Step 1 · Pharmacology Principles

Drug Interactions Beyond CYP450

Name: Drug Interactions Beyond CYP450
Creator: Veli Bakalov, MD

When drugs collide at receptors, transporters and non-CYP enzymes

Pharmacology Principles·Drug Metabolism & Interactions·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Pharmacodynamic interactions change effect, not level: stacked QT drugs, serotonergics, opioids with sedatives, potassium-raising drugs, antithrombotics, PDE5 inhibitors with nitrates and anticholinergics.
Serotonin syndrome develops within hours with hyperthermia, hyperreflexia and clonus; stop the drugs and give benzodiazepines and cyproheptadine.
Wait 2 weeks after stopping an MAOI (or most SSRIs) and 5 weeks after fluoxetine before switching.
ACE inhibitor or ARB plus spironolactone, amiloride, trimethoprim or NSAIDs causes hyperkalemia.
No nitrates within 24 hours of sildenafil or vardenafil or 48 hours of tadalafil.
P-gp inhibitors (verapamil, amiodarone, quinidine, clarithromycin) raise digoxin and dabigatran; halve digoxin when starting amiodarone.
Probenecid blocks OAT secretion of penicillins and cidofovir; NSAIDs, PPIs and TMP-SMX raise methotrexate; thiazides, NSAIDs and ACE inhibitors raise lithium.
Allopurinol or febuxostat with azathioprine or 6-MP causes marrow suppression; reduce the thiopurine dose to about one-quarter to one-third.
Metronidazole, chlorpropamide, procarbazine and cefotetan cause disulfiram-like reactions; cations chelate tetracyclines, fluoroquinolones and levothyroxine.

Two kinds of interaction beyond CYP450

Pharmacodynamic interactions leave drug concentrations unchanged. Two drugs act on the same physiologic system, so their effects add, multiply or cancel: hERG block, serotonergic tone, respiratory drive, potassium handling, hemostasis, vascular cGMP or muscarinic blockade.

Pharmacokinetic interactions outside CYP450 change concentrations through other routes: efflux transporters such as P-glycoprotein, renal secretion and reabsorption (organic anion transporters, lithium handling), non-CYP enzymes (xanthine oxidase, aldehyde dehydrogenase) and gut absorption (chelation).

Pharmacodynamic stacking

Additive and synergistic effects

Effect	Typical combination	Consequence	Prevention
QT prolongation	Azithromycin + haloperidol + ondansetron	Torsades de pointes	Baseline QTc; correct K⁺ and Mg²⁺; avoid stacking
Serotonin excess	SSRI/SNRI + MAOI, linezolid, tramadol, meperidine	Serotonin syndrome	Avoid combinations; observe washouts
CNS and respiratory depression	Opioid + benzodiazepine or alcohol	Apnea, overdose death	Avoid co-prescribing; naloxone
Hyperkalemia	ACE inhibitor/ARB + spironolactone or TMP-SMX	Arrhythmia	Monitor K⁺ and creatinine
Bleeding	Warfarin + NSAID, aspirin or clopidogrel	GI bleeding at the same INR	Acetaminophen; PPI if combination needed
Hypotension	PDE5 inhibitor + nitrate	Profound, possibly fatal hypotension	No nitrate within 24–48 h
Anticholinergic load	TCA + diphenhydramine + oxybutynin	Delirium, urinary retention	Deprescribe (Beers criteria)

QT stacking. Each drug may block hERG only modestly, but a hypokalemic inpatient given azithromycin for pneumonia, haloperidol for delirium and ondansetron for nausea can develop torsades. A QTc above 500 ms marks high risk.

Serotonin syndrome. An SSRI or SNRI combined with an MAOI such as phenelzine, tranylcypromine or isocarboxazid (the most dangerous pairing), linezolid (a weak nonselective MAOI), tramadol, meperidine, a triptan, dextromethorphan, fentanyl or St John's wort can cause serotonin toxicity within hours. Features are altered mental status and agitation; autonomic instability with hyperthermia, diaphoresis, tachycardia, mydriasis and diarrhea; and neuromuscular hyperactivity with hyperreflexia and inducible or ocular clonus, more prominent in the legs. Treatment is stopping the drugs, benzodiazepines and cyproheptadine, a 5-HT_2A antagonist. Neuroleptic malignant syndrome, by contrast, follows D₂ blockade, evolves over days, and shows lead-pipe rigidity with reduced reflexes; it is treated with dantrolene or bromocriptine.

Stopping an MAOIwait at least 2 weeks for new enzyme to be synthesized before any serotonergic drug
Stopping most SSRIswait at least 2 weeks before an MAOI
Stopping fluoxetinewait at least 5 weeks, because fluoxetine and norfluoxetine have long half-lives

Respiratory depression. Opioids suppress brainstem respiratory drive through μ receptors, and benzodiazepines, alcohol, barbiturates, gabapentinoids and sedating antihistamines add to it synergistically. The opioid–benzodiazepine pairing carries a boxed warning and underlies many overdose deaths, so co-prescribing is avoided, doses are kept low and naloxone is supplied. Naloxone reverses only the opioid component; flumazenil can precipitate withdrawal seizures in chronic benzodiazepine users.

Hyperkalemia. ACE inhibitors and ARBs lower aldosterone. Spironolactone, eplerenone, amiloride, triamterene, trimethoprim (which blocks ENaC like amiloride), NSAIDs (which suppress renin), heparin (which suppresses aldosterone) and potassium supplements push K⁺ higher, especially in CKD, diabetes and older adults.

Bleeding. NSAIDs, aspirin and clopidogrel inhibit platelets and injure gastric mucosa, so adding them to warfarin or a DOAC multiplies bleeding even when the INR does not change. Some NSAIDs also displace warfarin from albumin, but the pharmacodynamic effect dominates. SSRIs add risk by depleting platelet serotonin.

PDE5 inhibitors and nitrates. Nitrates raise cGMP by releasing nitric oxide, while sildenafil, vardenafil and tadalafil block cGMP breakdown. Nitrates are contraindicated within 24 hours of sildenafil or vardenafil and 48 hours of tadalafil, and α₁-blockers need caution.

Anticholinergic burden. TCAs such as amitriptyline, first-generation antihistamines (diphenhydramine, hydroxyzine), antipsychotics (chlorpromazine, clozapine, olanzapine), oxybutynin and benztropine sum their muscarinic blockade, causing dry mouth, constipation, urinary retention, tachycardia, blurred vision, hyperthermia and delirium in older adults. Adding an anticholinergic to donepezil or rivastigmine directly opposes the dementia therapy.

Transporters and renal elimination

Transporter and elimination interactions

Victim drug	Interacting drugs	Mechanism
Digoxin, dabigatran	Verapamil, amiodarone, quinidine, clarithromycin	P-glycoprotein inhibition
Penicillins, cidofovir	Probenecid	OAT1/OAT3 secretion blocked
Methotrexate	NSAIDs, PPIs, penicillins, probenecid, TMP-SMX	Reduced renal excretion (plus a second antifolate with TMP-SMX)
Lithium	Thiazides, NSAIDs, ACE inhibitors, ARBs	More proximal reabsorption or lower GFR

P-glycoprotein. This ABCB1 efflux pump returns drugs to the gut lumen and secretes them into urine and bile. Inhibitors (verapamil, amiodarone, quinidine, clarithromycin, ketoconazole, cyclosporine, ritonavir) raise digoxin and dabigatran levels, causing arrhythmias or bleeding; the digoxin dose is halved when amiodarone starts. Inducers such as rifampin and St John's wort lower them.

Probenecid. By inhibiting OAT1 and OAT3 in the proximal tubule, probenecid prolongs penicillin and cephalosporin levels (sometimes deliberately) and reduces tubular uptake of cidofovir, which is given with probenecid and hydration to protect the kidney. It also inhibits URAT1, which is why it is uricosuric.

Methotrexate is cleared by filtration and OAT-mediated secretion. Toxicity (mucositis, pancytopenia, hepatic and renal injury) is worst with high-dose regimens and renal impairment. Leucovorin bypasses DHFR, and glucarpidase, which cleaves methotrexate, is reserved for toxic levels with renal failure.

Lithium has a narrow therapeutic range of about 0.6–1.2 mEq/L and is neither metabolized nor protein bound; it is filtered and reabsorbed with sodium in the proximal tubule. Thiazides (volume contraction), NSAIDs (reduced renal blood flow), ACE inhibitors or ARBs (lower GFR), dehydration and low-salt diets raise levels; loop diuretics have a smaller effect, while acetazolamide and osmotic diuretics increase lithium excretion. Toxicity progresses from coarse tremor, ataxia, confusion, vomiting and diarrhea to seizures, and severe cases need hemodialysis.

Non-CYP enzymes and absorption

Xanthine oxidase. Azathioprine is converted to 6-mercaptopurine, which xanthine oxidase inactivates to 6-thiouric acid (TPMT is the other inactivating enzyme). Allopurinol or febuxostat blocks the xanthine oxidase route and shunts drug toward cytotoxic thioguanine nucleotides, causing severe marrow suppression. The azathioprine or 6-MP dose is cut to about one-quarter to one-third, or the combination is avoided, with close CBC monitoring.

Disulfiram-like reactions. When aldehyde dehydrogenase is impaired, acetaldehyde accumulates after alcohol and causes flushing, throbbing headache, nausea, vomiting, tachycardia and hypotension. Culprits are metronidazole (classically; avoid alcohol during therapy and for 3 days after), first-generation sulfonylureas such as chlorpropamide, procarbazine, and cephalosporins with an N-methylthiotetrazole side chain (cefotetan, cefoperazone).

Chelation. Calcium (dairy, supplements), magnesium and aluminum (antacids), iron, zinc and sucralfate bind tetracyclines and fluoroquinolones in the gut and sharply cut absorption. Calcium, iron, bile-acid resins and PPIs also reduce levothyroxine absorption.

Timing rules: give a tetracycline or fluoroquinolone at least 2 hours before or 4–6 hours after polyvalent cations, and keep levothyroxine at least 4 hours apart from calcium or iron.