Makindo Medical Notes

💊 Drug metabolism (biotransformation) is the biochemical modification of drugs by the body to facilitate their elimination. Most drugs are lipid-soluble to enable absorption, but this property makes them difficult to excrete. Through enzymatic reactions — primarily in the liver — lipophilic compounds are converted into hydrophilic metabolites that can be excreted via the kidneys or bile. While metabolism generally detoxifies drugs, some pathways produce active or toxic metabolites, underscoring the clinical importance of understanding these reactions.

🧠 Key Concepts

• Phases of Drug Metabolism:
  • Phase I – Functionalisation Reactions:
    • Introduce or expose polar groups (–OH, –NH₂, –COOH).
    • Include oxidation, reduction, and hydrolysis.
    • Main enzymes: Cytochrome P450 (CYP) superfamily.
    • May activate prodrugs (e.g. codeine → morphine).
  • Phase II – Conjugation Reactions:
    • Attach endogenous hydrophilic groups (e.g. glucuronic acid, sulfate, glutathione).
    • Facilitates renal or biliary excretion.
    • Main enzymes: transferases (UGTs, SULTs, GSTs, NATs).
• Sites of Drug Metabolism:
  • Liver: Primary site via smooth endoplasmic reticulum of hepatocytes.
  • Extrahepatic sites: Gut wall, lungs, kidneys, plasma, and skin contribute to presystemic (first-pass) metabolism.
• Factors Influencing Drug Metabolism:
  • Genetics: Polymorphisms affect enzyme activity (e.g. CYP2D6 poor metabolisers for codeine).
  • Age: Neonates and elderly have reduced hepatic enzyme capacity — important for drugs like morphine or chloramphenicol.
  • Sex: Hormonal differences influence enzymes such as CYP3A4 and alcohol dehydrogenase.
  • Disease: Hepatic cirrhosis, heart failure, and renal disease reduce clearance.
  • Induction and Inhibition: Smoking, alcohol, or certain drugs alter enzyme activity (e.g. rifampicin induces CYPs; erythromycin inhibits CYP3A4).

⚙️ Detailed Pathways

• Phase I Reactions:
  • Oxidation:
    • Catalysed by CYP enzymes (notably CYP3A4, CYP2C9, CYP2D6, CYP1A2).
    • Example: CYP3A4 oxidises statins and benzodiazepines; CYP2D6 converts codeine into morphine (its active form).
    • Clinical Case: A patient with CYP2D6 deficiency given codeine experiences little analgesia due to failure of activation.
  • Reduction:
    • Less common; involves nitro or azo group reduction under low oxygen conditions.
    • Example: Reduction of chloramphenicol nitro groups in the liver.
  • Hydrolysis:
    • Mediated by esterases or amidases in plasma and liver.
    • Example: Procaine hydrolysed to para-aminobenzoic acid (PABA) and diethylaminoethanol.
    • Clinical Note: Succinylcholine is hydrolysed by plasma pseudocholinesterase — deficiency causes prolonged paralysis post-anaesthesia.
• Phase II Reactions:
  • Glucuronidation:
    • Via UDP-glucuronosyltransferases (UGTs).
    • Example: Bilirubin and morphine conjugation.
    • Clinical Case: Neonatal jaundice arises from immature UGT activity → unconjugated bilirubin accumulates (kernicterus risk).
  • Sulfation:
    • Sulfotransferases add sulfate groups to hormones, catecholamines, and paracetamol.
    • Example: Phase II sulfation of paracetamol’s safe pathway.
  • Glutathione Conjugation:
    • Glutathione-S-transferases (GSTs) detoxify reactive electrophiles.
    • Example: Detoxification of NAPQI (a toxic paracetamol metabolite).
    • Clinical Case: Paracetamol overdose overwhelms glutathione → hepatic necrosis; treated with N-acetylcysteine to replenish stores.
  • Acetylation:
    • N-acetyltransferases (NATs) in liver add acetyl groups to isoniazid, hydralazine, and sulfonamides.
    • Clinical Note: “Slow acetylators” (common in Caucasian populations) have higher risk of isoniazid-induced peripheral neuropathy and drug-induced lupus.

🧬 Clinical Relevance and Real-World Examples

• Drug Interactions:
  • Enzyme Induction: Rifampicin, carbamazepine, and chronic alcohol increase CYP activity → ↓ plasma concentration of warfarin or oral contraceptives (→ contraceptive failure).
  • Enzyme Inhibition: Erythromycin, ciprofloxacin, and grapefruit juice inhibit CYP3A4 → ↑ toxicity risk (e.g. statin-induced myopathy).
• Pharmacogenomics:
  • CYP2C19 polymorphisms: Affect clopidogrel activation — poor metabolisers have inadequate antiplatelet response and increased risk of stent thrombosis.
  • Thiopurine methyltransferase (TPMT) deficiency: Leads to severe myelosuppression after azathioprine or 6-mercaptopurine therapy.
• Adverse Drug Reactions (Toxic Metabolites):
  • Paracetamol toxicity: NAPQI accumulation damages hepatic mitochondria.
  • Halothane hepatitis: Rare, immune-mediated response to reactive metabolites of volatile anaesthetics.
  • Clozapine agranulocytosis: Possibly due to toxic nitrenium ion intermediates.
• Case Example:

  A 65-year-old man on warfarin develops bruising after starting erythromycin for pneumonia. CYP3A4 inhibition by erythromycin reduced warfarin metabolism → elevated INR and bleeding risk. Lesson: Always review CYP interactions before prescribing antibiotics in patients on anticoagulants.

• Personalised and Precision Medicine:
  • Pharmacogenetic testing (e.g. CYP2D6, TPMT, HLA-B*57:01) helps tailor drug choice and dosing.
  • In the UK, CPIC and MHRA guidance now recommend genotyping before certain therapies (e.g. abacavir, carbamazepine).

🩺 Summary and Integration

Drug metabolism transforms lipophilic drugs into hydrophilic compounds through Phase I (functionalisation) and Phase II (conjugation) reactions. These reactions determine a drug’s half-life, efficacy, and toxicity. Genetic polymorphisms, comorbidities, and drug interactions can profoundly alter outcomes. For clinicians, understanding metabolism is the cornerstone of safe prescribing, rational polypharmacy management, and personalised therapy.

💡 Teaching Tip: Think of the liver as a “biochemical customs office.” Drugs enter as foreign visitors, undergo inspection (Phase I), and are tagged or stamped (Phase II) before being cleared for departure via kidneys or bile. Some are detained (toxic metabolites), others expedited (inactive conjugates) — understanding these pathways is what prevents pharmacological disasters.