{
  "slug": "pharmacy-pharmacology",
  "title": "Pharmacology & Drug Interactions",
  "domain_slug": "pharmacy",
  "subdomain_slug": null,
  "difficulty": "intermediate",
  "tags": [
    "pharmacokinetics",
    "drug-interactions",
    "clinical-pharmacy",
    "adverse-effects",
    "pharmacodynamics"
  ],
  "is_free": false,
  "token_count": 4500,
  "uncompressed_estimate": 5170,
  "savings_pct": 13.0,
  "rosetta": "[DECODE] PK=pharmacokinetics|PD=pharmacodynamics|Vd=volume of distribution|t\u00bd=half-life|Cmax=peak concentration|Tmax=time to peak|AUC=area under the curve|CL=clearance|SS=steady state|DDI=drug-drug interaction|ADR=adverse drug reaction|TDM=therapeutic drug monitoring|CYP=cytochrome P450|UGT=UDP-glucuronosyltransferase|Pgp=P-glycoprotein|GFR=glomerular filtration rate|CrCl=creatinine clearance|NSAID=nonsteroidal anti-inflammatory drug|PPI=proton pump inhibitor|SSRI=selective serotonin reuptake inhibitor|SNRI=serotonin-norepinephrine reuptake inhibitor|ACEi=ACE inhibitor|ARB=angiotensin receptor blocker|QTc=corrected QT interval|NNT=number needed to treat",
  "content_compressed": "# Pharmacology & Drug Interactions Knowledge Pack\n\n## Pharmacokinetics Fundamentals\n\n### ADME \u2014 Absorption, Distribution, Metabolism, Excretion\n\n**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).\n\nFactors affecting oral absorption: gastric pH (PPIs increase pH \u2192 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 \u2192 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 \u2014 inhibiting Pgp increases absorption of its substrates).\n\n**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 \u2014 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 \u2014 lipophilic drugs accumulate in fat, muscle, organs. Examples: amiodarone (Vd 60 L/kg, distributes into fat with t\u00bd of 40-55 days).\n\nProtein 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 \u2014 free concentration normalizes). Clinically significant for drugs with small Vd, narrow therapeutic index, and high protein binding \u2014 primarily warfarin.\n\n**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.\n\nKey CYP enzymes and their substrates:\n- **CYP3A4** (metabolizes ~50% of all drugs): statins (atorvastatin, simvastatin \u2014 NOT pravastatin or rosuvastatin), calcium channel blockers (amlodipine, felodipine), benzodiazepines (midazolam, triazolam \u2014 NOT lorazepam, oxazepam), calcineurin inhibitors (tacrolimus, cyclosporine), many HIV protease inhibitors.\n- **CYP2D6** (metabolizes ~25% of drugs): codeine\u2192morphine (poor metabolizers get no analgesia; ultra-rapid metabolizers get toxicity), tamoxifen\u2192endoxifen (poor metabolizers may have reduced efficacy), metoprolol, many antidepressants.\n- **CYP2C19**: clopidogrel\u2192active metabolite (poor metabolizers have reduced antiplatelet effect \u2014 FDA boxed warning), PPIs (omeprazole \u2014 dose adjustment may be needed for ultra-rapid metabolizers), some antidepressants.\n- **CYP2C9**: warfarin (S-enantiomer, the active form), phenytoin, many NSAIDs. CYP2C9 polymorphisms (*2, *3 alleles) cause 30-50% reduction in warfarin metabolism \u2014 lower dose requirements.\n\n**Excretion**: Renal excretion involves glomerular filtration (free drug filtered), tubular secretion (active transport \u2014 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 \u2014 reduce dose or extend interval as renal function declines.\n\n### Steady State and Loading Doses\nSS 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 t\u00bd = 12 hours dosed every 12 hours, SS is reached in ~48-60 hours.\n\nWhen therapeutic effect is needed immediately (infections, arrhythmias, anticoagulation), a loading dose achieves target concentration rapidly. Loading dose = (target concentration \u00d7 Vd) / F. After loading, maintenance dosing maintains SS. Common example: digoxin loading \u2014 t\u00bd is 36-48 hours; without loading, SS takes 7-10 days.\n\n## Drug Interactions\n\n### Pharmacokinetic Interactions\n\n**CYP inhibitors** decrease metabolism of substrate drugs \u2192 increased plasma levels \u2192 potential toxicity:\n- **Strong CYP3A4 inhibitors**: ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice (intestinal CYP3A4 only). Clinical impact: simvastatin + itraconazole \u2192 20-fold increase in simvastatin AUC \u2192 rhabdomyolysis risk. Contraindicated combination.\n- **Strong CYP2D6 inhibitors**: fluoxetine, paroxetine, bupropion, quinidine. Clinical impact: codeine + fluoxetine \u2192 blocked conversion to morphine \u2192 no analgesic effect. Tamoxifen + paroxetine \u2192 reduced endoxifen \u2192 potentially reduced breast cancer protection.\n\n**CYP inducers** increase metabolism \u2192 decreased plasma levels \u2192 potential therapeutic failure:\n- **Strong inducers**: rifampin (induces CYP3A4, 2C9, 2C19, Pgp \u2014 the most potent inducer known), carbamazepine, phenytoin, phenobarbital, St. John's wort. Clinical impact: rifampin + oral contraceptives \u2192 contraceptive failure (50% reduction in ethinyl estradiol levels). Rifampin + warfarin \u2192 2-3 fold increase in warfarin dose requirements. Rifampin + tacrolimus \u2192 subtherapeutic levels \u2192 organ rejection.\n\nInduction takes 1-2 weeks to reach maximum effect (new enzyme synthesis required). When the inducer is stopped, enzyme levels normalize over 1-2 weeks \u2014 dose adjustments needed in both directions.\n\n### Pharmacodynamic Interactions\n\n**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 \u2014 14-day washout required between MAOIs and SSRIs), tramadol + SSRIs, linezolid (weak MAOI) + SSRIs.\n\n**QTc prolongation**: Drugs that block hERG potassium channels prolong cardiac repolarization \u2192 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.\n\n**Bleeding risk**: Anticoagulants + antiplatelet agents + NSAIDs create additive/synergistic bleeding risk. Warfarin + aspirin \u2192 2-fold increase in major bleeding. Triple therapy (warfarin + aspirin + clopidogrel) after coronary stenting with atrial fibrillation requires careful risk-benefit analysis \u2014 use shortest duration possible, consider PPI for GI protection.\n\n**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 \u2014 frequently overlooked interaction.\n\n### Renal and Hepatic Considerations\n\n**Renal dosing**: Drugs requiring adjustment in renal impairment include: aminoglycosides (gentamicin \u2014 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 \u2014 lactic acidosis risk), DOACs (rivaroxaban, apixaban \u2014 specific GFR thresholds for dose reduction), gabapentin/pregabalin (accumulation causes excessive sedation).\n\n**Hepatic impairment**: Less predictable than renal. Child-Pugh score (A, B, C) guides dosing for drugs with hepatic metabolism. CYP activity decreases in cirrhosis \u2014 CYP2C19 and CYP1A2 affected first, CYP2D6 relatively preserved until severe disease. First-pass metabolism is reduced (portosystemic shunting bypasses liver) \u2192 oral bioavailability increases dramatically for high-extraction drugs (morphine, propranolol, verapamil). Albumin synthesis decreases \u2192 increased free fraction of highly protein-bound drugs.\n\n## Clinical Pharmacy Practice\n\n### Therapeutic Drug Monitoring\nTDM 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).\n\nDrugs requiring routine TDM: vancomycin (AUC-guided dosing for efficacy and nephrotoxicity prevention), aminoglycosides (prevent ototoxicity and nephrotoxicity), phenytoin (non-linear PK \u2014 small dose increases cause disproportionate concentration increases near Km), lithium (narrow index \u2014 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 \u2014 prevent rejection while minimizing nephrotoxicity), theophylline (10-20 mcg/mL \u2014 narrow index, multiple DDIs), and certain antiepileptics (valproic acid, carbamazepine).\n\n### Medication Reconciliation\nThe 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.\n\nBest 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 \u2014 ensure all pre-admission medications are intentionally continued, held, or discontinued with documented rationale.\n\n### Antimicrobial Stewardship\nGoal: optimize antimicrobial use to improve outcomes while minimizing resistance selection and adverse effects.\n\n**Empiric therapy**: Select based on likely pathogens (site of infection + patient risk factors), local antibiogram (facility-specific resistance patterns \u2014 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).\n\n**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.\n\n**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 \u2014 every additional day of antibiotic exposure increases CDI risk by ~2%.\n\n### Adverse Drug Reactions\nType 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.\n\nType B (bizarre, idiosyncratic): Unpredictable, not dose-dependent, often immune-mediated. Examples: Stevens-Johnson syndrome (sulfonamides, carbamazepine, allopurinol, lamotrigine \u2014 HLA-B*5801 screening for allopurinol in high-risk populations reduces risk), drug-induced liver injury (isoniazid \u2014 monitor LFTs monthly, drug-induced lupus (hydralazine, procainamide), agranulocytosis (clozapine \u2014 mandatory CBC monitoring).\n\nType C (chronic/cumulative): Time and dose-dependent cumulative toxicity. Examples: aminoglycoside nephrotoxicity (cumulative dose exposure), anthracycline cardiomyopathy (doxorubicin lifetime dose limit 450-550 mg/m\u00b2), methotrexate hepatotoxicity (cumulative dose monitoring with liver biopsy or FibroScan).\n\nPharmacogenomics 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 \u2014 prevents life-threatening myelosuppression in poor metabolizers)."
}