Pharmacokinetics for 5 marks
Reading File
Finding Sources
Finding Sources
Reading File
Finding Sources
Reading File
Reading File
Reading File
I now have comprehensive content. Let me compile the complete 5-mark pharmacokinetics answer:
Pharmacokinetics
Definition
Pharmacokinetics (PK) is the study of what the body does to a drug - encompassing the processes of Absorption, Distribution, Metabolism, and Excretion (ADME). Understanding these processes and their interplay increases the probability of therapeutic success and reduces adverse drug events and drug-drug interactions.
(Goodman & Gilman's The Pharmacological Basis of Therapeutics)
1. Absorption
Absorption is the movement of a drug from its site of administration into the systemic circulation.
Key factors governing absorption:
- Surface area at the absorption site (the intestinal villi provide ~200 m² - far more than the stomach)
- Blood flow to the site
- Physical state of the drug (solution > suspension > solid)
- Aqueous solubility and concentration at the absorption site
- Degree of ionization - nonionized, lipophilic forms cross membranes more readily (the pH-partition hypothesis)
First-pass effect: Drugs absorbed from the GI tract pass through the portal circulation to the liver before reaching systemic circulation. Extensive hepatic metabolism at this stage greatly reduces the amount of active drug available - this is called the first-pass (pre-systemic) effect. It reduces bioavailability (F).
Bioavailability (F) = the fraction of an administered dose that reaches the systemic circulation unchanged.
- IV route: F = 1.0 (100%) by definition
- Oral route: F < 1 due to incomplete absorption and/or first-pass metabolism
Routes of administration and bioavailability:
| Route | Bioavailability | Key Feature |
|---|---|---|
| Intravenous (IV) | F = 1 | Immediate effect; no absorption step |
| Intramuscular (IM) | 0.75 < F < 1 | Prompt from aqueous solutions |
| Subcutaneous (SC) | 0.75 < F < 1 | Slow/sustained from depot preparations |
| Oral | Variable (often < 1) | Most convenient; subject to first-pass |
| Sublingual | High | Avoids first-pass; rapid onset |
| Transdermal | Low-moderate | Sustained release; avoids first-pass |
2. Distribution
Distribution is the reversible transfer of a drug from the blood into tissues and organs.
Factors affecting distribution:
- Lipid solubility - lipophilic drugs penetrate cell membranes easily and distribute widely
- Plasma protein binding - only unbound (free) drug is pharmacologically active; binding to albumin (acidic drugs) or alpha-1 acid glycoprotein (basic drugs) limits distribution
- Tissue binding - drugs may accumulate in fat, bone, or other tissues
- Blood-brain barrier (BBB) - highly lipid-soluble drugs cross more readily
- Placental transfer - all drugs cross to some degree; more so if lipophilic and nonionized
Volume of Distribution (Vd):
Vd = Amount of drug in the body / Plasma drug concentration
A large Vd indicates extensive tissue binding (e.g., chloroquine, amiodarone: Vd > 100 L). A small Vd suggests confinement to plasma (e.g., warfarin, heparin).
Redistribution: Lipid-soluble drugs acting on the brain (e.g., thiopental) have a rapid onset because of high cerebral blood flow, and rapid termination because the drug redistributes to muscle and fat - not due to elimination.
3. Metabolism (Biotransformation)
Metabolism converts lipophilic drugs into more hydrophilic (water-soluble) metabolites that can be excreted renally. Without metabolism, many drugs would remain in the body indefinitely.
Phases of Metabolism:
| Phase | Reactions | Result |
|---|---|---|
| Phase I | Oxidation, Reduction, Hydrolysis | Adds/unmasks a reactive group (-OH, -NH₂, -SH); often partially active |
| Phase II | Conjugation (glucuronidation, sulfation, acetylation, methylation, glutathione conjugation) | Inactivates and makes metabolite highly water-soluble for excretion |
Cytochrome P450 (CYP) enzymes - located mainly in the liver (endoplasmic reticulum) - are the most important Phase I enzymes. Key isoforms: CYP3A4 (most abundant, ~50% of drug metabolism), CYP2D6, CYP2C9, CYP2C19.
Prodrugs - some drugs are inactive until metabolized to their active form (e.g., codeine → morphine via CYP2D6; enalapril → enalaprilat).
Enzyme induction/inhibition:
- Inducers (e.g., rifampicin, phenytoin, carbamazepine) increase CYP enzyme activity → faster metabolism → reduced drug effect
- Inhibitors (e.g., erythromycin, ketoconazole, cimetidine) decrease CYP activity → increased drug levels → toxicity risk
Hepatic clearance (CLH):
- High-extraction drugs (e.g., lidocaine, morphine, propranolol): clearance is limited by hepatic blood flow - flow-dependent
- Low-extraction drugs (e.g., warfarin, phenytoin): clearance depends on the unbound fraction in blood and intrinsic enzymatic capacity - capacity-dependent
4. Excretion (Elimination)
Excretion is the irreversible removal of a drug or its metabolites from the body.
Main routes:
-
Renal (most important) - involves:
- Glomerular filtration (only free/unbound drug is filtered)
- Active tubular secretion (via transporters, e.g., OAT, OCT - can be saturated)
- Passive tubular reabsorption (nonionized, lipophilic drugs get reabsorbed back)
- Manipulation of urinary pH can alter excretion of weak acids/bases (e.g., alkalinizing urine to enhance salicylate excretion in overdose)
-
Biliary/Fecal - large molecular weight drugs/conjugates are excreted in bile → can undergo enterohepatic circulation (reabsorbed from gut, prolonging drug action)
-
Others - lungs (volatile anesthetics), breast milk, sweat, saliva
Key Pharmacokinetic Parameters
| Parameter | Definition | Formula | Clinical Relevance |
|---|---|---|---|
| Clearance (CL) | Volume of plasma completely cleared of drug per unit time | CL = Rate of elimination / Plasma concentration | Determines maintenance dose |
| Volume of Distribution (Vd) | Apparent volume in which drug distributes | Vd = Total drug in body / Plasma concentration | Determines loading dose |
| Half-life (t½) | Time for plasma concentration to fall by 50% | t½ = 0.693 × Vd / CL | Determines dosing interval; ~4-5 half-lives to reach steady state |
| Bioavailability (F) | Fraction of dose reaching systemic circulation | F = AUC(oral) / AUC(IV) | Determines oral dose |
| Steady-state concentration (Css) | Plateau concentration when rate of administration = rate of elimination | Css = Dose rate / CL | Target for therapeutic drug monitoring |
5. Nonlinear (Saturation) Pharmacokinetics
Most drugs follow first-order (linear) kinetics - a constant fraction of drug is eliminated per unit time (t½ is constant, independent of dose).
Some drugs follow zero-order kinetics when elimination pathways are saturated - a constant amount is eliminated per unit time (t½ increases with dose). Example: phenytoin, ethanol, aspirin at high doses. This is clinically dangerous because small dose increases can cause disproportionately large rises in plasma concentration.
Summary Mnemonic: ADME
| Letter | Process | Key Organ |
|---|---|---|
| A | Absorption | GI tract |
| D | Distribution | Blood, tissues |
| M | Metabolism | Liver (mainly) |
| E | Excretion | Kidney (mainly) |
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Comprehensive Clinical Nephrology, 7th Edition
This is a shared conversation. Sign in to Orris to start your own chat.