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Premed Pharmacology
Mechanisms → PK/PD → bedside prescribing: high-yield facts, equations, and UK-centric safety pearls for medical exams. 🔥
🔢 Key Areas of Study
- General Principles: Receptor pharmacodynamics (agonism/antagonism, efficacy vs potency, spare receptors), signal transduction (GPCR, RTK, ion channels), therapeutic index, receptor desensitisation/tolerance.
- Pharmacokinetics: ADME; absorption (pH/ionisation), first-pass effect, distribution (V\(_d\)), metabolism (Phase I/II; CYPs), excretion (renal/hepatic/biliary), clearance, half-life, steady-state, loading vs maintenance dosing.
- Autonomic Pharmacology: Cholinergic (muscarinic/nicotinic) and adrenergic (α/β) systems; agonists, antagonists, mixed-action drugs; baroreflex interactions.
- Cardiovascular: Antihypertensives, antianginals, antiarrhythmics (Vaughan–Williams), heart failure therapies (RAAS inhibitors, diuretics, SGLT2i, ARNI), antiplatelets/anticoagulants, thrombolytics.
- Respiratory: β\(_2\) agonists, antimuscarinics, inhaled corticosteroids, leukotriene modifiers, theophylline, antifibrotics.
- Renal & Fluids: Diuretics (sites/actions), vasopressin agents, alkalinisers/acidifiers, fluid prescribing basics, electrolyte pharmacology.
- Endocrine & Metabolic: Insulins & non-insulin agents (metformin, SGLT2i, GLP-1 RA, DPP-4), thyroid drugs, steroids & mineralocorticoids, bone agents (bisphosphonates, denosumab), reproductive pharmacology.
- CNS: Sedatives/hypnotics, antidepressants, antipsychotics, mood stabilisers, antiepileptics, analgesics (opioid & non-opioid), anaesthetics, Parkinson’s therapy.
- Infection & Inflammation: Antibiotic classes & PK/PD targets, antivirals/antifungals/antiparasitics (principles), NSAIDs/DMARDs/biologics.
- GI & Hepatology: Acid suppression, prokinetics/antiemetics, laxatives/antidiarrhoeals, bile acids, hepatic encephalopathy agents.
- Oncology & Immunotherapy: Cytotoxics (cell cycle), targeted therapy (TKIs, mAbs), immune checkpoint inhibitors, toxicity syndromes & rescue agents.
- Special Populations & Safety: Pregnancy & lactation, paediatrics, older adults, renal/hepatic impairment, pharmacogenomics, UK BNF/MHRA Yellow Card/black triangle, controlled drugs.
⚙️ PD fundamentals – potency vs efficacy
- Potency (EC\(_{50}\)) is the concentration achieving 50% maximal effect; efficacy (E\(_{max}\)) is maximal possible effect. A partial agonist has lower E\(_{max}\) even if highly potent, and can antagonise a full agonist at the same receptor.
- Competitive antagonists shift the dose–response curve right (↑EC\(_{50}\), E\(_{max}\) unchanged); non-competitive antagonists reduce E\(_{max}\) (insurmountable).
- Desensitisation: GPCR phosphorylation & β-arrestin, receptor internalisation; explains tachyphylaxis with repeated doses (e.g., decongestants).
🧪 PK pearls – how numbers guide dosing
- V\(_d\) relates dose to plasma concentration (\(V_d=\tfrac{\text{amount in body}}{C_p}\)); high V\(_d\) drugs are lipophilic/tissue-bound (e.g., TCAs), low V\(_d\) remain intravascular (e.g., heparin).
- Clearance is the “volume cleared” per time (\(Cl=\tfrac{\text{rate of elimination}}{C_p}\)); \(t_{1/2}=\tfrac{0.693\,V_d}{Cl}\). Five half-lives ≈ steady-state/washout for first-order kinetics.
- Capacity-limited (zero-order) elimination (e.g., phenytoin, ethanol) risks disproportionate toxicity with small dose increases; monitor levels and adjust carefully.
🧬 Pharmacogenomics – when genes matter
- HLA-B*57:01 → abacavir hypersensitivity (screen prior to use). HLA-B*15:02 (certain ancestries) → SJS/TEN risk with carbamazepine.
- TPMT/NUDT15 variants → azathioprine/6-MP myelotoxicity; DPD (DPYD) deficiency → 5-FU/capecitabine toxicity; UGT1A1*28 → irinotecan neutropenia.
- CYP2C19 poor metabolisers → reduced clopidogrel activation; consider alternatives if high-risk indications.
📏 Core Tables & Equations
| Equation | Form | Use / Memory Tip |
|---|---|---|
| Clearance | \(Cl=\dfrac{\text{Rate of elimination}}{C_p}\) | Sum organ clearances (renal + hepatic) |
| Half-life | \(t_{1/2}=\dfrac{0.693\,V_d}{Cl}\) | 5 × \(t_{1/2}\) ≈ steady state |
| Loading dose | \(D_L=\dfrac{C_{ss}\,V_d}{F}\) | Use for rapid effect; beware toxicity |
| Maintenance | \(\text{Rate}=\dfrac{C_{ss}\,Cl}{F}\) | Adjust to organ function |
| Bioavailability | \(F=\dfrac{\text{AUC}_{po}}{\text{AUC}_{iv}}\times \dfrac{Dose_{iv}}{Dose_{po}}\) | First-pass reduces \(F\) |
| Henderson–Hasselbalch | \(\mathrm{pH}=pK_a+\log\dfrac{[\text{base}]}{[\text{acid}]}\) | Trapping weak acids/bases in urine |
| Emax model | \(E=\dfrac{E_{max}[A]}{EC_{50}+[A]}\) | Potency vs efficacy separation |
| Therapeutic index | \(\text{TI}=\dfrac{\text{TD}_{50}}{\text{ED}_{50}}\) | Narrow TI = monitor (e.g., lithium) |
🧠 Autonomic receptor map – agonists/antagonists
| Receptor | Main effects | Agonists | Antagonists |
|---|---|---|---|
| α\(_1\) | Vasoconstriction, mydriasis | Phenylephrine | Doxazosin |
| α\(_2\) | ↓NE release (presynaptic) | Clonidine | Mirtazapine |
| β\(_1\) | ↑HR/contractility, renin | Dobutamine | Metoprolol, bisoprolol |
| β\(_2\) | Broncho/vasodilation, tocolysis | Salbutamol | Non-selective β-blockers |
| M\(_2\) | ↓SA/AV node activity | Muscarine | Atropine |
| M\(_3\) | Smooth muscle/gland ↑, miosis | Pilocarpine | Ipratropium/oxybutynin |
| Nicotinic | Ganglia/neuromuscular | Nicotine | Varenicline (partial); NMJ blockers |
💉 Antihypertensives – mechanisms & pearls
| Class | Mechanism | Key adverse effects | Notes |
|---|---|---|---|
| ACEi (ramipril) | ↓Ang II, ↑bradykinin | Cough, hyperkalaemia, angio-oedema | Renoprotective in proteinuric CKD; avoid in pregnancy/bilateral RAS |
| ARB (losartan) | AT\(_1\) blockade | Hyperkalaemia | No cough; similar outcomes |
| CCB (amlodipine) | L-type Ca\(^{2+}\) block | Ankle oedema, flushing | Dihydropyridines for BP; rate-limiting (verapamil) for arrhythmias |
| Thiazide(-like) | NaCl block DCT | Hyponatraemia, hypokalaemia, ↑uric acid | Indapamide/chlortalidone long-acting |
| β-blockers | β\(_1\) antagonism | Bradycardia, bronchospasm (non-selective) | Post-MI, HFrEF (select agents) |
| MRA (spironolactone) | Aldosterone block | Hyperkalaemia, gynaecomastia | Eplerenone fewer endocrine effects |
🩸 Antiplatelets & anticoagulants – quick grid
| Drug | Target | Reversal / monitoring | Notes |
|---|---|---|---|
| Aspirin | COX-1 irreversible | Platelet transfusion if severe bleed | GI bleed risk; use PPI if high risk |
| Clopidogrel | P2Y\(_{12}\) irreversible | Platelet transfusion | Prodrug (CYP2C19) |
| DOACs (apixaban, rivaroxaban) | Xa inhibitors | Andexanet alfa (selected), PCC | Check renal function; fewer interactions |
| Dabigatran | Direct thrombin | Idarucizumab | Renal clearance; dyspepsia |
| Warfarin | VKORC1 (II, VII, IX, X) | Vitamin K, PCC | INR monitoring; many interactions |
| Heparins | ATIII-mediated | Protamine (UFH > LMWH) | HIT risk (monitor platelets) |
🧯 Emergency antidotes – must-know
- Paracetamol: N-acetylcysteine (follow nomogram timing).
- Opioids: Naloxone (titrate to respirations).
- β-blocker/CCB: Glucagon / calcium, ± high-dose insulin euglycaemia therapy.
- Organophosphates: Atropine + pralidoxime; decontaminate.
- Digoxin: Digoxin-specific Fab fragments.
- MetHb: Methylene blue (if G6PD normal).
- Toxic alcohols: Fomepizole (or ethanol), dialysis as indicated.
- Cyanide: Hydroxocobalamin.
🧭 Pathways & Checklists – Prescribing That Thinks
| Scenario | Checklist | Why it matters |
|---|---|---|
| Starting a new drug | Indication → contraindications → baseline obs/labs → interactions (CYP/P-gp/QT) → patient factors (renal/hepatic, pregnancy, frailty) → counselling → monitoring plan | Prevents predictable harm; documents “indication + stop/review date” (UK practice) |
| Renal dosing | Estimate eGFR/CrCl → identify renally cleared drugs → adjust dose/interval → avoid nephrotoxins → monitor levels (TDM) & electrolytes | Gentamicin/vancomycin, DOACs, metformin require vigilance |
| QT risk | Baseline ECG if risk → avoid multiple QT-prolongers → correct K/Mg/Ca → monitor if adding macrolide/fluoroquinolone/antipsychotic/methadone | Prevents torsades; consider alternatives |
| Opioid initiation | Assess pain type → non-opioids first → start low/go slow → prescribe laxative + antiemetic PRN → set functional goals → review in 48–72 h | Reduces adverse events & dependence risk |
| Biologic DMARD | Screen TB/hepatitis → update vaccines (avoid live post-start) → counsel on infection risk → plan monitoring (FBC/LFTs) | Prevents reactivation & missed toxicity |
🧑🏫 Exam hack: Say the mechanism, one key adverse effect, one interaction, and the monitoring-four sentences that impress markers every time.
💥 Drug–drug interactions – pattern spotting
- CYP3A4 inhibitors (azoles, macrolides except azithro, protease inhibitors, grapefruit) ↑ levels of statins, DOACs, some CCBs-watch for myopathy/bleeding/hypotension.
- CYP inducers (rifampicin, carbamazepine, phenytoin, St John’s wort) ↓ many drugs’ levels-loss of anticoagulation/contraception/anti-epileptic control.
- Serotonergic stacking (SSRI + MAOI + triptan + tramadol + linezolid) → serotonin syndrome (agitation, hyperreflexia, clonus, hyperthermia).
- Hyperkalaemia triad: ACEi/ARB + MRA + trimethoprim (amiloride-like) → check K\(^+\) & renal function.
📦 UK safety culture – bullets to remember
- BNF is your default reference; use generic names; avoid dangerous abbreviations (e.g., “u” for units).
- MHRA Yellow Card for suspected ADRs; black triangle ▼ indicates additional monitoring.
- Controlled drugs: legal writing requirements; safe storage & witnessed destruction; avoid decimals for whole-number doses.
🩺 Therapeutics & Clinical Scenarios
- STEMI: Dual antiplatelet (aspirin + P2Y\(_{12}\)), anticoagulation, statin, β-blocker, ACEi; primary PCI pathway. Watch bleeding & hypotension (nitrates in RV infarct).
- AF stroke prevention: CHA\(_2\)DS\(_2\)-VASc & HAS-BLED; DOAC first-line in most; adjust for renal function; periprocedural holds depend on bleeding risk and eGFR.
- HFrEF: Quadruple therapy (ACEi/ARB or ARNI, β-blocker, MRA, SGLT2i) unless contraindicated; diuretic for symptoms. Titrate slowly; monitor K\(^+\), renal function, BP.
- Asthma: Reliever (SABA) + ICS backbone; add LABA → MART strategies; antimuscarinic (LAMA) in selected; biologics (anti-IgE/IL-5/IL-4R) in severe phenotypes.
- T2DM: Metformin (if eGFR adequate) → add SGLT2i (HF/CKD benefit) or GLP-1 RA (CV benefit/weight). Watch DKA risk with SGLT2i during acute illness (sick-day rules).
- Seizure control: Focal: lamotrigine/levetiracetam; generalised: valproate (avoid in pregnancy) or levetiracetam; status: benzodiazepine → levetiracetam/valproate/phenytoin.
- Antibiotics (general): Source control + empiric per syndrome & local resistance → de-escalate. PK/PD targets: β-lactams (time>MIC), aminoglycosides (C\(_{max}\)/MIC), vanc (AUC/MIC).
- PUD/UGIB risk on NSAIDs: Co-prescribe PPI in high-risk (age, steroids, anticoagulants, prior ulcer). Consider COX-2 selective in GI risk (balance CV risk).
- Thyrotoxicosis: Thionamide (carbimazole), β-blocker for symptoms; watch agranulocytosis (sore throat/fever → stop & FBC). Radioiodine/thyroidectomy per case.
🧯 Toxicology vignettes – spot & treat
- Opioid toxidrome: Miosis, hypoventilation, bradycardia → airway & naloxone titration; long-acting opioids may require infusion.
- Anticholinergic toxidrome: Hot, dry, flushed, delirious, mydriasis, urinary retention → benzodiazepines for agitation; physostigmine only with expert advice.
- Cholinergic toxidrome: Salivation, lacrimation, urination, defecation, GI upset, emesis + bronchorrhoea/bronchospasm → atropine until dry chest + pralidoxime.
- Tricyclic overdose: Wide QRS, arrhythmia, seizures → sodium bicarbonate boluses; avoid class Ia/Ic antiarrhythmics.
🧪 Therapeutic drug monitoring (TDM) – where & why
- Vancomycin: Target AUC/MIC (commonly 400–600) or troughs per local policy; adjust to renal function.
- Gentamicin: Once-daily peaks/troughs or Hartford nomogram; watch ototoxicity/nephrotoxicity.
- Lithium: Narrow TI; check level 12 h post-dose; toxicity with dehydration, ACEi/ARB, thiazides, NSAIDs.
- Phenytoin: Capacity-limited kinetics; small dose changes → big level changes; albumin-bound (adjust for hypoalbuminaemia).
👶 Pregnancy & lactation – safer choices
- Avoid ACEi/ARB, statins, warfarin (teratogenic); prefer labetalol/nifedipine/methyldopa for hypertension; LMWH for anticoagulation.
- SSRIs generally compatible (sertraline often preferred); avoid sodium valproate (major teratogen).
- Use BNF and local maternity guidelines; consider trimester-specific risks and lactation transfer.
🧠 Study & Exam Tips
- Four sentences per drug: Mechanism → key indication → one dangerous adverse effect → one interaction/monitoring plan.
- Numbers that matter: \(t_{1/2}\), \(V_d\), \(Cl\), time to steady-state, PK/PD target (time>MIC, C\(_{max}\)/MIC, AUC/MIC).
- Map to physiology: For adverse effects, identify which receptor/pathway explains it (e.g., β\(_2\) agonist → tremor/hypokalaemia).
- Safety first: Write “Indication + dose + route + frequency + duration + monitoring + stop/review date” every time.
- Active recall: Build one-page class summaries (MOA, examples, ADRs, interactions); daily five-minute drills.
🚀 Rapid drill (answers hidden)
- How many half-lives to ~95% steady-state? Ans: ~4–5.
- ACE inhibitor cough mechanism? Ans: ↑Bradykinin.
- Why add β-blocker to nitrate in angina? Ans: Blunts reflex tachycardia from vasodilation.
- Which drugs raise lithium levels? Ans: Thiazides, ACEi/ARB, NSAIDs (↓renal clearance).
- Warfarin + metronidazole effect? Ans: ↑INR/bleeding (CYP inhibition).
Final thought: Say the mechanism, predict the effect, prevent the harm. If you can follow the molecule from receptor to monitoring plan, pharmacology turns from a list into logic. 💪