Morning Rounds \u00b7 Pharmacokinetics \u00b7 Summative Revision<\/title>\n<link href=\"https:\/\/fonts.googleapis.com\/css2?family=Playfair+Display:ital,wght@0,400;0,600;0,700;1,400;1,600&family=Source+Serif+4:ital,wght@0,300;0,400;0,600;1,400&display=swap\" rel=\"stylesheet\">\n<style>\n#npk-sr *,#npk-sr *::before,#npk-sr *::after{box-sizing:border-box;margin:0;padding:0}\n#npk-sr{\n --ob:#1A5F7A;--ob-dark:#114455;--ob-pale:#E6F3F7;--ob-mid:#236E8C;\n --acc:#1A7A5F;--acc-pale:#E6F5F1;\n --ink:#0F2A35;--ink-mid:#2A4D5A;--ink-soft:#5A7D8A;\n --line:#B8D8E3;--cream:#F2F8FA;--warm:#F8FCFD;\n --correct:#2D6B47;--correct-bg:#EAF6EF;\n font-family:'Source Serif 4',Georgia,serif;\n font-size:16px;color:var(--ink);background:var(--cream);\n line-height:1.78;padding:0 0 72px;\n}\n#npk-sr .rv-header{\n background:linear-gradient(135deg,var(--ob-dark) 0%,var(--ob) 60%,var(--ob-mid) 100%);\n color:#E4F4F9;padding:36px 24px 30px;text-align:center;\n position:relative;overflow:hidden;\n}\n#npk-sr 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class=\"rv-eyebrow\">Morning Rounds \u00b7 Numerical Series \u00b7 Pharmacokinetics<\/div>\n <div class=\"rv-title\">Pharmacokinetics<br><em>Summative Revision Notes<\/em><\/div>\n <div class=\"rv-subtitle\">Seven rounds \u00b7 NEET-PG \/ INI-CET \/ UPSC CMS \u00b7 Formulae, thresholds, clinical anchors & traps<\/div>\n <div class=\"rv-chips\">\n <span class=\"rv-chip\">Zero & First Order<\/span>\n <span class=\"rv-chip\">Half-Life & Washout<\/span>\n <span class=\"rv-chip\">Vd & Loading Dose<\/span>\n <span class=\"rv-chip\">Clearance & Steady State<\/span>\n <span class=\"rv-chip\">TI \u00b7 ED50 \u00b7 LD50<\/span>\n <span class=\"rv-chip\">Clinical Numericals<\/span>\n <span class=\"rv-chip\">Special Populations<\/span>\n <\/div>\n <\/div>\n\n <div class=\"rv-body\">\n\n <div class=\"rv-intro\">\n <p>These notes consolidate all seven Pharmacokinetics Morning Rounds. They are written for rapid pre-exam revision \u2014 not first-time learning. Each section heading links to its quiz. The formula reference blocks are printed in the format examiners expect. Every trap identified in the round debriefs appears here as a single-line recall badge.<\/p>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-01.html\">\n <div class=\"rv-sec-num\">Round 01 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Zero-Order vs First-Order Kinetics <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">The Core Distinction<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Feature<\/th><th>Zero-Order<\/th><th>First-Order<\/th><\/tr>\n <tr><td>What is constant?<\/td><td><strong>Amount<\/strong> eliminated per unit time<\/td><td><strong>Fraction<\/strong> (%) eliminated per unit time<\/td><\/tr>\n <tr><td>Rate depends on concentration?<\/td><td>No \u2014 rate is fixed<\/td><td>Yes \u2014 rate falls as concentration falls<\/td><\/tr>\n <tr><td>Half-life concept<\/td><td>Does not apply (changes with dose)<\/td><td>Constant; independent of dose<\/td><\/tr>\n <tr><td>Plasma conc. vs time plot<\/td><td>Straight line (linear)<\/td><td>Exponential decay (log-linear straight)<\/td><\/tr>\n <tr><td>Clinical examples<\/td><td>Alcohol, phenytoin (high dose), aspirin (OD)<\/td><td>Most drugs at therapeutic doses<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">First-order: Amount remaining after n half-lives = C\u2080 \u00d7 (\u00bd)\u207f<\/span>\n <span class=\"rv-formula\">% eliminated after n half-lives = 100 \u2212 [100 \u00d7 (\u00bd)\u207f]<\/span>\n <span class=\"rv-formula\">Zero-order: Amount remaining = Initial dose \u2212 (Rate \u00d7 Time)<\/span>\n\n <div class=\"rv-sub\">The Vd Analogy \u2014 Why It Matters<\/div>\n <p>Vd is not a real anatomical volume. It is the <strong>hypothetical volume<\/strong> needed to contain all the drug in the body at the same concentration as measured in plasma. A drug with Vd = 700 L in a 70 kg person has not disappeared \u2014 it has been <strong>sequestered in tissues<\/strong>, leaving almost nothing in plasma. This is why haemodialysis, which filters only plasma, is futile for drugs with large Vd. The swimming pool analogy: dissolve a teaspoon of salt in a glass (high plasma concentration, small Vd) versus a swimming pool (undetectable in plasma, but the drug is still there \u2014 in tissues).<\/p>\n\n <p><span class=\"rv-pill\">3 half-lives \u2192 87.5% eliminated (not 75%)<\/span> <span class=\"rv-pill\">Zero-order: constant amount, not fraction<\/span> <span class=\"rv-pill-teal\">Alcohol, phenytoin OD, aspirin OD = zero-order<\/span> <span class=\"rv-pill-green\">Most therapeutic drugs = first-order<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-01.html\">\u25b6 Open Round 01<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-02.html\">\n <div class=\"rv-sec-num\">Round 02 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Half-Life & the Arithmetic of Washout <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">k (elimination rate constant) = 0.693 \u00f7 t\u00bd<\/span>\n <span class=\"rv-formula\">Back-calculate t\u00bd: count the number of halvings in the interval, then t\u00bd = Time \u00f7 n<\/span>\n <span class=\"rv-formula\">Time to steady state = 4\u20135 \u00d7 t\u00bd (independent of dose or dosing interval)<\/span>\n <span class=\"rv-formula\">Time to 95% elimination \u2248 5 \u00d7 t\u00bd<\/span>\n\n <div class=\"rv-sub\">The 4\u20135 Half-Life Rules<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Half-lives elapsed<\/th><th>% Eliminated<\/th><th>% Remaining<\/th><\/tr>\n <tr><td>1<\/td><td>50%<\/td><td>50%<\/td><\/tr>\n <tr><td>2<\/td><td>75%<\/td><td>25%<\/td><\/tr>\n <tr><td>3<\/td><td>87.5%<\/td><td>12.5%<\/td><\/tr>\n <tr><td>4<\/td><td>93.75%<\/td><td>6.25%<\/td><\/tr>\n <tr><td>5<\/td><td>96.875%<\/td><td>~3%<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Critical Distinction \u2014 PK Half-Life vs Clinical Duration<\/div>\n <p><strong>Half-life governs plasma concentration, not always duration of clinical effect.<\/strong> Phenelzine (MAOI) has a plasma t\u00bd of ~2 hours but requires a <strong>14-day washout<\/strong> before starting serotonergic drugs \u2014 because it <em>irreversibly<\/em> destroys MAO enzyme, and new enzyme synthesis takes 14 days. Being at steady state does not mean reaching a new steady state instantly after a dose change \u2014 re-equilibration always takes another 4\u20135 half-lives.<\/p>\n\n <p><span class=\"rv-pill\">Steady state reached in 4\u20135 t\u00bd regardless of dose<\/span> <span class=\"rv-pill\">95% elimination \u2248 5 \u00d7 t\u00bd<\/span> <span class=\"rv-pill-teal\">MAOI washout = enzyme resynthesis, not PK clearance<\/span> <span class=\"rv-pill-green\">k = 0.693 \u00f7 t\u00bd \u2014 memorise this<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-02.html\">\u25b6 Open Round 02<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-03.html\">\n <div class=\"rv-sec-num\">Round 03 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Volume of Distribution & Loading Dose <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Vd = Dose \u00f7 C\u2080 (initial plasma concentration)<\/span>\n <span class=\"rv-formula\">IV Loading Dose = Target Cp \u00d7 Vd<\/span>\n <span class=\"rv-formula\">Oral Loading Dose = (Target Cp \u00d7 Vd) \u00f7 F (bioavailability)<\/span>\n\n <div class=\"rv-sub\">Compartment Benchmarks \u2014 Memorise These Three<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Vd value<\/th><th>Drug location<\/th><th>Example<\/th><\/tr>\n <tr><td>~3\u20135 L<\/td><td>Confined to plasma<\/td><td>Heparin, warfarin, monoclonal antibodies<\/td><\/tr>\n <tr><td>~15 L<\/td><td>Extracellular fluid<\/td><td>Gentamicin, mannitol<\/td><\/tr>\n <tr><td>~42 L<\/td><td>Total body water<\/td><td>Ethanol, theophylline<\/td><\/tr>\n <tr><td>>100 L<\/td><td>Extensive tissue sequestration<\/td><td>Chloroquine (>200 L\/kg), amiodarone (~5000 L), digoxin (~500 L)<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Clinical Corollaries of Large Vd<\/div>\n <p><strong>Haemodialysis is futile<\/strong> for drugs with large Vd \u2014 dialysis filters plasma only. With Vd = 500 L (digoxin), less than 1% of total body drug is in plasma at any time. <strong>Loading doses are necessary<\/strong> when Vd is large AND half-life is long \u2014 waiting for steady state with amiodarone (t\u00bd ~50 days, Vd ~5000 L) would take up to <strong>275 days<\/strong>. The loading dose rapidly fills the large distribution volume to achieve therapeutic levels immediately.<\/p>\n\n <p><span class=\"rv-pill\">Vd = Dose \u00f7 C\u2080<\/span> <span class=\"rv-pill\">Oral LD = (Cp \u00d7 Vd) \u00f7 F<\/span> <span class=\"rv-pill-teal\">Large Vd \u2192 dialysis futile<\/span> <span class=\"rv-pill-teal\">Large Vd + long t\u00bd \u2192 loading dose needed<\/span> <span class=\"rv-pill-green\">Benchmarks: 3 L plasma, 15 L ECF, 42 L TBW<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-03.html\">\u25b6 Open Round 03<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-04.html\">\n <div class=\"rv-sec-num\">Round 04 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Clearance & Steady-State Concentration <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Css = Infusion rate \u00f7 Clearance [UNITS MUST MATCH]<\/span>\n <span class=\"rv-formula\">CL = 0.693 \u00d7 Vd \u00f7 t\u00bd (or CL = k \u00d7 Vd)<\/span>\n <span class=\"rv-formula\">Maintenance dose = Css \u00d7 CL \u00f7 F<\/span>\n <span class=\"rv-formula\">Renal dose adjustment: New dose = Normal dose \u00d7 (Patient CrCl \u00f7 Normal CrCl)<\/span>\n\n <div class=\"rv-sub\">The Units Trap \u2014 The Most Common Exam Error<\/div>\n <p>Infusion rate is given in <strong>mg\/hour<\/strong>. Clearance is given in <strong>mL\/min<\/strong>. You cannot divide directly. Convert first:<\/p>\n <span class=\"rv-formula\">mL\/min \u00d7 60 = mL\/hour \u2192 \u00f7 1000 = L\/hour<\/span>\n <p>Example: clearance 100 mL\/min = 6000 mL\/hr = <strong>6 L\/hr<\/strong>. Infusion rate 200 mg\/hr \u00f7 6 L\/hr = 33.33 mg\/L. The distractor 50 mg\/L comes from dividing by 4 (using 100 mL\/min as if it were L\/hr).<\/p>\n\n <div class=\"rv-sub\">Hepatic Extraction Ratio \u2014 Flow vs Capacity<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Extraction ratio<\/th><th>Clearance depends on<\/th><th>Effect of cirrhosis<\/th><th>Examples<\/th><\/tr>\n <tr><td>High (>0.7)<\/td><td>Liver blood flow<\/td><td>Dramatic rise in oral bioavailability; toxicity on normal doses<\/td><td>Propranolol, morphine, lignocaine, labetalol<\/td><\/tr>\n <tr><td>Low (<0.3)<\/td><td>Enzyme capacity<\/td><td>Modest effect on bioavailability<\/td><td>Warfarin, diazepam, theophylline<\/td><\/tr>\n <\/table>\n <\/div>\n\n <p><span class=\"rv-pill\">Css = Rate \u00f7 CL \u2014 convert units first<\/span> <span class=\"rv-pill\">CL = 0.693 \u00d7 Vd \u00f7 t\u00bd<\/span> <span class=\"rv-pill-teal\">High extraction drugs dangerous in cirrhosis<\/span> <span class=\"rv-pill-teal\">New steady state after rate change = another 4\u20135 t\u00bd<\/span> <span class=\"rv-pill-green\">mL\/min \u00d7 60 \u00f7 1000 = L\/hr<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-04.html\">\u25b6 Open Round 04<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-05.html\">\n <div class=\"rv-sec-num\">Round 05 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Therapeutic Index, ED50 & LD50 <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Therapeutic Index (TI) = LD50 \u00f7 ED50 [higher = safer]<\/span>\n <span class=\"rv-formula\">Certain Safety Factor (CSF) = TD1 \u00f7 ED99 [more clinically honest]<\/span>\n\n <div class=\"rv-sub\">TI Interpretation Anchors<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>TI value<\/th><th>Interpretation<\/th><th>Examples<\/th><\/tr>\n <tr><td>>100<\/td><td>Very wide safety margin<\/td><td>Penicillin, paracetamol (therapeutic range)<\/td><\/tr>\n <tr><td>~10<\/td><td>Reasonable margin<\/td><td>Most antihypertensives<\/td><\/tr>\n <tr><td><2<\/td><td>Narrow therapeutic index (NTI) \u2014 requires monitoring<\/td><td>Digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Potency vs Efficacy \u2014 The Distinction Examiners Exploit<\/div>\n <p><strong>Potency<\/strong> = dose required for a given effect. Lower ED50 = more potent. <strong>Efficacy<\/strong> = maximum effect a drug can produce. These are <strong>independent axes<\/strong>. A more potent drug is not safer and not more efficacious. Botulinum toxin is the most potent substance known \u2014 its margin to lethality is correspondingly tiny. Codeine and morphine have the same ceiling effect (efficacy); morphine is simply more potent.<\/p>\n\n <div class=\"rv-sub\">Why CSF Matters More Than TI<\/div>\n <p>Classic TI uses median values \u2014 the middle of the population. CSF asks what happens when you give the dose needed to treat the <em>most resistant<\/em> 1% of patients (ED99) to the <em>most sensitive<\/em> 1% (TD1). A CSF of 2 means these two curves nearly overlap. Digoxin's CSF approaches 1 \u2014 explaining why routine therapeutic monitoring is mandatory.<\/p>\n\n <p><span class=\"rv-pill\">TI = LD50 \u00f7 ED50 (not inverted)<\/span> <span class=\"rv-pill\">NTI drugs: digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides<\/span> <span class=\"rv-pill-teal\">Potency \u2260 safety \u2260 efficacy<\/span> <span class=\"rv-pill-teal\">CSF = TD1 \u00f7 ED99<\/span> <span class=\"rv-pill-green\">Higher TI = wider safety margin<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-05.html\">\u25b6 Open Round 05<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-06.html\">\n <div class=\"rv-sec-num\">Round 06 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Mixed Clinical Numericals <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">High-Yield Clinical Integrations<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Drug \/ Scenario<\/th><th>Key calculation<\/th><th>Clinical lesson<\/th><\/tr>\n <tr><td>Digoxin toxicity<\/td><td>Total body burden = Cp \u00d7 Vd<br>(4 ng\/mL \u00d7 500 L = 2000 mcg)<\/td><td><1% in plasma \u2192 haemodialysis futile \u2192 use Digibind<\/td><\/tr>\n <tr><td>Theophylline maintenance<\/td><td>Dose = Css \u00d7 CL \u00f7 F<br>(convert mL\/min \u2192 L\/hr first)<\/td><td>Units trap: 40 mL\/min = 2.4 L\/hr, not 40<\/td><\/tr>\n <tr><td>Phenytoin dose increase<\/td><td>33% dose rise \u2192 200% Cp rise<\/td><td>Michaelis-Menten saturation: enzymes near-saturated at therapeutic levels<\/td><\/tr>\n <tr><td>Thiopentone offset<\/td><td>Wakes in 10 min; t\u00bd = 11 hours<\/td><td>Redistribution from brain to muscle\/fat \u2014 not elimination<\/td><\/tr>\n <tr><td>Bioavailability from AUC<\/td><td>F = (AUC<sub>oral<\/sub>\/Dose<sub>oral<\/sub>) \u00f7 (AUC<sub>IV<\/sub>\/Dose<sub>IV<\/sub>)<\/td><td>Dose-normalise before dividing \u2014 the most common error<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Michaelis-Menten (Saturation) Kinetics<\/div>\n <p>At low concentrations: first-order behaviour (enzymes not saturated). At high concentrations: zero-order behaviour (enzymes saturated). Phenytoin operates <strong>at the inflection point<\/strong> near therapeutic levels \u2014 small dose increases produce disproportionately large rises in plasma concentration. Clinical rule: adjust phenytoin in <strong>25\u201350 mg increments only<\/strong> and recheck levels after 2 weeks. Other MM drugs: aspirin (high dose), alcohol, salicylates.<\/p>\n\n <div class=\"rv-sub\">Two-Compartment Kinetics \u2014 Redistribution<\/div>\n <p>Thiopentone: highly lipophilic, rapidly enters <strong>brain<\/strong> (high blood flow) \u2192 unconsciousness. Then redistributes to <strong>muscle<\/strong> and <strong>fat<\/strong> (large mass) \u2192 brain concentration falls below anaesthetic threshold \u2192 patient wakes. Total body drug: barely changed. Terminal t\u00bd of 11 hours reflects <strong>slow release from fat + hepatic metabolism<\/strong>, not the clinical offset. Same principle applies to diazepam single-dose clinical duration.<\/p>\n\n <p><span class=\"rv-pill\">Total drug = Cp \u00d7 Vd<\/span> <span class=\"rv-pill\">Digoxin toxicity \u2192 Digibind, not dialysis<\/span> <span class=\"rv-pill-teal\">Phenytoin: MM kinetics, adjust in 25\u201350 mg steps<\/span> <span class=\"rv-pill-teal\">Thiopentone offset = redistribution, not elimination<\/span> <span class=\"rv-pill-green\">Bioavailability: dose-normalise AUCs before ratio<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-06.html\">\u25b6 Open Round 06<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-07.html\">\n <div class=\"rv-sec-num\">Round 07 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Bioavailability, Protein Binding & Special Populations <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Bioavailability & First-Pass \u2014 Route Anatomy<\/div>\n <p><strong>Oral route<\/strong>: gut \u2192 portal vein \u2192 liver \u2192 first-pass metabolism \u2192 systemic circulation. <strong>Sublingual<\/strong>: superior vena cava \u2192 systemic circulation directly (bypasses liver). <strong>GTN oral bioavailability <1%<\/strong>; sublingual ~80%. If a patient swallows a sublingual GTN tablet \u2014 no therapeutic effect. Transdermal and IV routes also bypass first-pass.<\/p>\n\n <div class=\"rv-sub\">Protein Binding \u2014 Free Drug Principle<\/div>\n <p>Only <strong>free (unbound) drug<\/strong> is pharmacologically active, distributes across membranes, and is available for elimination. Bound drug is inert reservoir. Warfarin 99% bound: displacing 1% of binding sites doubles the free fraction from 1% to 2% \u2014 doubling pharmacological effect on the same total dose. High-risk displacing drugs: phenylbutazone, aspirin, NSAIDs, sulfonamides.<\/p>\n\n <div class=\"rv-sub\">Special Populations \u2014 Rapid Reference<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Population<\/th><th>Key PK change<\/th><th>Dosing implication<\/th><\/tr>\n <tr><td><strong>Neonates<\/strong><\/td><td>GFR ~30% adult; immature CYP450; glucuronidation deficient; TBW 80%<\/td><td>Extend dosing intervals; higher mg\/kg Vd for water-soluble drugs; avoid chloramphenicol (grey baby syndrome)<\/td><\/tr>\n <tr><td><strong>Elderly<\/strong><\/td><td>Reduced muscle mass \u2192 low creatinine production \u2192 serum Cr appears normal despite reduced GFR<\/td><td>Always calculate CrCl (Cockcroft-Gault); never trust serum creatinine alone<\/td><\/tr>\n <tr><td><strong>Pregnancy<\/strong><\/td><td>Plasma volume +40%; albumin \u221220%; GFR increases; hepatic CYP activity changes<\/td><td>Expanded Vd dilutes drug; reduced albumin raises free fraction; NTI drugs need monitoring throughout<\/td><\/tr>\n <tr><td><strong>Hepatic failure<\/strong><\/td><td>High-extraction drugs: dramatically increased oral bioavailability (portosystemic shunting)<\/td><td>Propranolol, morphine, lignocaine \u2014 reduce dose substantially or avoid<\/td><\/tr>\n <tr><td><strong>Renal failure<\/strong><\/td><td>Clearance of renally-excreted drugs falls proportionally with GFR<\/td><td>Reduce dose OR extend interval; both strategies are pharmacokinetically valid<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">The Elderly Creatinine Trap<\/div>\n <p>Sarcopenia (reduced muscle mass) \u2192 less creatinine produced \u2192 serum creatinine appears \"normal\" despite severely impaired GFR. <strong>Cockcroft-Gault must be calculated<\/strong> in all elderly patients before prescribing renally-cleared drugs. A serum creatinine of 90 \u00b5mol\/L in an 80-year-old woman of 45 kg may correspond to a CrCl of only 22 mL\/min \u2014 severe renal impairment requiring significant gentamicin dose reduction and interval extension.<\/p>\n\n <p><span class=\"rv-pill\">Swallowed GTN \u2192 <1% bioavailability \u2192 no effect<\/span> <span class=\"rv-pill\">Free drug = active drug<\/span> <span class=\"rv-pill-teal\">Warfarin displacement: 1% \u2192 2% free = double effect<\/span> <span class=\"rv-pill-teal\">Elderly: calculate CrCl, never rely on serum Cr alone<\/span> <span class=\"rv-pill-green\">Neonates: extend intervals; immature CYP + GFR<\/span> <span class=\"rv-pill-green\">Pregnancy: monitor NTI drugs throughout<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-07.html\">\u25b6 Open Round 07<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <div class=\"rv-sec-num\">Cross-Series \u00b7 Pharmacokinetics<\/div>\n <div class=\"rv-sec-title\">Examiner's Favourites \u2014 Rapid Recall<\/div>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Formula reference \u2014 one line each<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Formula<\/th><th>Expression<\/th><\/tr>\n <tr><td>Vd<\/td><td>Dose \u00f7 C\u2080<\/td><\/tr>\n <tr><td>t\u00bd<\/td><td>0.693 \u00d7 Vd \u00f7 CL<\/td><\/tr>\n <tr><td>CL (total body)<\/td><td>0.693 \u00d7 Vd \u00f7 t\u00bd<\/td><\/tr>\n <tr><td>Css (infusion)<\/td><td>Infusion rate \u00f7 CL [units must match]<\/td><\/tr>\n <tr><td>Loading dose (IV)<\/td><td>Target Cp \u00d7 Vd<\/td><\/tr>\n <tr><td>Loading dose (oral)<\/td><td>(Target Cp \u00d7 Vd) \u00f7 F<\/td><\/tr>\n <tr><td>Maintenance dose<\/td><td>Css \u00d7 CL \u00f7 F<\/td><\/tr>\n <tr><td>Bioavailability (F)<\/td><td>(AUC<sub>oral<\/sub>\/Dose<sub>oral<\/sub>) \u00f7 (AUC<sub>IV<\/sub>\/Dose<sub>IV<\/sub>)<\/td><\/tr>\n <tr><td>Therapeutic Index<\/td><td>LD50 \u00f7 ED50<\/td><\/tr>\n <tr><td>Certain Safety Factor<\/td><td>TD1 \u00f7 ED99<\/td><\/tr>\n <tr><td>k (rate constant)<\/td><td>0.693 \u00f7 t\u00bd<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Unit conversion anchors \u2014 do these before every calculation<\/div>\n <p>\n <span class=\"rv-pill\">mL\/min \u2192 L\/hr: \u00d7 60 then \u00f7 1000<\/span>\n <span class=\"rv-pill\">ng\/mL = mcg\/L (equivalent units)<\/span>\n <span class=\"rv-pill-teal\">mL \u00d7 concentration \u2192 ng or mcg (watch the prefix)<\/span>\n <span class=\"rv-pill-green\">Always match time units (hr vs min) before dividing<\/span>\n <\/p>\n\n <div class=\"rv-sub\">Drugs with notable pharmacokinetics \u2014 exam anchors<\/div>\n <p>\n <span class=\"rv-pill\">Digoxin: Vd 500 L, t\u00bd 36 hr, NTI \u2014 Digibind for toxicity<\/span>\n <span class=\"rv-pill\">Amiodarone: Vd ~5000 L, t\u00bd 40\u201355 days \u2014 loading dose mandatory<\/span>\n <span class=\"rv-pill\">Chloroquine: Vd >200 L\/kg \u2014 dialysis futile in OD<\/span>\n <span class=\"rv-pill-teal\">Phenytoin: MM kinetics \u2014 25\u201350 mg increments only<\/span>\n <span class=\"rv-pill-teal\">GTN: oral bioavailability <1% \u2014 sublingual\/IV\/transdermal only<\/span>\n <span class=\"rv-pill-teal\">Propranolol\/morphine\/lignocaine: high extraction \u2014 dangerous in cirrhosis<\/span>\n <span class=\"rv-pill-green\">Thiopentone: offset by redistribution to fat, not elimination<\/span>\n <span class=\"rv-pill-green\">Warfarin 99% bound: displacement doubles free fraction<\/span>\n <\/p>\n\n <div class=\"rv-sub\">Sequence rules \u2014 act in order<\/div>\n <p>\n <span class=\"rv-pill\">Convert units \u2192 apply formula \u2192 interpret clinically<\/span>\n <span class=\"rv-pill\">Dose-normalise AUCs before calculating bioavailability<\/span>\n <span class=\"rv-pill-teal\">Calculate CrCl before prescribing in the elderly \u2014 serum Cr alone is unreliable<\/span>\n <span class=\"rv-pill-teal\">Adjust phenytoin in small increments, recheck after 2 weeks<\/span>\n <span class=\"rv-pill-green\">In overdose: calculate Vd before deciding on dialysis<\/span>\n <span class=\"rv-pill-green\">In loading dose: remember to divide by F for oral route<\/span>\n <\/p>\n\n <div class=\"rv-sub\">The traps examiners set repeatedly<\/div>\n <p>\n <span class=\"rv-pill\">mL\/min \u2260 L\/hr \u2014 convert before dividing for Css<\/span>\n <span class=\"rv-pill\">87.5% eliminated at 3 half-lives, not 75%<\/span>\n <span class=\"rv-pill-teal\">TI = LD50 \u00f7 ED50 (not inverted, not subtracted)<\/span>\n <span class=\"rv-pill-teal\">Potency \u2260 safety \u2260 efficacy \u2014 three independent properties<\/span>\n <span class=\"rv-pill-teal\">Serum Cr \"normal\" in elderly \u2260 normal renal function<\/span>\n <span class=\"rv-pill-green\">Doubling infusion rate doubles Css, but new SS still takes 4\u20135 t\u00bd<\/span>\n <span class=\"rv-pill-green\">MAOI washout = enzyme resynthesis (14 days), not PK clearance (2 hrs)<\/span>\n <span class=\"rv-pill-green\">Dose-normalise AUC before bioavailability ratio \u2014 not raw AUC<\/span>\n <\/p>\n\n <\/div>\n <\/div>\n\n <div class=\"rv-footer\">\n Pharmacokinetics Summative Revision \u00b7 atsixty.com \u00b7 Morning Rounds \u00b7 Numerical Series<br>\n <a href=\"mr-npk-index.html\">\u2190 Return to Pharmacokinetics Series Index<\/a>\n <\/div>\n\n <\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Morning Rounds \u00b7 Pharmacokinetics \u00b7 Summative Revision Morning Rounds \u00b7 Numerical Series \u00b7 Pharmacokinetics PharmacokineticsSummative Revision Notes Seven rounds \u00b7 NEET-PG \/ INI-CET \/ UPSC CMS \u00b7 Formulae, thresholds, clinical anchors & traps Zero & First Order Half-Life & Washout Vd & Loading Dose Clearance & Steady State TI \u00b7 ED50 \u00b7 LD50 Clinical Numericals… <\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"neve_meta_sidebar":"","neve_meta_container":"","neve_meta_enable_content_width":"","neve_meta_content_width":0,"neve_meta_title_alignment":"","neve_meta_author_avatar":"","neve_post_elements_order":"","neve_meta_disable_header":"","neve_meta_disable_footer":"","neve_meta_disable_title":"","footnotes":""},"categories":[74,79],"tags":[83],"class_list":["post-37358","post","type-post","status-publish","format-standard","hentry","category-morning-rounds","category-pharmacology","tag-neet-pg"],"yoast_head":"\n<title>Pharmacokinetics - Summative Revision Notes - atsixty<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/atsixty.com\/index.php\/morning-rounds\/pharmacokinetics-summative-revision-notes\/\" \/>\n<meta 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{"id":37358,"date":"2026-08-23T10:42:26","date_gmt":"2026-08-23T05:12:26","guid":{"rendered":"https:\/\/atsixty.com\/?p=37358"},"modified":"2026-08-23T10:46:03","modified_gmt":"2026-08-23T05:16:03","slug":"pharmacokinetics-summative-revision-notes","status":"publish","type":"post","link":"https:\/\/atsixty.com\/index.php\/morning-rounds\/pharmacokinetics-summative-revision-notes\/","title":{"rendered":"Pharmacokinetics – Summative Revision Notes"},"content":{"rendered":"\n\n\n\n\n\n\n\nMorning Rounds \u00b7 Pharmacokinetics \u00b7 Summative Revision<\/title>\n<link href=\"https:\/\/fonts.googleapis.com\/css2?family=Playfair+Display:ital,wght@0,400;0,600;0,700;1,400;1,600&family=Source+Serif+4:ital,wght@0,300;0,400;0,600;1,400&display=swap\" rel=\"stylesheet\">\n<style>\n#npk-sr *,#npk-sr *::before,#npk-sr *::after{box-sizing:border-box;margin:0;padding:0}\n#npk-sr{\n --ob:#1A5F7A;--ob-dark:#114455;--ob-pale:#E6F3F7;--ob-mid:#236E8C;\n --acc:#1A7A5F;--acc-pale:#E6F5F1;\n 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td{padding:7px 12px;border-bottom:1px solid var(--line);color:var(--ink-mid);vertical-align:top}\n#npk-sr tr:last-child td{border-bottom:none}\n#npk-sr tr:nth-child(even) td{background:#EAF4F8}\n#npk-sr td strong{color:var(--ink)}\n#npk-sr .rv-formula{display:block;background:rgba(26,95,122,0.07);border-left:3px solid var(--ob);border-radius:0 4px 4px 0;padding:7px 12px;margin:8px 0;font-family:Georgia,serif;font-size:0.88rem;color:var(--ob-dark);}\n#npk-sr .rv-rule{height:1px;background:var(--line);margin:6px 0 12px}\n#npk-sr .rv-quiz-wrap{text-align:right;margin-top:14px}\n#npk-sr .rv-quiz-link{display:inline-block;font-size:0.80rem;color:var(--ob);font-weight:600;text-decoration:none;border:1px solid var(--ob);border-radius:6px;padding:4px 13px}\n#npk-sr .rv-quiz-link:hover{background:var(--ob);color:#E4F4F9}\n#npk-sr .rv-footer{margin-top:32px;text-align:center;font-size:0.80rem;color:var(--ink-soft);font-style:italic;line-height:1.6}\n#npk-sr .rv-footer a{color:var(--ob);font-style:normal;font-weight:600;text-decoration:none;border-bottom:1px solid var(--ob)}\n#npk-sr .rv-footer a:hover{opacity:0.75}\n@media print{\n #npk-sr .rv-header{background:#1A5F7A !important;-webkit-print-color-adjust:exact}\n #npk-sr{padding-bottom:20px}\n #npk-sr .rv-section{break-inside:avoid;box-shadow:none}\n}\n@media(max-width:480px){\n #npk-sr .rv-title{font-size:1.45rem}\n #npk-sr .rv-sec-title{font-size:1rem}\n #npk-sr table{font-size:0.76rem}\n #npk-sr td,#npk-sr th{padding:6px 8px}\n}\n<\/style>\n\n<div id=\"npk-sr\">\n\n <div class=\"rv-header\">\n <div class=\"rv-eyebrow\">Morning Rounds \u00b7 Numerical Series \u00b7 Pharmacokinetics<\/div>\n <div class=\"rv-title\">Pharmacokinetics<br><em>Summative Revision Notes<\/em><\/div>\n <div class=\"rv-subtitle\">Seven rounds \u00b7 NEET-PG \/ INI-CET \/ UPSC CMS \u00b7 Formulae, thresholds, clinical anchors & traps<\/div>\n <div class=\"rv-chips\">\n <span class=\"rv-chip\">Zero & First Order<\/span>\n <span class=\"rv-chip\">Half-Life & Washout<\/span>\n <span class=\"rv-chip\">Vd & Loading Dose<\/span>\n <span class=\"rv-chip\">Clearance & Steady State<\/span>\n <span class=\"rv-chip\">TI \u00b7 ED50 \u00b7 LD50<\/span>\n <span class=\"rv-chip\">Clinical Numericals<\/span>\n <span class=\"rv-chip\">Special Populations<\/span>\n <\/div>\n <\/div>\n\n <div class=\"rv-body\">\n\n <div class=\"rv-intro\">\n <p>These notes consolidate all seven Pharmacokinetics Morning Rounds. They are written for rapid pre-exam revision \u2014 not first-time learning. Each section heading links to its quiz. The formula reference blocks are printed in the format examiners expect. Every trap identified in the round debriefs appears here as a single-line recall badge.<\/p>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-01.html\">\n <div class=\"rv-sec-num\">Round 01 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Zero-Order vs First-Order Kinetics <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">The Core Distinction<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Feature<\/th><th>Zero-Order<\/th><th>First-Order<\/th><\/tr>\n <tr><td>What is constant?<\/td><td><strong>Amount<\/strong> eliminated per unit time<\/td><td><strong>Fraction<\/strong> (%) eliminated per unit time<\/td><\/tr>\n <tr><td>Rate depends on concentration?<\/td><td>No \u2014 rate is fixed<\/td><td>Yes \u2014 rate falls as concentration falls<\/td><\/tr>\n <tr><td>Half-life concept<\/td><td>Does not apply (changes with dose)<\/td><td>Constant; independent of dose<\/td><\/tr>\n <tr><td>Plasma conc. vs time plot<\/td><td>Straight line (linear)<\/td><td>Exponential decay (log-linear straight)<\/td><\/tr>\n <tr><td>Clinical examples<\/td><td>Alcohol, phenytoin (high dose), aspirin (OD)<\/td><td>Most drugs at therapeutic doses<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">First-order: Amount remaining after n half-lives = C\u2080 \u00d7 (\u00bd)\u207f<\/span>\n <span class=\"rv-formula\">% eliminated after n half-lives = 100 \u2212 [100 \u00d7 (\u00bd)\u207f]<\/span>\n <span class=\"rv-formula\">Zero-order: Amount remaining = Initial dose \u2212 (Rate \u00d7 Time)<\/span>\n\n <div class=\"rv-sub\">The Vd Analogy \u2014 Why It Matters<\/div>\n <p>Vd is not a real anatomical volume. It is the <strong>hypothetical volume<\/strong> needed to contain all the drug in the body at the same concentration as measured in plasma. A drug with Vd = 700 L in a 70 kg person has not disappeared \u2014 it has been <strong>sequestered in tissues<\/strong>, leaving almost nothing in plasma. This is why haemodialysis, which filters only plasma, is futile for drugs with large Vd. The swimming pool analogy: dissolve a teaspoon of salt in a glass (high plasma concentration, small Vd) versus a swimming pool (undetectable in plasma, but the drug is still there \u2014 in tissues).<\/p>\n\n <p><span class=\"rv-pill\">3 half-lives \u2192 87.5% eliminated (not 75%)<\/span> <span class=\"rv-pill\">Zero-order: constant amount, not fraction<\/span> <span class=\"rv-pill-teal\">Alcohol, phenytoin OD, aspirin OD = zero-order<\/span> <span class=\"rv-pill-green\">Most therapeutic drugs = first-order<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-01.html\">\u25b6 Open Round 01<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-02.html\">\n <div class=\"rv-sec-num\">Round 02 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Half-Life & the Arithmetic of Washout <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">k (elimination rate constant) = 0.693 \u00f7 t\u00bd<\/span>\n <span class=\"rv-formula\">Back-calculate t\u00bd: count the number of halvings in the interval, then t\u00bd = Time \u00f7 n<\/span>\n <span class=\"rv-formula\">Time to steady state = 4\u20135 \u00d7 t\u00bd (independent of dose or dosing interval)<\/span>\n <span class=\"rv-formula\">Time to 95% elimination \u2248 5 \u00d7 t\u00bd<\/span>\n\n <div class=\"rv-sub\">The 4\u20135 Half-Life Rules<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Half-lives elapsed<\/th><th>% Eliminated<\/th><th>% Remaining<\/th><\/tr>\n <tr><td>1<\/td><td>50%<\/td><td>50%<\/td><\/tr>\n <tr><td>2<\/td><td>75%<\/td><td>25%<\/td><\/tr>\n <tr><td>3<\/td><td>87.5%<\/td><td>12.5%<\/td><\/tr>\n <tr><td>4<\/td><td>93.75%<\/td><td>6.25%<\/td><\/tr>\n <tr><td>5<\/td><td>96.875%<\/td><td>~3%<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Critical Distinction \u2014 PK Half-Life vs Clinical Duration<\/div>\n <p><strong>Half-life governs plasma concentration, not always duration of clinical effect.<\/strong> Phenelzine (MAOI) has a plasma t\u00bd of ~2 hours but requires a <strong>14-day washout<\/strong> before starting serotonergic drugs \u2014 because it <em>irreversibly<\/em> destroys MAO enzyme, and new enzyme synthesis takes 14 days. Being at steady state does not mean reaching a new steady state instantly after a dose change \u2014 re-equilibration always takes another 4\u20135 half-lives.<\/p>\n\n <p><span class=\"rv-pill\">Steady state reached in 4\u20135 t\u00bd regardless of dose<\/span> <span class=\"rv-pill\">95% elimination \u2248 5 \u00d7 t\u00bd<\/span> <span class=\"rv-pill-teal\">MAOI washout = enzyme resynthesis, not PK clearance<\/span> <span class=\"rv-pill-green\">k = 0.693 \u00f7 t\u00bd \u2014 memorise this<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-02.html\">\u25b6 Open Round 02<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-03.html\">\n <div class=\"rv-sec-num\">Round 03 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Volume of Distribution & Loading Dose <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Vd = Dose \u00f7 C\u2080 (initial plasma concentration)<\/span>\n <span class=\"rv-formula\">IV Loading Dose = Target Cp \u00d7 Vd<\/span>\n <span class=\"rv-formula\">Oral Loading Dose = (Target Cp \u00d7 Vd) \u00f7 F (bioavailability)<\/span>\n\n <div class=\"rv-sub\">Compartment Benchmarks \u2014 Memorise These Three<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Vd value<\/th><th>Drug location<\/th><th>Example<\/th><\/tr>\n <tr><td>~3\u20135 L<\/td><td>Confined to plasma<\/td><td>Heparin, warfarin, monoclonal antibodies<\/td><\/tr>\n <tr><td>~15 L<\/td><td>Extracellular fluid<\/td><td>Gentamicin, mannitol<\/td><\/tr>\n <tr><td>~42 L<\/td><td>Total body water<\/td><td>Ethanol, theophylline<\/td><\/tr>\n <tr><td>>100 L<\/td><td>Extensive tissue sequestration<\/td><td>Chloroquine (>200 L\/kg), amiodarone (~5000 L), digoxin (~500 L)<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Clinical Corollaries of Large Vd<\/div>\n <p><strong>Haemodialysis is futile<\/strong> for drugs with large Vd \u2014 dialysis filters plasma only. With Vd = 500 L (digoxin), less than 1% of total body drug is in plasma at any time. <strong>Loading doses are necessary<\/strong> when Vd is large AND half-life is long \u2014 waiting for steady state with amiodarone (t\u00bd ~50 days, Vd ~5000 L) would take up to <strong>275 days<\/strong>. The loading dose rapidly fills the large distribution volume to achieve therapeutic levels immediately.<\/p>\n\n <p><span class=\"rv-pill\">Vd = Dose \u00f7 C\u2080<\/span> <span class=\"rv-pill\">Oral LD = (Cp \u00d7 Vd) \u00f7 F<\/span> <span class=\"rv-pill-teal\">Large Vd \u2192 dialysis futile<\/span> <span class=\"rv-pill-teal\">Large Vd + long t\u00bd \u2192 loading dose needed<\/span> <span class=\"rv-pill-green\">Benchmarks: 3 L plasma, 15 L ECF, 42 L TBW<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-03.html\">\u25b6 Open Round 03<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-04.html\">\n <div class=\"rv-sec-num\">Round 04 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Clearance & Steady-State Concentration <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Css = Infusion rate \u00f7 Clearance [UNITS MUST MATCH]<\/span>\n <span class=\"rv-formula\">CL = 0.693 \u00d7 Vd \u00f7 t\u00bd (or CL = k \u00d7 Vd)<\/span>\n <span class=\"rv-formula\">Maintenance dose = Css \u00d7 CL \u00f7 F<\/span>\n <span class=\"rv-formula\">Renal dose adjustment: New dose = Normal dose \u00d7 (Patient CrCl \u00f7 Normal CrCl)<\/span>\n\n <div class=\"rv-sub\">The Units Trap \u2014 The Most Common Exam Error<\/div>\n <p>Infusion rate is given in <strong>mg\/hour<\/strong>. Clearance is given in <strong>mL\/min<\/strong>. You cannot divide directly. Convert first:<\/p>\n <span class=\"rv-formula\">mL\/min \u00d7 60 = mL\/hour \u2192 \u00f7 1000 = L\/hour<\/span>\n <p>Example: clearance 100 mL\/min = 6000 mL\/hr = <strong>6 L\/hr<\/strong>. Infusion rate 200 mg\/hr \u00f7 6 L\/hr = 33.33 mg\/L. The distractor 50 mg\/L comes from dividing by 4 (using 100 mL\/min as if it were L\/hr).<\/p>\n\n <div class=\"rv-sub\">Hepatic Extraction Ratio \u2014 Flow vs Capacity<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Extraction ratio<\/th><th>Clearance depends on<\/th><th>Effect of cirrhosis<\/th><th>Examples<\/th><\/tr>\n <tr><td>High (>0.7)<\/td><td>Liver blood flow<\/td><td>Dramatic rise in oral bioavailability; toxicity on normal doses<\/td><td>Propranolol, morphine, lignocaine, labetalol<\/td><\/tr>\n <tr><td>Low (<0.3)<\/td><td>Enzyme capacity<\/td><td>Modest effect on bioavailability<\/td><td>Warfarin, diazepam, theophylline<\/td><\/tr>\n <\/table>\n <\/div>\n\n <p><span class=\"rv-pill\">Css = Rate \u00f7 CL \u2014 convert units first<\/span> <span class=\"rv-pill\">CL = 0.693 \u00d7 Vd \u00f7 t\u00bd<\/span> <span class=\"rv-pill-teal\">High extraction drugs dangerous in cirrhosis<\/span> <span class=\"rv-pill-teal\">New steady state after rate change = another 4\u20135 t\u00bd<\/span> <span class=\"rv-pill-green\">mL\/min \u00d7 60 \u00f7 1000 = L\/hr<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-04.html\">\u25b6 Open Round 04<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-05.html\">\n <div class=\"rv-sec-num\">Round 05 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Therapeutic Index, ED50 & LD50 <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Key Formulae<\/div>\n <span class=\"rv-formula\">Therapeutic Index (TI) = LD50 \u00f7 ED50 [higher = safer]<\/span>\n <span class=\"rv-formula\">Certain Safety Factor (CSF) = TD1 \u00f7 ED99 [more clinically honest]<\/span>\n\n <div class=\"rv-sub\">TI Interpretation Anchors<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>TI value<\/th><th>Interpretation<\/th><th>Examples<\/th><\/tr>\n <tr><td>>100<\/td><td>Very wide safety margin<\/td><td>Penicillin, paracetamol (therapeutic range)<\/td><\/tr>\n <tr><td>~10<\/td><td>Reasonable margin<\/td><td>Most antihypertensives<\/td><\/tr>\n <tr><td><2<\/td><td>Narrow therapeutic index (NTI) \u2014 requires monitoring<\/td><td>Digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Potency vs Efficacy \u2014 The Distinction Examiners Exploit<\/div>\n <p><strong>Potency<\/strong> = dose required for a given effect. Lower ED50 = more potent. <strong>Efficacy<\/strong> = maximum effect a drug can produce. These are <strong>independent axes<\/strong>. A more potent drug is not safer and not more efficacious. Botulinum toxin is the most potent substance known \u2014 its margin to lethality is correspondingly tiny. Codeine and morphine have the same ceiling effect (efficacy); morphine is simply more potent.<\/p>\n\n <div class=\"rv-sub\">Why CSF Matters More Than TI<\/div>\n <p>Classic TI uses median values \u2014 the middle of the population. CSF asks what happens when you give the dose needed to treat the <em>most resistant<\/em> 1% of patients (ED99) to the <em>most sensitive<\/em> 1% (TD1). A CSF of 2 means these two curves nearly overlap. Digoxin's CSF approaches 1 \u2014 explaining why routine therapeutic monitoring is mandatory.<\/p>\n\n <p><span class=\"rv-pill\">TI = LD50 \u00f7 ED50 (not inverted)<\/span> <span class=\"rv-pill\">NTI drugs: digoxin, lithium, phenytoin, warfarin, theophylline, aminoglycosides<\/span> <span class=\"rv-pill-teal\">Potency \u2260 safety \u2260 efficacy<\/span> <span class=\"rv-pill-teal\">CSF = TD1 \u00f7 ED99<\/span> <span class=\"rv-pill-green\">Higher TI = wider safety margin<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-05.html\">\u25b6 Open Round 05<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-06.html\">\n <div class=\"rv-sec-num\">Round 06 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Mixed Clinical Numericals <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">High-Yield Clinical Integrations<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Drug \/ Scenario<\/th><th>Key calculation<\/th><th>Clinical lesson<\/th><\/tr>\n <tr><td>Digoxin toxicity<\/td><td>Total body burden = Cp \u00d7 Vd<br>(4 ng\/mL \u00d7 500 L = 2000 mcg)<\/td><td><1% in plasma \u2192 haemodialysis futile \u2192 use Digibind<\/td><\/tr>\n <tr><td>Theophylline maintenance<\/td><td>Dose = Css \u00d7 CL \u00f7 F<br>(convert mL\/min \u2192 L\/hr first)<\/td><td>Units trap: 40 mL\/min = 2.4 L\/hr, not 40<\/td><\/tr>\n <tr><td>Phenytoin dose increase<\/td><td>33% dose rise \u2192 200% Cp rise<\/td><td>Michaelis-Menten saturation: enzymes near-saturated at therapeutic levels<\/td><\/tr>\n <tr><td>Thiopentone offset<\/td><td>Wakes in 10 min; t\u00bd = 11 hours<\/td><td>Redistribution from brain to muscle\/fat \u2014 not elimination<\/td><\/tr>\n <tr><td>Bioavailability from AUC<\/td><td>F = (AUC<sub>oral<\/sub>\/Dose<sub>oral<\/sub>) \u00f7 (AUC<sub>IV<\/sub>\/Dose<sub>IV<\/sub>)<\/td><td>Dose-normalise before dividing \u2014 the most common error<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Michaelis-Menten (Saturation) Kinetics<\/div>\n <p>At low concentrations: first-order behaviour (enzymes not saturated). At high concentrations: zero-order behaviour (enzymes saturated). Phenytoin operates <strong>at the inflection point<\/strong> near therapeutic levels \u2014 small dose increases produce disproportionately large rises in plasma concentration. Clinical rule: adjust phenytoin in <strong>25\u201350 mg increments only<\/strong> and recheck levels after 2 weeks. Other MM drugs: aspirin (high dose), alcohol, salicylates.<\/p>\n\n <div class=\"rv-sub\">Two-Compartment Kinetics \u2014 Redistribution<\/div>\n <p>Thiopentone: highly lipophilic, rapidly enters <strong>brain<\/strong> (high blood flow) \u2192 unconsciousness. Then redistributes to <strong>muscle<\/strong> and <strong>fat<\/strong> (large mass) \u2192 brain concentration falls below anaesthetic threshold \u2192 patient wakes. Total body drug: barely changed. Terminal t\u00bd of 11 hours reflects <strong>slow release from fat + hepatic metabolism<\/strong>, not the clinical offset. Same principle applies to diazepam single-dose clinical duration.<\/p>\n\n <p><span class=\"rv-pill\">Total drug = Cp \u00d7 Vd<\/span> <span class=\"rv-pill\">Digoxin toxicity \u2192 Digibind, not dialysis<\/span> <span class=\"rv-pill-teal\">Phenytoin: MM kinetics, adjust in 25\u201350 mg steps<\/span> <span class=\"rv-pill-teal\">Thiopentone offset = redistribution, not elimination<\/span> <span class=\"rv-pill-green\">Bioavailability: dose-normalise AUCs before ratio<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-06.html\">\u25b6 Open Round 06<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <a href=\"mr-npk-07.html\">\n <div class=\"rv-sec-num\">Round 07 \u00b7 Pharmacokinetics Numerical Series<\/div>\n <div class=\"rv-sec-title\">Bioavailability, Protein Binding & Special Populations <span class=\"rv-arrow\">\u2197<\/span><\/div>\n <\/a>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Bioavailability & First-Pass \u2014 Route Anatomy<\/div>\n <p><strong>Oral route<\/strong>: gut \u2192 portal vein \u2192 liver \u2192 first-pass metabolism \u2192 systemic circulation. <strong>Sublingual<\/strong>: superior vena cava \u2192 systemic circulation directly (bypasses liver). <strong>GTN oral bioavailability <1%<\/strong>; sublingual ~80%. If a patient swallows a sublingual GTN tablet \u2014 no therapeutic effect. Transdermal and IV routes also bypass first-pass.<\/p>\n\n <div class=\"rv-sub\">Protein Binding \u2014 Free Drug Principle<\/div>\n <p>Only <strong>free (unbound) drug<\/strong> is pharmacologically active, distributes across membranes, and is available for elimination. Bound drug is inert reservoir. Warfarin 99% bound: displacing 1% of binding sites doubles the free fraction from 1% to 2% \u2014 doubling pharmacological effect on the same total dose. High-risk displacing drugs: phenylbutazone, aspirin, NSAIDs, sulfonamides.<\/p>\n\n <div class=\"rv-sub\">Special Populations \u2014 Rapid Reference<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Population<\/th><th>Key PK change<\/th><th>Dosing implication<\/th><\/tr>\n <tr><td><strong>Neonates<\/strong><\/td><td>GFR ~30% adult; immature CYP450; glucuronidation deficient; TBW 80%<\/td><td>Extend dosing intervals; higher mg\/kg Vd for water-soluble drugs; avoid chloramphenicol (grey baby syndrome)<\/td><\/tr>\n <tr><td><strong>Elderly<\/strong><\/td><td>Reduced muscle mass \u2192 low creatinine production \u2192 serum Cr appears normal despite reduced GFR<\/td><td>Always calculate CrCl (Cockcroft-Gault); never trust serum creatinine alone<\/td><\/tr>\n <tr><td><strong>Pregnancy<\/strong><\/td><td>Plasma volume +40%; albumin \u221220%; GFR increases; hepatic CYP activity changes<\/td><td>Expanded Vd dilutes drug; reduced albumin raises free fraction; NTI drugs need monitoring throughout<\/td><\/tr>\n <tr><td><strong>Hepatic failure<\/strong><\/td><td>High-extraction drugs: dramatically increased oral bioavailability (portosystemic shunting)<\/td><td>Propranolol, morphine, lignocaine \u2014 reduce dose substantially or avoid<\/td><\/tr>\n <tr><td><strong>Renal failure<\/strong><\/td><td>Clearance of renally-excreted drugs falls proportionally with GFR<\/td><td>Reduce dose OR extend interval; both strategies are pharmacokinetically valid<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">The Elderly Creatinine Trap<\/div>\n <p>Sarcopenia (reduced muscle mass) \u2192 less creatinine produced \u2192 serum creatinine appears \"normal\" despite severely impaired GFR. <strong>Cockcroft-Gault must be calculated<\/strong> in all elderly patients before prescribing renally-cleared drugs. A serum creatinine of 90 \u00b5mol\/L in an 80-year-old woman of 45 kg may correspond to a CrCl of only 22 mL\/min \u2014 severe renal impairment requiring significant gentamicin dose reduction and interval extension.<\/p>\n\n <p><span class=\"rv-pill\">Swallowed GTN \u2192 <1% bioavailability \u2192 no effect<\/span> <span class=\"rv-pill\">Free drug = active drug<\/span> <span class=\"rv-pill-teal\">Warfarin displacement: 1% \u2192 2% free = double effect<\/span> <span class=\"rv-pill-teal\">Elderly: calculate CrCl, never rely on serum Cr alone<\/span> <span class=\"rv-pill-green\">Neonates: extend intervals; immature CYP + GFR<\/span> <span class=\"rv-pill-green\">Pregnancy: monitor NTI drugs throughout<\/span><\/p>\n\n <div class=\"rv-quiz-wrap\"><a class=\"rv-quiz-link\" href=\"mr-npk-07.html\">\u25b6 Open Round 07<\/a><\/div>\n <\/div>\n <\/div>\n\n \n <div class=\"rv-section\">\n <div class=\"rv-sec-head\">\n <div class=\"rv-sec-num\">Cross-Series \u00b7 Pharmacokinetics<\/div>\n <div class=\"rv-sec-title\">Examiner's Favourites \u2014 Rapid Recall<\/div>\n <\/div>\n <div class=\"rv-sec-body\">\n\n <div class=\"rv-sub\">Formula reference \u2014 one line each<\/div>\n <div class=\"rv-table-wrap\">\n <table>\n <tr><th>Formula<\/th><th>Expression<\/th><\/tr>\n <tr><td>Vd<\/td><td>Dose \u00f7 C\u2080<\/td><\/tr>\n <tr><td>t\u00bd<\/td><td>0.693 \u00d7 Vd \u00f7 CL<\/td><\/tr>\n <tr><td>CL (total body)<\/td><td>0.693 \u00d7 Vd \u00f7 t\u00bd<\/td><\/tr>\n <tr><td>Css (infusion)<\/td><td>Infusion rate \u00f7 CL [units must match]<\/td><\/tr>\n <tr><td>Loading dose (IV)<\/td><td>Target Cp \u00d7 Vd<\/td><\/tr>\n <tr><td>Loading dose (oral)<\/td><td>(Target Cp \u00d7 Vd) \u00f7 F<\/td><\/tr>\n <tr><td>Maintenance dose<\/td><td>Css \u00d7 CL \u00f7 F<\/td><\/tr>\n <tr><td>Bioavailability (F)<\/td><td>(AUC<sub>oral<\/sub>\/Dose<sub>oral<\/sub>) \u00f7 (AUC<sub>IV<\/sub>\/Dose<sub>IV<\/sub>)<\/td><\/tr>\n <tr><td>Therapeutic Index<\/td><td>LD50 \u00f7 ED50<\/td><\/tr>\n <tr><td>Certain Safety Factor<\/td><td>TD1 \u00f7 ED99<\/td><\/tr>\n <tr><td>k (rate constant)<\/td><td>0.693 \u00f7 t\u00bd<\/td><\/tr>\n <\/table>\n <\/div>\n\n <div class=\"rv-sub\">Unit conversion anchors \u2014 do these before every calculation<\/div>\n <p>\n <span class=\"rv-pill\">mL\/min \u2192 L\/hr: \u00d7 60 then \u00f7 1000<\/span>\n <span class=\"rv-pill\">ng\/mL = mcg\/L (equivalent units)<\/span>\n <span class=\"rv-pill-teal\">mL \u00d7 concentration \u2192 ng or mcg (watch the prefix)<\/span>\n <span class=\"rv-pill-green\">Always match time units (hr vs min) before dividing<\/span>\n <\/p>\n\n <div class=\"rv-sub\">Drugs with notable pharmacokinetics \u2014 exam anchors<\/div>\n <p>\n <span class=\"rv-pill\">Digoxin: Vd 500 L, t\u00bd 36 hr, NTI \u2014 Digibind for toxicity<\/span>\n <span class=\"rv-pill\">Amiodarone: Vd ~5000 L, t\u00bd 40\u201355 days \u2014 loading dose mandatory<\/span>\n <span class=\"rv-pill\">Chloroquine: Vd >200 L\/kg \u2014 dialysis futile in OD<\/span>\n <span class=\"rv-pill-teal\">Phenytoin: MM kinetics \u2014 25\u201350 mg increments only<\/span>\n <span class=\"rv-pill-teal\">GTN: oral bioavailability <1% \u2014 sublingual\/IV\/transdermal only<\/span>\n <span class=\"rv-pill-teal\">Propranolol\/morphine\/lignocaine: high extraction \u2014 dangerous in cirrhosis<\/span>\n <span class=\"rv-pill-green\">Thiopentone: offset by redistribution to fat, not elimination<\/span>\n <span class=\"rv-pill-green\">Warfarin 99% bound: displacement doubles free fraction<\/span>\n <\/p>\n\n <div class=\"rv-sub\">Sequence rules \u2014 act in order<\/div>\n <p>\n <span class=\"rv-pill\">Convert units \u2192 apply formula \u2192 interpret clinically<\/span>\n <span class=\"rv-pill\">Dose-normalise AUCs before calculating bioavailability<\/span>\n <span class=\"rv-pill-teal\">Calculate CrCl before prescribing in the elderly \u2014 serum Cr alone is unreliable<\/span>\n <span class=\"rv-pill-teal\">Adjust phenytoin in small increments, recheck after 2 weeks<\/span>\n <span class=\"rv-pill-green\">In overdose: calculate Vd before deciding on dialysis<\/span>\n <span class=\"rv-pill-green\">In loading dose: remember to divide by F for oral route<\/span>\n <\/p>\n\n <div class=\"rv-sub\">The traps examiners set repeatedly<\/div>\n <p>\n <span class=\"rv-pill\">mL\/min \u2260 L\/hr \u2014 convert before dividing for Css<\/span>\n <span class=\"rv-pill\">87.5% eliminated at 3 half-lives, not 75%<\/span>\n <span class=\"rv-pill-teal\">TI = LD50 \u00f7 ED50 (not inverted, not subtracted)<\/span>\n <span class=\"rv-pill-teal\">Potency \u2260 safety \u2260 efficacy \u2014 three independent properties<\/span>\n <span class=\"rv-pill-teal\">Serum Cr \"normal\" in elderly \u2260 normal renal function<\/span>\n <span class=\"rv-pill-green\">Doubling infusion rate doubles Css, but new SS still takes 4\u20135 t\u00bd<\/span>\n <span class=\"rv-pill-green\">MAOI washout = enzyme resynthesis (14 days), not PK clearance (2 hrs)<\/span>\n <span class=\"rv-pill-green\">Dose-normalise AUC before bioavailability ratio \u2014 not raw AUC<\/span>\n <\/p>\n\n <\/div>\n <\/div>\n\n <div class=\"rv-footer\">\n Pharmacokinetics Summative Revision \u00b7 atsixty.com \u00b7 Morning Rounds \u00b7 Numerical Series<br>\n <a href=\"mr-npk-index.html\">\u2190 Return to Pharmacokinetics Series Index<\/a>\n <\/div>\n\n <\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Morning Rounds \u00b7 Pharmacokinetics \u00b7 Summative Revision Morning Rounds \u00b7 Numerical Series \u00b7 Pharmacokinetics PharmacokineticsSummative Revision Notes Seven rounds \u00b7 NEET-PG \/ INI-CET \/ UPSC CMS \u00b7 Formulae, thresholds, clinical anchors & traps Zero & First Order Half-Life & Washout Vd & Loading Dose Clearance & Steady State TI \u00b7 ED50 \u00b7 LD50 Clinical Numericals… 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