Pharmacokinetics FAQ & Answers

STRONG inhibitor. FDA classification: Strong inhibitors increase AUC of CYP3A4 substrates >=5-fold. Clarithromycin causes mechanism-based (irreversible) inhibition - it forms a metabolite that covalently binds to CYP3A4, inactivating it until new enzyme is synthesized. Clinical implication: Co-administration with CYP3A4 substrates (simvastatin, lovastatin, certain statins) can increase their concentration 5-20x, causing toxicity. Fatal interactions reported with colchicine. Other strong CYP3A4 inhibitors: ketoconazole, itraconazole, ritonavir.

CYP3A4 substrates (HIGH interaction risk): Simvastatin, Lovastatin (highest risk - up to 20x increase with strong inhibitors), Atorvastatin (moderate risk). NOT CYP3A4 substrates (LOWER interaction risk): Pravastatin (no CYP450 metabolism - safest), Rosuvastatin (minimal CYP2C9, mostly excreted unchanged), Pitavastatin (minimal CYP2C9), Fluvastatin (CYP2C9, not 3A4). Clinical rule: When starting a strong CYP3A4 inhibitor (clarithromycin, itraconazole, ritonavir, diltiazem, verapamil), switch from simvastatin/lovastatin to pravastatin, rosuvastatin, or pitavastatin. FDA contraindication: Simvastatin with strong CYP3A4 inhibitors. Rhabdomyolysis risk is dose-dependent and interaction-dependent.

STRONG inhibitor. FDA classification: Strong inhibitors increase AUC of CYP3A4 substrates >=5-fold. Clarithromycin causes mechanism-based (irreversible) inhibition - it forms a metabolite that covalently binds to CYP3A4, inactivating it until new enzyme is synthesized. Clinical implication: Co-administration with CYP3A4 substrates (simvastatin, lovastatin, certain statins) can increase their concentration 5-20x, causing toxicity. Fatal interactions reported with colchicine. Other strong CYP3A4 inhibitors: ketoconazole, itraconazole, ritonavir.

CYP3A4 substrates (HIGH interaction risk): Simvastatin, Lovastatin (highest risk - up to 20x increase with strong inhibitors), Atorvastatin (moderate risk). NOT CYP3A4 substrates (LOWER interaction risk): Pravastatin (no CYP450 metabolism - safest), Rosuvastatin (minimal CYP2C9, mostly excreted unchanged), Pitavastatin (minimal CYP2C9), Fluvastatin (CYP2C9, not 3A4). Clinical rule: When starting a strong CYP3A4 inhibitor (clarithromycin, itraconazole, ritonavir, diltiazem, verapamil), switch from simvastatin/lovastatin to pravastatin, rosuvastatin, or pitavastatin. FDA contraindication: Simvastatin with strong CYP3A4 inhibitors. Rhabdomyolysis risk is dose-dependent and interaction-dependent.

Contraindicated below 30 mL/min/1.73m2. FDA guidance (updated 2016): Do NOT start metformin if eGFR 30-45 mL/min. Contraindicated if eGFR <30 mL/min. If patient already on metformin and eGFR falls below 45: assess benefit/risk. If eGFR falls below 30: discontinue. Risk: Lactic acidosis due to metformin accumulation when renal clearance is impaired. Historical context: Prior to 2016, contraindication was based on serum creatinine (>1.5 mg/dL men, >1.4 mg/dL women). The 2016 change to eGFR-based criteria allows more patients with mild-moderate CKD to use metformin safely.

Normal renal function: 36-48 hours (1.5-2 days). Renal impairment: Progressively prolonged. Anuria/ESRD: 3.5-6 days (up to 6 days in some patients). Mechanism: Digoxin is primarily renally excreted (glomerular filtration), so reduced GFR = reduced clearance = accumulation. Time to steady state: Normal: 7-10 days. ESRD: 15-25 days. Clinical implications: Reduce maintenance dose in renal impairment (loading dose unchanged). Monitor digoxin levels more frequently. Target trough level: 0.5-1.0 ng/mL (lower than historical targets). Toxicity signs: Nausea, visual disturbances (yellow halos), arrhythmias. Digoxin is NOT effectively removed by dialysis (large volume of distribution, tissue-bound).

Contraindicated below 30 mL/min/1.73m2. FDA guidance (updated 2016): Do NOT start metformin if eGFR 30-45 mL/min. Contraindicated if eGFR <30 mL/min. If patient already on metformin and eGFR falls below 45: assess benefit/risk. If eGFR falls below 30: discontinue. Risk: Lactic acidosis due to metformin accumulation when renal clearance is impaired. Historical context: Prior to 2016, contraindication was based on serum creatinine (>1.5 mg/dL men, >1.4 mg/dL women). The 2016 change to eGFR-based criteria allows more patients with mild-moderate CKD to use metformin safely.

Normal renal function: 36-48 hours (1.5-2 days). Renal impairment: Progressively prolonged. Anuria/ESRD: 3.5-6 days (up to 6 days in some patients). Mechanism: Digoxin is primarily renally excreted (glomerular filtration), so reduced GFR = reduced clearance = accumulation. Time to steady state: Normal: 7-10 days. ESRD: 15-25 days. Clinical implications: Reduce maintenance dose in renal impairment (loading dose unchanged). Monitor digoxin levels more frequently. Target trough level: 0.5-1.0 ng/mL (lower than historical targets). Toxicity signs: Nausea, visual disturbances (yellow halos), arrhythmias. Digoxin is NOT effectively removed by dialysis (large volume of distribution, tissue-bound).

QTc >500ms or increase >60ms from baseline = high Torsades de Pointes (TdP) risk. Normal QTc: Males <450ms, Females <460ms. Abnormally prolonged (99th percentile): Males >470ms, Females >480ms. DANGEROUS: QTc >500ms associated with 2-3x increased TdP risk. Each 10ms increase adds ~5-7% exponential risk increase. Clinical action at 470-500ms: Consider dose reduction or discontinuation. Clinical action at >=500ms: Discontinue offending drug, continuous ECG monitoring, repeat ECG every 2-4 hours until normalized. Treatment of TdP: IV magnesium sulfate 1-2g over 5-60 minutes.

Macrolides: Erythromycin (highest risk), clarithromycin, azithromycin (lower but still significant risk). Fluoroquinolones: Moxifloxacin (highest), levofloxacin, ciprofloxacin. Risk factors that compound: Hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, age >65, heart disease, concurrent QT-prolonging drugs. Azithromycin FDA warning (2013): Small increased risk of fatal arrhythmias, especially in patients with existing QT prolongation, hypokalemia, hypomagnesemia, or on other QT-prolonging drugs. Clinical rule: Avoid combining multiple QT-prolonging drugs. If unavoidable, check baseline ECG and electrolytes.

QTc >500ms or increase >60ms from baseline = high Torsades de Pointes (TdP) risk. Normal QTc: Males <450ms, Females <460ms. Abnormally prolonged (99th percentile): Males >470ms, Females >480ms. DANGEROUS: QTc >500ms associated with 2-3x increased TdP risk. Each 10ms increase adds ~5-7% exponential risk increase. Clinical action at 470-500ms: Consider dose reduction or discontinuation. Clinical action at >=500ms: Discontinue offending drug, continuous ECG monitoring, repeat ECG every 2-4 hours until normalized. Treatment of TdP: IV magnesium sulfate 1-2g over 5-60 minutes.

Macrolides: Erythromycin (highest risk), clarithromycin, azithromycin (lower but still significant risk). Fluoroquinolones: Moxifloxacin (highest), levofloxacin, ciprofloxacin. Risk factors that compound: Hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, age >65, heart disease, concurrent QT-prolonging drugs. Azithromycin FDA warning (2013): Small increased risk of fatal arrhythmias, especially in patients with existing QT prolongation, hypokalemia, hypomagnesemia, or on other QT-prolonging drugs. Clinical rule: Avoid combining multiple QT-prolonging drugs. If unavoidable, check baseline ECG and electrolytes.

Significantly prolonged. S-warfarin (the more potent enantiomer, 3-5x more potent than R-warfarin) is metabolized by CYP2C9. In CYP2C9*3/*3 homozygotes (poor metabolizers), S-warfarin clearance is reduced by 75-90%. Normal half-life: 20-40 hours for racemic warfarin. Poor metabolizers: Effective half-life can extend to 40-60+ hours due to impaired S-warfarin metabolism. Clinical implication: DPWG recommends reducing initial dose to 20% of standard dose in known poor metabolizers. Requires more frequent INR monitoring and slower dose titration.

Significantly prolonged. S-warfarin (the more potent enantiomer, 3-5x more potent than R-warfarin) is metabolized by CYP2C9. In CYP2C9*3/*3 homozygotes (poor metabolizers), S-warfarin clearance is reduced by 75-90%. Normal half-life: 20-40 hours for racemic warfarin. Poor metabolizers: Effective half-life can extend to 40-60+ hours due to impaired S-warfarin metabolism. Clinical implication: DPWG recommends reducing initial dose to 20% of standard dose in known poor metabolizers. Requires more frequent INR monitoring and slower dose titration.

2.0-3.0 for most patients with non-valvular atrial fibrillation. Below 2.0: Inadequate anticoagulation, increased stroke risk. Above 3.0: Increased bleeding risk. Above 4.0: Significant bleeding risk, may require intervention. For mechanical heart valves: Target often higher (2.5-3.5 depending on valve type and position). Monitoring frequency: Weekly initially until stable, then every 4-12 weeks. Time in Therapeutic Range (TTR) goal: >70% for optimal outcomes. Warfarin has narrow therapeutic index - small dose changes cause large INR changes.

2.0-3.0 for most patients with non-valvular atrial fibrillation. Below 2.0: Inadequate anticoagulation, increased stroke risk. Above 3.0: Increased bleeding risk. Above 4.0: Significant bleeding risk, may require intervention. For mechanical heart valves: Target often higher (2.5-3.5 depending on valve type and position). Monitoring frequency: Weekly initially until stable, then every 4-12 weeks. Time in Therapeutic Range (TTR) goal: >70% for optimal outcomes. Warfarin has narrow therapeutic index - small dose changes cause large INR changes.

97-99% bound to plasma proteins (primarily albumin). Only 1-3% circulates as free (unbound) drug, which is the pharmacologically active fraction. Clinical significance of displacement: Highly protein-bound drugs (NSAIDs, sulfonamides, phenylbutazone) can displace warfarin, transiently increasing free warfarin concentration. However, modern understanding: Displacement alone rarely causes clinically significant interactions because increased free drug is rapidly cleared. More important: Drugs that BOTH displace AND inhibit warfarin metabolism (like phenylbutazone) cause dangerous interactions. The narrow therapeutic index means even small increases in free warfarin can cause bleeding.

97-99% bound to plasma proteins (primarily albumin). Only 1-3% circulates as free (unbound) drug, which is the pharmacologically active fraction. Clinical significance of displacement: Highly protein-bound drugs (NSAIDs, sulfonamides, phenylbutazone) can displace warfarin, transiently increasing free warfarin concentration. However, modern understanding: Displacement alone rarely causes clinically significant interactions because increased free drug is rapidly cleared. More important: Drugs that BOTH displace AND inhibit warfarin metabolism (like phenylbutazone) cause dangerous interactions. The narrow therapeutic index means even small increases in free warfarin can cause bleeding.

Inhibits intestinal CYP3A4 (not hepatic), increasing oral bioavailability of CYP3A4 substrates by 2-3x or more. Mechanism: Furanocoumarins in grapefruit irreversibly inactivate intestinal CYP3A4. Duration: Effect persists 24-72 hours (until new enzyme is synthesized in intestinal cells). Amount matters: As little as 200mL can cause significant interaction. Affected drugs: Simvastatin, lovastatin, atorvastatin (statins), felodipine, nifedipine (calcium channel blockers), cyclosporine, midazolam, buspirone. NOT affected: Drugs with high bioavailability already, or those not metabolized by intestinal CYP3A4. Clinical advice: Avoid grapefruit entirely with sensitive CYP3A4 substrates, not just timing separation.

Inhibits intestinal CYP3A4 (not hepatic), increasing oral bioavailability of CYP3A4 substrates by 2-3x or more. Mechanism: Furanocoumarins in grapefruit irreversibly inactivate intestinal CYP3A4. Duration: Effect persists 24-72 hours (until new enzyme is synthesized in intestinal cells). Amount matters: As little as 200mL can cause significant interaction. Affected drugs: Simvastatin, lovastatin, atorvastatin (statins), felodipine, nifedipine (calcium channel blockers), cyclosporine, midazolam, buspirone. NOT affected: Drugs with high bioavailability already, or those not metabolized by intestinal CYP3A4. Clinical advice: Avoid grapefruit entirely with sensitive CYP3A4 substrates, not just timing separation.

4g/day (4000mg) is the FDA-established maximum for healthy adults. However, practical recommendations vary: FDA OTC labeling: 4000mg/day maximum stated in warnings. Manufacturer (Tylenol) voluntary reduction: 3000-3250mg/day recommended. Chronic use or liver disease: Limit to 2-3g/day. Alcohol use (3+ drinks/day): Limit to 2g/day or avoid. Hepatotoxic threshold: Acute ingestion >150mg/kg or >12g poses high liver damage risk. Context: Acetaminophen toxicity is the leading cause of acute liver failure in the US and most common cause of drug-induced liver injury. No evidence that 4g/day in healthy adults causes liver damage, but lower doses recommended to provide safety margin.

4g/day (4000mg) is the FDA-established maximum for healthy adults. However, practical recommendations vary: FDA OTC labeling: 4000mg/day maximum stated in warnings. Manufacturer (Tylenol) voluntary reduction: 3000-3250mg/day recommended. Chronic use or liver disease: Limit to 2-3g/day. Alcohol use (3+ drinks/day): Limit to 2g/day or avoid. Hepatotoxic threshold: Acute ingestion >150mg/kg or >12g poses high liver damage risk. Context: Acetaminophen toxicity is the leading cause of acute liver failure in the US and most common cause of drug-induced liver injury. No evidence that 4g/day in healthy adults causes liver damage, but lower doses recommended to provide safety margin.

N-acetylcysteine (NAC). Critical window: Nearly 100% hepatoprotective if given within 8 hours of acute ingestion. Efficacy by timing: 0-8 hours: ~100% prevention of hepatotoxicity. 8-10 hours: Still highly effective. 10-24 hours: Reduced but significant benefit (hepatotoxicity in 6% vs 26%). >24 hours: Still beneficial, should be given. Dosing (oral): Loading 140mg/kg, then 70mg/kg every 4 hours x 17 doses (72-hour protocol). Dosing (IV): 21-hour protocol preferred for faster onset. Mechanism: NAC replenishes glutathione, which detoxifies the toxic metabolite NAPQI. Use Rumack-Matthew nomogram to assess treatment need based on serum acetaminophen level and time since ingestion.

N-acetylcysteine (NAC). Critical window: Nearly 100% hepatoprotective if given within 8 hours of acute ingestion. Efficacy by timing: 0-8 hours: ~100% prevention of hepatotoxicity. 8-10 hours: Still highly effective. 10-24 hours: Reduced but significant benefit (hepatotoxicity in 6% vs 26%). >24 hours: Still beneficial, should be given. Dosing (oral): Loading 140mg/kg, then 70mg/kg every 4 hours x 17 doses (72-hour protocol). Dosing (IV): 21-hour protocol preferred for faster onset. Mechanism: NAC replenishes glutathione, which detoxifies the toxic metabolite NAPQI. Use Rumack-Matthew nomogram to assess treatment need based on serum acetaminophen level and time since ingestion.

Triad: Mental status changes + Autonomic instability + Neuromuscular abnormalities. Mental status: Agitation, confusion, hypomania, anxiety. Autonomic: Hyperthermia (can be >40C), diaphoresis, tachycardia, hypertension, diarrhea, mydriasis. Neuromuscular: Tremor, myoclonus (characteristic), hyperreflexia, rigidity, incoordination. Onset: Usually within 24 hours of drug initiation/dose increase/combination. Severity spectrum: Mild (tremor, hyperreflexia) to life-threatening (hyperthermia >41C, seizures, rhabdomyolysis). Common precipitants: SSRIs + MAOIs, SSRIs + tramadol, SSRIs + triptans, SSRIs + linezolid. Treatment: Stop serotonergic drugs, supportive care, cyproheptadine for moderate-severe cases, benzodiazepines for agitation.

Triad: Mental status changes + Autonomic instability + Neuromuscular abnormalities. Mental status: Agitation, confusion, hypomania, anxiety. Autonomic: Hyperthermia (can be >40C), diaphoresis, tachycardia, hypertension, diarrhea, mydriasis. Neuromuscular: Tremor, myoclonus (characteristic), hyperreflexia, rigidity, incoordination. Onset: Usually within 24 hours of drug initiation/dose increase/combination. Severity spectrum: Mild (tremor, hyperreflexia) to life-threatening (hyperthermia >41C, seizures, rhabdomyolysis). Common precipitants: SSRIs + MAOIs, SSRIs + tramadol, SSRIs + triptans, SSRIs + linezolid. Treatment: Stop serotonergic drugs, supportive care, cyproheptadine for moderate-severe cases, benzodiazepines for agitation.

Mild hypokalemia: 3.0-3.5 mEq/L - Often asymptomatic. Moderate hypokalemia: 2.5-3.0 mEq/L - Muscle weakness, cramps, arrhythmia risk. SEVERE/DANGEROUS: <2.5 mEq/L - Life-threatening arrhythmias, paralysis, respiratory failure. Critical interactions: Hypokalemia + digoxin = greatly increased digoxin toxicity (arrhythmias). Hypokalemia + QT-prolonging drugs = increased Torsades de Pointes risk. Common causes: Diuretics (thiazides, loop), vomiting, diarrhea, hyperaldosteronism. Urgent treatment if <2.5 or symptomatic: IV potassium replacement (max 10-20 mEq/hour via peripheral, 40 mEq/hour via central line with cardiac monitoring). Always check magnesium - hypomagnesemia makes hypokalemia refractory to treatment.

Mild hypokalemia: 3.0-3.5 mEq/L - Often asymptomatic. Moderate hypokalemia: 2.5-3.0 mEq/L - Muscle weakness, cramps, arrhythmia risk. SEVERE/DANGEROUS: <2.5 mEq/L - Life-threatening arrhythmias, paralysis, respiratory failure. Critical interactions: Hypokalemia + digoxin = greatly increased digoxin toxicity (arrhythmias). Hypokalemia + QT-prolonging drugs = increased Torsades de Pointes risk. Common causes: Diuretics (thiazides, loop), vomiting, diarrhea, hyperaldosteronism. Urgent treatment if <2.5 or symptomatic: IV potassium replacement (max 10-20 mEq/hour via peripheral, 40 mEq/hour via central line with cardiac monitoring). Always check magnesium - hypomagnesemia makes hypokalemia refractory to treatment.

Loading needed because of extremely long half-life: 40-55 days (range 26-107 days). Without loading: Would take 130-535 days (average 265 days) to reach steady state. Oral loading regimen: 800-1600mg/day for 1-3 weeks, then reduce to 600-800mg/day for 1 month, then maintenance 200-400mg/day. Alternative: 200-400mg TID for 10-14 days, then maintenance. IV loading (for acute arrhythmias): 150mg over 10 min, then 1mg/min x 6 hours, then 0.5mg/min. Onset with loading: 2-3 days to 1-3 weeks. Without loading: Weeks to months. Persistence after discontinuation: Effects last 1-3 months due to slow release from lipid-rich tissues. The long half-life is due to extremely large volume of distribution and high lipophilicity.

Loading needed because of extremely long half-life: 40-55 days (range 26-107 days). Without loading: Would take 130-535 days (average 265 days) to reach steady state. Oral loading regimen: 800-1600mg/day for 1-3 weeks, then reduce to 600-800mg/day for 1 month, then maintenance 200-400mg/day. Alternative: 200-400mg TID for 10-14 days, then maintenance. IV loading (for acute arrhythmias): 150mg over 10 min, then 1mg/min x 6 hours, then 0.5mg/min. Onset with loading: 2-3 days to 1-3 weeks. Without loading: Weeks to months. Persistence after discontinuation: Effects last 1-3 months due to slow release from lipid-rich tissues. The long half-life is due to extremely large volume of distribution and high lipophilicity.