Pharmacology & Drug Interactions

# Pharmacology & Drug Interactions Knowledge Pack

## Pharmacokinetics Fundamentals

### ADME — Absorption, Distribution, Metabolism, Excretion

**Absorption**: The process by which a drug moves from its site of administration into systemic circulation. Oral bioavailability (F) is the fraction reaching systemic circulation after oral administration. F depends on: fraction absorbed from GI tract (dissolution, permeability across intestinal epithelium), first-pass metabolism in gut wall (CYP3A4 expressed in enterocytes) and liver (portal circulation delivers all absorbed drug to liver before systemic circulation).

Factors affecting oral absorption: gastric pH (PPIs increase pH → reduce absorption of pH-dependent drugs like ketoconazole, iron, and some HIV protease inhibitors; increase absorption of drugs degraded by acid), gastric emptying rate (faster emptying → faster absorption for most drugs; food slows emptying), intestinal motility, drug interactions at transporter level (Pgp efflux pumps in enterocytes actively expel substrates back into GI lumen — inhibiting Pgp increases absorption of its substrates).

**Distribution**: After reaching systemic circulation, drugs distribute to tissues based on blood flow, permeability, and binding. Vd indicates the apparent volume into which a drug distributes. Low Vd (~0.1 L/kg = plasma volume) means drug stays in blood — highly protein-bound, large molecular weight. Examples: warfarin (Vd 0.14 L/kg, 99% protein-bound). High Vd (>1 L/kg) means extensive tissue distribution — lipophilic drugs accumulate in fat, muscle, organs. Examples: amiodarone (Vd 60 L/kg, distributes into fat with t½ of 40-55 days).

Protein binding: Only unbound (free) drug is pharmacologically active, can cross membranes, and is available for metabolism/excretion. Albumin binds acidic drugs (warfarin, phenytoin, NSAIDs), alpha-1 acid glycoprotein binds basic drugs (lidocaine, propranolol). Displacement interactions are rarely clinically significant for drugs with large Vd (the displaced drug distributes into tissues, increasing Vd and CL proportionally — free concentration normalizes). Clinically significant for drugs with small Vd, narrow therapeutic index, and high protein binding — primarily warfarin.

**Metabolism**: Phase I reactions (CYP enzymes: oxidation, reduction, hydrolysis) create or expose functional groups. Phase II reactions (conjugation: glucuronidation via UGT, sulfation, acetylation, glutathione conjugation) attach polar molecules to increase water solubility for excretion. Most metabolism occurs in the liver; some in gut wall, kidneys, lungs.

Key CYP enzymes and their substrates:
- **CYP3A4** (metabolizes ~50% of all drugs): statins (atorvastatin, simvastatin — NOT pravastatin or rosuvastatin), calcium channel blockers (amlodipine, felodipine), benzodiazepines (midazolam, triazolam — NOT lorazepam, oxazepam), calcineurin inhibitors (tacrolimus, cyclosporine), many HIV protease inhibitors.
- **CYP2D6** (metabolizes ~25% of drugs): codeine→morphine (poor metabolizers get no analgesia; ultra-rapid metabolizers get toxicity), tamoxifen→endoxifen (poor metabolizers may have reduced efficacy), metoprolol, many antidepressants.
- **CYP2C19**: clopidogrel→active metabolite (poor metabolizers have reduced antiplatelet effect — FDA boxed warning), PPIs (omeprazole — dose adjustment may be needed for ultra-rapid metabolizers), some antidepressants.
- **CYP2C9**: warfarin (S-enantiomer, the active form), phenytoin, many NSAIDs. CYP2C9 polymorphisms (*2, *3 alleles) cause 30-50% reduction in warfarin metabolism — lower dose requirements.

**Excretion**: Renal excretion involves glomerular filtration (free drug filtered), tubular secretion (active transport — OAT and OCT transporters), and tubular reabsorption (lipophilic drugs passively reabsorbed). Renal dose adjustment is critical for drugs with >30% renal elimination and narrow therapeutic index. Use CrCl (Cockcroft-Gault formula) or estimated GFR to guide dosing — reduce dose or extend interval as renal function declines.

### Steady State and Loading Doses
SS is reached after approximately 4-5 half-lives of continuous dosing. At SS, rate of drug input equals rate of elimination. For a drug with t½ = 12 hours dosed every 12 hours, SS is reached in ~48-60 hours.

When therapeutic effect is needed immediately (infections, arrhythmias, anticoagulation), a loading dose achieves target concentration rapidly. Loading dose = (target concentration × Vd) / F. After loading, maintenance dosing maintains SS. Common example: digoxin loading — t½ is 36-48 hours; without loading, SS takes 7-10 days.

## Drug Interactions

### Pharmacokinetic Interactions

**CYP inhibitors** decrease metabolism of substrate drugs → increased plasma levels → potential toxicity:
- **Strong CYP3A4 inhibitors**: ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice (intestinal CYP3A4 only). Clinical impact: simvastatin + itraconazole → 20-fold increase in simvastatin AUC → rhabdomyolysis risk. Contraindicated combination.
- **Strong CYP2D6 inhibitors**: fluoxetine, paroxetine, bupropion, quinidine. Clinical impact: codeine + fluoxetine → blocked conversion to morphine → no analgesic effect. Tamoxifen + paroxetine → reduced endoxifen → potentially reduced breast cancer protection.

**CYP inducers** increase metabolism → decreased plasma levels → potential therapeutic failure:
- **Strong inducers**: rifampin (induces CYP3A4, 2C9, 2C19, Pgp — the most potent inducer known), carbamazepine, phenytoin, phenobarbital, St. John's wort. Clinical impact: rifampin + oral contraceptives → contraceptive failure (50% reduction in ethinyl estradiol levels). Rifampin + warfarin → 2-3 fold increase in warfarin dose requirements. Rifampin + tacrolimus → subtherapeutic levels → organ rejection.

Induction takes 1-2 weeks to reach maximum effect (new enzyme synthesis required). When the inducer is stopped, enzyme levels normalize over 1-2 weeks — dose adjustments needed in both directions.

### Pharmacodynamic Interactions

**Serotonin syndrome**: Excess serotonergic activity from combining serotonergic drugs. Triad: altered mental status (agitation, confusion), autonomic dysfunction (hyperthermia, tachycardia, diaphoresis), and neuromuscular abnormalities (clonus, hyperreflexia, tremor). Most dangerous combinations: MAOIs + SSRIs/SNRIs (contraindicated — 14-day washout required between MAOIs and SSRIs), tramadol + SSRIs, linezolid (weak MAOI) + SSRIs.

**QTc prolongation**: Drugs that block hERG potassium channels prolong cardiac repolarization → risk of torsades de pointes (polymorphic ventricular tachycardia). High-risk drugs: sotalol, dofetilide, droperidol, thioridazine. Moderate-risk: fluoroquinolones (especially moxifloxacin), azithromycin, ondansetron (dose-dependent), methadone, antipsychotics (haloperidol, ziprasidone). Risk factors: female sex, hypokalemia, hypomagnesemia, bradycardia, congenital long QT syndrome, combining multiple QTc-prolonging drugs.

**Bleeding risk**: Anticoagulants + antiplatelet agents + NSAIDs create additive/synergistic bleeding risk. Warfarin + aspirin → 2-fold increase in major bleeding. Triple therapy (warfarin + aspirin + clopidogrel) after coronary stenting with atrial fibrillation requires careful risk-benefit analysis — use shortest duration possible, consider PPI for GI protection.

**Hyperkalemia**: ACEi/ARBs + potassium-sparing diuretics (spironolactone) + potassium supplements + NSAIDs (reduce renal potassium excretion by decreasing GFR and aldosterone). Trimethoprim blocks ENaC channels, acting like a potassium-sparing diuretic — frequently overlooked interaction.

### Renal and Hepatic Considerations

**Renal dosing**: Drugs requiring adjustment in renal impairment include: aminoglycosides (gentamicin — TDM essential, nephrotoxic and ototoxic; target peak 5-10 mcg/mL and trough <2 mcg/mL for conventional dosing), vancomycin (target AUC/MIC 400-600 for MRSA; trough-based monitoring being replaced by AUC-based monitoring), metformin (contraindicated if GFR <30 mL/min — lactic acidosis risk), DOACs (rivaroxaban, apixaban — specific GFR thresholds for dose reduction), gabapentin/pregabalin (accumulation causes excessive sedation).

**Hepatic impairment**: Less predictable than renal. Child-Pugh score (A, B, C) guides dosing for drugs with hepatic metabolism. CYP activity decreases in cirrhosis — CYP2C19 and CYP1A2 affected first, CYP2D6 relatively preserved until severe disease. First-pass metabolism is reduced (portosystemic shunting bypasses liver) → oral bioavailability increases dramatically for high-extraction drugs (morphine, propranolol, verapamil). Albumin synthesis decreases → increased free fraction of highly protein-bound drugs.

## Clinical Pharmacy Practice

### Therapeutic Drug Monitoring
TDM is justified when: narrow therapeutic index (small difference between effective and toxic concentrations), unpredictable PK (large inter-patient variability), defined concentration-response relationship, and clinical endpoints that are difficult to measure directly (seizure prevention, organ rejection prevention).

Drugs requiring routine TDM: vancomycin (AUC-guided dosing for efficacy and nephrotoxicity prevention), aminoglycosides (prevent ototoxicity and nephrotoxicity), phenytoin (non-linear PK — small dose increases cause disproportionate concentration increases near Km), lithium (narrow index — 0.6-1.2 mEq/L therapeutic, >1.5 toxic, >2.0 life-threatening), digoxin (0.5-2.0 ng/mL; toxicity risk increased by hypokalemia), tacrolimus/cyclosporine (organ transplant — prevent rejection while minimizing nephrotoxicity), theophylline (10-20 mcg/mL — narrow index, multiple DDIs), and certain antiepileptics (valproic acid, carbamazepine).

### Medication Reconciliation
The process of creating an accurate list of all medications a patient takes and comparing it against orders at every transition of care (admission, transfer, discharge). Identifies: unintentional omissions (home medications not ordered), duplications (two SSRIs from different prescribers), DDIs introduced by new orders, and dose discrepancies.

Best practices: Use multiple sources (patient interview, pharmacy records, pill bottles, prior discharge summaries). Verify each medication: name, dose, route, frequency, indication, last dose taken. High-risk transition: hospital discharge — ensure all pre-admission medications are intentionally continued, held, or discontinued with documented rationale.

### Antimicrobial Stewardship
Goal: optimize antimicrobial use to improve outcomes while minimizing resistance selection and adverse effects.

**Empiric therapy**: Select based on likely pathogens (site of infection + patient risk factors), local antibiogram (facility-specific resistance patterns — a drug with 95% susceptibility nationally may have only 70% susceptibility locally), and patient factors (allergies, renal/hepatic function, prior cultures, recent antibiotic exposure). Start broad, narrow when culture results return (de-escalation).

**IV-to-PO conversion**: Switch IV to PO antibiotics when patient meets criteria: afebrile >24 hours, improving clinically, functioning GI tract, PO formulation achieves adequate levels at infection site. Many antibiotics have excellent oral bioavailability: fluoroquinolones (>90%), linezolid (100%), metronidazole (100%), fluconazole (>90%), trimethoprim-sulfamethoxazole (>90%). Early IV-to-PO switch reduces catheter-related complications, hospital length of stay, and cost.

**Duration of therapy**: Evidence increasingly supports shorter courses for many infections. Community-acquired pneumonia: 5 days (if clinically stable by day 3). Uncomplicated UTI in women: 3 days TMP-SMX or 5 days nitrofurantoin. Cellulitis: 5-6 days. Intra-abdominal infection with adequate source control: 4 days. Longer courses select for resistance and increase C. difficile risk — every additional day of antibiotic exposure increases CDI risk by ~2%.

### Adverse Drug Reactions
Type A (augmented, dose-dependent): Predictable extensions of pharmacological effect. Account for 80% of ADRs. Examples: hypoglycemia from insulin, bleeding from anticoagulants, sedation from benzodiazepines. Management: dose reduction or drug discontinuation.

Type B (bizarre, idiosyncratic): Unpredictable, not dose-dependent, often immune-mediated. Examples: Stevens-Johnson syndrome (sulfonamides, carbamazepine, allopurinol, lamotrigine — HLA-B*5801 screening for allopurinol in high-risk populations reduces risk), drug-induced liver injury (isoniazid — monitor LFTs monthly, drug-induced lupus (hydralazine, procainamide), agranulocytosis (clozapine — mandatory CBC monitoring).

Type C (chronic/cumulative): Time and dose-dependent cumulative toxicity. Examples: aminoglycoside nephrotoxicity (cumulative dose exposure), anthracycline cardiomyopathy (doxorubicin lifetime dose limit 450-550 mg/m²), methotrexate hepatotoxicity (cumulative dose monitoring with liver biopsy or FibroScan).

Pharmacogenomics increasingly guides therapy: HLA-B*5701 testing before abacavir (prevents hypersensitivity), HLA-B*1502 testing before carbamazepine in Southeast Asian populations (prevents SJS/TEN), CYP2C19 genotyping for clopidogrel (poor metabolizers may need prasugrel or ticagrelor instead), TPMT/NUDT15 testing before thiopurines (azathioprine, 6-mercaptopurine — prevents life-threatening myelosuppression in poor metabolizers).