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Pharmacokinetics of a Drug (ADME)

"The processes of absorption, distribution, and elimination (metabolism and excretion) govern the relationship between drug dose and drug concentration in plasma."

• Miller's Anesthesia, 10e

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1. ABSORPTION

Key Concepts:

Factors Affecting Absorption:

Routes of Administration:

• Oral (PO): Most common, safest, economical. Disadvantages: first-pass effect, food interactions, destroyed by GI enzymes. Most absorption occurs in small intestine by passive diffusion.
• Sublingual: Absorbed directly into systemic circulation; avoids first-pass (e.g., nitroglycerin).
• Intramuscular (IM): Absorption depends on blood flow and drug solubility. Example: penicillin, morphine.
• Intravenous (IV): F = 1; fastest, most reliable. Example: heparin, lignocaine in arrhythmia.
• Transdermal: Bypasses first-pass; used for lipid-soluble drugs. Example: fentanyl patch, nitroglycerin patch.
• Inhalation: Rapid absorption due to large surface area and high blood flow. Example: salbutamol, isoflurane.

First-Pass Effect:

• Example: Morphine (oral bioavailability ~25%), Propranolol (~30%), Lignocaine (nearly 100% first-pass - not given orally), Nitroglycerin (given sublingually/transdermally to avoid first-pass).

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2. DISTRIBUTION

Factors Affecting Distribution:

1. Plasma protein binding - Drug bound to plasma proteins (mainly albumin) cannot cross membranes or exert effect. Only free (unbound) drug is pharmacologically active.
   • Acidic drugs bind albumin (e.g., warfarin, phenytoin)
   • Basic drugs bind α₁-acid glycoprotein (e.g., lidocaine, propranolol)
   • Drug-drug interaction: warfarin + aspirin - aspirin displaces warfarin → increased free warfarin → bleeding risk
2. Volume of Distribution (Vd): $$V_d = \frac{\text{Total amount of drug in body}}{\text{Drug concentration in plasma}}$$
   • High Vd = drug distributed widely in tissues (e.g., chloroquine Vd ~300 L/kg)
   • Low Vd = drug confined to plasma (e.g., heparin ~0.06 L/kg)
3. Lipid solubility: Lipophilic drugs cross the blood-brain barrier. Example: thiopental rapidly enters CNS.
4. Blood-Brain Barrier (BBB): Tight junctions in CNS capillaries restrict polar/ionized drugs. Lipophilic drugs like diazepam, phenobarbitone cross readily.
5. Placental transfer: Most drugs cross by passive diffusion. Example: alcohol, tetracycline, thalidomide cross the placenta and are teratogenic.
6. Tissue binding: Some drugs accumulate in specific tissues. Example: chloroquine in liver/retina, tetracycline in bone and teeth.

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3. METABOLISM (Biotransformation)

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PHASE I REACTIONS (Functionalization Reactions)

• CYP3A4: metabolizes ~50% of drugs (e.g., midazolam, cyclosporine, simvastatin)
• CYP2D6: codeine (→ morphine), metoprolol, tamoxifen
• CYP2C9: warfarin, phenytoin, NSAIDs
• CYP1A2: theophylline, caffeine, clozapine

• Rifampicin (strongest inducer) → reduces OCP levels → contraceptive failure
• Phenobarbitone, carbamazepine, phenytoin - induce their own metabolism (autoinduction)

• Erythromycin, ketoconazole → increase midazolam/cyclosporine toxicity
• Grapefruit juice inhibits CYP3A4 intestinally

• May be inactive (most cases)
• May be active (prodrug activation): codeine → morphine, enalapril → enalaprilat, prednisone → prednisolone
• May be toxic: paracetamol → NAPQI (N-acetyl-p-benzoquinone imine) - toxic at overdose

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PHASE II REACTIONS (Conjugation/Synthetic Reactions)

• Fast acetylators: INH rapidly converted → less efficacy; higher hepatotoxicity risk
• Slow acetylators: INH accumulates → more drug toxicity (peripheral neuropathy); higher therapeutic response
• Slow acetylators more common in Europeans; fast acetylators common in Asians

• Phase I is not always required before Phase II. Some drugs undergo direct Phase II (e.g., lorazepam directly glucuronidated - safer in hepatic disease)
• Morphine-6-glucuronide (Phase II) is actually MORE potent than morphine itself

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4. EXCRETION

A. Renal Excretion (Primary Route for Water-Soluble Drugs)

• Alkalinization of urine (NaHCO₃): traps acidic drugs as ionized form → increased excretion of aspirin, phenobarbitone
• Acidification of urine (ammonium chloride): increased excretion of amphetamine, phencyclidine (basic drugs)

• Drugs eliminated by kidney (e.g., gentamicin, digoxin, metformin) require dose reduction in renal impairment (use creatinine clearance/GFR to guide dosing)
• Metformin is contraindicated in renal failure (risk of lactic acidosis)

B. Biliary and Fecal Excretion

• Drugs secreted into bile (e.g., rifampicin, steroids, ampicillin, erythromycin) → enter intestine → either excreted in feces OR reabsorbed (enterohepatic circulation).
• Enterohepatic circulation prolongs drug action: ethinyl estradiol (OCP), morphine, warfarin, chloramphenicol.
• Interruption by antibiotics (killing gut bacteria) → reduced OCP efficacy.

C. Other Routes of Excretion:

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5. CLINICAL PHARMACOKINETIC PARAMETERS (Quick Summary)

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SUMMARY DIAGRAM (ADME at a Glance)

Drug administered
       ↓
  ABSORPTION ←[First-pass effect reduces bioavailability]
       ↓
  SYSTEMIC CIRCULATION
  (free drug + protein-bound)
       ↓
  DISTRIBUTION → Tissues, CNS, Placenta
       ↓
  METABOLISM (Liver: Phase I → Phase II)
  Phase I: Oxidation/Reduction/Hydrolysis (CYP450)
  Phase II: Conjugation (Glucuronidation, Sulfation, Acetylation)
       ↓
  EXCRETION
  Renal (glomerular filtration + tubular secretion - reabsorption)
  Biliary/Fecal → Enterohepatic recycling
  Lungs (volatile agents)

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Key Examples for Exam (10-Mark Style)

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