Pharmacokinetics (PK) — Absorption, Distribution, Metabolism, Excretion

🟢 Lite — Quick Review (1h–1d)

Bioavailability (F):

• Fraction of drug that reaches systemic circulation unchanged
• IV drugs: F = 100% (reference standard)
• Oral drugs: F varies (first-pass metabolism reduces it)

First-Pass Metabolism:

• Oral drugs → portal circulation → liver → systemic circulation
• High first-pass: Propranolol, Lidocaine, Nitroglycerin, Morphine
• Bioavailability formula: F = (AUCoral / AUCiv) × 100

Volume of Distribution (Vd):

Vd = (Amount of drug in body) / (Plasma drug concentration)

Vd	Interpretation
< 5 L (body water ~5L)	Drug stays in plasma (highly protein-bound, hydrophilic)
10-20 L	Well-distributed to tissues
> 40 L	Extensive tissue binding (lipophilic, high tissue affinity)

Loading Dose Formula:

Loading Dose = (Vd × Target Cp) / Bioavailability (F)

Maintenance Dose Rate:

Dose rate = (Cl × Target Cp) / Bioavailability (F)

Clearance (Cl):

Cl = Vd × Ke (elimination rate constant) Also: Cl = (Dose / AUC)

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🟡 Standard — Regular Study (2d–2mo)

Routes of Administration:

Route	Bioavailability	Onset	Uses
IV	100%	Immediate	Emergency,病房 drugs
IM	Variable (faster than SC)	Minutes	Vaccines, antibiotics
SC	Slower absorption	~15-30 min	Insulin, heparin
Oral	Variable (first-pass)	Slow	Most chronic drugs
Inhalation	Rapid	Minutes	Asthma, anesthesia
Topical	Minimal systemic	Local action	Skin, eye, lung
Rectal	Partial bypass of liver	Variable	Antiemetics, analgesics

Factors Affecting Drug Absorption:

1. pH and ionization:

   • Weak acids (aspirin, sulfonamides) → absorbed in acidic stomach (pH 1-3)
   • Weak bases (morphine, amphetamines) → absorbed in basic intestine
   • Henderson-Hasselbalch equation:
     • For weak ACID: pH = pKa + log ([ionized]/[unionized])
     • For weak BASE: pH = pKa + log ([unionized]/[ionized])
   • Ionized drugs cannot cross lipid membranes (trapped in ionizable compartments)

2. Lipophilicity — higher lipid solubility → faster absorption

3. Surface area — intestinal villi (large surface area) >> stomach

4. Blood flow — active absorption sites need adequate perfusion

5. P-glycoprotein (P-gp) — efflux pump in gut → reduces drug absorption (e.g., digoxin)

Drug Distribution:

Protein Binding:

• Albumin — binds most acidic drugs (warfarin, sulfonamides, bilirubin)
• α1-acid glycoprotein (AAG) — binds basic drugs (propranolol, quinidine)
• ** lipoprotein** — binds lipid-soluble drugs
• Only FREE (unbound) drug is pharmacologically active and available for distribution/metabolism/excretion
• Displacement interactions: Two drugs competing for same binding site → ↑ free fraction of one drug (e.g., sulfonamides displacing warfarin → ↑ bleeding risk)

Special Barriers:

Barrier	Drugs That Cross	Clinical Relevance
Blood-brain barrier (BBB)	Lipophilic, low MW	CNS drugs; infection, tumor
Placenta	Most lipophilic drugs	Teratogenicity (thalidomide, alcohol)
Blood-testis barrier	Limited	Protects germ cells
Tissue barriers	Variable	Site-specific delivery

Cytochrome P450 Enzymes (Phase I Metabolism):

Enzyme	Substrates	Inducers	Inhibitors
CYP3A4	Most drugs (50% of Rx)	Carbamazepine, phenytoin, rifampin, OCPs, glucocorticoids	Ketoconazole, erythromycin, grapefruit juice, protease inhibitors
CYP2D6	Beta-blockers, antidepressants, opioids (codeine → morphine), antipsychotics	Not significantly induced	Quinidine, fluoxetine, paroxetine
CYP2C9	Warfarin, NSAIDs, phenytoin	Rifampin, phenobarbital	Amiodarone, fluconazole
CYP2C19	PPIs, clopidogrel (activation), diazepam	Rifampin	Omeprazole, fluoxetine
CYP1A2	Theophylline, caffeine, warfarin, clozapine	Smoking, charcoal-broiled meat, rifampin	Cimetidine, fluoroquinolones, omeprazole

Phase II Metabolism (Conjugation):

• Glucuronidation — most common; morphine, acetaminophen, chloramphenicol, carbamazepine
• Acetylation — sulfonamides, INH, procainamide (slow acetylators → ↑ toxicity)
• Sulfation — acetaminophen, catecholamines
• Methylation — catecholamines (COMT inhibitors: entacapone)
• Glutathione conjugation — acetaminophen (depleted in overdose → hepatotoxicity)

Excretion:

• Renal excretion — most important route

  • GFR (glomerular filtration) — free drug only
  • Active tubular secretion — organic anion/cation transporters (probenecid, cimetidine block this)
  • Tubular reabsorption — passive reabsorption of unionized drugs (pH-dependent)
  • pH-dependent excretion: Acidify urine → excrete weak bases; Alkalinize urine → excrete weak acids (e.g., salicylate overdose → sodium bicarbonate to enhance excretion)

• Biliary/fecal excretion — some drugs (glucuronide conjugates → hydrolyzed by gut bacteria → reabsorbed = enterohepatic circulation)

• Pulmonary excretion — volatile anesthetics (exhaled)

• Breast milk excretion — basic, lipid-soluble drugs

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🔴 Extended — Deep Study (3mo+)

Pharmacokinetics — Mathematical Models:

One-Compartment Model (IV bolus):

Cp = C0 × e^(-Ke × t) Half-life (t½) = 0.693 / Ke At steady state (after 4-5 half-lives): 94-97% of steady state achieved

Two-Compartment Model:

• Central compartment (plasma, well-perfused organs)
• Peripheral compartment (muscle, fat, less-perfused tissues)
• Context-sensitive half-life — time for plasma concentration to decline by 50% after stopping infusion; clinically relevant for anesthesia

Zero-order vs First-order Kinetics:

	Zero-order	First-order
Rate	Constant (independent of concentration)	Proportional to concentration
Half-life	Variable (↑ as [drug] ↓)	Constant
Graph	Linear (C vs t)	Exponential (log C vs t)
Examples	Phenytoin, ethanol, aspirin (high doses), warfarin	Most drugs at therapeutic doses

Michaelis-Menten Kinetics:

V = (Vmax × [S]) / (Km + [S])

• At low [S] (Km >> [S]): first-order kinetics
• At high [S] ([S] >> Km): zero-order kinetics (saturation)
• Phenytoin — follows MM kinetics; small dose increase → large plasma concentration increase → toxicity

Drug-Drug Interactions via PK Mechanisms:

1. Enzyme induction (↑ metabolism → ↓ drug effect):

   • Rifampin → ↓ warfarin, ↓ OCPs, ↓ cyclosporine, ↓ digoxin
   • Carbamazepine/Phenobarbital/Phenytoin → ↓ many drugs
   • St. John’s wort → ↓ OCPs, ↓ protease inhibitors

2. Enzyme inhibition (↓ metabolism → ↑ drug effect):

   • Ketoconazole/erythromycin → ↑ terfenadine → Torsades de Pointes (cardiotoxicity)
   • Grapefruit juice (furanocoumarins) → inhibits CYP3A4 → ↑ felodipine, simvastatin, cyclosporine
   • Cimetidine → ↓ CYP enzymes → ↑ many drugs
   • Disulfiram-like reaction: Metronidazole, first-generation sulfonylureas + alcohol

Protein Binding Displacement — Clinical Scenarios:

• Sulfonamides + Warfarin → ↑ free warfarin → bleeding
• Sulfonamides + Methotrexate → ↑ free methotrexate → myelosuppression
• NSAIDs + Lithium → ↓ renal excretion → lithium toxicity
• Probenecid + Penicillin → ↓ tubular secretion of penicillin → ↑ penicillin levels (probenecid used therapeutically for this)

Bioequivalence:

• Two formulations bioequivalent if AUC and Cmax are within 80-125%
• Therapeutic equivalence — same clinical effect

Therapeutic Drug Monitoring (TDM):

Drug	Therapeutic Range	Notes
Digoxin	0.5-2 ng/mL	Narrow therapeutic index
Lithium	0.6-1.2 mEq/L	Renal excretion
Phenobarbital	10-40 μg/mL	Enzyme inducer
Phenytoin	10-20 μg/mL	Nonlinear kinetics
Theophylline	10-20 μg/mL	Narrow TI; 1A2 substrate
Vancomycin	10-20 μg/mL (trough)	Nephrotoxicity
Aminoglycosides	Trough <1, Peak variable	Concentration-dependent killing

Drug Half-Lives — Key for NEET:

Drug	Half-life	Clinical Pearl
Warfarin	36-42 hours	Long; needs weeks to reach steady state
Digoxin	36-48 hours	Long; toxicities persist
Lithium	18-24 hours	Renal excretion; narrow TI
Phenytoin	12-36 hours	Dose-dependent (MM kinetics)
Aminoglycosides	2-4 hours	Concentration-dependent killing
Cephalosporins	1-8 hours	Most are short

Special Population Considerations:

• Elderly: ↓ hepatic blood flow, ↓ GFR, ↓ albumin → altered PK
• Hepatic impairment: ↓ Phase I > Phase II; ↓ albumin; ↓ hepatic blood flow
• Renal impairment: ↓ excretion of renally cleared drugs (adjust dose)
• Pregnancy: ↑ Vd for some drugs; ↑ hepatic metabolism for others

Key NEET-PG Clinical Pearls:

• Grapefruit juice — inhibits intestinal CYP3A4 + P-gp → ↑ simvastatin, felodipine, cyclosporine levels
• Smoking — induces CYP1A2 → ↓ theophylline, ↓ clozapine levels
• Charcoal-broiled meat — induces CYP1A2 (same as smoking)
• Cruciferous vegetables (cabbage, broccoli) — induce CYP450 → ↓ drug levels
• Alcohol — induces CYP2E1; acute use inhibits CYP2E1 (disulfiram reaction with metronidazole)
• Probenecid — blocks tubular secretion of penicillin; used to ↑ penicillin levels
• Cimetidine — non-selective CYP inhibitor; causes ↑ levels of many drugs; use famotidine or ranitidine instead (less interaction)
• pH会影响药物排泄： Sodium bicarbonate → alkalinize urine → ↑ excretion of aspirin, phenobarbital (acidic drugs)
• Acidification of urine (NH4Cl) → ↑ excretion of weak bases (amphetamines, PCP)
• Enterohepatic circulation — drug enters bile as glucuronide → gut bacteria hydrolyze → free drug reabsorbed → prolonged effect (e.g., morphine, estrogens, OCPs)

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