๐ฏ Module Objectives
- Define and apply the four pharmacokinetic parameters: ADME
- Calculate and interpret half-life, volume of distribution and bioavailability
- Explain dose-response relationships, agonism and antagonism
- Classify major drug categories by receptor/enzyme target and mechanism
- Predict clinically relevant drug interactions using CYP450 knowledge
- Identify common adverse effects by drug class
1. Pharmacokinetics โ What the Body Does to a Drug
Pharmacokinetics (PK) describes how a drug moves through the body over time. Summarised by the ADME framework.
Absorption โ Distribution โ Metabolism โ Excretion
Key PK Parameters
| Parameter | Definition | Clinical Significance |
|---|---|---|
| Half-life (tยฝ) | Time for plasma drug concentration to fall by 50% | Determines dosing frequency; after 5 tยฝ, drug is effectively eliminated |
| Volume of Distribution (Vd) | Apparent volume in which drug is distributed in the body | High Vd = extensive tissue binding; low Vd = stays in plasma |
| Bioavailability (F) | Fraction of administered dose reaching systemic circulation unchanged | IV = 100%; oral often <100% due to first-pass metabolism |
| Clearance (CL) | Volume of plasma cleared of drug per unit time | Determines maintenance dose; affected by renal/hepatic function |
| Steady State (Css) | Plasma concentration plateau reached after ~5 half-lives of regular dosing | Target for therapeutic drug monitoring |
2. ADME in Detail
Absorption
- Routes: oral (PO), intravenous (IV), intramuscular (IM), subcutaneous (SC), transdermal, inhalation
- First-pass effect: orally administered drugs absorbed from GI tract pass through the liver before reaching systemic circulation; extensive hepatic metabolism can significantly reduce bioavailability (e.g., nitroglycerin: ~1% oral bioavailability โ given sublingually)
- Lipid-soluble drugs are better absorbed passively; polar drugs require transporters
Distribution
- Drug distributes from blood into tissues based on: lipid solubility, plasma protein binding, tissue affinity
- Plasma protein binding: only free (unbound) drug is pharmacologically active; highly protein-bound drugs have smaller effective Vd
- Blood-brain barrier (BBB): only lipid-soluble, unbound drugs readily cross; protective against many toxins but limits CNS drug delivery
Metabolism
- Primary site: liver (also intestine, lungs, kidneys)
- Phase I: oxidation, reduction, hydrolysis โ often via CYP450 enzymes โ creates more polar metabolite (may be active or inactive)
- Phase II: conjugation (glucuronidation, sulfation, acetylation) โ makes metabolite water-soluble for excretion
- CYP450 enzymes: CYP3A4 (most common; ~50% of drugs), CYP2D6, CYP2C9, CYP2C19
Excretion
- Renal: most common route; glomerular filtration + tubular secretion โ tubular reabsorption
- Biliary/faecal: large/polar molecules secreted into bile; some undergo enterohepatic recirculation
- Dose reduction required in renal/hepatic impairment for renally/hepatically cleared drugs
๐ Clinical Pearl โ Always check renal function before dosing renally-excreted drugs (e.g., metformin, digoxin, aminoglycosides). Check liver function before hepatically-metabolised drugs with narrow therapeutic indices.
3. Pharmacodynamics โ What the Drug Does to the Body
Drug-Receptor Theory
- Affinity: drug's ability to bind its receptor
- Efficacy (intrinsic activity): ability to produce a maximal response once bound
- Potency: amount of drug needed to produce 50% of maximal effect (ECโ โ). High potency = low ECโ โ.
Agonists and Antagonists
| Drug Type | Binds Receptor? | Activates Receptor? | Example |
|---|---|---|---|
| Full Agonist | Yes | Yes (100%) | Morphine (ฮผ-opioid receptor) |
| Partial Agonist | Yes | Yes (<100%) | Buprenorphine (ฮผ-opioid receptor) |
| Antagonist | Yes | No | Naloxone (ฮผ-opioid receptor) |
| Inverse Agonist | Yes | Reduces basal activity | Some antihistamines (H1 receptor) |
Therapeutic Window
The range between the minimum effective dose and the minimum toxic dose. Drugs with a narrow therapeutic window (e.g., digoxin, warfarin, lithium, phenytoin) require careful monitoring.
- Therapeutic index (TI) = TDโ โ / EDโ โ. Higher TI = safer drug.
- MEC (Minimum Effective Concentration) and MTC (Minimum Toxic Concentration) define the therapeutic window in plasma
4. Major Drug Classes
| Class | Mechanism | Key Examples | Primary Use |
|---|---|---|---|
| ฮฒ-Blockers | Competitive antagonism of ฮฒ-adrenergic receptors (ฮฒ1 > ฮฒ2) | Metoprolol, Atenolol, Propranolol | Hypertension, angina, arrhythmia, heart failure |
| ACE Inhibitors | Inhibit ACE โ โ angiotensin II + โ aldosterone | Lisinopril, Enalapril, Ramipril | Hypertension, heart failure, diabetic nephropathy |
| Statins | Competitive inhibition of HMG-CoA reductase โ โ cholesterol synthesis | Atorvastatin, Rosuvastatin, Simvastatin | Hypercholesterolaemia, cardiovascular risk reduction |
| NSAIDs | Reversible inhibition of COX-1 and COX-2 โ โ prostaglandins | Ibuprofen, Naproxen, Diclofenac | Pain, inflammation, fever |
| Antibiotics (Penicillins) | Inhibit bacterial cell wall synthesis (ฮฒ-lactam binds PBP) | Amoxicillin, Flucloxacillin, Piperacillin | Gram-positive and some gram-negative bacterial infections |
| SSRIs | Block serotonin reuptake transporter (SERT) โ โ synaptic serotonin | Fluoxetine, Sertraline, Escitalopram | Depression, anxiety disorders, OCD |
| Metformin | Activates AMPK โ โ hepatic gluconeogenesis; โ peripheral glucose uptake | Metformin | Type 2 diabetes; first-line therapy |
| Warfarin | Inhibits vitamin K epoxide reductase โ โ clotting factors II, VII, IX, X | Warfarin | Anticoagulation (atrial fibrillation, DVT/PE prevention) |
| Opioids | Agonists at ฮผ, ฮด, ฮบ opioid receptors โ inhibit pain signalling | Morphine, Oxycodone, Fentanyl, Codeine | Moderate-severe pain; high addiction potential |
5. Drug Interactions
CYP450-Mediated Interactions
- CYP inhibitors โ reduce metabolism of co-administered drugs โ โ plasma levels โ risk of toxicity
Examples: fluconazole, erythromycin, grapefruit juice (CYP3A4 inhibitors) - CYP inducers โ increase metabolism โ โ plasma levels โ risk of treatment failure
Examples: rifampicin, carbamazepine, St John's Wort (CYP3A4 inducers)
Pharmacodynamic Interactions
- Additive โ effects of two drugs sum (e.g., two CNS depressants โ greater sedation)
- Synergistic โ combined effect greater than sum (e.g., ฮฒ-lactam + aminoglycoside against gram-negative bacteria)
- Antagonistic โ one drug reduces effect of another (e.g., naloxone reverses opioid effects)
โ ๏ธ High-Risk Combination โ Warfarin + any CYP2C9 inhibitor (e.g., fluconazole, amiodarone) dramatically increases bleeding risk by reducing warfarin metabolism. Requires immediate INR monitoring and dose adjustment.
Knowledge Check
1. A drug has a half-life of 8 hours. How long until it reaches steady state with regular dosing?
Steady state is reached after approximately 5 half-lives. 5 ร 8 hours = 40 hours (~1.7 days). This is true regardless of the dose or dosing interval โ it's determined solely by the half-life.
2. Why is the oral bioavailability of nitroglycerin very low and how is this overcome?
Nitroglycerin undergoes extensive first-pass metabolism in the liver (~99%), so almost none of an oral dose reaches systemic circulation. This is overcome by sublingual (under the tongue) administration, which allows direct absorption into the systemic circulation via the rich sublingual vasculature, bypassing first-pass metabolism.
3. A patient on warfarin is started on rifampicin for TB. What do you expect to happen and why?
Rifampicin is a potent CYP450 inducer (particularly CYP2C9, which metabolises warfarin). Induction increases warfarin metabolism โ lower warfarin plasma levels โ reduced anticoagulation โ risk of thrombosis. The warfarin dose will need to be significantly increased. When rifampicin is later stopped, the dose must be reduced again to avoid bleeding.
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