Drug Metabolism & Pharmacology Basics

Pharmacology is the science of how drugs affect the body. It has two major branches: - Pharmacodynamics (PD) — what the drug does to the body (mechanism of action, receptor interactions, effects) - Pharmacokinetics (PK) — what the body does to the drug (absorption, distribution, metabolism, excretion — ADME) Drug targets: Drugs produce their effects by interacting with specific molecular targets: 1. Receptors — the most common drug targets. A drug that binds a receptor and activates it is an agonist; one that binds and blocks it without activating is an antagonist. - Morphine: agonist at mu-opioid receptors (GPCRs) → pain relief, euphoria, respiratory depression - Naloxone (Narcan): antagonist at opioid receptors → reverses opioid overdose - Salbutamol: agonist at beta-2 adrenoceptors → bronchodilation in asthma - Propranolol: antagonist at beta-1 adrenoceptors → lowers heart rate 2. Enzymes — drugs inhibit (most commonly) or activate enzymes: - Aspirin: irreversibly inhibits COX-1 and COX-2 (prostaglandin synthesis) → analgesia, anti-inflammatory, antiplatelet - Statins: competitively inhibit HMG-CoA reductase → lower cholesterol - ACE inhibitors (ramipril): inhibit angiotensin-converting enzyme → lower blood pressure - Penicillin: inhibits transpeptidase (bacterial cell wall synthesis enzyme) 3. Ion channels — drugs block or open specific channels: - Local anaesthetics (lidocaine): block voltage-gated Na⁺ channels → prevent action potentials → local numbness - Calcium channel blockers (amlodipine): block L-type Ca²⁺ channels → lower blood pressure, slow heart rate 4. Transport proteins — drugs block transporters: - SSRIs (fluoxetine/Prozac): block serotonin reuptake transporter (SERT) → serotonin stays in synaptic cleft → antidepressant effect - Metformin: enters cells via OCT1 transporter; inhibits mitochondrial Complex I Key concepts: - Potency — how much drug is needed to produce an effect (related to receptor affinity — EC50) - Efficacy — the maximum effect achievable with a drug regardless of dose - Therapeutic window (index) — the range of doses that are effective without being toxic. Drugs with narrow therapeutic windows (digoxin, warfarin, lithium, phenytoin) require careful monitoring.

Pharmacokinetics describes the journey of a drug through the body from administration to elimination. The acronym ADME covers the four phases: A — Absorption: The process by which a drug enters the bloodstream from its site of administration. - Oral (enteral) drugs must survive stomach acid, be absorbed from the gut (usually small intestine), and survive first-pass metabolism before reaching systemic circulation - Bioavailability (F) = the fraction of administered drug that reaches systemic circulation unchanged. IV = 100%. Oral bioavailability varies widely (GTN has <10% oral bioavailability due to extensive first-pass metabolism — must be given sublingually) - Factors affecting absorption: lipophilicity (fat-soluble drugs cross membranes better), molecular weight, ionisation state at gut pH, gut motility, food interactions B — Distribution: How the drug spreads from blood to tissues. - Volume of distribution (Vd) = theoretical volume the drug distributes into. A drug with high Vd accumulates in tissues (e.g. chloroquine Vd = 200–800 L/kg — distributes heavily into red blood cells and tissues). Low Vd = drug stays mainly in plasma. - Protein binding — many drugs bind plasma proteins (mainly albumin). Only the free (unbound) fraction is pharmacologically active. Highly protein-bound drugs (warfarin >99% bound) can be displaced by other drugs, dramatically increasing free drug concentration. - Blood-brain barrier (BBB) — tight junctions between cerebral endothelial cells restrict drug entry to the brain. Only lipophilic, small, uncharged drugs cross readily. P-glycoprotein (an efflux transporter) actively pumps many drugs back out. C — Metabolism: The chemical transformation of drugs, primarily in the liver, into metabolites that are usually more water-soluble (and therefore easier to excrete). Occasionally metabolism activates a prodrug (e.g. codeine → morphine by CYP2D6; clopidogrel → active thienopyridine by CYP2C19). D — Excretion: Elimination of the drug or its metabolites from the body. - Primary route: kidney (glomerular filtration + tubular secretion of water-soluble compounds) - Secondary: bile → faeces (enterohepatic recirculation can prolong action) - Other: lungs (alcohol, volatile anaesthetics), sweat, breast milk

The cytochrome P450 (CYP) system is the most important drug-metabolising enzyme system in the body. Located primarily in hepatocytes (liver cells) and intestinal epithelium, CYP enzymes catalyse oxidation reactions that make drugs more polar and water-soluble — preparing them for excretion. Phase I and Phase II metabolism: Phase I reactions (primarily CYP enzymes): - Introduce or expose a functional group (–OH, –NH₂, –COOH, –SH) via oxidation, reduction, or hydrolysis - Products may be active (prodrug activation), inactive, or even more toxic - Key CYP enzymes: CYP3A4 (metabolises ~50% of all drugs), CYP2D6, CYP2C9, CYP2C19, CYP1A2 Phase II reactions (conjugation): - Attach a large polar molecule to the Phase I metabolite: glucuronic acid (glucuronidation), sulfate (sulphation), acetyl group (acetylation), glutathione (for reactive intermediates) - Products are almost always inactive and highly water-soluble → excreted in bile or urine Drug interactions via CYP: CYP inducers — drugs or substances that increase CYP enzyme expression → faster drug metabolism → lower plasma levels of co-administered drugs: - Rifampicin (antibiotic) — potent CYP3A4 inducer → reduces effectiveness of oral contraceptives, warfarin, antiretrovirals, many others. Patients on rifampicin need alternative contraception. - St John's Wort (herbal supplement) — CYP3A4 inducer → reduced levels of ciclosporin (transplant rejection), antiretrovirals, contraceptives CYP inhibitors — drugs that block CYP enzymes → slower drug metabolism → higher plasma levels → potential toxicity: - Clarithromycin (antibiotic) — potent CYP3A4 inhibitor → raises levels of statins → increased risk of statin myopathy/rhabdomyolysis - Fluconazole (antifungal) — inhibits CYP2C9 → raises warfarin levels → bleeding risk - Grapefruit juice — contains furanocoumarins that irreversibly inhibit intestinal CYP3A4 → significantly increases bioavailability of many drugs (statins, calcium channel blockers, immunosuppressants) Pharmacogenomics of CYP2D6: CYP2D6 exists in four major phenotypes based on gene variants: - Ultra-rapid metabolisers (~2% European population) — multiple CYP2D6 gene copies → very fast metabolism → standard codeine dose converts rapidly to toxic morphine → fatal respiratory depression in children - Poor metabolisers (~8%) — little or no CYP2D6 → codeine cannot be activated → no pain relief; tamoxifen (breast cancer) cannot be converted to active endoxifen → treatment failure - Normal and intermediate metabolisers — standard dosing appropriate The FDA has black-box warnings on codeine in children and nursing mothers because of CYP2D6 ultra-rapid metabolism risks.

Half-life (t½): The time required for the plasma concentration of a drug to fall by half. This depends on volume of distribution and clearance: t½ = 0.693 × Vd / Clearance Key implications: - After 5 half-lives, ~97% of a single dose is eliminated — effectively "gone" from the body - After 5 half-lives of regular dosing, plasma concentration reaches steady state — the point where rate of drug input = rate of elimination - Drugs with long half-lives (days to weeks) can accumulate gradually — relevant for amiodarone (t½ 40–55 days!), digoxin (36–48 hours), fluoxetine (1–6 days) Loading doses: For drugs with long half-lives, it can take weeks to reach therapeutic steady-state concentrations. A loading dose — a single large initial dose — rapidly achieves therapeutic levels, after which maintenance dosing sustains them. - Digoxin: loading dose followed by daily maintenance - Amiodarone: oral or IV loading over days followed by low maintenance dose - Warfarin: no standard loading dose (risk of over-anticoagulation) — start at predicted maintenance dose Renal dosing adjustments: Many drugs or their active metabolites are renally excreted. In patients with renal impairment (reduced GFR), drug accumulation can cause toxicity: - Metformin — contraindicated in severe renal impairment (lactic acidosis risk from accumulation) - Low molecular weight heparins (enoxaparin) — renally excreted; dose reduce in renal failure - Gentamicin (aminoglycoside antibiotic) — narrow therapeutic window; renal excretion → accumulates → nephrotoxicity and ototoxicity in renal impairment; requires serum level monitoring - NSAIDs — reduce renal blood flow (by inhibiting prostaglandin-mediated afferent arteriolar dilation) → acute kidney injury, especially in elderly and volume-depleted patients Therapeutic drug monitoring (TDM): Measuring drug concentrations in the blood to ensure they are in the therapeutic range: - Narrow therapeutic index drugs: phenytoin, lithium, gentamicin, vancomycin, digoxin, ciclosporin, methotrexate, theophylline - TDM allows dosing adjustments for individual patient variability, renal/hepatic impairment, and drug interactions

Toxicology is the study of how chemical substances cause harm. Understanding the biochemistry of drug toxicity helps explain treatment strategies. Paracetamol (acetaminophen) toxicity — the most important: Paracetamol is the leading cause of acute liver failure in the UK and US. It is safe at therapeutic doses (up to 4g/day) but highly toxic in overdose. Mechanism: At therapeutic doses: paracetamol is metabolised primarily by glucuronidation and sulphation (Phase II) → non-toxic conjugates excreted in urine Small amount goes via CYP2E1 → NAPQI (N-acetyl-p-benzoquinone imine) — a highly reactive, toxic metabolite NAPQI is rapidly detoxified by glutathione (GSH) → non-toxic mercapturate excreted In overdose: glucuronidation and sulphation are saturated → more goes via CYP2E1 → massive NAPQI formation → glutathione stores depleted → NAPQI binds hepatocyte proteins covalently → oxidative damage → centrilobular hepatic necrosis (zone 3 of the liver lobule — highest CYP2E1 activity) Treatment: N-acetylcysteine (NAC) — given as soon as possible after overdose. NAC replenishes glutathione stores → NAPQI detoxified. Highly effective if given within 8 hours; decreasing effectiveness up to 24 hours; essentially no benefit after 24 hours if severe liver failure has already developed. CYP2E1 is induced by alcohol — chronic drinkers are MORE susceptible to paracetamol toxicity at "therapeutic" doses because more goes through CYP2E1 → more NAPQI produced. Also, malnutrition reduces glutathione stores. Aspirin (salicylate) toxicity: Complex acid-base picture: initially respiratory alkalosis (salicylates directly stimulate the respiratory centre → hyperventilation → CO₂ blown off) followed by metabolic acidosis (salicylate is an acid; also uncouples oxidative phosphorylation → lactic acid). Treatment: urine alkalinisation with IV sodium bicarbonate (raises urine pH → ionises salicylate → cannot reabsorb → renal excretion enhanced), haemodialysis in severe cases. Organophosphate poisoning (nerve agents, pesticides): Irreversibly inhibit acetylcholinesterase (the enzyme that breaks down acetylcholine at synapses). Acetylcholine accumulates at: muscarinic receptors (excess gland secretions, bronchoconstriction, bradycardia, bowel cramps) and nicotinic receptors (muscle weakness → paralysis). Mnemonic: SLUDGE — Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis. Treatment: atropine (muscarinic antagonist) + pralidoxime (reactivates acetylcholinesterase if given early, before "aging" makes the inhibition permanent).