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💊 Diuretics — Complete Pharmacology

🔑 Definition

"Most diuretics act on the luminal membrane from within the renal tubules — secreted by the proximal tubule via the organic anion pump." — Morgan & Mikhail's Clinical Anesthesiology

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🗺️ Sites of Action — Nephron Diagram

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📚 Classification (5 Major Classes)

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1️⃣ OSMOTIC DIURETICS (Mannitol)

Mechanism

• Glomerulus mein filter hota hai, reabsorb nahi hota
• Tubule lumen mein osmotically active rehta hai
• Water passive reabsorption block karta hai (jahan Na⁺ reabsorb hota hai, wahan paani follow nahi kar paata)
• Large doses mein electrolyte excretion bhi badhata hai

Extra Benefits of Mannitol

• Renal blood flow (RBF) badhata hai
• Vasodilating prostaglandins synthesize karta hai
• Free radical scavenger bhi hai

Dose

• IV: 0.25 to 1 g/kg

Uses

⚠️ Note

High-dose mannitol nephrotoxic ho sakta hai — especially impaired kidney function mein. AKI se protection ka koi strong clinical evidence nahi hai.

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2️⃣ CARBONIC ANHYDRASE INHIBITORS (Acetazolamide)

Mechanism

• Proximal tubule mein NaHCO₃ reabsorption block karta hai
• Carbonic anhydrase enzyme inhibit → H⁺ kam banta hai → Na⁺/H⁺ exchange kam hota hai
• Weak diuretic — because loop of Henle compensate kar leta hai

Uses

Side Effects

• Hyperchloremic metabolic acidosis
• Hypokalemia (severe)
• Drowsiness, paresthesias (large doses)
• Topical forms: Dorzolamide, Brinzolamide (glaucoma ke liye)

Dose

• IV: 250–500 mg (acetazolamide)

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3️⃣ LOOP DIURETICS ⭐ (Most Potent)

Drugs

Mechanism

• Thick ascending limb of Loop of Henle pe kaam karta hai
• Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) ko block karta hai — Cl⁻ ke liye compete karta hai
• Sodium excretion upto 20–25% of filtered load (sabse zyada!)
• Free water clearance enhance karta hai
• Medullary hypertonicity destroy karta hai → concentrating ability impair

Extra Hemodynamic Effect

• IV furosemide venodilator hai — within minutes right atrial pressure aur PCWP girta hai
• Prostaglandins release se — NSAIDs se block ho sakta hai
• Acute SVR rise bhi ho sakta hai (RAAS activation se)

Drugs Are Secreted

• Protein-bound hain → filtration limited
• Proximal tubule se OAT1, OAT2 (organic anion transporters) via secreted hote hain
• CKD mein: tubular secretion slow → zyada dose chahiye

Uses

DOSE Trial (Important!)

• 2×2 factorial design — bolus vs continuous infusion, low vs high dose
• High dose → better dyspnea relief, more fluid loss (but transient creatinine rise)
• Bolus vs infusion → no significant difference

Side Effects

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4️⃣ THIAZIDE & THIAZIDE-LIKE DIURETICS

Drugs

• Thiazides: Hydrochlorothiazide (HCTZ), Chlorothiazide
• Thiazide-like: Chlorthalidone, Metolazone, Quinethazone, Indapamide

Mechanism

• Distal convoluted tubule (DCT) + connecting segment pe kaam karta hai
• Na⁺-Cl⁻ cotransporter ko block karta hai (Cl⁻ site pe compete karta hai)
• Na⁺ excretion sirf 3–5% of filtered load (loop se kam)
• Diluting capacity impair karta hai, but concentrating capacity normal rehti hai
• Ca²⁺ reabsorption BADHATA hai (DCT mein) ← loop diuretic se OPPOSITE!
• Carbonic anhydrase inhibition bhi hoti hai (proximal tubule mein) — but usually masked

Special Property of Indapamide

• Vasodilating properties bhi hain
• Significant hepatic excretion — sirf iska yeh property hai

Uses

⚠️ Limitation

• GFR < 30–40 mL/min mein ineffective ho jaate hain
• Exception: Metolazone — GFR 20–30 mL/min tak kaam karta hai

Side Effects

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5️⃣ POTASSIUM-SPARING DIURETICS

Two Sub-Types:

A) Aldosterone Antagonists

• Spironolactone aur Eplerenone
• Late DCT + Collecting duct mein aldosterone receptor block karte hain
• Aldosterone kam kaam karta hai → Na⁺ reabsorption kam → K⁺ bacha rehta hai
• Cardiac remodeling improve karte hain systolic HF mein ← extra benefit!

B) ENaC Blockers

• Amiloride aur Triamterene
• Late DCT + Collecting duct mein epithelial Na⁺ channel (ENaC) block karte hain
• Direct — aldosterone-independent
• K⁺ exchange nahi hota → potassium retain hota hai

Uses

Side Effects

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🔄 Diuretic Synergism

Loop + Thiazide/Metolazone combination — sequential nephron blockade → synergistic natriuresis

• Loop diuretic se jo Na⁺ bachta hai, DCT mein reabsorb hota hai
• Thiazide add karo → DCT bhi block → double blockade
• Metolazone is preferred because works even in CKD

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⚠️ DIURETIC RESISTANCE

Algorithm:

Common Causes:

Steps to Overcome:

1. Check for correctable causes first
2. Measure 24-hr urinary Na⁺
3. Double the daily dose (max: Furosemide 240 mg, Bumetanide 10 mg, Torsemide 200 mg)
4. Add DCT diuretic (thiazide/metolazone)
5. IV or continuous infusion — last resort

Quick Test:

FENa >2% (1–2 hr after diuretic) → true resistance unlikely — NKF Primer on Kidney Diseases

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💉 Special Note: SGLT2 Inhibitors (Modern "Diuretics")

• Empagliflozin, Dapagliflozin — SGLT2 block → glucose + Na⁺ excretion
• Proximal tubule mein 1:1 stoichiometric Na⁺ + glucose inhibition
• Volume contraction → modest BP lowering
• Tubuloglomerular feedback → afferent arteriole vasoconstriction → glomerular hyperfiltration kam
• HFrEF mein significant mortality benefit (EMPEROR-Reduced, DAPA-HF)

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📊 Quick Comparison Table

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🎯 High-Yield Points (Exam ke liye)

1. Most potent diuretic → Loop diuretics (furosemide)
2. First-line for hypertension → Thiazides
3. Ototoxicity → Loop diuretics (esp. ethacrynic acid > furosemide)
4. Hypercalciuria treatment → Thiazides (Ca²⁺ reabsorption badhate hain)
5. Hypercalcemia treatment → Furosemide + IV saline
6. Nephrogenic DI → Thiazides (paradoxical)
7. Gynecomastia → Spironolactone
8. Glaucoma + altitude sickness → Acetazolamide
9. Mortality benefit in HFrEF → Spironolactone (RALES), Eplerenone (EMPHASIS)
10. Mannitol → ICP kam karta hai, NOT kidney protection

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💊 Antihypertensive Drugs — Complete Pharmacology

🔑 Definition

Antihypertensive drugs ya toh CO kam karte hain, ya PVR kam karte hain, ya dono.

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🗺️ Sites of Action — Master Diagram

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📚 CLASSIFICATION (4 Major Groups)

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1️⃣ DIURETICS (Antihypertensive mechanism)

Mechanism in Hypertension

• Initial effect: Blood volume kam → Cardiac output kam → BP kam
• After 6-8 weeks: CO normal ho jaata hai, lekin PVR kam ho jaata hai
• Sodium vessel stiffness badhata hai → Na restriction se vessel reactivity kam hoti hai

BP lowering capacity

Diuretics akele 10-15 mmHg BP kam kar sakte hain

Drug of Choice for HTN

• Thiazides = First-line for uncomplicated hypertension
• Thiazide-like (Chlorthalidone, Indapamide) = preferred due to longer half-life
• Metolazone = CKD mein bhi kaam karta hai (GFR 20-30 mL/min tak)

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2️⃣ RAAS BLOCKERS ⭐ (Most important group)

RAAS Pathway (Samajhna zaroori hai):

Angiotensinogen
      ↓ (Renin) ← Aliskiren block karta hai
Angiotensin I
      ↓ (ACE) ← ACE Inhibitors block karte hain
Angiotensin II ← ARBs receptor level pe block karte hain
      ↓
Aldosterone → Na+ retention → BP ↑
      ↓
Vasoconstriction → PVR ↑ → BP ↑

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A) ACE INHIBITORS

Mechanism (Double Action):

1. ACE block → Angiotensin II nahi banta → Vasodilation, Aldosterone kam
2. Bradykinin inactivation nahi hoti → Bradykinin accumulate → Vasodilation (NO + Prostacyclin se)

Important Pharmacokinetics:

• Captopril = Direct active drug
• Enalapril = Prodrug → Liver mein Enalaprilat banta hai (IV form = Enalaprilat)
• Lisinopril = Lysine derivative of Enalaprilat (NOT a prodrug)
• Most others = Prodrugs, hepatic conversion

Hemodynamic Effect:

• PVR kam karta hai
• CO aur HR significant change nahi hoti
• No reflex tachycardia ← because baroreceptor resetting hoti hai (vasodilators se alag!)

Uses:

Side Effects (IMPORTANT!):

Drug Interactions:

• NSAIDs → prostaglandin-mediated vasodilation block → efficacy kam
• K⁺ sparing diuretics → Hyperkalemia risk
• ACE + ARB combination = NOT recommended (toxicity)

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B) ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

Mechanism:

• AT1 receptor ko competitive block karte hain
• ACE inhibitors se zyada selective (bradykinin metabolism affect nahi karte)
• Angiotensin II ke sab sources ko block karte hain (ACE ke alawa bhi enzymes hain)

ARBs vs ACE inhibitors:

Note: Valsartan + Sacubitril (Neprilysin inhibitor) = ARNI (Entresto) → HF treatment mein use hota hai

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C) ALISKIREN (Direct Renin Inhibitor)

• RAAS ka pehla step (Renin) block karta hai
• Oral bioavailability
• ACE/ARB ke saath combination = avoid (toxicity in trials)

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3️⃣ SYMPATHOPLEGIC DRUGS

Why Needed?

• BP badhane mein sympathetic system major role play karta hai
• Lekin ek important limitation: Sodium retain karne lagte hain → diuretic ke saath use karna chahiye

Compensatory response diagram:

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A) BETA-BLOCKERS (β-Blockers)

• Non-selective: Propranolol, Nadolol, Timolol, Carvedilol (α+β)
• Cardioselective (β1): Metoprolol, Atenolol, Bisoprolol, Esmolol
• Vasodilating β1-blocker: Nebivolol (β1 block + NO release)

Mechanism (Multiple):

1. Heart mein β1 block → Heart rate ↓ + Contractility ↓ → CO ↓ → BP ↓
2. Kidney mein β1 block (JGA cells) → Renin release ↓ → Angiotensin II ↓ → BP ↓
3. CNS mein sympathetic outflow ↓
4. Baroreceptor sensitivity reset

Uses in HTN:

Side Effects:

Contraindications:

• Asthma (non-selective)
• Bradycardia / 2nd-3rd degree heart block
• Severe peripheral vascular disease
• Acute decompensated HF

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B) ALPHA-1 BLOCKERS (α1-Blockers)

Mechanism:

• Vascular smooth muscle ke α1 receptors block → Arteriolar + venous dilation → PVR ↓ → BP ↓
• Reflex tachycardia ho sakti hai

Uses:

• HTN with BPH (best choice — symptoms bhi theek ho jaate hain)
• Pheochromocytoma (Phenoxybenzamine — non-selective)

Side Effect — "First Dose Effect"

Prazosin ki pehli dose mein severe postural hypotension + syncope ho sakti hai Solution: Bedtime pe low dose se start karein

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C) CENTRAL SYMPATHOLYTICS

Methyldopa

• L-dopa analog → α-methyldopamine → α-methylnorepinephrine banta hai
• False transmitter — vasomotor centers mein sympathetic outflow ↓ karta hai
• Drug of choice in PREGNANCY-induced hypertension ⭐
• Side effects: Sedation, hepatotoxicity, hemolytic anemia, positive Coombs test

Clonidine

• α2 agonist → Brainstem vasomotor center → Sympathetic outflow ↓
• Uses: HTN, opioid withdrawal, ADHD
• Withdrawal = Rebound hypertension (abruptly band mat karo!)
• Side effects: Sedation, dry mouth

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4️⃣ VASODILATORS

A) CALCIUM CHANNEL BLOCKERS (CCBs) ⭐

Mechanism:

• Vascular smooth muscle + Cardiac cells mein L-type Ca²⁺ channels block
• Ca²⁺ entry kam → Smooth muscle relaxation → Vasodilation → PVR ↓ → BP ↓
• DHP mainly arteriolar dilation
• Verapamil + Diltiazem = Heart rate bhi slow karte hain (AV node effect)

Uses:

Side Effects:

Verapamil + Beta-blocker = Dangerous combination → Complete heart block ka risk!

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B) HYDRALAZINE

Mechanism:

• Arterioles dilate karta hai, veins nahi
• Nitric oxide release → Guanylyl cyclase activate → cGMP ↑ → Smooth muscle relax

Important Points:

• Oral bioavailability 25% only (high first-pass metabolism)
• Slow vs Fast acetylators mein different response
• Reflex tachycardia + Na/water retention hoti hai → Beta-blocker + Diuretic ke saath use karo
• Uses: Pregnancy HTN (IV), Severe HTN, HF (Hydralazine + Isosorbide dinitrate)

Side Effects:

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C) MINOXIDIL

Mechanism:

• K⁺ channels open karta hai → Cell hyperpolarize → Ca²⁺ entry kam → Vasodilation
• Most potent oral vasodilator — severe/resistant HTN mein

Must Use With:

• Beta-blocker (reflex tachycardia rokne ke liye)
• Diuretic (Na/water retention rokne ke liye)

Side Effects:

• Hypertrichosis (har jagah baal ugna) ⭐ — Topical minoxidil = Rogaine (baldness treatment!)
• Tachycardia, edema, angina

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D) SODIUM NITROPRUSSIDE (IV — Emergency)

Mechanism:

• Arteries + Veins dono dilate karta hai (unique!)
• NO release → cGMP ↑ → Smooth muscle relax

Important Facts:

• Hypertensive Emergency drug of choice in most situations
• Onset: Immediate, Duration: 1-10 minutes after stopping
• Route: IV infusion only
• Light sensitive → Opaque foil se cover karo
• Fresh solution banana padta hai

Dose:

• Start: 0.5 mcg/kg/min
• Max: 10 mcg/kg/min

Toxicity:

• Cyanide toxicity — Nitroprusside → RBC mein NO + Cyanide release
• Cyanide → Rhodanese enzyme → Thiocyanate (less toxic)
• Thiocyanate accumulation → Nausea, confusion, hypothyroidism (renal failure mein zyada risk)

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E) FENOLDOPAM (IV — Emergency)

• Dopamine D1 receptor agonist
• Vasodilation + Renal blood flow badhata hai (unique advantage)
• HTN emergency mein — especially renal function preserve karna ho

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🚨 HYPERTENSIVE EMERGENCY vs URGENCY

Drugs for Hypertensive Emergency:

⚠️ "Rapid BP reduction as dangerous as hypertensive state itself" — Goldman-Cecil Medicine

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🎯 Compelling Indications Table (Must Know!)

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💊 Resistant Hypertension

Common Causes:

• Poor compliance
• Excessive salt intake
• NSAIDs use
• Secondary HTN (sleep apnea, renal artery stenosis, primary aldosteronism)
• Obesity, excessive alcohol

Management:

1. 3-drug combination (Diuretic + CCB + ACE-I/ARB) — kaafi patients ke liye standard
2. Add Spironolactone — 4th drug ke roop mein very effective
3. Sometimes 4+ drugs lagte hain

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📊 Quick Drug Summary Table

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🎯 High-Yield Exam Points

1. First-line HTN → Thiazide / CCB / ACE-I / ARB (any one)
2. ACE-I side effect → Dry cough (bradykinin se)
3. ARB advantage over ACE-I → No cough
4. Pregnancy HTN → Methyldopa / Labetalol / Hydralazine; ACE-I & ARB contraindicated
5. Hypertensive emergency → IV Nitroprusside (most cases)
6. Drug-induced SLE → Hydralazine (>200 mg, slow acetylators)
7. Hypertrichosis → Minoxidil (topically = Rogaine for baldness)
8. First dose hypotension → Prazosin (α1 blocker)
9. Verapamil + Beta-blocker → Complete heart block risk
10. Rebound hypertension on stopping → Clonidine
11. Pheochromocytoma → Alpha-blocker PEHLE, beta-blocker baad mein
12. BPH + HTN → Alpha-1 blocker (dual benefit)
13. Cyanide toxicity → Nitroprusside (overdose/prolonged use)
14. Constipation → Verapamil (classic SE)
15. Resistant HTN 4th drug → Spironolactone

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