Drug Interactions: Pharmacokinetic and Pharmacodynamic Mechanisms

Drug Interactions — Overview

A drug interaction occurs when the effect of one drug is altered by the presence of another drug, food, drink, or environmental chemical. Drug interactions are a major cause of preventable adverse events and hospital admissions. Pharmacists are uniquely positioned to identify and prevent drug interactions at the point of dispensing and during medicines review.

Pharmacokinetic (PK) Interactions

Pharmacokinetic interactions affect the absorption, distribution, metabolism, or excretion (ADME) of a drug.

Absorption interactions occur when one drug alters the absorption of another. Antacids, calcium, iron, and magnesium chelate fluoroquinolones and tetracyclines in the gut, reducing absorption by up to 90% — these must be separated by at least two hours. Proton pump inhibitors reduce stomach acid and can impair absorption of ketoconazole and itraconazole (which require an acidic environment for dissolution). Metoclopramide accelerates gastric emptying and may increase absorption of rapidly absorbed drugs.

Distribution interactions involve displacement from plasma protein binding. Although theoretically significant, most displacement interactions are clinically unimportant because the freed drug is also more available for metabolism and elimination. However, in patients with reduced clearance, displacement can transiently increase free drug concentrations. Warfarin is highly protein-bound — displacement by drugs such as aspirin in high doses may transiently increase anticoagulant effect.

Metabolic interactions are the most clinically important class of PK interactions. The cytochrome P450 (CYP) enzyme system in the liver is responsible for the metabolism of the majority of drugs. Interactions occur via:

• CYP inhibition: one drug inhibits CYP, reducing metabolism of a co-administered drug, raising its plasma concentration. Example: fluconazole inhibits CYP2C9, increasing warfarin levels and INR.
• CYP induction: one drug induces CYP enzyme production, increasing metabolism and reducing efficacy of co-administered drugs. Example: rifampicin induces CYP3A4, reducing plasma levels of oral contraceptives and tacrolimus.

Key CYP substrates and inhibitors relevant in NZ practice: CYP3A4 substrates include simvastatin, cyclosporin, tacrolimus, many antiretrovirals; inhibitors include erythromycin, clarithromycin, itraconazole, grapefruit juice; inducers include rifampicin, phenytoin, carbamazepine, St John's Wort.

Excretion interactions: Non-steroidal anti-inflammatory drugs (NSAIDs) reduce renal blood flow and can reduce clearance of methotrexate, leading to methotrexate toxicity. Probenecid inhibits renal tubular secretion of penicillins, raising their plasma concentrations (historically used therapeutically). Lithium excretion is closely coupled to sodium reabsorption — thiazide diuretics cause sodium depletion and compensatory lithium retention, raising lithium levels to potentially toxic concentrations.

Pharmacodynamic (PD) Interactions

Pharmacodynamic interactions occur at the site of action and are independent of drug concentration changes.

Additive or synergistic effects: Two drugs with the same pharmacological action produce combined effects. Example: codeine + paracetamol (additive analgesia — beneficial); two CNS depressants (opioids + benzodiazepines — additive respiratory depression, potentially fatal).

Antagonistic effects: One drug opposes the action of another. Example: warfarin anticoagulation antagonised by vitamin K; beta-blocker-induced bronchospasm in asthma exacerbated by salbutamol antagonism.

Additive toxicity: Two drugs with different mechanisms but overlapping toxicity. Example: aminoglycosides + loop diuretics — both ototoxic, risk of hearing loss; NSAIDs + ACE inhibitors + diuretics — "triple whammy" for acute kidney injury.

Clinically Important Drug Pairs

• Warfarin + NSAIDs: pharmacokinetic (CYP2C9 inhibition) AND pharmacodynamic (antiplatelet effect) — greatly increased bleeding risk
• ACE inhibitor + potassium-sparing diuretic: hyperkalaemia risk — monitor serum K+
• SSRI + triptans: serotonin syndrome risk — agitation, autonomic instability, hyperthermia
• Quinolones + antacids: chelation — separate by ≥2 hours
• Methotrexate + NSAIDs: reduced methotrexate clearance — toxicity (myelosuppression, mucositis)
• Simvastatin + clarithromycin: CYP3A4 inhibition — rhabdomyolysis risk (use azithromycin instead)