When to intubate in GCS?

GCS ≤ 8 requires intubation for airway protection. The patient cannot protect their own airway at this level of consciousness. Motor score is the most prognostically important component.

What is the best initial fluid for sepsis resuscitation?

Lactated Ringer's (LR) is the preferred resuscitation fluid. The SMART trial (2018) showed balanced crystalloids reduced death, new renal failure, and persistent renal dysfunction compared to normal saline.

When to start vasopressors in septic shock?

Start norepinephrine (first-line vasopressor) if MAP remains < 65 mmHg after initial 30 mL/kg crystalloid resuscitation, or earlier if patient is profoundly hypotensive. Do not delay pressors to complete full fluid resuscitation.

Why can serum uric acid be normal during acute gout?

During acute inflammation, IL-6 increases renal urate excretion and redistributes urate from plasma to tissues. Up to 40% of acute gout flares have normal serum uric acid. Joint aspiration with polarized microscopy is needed for definitive diagnosis.

How do you distinguish lupus flare from infection in SLE?

Key clues: CRP is low/normal in flare but elevated in infection. Complement (C3/C4) drops in flare but is normal/elevated in infection. Procalcitonin is elevated in bacterial infection but normal in flare. Anti-dsDNA rises in flare, stable in infection.

What is the difference between DKA and HHS?

DKA features acidosis (pH 600), hyperosmolality (> 320), and minimal ketosis -typically in Type 2 DM. DKA requires insulin drip; HHS requires aggressive fluid resuscitation first.

When to give tPA in acute ischemic stroke?

IV alteplase (tPA) can be given within 4.5 hours of last known well time in eligible patients. CT head must rule out hemorrhage first. For large vessel occlusion, mechanical thrombectomy can be performed up to 24 hours with favorable imaging.

What antibiotics for community-acquired pneumonia?

Inpatient non-ICU: ceftriaxone + azithromycin. ICU: ceftriaxone + azithromycin (add vancomycin if MRSA risk). Outpatient healthy: amoxicillin. Outpatient with comorbidities: augmentin + azithromycin or respiratory fluoroquinolone. Duration: 5 days if clinically stable for 48 hours.

How to interpret iron studies?

Iron deficiency: low ferritin (< 30), high TIBC, low iron, low transferrin saturation (< 20%). Anemia of chronic disease: normal/high ferritin (acute phase reactant), low TIBC, low iron. A ferritin of 50-100 in an inflamed patient may still represent iron deficiency.

What is the correction rate for hyponatremia?

Correct sodium no more than 8 mEq/L in 24 hours to avoid osmotic demyelination syndrome (ODS). For symptomatic severe hyponatremia with seizures, give 3% hypertonic saline 100-150 mL bolus over 10-20 minutes. If overcorrected, use D5W + DDAVP rescue protocol.

When to start antibiotics in meningitis?

Within 30-60 minutes. Do NOT delay antibiotics for LP or CT. Draw blood cultures, start empiric antibiotics (vancomycin + ceftriaxone ± ampicillin if > 50 or immunocompromised), then perform LP when possible. Dexamethasone should be given before or with the first antibiotic dose.

DOACs vs warfarin in antiphospholipid syndrome?

DOACs are contraindicated in APS. The TRAPS trial (2018) showed rivaroxaban was inferior to warfarin with more thrombotic events in triple-positive APS patients. Warfarin with INR target 2-3 is the standard for APS, indefinitely.

How to manage scleroderma renal crisis?

ACE inhibitors (captopril) are life-saving -start immediately and titrate aggressively. Do NOT hold for rising creatinine. Steroids > 15 mg prednisone per day precipitate scleroderma renal crisis. ARBs are NOT a substitute -evidence is only for ACEi.

What are the 4 pillars of heart failure treatment?

Guideline-directed medical therapy (GDMT) for HFrEF: (1) ARNI or ACEi/ARB, (2) beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) MRA (spironolactone or eplerenone), (4) SGLT2 inhibitor (dapagliflozin or empagliflozin). All four should be initiated and titrated to target doses.

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Drug Interactions

The combinations that actually hurt patients on the wards. QT prolongation, serotonin syndrome, and the high-risk pairs you need to catch before they cause harm.

⚡ QT-Prolonging Drugs

QTc > 500 ms = high risk for torsades de pointes. Risk multiplies when combining QT-prolonging drugs + hypokalemia + hypomagnesemia. Check ECG, K⁺, and Mg²⁺ before and during treatment.

Category	High-Risk Drugs	Ward Relevance
Antiarrhythmics	Amiodarone (Cordarone), sotalol (Betapace), dofetilide (Tikosyn), procainamide (Pronestyl)	Amiodarone is the most commonly prescribed. Check QTc before loading.
Antibiotics	Fluoroquinolones (levofloxacin, moxifloxacin > cipro), azithromycin, TMP-SMX (rare)	Moxifloxacin has the highest QT risk among FQs. Azithro risk is lower but additive with other drugs.
Antifungals	Fluconazole (Diflucan), voriconazole (Vfend)	Fluconazole at higher doses (> 400 mg). Also inhibits CYP2C9/3A4 → increases levels of warfarin, phenytoin.
Antiemetics	Ondansetron (Zofran), droperidol	Ondansetron at doses > 16 mg IV. FDA warning. 4 mg IV is generally safe but still additive. Check QTc if combining with other QT drugs.
Antipsychotics	Haloperidol (Haldol) (especially IV), ziprasidone, chlorpromazine	IV haloperidol has higher QT risk than IM/PO. Check QTc before and during use. Hold if QTc > 500.
Antidepressants	Citalopram, escitalopram (dose-dependent), TCAs	Citalopram max 20 mg in age > 60 (FDA). TCAs: QRS widening + QT prolongation.
Other	Methadone, sumatriptan, donepezil	Methadone: always check QTc at baseline and periodically. Dose-dependent.

Risk Multipliers

Hypokalemia -replete K⁺ > 4.0 if on QT drugs
Hypomagnesemia -replete Mg²⁺ > 2.0
Hypocalcemia
Bradycardia (more time in repolarization)
Female sex (baseline longer QT)
Combining ≥ 2 QT-prolonging drugs -the risk is synergistic, not just additive

🧠 Serotonin Syndrome

Onset within hours of adding/increasing a serotonergic drug. Classic triad: AMS + autonomic instability + neuromuscular excitation (CLONUS is the most specific sign).

Dangerous Combinations

Drug A	+ Drug B	Risk Level
SSRI / SNRI	MAOI (phenelzine, tranylcypromine, selegiline)	CONTRAINDICATED -14-day washout required between SSRI and MAOI
SSRI / SNRI	Linezolid (Zyvox) (weak MAOI)	HIGH RISK -hold SSRI if linezolid essential. Consult ID + psychiatry.
SSRI / SNRI	Tramadol	MODERATE -very common ward combination. Avoid if possible. Use alternative analgesic.
SSRI / SNRI	Fentanyl (Sublimaze) (especially IV/patch)	MODERATE -serotonergic at higher doses. Monitor closely.
SSRI / SNRI	Triptans (sumatriptan)	LOW-MODERATE -FDA warning but actual risk is very low. Can use with monitoring.
SSRI / SNRI	Methylene blue (IV)	HIGH RISK -methylene blue is an MAOI. Hold SSRI ≥ 2 weeks before elective use.
SSRI / SNRI	Ondansetron (Zofran)	LOW -5-HT3 antagonist. Theoretical risk. Clinically rare. Generally safe to use.

Treatment

Stop all serotonergic agents
Cyproheptadine 12 mg PO loading → 4 mg q6h (serotonin antagonist)
Benzodiazepines for agitation and muscle rigidity
Cooling if hyperthermic. Avoid paralysis (masks clonus -makes monitoring impossible).
Most cases resolve within 24–72h after stopping the offending drug

⚠️ Key Drug Combinations to Watch

Combination	Risk	What to Do
ACEi/ARB + K⁺-sparing diuretic + NSAID	"Triple whammy" → hyperkalemia + AKI	Avoid triple combination. If unavoidable → check K⁺ and Cr within 1 week. Stop NSAID if possible.
Warfarin + TMP-SMX	↑↑ INR (TMP-SMX inhibits CYP2C9)	INR can double within 3–5 days. Check INR 3 days after starting TMP-SMX. Reduce warfarin dose empirically.
Warfarin + fluconazole	↑↑ INR (fluconazole inhibits CYP2C9)	Same as above. Reduce warfarin dose by ~25–50%. Check INR frequently.
Warfarin + amiodarone	↑ INR (CYP inhibition) -effect persists weeks after stopping amio	Reduce warfarin dose by 30–50% when starting amiodarone. Monitor INR weekly.
Statin + clarithromycin/erythromycin	Rhabdomyolysis (CYP3A4 inhibition → statin levels ↑↑)	Hold statin during macrolide course. Or use azithromycin (no CYP3A4 inhibition).
Colchicine (Colcrys) + clarithromycin	Fatal toxicity (CYP3A4 + P-gp inhibition → colchicine accumulates)	Do NOT co-administer. Multiple reported deaths. Reduce colchicine dose or hold during macrolide.
Metformin + IV contrast	Lactic acidosis (if contrast causes AKI → metformin accumulates)	Updated (ACR 2022): If eGFR ≥ 45, no need to hold metformin. If eGFR 30–44, hold day of contrast, resume 48h later if Cr stable. eGFR < 30 → hold regardless. Old teaching to hold in all patients is outdated.
Digoxin + amiodarone	Digoxin toxicity (amio increases dig levels ~70%)	Reduce digoxin dose by 50% when starting amiodarone. Check dig level in 1 week.
Carbamazepine (Tegretol) + many drugs	↓ levels of warfarin, DOACs, OCP, steroids (potent CYP3A4 inducer)	Check for interactions with all co-medications. May need dose increases of affected drugs.
Allopurinol (Zyloprim) + azathioprine (Imuran)	Fatal myelosuppression (allopurinol blocks xanthine oxidase → azathioprine accumulates)	Reduce azathioprine dose by 75% if must co-administer. Or use mycophenolate instead. Monitor CBC closely.
Carbapenems + valproate (Depakote) AVOID	VPA levels drop 50–90% within 24–48h → breakthrough seizures / status epilepticus (inhibition of acylpeptide hydrolase blocks VPA-glucuronide recycling)	Avoid co-administration. Dose-escalating VPA does NOT rescue. If carbapenem is mandatory (CRE, ESBL), bridge AED to levetiracetam. Applies to meropenem, imipenem, ertapenem, doripenem.
Methotrexate + TMP-SMX (Bactrim) FATAL	Fatal pancytopenia / megaloblastic anemia (both are folate antagonists, synergistic marrow suppression)	Do NOT co-administer. Multiple reported deaths. Especially high-risk in elderly, renal impairment, low-dose weekly MTX for RA. Leucovorin rescue if accidentally given.
Clopidogrel (Plavix) + omeprazole / esomeprazole	↓ clopidogrel activation (CYP2C19 inhibition prevents clopidogrel → active metabolite)	FDA warning 2009. Use pantoprazole (minimal CYP2C19 effect) if PPI needed. Clinical significance debated (COGENT showed no difference) but boards test this, know it.
Warfarin + metronidazole (Flagyl)	↑↑ INR (CYP2C9 inhibition, same as TMP-SMX and fluconazole)	INR can double within 3–5 days. Reduce warfarin dose by 25–50% empirically. Check INR in 3 days.
Warfarin + NSAID	↑↑ GI bleed risk (platelet inhibition + gastric erosion + displacement from albumin)	Avoid combination when possible. If unavoidable, use shortest course, add PPI, avoid ketorolac entirely. Acetaminophen is the safer analgesic.
Spironolactone / eplerenone + TMP-SMX	Hyperkalemia (trimethoprim acts like amiloride on distal tubule + MRA blocks aldosterone)	Check K⁺ within 3–5 days. Elderly + renal impairment at highest risk. Consider alternative antibiotic (nitrofurantoin for UTI).
Digoxin + clarithromycin / erythromycin / amiodarone / verapamil / quinidine	Digoxin toxicity (P-gp and CYP3A4 inhibition → ↑ dig levels 50–100%)	Reduce digoxin dose by 50%. Check level in 5–7 days. Watch for N/V, visual disturbances, bradyarrhythmias.
Tacrolimus / cyclosporine + azole antifungals	Toxic CNI levels → nephrotoxicity, tremor, seizures (CYP3A4 inhibition by fluconazole < voriconazole < posaconazole)	Reduce CNI dose 50–75% when starting azole. Trough levels q2–3 days. Transplant pharmacy consult.
Rifampin + many (warfarin, DOACs, OCP, steroids, methadone, CNIs, statins)	↓↓ drug levels (potent CYP3A4, CYP2C9, P-gp INDUCER, broadest drug interaction profile of any common drug)	Review every co-medication when starting rifampin. Increase dose or switch. OCP failure is common, counsel on backup contraception. Effect persists 2 weeks after stopping.
Lithium + NSAID / ACEi / thiazide	Lithium toxicity (reduced renal clearance, tremor, ataxia, AMS, arrhythmias, death)	Check lithium level within 5–7 days of starting any of these. Narrow therapeutic window (0.6–1.2 mEq/L). Hold lithium if acute illness/volume depletion.
Amiodarone + simvastatin	Rhabdomyolysis (CYP3A4 inhibition → simvastatin levels ↑↑)	Max simvastatin dose 20 mg with amiodarone. Or switch to rosuvastatin/pravastatin (not CYP3A4 substrates).
Gabapentinoids (gabapentin, pregabalin) + opioids	Respiratory depression + death (FDA warning 2019, synergistic CNS depression, esp in elderly, COPD)	Avoid combination in opioid-naive, COPD, renal impairment. If needed: start lowest dose, monitor sedation/respiratory rate. Naloxone available.
MAOI + meperidine (Demerol) / linezolid / methylene blue CONTRAINDICATED	Serotonin syndrome, potentially fatal	Meperidine + MAOI has caused deaths. Use morphine or hydromorphone instead. 14-day washout from MAOI before any serotonergic agent.
Sulfonylureas (glipizide, glyburide) + fluoroquinolones / TMP-SMX	Hypoglycemia (mechanism varies, sulfa cross-reactivity + CYP2C9 inhibition for TMP-SMX)	Monitor fingersticks q4–6h during first 48h. Reduce sulfonylurea dose or hold. Elderly at highest risk. Gatifloxacin causes both hypo- AND hyperglycemia (withdrawn in US).
Levothyroxine + PPI / calcium / iron / sucralfate / bile acid binders	↓ levothyroxine absorption → persistent hypothyroidism	Separate by ≥ 4 hours. Levothyroxine should be taken 30–60 min before breakfast, fasting. PPI effect is smaller but real in gastric-acid-dependent absorption.
Fluoroquinolones + di/trivalent cations (Ca, Mg, Al, Fe, Zn, sucralfate, dairy)	↓↓ fluoroquinolone absorption (chelation)	Separate by 2h before or 6h after cation. Common missed interaction, nurse gives cipro with Tums or iron supplement → treatment failure.
ACEi + ARB / direct renin inhibitor (aliskiren) AVOID	Dual RAAS blockade → hyperkalemia, AKI, hypotension, no mortality benefit (ONTARGET, ALTITUDE)	Do NOT combine. Single-agent RAAS is adequate. Exception: add-on spironolactone is NOT dual blockade and is indicated in HFrEF.
, , VERY COMMON (you'll see these every day on the wards) , ,
Opioid + benzodiazepine	Respiratory depression, oversedation, death (FDA black box warning 2016). Leading cause of accidental overdose death.	Avoid combination when possible. If needed: lowest effective doses, observe, naloxone at bedside. Be especially cautious in elderly, opioid-naïve, COPD, OSA.
Opioid + alcohol / sedatives	Synergistic respiratory depression	Counsel patients. Caution in discharge planning with opioid prescriptions.
Aspirin + ibuprofen (or other NSAIDs)	Ibuprofen blocks the COX-1 site where ASA binds irreversibly → ↓ ASA antiplatelet effect	Dose ASA at least 2h before ibuprofen (or use acetaminophen / COX-2 inhibitor instead). Critical in patients with cardiac stents.
Warfarin + acetaminophen (APAP > 2g/day chronic)	↑ INR (mechanism unclear but consistent signal; risk rises with chronic 3–4g/day)	Check INR 3–5 days after starting chronic APAP. Most patients tolerate ≤ 2g/day without issue.
Warfarin + fluoroquinolones (cipro, levo, moxi)	↑ INR (disruption of gut flora producing vit K + mild CYP effects)	Check INR within 3–5 days of starting. Common outpatient over-anticoagulation scenario.
Warfarin + SSRI / SNRI	↑ bleed risk (platelet function + gastric erosion + CYP effects for some SSRIs)	Prefer sertraline, citalopram (least CYP interaction). Add PPI if GI bleed history. Monitor INR for fluoxetine/fluvoxamine (CYP2C9).
SSRI / SNRI + NSAID	↑↑ upper GI bleed risk (platelet dysfunction × 2 + gastric erosion)	Add PPI if combination is unavoidable. Risk doubles vs either agent alone.
Loop diuretic + digoxin	Hypokalemia potentiates digoxin toxicity	Check and replete K⁺ (keep > 4.0) and Mg²⁺ (> 2.0). Classic boards fact.
ACEi/ARB + K⁺ supplement / K-sparing diuretic	Hyperkalemia (especially in CKD, diabetes, elderly)	Check BMP within 1–2 weeks. Stop KCl supplementation when starting RAAS in most patients.
Vancomycin + piperacillin-tazobactam	↑ AKI vs cefepime + vanc (ACORN 2024)	2026 empiric sepsis default is vanc + cefepime unless anaerobic source. Add Zosyn or metronidazole only when clearly indicated.
Broad-spectrum abx + oral contraceptive	Theoretical ↓ OCP efficacy, only rifampin/rifabutin have real evidence. Non-rifamycin antibiotics have minimal clinical impact.	Counsel on backup contraception for rifampin course + 4 weeks after. Other antibiotics: reassure patients (the old teaching is outdated).
Metformin + IV contrast	See "Metformin + IV contrast" row above, updated per ACR 2022.	eGFR ≥ 45: don't hold. eGFR 30–44: hold day of, resume 48h later. eGFR < 30: hold.
, , COMMON (weekly ward encounters) , ,
Beta-blocker + non-DHP CCB (verapamil, diltiazem)	Bradycardia, AV block, heart failure (additive AV nodal blockade + negative inotropy)	Avoid combination unless cardiology specifically directs. Especially risky in HFrEF, baseline conduction disease.
Loop diuretic + aminoglycoside / vancomycin	Ototoxicity and nephrotoxicity (both classes independently ototoxic; additive when combined)	Minimize dose and duration. Check vanc troughs/AUC. Audiometry baseline for prolonged aminoglycoside courses.
Amphotericin B + any nephrotoxin (vancomycin, aminoglycoside, cyclosporine, tacrolimus, contrast)	Severe AKI	Pre-hydrate with NS before amphotericin. Use liposomal amphotericin. Avoid concurrent nephrotoxins when feasible.
Clonidine + beta-blocker (during taper)	Rebound hypertension / hypertensive crisis if clonidine stopped while BB continues (unopposed alpha stimulation)	Taper clonidine FIRST over 7–10 days, then taper BB. Never stop clonidine abruptly in patients on BB.
Ciprofloxacin + theophylline	Theophylline toxicity (seizures, arrhythmia), CYP1A2 inhibition	Avoid. Use azithromycin or non-FQ alternative. Check theophylline level if forced to combine.
Nitrates + PDE5 inhibitor (sildenafil, tadalafil) CONTRAINDICATED	Fatal hypotension (synergistic vasodilation)	Never give nitroglycerin to a patient who took sildenafil within 24h (or tadalafil within 48h). Ask the chest-pain patient about Viagra use.
Alpha-blocker (tamsulosin) + PDE5 inhibitor	Hypotension (synergistic vasodilation, less severe than nitrate + PDE5i but real)	Separate doses by ≥ 4h. Lower PDE5i dose. Counsel patients.
SGLT2i + insulin / sulfonylurea	Hypoglycemia + euglycemic DKA risk if insulin withdrawn	Reduce sulfonylurea or insulin dose when starting SGLT2i. Never stop basal insulin in T1DM on SGLT2i. Hold SGLT2i 3–4 days before surgery.
GLP-1 agonist + insulin / sulfonylurea	Hypoglycemia	Reduce background sulfonylurea ~50% when starting GLP-1. Basal insulin ~20%.
Epinephrine + non-selective beta-blocker (propranolol)	Unopposed alpha stimulation → hypertensive crisis	Use selective BB in anaphylaxis-risk patients. Classic pimp: why propranolol is avoided in pheochromocytoma (needs alpha-block first).
Beta-agonist (albuterol) + non-selective BB	Bronchospasm blockade (propranolol blocks β2 receptors in airways)	Use cardioselective BB (metoprolol, bisoprolol, nebivolol) in COPD/asthma patients.
Dronedarone + digoxin	Digoxin toxicity (P-gp inhibition, effect larger than amiodarone)	Reduce digoxin dose by 50%. Dronedarone also contraindicated in permanent AF (PALLAS trial: increased mortality).
Tramadol + warfarin	↑ INR (mechanism: CYP2C9 + CYP3A4 interactions)	Check INR in 3–5 days. Tramadol also serotonergic (avoid with SSRIs).
Aminoglycoside + non-depolarizing neuromuscular blocker (rocuronium, vecuronium)	Prolonged paralysis, respiratory failure (synergistic at NMJ)	Reduce NMB dose. Consider sugammadex for reversal. Especially relevant in OR/ICU.
Fluconazole + phenytoin	↑↑ phenytoin levels → ataxia, nystagmus, AMS, seizures (paradoxical). CYP2C9 inhibition.	Reduce phenytoin dose ~25% when starting fluconazole. Check level 5–7 days. Same mechanism as warfarin + fluconazole.
TMP-SMX + phenytoin	↑ phenytoin levels (CYP2C9 inhibition + protein-binding displacement) → toxicity	Monitor phenytoin level if course > 5 days. Often missed because TMP-SMX is short-course for UTI.
Isoniazid (INH) + phenytoin / carbamazepine	↑↑ AED levels (INH inhibits CYP2C9 + CYP2C19 + CYP3A4). Phenytoin toxicity classic teaching.	Reduce AED dose empirically. Check level 1–2 weeks into INH. Especially risky in slow INH acetylators.
Erythromycin / clarithromycin + carbamazepine	↑↑ carbamazepine levels → drowsiness, diplopia, ataxia, AMS (CYP3A4 inhibition)	Use azithromycin instead (no CYP3A4 effect). If macrolide mandatory, reduce CBZ dose 25–50% and check level within 3–5 days.
Metronidazole + phenytoin / phenobarbital	↑ AED levels (CYP2C9 inhibition)	Check phenytoin level if combined > 5 days. Same CYP2C9 mechanism as metronidazole + warfarin.
Ciprofloxacin + phenytoin	Unpredictable phenytoin levels (some patients rise, others fall, complex protein binding + metabolism)	Check level before and during. Avoid if possible, use levofloxacin instead (cleaner interaction profile).
Nafcillin / dicloxacillin + warfarin	↓↓ INR, these antistaphylococcal penicillins are potent CYP3A4 inducers (frequently forgotten, unlike most β-lactams)	Increase warfarin dose during nafcillin course. Monitor INR 2–3× per week. Effect persists 2 weeks after nafcillin stops.
Fluoroquinolones + methadone	↑ QT prolongation (additive, both independently prolong QT) + mild CYP3A4 inhibition by cipro	Check ECG. Prefer levofloxacin over moxifloxacin (less QT effect). Hold if QTc > 500.
Rifampin + methadone	Methadone withdrawal (CYP3A4 induction drops methadone levels, opioid withdrawal symptoms emerge)	Increase methadone dose ~50% when starting rifampin. Common pitfall in MAT + TB treatment overlap.
, , UNCOMMON BUT DANGEROUS (know these before they happen) , ,
Ciprofloxacin + tizanidine CONTRAINDICATED	Fatal hypotension, profound sedation, cipro is a CYP1A2 inhibitor; tizanidine levels rise 10–20×	Absolute contraindication per FDA. Use levofloxacin or moxifloxacin (no CYP1A2 effect), or switch muscle relaxant.
Voriconazole + warfarin / phenytoin / cyclosporine / tacrolimus	Significant toxicity of all co-meds, voriconazole inhibits CYP2C9, CYP2C19, CYP3A4 (broadest azole profile)	Reduce substrate doses 50%. Monitor levels. Consider switching to echinocandin if feasible.
Linezolid + tyramine-rich food / pseudoephedrine / meperidine AVOID	Hypertensive crisis or serotonin syndrome (linezolid is a weak MAOI)	Counsel on tyramine foods during linezolid. Screen OTC decongestants. Use morphine/hydromorphone instead of meperidine.
Digoxin + IV calcium HISTORIC WARNING	"Stone heart", fatal arrhythmia from intracellular Ca overload (classic teaching)	Modern data suggests risk is overstated but most clinicians still avoid. If hypocalcemia AND dig toxicity together → give Digibind first, then cautious calcium.
Valacyclovir / acyclovir high-dose + cyclosporine / tacrolimus	Thrombotic microangiopathy (TTP-HUS-like) in transplant patients	Rare but described. Monitor for MAHA + thrombocytopenia + AKI.
Statin + gemfibrozil AVOID	Rhabdomyolysis (gemfibrozil inhibits statin glucuronidation), highest-risk fibrate	Use fenofibrate instead (much lower rhabdo risk). Or statin + ezetimibe.
Colchicine + statin	Myopathy (independent muscle toxicity, additive)	Watch for muscle pain, weakness. Check CK if symptomatic. Higher risk with atorvastatin + high-dose colchicine.
Isoniazid + alcohol	Hepatotoxicity (additive)	Counsel abstinence during TB treatment. Screen LFTs monthly.
Metronidazole + alcohol / cefoperazone + alcohol	Disulfiram-like reaction (flushing, nausea, palpitations), contested for metronidazole but classic teaching	Counsel patients to avoid alcohol during and 3 days after metronidazole. Applies to any alcohol source (mouthwash, cough syrup).
Disulfiram + alcohol	Intended disulfiram reaction, severe flushing, hypotension, vomiting, rarely cardiovascular collapse	Never give disulfiram without patient consent. Watch for hidden alcohol (cough syrup, IV meds in propylene glycol).
Tyramine-rich food + MAOI	Hypertensive crisis (stroke, MI), classic "wine and cheese" reaction	Avoid aged cheese, cured meats, red wine, fava beans, soy sauce. Counsel thoroughly when starting any MAOI (phenelzine, tranylcypromine, selegiline, linezolid at high doses).
Tamoxifen + strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion)	↓ tamoxifen activation (CYP2D6 converts tamoxifen → endoxifen, the active metabolite) → ↑ breast cancer recurrence	Use sertraline, citalopram, or venlafaxine for depression/hot flashes in tamoxifen patients.
Codeine + CYP2D6 inhibitors (or ultra-rapid metabolizer phenotype)	Ultra-rapid metabolizers: morphine toxicity. Poor metabolizers: no analgesia (codeine is a prodrug)	Avoid codeine in kids (FDA boxed warning). Use alternative analgesic (hydrocodone, oxycodone).
Ginkgo biloba + antiplatelet / anticoagulant	↑ bleed risk (ginkgo has independent antiplatelet effect)	Screen for OTC supplements pre-operatively. Hold ginkgo 1 week before surgery.
, , RARE / HISTORICAL / BOARD-TESTED , ,
Allopurinol + ACEi / thiazide	↑ hypersensitivity reaction (SJS/TEN/DRESS), especially in CKD	Start allopurinol at low dose (100 mg, 50 mg if CKD) and titrate. Consider HLA-B*5801 testing in high-prevalence populations (SE Asian, African-American).
Allopurinol + warfarin	↑ INR (mild CYP2C9 inhibition)	Check INR 1–2 weeks after starting allopurinol.
Methotrexate + NSAID / PPI	↑ MTX levels / toxicity (reduced renal clearance)	Matters at chemotherapy doses, less at low-dose weekly RA dosing. Hold NSAIDs around high-dose MTX infusions.
Dextromethorphan + MAOI	Serotonin syndrome	Common hidden exposure, many OTC cough products contain DXM. Screen when starting MAOI.
Pseudoephedrine + MAOI	Hypertensive crisis (sympathomimetic + MAOI)	Screen OTC decongestants (Sudafed, cold meds) when on MAOI.
Serotonergic agents + St. John's Wort	Serotonin syndrome + CYP3A4 induction (complex dual risk)	Always ask patients about herbal supplements. Discontinue St. John's Wort ≥ 2 weeks before starting SSRI.
Ticagrelor + strong CYP3A4 inhibitors	↑ ticagrelor levels → bleeding	Avoid ketoconazole, clarithromycin, ritonavir with ticagrelor. Clopidogrel is the alternative (but has its own PPI interaction).
Cisplatin + aminoglycoside / loop diuretic	Nephrotoxicity + ototoxicity (synergistic)	Pre-hydrate before cisplatin. Avoid concurrent nephrotoxins. Audiometry baseline.
Methadone + benzodiazepine / alcohol	Respiratory depression, overdose death (also QT prolongation additive with other QT drugs)	High-risk combination in MAT programs. Start low, monitor carefully.

🧬 CYP450 & P-gp Cheat Sheet

Mental model: Inhibitor → drug levels ↑ (toxicity) within days. Inducer → drug levels ↓ (treatment failure) over 1–2 weeks. Always check when starting/stopping ANY antifungal, antibiotic, anticonvulsant, or antiretroviral.

Potent CYP3A4 Inhibitors, Raise Substrate Levels

Class	Examples	High-Risk Substrates Affected
Azole antifungals	Ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole (weaker)	Tacrolimus, cyclosporine, warfarin, statins (not pravastatin/rosuvastatin), DOACs, methadone, sildenafil
Macrolides	Clarithromycin, erythromycin (azithromycin is NOT a CYP inhibitor, safe)	Statins (→ rhabdo), colchicine (→ fatal), digoxin, warfarin, carbamazepine
Protease inhibitors	Ritonavir, cobicistat, darunavir	Inhaled corticosteroids (→ iatrogenic Cushing's), statins, PDE5i, benzodiazepines, steroids
Calcium channel blockers	Diltiazem, verapamil (amlodipine is weaker)	Simvastatin (max 10 mg with dilt/verap), tacrolimus, cyclosporine, sirolimus
Grapefruit juice	1 glass = inhibits intestinal CYP3A4 for 24–72h	Simvastatin, atorvastatin, amiodarone, tacrolimus, cyclosporine, CCBs, DOACs
Antidepressants	Fluoxetine, paroxetine, fluvoxamine, nefazodone (less common)	Warfarin, TCAs, tramadol, opioids, tamoxifen (↓ efficacy via CYP2D6)

Potent CYP3A4 Inducers, Lower Substrate Levels

Class	Examples	Impact
Anticonvulsants (enzyme-inducing)	Carbamazepine, phenytoin, phenobarbital, primidone	Lowers warfarin, DOACs, OCP, steroids, statins, CNIs. Many reasons to prefer levetiracetam/lamotrigine.
Rifamycins	Rifampin (most potent), rifabutin, rifapentine	Broadest inducer profile of any common drug. OCP failure, transplant rejection, warfarin subtherapeutic, methadone withdrawal.
St. John's Wort	OTC herbal supplement	Often overlooked, induces CYP3A4. Can cause transplant rejection, OCP failure, serotonin syndrome (also serotonergic).
Antiretrovirals	Efavirenz, nevirapine, etravirine (non-nucleoside RTIs)	Complex, some induce, some inhibit. Always consult HIV pharmacist.
Glucocorticoids (chronic)	Dexamethasone (mild inducer)	Relevant in long-term steroid + warfarin, DOACs.

CYP2C9 Inhibitors, Warfarin Amplifiers

Drug	Ward Relevance
TMP-SMX (Bactrim)	#1 outpatient cause of warfarin over-anticoagulation. Also via displacement from albumin.
Fluconazole	Dose-dependent. Higher fluconazole doses for esophageal/systemic candidiasis significantly raise INR.
Metronidazole (Flagyl)	Commonly missed. INR jumps within 3–5 days.
Amiodarone	Dual mechanism: CYP2C9 + 3A4 inhibition. Effect persists 3–4 weeks after stopping (long half-life).
Fibrates (gemfibrozil)	CYP2C9 + protein displacement.

P-Glycoprotein (P-gp) Inhibitors & Inducers

P-gp is an efflux pump in gut/BBB/renal tubules. Inhibition → ↑ substrate absorption/distribution. Critical for DOACs, digoxin, colchicine.

Type	Drugs	Key P-gp Substrates to Watch
Inhibitors	Amiodarone, verapamil, diltiazem, clarithromycin, ketoconazole, cyclosporine, ritonavir, quinidine	DOACs (especially dabigatran, dialyze if toxic), digoxin (↑ 50%), colchicine (fatal with clarithromycin + renal disease)
Inducers	Rifampin, carbamazepine, phenytoin, St. John's Wort	Lower DOAC levels → thrombotic failure. Lower digoxin.

Pimp Pearls

"SICKFACES.COM", CYP inhibitors mnemonic: Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin/clarithromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole, Grapefruit juice.
"CRAP GPS", CYP inducers mnemonic: Carbamazepine, Rifampin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbital, St. John's wort, Sulfonylureas.
Azithromycin does NOT inhibit CYP3A4, the safe macrolide when you need a statin to stay on board. Erythromycin and clarithromycin do inhibit.
Pravastatin and rosuvastatin are not CYP3A4 substrates, preferred statins when using strong CYP3A4 inhibitors.
Dabigatran is the only dialyzable DOAC, relevant when P-gp inhibitor + AKI causes toxicity.
Smoking induces CYP1A2, smokers need higher doses of theophylline, olanzapine, clozapine. Dose drops if they quit.