Pharmacodynamics and pharmacokinetics explain on exam pov
Reading File
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Reading File
Reading File
Reading File
Reading File
Reading File
Reading File
Reading File
Reading File
Reading File
I now have all the core content needed. Let me compile the complete exam-focused response:
Pharmacokinetics (PK) & Pharmacodynamics (PD) - Complete Exam Notes
Based on Katzung's Basic and Clinical Pharmacology, 16th Ed. (Chapters 1-3) and Goodman & Gilman's The Pharmacological Basis of Therapeutics
THE ONE-LINE DIFFERENCE (Always Tested)
| Definition | Mnemonic | |
|---|---|---|
| Pharmacokinetics (PK) | What the body does to the drug (ADME) | "Ki" = body Kills the drug |
| Pharmacodynamics (PD) | What the drug does to the body (mechanism/effect) | "D" = Drug Does things |
PART 1: PHARMACOKINETICS
The 4 Processes: ADME
A - Absorption
Key concept: Drug must cross membranes to reach systemic circulation.
Methods of membrane crossing:
- Passive diffusion - most common; follows Fick's Law (flux ∝ concentration gradient × area / thickness)
- Facilitated diffusion - carrier-mediated, no energy, down gradient
- Active transport - carrier-mediated, energy (ATP) needed, against gradient
- Endocytosis/Pinocytosis - for very large molecules (e.g., vitamin B12 via intrinsic factor)
Henderson-Hasselbalch Equation (high-yield):
pH = pKa + log [A-] / [HA]
- Weak acids (aspirin, pKa ~3.5): ionized in alkaline, un-ionized in acidic
- Weak bases (morphine, pKa ~7.9): ionized in acidic, un-ionized in alkaline
- Un-ionized = lipid-soluble = absorbed better
Ion Trapping (Exam Classic):
- Acidic drug (aspirin) traps in alkaline urine → treat aspirin overdose with NaHCO3 (alkalinizes urine, ionizes aspirin, prevents reabsorption)
- Basic drug traps in acidic urine
Bioavailability (F):
- Fraction of administered dose that reaches systemic circulation unchanged
- IV = 100% (by definition)
- Oral < 100% due to: incomplete absorption + first-pass metabolism
- First-pass effect: drug absorbed from gut passes through liver before systemic circulation; hepatic metabolism reduces bioavailability (e.g., morphine, propranolol, lidocaine have high first-pass)
Factors affecting absorption:
- Lipid solubility (higher = better absorption)
- Molecular size (< MW 1000 diffuse readily)
- pKa relative to pH
- Blood flow to absorption site
- Surface area (small intestine > stomach)
D - Distribution
Volume of Distribution (Vd):
Vd = Amount of drug in body / Plasma concentration Vd = Dose / C₀ (after IV bolus)
| Vd | Meaning | Examples |
|---|---|---|
| Low (~5 L) | Stays in plasma (large/charged) | Heparin, warfarin (plasma-bound) |
| ~15 L | Distributes to ECF | Aminoglycosides |
| High (>100 L) | Extensively tissue-bound | Chloroquine, amiodarone, digoxin |
- High Vd = drug sequestered in tissues, hard to dialyze
- High Vd → longer half-life (at same clearance)
Plasma Protein Binding:
- Mainly albumin (acidic drugs) and alpha-1-acid glycoprotein (basic drugs)
- Only free (unbound) drug is pharmacologically active
- Competition for binding sites = drug interactions (e.g., warfarin displaced by aspirin)
Blood-Brain Barrier: requires high lipid solubility + low MW + low protein binding to cross.
M - Metabolism (Biotransformation)
Goal: Convert lipid-soluble → water-soluble → excretable
Phase I reactions (CYP450): Oxidation, reduction, hydrolysis
- Make drug more polar
- Product may be active, inactive, or more toxic (e.g., acetaminophen → NAPQI)
- Located mainly in liver endoplasmic reticulum
- Major enzymes: CYP3A4 (most drugs), CYP2D6, CYP2C9, CYP2C19, CYP1A2
Phase II reactions (Conjugation): Glucuronidation, sulfation, acetylation, methylation, glutathione conjugation
- Products usually inactive and water-soluble
- Can occur without Phase I first
Enzyme Induction vs. Inhibition (High-Yield Clinically):
| Examples | Effect | |
|---|---|---|
| Inducers (CRAP GPS) | Carbamazepine, Rifampin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbital, St. John's Wort | Decrease drug levels → therapeutic failure |
| Inhibitors (SICKFACES.COM) | fluconazole, erythromycin, clarithromycin, amiodarone, metronidazole, etc. | Increase drug levels → toxicity |
Zero-Order vs. First-Order Kinetics:
| First-Order | Zero-Order | |
|---|---|---|
| Rate | Constant fraction eliminated/time | Constant amount eliminated/time |
| Half-life | Fixed (constant) | Not fixed (increases with dose) |
| Examples | Most drugs | Aspirin (at toxic doses), Ethanol, Phenytoin |
| Graph (plasma vs. time) | Exponential curve (linear on log scale) | Linear curve |
E - Excretion
Renal excretion (main route for most drugs):
- Glomerular filtration - free drug only (unbound)
- Active tubular secretion - e.g., penicillin (probenecid blocks this → increases penicillin levels)
- Tubular reabsorption - lipid-soluble (un-ionized) drugs reabsorbed
Other routes: Bile/feces (enterohepatic circulation), lungs (volatiles, ethanol), breast milk, sweat, saliva
Key PK Parameters (Must Know Formulas)
Clearance (Cl)
Cl = Rate of elimination / Plasma concentration Cl = Dose / AUC (area under curve)
- Represents volume of plasma cleared of drug per unit time (mL/min)
- Total clearance = hepatic + renal + other
Half-Life (t½)
t½ = 0.693 × Vd / Cl
- Time for plasma concentration to fall by 50%
- 4-5 half-lives to reach steady state
- 4-5 half-lives to eliminate drug
- Longer t½ = longer dosing interval acceptable
Steady State (Css)
Css = Dosing rate / Clearance = (F × Dose/τ) / Cl
- Reached after ~4-5 half-lives regardless of dose
- Higher dose = higher Css (same time to reach it)
Loading Dose
Loading Dose = Vd × Target Css / F
- Used when immediate therapeutic levels needed (e.g., digoxin, phenytoin)
- Larger Vd → larger loading dose needed
Maintenance Dose
Maintenance Dose = Cl × Target Css × τ / F
PART 2: PHARMACODYNAMICS
Receptors
Definition: Macromolecules (usually proteins) that bind drugs/endogenous ligands and trigger a response.
4 Major Receptor Superfamilies (Exam Table):
| Type | Mechanism | Onset | Examples |
|---|---|---|---|
| Type 1 - Ligand-gated ion channels (Ionotropic) | Direct ion channel opening | Milliseconds (fastest) | nAChR, GABA-A, glycine, 5-HT3 |
| Type 2 - G-protein coupled receptors (GPCRs) | 2nd messenger cascade | Seconds to minutes | α, β-adrenergic; M1-M5; dopamine; opioid |
| Type 3 - Enzyme-linked receptors | Tyrosine kinase activation | Minutes to hours | Insulin, GH, EGF receptors |
| Type 4 - Nuclear/Intracellular receptors | Gene transcription | Hours to days (slowest) | Glucocorticoids, thyroid hormone, sex steroids |
GPCR Second Messengers (Must Know):
| G protein | Effect | Receptors |
|---|---|---|
| Gs | ↑ adenylyl cyclase → ↑ cAMP | β1, β2, D1, H2, V2 |
| Gi | ↓ adenylyl cyclase → ↓ cAMP | α2, M2, D2, opioid |
| Gq | ↑ PLC → ↑ IP3 + DAG → ↑ Ca²⁺ | α1, M1, M3, H1 |
Drug-Receptor Terminology (Highly Tested)
| Term | Definition | Example |
|---|---|---|
| Agonist | Binds receptor AND activates it (efficacy = 1) | Morphine, adrenaline |
| Partial agonist | Binds + activates but submaximal efficacy (0 < E < 1) | Buprenorphine, pindolol |
| Antagonist | Binds receptor but NO intrinsic activity (blocks agonist) | Naloxone, propranolol |
| Inverse agonist | Binds receptor and produces effect OPPOSITE to agonist | Flumazenil (at GABA-A) |
| Affinity | Strength of binding to receptor (↑ affinity = ↓ Kd) | - |
| Efficacy (intrinsic activity) | Ability to activate receptor once bound | - |
| Potency | Dose needed to produce 50% effect (EC50 / ED50) | Lower dose = more potent |
Dose-Response Curves (Exam Favorite)
Graded Dose-Response (single tissue):
- X-axis: log [dose]; Y-axis: % maximal effect
- Sigmoidal curve
- Emax = maximum effect (reflects efficacy)
- EC50 = concentration producing 50% Emax (reflects potency)
Quantal Dose-Response (population):
- X-axis: log [dose]; Y-axis: % of population responding
- ED50 = dose effective in 50% of population
- LD50 = dose lethal in 50% of population
- Therapeutic Index (TI) = LD50 / ED50 (larger = safer)
- Certain Safety Factor = LD1 / ED99 (more clinically relevant)
Effects of Antagonists on Dose-Response:
| Type | Kd change? | Emax change? | Shift of curve? | Reversible? |
|---|---|---|---|---|
| Competitive reversible | ↑ (apparent) | No | Right shift (surmountable) | Yes |
| Competitive irreversible | - | ↓ | Right shift + ↓ Emax | No |
| Non-competitive | No | ↓ | Downward (same EC50) | Variable |
Spare receptors: Emax achieved when only a fraction of receptors occupied. Competitive antagonist must block all spare receptors before Emax falls.
Tolerance, Desensitization & Tachyphylaxis
| Term | Meaning | Mechanism |
|---|---|---|
| Tolerance | Decreased response with repeated dosing over days-weeks | Receptor downregulation, altered signaling |
| Tachyphylaxis | Rapid tolerance with a few doses (hours) | Receptor desensitization, depletion of transmitter |
| Desensitization | Receptor becomes unresponsive (phosphorylation/internalization) | GPCRs after prolonged agonist |
| Sensitization / Supersensitivity | Increased response after antagonist withdrawal | Receptor upregulation (e.g., β-blockers withdrawal) |
Signal Transduction Pathways (Common Exam Questions)
-
cAMP pathway (Gs): Agonist → Gs → Adenylyl cyclase → ↑cAMP → PKA activation → phosphorylates proteins → cell response. Terminated by phosphodiesterase (blocked by methylxanthines: caffeine, theophylline)
-
IP3/DAG pathway (Gq): Agonist → Gq → PLC → cleaves PIP2 into IP3 + DAG. IP3 → Ca²⁺ release from ER. DAG → PKC activation.
-
Tyrosine kinase (Receptor): Insulin → receptor dimerization → autophosphorylation → MAPK/PI3K cascade.
-
Nuclear receptors: Steroid/thyroid/retinoid → enter nucleus → bind DNA response elements → alter gene transcription (slow onset, prolonged effects).
Pharmacogenomics (Emerging Exam Topic)
- Slow acetylators (NAT2 enzyme): Higher isoniazid levels → peripheral neuropathy
- CYP2D6 poor metabolizers: Codeine not converted to morphine (no analgesia); tricyclics accumulate (toxicity)
- G6PD deficiency: Oxidant drugs (primaquine, dapsone) → hemolytic anemia
- HLA-B*5701: Abacavir hypersensitivity - screen before prescribing
- TPMT deficiency: Azathioprine → bone marrow toxicity
Quick Summary Table: PK vs PD
| Feature | PK | PD |
|---|---|---|
| Question | "Where does the drug go?" | "What does the drug do?" |
| Parameters | ADME, Vd, Cl, t½, F, Css | Emax, EC50, TI, receptor type |
| Graphs | Plasma conc. vs. time | Dose-response curve |
| Altered by | Liver/kidney disease, age, genetics | Receptor upregulation/downregulation, tolerance |
| Clinical use | Dosing interval, loading dose | Choice of drug, target effect |
High-Yield One-Liners for MCQs
- Larger Vd = longer t½ (at same clearance) - t½ = 0.693 × Vd/Cl
- 4-5 half-lives to reach steady state (and to fully eliminate)
- Loading dose needed when Vd is large (e.g., digoxin)
- First-order kinetics: t½ constant; most drugs
- Zero-order kinetics: t½ increases with dose; ethanol, phenytoin, aspirin overdose
- Competitive antagonist: shifts curve right, Emax preserved
- Irreversible/noncompetitive: Emax reduced
- Partial agonist in presence of full agonist = acts as antagonist (competes for receptor but produces less effect)
- Ion trapping: acid drugs trapped in alkaline environment; base drugs in acidic
- Therapeutic index = LD50/ED50: drugs with narrow TI require monitoring (lithium, digoxin, warfarin, phenytoin, aminoglycosides)
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed. (Chapters 1-3) | Goodman & Gilman's The Pharmacological Basis of Therapeutics | Goldman-Cecil Medicine
This is a shared conversation. Sign in to Orris to start your own chat.