Give me high yield pharmacology notes on all the drugs under these topics use katzung as the guide book for the drugs1) Lipid-lowering drugs (statins) & Anticoagulants 2) Antianginal drugs: Nitrates, Calcium channel Blockers 3) Digoxin, ACE lors, ARBS & Diseuretics in HF 4) Bronchodilators: beta2-agonists & Antimuscarinics 5)Inhaled Corticosteroids & Targeted Antibiotics 6) Insulin, Metformin & oral Hypoglycemic agents 7)Thyroid Hormones, Antithyroid drugs & Steroids 8) Diuretics (Loop, Thiazide)

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Here are your comprehensive high-yield pharmacology notes based on Katzung's Basic and Clinical Pharmacology, 16th Edition:

HIGH-YIELD PHARMACOLOGY NOTES

Based on Katzung's Basic & Clinical Pharmacology, 16e

TOPIC 1: Lipid-Lowering Drugs (Statins) & Anticoagulants

STATINS (HMG-CoA Reductase Inhibitors)

Drugs: Atorvastatin, Rosuvastatin, Simvastatin, Pravastatin, Lovastatin, Fluvastatin, Pitavastatin

Mechanism

Competitively inhibit HMG-CoA reductase - the rate-limiting enzyme in cholesterol synthesis (mevalonate pathway)
Reduce hepatic cholesterol synthesis → upregulate LDL receptors on hepatocytes → increased LDL clearance from plasma
Net effect: ↓↓ LDL (20-60%), ↓ TG (mild), ↑ HDL (modest)

Pleiotropic effects (beyond lipid lowering)

Anti-inflammatory, plaque stabilization, endothelial function improvement, ↓ CRP

High-yield facts

Atorvastatin and rosuvastatin = most potent (longest half-lives, no need for food)
Lovastatin and simvastatin = prodrugs (require hepatic activation)
Pravastatin = not CYP450 metabolized → safest in transplant patients (least drug interactions)
Rosuvastatin = least CYP450 involvement (minor CYP2C9)
Grapefruit juice inhibits CYP3A4 → increases levels of lovastatin, simvastatin, atorvastatin (NOT rosuvastatin or pravastatin)

Adverse Effects

Effect	Details
Myopathy/Rhabdomyolysis	Most serious; ↑ risk with fibrates (especially gemfibrozil), cyclosporine, niacin, azole antifungals
Hepatotoxicity	Transaminase elevation; monitor LFTs
New-onset diabetes	Class effect, dose-dependent
Teratogenic	Category X - Contraindicated in pregnancy

Drug Interactions

CYP3A4 inhibitors (erythromycin, azoles, HIV protease inhibitors) → ↑ statin levels → ↑ myopathy risk
Gemfibrozil (inhibits glucuronidation of statins) → highest risk of myopathy with any fibrate combination

Other lipid-lowering drugs (Katzung)

Drug	Class	Mechanism	Key Use
Cholestyramine, Colestipol	Bile acid sequestrants	↑ bile acid excretion → ↑ LDL-R expression	↓ LDL; safe in pregnancy
Ezetimibe	Cholesterol absorption inhibitor	Blocks NPC1L1 transporter in gut	Add-on to statins; ↓ LDL 15-20%
Niacin (nicotinic acid)	B-vitamin	↓ VLDL synthesis; ↑ HDL most of any drug	Best agent to ↑ HDL; causes flushing (↓ with aspirin)
Fenofibrate, Gemfibrozil	Fibrates	PPAR-α agonist → ↑ LPL → ↓ TG	Best for hypertriglyceridemia
PCSK9 inhibitors (evolocumab, alirocumab)	mAbs	Prevent PCSK9-mediated LDL-R degradation	Familial hypercholesterolemia
Lomitapide	MTP inhibitor	Blocks VLDL assembly	Homozygous FH

ANTICOAGULANTS

Heparin (Unfractionated Heparin - UFH)

Mechanism: Binds antithrombin III (AT-III) → conformational change → AT-III inhibits thrombin (IIa), Xa, IXa, XIa, XIIa (thrombin inhibition requires heparin to remain bound; Xa inhibition does not)

Administration: IV only (does NOT cross placenta = safe in pregnancy)

Monitoring: aPTT (target 1.5-2.5x normal); HIT antibody (anti-PF4)

Reversal: Protamine sulfate (positively charged; neutralizes heparin)

Adverse Effects

HIT (Heparin-Induced Thrombocytopenia): Type I (benign, direct effect, days 1-2) vs. Type II (immune, IgG anti-PF4 Ab, days 5-10) - STOP heparin immediately, use argatroban or bivalirudin (DTIs)
Osteoporosis (long-term use)
Hyperkalemia (↓ aldosterone)

Low Molecular Weight Heparins (LMWH)

Drugs: Enoxaparin, Dalteparin, Tinzaparin

Mechanism: Inhibit factor Xa >> thrombin (shorter chain; can't bridge AT-III to thrombin)

Key advantages over UFH:

Predictable pharmacokinetics → no routine monitoring (anti-Xa if needed)
Subcutaneous dosing
Less HIT risk

Reversal: Protamine (partial - ~60-80% reversal only)

Warfarin

Mechanism: Inhibits Vitamin K epoxide reductase (VKOR) → prevents regeneration of reduced Vitamin K → ↓ synthesis of clotting factors II, VII, IX, X and proteins C, S

Onset: Delayed 2-3 days (must wait for existing factors to be depleted); Factor VII depleted first (shortest half-life = earliest INR rise, but patient NOT fully anticoagulated)

Monitoring: INR (target 2-3 for most; 2.5-3.5 for mechanical mitral valve)

Bridge therapy: Use heparin for 5 days until INR is therapeutic for 2 days (to avoid early paradoxical thrombosis from protein C/S depletion)

Reversal:

Stop drug + Vitamin K (oral/IV) - takes hours
Fresh Frozen Plasma (FFP) - immediate
4-factor PCC (prothrombin complex concentrate) - fastest, preferred for major bleeding
Idarucizumab - NOT for warfarin (it's for dabigatran)

Drug interactions (critical)

↑ INR (bleeding risk): Amiodarone, azole antifungals, metronidazole, trimethoprim-sulfamethoxazole, cimetidine (CYP2C9 inhibitors)
↓ INR (clotting risk): Rifampin, barbiturates, carbamazepine (CYP2C9 inducers); Vitamin K-rich foods
Genetic factors: CYP2C9 and VKORC1 polymorphisms affect dosing

Direct Oral Anticoagulants (DOACs)

Drug	Target	Reversal Agent	Monitoring
Dabigatran	Direct thrombin (IIa) inhibitor	Idarucizumab	No routine monitoring
Rivaroxaban	Direct Xa inhibitor	Andexanet alfa	No routine monitoring
Apixaban	Direct Xa inhibitor	Andexanet alfa	No routine monitoring
Edoxaban	Direct Xa inhibitor	Andexanet alfa	No routine monitoring

Key facts:

All renally cleared (↓ dose or avoid in renal failure - dabigatran most dependent on renal clearance)
NOT safe in pregnancy (use heparin)
NOT for mechanical heart valves (warfarin preferred)
Dabigatran: only DOAC that can be removed by dialysis

Direct Thrombin Inhibitors (Parenteral)

Argatroban: Drug of choice in HIT (hepatically cleared - use in renal failure)
Bivalirudin: Used in percutaneous coronary intervention (PCI) + HIT
Lepirudin/Desirudin: Recombinant hirudins; renally cleared

Thrombolytics (Fibrinolytics)

Drugs: Alteplase (tPA), Tenecteplase, Reteplase, Streptokinase

Mechanism: Activate plasminogen → plasmin → degrades fibrin clot

Use: STEMI (door-to-balloon >120 min), massive PE, acute ischemic stroke (<4.5 h), DVT

Reversal: Aminocaproic acid (inhibits plasminogen activation)

Contraindications: Prior intracranial hemorrhage, active bleeding, recent surgery/trauma, uncontrolled hypertension

TOPIC 2: Antianginal Drugs - Nitrates & Calcium Channel Blockers

NITRATES

Drugs: Nitroglycerin (NTG), Isosorbide dinitrate (ISDN), Isosorbide mononitrate (ISMN), Amyl nitrite

Mechanism:

Converted to nitric oxide (NO) via mitochondrial aldehyde dehydrogenase (mtALDH2)
NO activates guanylyl cyclase → ↑ cGMP → smooth muscle relaxation
At low doses: primarily venodilation → ↓ preload → ↓ LVEDP → ↓ wall tension → ↓ O2 demand
At high doses: arteriodilation → ↓ afterload; also coronary vasodilation (relieves vasospasm)

Pharmacokinetics

Sublingual NTG: onset 1-3 min, duration 30 min (first-pass bypass)
IV NTG: immediate onset, titratable
Transdermal (patch): 24h duration (but tolerance develops with continuous use)
ISMN: no first-pass effect (active as given)

High-yield facts

Tolerance: Develops within 24h of continuous nitrate exposure. Due to depletion of -SH groups needed for NO generation and mtALDH2 oxidation. Prevented by nitrate-free interval (10-12 hours/day)
Headache = most common side effect (vasodilation of meningeal vessels)
Reflex tachycardia with rapid-acting nitrates (prevented by combining with beta-blockers)
Postural hypotension especially first dose
Methemoglobinemia (especially amyl nitrite at high doses; treat with methylene blue)
CONTRAINDICATION: PDE-5 inhibitors (sildenafil, tadalafil) - severe hypotension (additive ↑ cGMP)
Used in Prinzmetal (vasospastic) angina - relieves coronary vasospasm

CALCIUM CHANNEL BLOCKERS (CCBs)

Classification by subtype:

Class	Drugs	Selectivity	Primary Effect
Dihydropyridines (DHPs)	Nifedipine, Amlodipine, Felodipine, Nicardipine, Clevidipine	Vascular >> cardiac	Vasodilation, ↓ afterload
Non-DHPs (Phenylalkylamines)	Verapamil	Cardiac >> vascular	↓ HR, ↓ AV conduction, ↓ contractility
Non-DHPs (Benzothiazepines)	Diltiazem	Intermediate	↓ HR, vasodilation

Mechanism: Block L-type (long-lasting) voltage-gated Ca2+ channels in vascular smooth muscle and cardiac muscle → ↓ intracellular Ca2+ → ↓ smooth muscle contraction (vasodilation) and ↓ cardiac contractility/conduction

Antianginal use:

All CCBs: ↓ afterload → ↓ myocardial O2 demand
Verapamil/diltiazem: also ↓ HR → ↓ O2 demand
ALL CCBs: excellent for Prinzmetal/vasospastic angina (relieve coronary vasospasm) - first-line
Amlodipine: long-acting, no reflex tachycardia, preferred in stable angina

Adverse Effects

Drug	Key Side Effects
DHPs (nifedipine)	Reflex tachycardia, peripheral edema, flushing, headache
Verapamil	Constipation (most common), bradycardia, AV block, heart failure, ↑ digoxin levels (by 50-90%)
Diltiazem	Bradycardia, AV block, less constipation than verapamil

Contraindications:

Verapamil/diltiazem: AV block, sick sinus syndrome, HF with reduced EF (negative inotropy), WPW (may accelerate accessory pathway)
Dihydropyridines: can be used in HF (amlodipine and felodipine are safe)

Drug interaction: Verapamil + digoxin → ↑ digoxin toxicity (P-glycoprotein inhibition)

TOPIC 3: Digoxin, ACE Inhibitors, ARBs & Diuretics in Heart Failure

DIGOXIN (Cardiac Glycoside)

Mechanism:

Inhibits Na+/K+-ATPase → ↑ intracellular Na+ → less Ca2+ expelled by NCX → ↑ intracellular Ca2+ → positive inotropy
↑ vagal tone (parasympathomimetic) → ↓ HR (negative chronotropy), ↓ AV conduction (negative dromotropy)

Uses: HFrEF (↓ hospitalizations but no mortality benefit), Atrial fibrillation/flutter (rate control)

Pharmacokinetics:

Narrow therapeutic index: therapeutic range 0.5-0.9 ng/mL (toxicity >2 ng/mL)
Primarily renal excretion - dose reduce in renal failure
Long half-life ~36-48 hours
Distribution affected by lean body mass (use LBM for dosing, not total weight)

Toxicity - classic features:

GI: Nausea, vomiting, anorexia (earliest signs)
CNS: Visual disturbances (yellow-green halos, blurry vision), confusion
Cardiac: Premature ventricular contractions (PVCs), bigeminy, AV block, atrial tachycardia with AV block (pathognomonic), ventricular tachycardia/fibrillation

Factors that PRECIPITATE toxicity (↑ sensitivity):

Hypokalemia (most important - K+ competes with digoxin at Na/K-ATPase)
Hypomagnesemia, hypercalcemia
Hypothyroidism, hypoxia, renal failure
Drugs: verapamil, amiodarone, quinidine (all ↑ digoxin levels)

Treatment of toxicity:

Correct electrolytes (K+, Mg2+)
Lidocaine or phenytoin for arrhythmias
Digoxin-specific antibody fragments (Digibind/DigiFab) - definitive treatment

ACE INHIBITORS (ACEIs)

Drugs: Enalapril, Lisinopril, Captopril, Ramipril, Perindopril, Fosinopril

Mechanism: Inhibit Angiotensin Converting Enzyme (ACE/kininase II) → ↓ Angiotensin II → ↓ AT1 receptor stimulation + ↓ bradykinin breakdown

Effects in HF:

↓ Angiotensin II → ↓ aldosterone → ↓ Na+ retention → ↓ preload
Vasodilation → ↓ afterload
↓ ventricular remodeling → mortality benefit
↑ bradykinin → cough (most common SE), angioedema

First-line in HFrEF - proven mortality benefit (Consensus, SOLVD trials)

Key Adverse Effects:

Effect	Mechanism
Dry cough (10-20%)	↑ bradykinin (if intolerable → switch to ARB)
Angioedema	↑ bradykinin (switch to ARB - but ARB can also rarely cause it; if both fail → use sacubitril-valsartan)
Hyperkalemia	↓ aldosterone
First-dose hypotension	Especially with volume depletion
Renal failure	Bilateral renal artery stenosis (CONTRAINDICATION) - efferent arteriole dilation → ↓ GFR

Absolute Contraindications: Pregnancy (Category D/X - fetotoxic), bilateral RAS, angioedema history

Note: Captopril has extra SH group → causes taste disturbances, neutropenia, proteinuria

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

Drugs: Losartan, Valsartan, Candesartan, Olmesartan, Irbesartan, Telmisartan

Mechanism: Block AT1 receptors (more complete Ang II blockade than ACEIs - also blocks Ang II from non-ACE pathways like chymase)

Key differences from ACEIs:

Do NOT inhibit bradykinin breakdown → NO cough (first choice if ACEI cough)
But angioedema can still rarely occur
Losartan is uricosuric (unique among ARBs - useful in gout + HTN)
Same renal and K+ effects as ACEIs

Use in HF: Same as ACEIs - used when ACEI not tolerated. Candesartan, valsartan proven in HF.

ACEI + ARB combination: No longer recommended (doubles hyperkalemia/renal risk without additional mortality benefit)

SACUBITRIL-VALSARTAN (ARNi - Angiotensin Receptor Neprilysin Inhibitor)

Mechanism: Valsartan (ARB) + Sacubitril (neprilysin inhibitor → ↑ natriuretic peptides ANP, BNP, bradykinin)

Landmark trial: PARADIGM-HF - superior to enalapril in reducing CV mortality in HFrEF

Contraindication: Do NOT combine with ACEI (washout 36 hours required; risk of angioedema). Not with history of ACEI-related angioedema.

ALDOSTERONE ANTAGONISTS (in HF)

Drugs: Spironolactone, Eplerenone

Mechanism: Block mineralocorticoid (aldosterone) receptors → ↓ Na+ retention, ↓ K+ excretion, ↓ fibrosis/remodeling

Use: HFrEF (EF <35%) already on ACEI + beta-blocker (RALES, EPHESUS trials)

Spironolactone side effects: Gynecomastia, impotence (anti-androgen effects) - not seen with eplerenone (selective)

Key risk: Hyperkalemia - avoid if K+ >5.0 or CrCl <30

TOPIC 4: Bronchodilators - Beta2-Agonists & Antimuscarinics

BETA2-AGONISTS

Short-Acting Beta2-Agonists (SABAs) Drugs: Albuterol (salbutamol), Levalbuterol, Terbutaline

Mechanism: Stimulate β2 adrenergic receptors → ↑ cAMP → bronchodilation (relaxation of bronchial smooth muscle) + inhibit mast cell degranulation

Use: First-line rescue inhaler in acute asthma; exercise-induced bronchoconstriction

Onset: 5 min; Duration: 4-6 hours

Adverse Effects:

Tachycardia, palpitations (β1 spillover)
Tremor (skeletal muscle β2 activation)
Hypokalemia (↑ K+ entry into cells via Na-K-ATPase stimulation)
Hypoxemia (V/Q mismatch from vasodilation in poorly ventilated areas)

Long-Acting Beta2-Agonists (LABAs) Drugs: Salmeterol, Formoterol, Indacaterol, Vilanterol

Salmeterol: Partial agonist, onset slow (15-20 min) - NOT for acute attack Formoterol: Full agonist, rapid onset (like SABA) - can be used as rescue (SMART strategy) Indacaterol, Vilanterol: Once-daily dosing (COPD)

Black Box Warning (LABAs): ↑ risk of asthma-related death when used as monotherapy. Must always combine with ICS in asthma.

Beta2-agonists in other settings:

Terbutaline/ritodrine: tocolysis (stop premature labor)
Albuterol IV: acute severe hyperkalemia (shifts K+ intracellularly)

ANTIMUSCARINICS (ANTICHOLINERGICS)

Short-Acting (SAMA): Drug: Ipratropium bromide

Mechanism: Blocks M3 muscarinic receptors in bronchial smooth muscle → ↓ bronchoconstriction + ↓ mucus secretion

Properties:

Quaternary ammonium compound → does not cross BBB (no CNS effects)
Minimal systemic absorption when inhaled
Onset: 15-30 min; Duration: 4-6 hours

Use:

COPD first-line (cholinergic tone more important in COPD than asthma)
Acute asthma: combined with albuterol (additive bronchodilation)
Preferred over SABAs in patients with significant cardiac disease

Adverse Effects: Dry mouth, urinary retention, constipation (mild anticholinergic due to minimal systemic absorption)

Long-Acting Antimuscarinics (LAMAs): Drugs: Tiotropium (once daily), Aclidinium, Umeclidinium, Glycopyrronium

Tiotropium: Kinetically selective for M3 (dissociates slowly from M3 but quickly from M2) → once-daily dosing - preferred in COPD maintenance

Use: COPD maintenance (first-line); reduces exacerbations

Combination Inhalers (LABA + LAMA):

Indacaterol/glycopyrronium (Ultibro)
Vilanterol/umeclidinium (Anoro)
Olodaterol/tiotropium (Stiolto)
Superior to either alone in COPD

Methylxanthines (Theophylline/Aminophylline)

Mechanism: PDE inhibitor → ↑ cAMP; adenosine receptor antagonist

Use: Rarely used due to narrow therapeutic index; reserved for refractory COPD/asthma

Toxicity: Seizures, arrhythmias, tremor, nausea. Therapeutic level: 10-20 mcg/mL

TOPIC 5: Inhaled Corticosteroids & Targeted Antibiotics

INHALED CORTICOSTEROIDS (ICS)

Drugs: Beclomethasone, Budesonide, Fluticasone, Ciclesonide, Mometasone, Flunisolide

Mechanism:

Bind glucocorticoid receptor (GR) → GR-ligand complex enters nucleus → binds GRE
↓ transcription of pro-inflammatory cytokines (IL-4, IL-5, IL-13, TNF-α, RANTES)
↓ arachidonic acid release (↓ PLA2) → ↓ prostaglandins, leukotrienes
↓ eosinophil, mast cell, and lymphocyte activity
Restore β2 receptor sensitivity (upregulate β2 receptors)

Clinical use:

Asthma: Cornerstone of persistent asthma (mild, moderate, severe) - reduce airway inflammation, prevent exacerbations. NOT for acute attacks.
COPD: Used with LABA in patients with frequent exacerbations (FEV1 <50%)

Step therapy in asthma (Katzung):

Step 1: SABA alone (mild intermittent)
Step 2: Low-dose ICS + SABA rescue
Step 3: Low-dose ICS + LABA (or medium ICS)
Step 4: Medium/high ICS + LABA
Step 5: Add LAMA, biologics
Step 6: Add oral corticosteroids

Adverse Effects (Local):

Oropharyngeal candidiasis (thrush) - prevented by rinsing mouth after use + spacer
Dysphonia (hoarseness) - vocal cord myopathy

Adverse Effects (Systemic - dose/duration dependent):

Adrenal suppression (high doses), growth retardation in children, osteoporosis, cataracts
Ciclesonide = prodrug (activated in lungs) → less oral deposition → least systemic effects

Key: Always use spacer to reduce oropharyngeal deposition

TARGETED ANTIBIOTICS

(Katzung covers these under specific classes; "targeted" = antibiotics with narrow/specific spectrum or important mechanistic features)

Beta-Lactams

Penicillins - Mechanism: Inhibit transpeptidase (PBP) → prevent cross-linking of peptidoglycan → bacterial cell wall lysis (bactericidal)

Drug	Spectrum	Key Use
Penicillin G/V	Narrow (gram+, spirochetes, anaerobes above diaphragm)	Strep throat, syphilis, gas gangrene
Ampicillin/Amoxicillin	Extended spectrum (+ gram-negatives: H.flu, E.coli, Listeria)	UTI, otitis media, Listeria
Piperacillin-tazobactam	Anti-pseudomonal	Hospital-acquired infections, Pseudomonas
Nafcillin/Oxacillin	Penicillinase-resistant	MSSA (not MRSA)

Cephalosporins: Progressive gram-negative coverage with each generation; 3rd/4th generation for serious gram-negative + CNS infections; Ceftaroline (5th gen) covers MRSA

Carbapenems (Imipenem, Meropenem, Ertapenem): Broadest spectrum; empirical therapy for resistant infections; Imipenem given with cilastatin (inhibits renal dehydropeptidase that degrades imipenem)

Macrolides

Drugs: Azithromycin, Clarithromycin, Erythromycin

Mechanism: Bind 50S ribosome (23S rRNA) → inhibit translocation (bacteriostatic)

Key uses:

Community-acquired pneumonia (atypical organisms: Mycoplasma, Chlamydia, Legionella)
H. pylori (clarithromycin-based triple therapy)
MAC prophylaxis in HIV (azithromycin)

Azithromycin: Longest half-life (5 days) → 5-day course = 10 days of tissue levels; least CYP450 interaction

Erythromycin: Inhibits CYP3A4 (major drug interactions); GI side effects (motilin receptor agonist - used for gastroparesis); IV can cause QT prolongation

Fluoroquinolones

Drugs: Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin

Mechanism: Inhibit DNA gyrase (topoisomerase II) in gram-negatives and topoisomerase IV in gram-positives → bactericidal

Key uses:

Ciprofloxacin: Pseudomonas, gram-negatives, anthrax, traveler's diarrhea
Levofloxacin/Moxifloxacin: "Respiratory quinolones" - CAP (including drug-resistant S. pneumoniae)

Adverse Effects: Tendinopathy/tendon rupture (esp. Achilles), QT prolongation, CNS (seizures in elderly), phototoxicity, cartilage damage (avoid in children/pregnancy), ↑ INR with warfarin

Tetracyclines

Drugs: Doxycycline, Minocycline, Tetracycline

Mechanism: Bind 30S ribosome → inhibit aminoacyl-tRNA binding (bacteriostatic)

Uses: Atypicals (Mycoplasma, Chlamydia, Rickettsia), Lyme disease (doxycycline), malaria prophylaxis, acne, MRSA skin infections (doxycycline), cholera

Adverse Effects: Photosensitivity, GI upset, esophageal ulcers (take with water, upright), teeth discoloration in children <8 years (chelate Ca2+), NOT in pregnancy or children <8

Aminoglycosides

Drugs: Gentamicin, Tobramycin, Amikacin, Streptomycin, Neomycin

Mechanism: Bind 30S ribosome → misreading of mRNA → bactericidal (concentration-dependent)

Uses: Serious gram-negative infections (often synergistic with beta-lactams), TB (streptomycin), endocarditis (synergy)

Adverse Effects: Nephrotoxicity (proximal tubule) and ototoxicity (8th CN - both vestibular and cochlear); neuromuscular blockade; monitor peak and trough levels

Vancomycin

Mechanism: Binds D-Ala-D-Ala terminus of peptidoglycan precursor → inhibits cell wall synthesis (different site from beta-lactams)

Use: MRSA (IV); C. difficile colitis (oral - not absorbed); serious gram-positive infections

Adverse Effects:

"Red Man Syndrome": Flushing, pruritus, hypotension due to histamine release with rapid infusion (not allergic - slow infusion prevents this)
Nephrotoxicity + ototoxicity (monitor trough levels; target AUC/MIC)

TOPIC 6: Insulin, Metformin & Oral Hypoglycemic Agents

INSULIN

Types and Pharmacokinetics:

Preparation	Onset	Peak	Duration	Use
Lispro, Aspart, Glulisine (Rapid-acting analogs)	5-15 min	1-2 h	3-4 h	Mealtime (bolus)
Regular (Human)	30-60 min	2-4 h	5-8 h	Mealtime, DKA (IV)
NPH (Isophane)	1-2 h	4-8 h	12-18 h	Intermediate-acting
Glargine (Lantus)	2-4 h	No peak (flat)	20-24 h	Basal (once daily)
Detemir	1-2 h	Mild peak	12-18 h	Basal
Degludec	1 h	No peak	>42 h	Ultra-long basal

Mechanism: Binds insulin receptor (tyrosine kinase) → receptor autophosphorylation → PI3K/AKT pathway → GLUT4 translocation to cell surface (in muscle, adipose) → glucose uptake

Anabolic effects:

↑ glycogen synthesis, ↑ protein synthesis, ↑ lipogenesis
↓ glycogenolysis, ↓ gluconeogenesis, ↓ lipolysis, ↓ ketogenesis

Adverse Effects:

Hypoglycemia (most common and dangerous) - treat with oral glucose or IV dextrose (D50) or glucagon IM
Lipodystrophy at injection site (rotate sites)
Weight gain
Hypokalemia (insulin drives K+ into cells - use for hyperkalemia)

Key: Only Regular insulin and Insulin aspart can be given IV; Glargine must NOT be mixed with other insulins

METFORMIN (Biguanide)

Mechanism: Activates AMPK (AMP-activated protein kinase) via inhibition of mitochondrial complex I → ↓ hepatic gluconeogenesis (primary mechanism), ↓ glycogenolysis, modest ↑ peripheral glucose uptake, ↓ intestinal glucose absorption

Key properties:

Does NOT cause hypoglycemia (euglycemic only - requires endogenous insulin)
Weight neutral or weight loss
Reduces cardiovascular mortality (UKPDS trial) - first-line in T2DM
No effect on insulin secretion

Adverse Effects:

GI (most common): Nausea, diarrhea, metallic taste - start low, take with food, extended-release better tolerated
Lactic acidosis (rare but life-threatening) - risk ↑ with renal failure, hepatic failure, alcoholism, tissue hypoxia. Hold before IV contrast and surgery
Vitamin B12 deficiency (↓ IF-B12 complex absorption in terminal ileum) - monitor B12 levels
No hypoglycemia

Contraindications: eGFR <30 (hold if <45), hepatic failure, alcoholism, heart failure (relative)

Exam tip: Metformin is the only biguanide in clinical use (phenformin withdrawn due to lactic acidosis)

ORAL HYPOGLYCEMIC AGENTS

Sulfonylureas (Insulin Secretagogues)

Drugs:

1st gen: Chlorpropamide, Tolbutamide
2nd gen: Glipizide, Glyburide (Glibenclamide), Glimepiride

Mechanism: Block ATP-sensitive K+ channels (KATP) on beta-cell membrane → membrane depolarization → Ca2+ influx → insulin secretion (requires functioning beta cells)

Adverse Effects:

Hypoglycemia (most significant, especially glyburide in elderly and renal failure)
Weight gain (↑ insulin secretion)
Disulfiram reaction with alcohol (chlorpropamide, especially)
SIADH/hyponatremia (chlorpropamide)

Glyburide vs. Glipizide: Glyburide has active metabolites → accumulates in renal failure → hypoglycemia. Glimepiride safer in mild renal impairment.

Meglitinides (Glinides)

Drugs: Repaglinide, Nateglinide

Mechanism: Also block KATP channels but at different binding site; shorter duration than sulfonylureas - taken with each meal (prandial insulin secretagogues)

Adverse Effects: Hypoglycemia, weight gain (less than sulfonylureas); useful in patients with irregular meal schedules

GLP-1 Receptor Agonists (Incretin Mimetics)

Drugs: Exenatide, Liraglutide, Semaglutide, Dulaglutide, Albiglutide, Tirzepatide (GLP-1 + GIP)

Mechanism: Stimulate GLP-1 receptors → ↑ glucose-dependent insulin secretion (only when glucose elevated) + ↓ glucagon + ↓ gastric emptying + ↑ satiety → weight loss

Key advantages:

Weight loss (liraglutide, semaglutide: 5-15%)
Cardiovascular benefit: Liraglutide (LEADER trial), semaglutide (SUSTAIN-6) reduce MACE in T2DM with CVD
Low hypoglycemia risk

Adverse Effects: Nausea/vomiting, diarrhea (GI most common); pancreatitis risk; thyroid C-cell tumors in rodents → contraindicated in personal/family history of MTC or MEN2; injection site reactions

DPP-4 Inhibitors (Gliptins)

Drugs: Sitagliptin, Saxagliptin, Alogliptin, Linagliptin

Mechanism: Inhibit DPP-4 (dipeptidyl peptidase-4) → ↑ endogenous GLP-1 and GIP half-life → glucose-dependent insulin secretion; weight neutral

Adverse Effects: Nasopharyngitis, pancreatitis (rare but class effect with incretin therapy), joint pain; Saxagliptin: ↑ HF hospitalizations (avoid in HF)

Linagliptin: Excreted in bile (no renal adjustment needed)

SGLT-2 Inhibitors (Gliflozins)

Drugs: Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

Mechanism: Inhibit SGLT-2 (sodium-glucose cotransporter-2) in proximal tubule → ↓ renal glucose reabsorption → glucosuria → ↓ blood glucose

Remarkable benefits beyond glucose lowering:

Cardiovascular: Empagliflozin (EMPA-REG OUTCOME) - ↓ CV death and HF hospitalizations in T2DM + CVD
HF benefit: Dapagliflozin (DAPA-HF) + empagliflozin (EMPEROR-Reduced) - ↓ HF hospitalizations regardless of EF or diabetes status
Renal protection: ↓ progression of diabetic nephropathy (tubuloglomerular feedback via ↓ Na+ delivery)
Weight loss (caloric loss via glucosuria), ↓ BP

Adverse Effects:

Genital mycotic infections (glucosuria → fungal growth) - most common
UTIs
DKA (euglycemic DKA - even in T2DM with glucose <300; hold before surgery)
Fournier's gangrene (necrotizing fasciitis of perineum) - rare but serious
Lower limb amputations (canagliflozin - CANVAS trial)
Bone fractures (canagliflozin)
Polyuria, volume depletion

Thiazolidinediones (TZDs / Glitazones)

Drugs: Pioglitazone, Rosiglitazone

Mechanism: Activate PPAR-γ (peroxisome proliferator-activated receptor gamma) → ↑ adipogenesis, ↑ GLUT4 expression → ↓ insulin resistance; require endogenous insulin

Adverse Effects:

Weight gain (fluid retention + adipogenesis)
Edema, heart failure (fluid retention - CONTRAINDICATED in HF class III-IV)
Osteoporosis/fractures (especially in women)
Hepatotoxicity (troglitazone withdrawn from market)
Rosiglitazone: ↑ MI risk (restricted use); Pioglitazone: may ↑ bladder cancer risk

Alpha-Glucosidase Inhibitors

Drugs: Acarbose, Miglitol

Mechanism: Inhibit intestinal alpha-glucosidase → ↓ carbohydrate digestion → ↓ postprandial glucose spikes

Adverse Effects: GI (flatulence, bloating, diarrhea - common) due to fermentation of undigested carbohydrates

Key: If hypoglycemia occurs (unlikely with monotherapy; possible if combined), must treat with glucose (dextrose), NOT sucrose (sucrose digestion also impaired)

TOPIC 7: Thyroid Hormones, Antithyroid Drugs & Steroids

THYROID HORMONES

Physiology:

Thyroid gland secretes T4 (thyroxine, ~80%) and T3 (triiodothyronine, ~20%)
T4 is largely inactive; converted peripherally to active T3 by deiodinases (type I in liver/kidney, type II in brain/pituitary)
T3 is 4x more potent than T4

Drugs: Levothyroxine (T4), Liothyronine (T3), Liotrix (T3+T4 combo)

Levothyroxine:

Drug of choice for hypothyroidism
Once daily (long half-life ~7 days)
Narrow therapeutic window - monitor TSH (goal TSH 0.5-2.5 mIU/L)
Take on empty stomach (absorption affected by Ca2+, Fe2+, antacids, cholestyramine)
Excess → iatrogenic hyperthyroidism, osteoporosis, AF

Mechanism of T3: Enters nucleus → binds thyroid hormone receptor → regulates gene transcription → ↑ basal metabolic rate, protein synthesis, carbohydrate/lipid metabolism, thermogenesis, adrenergic sensitivity (↑ β-adrenergic receptors)

ANTITHYROID DRUGS

Thioamides

Drugs: Methimazole (MMI), Propylthiouracil (PTU)

Mechanism:

Both: Inhibit thyroid peroxidase (TPO) → ↓ organification and coupling (↓ T3/T4 synthesis)
PTU additionally: Inhibits peripheral conversion of T4 → T3 (Type I deiodinase); also useful in thyroid storm

Key differences:

Feature	Methimazole	PTU
Potency	~10x more potent	Less potent
Dosing	Once daily	3x daily
Onset	Slower	Faster
Crosses placenta	More	Less
Preferred in pregnancy	2nd & 3rd trimester	1st trimester (MMI - aplasia cutis, choanal atresia)
Thyroid storm	Less preferred	Drug of choice
Hepatotoxicity	Cholestatic	Fulminant - rare but fatal (especially in children)
Agranulocytosis	Yes (more common)	Yes

Adverse Effects (both):

Agranulocytosis (0.5%) - monitor WBC; tell patients to report sore throat/fever immediately
Rash, urticaria
Hepatotoxicity (PTU > MMI for severe)
Hypothyroidism (overdose)
ANCA-positive vasculitis (PTU especially)

Radioiodine (I-131)

Taken up by thyroid → beta-emitter → destroys thyroid follicular cells
Treatment of choice for Graves' disease (in non-pregnant adults) and thyroid cancer
Contraindicated in pregnancy and breastfeeding
Risk of post-treatment hypothyroidism (often intentional)
Pretreat with antithyroid drugs to normalize thyroid before I-131 (then stop PTU 5-7 days before as it may reduce uptake)

Iodine Solutions (Lugol's Solution, SSKI - Saturated KI)

Mechanism: High-dose iodine → Wolff-Chaikoff effect (↓ organification) + ↓ thyroid vascularity + inhibit release of T3/T4

Uses:

Pre-operative preparation for thyroidectomy (3-10 days prior; reduces vascularity and bleeding)
Thyroid storm (given after antithyroid drugs to prevent further hormone synthesis)
Radiation emergency (stable KI to block radioiodine uptake)

Thyroid Storm Management (Katzung high-yield)

Order of drugs: PTU (block synthesis + conversion) → then Iodine (block release) → Beta-blocker (propranolol) (↓ adrenergic symptoms + ↓ T4→T3 conversion) → Glucocorticoids (↓ T4→T3 conversion, ↓ adrenal crisis)

CORTICOSTEROIDS (GLUCOCORTICOIDS & MINERALOCORTICOIDS)

Glucocorticoids

Drugs: Hydrocortisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Budesonide (topical/inhaled), Beclomethasone

Mechanism:

Bind cytosolic glucocorticoid receptor (GR) → GR-ligand complex translocates to nucleus
Transactivation: ↑ anti-inflammatory proteins (lipocortin/annexin-1 → ↓ PLA2 → ↓ arachidonic acid → ↓ prostaglandins, leukotrienes)
Transrepression: ↓ NF-κB and AP-1 → ↓ pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, interferon)
↓ Eosinophils, T-lymphocytes, mast cells; ↑ neutrophils (demargination)

Relative potencies (anti-inflammatory vs. mineralocorticoid):

Drug	Anti-inflammatory	Mineralocorticoid	Duration
Hydrocortisone	1 (reference)	1	Short (8-12h)
Prednisolone	4	0.8	Intermediate (12-36h)
Methylprednisolone	5	0.5	Intermediate
Dexamethasone	25	~0	Long (36-54h)
Aldosterone	0.3	3000	-
Fludrocortisone	10	125	Intermediate

Key uses:

Addison's disease (primary adrenal insufficiency): Hydrocortisone + fludrocortisone
Asthma (inhaled/systemic)
Organ transplant rejection (immunosuppression)
Cerebral edema: Dexamethasone (no mineralocorticoid activity → no fluid retention; crosses BBB)
Antenatal lung maturity (betamethasone - best crosses placenta)
Autoimmune diseases (SLE, RA, IBD)
Septic shock: Hydrocortisone (if vasopressor-dependent)
Thyroid storm: reduces peripheral conversion and possible adrenal insufficiency

Adverse Effects (chronic use):

System	Effects
Metabolic	Hyperglycemia, dyslipidemia, weight gain, central obesity
Cushingnoid	Moon face, buffalo hump, striae, thin skin
Bone	Osteoporosis (↓ osteoblasts, ↑ osteoclasts, ↓ Ca2+ absorption) - prevent with bisphosphonates + Ca/Vit D
Immune	Infections (reactivation of TB, fungi), ↓ wound healing
GI	Peptic ulcer (especially with NSAIDs)
CNS	Euphoria, psychosis, insomnia
Adrenal suppression	With >2 weeks of use → taper dose; do not stop abruptly → adrenal crisis
Eye	Posterior subcapsular cataracts, glaucoma
Growth	Growth retardation in children
HPA axis	Morning cortisol ↓, ACTH ↓ (negative feedback)

Mineralocorticoids:

Fludrocortisone: Synthetic; potent mineralocorticoid; used in Addison's disease, orthostatic hypotension, Type IV RTA (hypoaldosteronism)
Aldosterone: Physiological; primary hyperaldosteronism (Conn's syndrome)

TOPIC 8: Diuretics - Loop & Thiazide

LOOP DIURETICS

Drugs: Furosemide, Ethacrynic acid, Bumetanide, Torsemide

Site of Action: Thick ascending limb (TAL) of Loop of Henle

Mechanism: Inhibit Na+/K+/2Cl- (NKCC2) cotransporter on apical membrane of TAL cells → ↓ Na+ reabsorption → most potent diuresis ("ceiling diuretics" - have dose-response curve without ceiling)

Pharmacokinetics:

Furosemide: IV onset 5 min; oral onset 30-60 min
Torsemide: better oral bioavailability than furosemide; longer duration
Bumetanide: most potent by weight (1 mg = 40 mg furosemide)

Clinical uses:

Acute pulmonary edema (first-line IV furosemide - venodilation within minutes before diuresis)
Chronic heart failure (edema management)
Hypertension (less commonly)
Hypercalcemia (promote Ca2+ excretion - "dilute and flush")
Hyperkalemia (enhance K+ excretion)
Edema of renal or hepatic origin
Ethacrynic acid: only loop diuretic for sulfa-allergic patients (not a sulfonamide)

Adverse Effects:

Effect	Mechanism
Hypokalemia	↑ K+ delivery to collecting duct → ↑ aldosterone-driven K+ secretion
Hyponatremia, Hypomagnesemia, Hypocalcemia	↑ excretion of Na+, Mg2+, Ca2+
Metabolic alkalosis	H+ loss + contraction alkalosis
Hypovolemia/dehydration	Excess diuresis
Ototoxicity	High doses, especially with aminoglycosides (additive)
Hyperuricemia	Competes with urate for secretion; precipitates gout
Hyperlipidemia	Mild
Hyperglycemia	↓ insulin secretion (mild)
Sulfa allergy	Furosemide, bumetanide, torsemide (all sulfa derivatives)

Drug interactions:

Aminoglycosides: Additive ototoxicity and nephrotoxicity
NSAIDs: ↓ diuretic effect (↓ prostaglandin-mediated renal vasodilation)
Lithium: ↑ lithium toxicity (volume depletion → compensatory ↑ Li reabsorption)

THIAZIDE DIURETICS

Drugs: Hydrochlorothiazide (HCTZ), Chlorthalidone, Metolazone, Indapamide

Site of Action: Early distal convoluted tubule (DCT)

Mechanism: Inhibit Na+/Cl- (NCC) cotransporter → ↓ Na+ and Cl- reabsorption → modest diuresis (less potent than loops)

Chlorthalidone: Longer half-life (45-60h) than HCTZ; preferred in hypertension (JNC guidelines favor over HCTZ); also reduces stone formation

Clinical uses:

Hypertension (first-line diuretic for uncomplicated HTN)
Mild heart failure/edema
Nephrogenic diabetes insipidus - paradoxically reduces urine output (volume contraction → ↑ proximal tubule Na+ absorption → ↓ water delivery to collecting duct)
Calcium nephrolithiasis - ↑ Ca2+ reabsorption in DCT → ↓ urinary Ca2+ → ↓ stone formation
Osteoporosis prevention (↑ bone Ca2+)
Hypercalciuria

Adverse Effects:

Effect	Mechanism
Hypokalemia	↑ Na+ delivery to collecting duct → aldosterone-driven K+ loss
Hyponatremia	↓ free water excretion (unlike loops, thiazides impair diluting ability but preserve concentrating ability)
Hyperuricemia	Competes with urate secretion in proximal tubule
Hyperglycemia	↓ insulin secretion + ↓ insulin sensitivity
Hyperlipidemia	↑ LDL, TG (mild)
Hypercalcemia	↑ Ca2+ reabsorption in DCT (↑ Ca2+ : Na+ exchange)
Metabolic alkalosis	H+ and K+ loss
Sulfa cross-reactivity	All thiazides are sulfonamide derivatives

Key contrast: Loops vs. Thiazides on Ca2+:

Loop diuretics → HYPOcalcemia (↓ Ca2+ reabsorption at TAL) → used for hypercalcemia
Thiazides → HYPERcalcemia (↑ Ca2+ reabsorption at DCT) → used for hypercalciuria/nephrolithiasis

Potassium-Sparing Diuretics (Bonus - often tested with loops/thiazides)

Drugs:

Spironolactone, Eplerenone - Aldosterone receptor antagonists (see also HF section)
Triamterene, Amiloride - Block ENaC (epithelial Na+ channels) in collecting duct

Mechanism: ↓ Na+ reabsorption at collecting duct without K+ loss

Use: Combined with loop/thiazide to prevent hypokalemia; HF, hyperaldosteronism

Key adverse effect: HYPERKALEMIA (↑↑ risk if combined with ACEI/ARB or NSAIDs)

Triamterene: kidney stones (triamterene crystalluria)
Spironolactone: gynecomastia, menstrual irregularities (anti-androgenic)
Amiloride: used in Liddle syndrome (gain-of-function ENaC mutation)

Carbonic Anhydrase Inhibitors:

Acetazolamide - inhibits CA in PCT → ↓ HCO3- reabsorption → metabolic acidosis, alkaline urine
Use: Glaucoma (↓ aqueous humor), altitude sickness (↓ CSF production), metabolic alkalosis correction, epilepsy (adjunct)
Causes hyperchloremic metabolic acidosis (non-anion gap)

QUICK REFERENCE: KEY HIGH-YIELD COMPARISONS

Question	Answer
Only DOAC reversible by dialysis	Dabigatran
Anticoagulant of choice in HIT	Argatroban (hepatically cleared)
Anticoagulant in pregnancy	LMWH (enoxaparin)
Antidote to warfarin (fastest)	4-factor PCC
Antidote to dabigatran	Idarucizumab
Antidote to Xa inhibitors	Andexanet alfa
Statin safest in transplant	Pravastatin (no CYP metabolism)
Statin contraindicated in pregnancy	ALL statins (Category X)
CCB for vasospastic angina	Any CCB (all work; verapamil/diltiazem also ↓ HR)
CCB safe in HFrEF	Amlodipine, Felodipine (not verapamil/diltiazem)
Nitrate + which drug = dangerous	PDE-5 inhibitors (sildenafil)
Drug of choice for Graves in 1st trimester	PTU
Drug of choice for thyroid storm	PTU
Thyroid prep before surgery	Lugol's iodine
Best to raise HDL	Niacin
Best for hypertriglyceridemia	Fibrates
Metformin contraindicated when	eGFR <30; contrast study; surgery
SGLT-2 benefit in HF	Reduces hospitalizations (even without DM)
Loop vs. thiazide on calcium	Loop ↓ Ca2+ (hypocalcemia); Thiazide ↑ Ca2+ (hypercalcemia)
Thiazide for nephrogenic DI	Yes (paradoxical - volume contraction)
Furosemide for sulfa allergy	Use Ethacrynic acid instead
Inhaled steroid causing least systemic effects	Ciclesonide (prodrug, lung-activated)
Oropharyngeal candidiasis prevention with ICS	Rinse mouth + spacer
Digoxin toxicity precipitated by	Hypokalemia (most important)
Digoxin antidote	Digibind (digoxin-specific Ab fragments)
ACEI cough - switch to	ARB
ACEIs contraindicated in	Pregnancy, bilateral RAS, angioedema history

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition (ISBN 9781260463309); supplemented by Goodman & Gilman's Pharmacological Basis of Therapeutics

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