5.3: Adverse Drug Reactions & Drug-Drug Interactions

Adverse Drug Reactions & Drug-Drug Interactions

Understanding the mechanisms, classification, and prevention of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) is a primary focus of the OPRA exam.

Classification of Adverse Drug Reactions (ADRs)

ADRs are classified into distinct categories (Types A to E) based on their predictability, dose-dependence, and timing:

---

Severe Cutaneous Adverse Reactions (SCARs): SJS and TEN

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are life-threatening dermatological emergencies characterized by widespread epidermal necrosis, mucosal ulcerations, and skin detachment.

Diagnostic Criteria (Body Surface Area Detachment):

• SJS: Epidermal detachment involving less than 10% of total body surface area (BSA).
• SJS/TEN Overlap: Epidermal detachment involving 10% to 30% of BSA.
• TEN: Epidermal detachment involving greater than 30% of BSA.

High-Risk Offending Medications:

• Anticonvulsants: Carbamazepine, Phenytoin, Phenobarbital, and Lamotrigine (particularly if titrated too rapidly).
• Allopurinol: Used for gout management.
• Antibiotics: Sulfonamides (e.g., Sulfamethoxazole in trimethoprim/sulfamethoxazole).
• NSAIDs: Especially the oxicam class (e.g., Piroxicam).

Pharmacogenomics and Risk Mitigation:

• HLA-B*1502: This allele is strongly associated with carbamazepine-induced SJS/TEN. Screening is mandatory under Australian guidelines for patients of Asian ancestry before starting carbamazepine. If positive, carbamazepine is contraindicated.
• HLA-B*5801: Strongly associated with allopurinol-induced SJS/TEN, particularly in Han Chinese, Thai, and Korean populations.

---

Pharmacokinetic vs. Pharmacodynamic Drug Interactions

Drug-drug interactions are broadly classified into pharmacokinetic (what the body does to the drug) or pharmacodynamic (what the drug does to the body).

1. Pharmacokinetic (PK) Interactions

PK interactions alter the absorption, distribution, metabolism, or excretion (ADME) of a drug:

• Absorption (Chelation): Divalent and trivalent cations (e.g., calcium, iron, magnesium, aluminium in antacids or supplements) bind to tetracyclines (e.g., doxycycline) and fluoroquinolones (e.g., ciprofloxacin) in the GI tract. This forms insoluble chelates, preventing absorption. Counselling: Space doses by at least 2 hours before or 4-6 hours after.
• Distribution (Protein Displacement): Highly protein-bound drugs can displace each other from albumin. For example, sodium valproate displaces phenytoin from plasma proteins, increasing the free (active) fraction of phenytoin, which can lead to toxicity even if total phenytoin levels appear normal.
• Metabolism (CYP450 Inhibition vs. Induction):
  • CYP inhibitors (e.g., erythromycin, ketoconazole, metronidazole, amiodarone, grapefruit juice) block enzyme activity. The onset is rapid (within 24-48 hours). This increases the concentration of substrate drugs, leading to toxicity.
  • CYP inducers (e.g., rifampicin, carbamazepine, phenytoin, St John's wort) stimulate the synthesis of more CYP enzymes. The onset is delayed (1-2 weeks). This decreases substrate drug concentration, leading to therapeutic failure.
• Excretion (Active Tubular Secretion Competition): Drugs that utilize the same active transport pathway in the proximal tubule can compete for excretion. For example, NSAIDs compete with methotrexate for Organic Anion Transporters (OAT1/OAT3), reducing methotrexate clearance and causing severe systemic toxicity (bone marrow suppression, mucositis).

2. Pharmacodynamic (PD) Interactions

PD interactions occur when drugs have additive, synergistic, or antagonistic effects without altering plasma concentrations:

• Additive/Synergistic: Combining multiple serotonergic agents (e.g., SSRIs + tramadol, linezolid, or MAOIs) can precipitate life-threatening serotonin syndrome. Combining QTc-prolonging drugs (e.g., sotalol + erythromycin) increases the risk of Torsades de Pointes.
• Antagonistic: Combining a beta-2 agonist (salbutamol) with a non-selective beta-blocker (propranolol) negates the bronchodilating effect. Combining levodopa (dopamine agonist) with metoclopramide (dopamine antagonist) worsens Parkinsonian symptoms and reduces drug efficacy.

---

High-Risk Clinical Pairs

1. The 'Triple Whammy'

This refers to the co-administration of an ACE inhibitor or ARB, a diuretic, and an NSAID. This combination carries an extremely high risk of precipitating acute kidney injury (AKI).

'Triple Whammy' Renal Hemodynamics:

                   [Afferent Arteriole]
                             |
                             v (Constricted by NSAIDs)
                       +-----------+
                       |Glomerulus | <--- (Volume depleted by Diuretics)
                       +-----------+
                             |
                             v (Dilated by ACEi/ARBs)
                   [Efferent Arteriole]

• Diuretics: Reduce intravascular volume, decreasing renal perfusion.
• NSAIDs: Inhibit prostaglandins (PGE2 and PGI2), which normally dilate the afferent arteriole. This leads to afferent arteriole vasoconstriction, reducing blood flow into the glomerulus.
• ACE Inhibitors / ARBs: Prevent Angiotensin II-mediated constriction of the efferent arteriole, leading to efferent arteriole vasodilation. This prevents the maintenance of glomerular filtration pressure.
• Outcome: The combined reduction in renal blood flow and inability to maintain filtration pressure causes a steep drop in GFR, leading to acute kidney injury.

2. Warfarin Interactions

Warfarin is a narrow therapeutic index drug metabolized by CYP2C9 (specifically the active S-enantiomer):

• CYP2C9 Inhibitors (e.g., Metronidazole, Sulfamethoxazole/Trimethoprim, Amiodarone): Dramatically reduce the clearance of S-warfarin, leading to rapid accumulation, significant elevations in the International Normalized Ratio (INR), and life-threatening bleeding.
• NSAIDs: Increase bleeding risk via pharmacodynamic pathways (platelet inhibition and gastric mucosal irritation) without changing the INR.
• Broad-Spectrum Antibiotics (e.g., Amoxicillin, Doxycycline): Eradicate gut flora responsible for synthesizing Vitamin K. A decrease in Vitamin K production amplifies the anticoagulant effect of warfarin, raising the INR.