Drug Interactions

Drug interactions occur when one drug alters the pharmacological effect of another. In clinical pharmacy practice — particularly in South Africa where polypharmacy is common in primary healthcare settings, and where traditional herbal medicines are frequently co-administered with conventional medicines — understanding, identifying, and managing drug interactions is essential for safe and effective therapy. The SAPC examination frequently tests candidates on interaction mechanisms, clinical significance assessment, and management strategies.

This topic integrates pharmacokinetic and pharmacodynamic principles covered in earlier sections. Before studying this chapter, ensure solid understanding of absorption (pharma-003), distribution (pharma-004), metabolism (pharma-005), and elimination (pharma-007).

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Classification of Drug Interactions

Pharmacokinetic Interactions

Pharmacokinetic interactions alter the concentration of a drug at its site of action by affecting absorption, distribution, metabolism, or elimination. These interactions are often predictable based on the drug’s pharmacokinetic profile.

Absorption Interactions

Drugs may reduce or increase the absorption of co-administered medicines through several mechanisms:

Chelation and binding in the GI tract:

• Tetracyclines and fluoroquinolones bind divalent and trivalent cations (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺) forming insoluble complexes that cannot be absorbed
• Examples: Ciprofloxacin + calcium supplements (↓ absorption by 40–90%); Doxycycline + iron supplements; Azithromycin + antacids
• Management: Separate administration by at least 2 hours (fluoroquinolones) or 3–4 hours (tetracyclines)

Altered GI motility:

• Anticholinergics (e.g., hyoscine, atropine) delay gastric emptying → reduced absorption of drugs requiring rapid GI transit
• Prokinetics (e.g., metoclopramide) accelerate gastric emptying → faster absorption of some drugs but reduced absorption of others (e.g., digoxin capsules in gastroparesis)
• Opioids delay gastric emptying significantly → important interaction with modified-release formulations

pH-dependent absorption:

• Acid-reducing drugs (PPIs, H2-antagonists, antacids) increase gastric pH
• Drugs requiring acidic environment for absorption: ketoconazole, itraconazole, posaconazole (voriconazole less affected)
• PPIs can reduce bioavailability of clopidogrel (clinical significance debated; SAHPRA advises caution)

Drug transporters in the gut:

• P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expressed on enterocytes pump drugs back into the intestinal lumen
• Inhibitors: Quinidine, verapamil, erythromycin, ketoconazole → increased bioavailability of substrates (e.g., digoxin)
• Inducers: Rifampicin, St. John’s wort → decreased bioavailability of substrates
• OATP2B1 on enterocytes facilitates absorption of certain drugs; inhibitors include grapefruit juice (naringin), orange juice (hesperidin)

Grapefruit juice — a classic absorption interaction: Grapefruit juice irreversibly inhibits intestinal CYP3A4 and intestinal transporters (P-gp, OATP, BCRP). Drugs with significant first-pass metabolism through intestinal CYP3A4 show markedly increased bioavailability:

• Felodipine: ↑ bioavailability 280% (contraindicated combination)
• Simvastatin: ↑ bioavailability 360% (increased myopathy risk)
• Amlodipine: modest increase; less clinically significant
• Mechanism: Furanocoumarins (naringin, bergamottin) in grapefruit juice mechanism-based inactivate CYP3A4 irreversibly; new enzyme synthesis takes 24–48 hours
• Clinical relevance in South Africa: Grapefruit juice is commonly consumed; pharmacists should specifically ask when dispensing relevant medicines

Metabolism Interactions

Enzyme induction — increase in metabolising enzyme activity leading to reduced plasma concentrations of the affected drug:

Inducer	Enzyme(s)	Affected Drugs	Onset/Offset
Rifampicin	CYP1A2, 2C9, 2C19, 3A4	Warfarin, oestrogens, protease inhibitors, zidovudine ( ↓ )	1–2 weeks; 2–4 weeks offset
Carbamazepine	CYP1A2, 2C9, 3A4	Phenytoin, valproate, warfarin, oral contraceptives	2–3 weeks; 2–4 weeks offset
Phenytoin	CYP2C9, 2C19, 3A4	Lamotrigine (↓ effect), warfarin	2–3 weeks
St. John’s wort	CYP1A2, 2C9, 2C19, 3A4, P-gp	Protease inhibitors, NNRTIs, warfarin, digoxin, oral contraceptives	2–4 weeks
Efavirenz	CYP2B6, 2C9, 3A4	Methadone, warfarin	1–2 weeks
Alcohol (chronic)	CYP2E1 (induces)	Chlorpropamide, isoniazid	Chronic use

Enzyme inhibition — decrease in metabolising enzyme activity leading to increased plasma concentrations and potential toxicity:

Inhibitor	Enzyme(s)	Affected Drugs	Clinical Effect
Cimetidine	CYP1A2, 2C9, 2C19, 2D6, 3A4	Warfarin, phenytoin, theophylline, many drugs	Broad inhibition
Erythromycin	CYP3A4	Simvastatin (↑ myopathy risk), carbamazepine, cisapride (← withdrawn)	High-risk interaction
Clarithromycin	CYP3A4	Simvastatin, midazolam, carbamazepine	High-risk interaction
Ketoconazole	CYP3A4	Fentanyl, simvastatin, carbamazepine	Very potent inhibitor
Fluconazole	CYP2C9, 2C19, 3A4	Warfarin, phenytoin, sulfonylureas	Moderate inhibition
Valproic acid	CYP2C9, glucuronidation	Lamotrigine (↓ clearance 50%)	Important interaction
Disulfiram	CYP2E1, aldehyde dehydrogenase	Chlorpropamide, metronidazole	Accumulation risk
Ciprofloxacin	CYP1A2	Theophylline, tizanidine	Severe toxicity possible
Levofloxacin	CYP1A2	Theophylline	Less marked than ciprofloxacin

SAPC examination note: Questions frequently test enzyme induction and inhibition through the “substrate-precipitant” framework. Remember that enzyme induction always requires time to develop (protein synthesis takes days) while enzyme inhibition often occurs rapidly (within hours for competitive inhibition).

Distribution Interactions

Protein binding displacement:

• Two highly protein-bound drugs may compete for the same binding site on albumin or α₁-acid glycoprotein
• The displaced (more loosely bound) drug becomes free and available for elimination — initially increased concentration of free drug may be offset by increased clearance
• Clinically significant only when: drug has narrow TI, displaced drug has high extraction ratio, displacement occurs at tissue sites rather than plasma
• Classic example: Warfarin (99% albumin-bound) + sulfonamides → free warfarin increases → bleeding risk; OR + NSAIDs → also displace but bleeding risk more from antiplatelet effect
• Valproic acid displaces phenytoin from protein binding → initial ↑ free phenytoin; but also inhibits phenytoin metabolism → net effect unpredictable

Distribution into tissue compartments:

• Digoxin and amiodarone have large volumes of distribution; drugs that displace digoxin from tissue binding (e.g., quinidine — now withdrawn) can increase serum digoxin concentrations significantly
• Thiopentone redistribution: interactions affecting cardiac output can alter distribution and thus clinical effect

Elimination Interactions

Renal tubular secretion competition:

• Probenecid inhibits renal OAT1/OAT3 transporters → reduced secretion of methotrexate, cefoxitin, rifampin (active metabolite)
• NSAIDs inhibit renal prostaglandins → reduced renal blood flow → reduced clearance of drugs eliminated renally (e.g., lithium, methotrexate)
• Trimethoprim (in high doses, as in Bactrim/Co-trimoxazole) inhibits renal creatinine secretion → ↑ serum creatinine (without affecting actual renal function) and can increase methotrexate and dofetilide toxicity

Renal reabsorption:

• Urinary acidification increases reabsorption of basic drugs (amphetamines, ephedrine); urinary alkalinisation increases reabsorption of acidic drugs (phenobarbital, salicylic acid)
• Used therapeutically in poisoning management (see pharma-015)

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Pharmacodynamic Interactions

Pharmacodynamic interactions occur when drugs with opposing or synergistic mechanisms are co-administered, without any change in the pharmacokinetics of either drug. These are often predictable from knowledge of drug pharmacology.

Additive and Synergistic Effects

Additive effects — the combined effect equals the arithmetic sum of individual effects. This occurs when drugs act on the same receptor or pathway through different mechanisms.

Synergistic effects — the combined effect is greater than the sum of individual effects.

Combination	Interaction Type	Clinical Consequence
Aspirin + Warfarin	Additive (antiplatelet + anticoagulant)	↑ Bleeding risk
ACE inhibitor + potassium chloride	Additive	Severe hyperkalaemia
β-blocker + verapamil	Additive (negative inotropy/chronotropy)	Heart block, hypotension
Opioid + benzodiazepine	Synergistic (CNS depression)	Profound sedation, respiratory depression, death
Tramadol + serotonergic drugs (SSRIs)	Additive	Serotonin syndrome
NSAIDs + methotrexate	Additive (renal clearance ↓)	Methotrexate toxicity
Co-trimoxazole + pyrimethamine	Synergistic (sequential folate blockade)	Enhanced antifolate effect (therapeutic and toxic)

Specific high-risk pharmacodynamic interactions:

Serotonin syndrome — combination of serotonergic drugs:

• SSRIs (fluoxetine, sertraline) + MAOIs (phenelzine, selegiline) — contraindicated (10–14 day washout for SSRI before MAOI)
• SSRIs + Tramadol (both serotonergic) — risk with high doses
• SSRIs + St. John’s wort — common in SA where St. John’s wort is used for depression
• SSRIs + linezolid (weak MAOI) — avoid concurrent use
• SSRIs + meperidine (pethidine) — contraindicated

Neuroleptic malignant syndrome (NMS):

• Dopamine antagonists (antipsychotics) + dopaminergic drugs (levodopa, bromocriptine, amantadine) — precipitates NMS
• Also triggered by rapid antipsychotic dose escalation, dehydration, agitation

QT prolongation:

• Class IA antiarrhythmics (quinidine, procainamide) + other QT-prolonging drugs (thioridazine, ziprasidone, fluoroquinolones, mefloquine, co-trimoxazole) → torsades de pointes
• Particular risk in patients with hypokalaemia, bradycardia, congenital long QT

Potassium-wasting diuretics + other hypokalaemia-inducing drugs:

• Thiazides/furosemide + corticosteroids + laxative abuse + amphotericin B → severe hypokalaemia
• Severe hypokalaemia predisposes to digoxin toxicity (narrow TI)

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Cytochrome P450 Interactions in Detail

CYP450-mediated interactions are the most clinically important drug interactions in pharmacotherapy. The SAPC examination frequently tests knowledge of the major CYP isoforms, their substrates, inducers, and inhibitors.

CYP3A4 — The Most Clinically Significant Isoform

CYP3A4 is the most abundant CYP enzyme in the liver and intestinal wall (enterocytes). It metabolises approximately 50% of all drugs. Because of its broad substrate specificity and location in both gut wall and liver, it is responsible for the most clinically significant interactions.

High-risk CYP3A4 interactions in South African practice:

Drug	Interaction	Mechanism	Clinical Effect
Simvastatin	+ Erythromycin, clarithromycin, ketoconazole, grapefruit juice	CYP3A4 inhibition	↑ Simvastatin levels → myopathy/rhabdomyolysis
Simvastatin	+ Rifampicin	CYP3A4 induction	↓ Simvastatin levels → loss of efficacy
Midazolam	+ Ketoconazole, itraconazole, clarithromycin	CYP3A4 inhibition	↑ Midazolam levels → excessive sedation
Ciclosporin	+ Rifampicin (↓ levels), ketoconazole (↑ levels), erythromycin	Multiple	Transplant rejection or toxicity
Tacrolimus	+ Rifampicin (↓), fluconazole (↑)	CYP3A4	Organ rejection or toxicity
Protease inhibitors	+ Rifampicin (↓ all PI levels)	CYP3A4 induction	Loss of antiretroviral efficacy
Efavirenz	+ Rifampicin	CYP3A4/2B6 induction	↓ Efavirenz levels; clinical significance debated

Practical note: Rifampicin is one of the most powerful enzyme inducers in clinical medicine. Patients on rifampicin for TB require significantly higher doses of many drugs (e.g., warfarin, oestrogens, some antiepileptics). This is particularly relevant in South Africa where rifampicin is widely used for TB treatment and drug-resistant TB.

CYP2D6 — Polymorphism-Rich Isoform

CYP2D6 is clinically important because it exhibits genetic polymorphism (poor, extensive, and ultrarapid metabolisers). Key substrates and interactions:

CYP2D6 substrates: Codeine, tramadol, tamoxifen, metoprolol, carvedilol, flecainide, tramadol, risperidone

CYP2D6 interactions:

• Quinidine (potent inhibitor) + metoprolol → excessive β-blockade
• Fluoxetine, paroxetine (potent inhibitors) + tamoxifen → reduced conversion to active endoxifen → reduced anti-breast cancer efficacy
• Bupropion (used for smoking cessation and depression in SA) is a potent CYP2D6 inhibitor

Codeine and CYP2D6 — particularly important in South Africa: Codeine is a prodrug requiring CYP2D6 for activation to morphine. In South Africa, where over-the-counter codeine-containing products (e.g., cough syrups, analgaesic combinations) are widely used, the interaction of codeine with CYP2D6 inhibitors is significant. CYP2D6 poor metabolisers experience little analgesia; ultrarapid metabolisers may experience morphine overdose even from standard doses.

CYP2C9, CYP2C19 — Warfarin and Clopidogrel Interactions

CYP2C9 metabolises warfarin (S-isomer), phenytoin, some sulfonylureas, NSAIDs:

• Fluconazole, metronidazole, cotrimoxazole (sulfamethoxazole) inhibit CYP2C9 → ↑ warfarin effect → bleeding
• Rifampicin induces CYP2C9 → ↓ warfarin effect → subtherapeutic INR
• Amiodarone inhibits CYP2C9 → warfarin dose requirement often drops by 30–50%

CYP2C19 metabolises omeprazole, lansoprazole, pantoprazole, clopidogrel (activation step), diazepam:

• Omeprazole is both a substrate and weak inhibitor of CYP2C19
• Fluvoxamine (SSRI) strongly inhibits CYP2C19
• Proton pump inhibitors may reduce clopidogrel activation (clinical significance debated, but SAHPRA advises caution with omeprazole + clopidogrel)

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Herbal Medicine Interactions

In South Africa, traditional and herbal medicines are frequently co-administered with conventional medicines. Pharmacists must be aware of major herbal interactions.

St. John’s Wort (Hypericum perforatum)

This is one of the most powerful herbal enzyme inducers in clinical use. It induces CYP1A2, 2C9, 2C19, 3A4, and P-gp.

Major interactions:

• ↓ Protease inhibitors, NNRTIs (especially efavirenz) → treatment failure and resistance
• ↓ Digoxin → subtherapeutic levels
• ↓ Warfarin → subtherapeutic INR
• ↓ Oral contraceptives → breakthrough pregnancy
• ↓ Cyclosporine, tacrolimus → organ transplant rejection
• ↑ Serotonin (with SSRIs) → serotonin syndrome (similar to drug-drug interaction risk)

South African context: St. John’s wort is available in health shops and pharmacies in South Africa for mild to moderate depression. Patients on antiretroviral therapy, immunosuppressants, or anticoagulants should be specifically counselled about this interaction.

Garlic (Allium sativum)

Garlic supplements induce CYP3A4 and P-gp. May reduce plasma concentrations of saquinavir ( protease inhibitor) by approximately 35%. May enhance the effect of anticoagulants (warfarin).

Ginkgo biloba

Inhibits platelet aggregation; increases bleeding risk when combined with warfarin, aspirin, or NSAIDs. Also induces CYP3A4.

Evening Primrose Oil / Dong Quai

Inhibit platelet aggregation; may increase bleeding risk with anticoagulants.

Echinacea

Inhibits CYP3A4 in the gut (short-term use); may increase levels of drugs metabolised by intestinal CYP3A4. Long-term use may induce CYP3A4 in the liver.

Liquorice (Glycyrrhiza glabra)

Inhibits cortisol metabolism; may increase plasma concentrations of corticosteroids and enhance their side effects. May reduce plasma concentrations of some drugs through enzyme induction.

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Drug-Food Interactions

Food Effects on Drug Absorption

Food Type	Drugs Affected	Effect
High-fat meal	Griseofulvin, haloperidol, carbamazepine	↑ Absorption (fat enhances dissolution)
Food generally	Tetracyclines, fluoroquinolones, bisphosphonates	↓ Absorption (chelation with minerals)
Food generally	Captopril, imatinib	↓ Absorption (food reduces F)
Protein-rich	Levodopa	↓ Absorption (competitive transport)
Dairy products	Tetracyclines	↓ Absorption (Ca²⁺ chelation)
Grapefruit juice	Felodipine, nifedipine, simvastatin, lovastatin, ciclosporin, tacrolimus, midazolam	↑ F (CYP3A4 inhibition in gut)

Food and Drug Metabolism

Warfarin and Vitamin K: Warfarin acts by inhibiting vitamin K epoxide reductase. Foods high in vitamin K (leafy green vegetables — spinach, kale, broccoli, brussels sprouts) can antagonise warfarin’s anticoagulant effect. Patients on warfarin should be counselled to maintain consistent vitamin K intake and avoid sudden changes.

This is particularly important in South Africa where leafy vegetables are dietary staples. Anticoagulation counselling for warfarin patients in SA should specifically address vegetable intake consistency.

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Drug Interaction Severity Classification

SAHPRA and International Classification

Interactions are typically classified by severity:

Severity	Description	Example
Contraindicated	Combination should not be used	Fluconazole + cisapride; MAOI + SSRI
Major	Monitor closely; may require dose adjustment	Warfarin + NSAIDs; Simvastatin + erythromycin
Moderate	May be used with caution; monitor for effect	Metformin + cimetidine; ACE-I + potassium
Minor	Unlikely to have clinical significance	Most interactions with wide TI drugs

Factors Determining Clinical Significance

Not all reported interactions are clinically significant. Clinical significance depends on:

1. Therapeutic index of the affected drug — narrow TI drugs are most vulnerable (warfarin, digoxin, phenytoin, lithium, aminoglycosides, methotrexate)
2. Patient-specific factors — age, renal/hepatic function, genetic polymorphisms, disease states
3. Dose and duration of exposure — single doses vs chronic therapy
4. Route of administration — IV vs oral may bypass the interaction
5. Therapeutic context — some interactions may be exploited therapeutically

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South African-Specific Drug Interaction Considerations

Antiretroviral Interactions

South Africa has the largest antiretroviral therapy (ART) programme in the world. Pharmacists must be knowledgeable about ARV drug interactions:

Rifampicin + ART:

• Rifampicin strongly induces CYP3A4 and CYP2B6
• Lopinavir/ritonavir, atazanavir: significantly reduced levels; dose adjustment required
• Efavirenz: moderately reduced levels; standard dose generally maintained but monitor
• NRTIs (tenofovir, emtricitabine, lamivudine, zidovudine): not significantly affected by rifampicin
• Maraviroc requires dose increase 2-fold with rifampicin

Protease inhibitors (ritonavir, lopinavir) as CYP3A4 inhibitors:

• Ritonavir is a potent CYP3A4 inhibitor — used intentionally to “boost” other PIs
• However, this means ritonavir also increases levels of many other drugs: statins, benzodiazepines, ergot derivatives, some opioids

Drugs that should NOT be given with ART:

• St. John’s wort: reduces all PI and NNRTI levels → treatment failure
• Cisapride, pimozide, ergot derivatives: contraindicated with CYP3A4 inhibitors (ritonavir, lopinavir/ritonavir, atazanavir/ritonavir)
• Simvastatin and lovastatin: contraindicated with PIs (myopathy risk); pravastatin and rosuvastatin preferred

TB-HIV Drug Interactions

The TB-HIV co-epidemic in South Africa makes this a high-priority area:

Drug	With ARV	Effect
Rifampicin	All PIs, NNRTIs (except perhaps efavirenz)	↓ ARV levels; avoid or adjust
Rifampicin	Tenofovir, NRTIs	Minimal interaction; generally safe
Rifampicin	NVP	↓ NVP levels; clinical significance unclear
Rifampicin	Dolutegravir	↓ Dolutegravir; increase dolutegravir dose to 50mg BD
Isoniazid	Rifampicin	Combined hepatotoxicity risk
Pyrazinamide	Lopinavir/ritonavir	↓ LPV levels

Traditional Medicine Use in South Africa

Traditional medicines (muti) are widely used in South Africa, often concurrently with conventional medicines. Key considerations:

• Imithi (traditional medicines) may contain undefined quantities of pharmacologically active compounds
• Patients may not volunteer use of traditional medicines — pharmacists should specifically ask
• ** Devil’s Claw (Harpagophytum)** — may interact with anticoagulants/antiplatelets
• Buchu — diuretic-like effects; may potentiate diuretics and antihypertensives
• Traditional medicines are not regulated by SAHPRA for quality and safety; contamination with heavy metals or undeclared conventional drugs has been documented

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Clinical Management of Drug Interactions

When Dispensing

1. Screen all prescriptions for interactions using pharmacy software or reference database
2. Assess clinical significance based on patient-specific factors (age, comorbidities, TI)
3. Consult reference sources when uncertain
4. Apply “5 rights” of medication counselling: right drug, right dose, right route, right time, right patient — an interaction may require adjusting any of these
5. Document and report significant interactions to the prescriber

Pharmacist Interventions

Scenario	Intervention
Contraindicated combination	Do not dispense; contact prescriber immediately
Major interaction	Contact prescriber; suggest alternative; counsel patient on monitoring signs
Moderate interaction	Counsel patient; advise on monitoring; document in patient record
Minor interaction	Note in counselling; no immediate action required

Monitoring Parameters

Interaction	Parameter to Monitor
Warfarin + CYP2C9 inhibitor	INR, bleeding signs
Digoxin + amiodarone, quinidine	Serum digoxin levels, ECG, electrolytes
Methotrexate + NSAIDs	Serum methotrexate, renal function, FBC
Lithium + NSAIDs, thiazides	Serum lithium, renal function
Aminoglycosides + furosemide	Serum levels, audiometry, renal function

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SAPC Examination Focus Areas

Drug interactions are frequently examined in the SAPC exam, usually as clinical case scenarios or “select the contraindicated combination” questions.

High-yield topics for the SAPC exam:

1. CYP3A4 inducers and inhibitors — Rifampicin, carbamazepine, phenytoin, St. John’s wort, macrolides, azoles
2. Grapefruit juice interaction — mechanism and examples (felodipine, simvastatin, midazolam)
3. Codeine + CYP2D6 — poor metabolisers (no analgesia), ultrarapid metabolisers (morphine toxicity)
4. Serotonin syndrome — SSRIs + MAOIs, SSRIs + St. John’s wort, SSRIs + tramadol
5. warfarin + drug interactions — CYP2C9 interactions (azoles, metronidazole, cotrimoxazole), vitamin K interaction, aspirin interaction
6. Digoxin + amiodarone — amiodarone inhibits P-gp and reduces digoxin renal clearance → dose must be reduced 30–50%
7. Antiretroviral + rifampicin — dose adjustments needed; nevirapine particularly problematic
8. Narrow therapeutic index drugs — phenytoin, digoxin, lithium, warfarin, aminoglycosides — require concentration monitoring and careful dose adjustment

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Summary of Key Concepts

• Drug interactions are classified as pharmacokinetic (affecting drug concentrations) or pharmacodynamic (affecting drug effect at target)
• Pharmacokinetic interactions occur at the level of absorption, distribution, metabolism, and elimination
• CYP450 enzymes are the most common site of metabolism-based interactions; CYP3A4 is the most important clinically
• Enzyme induction requires days to weeks (protein synthesis time); inhibition can occur rapidly
• Pharmacodynamic interactions include additive, synergistic, and antagonistic effects
• Severity assessment depends on the therapeutic index of the affected drug and patient-specific factors
• In South Africa, antiretroviral interactions (especially with rifampicin), traditional medicine use, and warfarin counselling are particularly important
• Pharmacists have a professional responsibility to identify, assess, manage, and document drug interactions