/water retention)                  │
│ • Hypokalemia (↑ K⁺ excretion)                          │
│ • Peptic ulceration (↓ mucosal prostaglandins)          │
│ • Acne, hirsutism                                       │
└─────────────────────────────────────────────────────────┘

---

• Virilization in women (deepening voice, hirsutism, clitoromegaly - irreversible)
• Hepatotoxicity (especially 17α-alkylated oral forms - peliosis hepatis, hepatocellular carcinoma)
• Premature closure of epiphyses (stunted growth in adolescents)
• Spermatogenesis suppression (↓ FSH/LH via feedback)
• Dyslipidemia (↑ LDL, ↓ HDL)
• Abuse in sports (banned by WADA)

---

1. Oral Contraception - Combined with progestins (Ethinyl estradiol in OCP)
2. Hormone Replacement Therapy (HRT) - Menopausal symptoms (hot flushes, vaginal atrophy, mood changes)
3. Osteoporosis prevention in postmenopausal women (maintains bone density)
4. Hypogonadism in females - Primary amenorrhea, Turner's syndrome
5. Prostate cancer (DES - high dose; anti-gonadotrophic → ↓ testosterone)
6. Dysfunctional uterine bleeding (high dose to stop bleeding)
7. Atrophic vaginitis (topical vaginal estrogen cream)

---

EMERGENCY CONTRACEPTION (EC)
          ↓
┌────────────────────────────────────────────────────────────┐
│ METHOD 1: LEVONORGESTREL (Plan B, i-Pill)                  │
│ Dose: 1.5 mg single oral dose (or 0.75 mg × 2, 12 hrs apart)│
│ Timing: Within 72 hours (ideally <24 hrs for best efficacy) │
│ Mechanism:                                                  │
│ • ↓ LH surge → Inhibits/delays ovulation (PRIMARY)         │
│ • ↑ Cervical mucus viscosity → ↓ Sperm penetration         │
│ • Alters endometrium (anti-implantation) - controversial    │
│ Efficacy: 85-95% if used within 72 hrs                      │
│ ADRs: Nausea, vomiting, irregular bleeding                  │
├────────────────────────────────────────────────────────────┤
│ METHOD 2: ULIPRISTAL ACETATE (ellaOne)                      │
│ Dose: 30 mg single oral dose                               │
│ Timing: Within 120 hours (5 days) - longer window than LNG  │
│ Mechanism: Selective Progesterone Receptor Modulator (SPRM) │
│ • Inhibits/delays ovulation even after LH surge begins      │
│ • More effective than LNG at 72-120 hrs window              │
│ Efficacy: ~98% within 24 hrs                               │
├────────────────────────────────────────────────────────────┤
│ METHOD 3: COPPER IUD (Cu-T 380A)                           │
│ Timing: Inserted within 5 DAYS of unprotected intercourse  │
│ Mechanism:                                                  │
│ • Cu²⁺ ions toxic to sperm (↓ motility, ↓ fertilization)   │
│ • Prevents implantation (endometrial changes)               │
│ Efficacy: >99% (MOST EFFECTIVE emergency contraception)     │
│ Advantage: Provides ongoing contraception for 10 years      │
│ Disadvantage: Invasive, requires clinical insertion         │
├────────────────────────────────────────────────────────────┤
│ METHOD 4: MIFEPRISTONE 10-25 mg single dose                 │
│ (Used in some countries as EC; India: 25 mg dose)          │
│ Mechanism: Progesterone receptor antagonist → Prevents      │
│ implantation, alters endometrium                           │
└────────────────────────────────────────────────────────────┘

---

1. Oral Contraception - Combined OCP (Levonorgestrel + EE) or Progestin-only pill (POP - Norethisterone)
2. Threatened/Habitual Abortion - Progesterone/Dydrogesterone vaginal/oral (luteal phase support, IVF)
3. Dysfunctional Uterine Bleeding (DUB) - Norethisterone 5 mg TDS for 21 days (medical curettage)
4. Endometriosis - Continuous progestins cause pseudodecidualization → Regression of ectopic endometrium
5. HRT - Combined with estrogen in women with intact uterus (prevent endometrial hyperplasia/cancer)
6. Endometrial cancer prevention/treatment - High-dose MPA

---

---

---

GnRH (Gonadotropin Releasing Hormone) → Normally released in PULSES from hypothalamus
Pulsatile GnRH → Stimulates FSH + LH from pituitary

GnRH ANALOGUES (continuous/depot administration):
→ DOWNREGULATE GnRH receptors (receptor desensitization)
→ ↓ FSH and LH secretion (paradoxical suppression)
→ ↓ Sex hormones (Estrogen in women, Testosterone in men)
= "Medical Castration"

• Initial use of GnRH agonists → Transient ↑ in FSH/LH/Sex hormones (flare) for 1-2 weeks before suppression
• In prostate cancer: Flare can worsen symptoms → Cover with anti-androgen (bicalutamide) for first 2-4 weeks

---

Octreotide = Synthetic somatostatin analogue (8 amino acid cyclic peptide)
t½ = 1.5-2 hrs (vs natural somatostatin t½ = 2 min)
Long-acting depot: Octreotide LAR (monthly IM injection)
Acts on SSTR2 > SSTR5 receptors (G protein coupled)

---

---

5 MARKS QUESTIONS

---

PROPYLTHIOURACIL (PTU)
          ↓
DUAL MECHANISM:

1. INHIBITS THYROID PEROXIDASE (TPO) enzyme:
   TPO normally catalyzes:
   • Oxidation of I⁻ → I₂ (organification)
   • Incorporation of iodine into tyrosine residues (MIT, DIT)
   • Coupling of MIT + DIT → T₃; DIT + DIT → T₄
   PTU blocks TPO → ↓ T₃ and T₄ synthesis
   (Onset of action: DELAYED - existing hormone stores must deplete; 3-4 weeks)

2. INHIBITS PERIPHERAL CONVERSION of T4 → T3:
   Inhibits Type 1 5'-deiodinase (in liver, kidney, muscle)
   → ↓ Active T₃ formation from T₄ in peripheral tissues
   (This is UNIQUE to PTU; Carbimazole/Methimazole lack this action)
   → FASTER clinical effect than carbimazole
   → REASON PTU is DOC for Thyroid Storm

1. Hyperthyroidism (Graves' disease) - Primary treatment; 100-200 mg TDS
2. Thyroid storm (Thyrotoxic crisis) - DRUG OF CHOICE (dual mechanism); 600-1000 mg loading, then 200-250 mg QID
3. Preparation for thyroidectomy (render euthyroid before surgery + reduce vascularity when combined with iodine)
4. Hyperthyroidism in pregnancy (1st trimester) - Preferred over carbimazole in 1st trimester
5. Neonatal thyrotoxicosis (maternal antibodies)
6. Adjunct before Radioactive Iodine therapy

• Nausea, GI disturbance
• Rash, urticaria, pruritus (5%)
• Arthralgia, fever

• Agranulocytosis (0.2-0.5%) - Most serious; sudden onset; sore throat/fever → STOP drug, check WBC immediately; can be fatal
• HEPATOTOXICITY - Severe, potentially FATAL fulminant hepatic failure (PTU-specific; black box warning; more than carbimazole) - monitor LFTs; switch to carbimazole/methimazole if LFT raised
• Drug-induced lupus (PTU > carbimazole) - anti-MPO ANCA-positive vasculitis
• Hypothyroidism (dose-dependent - overtreatment)
• Cholestatic jaundice (rare)

• Crosses placenta (though less than carbimazole/methimazole)
• Can cause fetal hypothyroidism/goiter (monitor fetal thyroid)
• Preferred in 1st trimester only (switch to carbimazole after)

---

Radioactive Iodine = ¹³¹I (Iodine-131)
• Beta emitter (β⁻ rays - 90% of radiation effect) + Gamma emitter
• t½ = 8 days
• Beta rays travel only 2mm → Local tissue destruction
• Gamma rays allow external scanning (diagnostic use)

¹³¹I administered orally
     ↓
Thyroid gland concentrates iodine (Na⁺/I⁻ symporter - active uptake)
     ↓
Thyroid cells accumulate ¹³¹I (same as stable iodine)
     ↓
β⁻ radiation emitted WITHIN thyroid follicular cells
     ↓
Local radiation damage → DNA double strand breaks → Cell death
     ↓
↓ Thyroid gland mass and function → ↓ T₃/T₄ production
     ↓
Euthyroid or Hypothyroid state (effect over 6-12 weeks)

1. Hyperthyroidism (Graves' disease) - DOC in USA (preferred first-line); good for relapse after antithyroid drugs; elderly patients; patients refusing surgery
2. Toxic nodular goiter (Toxic adenoma, Toxic multinodular goiter)
3. Differentiated Thyroid Cancer (Papillary and Follicular carcinoma) - Post-thyroidectomy ablation of residual thyroid tissue; treatment of metastases

• Pregnancy (absolute) - Fetal thyroid ablation after 12 weeks; teratogenic
• Breastfeeding - Concentrates in breast milk; stop breastfeeding (avoid for 6 months if planning RAI)
• Children <5 years (relative) - risk of secondary malignancy
• Pre-existing ophthalmopathy in Graves' (may worsen)

• Hypothyroidism (most common long-term - ~80% at 10 years; requires lifelong thyroxine)
• Radiation thyroiditis (2-3 weeks after - pain, transient worsening of hyperthyroidism)
• Transient worsening of hyperthyroidism after RAI (pretreat with antithyroid drugs; stop 3-7 days before RAI, restart 7 days after)
• Risk of secondary malignancy (rare; minimal with therapeutic doses)
• Worsening of Graves' ophthalmopathy (cover with steroids)

---

Lugol's Iodine = Strong Iodine Solution
Composition: Iodine 5% + Potassium Iodide 10% in water
= 5 mg total iodine per drop

WOLFF-CHAIKOFF EFFECT:
High concentration of iodide → Acute inhibition of thyroid hormone synthesis
     ↓
• ↓ Organification of iodine (blocks TPO paradoxically)
• ↓ Iodine uptake (↓ Na⁺/I⁻ symporter activity)
• ↓ T₃ and T₄ release from thyroglobulin (most rapid effect)
• ↓ Vascularity of thyroid gland (↓ blood flow)
          ↓
EFFECT: Rapid reduction in T₃/T₄ levels + ↓ Thyroid vascularity
ONSET: Within hours (fastest antithyroid effect)
DURATION: 10-14 days (escape phenomenon - gland adapts after 2 weeks)

1. Pre-operative preparation for thyroidectomy - Given 10-14 days before surgery; ↓ Vascularity (↓ bleeding during surgery), ↓ friability of gland; MUST be combined with antithyroid drugs (given after rendering euthyroid with PTU/carbimazole)
2. Thyroid storm (Thyrotoxic crisis) - Given 1 hour AFTER PTU (to prevent using iodine for new hormone synthesis); SSKI (Saturated Solution of Potassium Iodide) or Lugol's given hourly; rapid ↓ thyroid hormone release
3. Radiation emergency - Stable iodine (potassium iodide) given to block thyroid uptake of radioactive iodine (nuclear accident) - DOC for radiation emergency prophylaxis; 130 mg KI (adult)

• Metallic/brassy taste
• Increased salivation, lacrimation, rhinorrhea
• Sneezing, headache ("iodine headache")
• Acneiform rash (iododerma)
• Parotid/submandibular swelling (iodide mumps)
• Hypothyroidism with goiter (Wolff-Chaikoff effect becomes persistent in susceptible patients)
• Hyperthyroidism (Jod-Basedow effect - in iodine-deficient patients given excess iodine)
• Not suitable for long-term use (escape phenomenon + iodism)

---

Myxoedema Coma = Severe life-threatening decompensated hypothyroidism
= Medical emergency; mortality 20-50%
Precipitants: Infection (most common), Cold exposure, Sedatives/opioids,
              Trauma, Surgery, Stroke, Cardiac failure

Classic Triad:
1. Altered consciousness / Coma
2. Hypothermia (core temp <35°C)
3. Precipitating factor

Other features:
• Bradycardia, Hypotension
• Hypoventilation, CO₂ retention, Hypoxia
• Hyponatremia (SIADH), Hypoglycemia
• Classic hypothyroid features: dry skin, coarse hair, myxoedema, delayed reflexes
• Mega colon (ileus), urinary retention

MYXOEDEMA COMA
          ↓
RESUSCITATION (ABC):
• Airway: Intubate and mechanically ventilate (hypoventilation, CO₂ retention)
• IV access, ECG monitoring
• Blood: TFT (T₃, T₄, TSH), Cortisol, ABG, Electrolytes, Glucose, CBC
          ↓
SPECIFIC TREATMENT:

1. THYROID HORMONE REPLACEMENT:
   IV Levothyroxine (T₄): 300-500 μg IV loading dose (passive warming for conversion to T₃)
   THEN 50-100 μg IV daily
   + IV T₃ (Liothyronine) 10-20 μg if available (faster onset - active hormone)
   Oral T₄ can be given via NG tube if IV unavailable
          ↓
2. CORTICOSTEROIDS (MUST be given BEFORE or WITH thyroid hormone):
   Hydrocortisone 100 mg IV every 8 hours
   RATIONALE: Myxoedema coma may coexist with adrenal insufficiency (Schmidt syndrome)
   Replacing thyroid hormone increases cortisol metabolism → Precipitates Addisonian crisis
   Continue until adrenal insufficiency excluded (serum cortisol >550 nmol/L)
          ↓
3. REWARM PASSIVELY:
   Passive external rewarming (warm blankets, warm room)
   AVOID active external rewarming (vasodilation → Cardiovascular collapse)
          ↓
4. CORRECT METABOLIC ABNORMALITIES:
   • Hyponatremia: Fluid restriction (SIADH); severe: Normal saline (AVOID free water)
   • Hypoglycemia: IV Dextrose
   • Hypoventilation: Mechanical ventilation (avoid sedatives - exquisitely sensitive)
          ↓
5. TREAT PRECIPITATING CAUSE:
   • Antibiotics (broad spectrum - if infection suspected)
   • Avoid sedatives, opioids, anticholinergics
          ↓
6. ICU MONITORING:
   • Temperature, BP, HR, ECG, SpO₂
   • Daily TFT monitoring
   • Fluid balance

---

Thyroid Storm = Acute, severe, life-threatening exacerbation of hyperthyroidism
= Life-threatening hyperthyroid emergency; Mortality 10-30%
Precipitants: Surgery (thyroid/non-thyroid), Infection, RAI, Trauma,
              Iodine load, Childbirth, Stress

BURCH-WARTOFSKY CRITERIA:
• Hyperpyrexia (>40°C - hallmark)
• Severe tachycardia (AF, SVT - HR >140/min)
• Agitation, psychosis, confusion → Coma
• Nausea, vomiting, diarrhea, jaundice
• Hypotension (late - cardiac failure)
• Profuse sweating

THYROID STORM
          ↓
STEP 1: ICU ADMISSION + SUPPORTIVE CARE
• IV fluids (aggressive - sweating, fever, GI losses)
• Cooling: Paracetamol (NOT aspirin - displaces T₄ from protein)
           Cooling blankets, ice packs
• O₂, cardiac monitoring, vasopressors if needed
          ↓
STEP 2: PTU (FIRST and MOST IMPORTANT)
Propylthiouracil 600-1000 mg STAT, then 200-250 mg every 4 hours
(via NG tube/oral/rectal)
RATIONALE: Blocks NEW hormone synthesis + Blocks peripheral T4→T3 conversion
(Dual mechanism - CANNOT substitute carbimazole here)
          ↓
STEP 3: IODINE (1 HOUR AFTER PTU - CRITICAL)
Lugol's iodine 8 drops (0.5 mL) every 6 hrs OR
SSKI 5 drops every 6 hrs OR
Sodium iodide 1g IV every 8-12 hrs
(Wait 1 hr after PTU: Prevents iodine being used to synthesize NEW hormone)
RATIONALE: Rapidly ↓ thyroid hormone RELEASE from gland (Wolff-Chaikoff)
          ↓
STEP 4: BETA BLOCKER
Propranolol 60-80 mg oral every 4-6 hrs OR 1-2 mg IV every 15 min
RATIONALE:
• ↓ Tachycardia, hypertension (sympathetic effects)
• ↓ Peripheral T4→T3 conversion (additional benefit)
• Controls cardiac manifestations
If asthma/contraindication: Use Diltiazem (Ca²⁺ blocker)
          ↓
STEP 5: CORTICOSTEROIDS
Hydrocortisone 100 mg IV every 8 hrs OR Dexamethasone 2 mg every 6 hrs
RATIONALE:
• ↓ Peripheral T4→T3 conversion
• Treats possible adrenal insufficiency (↑ cortisol metabolism in storm)
• Anti-inflammatory effects
          ↓
STEP 6: TREAT PRECIPITATING CAUSE
• Broad-spectrum antibiotics if infection
• Cooling measures
          ↓
STEP 7: IF ABOVE FAILS
• Plasmapheresis / Plasma exchange (removes circulating T₃/T₄)
• Cholestyramine (binds T₃/T₄ in gut → ↓ enterohepatic recirculation)
• Emergency thyroidectomy (last resort)

PTU → 1 hour wait → Iodine (simultaneously with) → Beta blocker + Steroids

---

Human Regular Insulin problem: Forms HEXAMERS at injection site → slow dissociation to monomers → Delayed absorption (30-60 min onset)

Rapid-acting analogues: Modified to form MONOMERS immediately → Fast absorption
Long-acting analogues: Form precipitates or albumin-bound → Slow absorption

Drug          Modification              Onset    Peak    Duration
Insulin Lispro  Pro28-Lys29 reversed    15 min   1-2 hr  3-4 hr
Insulin Aspart  Pro28→Asp28             15 min   1-2 hr  3-4 hr
Insulin Glulisine Asn3→Lys, Lys29→Glu  15 min   1 hr    3-4 hr

→ Given 0-15 min before meals (vs 30 min for Regular)
→ Mimics physiological postprandial insulin spike
→ Less hypoglycemia between meals

Drug          Modification              Onset    Peak      Duration
Insulin Glargine Gly21→Arg+2 Arg at C  2-4 hr  PEAKLESS  24 hr
               terminal (isoelectric at pH 7.4 → precipitates SC)
Insulin Detemir Thr30 deleted; C14 FA  1-2 hr  Relatively  12-20 hr
               attached (albumin binding)        flat
Insulin Degludec Desb30; C16 FA (forms  1-2 hr  PEAKLESS  >42 hr
                 large subcutaneous depot)

→ Once daily (Glargine, Degludec) or twice daily (Detemir)
→ Peakless → ↓ Nocturnal hypoglycemia
→ Degludec: Ultra-long, most stable day-to-day variability

1. Type 1 Diabetes (Basal-Bolus regimen with long + rapid acting analogues)
2. Type 2 Diabetes (when oral drugs inadequate)
3. Gestational diabetes (rapid-acting preferred - lispro, aspart - safe in pregnancy)
4. Critically ill patients (IV insulin - regular or analogues)

---

DKA = Acute metabolic emergency in Diabetes
TRIAD: Hyperglycemia (>250 mg/dL) + Ketosis + Metabolic acidosis (pH<7.3, HCO₃<18)
Most common in T1DM; precipitated by: Infection (most common), Missed insulin, New-onset T1DM

↓ Insulin + ↑ Counter-regulatory hormones (glucagon, cortisol, catecholamines)
     ↓
↑ Gluconeogenesis + ↑ Glycogenolysis → Hyperglycemia
↑ Lipolysis → ↑ FFA → ↑ Ketogenesis (acetoacetate, β-hydroxybutyrate)
     ↓
Osmotic diuresis → Dehydration + Electrolyte loss
Keto acids accumulate → Metabolic acidosis (High Anion Gap)

DKA MANAGEMENT (4 PILLARS)
          ↓
┌───────────────────────────────────────────────────────────┐
│ PILLAR 1: FLUIDS (MOST URGENT - correct dehydration)      │
│ Average deficit: 3-6 liters                               │
│ Normal Saline (0.9% NaCl):                               │
│ • 1L over first 30-60 min (fast correction of shock)      │
│ • Then 1L over 2nd hour, 1L over 3rd hour                 │
│ • Then 1L every 4-6 hrs as per clinical status            │
│ When BG < 200-250 mg/dL: Switch to 5% Dextrose (D5 NS)   │
│ to prevent hypoglycemia while continuing insulin          │
├───────────────────────────────────────────────────────────┤
│ PILLAR 2: INSULIN                                         │
│ Regular (Soluble) Insulin IV infusion:                    │
│ • 0.1 unit/kg/hr IV infusion (no loading dose needed)     │
│ • Target: ↓ BG by 50-75 mg/dL/hour                       │
│ • CONTINUE INSULIN until ketosis cleared (anion gap       │
│   normalized, pH > 7.3, HCO₃ > 18) NOT until BG normal   │
│ • When eating + gap closed: Switch to SC insulin          │
│ • Overlap IV and SC insulin by 1-2 hrs before stopping IV  │
├───────────────────────────────────────────────────────────┤
│ PILLAR 3: POTASSIUM (Critical - MONITOR CLOSELY)          │
│ Total body K⁺ is DEPLETED in DKA (urinary losses)        │
│ BUT serum K⁺ may be normal/HIGH initially (acidosis →    │
│ K⁺ out of cells; insulin deficiency also → ↑ K⁺)         │
│                                                           │
│ K⁺ REPLACEMENT:                                           │
│ If K⁺ < 3.5 mEq/L: Give 40 mEq/hr KCl; DELAY insulin    │
│ If K⁺ 3.5-5.5 mEq/L: Give 20-40 mEq/hr; start insulin   │
│ If K⁺ > 5.5 mEq/L: Do NOT give K⁺; start insulin        │
│ Recheck K⁺ every 2 hours                                  │
├───────────────────────────────────────────────────────────┤
│ PILLAR 4: BICARBONATE (CONTROVERSIAL)                     │
│ Generally NOT recommended unless:                         │
│ • pH < 6.9 (severe life-threatening acidosis)             │
│ • Severe hyperkalemia with ECG changes                    │
│ Dose: 100 mEq NaHCO₃ over 2 hrs if pH < 6.9              │
│ Risk: Cerebral edema, hypokalemia (HCO₃ drives K⁺ into   │
│ cells), paradoxical CSF acidosis                          │
└───────────────────────────────────────────────────────────┘
          ↓
MONITORING:
• Hourly: Vitals, urine output, BG, mental status
• 2-hourly: Serum K⁺, Na⁺, Anion gap
• 4-hourly: ABG, Ketones
• ECG monitoring (K⁺ changes → Arrhythmia)
          ↓
TREAT PRECIPITATING CAUSE:
• Broad-spectrum antibiotics (infection)
• Continue antibiotics if infection confirmed
          ↓
TRANSITION TO SUBCUTANEOUS INSULIN:
• When: Eating + pH > 7.3 + HCO₃ > 18 + AG normalized
• Give SC insulin 1-2 hrs before stopping IV insulin

---

Sulfonylurea
     ↓
Binds SUR1 (Sulfonylurea Receptor 1) subunit of ATP-sensitive K⁺ channel
on pancreatic β-cell membrane
     ↓
CLOSES K_ATP channel (mimics effect of high glucose/ATP)
     ↓
↓ K⁺ efflux → Membrane DEPOLARIZATION
     ↓
Opens Voltage-gated Ca²⁺ channels
     ↓
↑ Intracellular Ca²⁺
     ↓
Insulin SECRETION (exocytosis of insulin granules)
     ↓
↓ Blood glucose

REQUIRE FUNCTIONAL β-CELLS → Not effective in T1DM or late T2DM

1. Type 2 Diabetes mellitus - 2nd line after Metformin (or combined with Metformin from start)
2. Not useful in T1DM (no functional β-cells)
3. MODY type 3 (HNF1α mutation) - Exquisitely sensitive to sulfonylureas

• Hypoglycemia - MOST IMPORTANT and common; especially: Long-acting (Glibenclamide - avoid in elderly), renal failure (↓ drug excretion), skipped meals, alcohol use
  • Glibenclamide: Most hypoglycemia (most potent, active metabolites)
  • Gliclazide, Glimepiride: Less hypoglycemia
• Weight gain (insulin secretion → anabolic effects)
• GI: Nausea, vomiting, cholestatic jaundice (rare)
• Hyponatremia (Chlorpropamide - potentiates ADH action - SIADH)
• Disulfiram-like reaction with alcohol (Chlorpropamide, Tolbutamide)
• Bone marrow suppression (rare - agranulocytosis)
• Teratogenicity (Category C; switch to insulin in pregnancy)

---

METFORMIN
     ↓
PRIMARY MECHANISM:
Activates AMP-activated Protein Kinase (AMPK) - cellular energy sensor
[Metformin inhibits Complex I of mitochondrial respiratory chain → ↑ AMP:ATP ratio → Activates AMPK]
     ↓
AMPK activation:
1. LIVER (main site): ↓ Gluconeogenesis (↓ G6P, ↓ PEPCK, ↓ F1,6-BPase)
   → ↓ Hepatic glucose output (PRIMARY mechanism - 30% ↓ fasting glucose)

2. MUSCLE: ↑ Glucose uptake (↑ GLUT4 translocation, ↑ Glycogenesis)
   → ↑ Peripheral glucose utilization

3. GUT: Slows glucose absorption from intestine
   Also: ↑ GLP-1 secretion, alters gut microbiome

KEY: Does NOT stimulate insulin secretion → NO HYPOGLYCEMIA (as monotherapy)
KEY: INSULIN SENSITIZER (requires insulin to act) - does not work in T1DM

1. Type 2 Diabetes - DRUG OF FIRST CHOICE (ADA/WHO/IDF guidelines)
   • Especially overweight/obese T2DM (↓ Weight - weight neutral or slight loss)
   • 500-2550 mg/day oral (OD to TDS)
2. Polycystic Ovarian Syndrome (PCOS) - Improves insulin resistance → Restores ovulation, reduces androgen levels; improves menstrual regularity
3. Prediabetes - Prevents/delays progression to T2DM
4. Gestational diabetes (off-label; increasing use; crosses placenta but appears safe)

• No hypoglycemia as monotherapy
• Weight neutral/modest weight loss
• Cardioprotective (UKPDS: Reduces macrovascular complications)
• Cheap, widely available
• Reduces cancer risk (colorectal, breast - emerging evidence)

• GI side effects (most common - 30%): Nausea, vomiting, diarrhea, metallic taste, abdominal discomfort
  • Take with/after food; start low dose and titrate slowly; extended-release (XR) formulation reduces GI effects
• Lactic Acidosis - Rare but potentially FATAL (1-5/100,000 patient-years)
  • Risk factors: Renal impairment (eGFR <30 - absolute contraindication), liver disease, heart failure, alcohol, hypoxic states
  • Mechanism: Metformin inhibits hepatic lactate metabolism
• Vitamin B12 deficiency (long-term use - ↓ ileal absorption of B12; monitor annually)
• Not an allergen (no hypersensitivity)

• eGFR < 30 mL/min (ABSOLUTE - lactic acidosis risk)
• eGFR 30-45: Use with caution (reduce dose)
• Iodinated contrast media: Hold 48 hrs before and after (if eGFR risk)
• Major surgery (hold day of surgery)
• Acute illness with dehydration
• Liver disease, Alcohol excess

---

Sodium-Glucose Cotransporter 2 (SGLT-2)
located in PROXIMAL TUBULE of kidney (S1 segment)
Normally: Reabsorbs ~90% of filtered glucose (threshold ~180 mg/dL)
          ↓
SGLT-2 INHIBITOR (Glifozin)
          ↓
Inhibits SGLT-2 → ↓ Glucose reabsorption in proximal tubule
          ↓
↑ Urinary glucose excretion (GLUCOSURIA - 70-80g glucose/day in urine)
          ↓
↓ Blood glucose (INSULIN-INDEPENDENT mechanism)
Also:
• Osmotic diuresis (glucose) → ↓ Blood pressure, ↓ Volume (↓ preload)
• Natriuresis → ↓ BP
• ↓ Weight (caloric loss in urine ~280 kcal/day)
• ↓ Uric acid (uricosuric effect - SGLT-2 also transports urate)

1. Type 2 Diabetes (add-on to metformin)
2. Heart Failure with reduced ejection fraction (HFrEF) - Empagliflozin, Dapagliflozin - REDUCE MORTALITY significantly (EMPA-REG, DAPA-HF trials) - now approved regardless of diabetes status
3. Chronic Kidney Disease (CKD) - Dapagliflozin, Canagliflozin - Slow progression of CKD (DAPA-CKD trial); reduce proteinuria
4. Cardiovascular risk reduction - Empagliflozin reduces CV death, MI, stroke in T2DM with established CVD

• Genital mycotic infections (thrush) - MOST COMMON; women > men (glucosuria → Candida growth in genital area); Treat: Topical antifungals, hygiene
• UTI - Increased risk (glucosuria promotes bacterial growth)
• Euglycemic DKA - Rare but serious; Blood glucose may not be very elevated; triggers: Low carb diet, surgery, illness, fasting (more common with canagliflozin); mechanism: ↑ ketogenesis
• Volume depletion / Orthostatic hypotension - Osmotic diuresis; caution in elderly/diuretics
• Fournier's Gangrene - Rare, necrotizing fasciitis of perineum (FDA black box warning)
• Hypoglycemia - Rare as monotherapy (insulin-independent); risk with sulfonylurea/insulin combinations
• ↑ Fractures, ↑ LDL (Canagliflozin - bone and lipid effects)
• Urosepsis - Rare
• Polyuria, polydipsia (glucosuria)

---

GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Peptide)
= Incretin hormones secreted by gut after meals
NORMALLY: Rapidly degraded by DPP-4 enzyme (t½ = 2 min)
          ↓
DPP-4 INHIBITOR
          ↓
↓ Breakdown of endogenous GLP-1 and GIP
          ↓
↑ Active incretin levels (GLP-1 increases 2-3 fold)
          ↓
GLP-1 effects (GLUCOSE-DEPENDENT):
• β-cells: ↑ Insulin secretion (ONLY when glucose is high)
• α-cells: ↓ Glucagon secretion (ONLY when glucose is high)
          ↓
↓ Post-meal and fasting blood glucose
Glucose-dependent mechanism → LOW RISK OF HYPOGLYCEMIA

1. Add-on to Metformin (Step 2) - Common combination
2. Elderly patients - Low hypoglycemia risk; weight neutral; once daily; well tolerated
3. Renal impairment - Linagliptin (hepatically eliminated; no dose adjustment in renal failure - unique)
4. Triple therapy - Metformin + Sulfonylurea + DPP-4 inhibitor

• No hypoglycemia (glucose-dependent action)
• Weight neutral
• Oral, once daily (mostly)
• Well tolerated (minimal GI effects)
• Can be used in renal failure (Linagliptin)

• Generally well tolerated
• Nasopharyngitis, URTI (altered mucosal immunity - T cells, NK cells express DPP-4)
• Pancreatitis (rare - reports with sitagliptin; mechanism unclear; monitor if abdominal pain)
• Arthralgia (joint pain - FDA warning for sitagliptin)
• Bullous pemphigoid (skin blistering - rare; reported with gliptins)
• Heart failure (Saxagliptin - SAVOR-TIMI trial: ↑ hospitalization for HF; avoid in HF)
• No weight loss (weight neutral - disadvantage vs SGLT-2/GLP-1)

---

SGLT-2 INHIBITORS - BEYOND GLYCEMIC CONTROL:

CARDIOVASCULAR:
Empagliflozin (EMPA-REG OUTCOME): ↓ CV death 38%, ↓ HF hospitalization 35%
Canagliflozin (CANVAS): ↓ MACE events
→ Now RECOMMENDED in T2DM with established CVD or high CV risk

HEART FAILURE (WITH OR WITHOUT DM):
Dapagliflozin (DAPA-HF): ↓ CV death + worsening HF in HFrEF (with OR without T2DM)
Empagliflozin (EMPEROR-Reduced): Similar benefit
→ 4th PILLAR of HFrEF treatment (alongside ACE inhibitor/ARB, β-blocker, MRA)

KIDNEY PROTECTION:
Dapagliflozin (DAPA-CKD): ↓ Renal progression and CV death in CKD (eGFR 25-75)
→ Approved for CKD regardless of T2DM
Mechanism: ↓ Glomerular hyperfiltration (↓ SGLT-2 → ↑ Na⁺ delivery to macula densa → TGF → ↓ GFR)

---

SHORT-ACTING: Hydrocortisone (Cortisol) - t½ 8-12 hrs
INTERMEDIATE: Prednisolone, Methylprednisolone - t½ 12-36 hrs
LONG-ACTING: Dexamethasone, Betamethasone - t½ 36-54 hrs
TOPICAL: Clobetasol (super-potent), Betamethasone (potent), Hydrocortisone (mild)

Glucocorticoids (Lipophilic)
     ↓ Crosses cell membrane
Binds Glucocorticoid Receptor (GR) in cytoplasm
     ↓
GR-drug complex → Nucleus → Binds GRE on DNA
     ↓
ANTI-INFLAMMATORY EFFECTS:
• ↑ Annexin-1 (Lipocortin) → ↓ PLA₂ → ↓ ALL prostaglandins + Leukotrienes
• ↓ NF-κB → ↓ IL-1, IL-2, IL-6, TNF-α, GM-CSF
• ↓ COX-2, iNOS
• ↓ Inflammatory cell migration (neutrophils, macrophages, lymphocytes)
• ↑ β₂ receptor expression
     ↓
IMMUNOSUPPRESSIVE EFFECTS:
• ↓ T-lymphocyte proliferation (↓ IL-2)
• Lymphocytopenia, Eosinopenia, Monocytopenia
• Neutrophilia (demargination - WBC count rises)

1. Bronchial asthma - ICS (prophylaxis); Systemic (acute severe/status)
2. Allergic conditions - Urticaria, Angioedema, Anaphylaxis (adjunct)
3. Rheumatoid arthritis - Low dose prednisolone (bridge therapy while DMARDs take effect)
4. SLE, Vasculitis - Moderate-high dose
5. IBD - Ulcerative colitis, Crohn's (acute flares)
6. Nephrotic syndrome - Prednisolone first-line (1 mg/kg/day)

---

SERMs = Compounds that bind Estrogen Receptors (ERα and ERβ)
but produce TISSUE-SELECTIVE agonist OR antagonist effects
depending on tissue type (due to differential coactivator/corepressor expression)

SERM + Estrogen Receptor
     ↓
Conformational change of ER varies by tissue:
In some tissues → Activates transcription (AGONIST effect)
In other tissues → Inhibits transcription (ANTAGONIST effect)

---

Mifepristone (RU-486) = Synthetic steroid
= Selective Progesterone Receptor Modulator (SPRM)
= Antiglucocorticoid + Antiprogestogen

MIFEPRISTONE
     ↓
1. PROGESTERONE RECEPTOR ANTAGONIST (primary):
   Binds PR with higher affinity than progesterone
   → Blocks progesterone effects on uterus
   → Endometrium becomes unfavorable for implantation
   → Increased uterine contractility (↓ Progesterone = ↑ Prostaglandin sensitivity)
   → Cervical softening/dilation (↑ cervical matrix metalloproteinases)

2. GLUCOCORTICOID RECEPTOR ANTAGONIST:
   Binds GR with high affinity
   → Anti-glucocorticoid effect (used in Cushing's syndrome)

3. Sensitizes uterus to Prostaglandins (↑ PG receptor expression)
   → Synergism with Misoprostol (PGE₁)

1. MEDICAL TERMINATION OF PREGNANCY (MTP) - PRIMARY USE:
   • Mifepristone 200 mg oral (Day 1)
   • Misoprostol 800 μg vaginal/sublingual/buccal (Day 2-3, 24-48 hrs later)
   • Effective for: Up to 63 days (9 weeks) gestation (WHO/India)
   • Efficacy: 95-98% complete abortion
   • Mechanism: Mifepristone → Cervical ripening + ↑ PG sensitivity
                Misoprostol → Uterine contractions + Cervical dilation
   • Legal in India: MTP Act 1971 (amended 2021 - up to 20 weeks with approval)

2. EMERGENCY CONTRACEPTION:
   • 25-600 mg (various studies) within 72-120 hrs of unprotected intercourse
   • Very effective; used in some countries as EC

3. MISSED ABORTION / FETAL DEATH IN UTERO:
   • With Misoprostol to expel retained products of conception

4. CERVICAL PRIMING before:
   • Surgical termination
   • Labor induction (given 24-48 hrs before)

5. INDUCTION OF LABOR (prolonged pregnancy > 41 weeks):
   • Cervical ripening before oxytocin induction

6. CUSHING'S SYNDROME (Ectopic ACTH / Adrenal):
   • Mifepristone 300-1200 mg/day (anti-glucocorticoid)
   • Used when surgery not possible; controls hyperglycemia of Cushing's
   • FDA approved (Korlym) for Cushing's syndrome with hyperglycemia

7. UTERINE FIBROIDS / ENDOMETRIOSIS:
   • Anti-progesterone → Regression of fibroids (intermediate doses)
   • Research/investigational

• Cramping, abdominal pain (uterine contractions)
• Heavy bleeding, passage of clots
• Nausea, vomiting, diarrhea
• Headache
• Incomplete abortion requiring surgical intervention (~5%)
• Serious infection (rare) - Toxic shock syndrome (Clostridium sordellii - very rare)

---

COMBINED OCP: Estrogen (Ethinyl Estradiol - EE) + Progestin
  Monophasic: Fixed EE + Progestin throughout
  e.g., EE 30 μg + Levonorgestrel 150 μg (Ovral-L)
       EE 30 μg + Norethisterone (Primolut)
       EE 30 μg + Desogestrel (Marvelon)

PROGESTIN-ONLY PILL (POP / Mini-pill): Norethisterone, Levonorgestrel
  Used when estrogen contraindicated (breastfeeding, thrombosis risk, >35 smokers)

COMBINED OCP:

ESTROGEN COMPONENT:
• ↓ FSH (↓ follicular development → prevents recruitment of dominant follicle)
• Ovulation inhibition (but minor role vs progestin)
• ↑ SHBG → ↓ Free androgens (beneficial in acne, PCOS)

PROGESTIN COMPONENT (PRIMARY contraceptive mechanisms):
• ↓ LH surge → INHIBITS OVULATION (main mechanism)
• ↑ Cervical mucus viscosity → Thick, impenetrable to sperm
• ↓ Endometrial proliferation → Unfavorable thin endometrium
• ↓ Tubal motility

COMBINED: Failure rate = 0.1-0.3 per 100 woman-years (perfect use)
                       = 3-9 per 100 woman-years (typical use)

1. Contraception - Primary indication
2. Dysmenorrhea (↓ prostaglandins → ↓ pain)
3. Menorrhagia/DUB (↓ endometrial proliferation → ↓ menstrual blood loss)
4. Endometriosis (continuous use → Pseudodecidualization → Regression)
5. PCOS (↓ androgens → ↓ acne, hirsutism; regulate menstrual cycle)
6. Acne vulgaris (EE + Cyproterone acetate = Diane-35; anti-androgen)
7. PMS/PMDD (EE + Drospirenone - Yaz; drospirenone has anti-mineralocorticoid + anti-androgen)
8. Ovarian cysts (functional cysts - OCPs prevent recurrence)
9. Anemia from heavy periods
10. Ovarian and Endometrial Cancer prevention (long-term OCP use ↓ risk by 50%)
11. Emergency Contraception (Yuzpe method - high dose EE + LNG x2 - now replaced by LNG alone)

• Nausea, breast tenderness (estrogen)
• Breakthrough bleeding, spotting (common in first 3 cycles)
• Headache, mood changes
• Weight gain (controversial - minimal)
• Decreased libido

• VTE (Venous ThromboEmbolism) - DVT, Pulmonary Embolism:
  • Estrogen → ↑ Clotting factors (II, VII, VIII, X, fibrinogen) + ↑ Platelet aggregation
  • Risk ↑ with: Smoking + age >35 (absolute contraindication), obesity, personal/family history VTE
  • 3rd generation progestins (desogestrel, gestodene) > 2nd gen (LNG) for VTE risk
• Hypertension (estrogen → ↑ renin-angiotensin-aldosterone)
• Stroke / MI (rare; ↑ risk with smoking, migraine with aura)
• Breast cancer (slight ↑ risk with long-term use; returns to baseline 10 yrs after stopping)
• Cervical cancer (slight ↑ risk; confounded by sexual behavior)
• Benign hepatic adenoma (rare; risk with high-dose, long-term)
• Gallstones (estrogen → ↑ cholesterol in bile)
• Amenorrhea after stopping (post-pill amenorrhea - usually transient)

• Enzyme inducers (Rifampicin, Phenytoin, Carbamazepine, St. John's Wort) → ↓ EE levels → Contraceptive failure → Use additional barrier method

• Active/history of DVT/PE, Stroke, MI
• Breast cancer (current)
• Migraine with aura
• Smoking age >35 years
• Severe hypertension (>160/100)
• Liver disease
• Pregnancy

---

MALE CONTRACEPTION
          ↓
┌─────────────────────────────────────────────────────────┐
│ BARRIER METHODS (Widely Used):                          │
│ Male Condom:                                            │
│ • Most effective male contraceptive method              │
│ • 85% typical use; 98% perfect use                     │
│ • Also protects against STIs (dual benefit)             │
│ • No hormonal side effects; readily available           │
├─────────────────────────────────────────────────────────┤
│ PERMANENT (Vasectomy):                                  │
│ • Surgical ligation/division of vas deferens           │
│ • Most effective male method (>99%)                     │
│ • Outpatient procedure under local anesthesia           │
│ • Reversibility: 30-75% (microsurgical reversal)       │
│ • No hormonal changes; sexual function preserved        │
├─────────────────────────────────────────────────────────┤
│ HORMONAL (Research/Investigational):                    │
│                                                         │
│ TESTOSTERONE-BASED:                                     │
│ • Testosterone enanthate 200mg IM weekly → ↓ FSH/LH    │
│   → ↓ Spermatogenesis (azoospermia in ~70%)            │
│ • Problem: Not effective in all men (~30% remain fertile)│
│ • Testosterone Undecanoate (injectable) - trials        │
│                                                         │
│ COMBINATION (T + Progestin):                           │
│ • Testosterone + DMPA (depot medroxyprogesterone)       │
│ • Testosterone + Levonorgestrel implant                 │
│ • More effective than T alone                           │
│ • WHO trial (2016): Effective (azoospermia ~90%)        │
│   but stopped due to depression, mood changes           │
│                                                         │
│ NON-HORMONAL (Research):                               │
│ • Gossypol (cottonseed extract) - ↓ Sperm motility     │
│ • Ouabain (G-protein inhibitor) - sperm acrosome        │
│ • RISUG/Vasalgel (polymer gel into vas deferens) - India │
│   • Reversible inhibition of sperm (charge-based)       │
│   • Phase 3 trials in India                            │
│ • EP055 - sperm motility inhibitor                     │
│ • Compounds targeting: Spermatogenesis, sperm function, │
│   fertilization                                        │
└─────────────────────────────────────────────────────────┘

• Must suppress spermatogenesis (millions of sperm/day - harder than blocking 1 egg/month)
• Hormonal methods: Mood changes, reduced libido side effects
• Reversibility required
• Cultural and social acceptance barriers
• Long development pipeline

---

Bisphosphonates (Pyrophosphate analogues)
     ↓
Administered orally/IV → Deposited at bone surfaces (high affinity for Ca²⁺ in hydroxyapatite)
     ↓
OSTEOCLASTS engulf bone → Ingest bisphosphonates
     ↓
NITROGEN-CONTAINING: Inhibit FARNESYL PYROPHOSPHATE SYNTHASE
(Key enzyme in mevalonate/cholesterol pathway)
     ↓
↓ Prenylation of Ras, Rho, Rab GTPases
     ↓
↓ Osteoclast function, ↓ Osteoclast survival (apoptosis)
     ↓
↓ BONE RESORPTION → Net increase in bone mineral density

1. Postmenopausal osteoporosis - First-line (Alendronate 70 mg once weekly / Zoledronic acid 5mg IV yearly)
2. Glucocorticoid-induced osteoporosis - Alendronate (prevention and treatment)
3. Paget's disease of bone - Zoledronic acid (most effective)
4. Hypercalcemia of malignancy - Zoledronic acid IV (rapidly ↓ Ca²⁺)
5. Bone metastases (breast, prostate cancer) - ↓ Skeletal-related events (fractures, spinal cord compression)
6. Multiple myeloma - Zoledronic acid ↓ bone pain and skeletal events
7. Osteogenesis Imperfecta (children) - Pamidronate/Zoledronic acid
8. Male osteoporosis (Alendronate, Zoledronic acid)
9. Fibrous dysplasia

• Upper GI irritation - Esophageal ulcers, gastritis (MOST COMMON with oral) Prevention: Take with full glass of water, remain upright for 30 min, take on empty stomach
• Nausea, dyspepsia, diarrhea

• Acute phase reaction (1st infusion): Flu-like illness, fever, myalgia, arthralgia (24-72 hrs; subsides with subsequent infusions; Paracetamol prophylaxis)

• Osteonecrosis of the Jaw (ONJ) - Avascular necrosis of mandible/maxilla; risk ↑ with IV bisphosphonates (zoledronic acid), dental procedures, cancer patients; Dental check before starting
• Atypical Femoral Fractures - Low-energy transverse sub-trochanteric fractures; after prolonged use (>3-5 years); consider "drug holiday" after 5 years
• Esophageal Cancer (oral bisphosphonates - debated association)
• Renal toxicity (IV bisphosphonates - zoledronic acid; check eGFR; contraindicated if eGFR <35)

• Hypocalcemia (especially with zoledronic acid + pre-existing vitamin D deficiency; supplement Ca²⁺ and Vit D)
• Ocular inflammation (scleritis, uveitis - rare)
• Heartburn (oral)

---

HRT = Administration of estrogen (with or without progestogen)
to replace the declining hormones after menopause
Menopause = Cessation of menstruation for 12 months (average age 51 years)
Estrogen deficiency symptoms → Target of HRT

1. COMBINED HRT (Estrogen + Progestogen):
   For women WITH intact UTERUS (most women)
   Progestogen MANDATORY to prevent endometrial hyperplasia/cancer from unopposed estrogen
   Forms:
   • Cyclic/Sequential: Estrogen daily + Progestogen 10-14 days/month
     → Regular withdrawal bleed (for perimenopausal women)
   • Continuous Combined: Both daily → No bleed (for postmenopausal >1 yr)
   Preparations: Estradiol + Norethisterone; Estradiol + MPA; Tibolone (synthetic steroid - weak E+P+A)

2. ESTROGEN-ONLY HRT:
   For women WITHOUT UTERUS (after hysterectomy)
   No progestogen needed; safer (no VTE/breast cancer risk of progestogens)
   Oral estradiol, Transdermal estradiol patch/gel (preferred - avoids first pass → safer)

MENOPAUSAL SYMPTOMS (PRIMARY INDICATION - MOST BENEFIT):
• HOT FLUSHES and NIGHT SWEATS (vasomotor symptoms) - MOST EFFECTIVE treatment
  (70-90% reduction vs placebo)
• Vaginal dryness, dyspareunia, UTI (Genitourinary Syndrome of Menopause)
• Mood changes, sleep disturbance (directly related to estrogen deficiency)
• Cognitive symptoms (mild)

OSTEOPOROSIS PREVENTION:
• Estrogen ↓ Osteoclast activity → ↑ BMD
• HRT ↓ Vertebral and hip fractures
• Used when other osteoporosis drugs not tolerated

UROGENITAL ATROPHY:
• Topical/vaginal estrogen (minimal systemic absorption)
• Safe for vaginal atrophy/dyspareunia with minimal systemic risk

PREMATURE OVARIAN INSUFFICIENCY (POI, age <40):
• HRT until natural menopause age (51 yrs) - strongly recommended
• Reduces cardiovascular and bone disease risk from prolonged estrogen deficiency

• SHORTEST duration at LOWEST effective dose
• Transdermal route PREFERRED (safer - no hepatic first pass)
• Individualize based on: Symptom severity, age, risk profile, patient preference
• Regular review (annually)
• CONTRAINDICATED in: Breast/endometrial cancer, active VTE, stroke, unexplained vaginal bleeding, liver disease
• "Timing Hypothesis": HRT started WITHIN 10 years of menopause or age <60 = Cardioprotective benefits
  HRT started LATE (>10 yrs postmenopause) = Possibly harmful cardiovascularly

---

HYPOLIPIDEMIC DRUGS, TUBERCULOSIS, BLOOD & RESPIRATORY SYSTEM

Reference: KDT (Tripathi) 8th Ed & Shanbhag's Pharmacology

---

3 MARKS QUESTIONS

---

Platelet activation → COX-1 → TXA₂ synthesis
→ Platelet aggregation + Vasoconstriction → Coronary thrombus → MI

LOW-DOSE ASPIRIN (75-150 mg/day)
     ↓
Irreversible acetylation of COX-1 in PLATELETS
     ↓
↓ TXA₂ synthesis
(Platelets = anucleate → Cannot synthesize new COX → PERMANENT effect for platelet lifetime 7-10 days)
     ↓
↓ Platelet aggregation → ↓ Coronary thrombus → Prophylaxis of MI

• High dose also inhibits vascular endothelial PGI₂ (prostacyclin - anti-aggregatory)
• Low dose selectively inhibits platelet COX-1 > vascular COX
• Endothelial cells can regenerate COX (nucleated); platelets cannot

---

---

---

PARENTERAL IRON INDICATED WHEN:
     ↓
1. MALABSORPTION SYNDROMES
   • Celiac disease, Inflammatory bowel disease (Crohn's)
   • Post-gastrectomy, Short bowel syndrome
   • Oral iron not absorbed properly from GI tract

2. INTOLERANCE TO ORAL IRON (persistent despite trials)
   • Severe GI side effects (nausea, vomiting, constipation, pain)
   • Despite trying different oral preparations and dose titration
   • Patient cannot comply with oral therapy

3. NEED FOR RAPID IRON REPLETION
   • Pre-operative optimization (before major surgery, cardiac surgery)
   • Severe IDA requiring rapid correction (symptomatic anemia, Hb <7g/dL)
   • End-stage renal failure on hemodialysis (routine use with EPO)

4. INFLAMMATORY BOWEL DISEASE (active disease)
   • Oral iron worsens intestinal inflammation and oxidative stress
   • IV iron preferred (ECCO guidelines - IBD + IDA)

5. CHRONIC KIDNEY DISEASE (CKD) on EPO therapy
   • Functional iron deficiency despite normal stores
   • IV iron needed to support erythropoiesis stimulated by EPO

6. ONGOING BLOOD LOSS EXCEEDING ORAL REPLACEMENT CAPACITY
   • GI bleeding, menorrhagia, hereditary hemorrhagic telangiectasia

7. NON-COMPLIANCE with oral iron

---

---

Excessive anticoagulation → Bleeding:
• Spontaneous bruising, hematomas
• Hematuria, GI bleeding
• Intracranial hemorrhage (serious)
• aPTT >100 seconds (therapeutic: 60-80 sec = 1.5-2.5x normal)

HEPARIN OVERDOSE
          ↓
STEP 1: STOP HEPARIN INFUSION IMMEDIATELY
(UFH t½ = 1-2 hrs → Effect wears off rapidly with time alone)
Minor bleeding → Often no antidote needed; just stop heparin
          ↓
STEP 2: SERIOUS/LIFE-THREATENING BLEEDING
PROTAMINE SULPHATE - SPECIFIC ANTIDOTE

DOSE: 1 mg Protamine neutralizes 100 units Heparin
(Based on amount of heparin given in last 2 hours)
• IV slow injection (over 10 minutes - rapid injection → hypotension)
• Maximum 50 mg in single dose

RATIONALE OF PROTAMINE:
• Protamine = Strongly POSITIVELY CHARGED (cationic) protein (from salmon sperm)
• Heparin = Strongly NEGATIVELY CHARGED (anionic) molecule
• Electrostatic/Ionic binding between protamine and heparin
  → Formation of stable, inactive protamine-heparin complex
  → Loss of anticoagulant activity of heparin
  → Immediate reversal of anticoagulation
          ↓
STEP 3: BLOOD PRODUCTS (if required)
• Fresh Frozen Plasma (FFP) - if severe coagulopathy
• Platelet transfusion - if thrombocytopenia
• Packed Red Blood Cells - if significant blood loss
          ↓
CAUTIONS WITH PROTAMINE:
• Excess protamine itself has ANTICOAGULANT properties
• Hypersensitivity reactions (fish allergy, previous protamine exposure, vasectomy, diabetics on NPH insulin - contain protamine)
• Cardiovascular collapse with rapid IV injection
• Rebound anticoagulation (heparin-protamine complex dissociates)

---

Warfarin (Vitamin K antagonist)
→ Inhibits Vitamin K epoxide reductase (VKORC1)
→ Vitamin K cannot be recycled (KH₂ → K → K epoxide cycle blocked)
→ ↓ Carboxylation of Factors II, VII, IX, X, Protein C, Protein S
→ These factors are inactive → ↓ Coagulation

INR >4 → ↑ Bleeding risk
INR >5 → Significant spontaneous bleeding risk
Bleeding: Skin, GI, Urinary tract, Intracranial (most dangerous)

WARFARIN OVERDOSE - Based on INR and Bleeding Status:
          ↓
CASE 1: INR 4-10, NO BLEEDING:
• WITHHOLD 1-2 doses of Warfarin
• Oral Vitamin K₁ (Phytomenadione) 1-2.5 mg
• Recheck INR in 24 hours; restart at lower dose
          ↓
CASE 2: INR >10, NO BLEEDING:
• WITHHOLD Warfarin
• Oral Vitamin K₁ 5 mg
• Recheck INR in 24 hours
          ↓
CASE 3: ANY INR, MINOR BLEEDING:
• Withhold Warfarin
• Vitamin K₁ 2-5 mg IV slow infusion (onset 4-6 hours)
          ↓
CASE 4: SERIOUS/LIFE-THREATENING BLEEDING (ANY INR):
• Stop Warfarin IMMEDIATELY
• PROTHROMBIN COMPLEX CONCENTRATE (PCC - 4-factor: Beriplex, Octaplex)
  Dose: 25-50 units/kg IV - Contains Factors II, VII, IX, X + Proteins C, S
  IMMEDIATE reversal (within minutes) - DOC for serious bleeding
  RATIONALE: Directly replaces depleted clotting factors → Immediate hemostasis
• PLUS Vitamin K₁ 10 mg IV slow infusion (prevents rebound when PCC wears off)
• If PCC unavailable: Fresh Frozen Plasma (FFP) 15 mL/kg IV
  (Contains all clotting factors; but large volume, takes time)
          ↓
RATIONALE OF VITAMIN K₁:
• Vitamin K₁ (Phytomenadione = Phylloquinone) = Natural Vitamin K
• Provides fresh substrate for VKORC1 enzyme
• Overcomes Warfarin blockade (competitive substrate + high dose)
• ↑ Carboxylation of Factors II, VII, IX, X
• Onset: 4-6 hrs (oral), 1-2 hrs (IV)
• Duration: 24-48 hours
• IV administration: Slow (anaphylaxis risk with rapid injection)
          ↓
SPECIFIC REVERSAL AGENT (newer):
ANDEXANET ALFA - Not for warfarin (for direct Xa inhibitors)
IDARUCIZUMAB (Praxbind) - For Dabigatran (direct thrombin inhibitor)

---

Anti-fibrinolytics = Inhibit FIBRINOLYSIS (dissolution of clot)
→ Preserve clot once formed
→ Reduce bleeding

---

ABSOLUTE CONTRAINDICATIONS TO THROMBOLYTICS:

1. HISTORY OF INTRACRANIAL HEMORRHAGE (EVER)
   Any prior ICH → Re-bleeding risk → Fatal
   Includes: Hemorrhagic stroke (any time), AVM, CNS tumor

2. ISCHEMIC STROKE WITHIN LAST 3 MONTHS
   (Exception: Ischemic stroke within 4.5 hrs can be treated with alteplase)
   Recent ischemic stroke → Hemorrhagic transformation risk

3. ACTIVE INTERNAL BLEEDING (excluding menses)
   Any active significant bleeding → Thrombolytics worsen → Uncontrollable hemorrhage

4. RECENT MAJOR SURGERY, TRAUMA OR HEAD INJURY WITHIN 3 MONTHS
   Fresh surgical/traumatic wounds → Bleeding into wound → Cannot achieve hemostasis

5. SUSPECTED AORTIC DISSECTION
   Thrombolytics → Bleeding into mediastinum → Catastrophic

6. SEVERE UNCONTROLLED HYPERTENSION (BP >180/110 mmHg at presentation)
   Risk of hypertensive hemorrhagic stroke

7. INTRACRANIAL NEOPLASM (primary or metastatic)
   Tumor bleeding

8. SIGNIFICANT CLOSED HEAD OR FACIAL TRAUMA WITHIN 3 MONTHS

• Active peptic ulcer disease
• Pregnancy
• BP 160-180/100-110 mmHg
• Prior streptokinase use (for streptokinase only - antibodies; use tPA instead)

---

---

5 MARKS QUESTIONS

---

Stage 1 (0-6 hrs): GI toxicity - Nausea, vomiting, hematemesis, abdominal pain, diarrhea
                   (Direct corrosive effect on GI mucosa)
Stage 2 (6-24 hrs): Apparent improvement ("latent phase") - DECEPTIVE
Stage 3 (12-48 hrs): Systemic toxicity - Shock, Acidosis, hepatotoxicity, coagulopathy, CNS depression
Stage 4 (2-6 weeks): GI scarring - Pyloric/intestinal strictures (late)

ACUTE IRON INTOXICATION
          ↓
IMMEDIATE ASSESSMENT:
• Amount ingested, time since ingestion
• Serum iron level (SI): >300 μg/dL = toxic; >500 μg/dL = severe
• TIBC (Total Iron Binding Capacity)
• ABG, Glucose, LFT, RFT, CBC, Coagulation
• X-Ray abdomen (radiopaque iron tablets visible)
          ↓
DECONTAMINATION:
• Gastric lavage (within 1-2 hrs if large ingestion)
  (Activated charcoal does NOT bind iron - NOT useful)
• Whole Bowel Irrigation (WBI) with PEG solution 
  (1-2 L/hr) if radiopaque tablets visible on X-ray
          ↓
SUPPORTIVE CARE:
• IV fluids (aggressive - replace GI fluid losses, treat shock)
• Correct acidosis (NaHCO₃)
• Blood transfusion if significant bleeding
• Glucose for hypoglycemia
• Monitor urine output (chelation therapy indicator)
          ↓
SPECIFIC ANTIDOTE: DESFERRIOXAMINE (Deferoxamine)

INDICATIONS for Desferrioxamine:
• Serum iron >350-500 μg/dL
• Serum iron > TIBC
• Symptomatic patient (shock, acidosis, altered consciousness)
• Positive "vin rose" urine test (ferrioxamine = orange-red/vin rosé colored urine)

DESFERRIOXAMINE:
• Chelates FREE iron (Fe³⁺) in blood and tissues
• Forms FERRIOXAMINE complex (water-soluble, non-toxic, excreted in urine)
• Dose: 15 mg/kg/hr IV infusion (max 80 mg/kg/day)
• Continue until: Urine clears to normal color, SI <150 μg/dL, asymptomatic
• IM route: 1-2g IM if no IV access (less effective in severe toxicity)

ADRs of Desferrioxamine:
• Hypotension (rapid IV infusion)
• Pulmonary toxicity (ARDS with prolonged infusion >24 hrs)
• Yersinia infections (iron chelation promotes growth of Yersinia - broad-spectrum antibiotics if fever develops)
• Ocular/Auditory toxicity (long-term use)
          ↓
SUPPORTIVE MANAGEMENT:
• Dialysis: NOT useful (ferrioxamine complex dialyzable but rarely needed)
• Exchange transfusion (severe toxicity in infants - rare)
• Monitor and treat late complications (liver failure, GI strictures)
          ↓
FOLLOW-UP:
• Endoscopy at 4-6 weeks (look for pyloric stenosis/stricture)
• Psychiatric evaluation (suicidal intent)

---

Oral Iron Limitations:
• Requires normal GI absorption
• GI side effects (30%)
• Slow correction rate (1g Hb/dL increase per 2 weeks)
• Non-compliance
→ Parenteral iron overcomes all these

Total Iron Deficit (mg) = Body weight (kg) × (Target Hb - Actual Hb) g/dL × 0.24 + Iron stores (500 mg)

• Vital signs for 30 min post-infusion
• Watch for: Anaphylaxis (urticaria, bronchospasm, hypotension)
• Delayed reactions: Arthralgia, myalgia, fever (24-48 hrs) - especially iron dextran

---

Megaloblastic Anemia = Macrocytic anemia with nuclear-cytoplasmic maturation
dissociation in bone marrow
= Deficiency of Vitamin B12 and/or Folate
→ Impaired DNA synthesis → Large, immature RBCs (megaloblasts)

Blood: ↓ Hb, ↑ MCV (>100 fL), Macro-ovalocytes, Hypersegmented neutrophils (>5 lobes)
Bone marrow: Megaloblasts, giant metamyelocytes
Serum B12: <200 pg/mL (normal 200-900)
Serum Folate: <3 ng/mL

VITAMIN B12 DEFICIENCY:
• Pernicious anemia (Intrinsic Factor deficiency - autoimmune - most common cause in adults)
• Strict vegan diet (no animal products)
• Gastrectomy, Ileal disease (Crohn's), Ileal resection
• Fish tapeworm (Diphyllobothrium latum)
• Drugs: Metformin (↓ B12 absorption), Nitrous oxide (inactivates B12)

FOLATE DEFICIENCY:
• Poor dietary intake (elderly, alcoholics, poverty)
• Pregnancy (↑ demand - most common in India)
• Hemolytic anemia (↑ turnover)
• Drugs: Methotrexate, Trimethoprim, Phenytoin (↓ absorption)
• Malabsorption (celiac disease)

HYDROXOCOBALAMIN (Preferred over cyanocobalamin):
• IM injection: 1000 μg IM daily × 7 days (loading)
  then 1000 μg every 2 weeks × 4 weeks
  then 1000 μg every 3 months (maintenance - LIFELONG in pernicious anemia)
• Oral high-dose B12: 1000-2000 μg daily (for dietary deficiency only - 
  passive absorption without IF in gut mucosa sufficient at high doses)
• IMPORTANT: In pernicious anemia - LIFELONG IM therapy (no IF → oral route inadequate)

NEVER give Folic acid ALONE in B12 deficiency:
• Folic acid corrects anemia but WORSENS neurological features (Subacute Combined Degeneration of Cord)
• B12 deficiency → Combined systems disease: Posterior + Lateral column degeneration
• Always replace BOTH if diagnosis unclear

FOLIC ACID:
• 5 mg oral OD for 4 months (clears stores and provides full replacement)
• Prophylaxis:
  - Pregnancy: 400 μg/day (0.4 mg) from preconception to 12 weeks
    (Prevents neural tube defects)
  - High risk (previous NTD, on antiepileptics, BMI>30): 5 mg/day
  - Hemolytic anemia (ongoing high turnover): 5 mg OD
  - Chronic malabsorption, chronic hemodialysis

FOLINIC ACID (Leucovorin):
  - Used when deficiency caused by DHFR inhibitors (Methotrexate, Trimethoprim)
  - Bypasses the blocked enzyme (already reduced form)

• Reticulocytosis: Peaks at 5-7 days (earliest sign of response)
• Hb: Rises by 1-2 g/dL per week
• Full normalization: 6-8 weeks
• Neurological recovery (B12 deficiency): Months to incomplete (irreversible if prolonged)
• Monitor K⁺ (hypokalemia on initiation - rapid RBC production uses K⁺)

---

FERROUS (Fe²⁺) form: Absorbed in DUODENUM and upper jejunum
                     via DMT-1 (Divalent Metal Transporter-1)
                     Facilitated by Vitamin C (Ascorbic acid - reduces Fe³⁺→Fe²⁺)
                     Bound to Transferrin in blood → Transported to bone marrow/stores

FERRIC (Fe³⁺) form: Must be reduced to Fe²⁺ first by Dcytb (ferrireductase) at brush border
                    Less well absorbed than Fe²⁺ (Iron polymaltose = Fe³⁺ - less bioavailable)

Ferrous sulphate 200mg = 65mg elemental Fe (32%)
Ferrous gluconate 300mg = 34mg elemental Fe (12%)
Ferrous fumarate 200mg = 65mg elemental Fe (33%)
Ferrous ascorbate = Variable; enhanced absorption
Iron polymaltose complex = Fe³⁺; 100mg elemental/tab

• Nausea, vomiting, epigastric pain, constipation, diarrhea
• Dark/black stools (harmless; warn patient)
• Reduce by: Taking with food (but ↓ absorption), starting low dose and titrating,
  switching preparation, using SR formulations, iron polymaltose

• Tetracyclines, Fluoroquinolones → Chelation → ↓ Antibiotic absorption (separate by 2-4 hrs)
• Antacids, PPIs → ↑ Gastric pH → ↓ Fe²⁺ absorption
• Calcium, Zinc → Compete for DMT-1
• Vitamin C → ↑ Absorption (reduce Fe³⁺→Fe²⁺)
• Tea/Coffee, Phytates (whole grains) → ↓ Absorption

---

DIRECT THROMBIN INHIBITORS (DTIs)
          ↓
PARENTERAL:                    ORAL:
Hirudin (leech-derived)        Dabigatran etexilate (Pradaxa)
Bivalirudin (synthetic)
Argatroban (synthetic)
Desirudin

THROMBIN (Factor IIa) - Key enzyme in coagulation:
• Converts Fibrinogen → Fibrin
• Activates Factors V, VIII, XI, XIII
• Activates Platelets (PAR-1 receptor)
• Activates Protein C (anticoagulant pathway)
          ↓
DTIs directly bind and inhibit THROMBIN
(Both FREE thrombin and CLOT-BOUND thrombin)
[Heparin cannot inhibit clot-bound thrombin - DTIs can]
NO dependence on Antithrombin III (unlike Heparin)

• Synthetic hirudin analogue; reversible thrombin inhibitor
• IV use; t½ = 25 min; Renal/enzymatic clearance
• Uses: PCI (alternative to heparin + GpIIb/IIIa); HIT patients undergoing PCI
• Advantage: Short t½; Less bleeding than UFH + GpIIb/IIIa

• Synthetic; reversible; IV infusion
• t½ = 40-50 min; HEPATIC clearance (use in renal failure)
• Uses: HIT (Heparin-Induced Thrombocytopenia) - DOC for HIT
• Also: PCI in HIT patients

• ORAL prodrug → Dabigatran (active)
• Competitive, reversible direct thrombin inhibitor
• Fixed dose (150 mg or 110 mg BD); No monitoring needed
• t½ = 12-17 hrs; 80% RENAL excretion
• USES:
  - Non-valvular AF (↓ Stroke/systemic embolism - RE-LY trial)
  - VTE treatment (DVT/PE)
  - VTE prophylaxis post hip/knee replacement surgery
• ANTIDOTE: IDARUCIZUMAB (Praxbind) - Monoclonal antibody fragment
  Binds dabigatran with 350x affinity > thrombin → Complete reversal
  Approved 2015; 5g IV for life-threatening bleeding
• Advantages over Warfarin: No monitoring, predictable, few drug interactions, rapid onset/offset
• Disadvantages: Expensive, no routine monitoring, renal elimination (avoid CrCl <30), dyspepsia

• Natural (leech saliva) / Recombinant
• Irreversible thrombin inhibitor (bivalent - exosite 1 + active site)
• Desirudin: SC; DVT prophylaxis post hip surgery
• No antidote available

---

HEPARIN
     ↓
UFH (Unfractionated Heparin): MW 3000-30,000 Da; Average 15,000 Da
LMWH (Low Molecular Weight Heparin): MW 4000-6500 Da
  e.g., Enoxaparin (Clexane), Dalteparin (Fragmin), Tinzaparin

HEPARIN
     ↓
Binds ANTITHROMBIN III (AT-III) - Endogenous serine protease inhibitor
     ↓
Heparin-AT-III complex: 1000-fold ↑ activity of AT-III
     ↓
Inactivates (via AT-III):
• Thrombin (Factor IIa) ← Both UFH and LMWH
• Factor Xa ← BOTH UFH and LMWH
• Factors IXa, XIa, XIIa (less important)
          ↓
↓ Fibrin formation → Anticoagulation

UFH: Anti-IIa = Anti-Xa (equal)
LMWH: Anti-Xa >> Anti-IIa (more specific, more predictable)

Also:
• ↑ Release of TFPI (Tissue Factor Pathway Inhibitor)
• ↑ Lipoprotein lipase release (↓ triglycerides)
• Heparin does NOT dissolve existing clots (no fibrinolytic activity)

• IV: Immediate action (given as bolus + infusion)
• SC: 1-2 hours onset (LMWH preferred SC route)
• Does NOT cross placenta (safe in pregnancy)
• Monitored by aPTT (UFH): Target 60-80 seconds (1.5-2.5 × normal)
• LMWH monitored by Anti-Xa level

1. DVT and PE treatment - IV UFH or SC LMWH (LMWH preferred now - outpatient)
2. DVT/PE prophylaxis (post-surgical, immobilized patients) - LMWH SC
3. ACS (Unstable Angina, NSTEMI, STEMI) - UFH/LMWH during PCI
4. Atrial Fibrillation - Bridging anticoagulation during cardioversion or warfarin initiation
5. Dialysis and cardiopulmonary bypass - Anticoagulation of extracorporeal circuits (UFH)
6. DIC - UFH (controversial; in thrombotic DIC phase)
7. Venous thrombosis in pregnancy - LMWH (does not cross placenta; safe)
8. Bridging therapy - Before/after procedures when warfarin interrupted

1. BLEEDING - Most common and serious; Treat with Protamine sulphate
2. HIT (Heparin-Induced Thrombocytopenia):

   Type I (Non-immune): Days 1-4; Mild thrombocytopenia (>100,000); Resolves spontaneously; Not serious
   
   Type II (Immune - HITT): Days 5-14; SERIOUS
   • Heparin-PF4 complex → IgG antibodies → Platelet activation → THROMBOSIS + Thrombocytopenia
   • PARADOX: Heparin causes CLOTTING despite anticoagulation
   • Platelet <100,000 or >50% fall from baseline
   • STOP ALL HEPARIN IMMEDIATELY (including flushes, LMWH)
   • Switch to DTI (Argatroban, Bivalirudin) or Fondaparinux
   • 4T score to assess probability
   

3. OSTEOPOROSIS (prolonged use >3 months; ↓ bone density via ↓ osteoblasts + ↑ osteoclasts)
4. Hypoaldosteronism → Hyperkalemia (inhibits aldosterone secretion)
5. Alopecia (reversible)
6. Hypersensitivity reactions (rash, urticaria)

---

Vitamin K Cycle:
K (Quinone) → VKORC1 (Vit K Epoxide Reductase) → KH₂ (Hydroquinone)
KH₂ acts as cofactor for gamma-carboxylation of:
Factors II, VII, IX, X (Clotting)
Protein C, Protein S (Anticoagulant)
          ↓
WARFARIN: Competitive inhibitor of VKORC1
     ↓
↓ Regeneration of KH₂ → Vitamin K epoxide accumulates
     ↓
↓ Gamma-carboxylation → Inactive (des-carboxy) forms of Factors II, VII, IX, X
     ↓
↓ Coagulation

ONSET: DELAYED (2-3 days) because:
• Existing active clotting factors must deplete first
• t½: Factor VII = 6 hrs (first to fall), Factor II = 60 hrs (last to fall)
• Full anticoagulation: 4-5 days

First factor to fall: VII (shortest t½) → PT/INR rises early
Full anticoagulation: When Factor II falls (3-5 days)

PHARMACOGENETICS (Important):
• VKORC1 gene polymorphism → ↑ Sensitivity to warfarin (lower dose needed)
• CYP2C9 polymorphism → ↓ Metabolism → Higher warfarin levels
• These explain 30-50% of warfarin dose variability between patients

1. Atrial Fibrillation - Stroke prevention (INR 2-3)
2. DVT/PE treatment and prevention (INR 2-3); INR 2.5-3.5 for massive PE
3. Mechanical heart valves (INR 2.5-3.5 - higher target due to thrombogenicity)
4. Antiphospholipid syndrome (INR 2-3 or 3-4 depending on history)
5. Post-MI (in patients with LV thrombus, AF) - less common now (replaced by DOACs)

• PT/INR (Prothrombin Time / International Normalized Ratio)
• Therapeutic INR: Usually 2-3 (most indications)
• Mechanical valves: 2.5-3.5
• Check INR at baseline → 2-3 days after each dose change → Weekly when stable → Monthly maintenance

INCREASE anticoagulation (↑ INR → ↑ Bleeding risk):
• Enzyme INHIBITORS: Erythromycin, Clarithromycin, Metronidazole, Fluconazole,
  Amiodarone, Cimetidine, Ciprofloxacin
• Displace from albumin: Aspirin, NSAIDs (↑ free warfarin)
• ↓ Vitamin K: Antibiotics (kill gut flora → ↓ Vit K synthesis), Poor diet

DECREASE anticoagulation (↓ INR → ↑ Clot risk):
• Enzyme INDUCERS: Rifampicin, Carbamazepine, Phenytoin, Phenobarbitone, St. John's Wort
• ↑ Vitamin K: Green leafy vegetables (broccoli, spinach, kale)

1. BLEEDING - Most common (GI, urinary, intracranial - most dangerous) Risk factors: INR >4, age >65, prior GI bleed, NSAIDs, hypertension
2. WARFARIN EMBRYOPATHY (Teratogenicity):
   • 1st trimester (6-9 weeks): Nasal hypoplasia, stippled epiphyses (calcification)
   • 2nd/3rd trimester: CNS defects, microcephaly, optic atrophy
   • AVOID in pregnancy → Use LMWH (does not cross placenta)
3. Warfarin skin necrosis (rare, 3-5 days after starting):
   • Protein C has shortest t½ after Factors II, VII → Falls first → Transient hypercoagulable state → Skin necrosis
   • Avoid by overlapping with heparin for ≥5 days when starting warfarin
4. Purple toe syndrome (rare - cholesterol micro-emboli)
5. Alopecia
6. Nausea, GI upset

---

EPO = Glycoprotein hormone
Produced by: Peritubular interstitial cells of kidney (90%) + Liver (10%)
Stimulus: Hypoxia (↓ O₂ delivery to kidney → ↑ HIF-1α → ↑ EPO gene transcription)
Action: Acts on BFU-E and CFU-E (erythroid progenitors) in bone marrow
→ ↑ Proliferation, differentiation, survival → ↑ RBC production

SC/IV administration → Binds EPO receptor on erythroid progenitors
     ↓
Receptor dimerization → JAK2-STAT5 signaling
     ↓
↑ Transcription of erythroid genes
     ↓
↑ Proliferation + Differentiation of BFU-E/CFU-E
↑ Reticulocyte release from marrow
↑ RBC production

1. Anemia of Chronic Kidney Disease (CKD) - PRIMARY INDICATION; used with IV iron supplementation; Target Hb 10-12 g/dL (AVOID >13 g/dL - ↑ CV events)
2. Anemia of prematurity (preterm neonates) - to reduce transfusions
3. HIV/AIDS-associated anemia (especially Zidovudine-induced)
4. Chemotherapy-induced anemia (cancer patients on platinum-based chemo)
5. Autologous blood donation - Pre-surgical donation (stimulates RBC regeneration)
6. Anemia in Myelodysplastic Syndrome (MDS)
7. Reducing need for blood transfusions in elective surgery

• Hypertension (most common) - ↑ Blood viscosity + Direct vasoconstriction; Monitor BP; May need antihypertensives
• Thrombosis (DVT, AV fistula thrombosis, stroke) - ↑ Platelet reactivity + ↑ Viscosity; Especially if Hb overshoots >13 g/dL
• Pure Red Cell Aplasia (PRCA) - Rare but serious; Antibodies against EPO + Endogenous EPO; Switch to darbepoetin NOT helpful (cross-reactive); Immunosuppression needed
• Flu-like symptoms (injection site reactions, fever, myalgia)
• Iron deficiency (EPO accelerates erythropoiesis → Functional iron deficiency; always give with IV iron supplementation)
• Headache, seizures (rare, with rapid Hb rise + hypertension)
• In cancer patients: ↑ Mortality concern (EPO stimulates tumor growth via EPO-R on tumor cells) - use lowest effective dose

---

UROKINASE (u-PA = Urokinase-type Plasminogen Activator)
Naturally produced by renal tubular cells, endothelial cells
     ↓
Directly cleaves Plasminogen → PLASMIN
(Does NOT require fibrin as cofactor - NON-FIBRIN SPECIFIC)
          ↓
PLASMIN:
• Cleaves Fibrin (dissolves clot) → Fibrin degradation products (D-dimers)
• Also cleaves Fibrinogen, Factor V, Factor VIII → Systemic fibrinolysis
     ↓
THROMBOLYSIS (clot dissolution)

Comparison with tPA:
• tPA (Alteplase): Fibrin-SPECIFIC (activates plasminogen preferentially ON fibrin clot)
• Urokinase: NON-SPECIFIC (activates plasminogen in circulation + on clot)
  → More systemic fibrinolysis with urokinase

1. Massive Pulmonary Embolism - Hemodynamically compromised (shock, right heart failure); 4400 IU/kg/hr IV × 12-24 hours
2. Massive DVT (Ileofemoral) - Catheter-directed thrombolysis
3. Clearing occluded IV catheters/dialysis grafts - Low-dose local instillation (most common current use)
4. Peripheral arterial occlusion - Catheter-directed thrombolysis
5. Ischemic stroke (limited; tPA preferred)
6. Viscosupplementation - Intrapleural for loculated parapneumonic effusion/empyema (breaks fibrinous septations)

1. BLEEDING - Most common and serious (systemic fibrinolysis → all hemostatic clots dissolved)
   • Minor: Bruising, oozing at puncture sites (avoid unnecessary venipuncture)
   • Major: GI hemorrhage, Intracranial hemorrhage (most dangerous - 0.5-1%)
2. Fever, chills, rigors (pyrogenic reaction - especially with older preparations)
3. Allergic reactions (less than streptokinase - urokinase is human protein)
4. Hypotension (rare)
5. Embolization - Lysis of thrombus → Fragment embolism

---

ANTIPLATELET DRUGS - MECHANISMS:

1. COX-1 INHIBITORS: Aspirin (irreversible), NSAIDs (reversible)
   ↓ TXA₂ → ↓ Platelet aggregation

2. P2Y₁₂ (ADP) RECEPTOR ANTAGONISTS:
   Thienopyridines (PRODRUGS): Clopidogrel, Prasugrel (both irreversible)
   Direct: Ticagrelor (reversible), Cangrelor (IV, reversible, ultrashort)

3. GP IIb/IIIa INHIBITORS (Final common pathway):
   Abciximab (mAb), Eptifibatide (cyclic peptide), Tirofiban (small molecule)
   IV only; Used during PCI

4. PDE INHIBITORS (↑ cAMP/cGMP):
   Dipyridamole (PDE + adenosine uptake inhibitor)
   Cilostazol (PDE3 inhibitor) - also vasodilator; PAD

5. PAR-1 ANTAGONISTS (Thrombin receptor on platelets):
   Vorapaxar - Reduces recurrent MI (adjunct)

6. PROSTACYCLIN ANALOGUES (↑ cAMP):
   Epoprostenol, Iloprost - IV; Pulmonary hypertension

---

HMG-CoA Reductase = Rate-limiting enzyme in Cholesterol biosynthesis pathway
(In liver: HMG-CoA → Mevalonate → Cholesterol)
          ↓
ATORVASTATIN (competitive inhibitor of HMG-CoA Reductase)
     ↓
↓ Hepatic Cholesterol synthesis
     ↓
↓ Intracellular Cholesterol in hepatocytes
     ↓
↑ LDL RECEPTOR expression (UPREGULATION on hepatocyte surface)
     ↓
↑ LDL clearance from circulation
     ↓
↓ LDL-C (PRIMARY EFFECT: 36-54% ↓ with 10-80 mg)
↓ VLDL, ↓ IDL, ↓ Triglycerides (modest)
↑ HDL-C (modest 5-8%)

PLEIOTROPIC (non-lipid) EFFECTS:
• ↑ Endothelial function (↑ NO production)
• ↓ Inflammatory markers (↓ CRP, ↓ IL-6)
• Plaque stabilization (↑ fibrous cap, ↓ macrophage content)
• ↓ Thrombogenicity (↓ tissue factor, ↓ platelet aggregation)

1. Primary hypercholesterolemia (Type IIa, IIb hyperlipidemia) - Most common indication
2. Mixed dyslipidemia (↑ LDL + ↑ TG)
3. Secondary prevention of cardiovascular events (Post-MI, Post-stroke, Established CVD) - Reduces MI, Stroke, CV death by 25-35%
4. Primary prevention in high-risk patients (Diabetes + CVD risk factors, Hypertension, Family history)
5. Diabetic patients - All T2DM with CVD risk (ADA: Moderate-high intensity statin)
6. Familial Hypercholesterolemia (FH) - High-intensity statin (Atorvastatin 40-80 mg or Rosuvastatin)
7. Acute Coronary Syndrome (ACS) - High-intensity statin IMMEDIATELY (plaque stabilization)
8. CKD patients - Statin for CV protection
9. Post-cardiac transplantation - Immunosuppressive + CV benefit

1. Myopathy (MOST IMPORTANT class effect):
   • Myalgia (muscle pain) - 5-10%
   • Myositis (muscle inflammation + ↑ CK)
   • Rhabdomyolysis (rare but serious: massive CK elevation, myoglobinuria, Acute Kidney Injury)
   • Risk ↑ with: High dose, CYP3A4 inhibitors (diltiazem, amiodarone, erythromycin, ketoconazole - all ↑ atorvastatin levels), Hypothyroidism, Renal failure, Fibrates (especially gemfibrozil)
   • Monitor CK if symptoms occur; Stop if CK >10x ULN
2. Hepatotoxicity - Transaminase elevation (dose-dependent); usually mild and transient; Severe hepatitis rare; Check LFT baseline + if symptoms; Stop if ALT/AST >3x ULN persisting
3. New-onset Diabetes - Modest ↑ risk (especially high-intensity statins; mechanism: ↓ GLUT4, ↓ β-cell function); Outweighed by CV benefit
4. Cognitive impairment - Mild memory issues (FDA warning 2012; reversible on stopping; rare)
5. GI: Nausea, constipation, dyspepsia (mild)
6. Statin intolerance (~10-15% - due to myalgia mainly; try: Rosuvastatin 5-10mg, Pravastatin, Pitavastatin - less CYP3A4 dependent)

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Mnemonic: RIPE / HRZE
H - Isoniazid (INH)
R - Rifampicin
Z - Pyrazinamide
E - Ethambutol
S - Streptomycin (less used now)

Intensive Phase (2 months): H + R + Z + E (daily)
Continuation Phase (4 months): H + R (daily)

MOA:
• Prodrug → Activated by KatG (catalase-peroxidase) in Mycobacterium
• Active metabolite inhibits InhA (Enoyl-ACP reductase)
  → ↓ Mycolic acid synthesis (essential for mycobacterial cell wall)
• Bactericidal for actively dividing bacilli
• Bacteriostatic for dormant bacilli

ADVERSE EFFECTS:
• PERIPHERAL NEUROPATHY (most common) - ↓ Pyridoxine (B6) metabolism
  → PREVENTED and TREATED with Pyridoxine (B6) 10-25 mg/day co-administration
  → High-risk patients MUST receive B6 (elderly, malnourished, HIV, alcoholics, pregnancy, diabetes)
• HEPATOTOXICITY - ↑ with age, alcohol, rifampicin combination; Monitor LFT; Stop if 3x ↑
• Drug-induced lupus (ANA-positive; slow acetylators more)
• CNS: Seizures (rare, ↓ B6 → ↓ GABA)
• Pyridoxine-responsive sideroblastic anemia (rare)

MOA:
• Inhibits bacterial DNA-dependent RNA Polymerase (β subunit)
  → ↓ mRNA synthesis → ↓ Protein synthesis → Bactericidal
• Kills ALL populations: Rapidly dividing, semi-dormant (caseous foci, intracellular)
• MOST IMPORTANT sterilizing drug (with Pyrazinamide)
• Bactericidal

ADVERSE EFFECTS:
• HEPATOTOXICITY - Most serious; Monitor LFT
• ENZYME INDUCER (CYP3A4, CYP2C9, P-gp) - MOST POTENT inducer:
  ↓ OCP efficacy (contraceptive failure), ↓ Warfarin, ↓ HIV drugs, ↓ Methadone, ↓ Antifungals
• ORANGE-RED DISCOLORATION of urine, tears, sweat, saliva, contact lenses (HARMLESS; warn patient)
• Flu-like syndrome (intermittent therapy) - fever, chills, headache
• Thrombocytopenia, hemolytic anemia (intermittent)
• GI: Nausea, abdominal pain
• Self-induction (accelerates own metabolism over 10-14 days)

MOA:
• Prodrug → Converted to Pyrazinoic acid by Pyrazinamidase in Mycobacterium
• Active in ACIDIC pH (inside macrophage phagolysosomes - acidic environment)
• Bactericidal against semi-dormant intracellular bacilli (unique - no other first-line drug effective here)
• ESSENTIAL for SHORTENING treatment to 6 months (kills "persisters" in macrophages)

ADVERSE EFFECTS:
• HEPATOTOXICITY - Most hepatotoxic of the 4 first-line drugs; Monitor LFT
• HYPERURICEMIA - ↓ Renal urate excretion (pyrazinoic acid competes) → Gout flare (cover with allopurinol)
• Arthralgia (polyarthralgia - very common, 40%)
• GI: Nausea, vomiting
• Photosensitivity (mild)
• Non-gouty polyarthritis (benign)

MOA:
• Inhibits ARABINOSYL TRANSFERASE (embB gene product)
  → ↓ Arabinan polymerization → ↓ Arabinogalactan (cell wall component)
  → ↓ Mycobacterial cell wall synthesis
• Bacteriostatic (prevents resistance to other drugs)

ADVERSE EFFECTS:
• OPTIC NEURITIS (dose-related, most important) - Retrobulbar neuritis
  → ↓ Visual acuity, ↓ Color vision (red-green discrimination impaired - EARLIEST sign)
  → Monitor: Monthly visual acuity and color vision testing
  → USUALLY REVERSIBLE if detected early and drug stopped
  → AVOID in children <5 years (cannot report visual symptoms), patients who cannot be monitored
• GI: Nausea, abdominal discomfort
• Peripheral neuropathy (rare)
• Hyperuricemia (mild)
• Hepatotoxicity (rare)

MOA: Aminoglycoside; Binds 30S ribosome → Misreading of mRNA → ↓ Protein synthesis; Bactericidal
ADVERSE EFFECTS:
• OTOTOXICITY (Vestibular > Cochlear): Vertigo, ataxia, hearing loss
• NEPHROTOXICITY: ↑ Creatinine, tubular damage
• Neuromuscular blockade (rare)
• Pain at injection site (IM injection)
• AVOID in pregnancy (cochlear damage to fetus)

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MDR-TB = Multidrug-Resistant TB
= Resistant to at LEAST Isoniazid AND Rifampicin (the two most important first-line drugs)

Pre-XDR TB (WHO 2021): MDR-TB + Resistance to any fluoroquinolone
XDR-TB (Extensive Drug Resistant): MDR-TB + Resistance to any fluoroquinolone 
                                    + at least one of Bedaquiline or Linezolid

PREFERRED REGIMEN: BPaL(M) - "SHORTER" ORAL REGIMEN

BPaL (6 months): BEDAQUILINE + PRETOMANID + LINEZOLID
(± Moxifloxacin)

OR

LONGER REGIMEN (18-20 months traditional):
Intensive Phase (6-8 months): Bedaquiline + Levofloxacin/Moxifloxacin + 
                               Cycloserine + Linezolid +/- Clofazimine
Continuation Phase (12 months): Levofloxacin/Moxifloxacin + Cycloserine + 
                                  Linezolid + Clofazimine

GROUP A (Include all 3 if possible):
1. Levofloxacin OR Moxifloxacin (Fluoroquinolones) - MOA: DNA gyrase/Topoisomerase IV inhibitor
2. Bedaquiline - MOA: ATP Synthase inhibitor (inhibits F₁F₀ ATP synthase → ↓ Energy production)
3. Linezolid - MOA: Binds 23S rRNA of 50S subunit → ↓ Translation initiation

GROUP B (Add one or both):
4. Clofazimine - MOA: Generates reactive oxygen species; anti-inflammatory; causes skin discoloration (reversible red-brown pigmentation)
5. Cycloserine - MOA: D-Ala-D-Ala synthetase inhibitor → ↓ Peptidoglycan synthesis; Neuropsychiatric side effects (cover with Pyridoxine)

GROUP C (Add to complete regimen when Group A/B drugs cannot be used):
6. Ethambutol
7. Delamanid - MOA: Inhibits mycolic acid synthesis
8. Pyrazinamide
9. Imipenem-Cilastatin + Clavulanic acid (IV)
10. Amikacin (injectable)
11. Ethionamide/Prothionamide
12. p-Aminosalicylic Acid (PAS)

SHORT ORAL BEDAQUILINE REGIME (SOBR) or
Longer Regimen (IP 6-9 months + CP 12-18 months)
Directly Observed Treatment (DOT) - mandatory
Culture and Drug Sensitivity Test (DST) - before initiating
Monthly sputum smear + culture monitoring

Bedaquiline: QT prolongation (ECG monthly)
Linezolid: Myelosuppression, Peripheral neuropathy, Optic neuritis (CBC, LFT)
Levofloxacin: QT prolongation, Tendinitis, CNS (Seizures)
Cycloserine: Neuropsychiatric (seizures, psychosis, depression) - Pyridoxine B6 mandatory
Clofazimine: Skin discoloration, GI
Delamanid: QT prolongation

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XDR-TB (Extensively Drug Resistant TB) [WHO 2021 revised definition]:
= MDR-TB (Resistant to H + R)
+ Resistant to ANY FLUOROQUINOLONE (Levofloxacin/Moxifloxacin)
+ Resistant to AT LEAST ONE of: Bedaquiline OR Linezolid

MDR-TB loses H + R
Pre-XDR-TB loses H + R + Fluoroquinolone
XDR-TB loses H + R + Fluoroquinolone + Bedaquiline OR Linezolid
→ Very few effective drugs remain
→ Treatment success rates <50%
→ Requires highly individualized regimens based on full DST (Drug Sensitivity Testing)

XDR-TB MANAGEMENT
          ↓
STEP 1: CONFIRM XDR-TB
• Sputum culture and COMPREHENSIVE Drug Sensitivity Testing (DST)
• Whole Genome Sequencing (WGS) - gold standard for resistance pattern
• Refer to specialized XDR-TB center
          ↓
STEP 2: REGIMEN DESIGN (Individualized based on DST)
Aim: At least 4-5 EFFECTIVE drugs in the regimen

Available drugs for XDR-TB:
BACKBONE (if susceptible):
• Bedaquiline (if not resistant) - Group A
• Linezolid (if not resistant) - Group A
• Pretomanid (New - TB Alliance) - Used in BPaLM/BPaL regime
• Clofazimine (Group B)
• Cycloserine/Terizidone (Group B)

ADDITIONAL:
• Delamanid (New nitroimidazole; can be combined with Bedaquiline cautiously)
• Imipenem-Cilastatin + Clavulanic acid IV (powerful combination)
• Amikacin IV (if susceptible - injectable Group C)
• Ethionamide/Prothionamide
• High-dose Isoniazid (if low-level resistance only)
• PAS (para-Aminosalicylic acid)
          ↓
STEP 3: BPaL OR BPaLM REGIMEN (for pre-XDR and some XDR-TB)
BPaL = Bedaquiline + Pretomanid + Linezolid × 6 months
BPaLM = Bedaquiline + Pretomanid + Linezolid + Moxifloxacin × 6 months
(ZeNix and TB-PRACTECAL trials - >89% treatment success in pre-XDR/XDR-TB)
          ↓
STEP 4: DURATION
• Minimum 18-24 months depending on response
• Extend if culture conversion delayed
• Monthly sputum smear and culture
          ↓
STEP 5: SURGICAL OPTION
• Adjunct pulmonary resection in localized disease (lobectomy/pneumonectomy)
  when: Localized disease + No improvement after 3-4 months + Technically feasible
• Improves outcomes when combined with drug therapy
          ↓
STEP 6: MONITORING AND SUPPORTIVE CARE
• ECG monitoring (QT prolongation - Bedaquiline + Delamanid + Moxifloxacin)
• CBC, LFT, RFT monthly (Linezolid myelosuppression, hepatotoxicity)
• Visual acuity (Linezolid optic neuritis)
• Neuropsychiatric assessment (Cycloserine)
• Nutritional support, psychological support
• HIV testing and antiretroviral therapy if HIV co-infected
• Contact tracing and infection control
          ↓
OUTCOMES:
• XDR-TB treatment success rate: 40-60% with new regimens
• BPaL regimen: >80% success in ZeNix trial (if susceptible to all 3 components)

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