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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

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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

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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

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