Pharmacokinetics : Drug Excretion, Renal Clearance, Half-Life, Elimination Kinetics, Loading Dose, Maintenance Dose & Therapeutic Drug Monitoring (TDM)

🌟 Pharmacokinetics : Drug Excretion, Renal Clearance, Half-Life, Elimination Kinetics, Loading Dose, Maintenance Dose & Therapeutic Drug Monitoring (TDM)

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🌟 INTRODUCTION TO DRUG EXCRETION

🔷 Drug excretion = body से drug या metabolites को बाहर निकालने की process।

➡️ Drug हमेशा body में नहीं रह सकती

➡️ Remove न होने पर accumulation होता है

➡️ Accumulation → toxicity → organ damage

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🌟 Why Drug Excretion Important?

✔️ Drug toxicity रोकता है

✔️ Drug concentration control करता है

✔️ Duration of action decide करता है

✔️ Dosing interval decide करता है

✔️ Steady state maintain करता है

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🌟 Example

✔️ Aminoglycosides kidney से excrete होती हैं

➡️ Renal failure में accumulation

➡️ Ototoxicity + nephrotoxicity

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🌟 MAIN ROUTES OF EXCRETION

🎯 Kidney (Most important)

🎯 Liver/Bile

🎯 Intestine/Feces

🎯 Lungs

🎯 Sweat

🎯 Saliva

🎯 Breast milk

━━━━━━━━━━━━━━━━━━

🌟 RENAL EXCRETION

🔷 Kidney pharmacokinetics का major excretory organ है।

➡️ About 25% cardiac output kidney को जाता है

➡️ Large blood flow = rapid filtration

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🌟 Why Kidney Important?

✔️ Large surface area

✔️ High blood flow

✔️ Specialized transporters

✔️ Filtration + secretion + reabsorption system

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🌟 STEPS OF RENAL EXCRETION

🎯 1. Glomerular Filtration

🎯 2. Tubular Secretion

🎯 3. Tubular Reabsorption

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🌟 1. GLOMERULAR FILTRATION

🔷 Blood glomerulus में आता है

➡️ Pressure generated

➡️ Water + small molecules filter

➡️ Bowman capsule में enter

✔️ ONLY FREE DRUG FILTERED

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🌟 Why Protein Bound Drug Filter नहीं होती?

🔷 Albumin-drug complex large size का होता है

➡️ Glomerular pores cross नहीं कर सकता

━━━━━━━━━━━━━━━━━━

🌟 Examples

✔️ Warfarin

✔️ Phenytoin

✔️ Diazepam

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🌟 Clinical Importance

✔️ Highly protein-bound drugs slowly excrete होती हैं

✔️ Hypoalbuminemia → free drug increase → toxicity increase

➡️ Example: Liver disease में Warfarin toxicity

━━━━━━━━━━━━━━━━━━

🌟 GFR

GFR \approx 125\ mL/min

✔️ GFR decrease causes:

➡️ Renal failure

➡️ Shock

➡️ Dehydration

➡️ Heart failure

✔️ GFR कम → elimination कम → toxicity increase

➡️ Example: Digoxin toxicity in renal failure

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🌟 2. TUBULAR SECRETION

🔷 Proximal convoluted tubule में active secretion होती है

➡️ Carrier mediated

➡️ Energy dependent

✔️ Protein-bound drugs भी remove हो सकती हैं

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🌟 Mechanism

Blood → transporter → tubular lumen

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🌟 Transport Systems

🎯 Organic Acid Transport System

🎯 Organic Base Transport System

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🌟 Organic Acid Drugs

✔️ Penicillin

✔️ Aspirin

✔️ Furosemide

✔️ Methotrexate

━━━━━━━━━━━━━━━━━━

🌟 Organic Base Drugs

✔️ Morphine

✔️ Quinidine

✔️ Histamine

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🌟 Why Active Transport Needed?

➡️ Drug कभी concentration gradient के opposite जाती है

➡️ इसलिए ATP energy required

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🌟 Important Features

✔️ Saturable process

✔️ Competitive process

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🌟 Competition Example

✔️ Probenecid + Penicillin

➡️ Same transporter use करते हैं

➡️ Probenecid transporter occupy करता है

➡️ Penicillin secretion कम

➡️ Plasma concentration increase

✔️ Clinical use → Penicillin action prolong

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🌟 3. TUBULAR REABSORPTION

🔷 Distal tubule से drug वापस blood में जा सकती है

✔️ Lipid soluble drugs easily reabsorbed

✔️ Non-ionized drugs easily reabsorbed

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🌟 Why?

🔷 Lipid membrane easily cross कर लेते हैं

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🌟 Ionized Drug Reabsorb क्यों नहीं होती?

🔷 Ionized drugs water soluble होती हैं

➡️ Lipid membrane cross नहीं कर सकती

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🌟 Ion Trapping

🔷 Ionized drug compartment में trap हो जाती है

➡️ Excretion increase

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🌟 Weak Acidic Drugs

✔️ Aspirin

✔️ Phenobarbital

✔️ Salicylates

━━━━━━━━━━━━━━━━━━

🌟 Weak Basic Drugs

✔️ Amphetamine

✔️ Morphine

✔️ Quinidine

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🌟 Urine pH Effect

🌟 Acidic Urine

✔️ Weak acids non-ionized → reabsorption increase

✔️ Weak bases ionized → excretion increase

🌟 Alkaline Urine

✔️ Weak acids ionized → excretion increase

✔️ Weak bases non-ionized → reabsorption increase

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🌟 Phenobarbital Poisoning

🔷 Phenobarbital weak acid है

➡️ Sodium bicarbonate दिया जाता है

➡️ Urine alkaline होती है

➡️ Drug ionized हो जाती है

➡️ Reabsorption कम

➡️ Excretion increase

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🌟 Amphetamine Poisoning

🔷 Amphetamine weak base है

➡️ Urine acidify करते हैं

➡️ Drug ionized होती है

➡️ Excretion increase

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🌟 BILIARY EXCRETION

🔷 Liver drugs को bile में secrete करता है

➡️ Bile → intestine

✔️ Large molecular weight drugs

✔️ Polar conjugated drugs bile से excrete

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🌟 Examples

✔️ Rifampicin

✔️ Erythromycin

✔️ Oral contraceptives

✔️ Morphine glucuronide

━━━━━━━━━━━━━━━━━━

🌟 Enterohepatic Circulation

🔷 Intestinal bacteria conjugate तोड़ती हैं

➡️ Drug फिर absorb हो जाती है

➡️ Duration of action increase

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🌟 Important Example

✔️ Oral contraceptive failure with antibiotics

➡️ Antibiotics gut flora destroy

➡️ Reabsorption कम

➡️ OCP efficacy decrease

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🌟 FECAL EXCRETION

✔️ Unabsorbed drugs feces से निकलती हैं

✔️ Examples:

➡️ Vancomycin oral

➡️ Activated charcoal bound toxins

━━━━━━━━━━━━━━━━━━

🌟 PULMONARY EXCRETION

🔷 Volatile drugs lungs से निकलती हैं

✔️ Examples:

➡️ Nitrous oxide

➡️ Alcohol

➡️ Halothane

✔️ Mechanism → alveolar diffusion

✔️ Lungs highly vascular → rapid excretion

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🌟 SWEAT EXCRETION

✔️ Rifampicin

✔️ Heavy metals

✔️ Rifampicin → orange-red discoloration

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🌟 SALIVA EXCRETION

✔️ Metronidazole

✔️ Lithium

✔️ Metallic taste produce कर सकती हैं

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🌟 BREAST MILK EXCRETION

🔷 Milk slightly acidic होती है

➡️ Weak basic drugs accumulate

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🌟 Dangerous Drugs

✔️ Chloramphenicol

✔️ Tetracycline

✔️ Diazepam

✔️ Opioids

➡️ Infant liver immature → toxicity risk high

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🌟 CLEARANCE

🔷 Clearance = body drug को कितनी efficiently remove कर रही है

CL = \frac{Rate\ of\ elimination}{Plasma\ concentration}

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🌟 High Clearance Drugs

✔️ Lidocaine

✔️ Morphine

➡️ Rapid elimination

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🌟 Low Clearance Drugs

✔️ Digoxin

➡️ Slow elimination

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🌟 HALF-LIFE (t½)

🔷 Plasma concentration आधी होने का समय

t_{1/2} = \frac{0.693 \times V_d}{CL}

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🌟 Why High Vd Increases Half-Life?

➡️ Drug tissues में store होती है

➡️ Plasma में slowly वापस आती है

➡️ Elimination slow

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🌟 Why Low Clearance Increases Half-Life?

➡️ Drug slowly remove होगी

➡️ Body में ज्यादा देर रहेगी

━━━━━━━━━━━━━━━━━━

🌟 Half-Life Elimination Pattern

✔️ 1 Half-life → 50% left

✔️ 2 Half-life → 25% left

✔️ 3 Half-life → 12.5% left

✔️ 4 Half-life → 6.25% left

✔️ 5 Half-life → 3.125% left

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🌟 FIRST ORDER KINETICS

🔷 Fixed FRACTION eliminated

➡️ Concentration ज्यादा → elimination ज्यादा

✔️ Most drugs follow first order kinetics

✔️ Examples:

➡️ Penicillin

➡️ Paracetamol

➡️ Metoprolol

Rate\ of\ elimination \propto Drug\ concentration

━━━━━━━━━━━━━━━━━━

🌟 ZERO ORDER KINETICS

🔷 Fixed AMOUNT eliminated

➡️ Enzymes saturated

✔️ Example:

100 → 90 → 80 → 70

✔️ Dangerous because small dose increase → toxicity

━━━━━━━━━━━━━━━━━━

🌟 Important Zero Order Drugs

🎯 “PEA”

✔️ Phenytoin

✔️ Ethanol

✔️ Aspirin (high dose)

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🌟 NON-LINEAR KINETICS

🔷 Dose proportionality lost

✔️ Example: Phenytoin

➡️ Small dose increase → huge plasma increase

━━━━━━━━━━━━━━━━━━

🌟 LOADING DOSE

🔷 Initial high dose for rapid therapeutic concentration

Loading\ Dose = \frac{V_d \times Target\ concentration}{Bioavailability}

✔️ Needed in long half-life drugs

✔️ Examples:

➡️ Digoxin

➡️ Phenytoin

➡️ Amiodarone

━━━━━━━━━━━━━━━━━━

🌟 MAINTENANCE DOSE

🔷 Steady-state concentration maintain करने वाली dose

Maintenance\ Dose = Clearance \times Target\ concentration

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🌟 THERAPEUTIC DRUG MONITORING (TDM)

🔷 Plasma drug concentration measurement

✔️ Needed when:

➡️ Narrow therapeutic index

➡️ Toxicity risk high

➡️ Variable metabolism

➡️ Organ failure present

━━━━━━━━━━━━━━━━━━

🌟 Important TDM Drugs

🎯 “Very Toxic Drugs Need Monitoring”

✔️ Vancomycin

✔️ Theophylline

✔️ Digoxin

✔️ Lithium

✔️ Phenytoin

✔️ Carbamazepine

✔️ Aminoglycosides

✔️ Valproate

━━━━━━━━━━━━━━━━━━

🌟 DIGOXIN TOXICITY

✔️ Yellow vision

✔️ Arrhythmia

✔️ Vomiting

━━━━━━━━━━━━━━━━━━

🌟 LITHIUM TOXICITY

✔️ Tremor

✔️ Ataxia

✔️ Nephrogenic diabetes insipidus

━━━━━━━━━━━━━━━━━━

🌟 AMINOGLYCOSIDE TOXICITY

✔️ Ototoxicity

✔️ Nephrotoxicity

━━━━━━━━━━━━━━━━━━

🌟 STEADY STATE

🔷 Drug input = drug elimination

✔️ Steady state achieved after 4–5 half-lives

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🌟 ULTRA FAST FINAL REVISION

🎯 Free drug filtered

🎯 Lipid soluble drugs reabsorbed

🎯 Ionized drugs excreted

🎯 First order = fixed fraction

🎯 Zero order = fixed amount

🎯 Half-life = time for 50% reduction

🎯 Loading dose = rapid effect

🎯 Maintenance dose = maintain steady state

🎯 TDM important for narrow therapeutic index drugs