Pharmacokinetics = what the body does to the drug (ADME). Key concepts: bioavailability (IV = 100%, oral varies due to first-pass), Vd (how widely the drug spreads), and transporters like P-gp that pump drugs OUT of the brain. Henderson-Hasselbalch tells you whether a weak acid or base gets absorbed in the stomach vs intestine.
Key exam topics:
Bioavailability: IV = 100%; oral is reduced by first-pass metabolism
P-gp is an EFFLUX transporter (pumps drugs OUT of brain, contributes to MDR)
Routes that bypass first-pass: IV, sublingual, transdermal, inhalational, rectal (partial)
Most common trap:
P-gp pumps drugs OUT of tissues (brain, cancer cells). Students always get the direction wrong — it's an efflux pump, not an uptake transporter!
IV (100% bioavailability, immediate), IM, SC, Intrathecal, Inhalational, Topical
Bioavailability (F) = fraction of dose reaching systemic circulation unchanged. IV = 100%. Oral = less, thanks to first-pass.
Henderson-Hasselbalch — The Ion Trap
pH = pKa + log [A-]/[HA]
. Sounds scary but the takeaway is simple:
weak acids (like aspirin, pKa ~3.5) are unionized in the acidic stomach → get absorbed there. Weak bases (like morphine, pKa ~8) are ionized in the stomach → wait until they reach the alkaline small intestine.
Volume of Distribution (Vd)
Vd = Dose / C0
— how much space the drug appears to occupy.
Vd > 0.6 L/kg = drug hides in tissues (think digoxin, chloroquine). Vd ~ 0.05 L/kg = stays in plasma (think heparin, warfarin — stays in blood).
Only the free (unbound) drug is active.
The rest is stuck to albumin (for acidic drugs) or α1-acid glycoprotein (for basic drugs).
Transporters — The Bouncers
Membrane transporters control who gets in and who gets kicked out. Here are the ones you need to know:
Transporter
Family
Location
Key Drugs Affected
P-glycoprotein (P-gp, ABCB1)
ABC efflux
Intestine, BBB, liver, kidney, placenta
Digoxin, cyclosporine, vinca alkaloids, tacrolimus, HIV protease inhibitors
A patient on simvastatin develops severe myalgia and elevated CK levels. Consider OATP1B1 polymorphism reducing hepatic uptake of statins, leading to increased systemic exposure. Switch to a statin less dependent on OATP1B1 (e.g., pravastatin) or reduce dose.
PYQ: SLCO1B1 polymorphism is associated with increased risk of myopathy with which drug? Answer: Simvastatin — reduced OATP1B1 function -> increased plasma statin levels.
Blood-Brain Barrier
Tight junctions between brain capillary endothelial cells (with help from pericytes and astrocytes).
Only lipid-soluble, non-ionized, small molecules (<500 Da) sneak through passively.
Nutrients get a ride via transporters (GLUT-1, LAT1).
P-glycoprotein (P-gp) sits on the luminal surface of brain capillaries and actively pumps drugs BACK into the blood.
This is why many cancer drugs can't reach brain tumours and why digoxin barely touches the CNS.
A common exam trap: P-gp is an efflux transporter — it pumps drugs OUT of the brain (not into it). Students often confuse this with an uptake transporter. This is also a key mechanism of multidrug resistance in cancer.
P-gp = "Pumps drugs out, Protects the brain, Problems for therapy"
PGI/NET/AIIMS PYQ: A drug with high first-pass metabolism should be given by which route? Answer: Sublingual, transdermal, or IV — any route that bypasses portal circulation.
PYQ: Which of the following has the highest bioavailability? (a) Oral propranolol (b) IV morphine (c) Oral lidocaine (d) Sublingual NTG Answer: (b) IV morphine — IV drugs have 100% bioavailability.
Only free (unbound) drug is pharmacologically active
BBB: only lipid-soluble, non-ionized, <500 Da pass; P-gp efflux limits CNS penetration
Drug Dosage Forms and Routes of Administration
The dosage form determines the rate and extent of drug absorption — the pharmaceutical equivalence of two products does not guarantee therapeutic equivalence (biopharmaceutics).
Route
Bioavailability
Onset
Key Features
First-Pass
Intravenous (IV)
100%
Immediate
Complete control over dosing; risk of embolism, infection, extravasation
No
Intramuscular (IM)
75-100%
Rapid (aqueous) to slow (depot)
Suitable for moderate volumes; pain, abscess risk; diazepam absorption unreliable
No
Subcutaneous (SC)
75-100%
Slow/controlled
Small volumes; insulin, heparin, LMWH; depot formulations (leuprolide)
No
Oral (PO)
Variable
30-90 min
Most convenient; subject to first-pass and GI factors; food interactions
Yes
Sublingual
High
Rapid (1-3 min)
Bypasses first-pass; NTG, buprenorphine; must remain in mouth until dissolved
Large surface area; rapid absorption; for asthma (beta2-agonists, ICS), general anesthetics
No
Rectal
~50%
Variable
Partial bypass of first-pass; useful in vomiting/unconscious patients; unreliable absorption
Partial
Sustained-release (SR/ER/XR) formulations maintain therapeutic levels with less frequent dosing. Enteric coating protects acid-labile drugs (omeprazole) or prevents gastric irritation (enteric-coated aspirin).
PYQ: Which route of administration bypasses first-pass metabolism? (a) Oral (b) IV (c) Sublingual (d) Both b and c Answer: (d) Both IV and sublingual bypass hepatic first-pass.
PYQ: A depot IM injection of haloperidol decanoate provides sustained antipsychotic effect for 2-4 weeks. What is the rationale? Answer: Esterification with decanoic acid increases lipophilicity -> slow release from muscle depot -> prolonged duration. Used for medication adherence in chronic psychiatric illness.
Pharmacokinetic processes: absorption, distribution and protein binding of drugs.
Pharmacokinetics: Metabolism and Excretion
Pharmacokinetics: Metabolism and Excretion
Drug metabolism (biotransformation) is the enzymatic conversion of a drug into a more water-soluble form to facilitate elimination.
Metabolism occurs primarily in the liver (smooth ER of hepatocytes) but also in the GI tract, kidneys, lungs, and skin.
Phase I Reactions (Functionalization)
Phase I reactions introduce or expose a functional group through
oxidation, reduction, or hydrolysis
, catalyzed primarily by the cytochrome P450 (CYP450) superfamily.
CYP3A4: "3 and 4 — Half or more" (metabolizes ~50% of drugs)
Phase II Reactions (Conjugation)
Phase II reactions couple the drug (or its Phase I metabolite) with an endogenous substrate —
glucuronic acid (UGT), sulfate (SULT), glutathione (GST), acetyl group (NAT), or methyl group (MT)
— forming inactive, highly water-soluble products excreted in bile or urine.
UDP-glucuronosyltransferases (UGTs) are the major Phase II enzymes.
First-Pass Effect
The first-pass effect (presystemic elimination) substantially reduces bioavailability of many orally administered drugs.
Drugs with significant first-pass metabolism: propranolol, lidocaine, verapamil, nifedipine.
Routes that bypass first-pass metabolism:
sublingual, transdermal, IV, rectal (partial).
Prodrugs
Prodrugs are pharmacologically inactive compounds that are converted to active metabolites in vivo.
Prodrug
Activation
Active Metabolite
Codeine
CYP2D6 O-demethylation
Morphine
Enalapril
Hydrolysis
Enalaprilat
Levodopa
Decarboxylation
Dopamine
Clopidogrel
CYP2C19
Active thiol metabolite
Codeine is a prodrug activated by CYP2D6. Poor CYP2D6 metabolizers get NO analgesia from codeine. Ultrarapid metabolizers risk toxicity (CNS depression, respiratory arrest) from rapid morphine accumulation. This is a classic exam trap!
Drug Excretion
Drug excretion is the irreversible removal of the drug from the body. The kidney is the primary organ of excretion for most drugs and their metabolites.
Renal elimination involves three processes:
Glomerular filtration
— only free, unbound drug is filtered (180 L/day in adults)
Active tubular secretion
— via OAT and OCT transporters in proximal tubule; can eliminate protein-bound drugs
Passive tubular reabsorption
— non-ionized lipid-soluble drugs diffuse back; influenced by urinary pH and drug pKa
Clearance (CL) is the volume of plasma from which the drug is completely removed per unit time (L/hr or mL/min) — determines the maintenance dose rate.
Elimination half-life (t½) is the time required for the plasma concentration to fall by 50%: t½ = 0.693 × Vd / CL.
Steady-state concentration (Css) is reached after approximately 5 half-lives.
PYQ: How many half-lives are required to reach steady state? Answer: Approximately 5 half-lives.
PYQ: Which CYP isoform metabolizes the majority of clinically used drugs? Answer: CYP3A4 (~50% of all drugs).
Phase I (CYP450) = oxidation, reduction, hydrolysis; Phase II (UGT, SULT, GST, etc.) = conjugation
CYP3A4 metabolizes ~50% of drugs; CYP2D6 is polymorphic (codeine metabolism)
First-pass effect reduces oral bioavailability; bypass with sublingual/IV/transdermal routes
t½ = 0.693 × Vd / CL; steady state in ~5 half-lives
Therapeutic Drug Monitoring (TDM)
TDM measures drug concentrations in plasma to optimize dosing for drugs with narrow therapeutic index and high interindividual pharmacokinetic variability.
Michaelis-Menten drugs: "PAT" — Phenytoin, Aspirin (high dose), Theophylline — zero-order kinetics: constant amount eliminated per unit time, not constant fraction.
Phenytoin follows non-linear (Michaelis-Menten) kinetics at therapeutic doses. A small dose increase can cause a disproportionate rise in plasma concentration leading to toxicity. This is different from most drugs that follow first-order kinetics where clearance is proportional to concentration. Always check for nystagmus, ataxia, and sedation when titrating phenytoin.
A patient on phenytoin develops nystagmus, ataxia, and slurred speech. Serum phenytoin level is 28 mcg/mL (therapeutic: 10-20). Because phenytoin follows Michaelis-Menten kinetics, hold the dose, recheck levels, and restart at a lower dose when toxicity resolves. Consider monitoring free phenytoin if the patient has hypoalbuminemia (free fraction increases, causing toxicity even with "normal" total levels).
PYQ: For a drug with first-order kinetics, what is the time to reach steady state? Answer: Approximately 4-5 half-lives regardless of dose or dosing interval.
PYQ: Which drug follows zero-order (non-linear) kinetics at therapeutic doses requiring careful dose titration? Answer: Phenytoin — as dose increases, clearance becomes saturated, leading to disproportionate increases in plasma concentration.
Hepatic drug metabolism (Phase I and Phase II) and renal excretion pathways.
Pharmacodynamics and Drug-Receptor Interactions
Pharmacodynamics and Drug-Receptor Interactions
Pharmacodynamics describes the biochemical and physiological effects of drugs on the body — what the drug does to the body.
The drug-receptor interaction is the fundamental concept: receptors are macromolecular protein structures (cell surface, nuclear, or intracellular) that bind a ligand and initiate a signal transduction cascade leading to a biological response.
Key Receptor Parameters
Affinity is measured by the dissociation constant Kd — the concentration of drug that occupies 50% of receptors at equilibrium.
Intrinsic efficacy is the ability of a drug, once bound, to activate the receptor and produce a response.
Agonists vs Antagonists
Type
Definition
Key Feature
Full agonist
Binds and produces maximal response
High intrinsic efficacy
Partial agonist
Submaximal response even at full occupancy
Low intrinsic efficacy
Competitive antagonist
Reversible block, parallel rightward shift of D-R curve
Surmountable; Emax unchanged
Non-competitive antagonist
Covalent/irreversible binding
Insurmountable; Emax reduced
Inverse agonist
Produces opposite effect at constitutively active receptors
e.g., at GABAA receptors
Competitive antagonism can be overcome by increasing the agonist concentration; non-competitive antagonism cannot — this is why in cases of irreversible β-blocker overdose (e.g., propranolol), high-dose glucagon (acting via glucagon receptors, not β-receptors) is used instead of β-agonists.
Receptor Theory Parameters
EC50
— molar concentration producing 50% of maximal effect (measure of potency)
Emax
— maximal effect (measure of efficacy)
Therapeutic Index (TI)
= TD50/ED50 or TC50/EC50 — ratio of toxic dose to effective dose; a measure of drug safety
Drugs with a narrow therapeutic index require therapeutic drug monitoring (TDM): warfarin, digoxin, lithium, theophylline, phenytoin, aminoglycosides.
Potency (EC50) is NOT the same as efficacy (Emax). A drug can be highly potent (low EC50) but have low efficacy (low Emax) — e.g., partial agonists. Exam questions often test this distinction.
Major Receptor Families
1. Ligand-Gated Ion Channels (Ionotropic)
Fast response (milliseconds).
Nicotinic ACh receptor
— Na+/Ca2+ influx → depolarization
GABAA receptor
— Cl- influx → hyperpolarization/inhibition (target of BZDs, barbiturates)
2. G Protein-Coupled Receptors (GPCRs, Metabotropic)
Response in seconds to minutes. The largest family of drug targets.
GPCRs have 7 transmembrane domains coupled to heterotrimeric G proteins.
Steroid/thyroid hormone receptors, PPARs, vitamin D receptor. Drug-receptor complex translocates to nucleus, binds to
hormone response elements (HREs)
on DNA, and modulates gene transcription — response over hours to days.
PYQ: A drug causes a parallel rightward shift of the dose-response curve without reducing maximal response. What type of antagonism is this? Answer: Competitive antagonism.
PYQ: Which G protein subtype activates phospholipase C? Answer: Gq → ↑IP3, DAG → ↑Ca2+.
Pharmacodynamics = what the drug does to the body (vs pharmacokinetics = what the body does to the drug)
Therapeutic Index = TD50/ED50; narrow TI drugs need TDM (WDLT PA)
Four receptor families: Ion channels (fast), GPCRs (Gs/Gi/Gq), RTKs (slow), Nuclear (hours-days)
GPCR Gs → ↑cAMP; Gi → ↓cAMP; Gq → ↑IP3/DAG
Drug Tolerance, Dependence and Desensitization
Tolerance is a diminished response to a drug after repeated administration, requiring higher doses to achieve the same effect.
Type of Tolerance
Mechanism
Examples
Pharmacokinetic (metabolic)
↑ Drug metabolism (CYP450 induction)
Barbiturates, carbamazepine, rifampin, alcohol
Pharmacodynamic
Receptor downregulation or desensitization
β-agonists in asthma (β-receptor desensitization), BZDs, opioids
Tachyphylaxis
Rapid, acute tolerance — develops within minutes to hours
NTG (requires nitrate-free interval), ephedrine (depletes NE stores)
Receptor desensitization can occur through: (1) uncoupling from G proteins (β-arrestin mediated), (2) receptor internalization (endocytosis), (3) receptor downregulation (decreased synthesis).
Quantal vs Graded Dose-Response Curves
Graded dose-response curves
show the effect of increasing drug concentration in a single biological unit — used to determine EC50 and Emax.
Quantal (all-or-none) dose-response curves
plot the percentage of a population responding to a given dose — used to determine ED50, TD50, and the therapeutic index.
The therapeutic index (TI = TD50/ED50) is a population-based measure. A high TI (>10) indicates a wide safety margin; a low TI (<3) indicates a narrow safety margin requiring TDM.
A patient using sublingual NTG for angina reports that the same dose is no longer as effective after several weeks. This is nitrate tolerance due to depletion of intracellular thiols and reduced NO bioavailability. Management: implement a 10-12 hour nitrate-free interval each day to restore responsiveness.
PYQ: The development of tolerance to nitroglycerin is best described as: (a) Pharmacokinetic tolerance (b) Tachyphylaxis (c) Pharmacodynamic tolerance (d) Metabolic tolerance Answer: (b) Tachyphylaxis — rapid development of tolerance, requires nitrate-free interval.
PYQ: Which type of dose-response curve is used to determine ED50 and TD50 in a population? Answer: Quantal (all-or-none) dose-response curve — plots cumulative percentage of population responding at each dose.
Major receptor families and signal transduction pathways in pharmacodynamics.
ADME, Adverse Effects and Drug Interactions
ADME, Adverse Effects and Drug Interactions
Adverse Drug Reactions (ADRs)
Adverse drug reactions are noxious, unintended responses to a drug occurring at normal therapeutic doses.
The modified classification system includes Types A through F.
Type
Name
Characteristics
Examples
A
Augmented
Predictable, dose-dependent (~80% of ADRs)
Dry mouth (antihistamines), paracetamol hepatotoxicity, C. difficile colitis (antibiotics)
Abrupt cessation of β-blockers, BZDs, opioids, clonidine
F
Failure
Therapy failure
Resistance, tolerance
ADR Types: "A B C D E F" — Always Be Checking Drug Effects Fully
A patient on carbamazepine develops fever, sore throat, and a blistering rash with mucosal involvement. This is Stevens-Johnson syndrome (Type B ADR). Immediate drug withdrawal and supportive care are required. Carbamazepine is one of the most common culprits along with lamotrigine and allopurinol.
Drug Interactions
Drug interactions occur when one drug alters the pharmacokinetics or pharmacodynamics of another.
Pharmacokinetic Interactions
1. Absorption interactions:
Chelation
— tetracyclines with Ca2+/Fe2+/Mg2+-containing antacids
Altered GI motility — metoclopramide accelerates gastric emptying
P-gp inhibition
— verapamil, amiodarone increase digoxin levels
2. Distribution (protein binding displacement):
Sulfonamides displace bilirubin in neonates → kernicterus
Warfarin displaced by phenylbutazone → bleeding
Protein binding displacement interactions are clinically significant only for drugs that are highly protein-bound (>90%) AND have a narrow therapeutic index. Simply displacing warfarin from albumin transiently increases free fraction, but clearance also increases — the clinical relevance is often overstated in exams unless a narrow TI drug is involved.
3. Metabolism interactions:
Type
Drugs
Effect
Enzyme inducers
Rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort
↓ levels of oral contraceptives, warfarin, cyclosporine (CYP3A4 induction)
Enzyme inhibitors
Azole antifungals, macrolides, cimetidine, amiodarone, grapefruit juice
↑ levels of many drugs (CYP3A4 inhibition)
CYP3A4 Inducers: "Rifampin, Phenytoin, Carbamazepine, Phenobarbital" → "RPCaP" (rifampin is the MOST potent inducer)
One drug enhances another's effect without having its own effect
Trimethoprim-sulfamethoxazole (sequential blockade of folate synthesis)
PYQ: Which of the following is a CYP3A4 inducer? (a) Ketoconazole (b) Grapefruit juice (c) Rifampin (d) Cimetidine Answer: (c) Rifampin. The others are inhibitors.
PYQ: Probenecid is used to prolong the action of penicillin by which mechanism? Answer: Inhibits active tubular secretion of penicillin in the proximal tubule.
ADR types: A (augmented, dose-dependent) through F (failure of therapy)
Type B includes SJS/TEN (carbamazepine, lamotrigine, allopurinol) and drug-induced lupus (procainamide, hydralazine)
Enzyme inducers (Rifampin, Phenytoin, Carbamazepine, Phenobarbital) ↓ drug levels; inhibitors (Azoles, Macrolides, Cimetidine, Amiodarone, Grapefruit) ↑ drug levels
P-gp inhibition by verapamil/amiodarone ↑ digoxin levels
Probenecid inhibits tubular secretion of penicillin and methotrexate
Pharmacogenetics in Drug Interactions
Genetic polymorphisms in drug-metabolizing enzymes, transporters, and receptors contribute to interindividual variability in drug response and toxicity.
↑ toxicity of isoniazid (peripheral neuropathy), hydralazine (lupus), procainamide (lupus)
DPD (DPYD)
DPD deficiency
Severe 5-FU/capecitabine toxicity: mucositis, diarrhea, neutropenia, neurotoxicity;
pre-treatment screening recommended
A 35-year-old with depression on nortriptyline (TCA) develops severe dry mouth, constipation, and orthostatic hypotension at standard doses. Genotyping reveals CYP2D6 poor metabolizer phenotype. TCAs are metabolized by CYP2D6; poor metabolizers have 4-5× higher plasma levels. Dose reduction or switch to a non-CYP2D6 dependent antidepressant (e.g., citalopram) is warranted.
TPMT = "ThioPurine MethylTransferase" — "Tiny People Make Trouble" (deficiency → toxicity with thiopurines)
PYQ: A patient on warfarin requires unusually low doses to achieve target INR. Genetic variation in which enzyme is most likely responsible? Answer: CYP2C9 polymorphism — *2 and *3 alleles reduce warfarin metabolism → lower dose requirement.
PYQ: Which enzyme deficiency is associated with severe 5-fluorouracil toxicity? Answer: Dihydropyrimidine dehydrogenase (DPD) deficiency — leads to accumulation of 5-FU.
The Inflammation Process and Anti-Inflammatory Drugs
Inflammation is a protective response to tissue injury or infection — orchestrated by chemical mediators (cytokines, prostaglandins, leukotrienes, histamine, bradykinin, complement) that regulate vascular permeability, leukocyte recruitment, and tissue repair.
A patient with rheumatoid arthritis and active inflammation (swollen joints, morning stiffness, elevated CRP and ESR) is started on an NSAID (naproxen) for symptom relief. If disease-modifying antirheumatic drugs (DMARDs) are needed, consider methotrexate (first-line), then TNFα inhibitors (infliximab, adalimumab) or JAK inhibitors (tofacitinib, baricitinib). NSAIDs provide symptomatic relief but do NOT alter disease progression — DMARDs are required to prevent joint destruction.
PYQ: NSAIDs exert their anti-inflammatory effect primarily by inhibiting which enzyme? Answer: Cyclooxygenase (COX) — both COX-1 (constitutive, housekeeping) and COX-2 (induced by inflammation). Aspirin irreversibly acetylates COX; ibuprofen/naproxen reversibly inhibit COX.
Dose-Response Relationships and Drug Safety
The dose-response curve describes the relationship between drug dose (or concentration) and the magnitude of pharmacological effect — the cornerstone of quantitative pharmacology.
Graded Dose-Response Curves
Graded (concentration-effect) curves
record the response of a single biological system to increasing drug concentrations. Key parameters derived:
EC50
— concentration producing 50% of maximal effect (index of potency); the lower the EC50, the more potent the drug
Emax
— maximal achievable effect (index of efficacy); independent of potency
Hill coefficient (n)
— reflects the steepness of the curve; n>1 suggests positive cooperativity (e.g., allosteric enzymes, ion channels with multiple binding sites)
Potency (EC50) and efficacy (Emax) are independent parameters. A drug can be potent (low EC50) but have low efficacy (partial agonist — e.g., buprenorphine). Conversely, a drug can be less potent but have greater efficacy (e.g., aspirin vs ibuprofen — aspirin is less potent but has greater analgesic efficacy at high doses). In clinical practice, efficacy is usually more important than potency.
Quantal Dose-Response Curves
Quantal (all-or-none) curves
plot the cumulative percentage of a population that exhibits a specified effect (therapeutic or toxic) at each dose. From these curves we derive:
ED50
— median effective dose (effective in 50% of population)
TD50
— median toxic dose (toxic in 50% of population)
LD50
— median lethal dose (lethal in 50% of population) — used in preclinical studies
Therapeutic Index (TI)
= TD50/ED50 — margin of safety
Certain Safety Factor (CSF)
= TD1/ED99 — more stringent measure of safety
A high therapeutic index (TI >10) indicates a wide safety margin. A low TI (<3) indicates a narrow margin requiring therapeutic drug monitoring. Drugs with the narrowest TIs: warfarin, digoxin, lithium, theophylline, phenytoin, aminoglycosides, vancomycin, cyclosporine, tacrolimus.
A 70-year-old on warfarin for AF has INR of 6.2 (therapeutic target 2-3). Warfarin has a narrow TI — small dose changes significantly alter INR. Management: hold warfarin, consider low-dose vitamin K if INR >4.5 with bleeding risk, check for drug interactions (recent antibiotics?), and restart at a lower dose when INR <4. Investigate potential CYP2C9 or VKORC1 polymorphisms.
Drug-Receptor Binding and Signal Amplification
Spare receptors exist when maximal response is achieved at less than 100% receptor occupancy — providing signal amplification and a reservoir of functional receptors.
Spare receptors allow a drug to produce Emax at fractional occupancy. For example, if Emax occurs at 10% occupancy, the remaining 90% are spare receptors. The Kd (binding affinity) is much lower than EC50 in this case.
Clinical implications of spare receptors:
Tolerance with irreversible antagonists
— many receptors must be blocked before function is impaired (e.g., atropine blocks M3 receptors; significant effects only after >75% occupancy)
Partial agonists
— may act as antagonists in systems with high receptor reserve (buprenorphine at μ-opioid receptors — partial agonist that antagonizes full agonists)
Desensitization
— chronic agonist exposure can reduce receptor number (downregulation) and spare receptor reserve
PYQ: A drug with a Hill coefficient of 2 produces a steeper dose-response curve. What does this indicate? Answer: Positive cooperativity — binding of one drug molecule increases affinity for subsequent molecules (e.g., at ligand-gated ion channels with multiple binding sites).
PYQ: If Emax is achieved at 5% receptor occupancy, what is the receptor reserve? Answer: 95% are spare receptors. The Kd is much lower than the EC50.
Spare receptors: Emax reached at fractional occupancy; partial agonists can act as antagonists
Hill coefficient >1 = positive cooperativity (steeper curve)
Potency ≠ Efficacy; clinical efficacy is usually more important than potency
Compartment Models in Pharmacokinetics
Compartment models mathematically describe drug distribution in the body to predict concentration-time profiles.
One-compartment model:
The drug distributes instantaneously into a single homogeneous compartment (plasma and tissues equilibrate rapidly). Plasma concentration declines monoexponentially after IV bolus.
Two-compartment model:
The drug distributes into a central compartment (plasma, highly perfused organs — rapid distribution phase, α) and a peripheral compartment (muscle, fat, less perfused tissues — slow elimination phase, β). Most drugs follow two-compartment kinetics. Biexponential concentration decline.
Loading dose is used when time to steady state is too long (drugs with long t½):
Digoxin (t½ ~36-48 h) — LD needed for AF rate control
Amiodarone (t½ ~40-60 days) — large LD followed by maintenance
Phenytoin — LD for status epilepticus (non-linear kinetics, careful titration)
Lidocaine — IV LD for ventricular arrhythmias post-MI
Theophylline — IV LD for acute severe asthma
For drugs with first-order kinetics, steady state is reached after ~5 half-lives regardless of dose. Loading dose achieves therapeutic levels instantly but does NOT change the time to steady state.
Loading dose depends on Vd, NOT on clearance. Maintenance dose depends on clearance, NOT on Vd. Students often confuse this: LD = Vd × Css/F; MD = CL × Css × τ/F. A patient with renal failure has reduced CL (need lower MD) but if Vd is unchanged, the LD stays the same.
A patient with atrial fibrillation needs rapid rate control. Digoxin has a long half-life (~36 h) — without a loading dose, it would take 7-8 days to reach steady state. Administer a loading dose (0.5-1 mg in divided doses over 24 h) followed by a maintenance dose (0.125-0.25 mg daily). Monitor digoxin levels, renal function, and ECG for toxicity.
PYQ: A drug has a Vd of 100 L and desired plasma concentration of 10 mg/L. Bioavailability is 100%. What is the loading dose? Answer: LD = Vd × Css/F = 100 × 10/1 = 1000 mg.
PYQ: Loading dose depends on which pharmacokinetic parameter? Answer: Volume of distribution (Vd). Maintenance dose depends on clearance (CL).
