Drug Interactions Stephen Kravcik MD FRCPC Division of General Medicine University of Ottawa
Conflicts of Interest • None with pharmaceutical industry • Consultant with – PHAC – CADTH – CMPA – WSIB
Clinical Burden of DDIs • 3-5% of preventable in-hospital adverse drug reactions – Majority are unanticipated and unrecognized until after the occurrence
Two big players • P-glycoprotein
• Cytochrome P450
Teaching about DDIs • Interesting, if you’re a nerd • Pretty dry otherwise
Cool drug Warfarin HIV Meds Miscellaneous Antibiotics DOACs AEs 100 100 100 100 100 100 200 200 200 200 200 200 300 300 300 300 300 300 400 400 400 400 400 400 500 500 500 500 500 500
DOACS 100 A 57yo woman with severe COPD, on chronic azithromycin, develops A fib and requires OAC. With which DOAC are macrolides safely taken?
DOACS 100 • None – DOAC metabolism is, at least in part, controlled by P-glycoprotein – All macrolides are strong PGP inhibitors – Therefore, macrolide use will increase all DOAC activity, and may lead to an increase in bleeding Fralick M, Juurlink DN, Marras T. Bleeding associated with coadministration of rivaroxaban and clarithromycin. CMAJ. 2016 Jun 14;188(9):669-72
DOACS 200 An HIV+ man on Genvoya, which has a strong CYP3A4 inhibitor, is found to have A fib. He has terrible veins and wishes to avoid warfarin use. Which DOAC is safest with a strong inhibitor of CYP450 3A4?
DOACS 200 – Dabigatran • Its is minimally metabolized by any of the cytochromes • The other DOACS are significantly metabolized by CYP450, so inhibitors or inducers of these enzymes will have a significant effect on the effectiveness or safety of DOACs • But dabigatran is still not terribly safe with HIV Pis as they inhibit Pgp – So best change ARVs or use warfarin
DOACs 300 Which is least safe with a DOAC when treating a fib: a beta blocker, verapamil or digoxin?
DOACs 300 • Verapamil is a strong inhibitor of PGP, and may lead to an increased risk of bleeding if on a DOAC.
DOACs 400 Which anticonvulsant is safest with a rivaroxaban or apixaban: phenytoin, carbamazepine or valproic acid?
DOACs 400 • Valproic acid – Phenytoin and carbamazepine are strong inducers of CYP450 3A4 and inducers of PGP, so may dramatically reduce DOAC effectiveness – If these are required, use warfarin: affected by CYP450 but can follow the INR
DOACs 500 Is amiodarone safe with DOACS?
DOACs 500 • Moderate CYP3A4 and mild-mod P- gp inhibitor – Dabi levels increase 40% – Use with caution with any DOAC
Antibiotics 100 • Which antituberculous drug is the most potent known CYP450 inducer?
Antibiotics 100 • Rifampin • Potential substrates: – All calcium channel blockers – All benzos except for lorazepam, oxazepam and temazepam – Statins (not much with pravastatin) – Estrogens – Apixaban, rivaroxaban, warfarin
Antibiotics 200 A 65 yo female with dyspepsia, who loves her TUMS, who has not seen a doctor in years, fails treatment of a sensitive gram- UTI with cipro. Why?
Antibiotics 200 • Tums and any other di- or tri-valent cations may bind quinolones and reduce their absorption – Tums et al should be given at least 2 hours before or 6 hours after a quinolone dose – The same holds for iron, calcium supps and phosphate binders – Do not take with dairy products • Also happens with tetracyclines
Antibiotics 300 A depressed middle aged bodybuilder on citalopram receives linezolid for an MRSA cellulitis. He develops myoclonus and hyperreflexia. Why?
Antibiotics 300 • Linezolid use may lead to serotonin syndrome if taken with drugs that increase serum serotonin levels: Antidepressants Analgesics SSRIs Tramadol Paroxetine Meperidine Sertraline Methadone Fluoxetine Dextromethorphan Fluvoxamine Dextropropoxyphene Citalopram Pentazocine Escitalopram Antituberculosis SNRIs Isoniazid Venlafaxine Anxiolytics Duloxetine Buspirone Mirtazapine Hypnotics Tricyclic antidepressants l-tryptophan Amitriptyline Migraine Clomipramine Sumatriptan and other triptans Desipramine Stimulants Doxepin Amphetamine and derivatives Antineoplastic Imipramine Nortriptyline Procarbazine Protriptyline Dopamine agonists NRIs Bromocriptine Trazodone Illicit psychotropics Nefazodone Cocaine MAOIs Lysergic acid diethylamide Tranylcypromine Ecstasy Phenelzine Methylenedioxyamphetamine Selegiline N-methyldiethanolamine Herbals 3,4-Methylenedioxymethamphetamine St. John's Wort ( Hypericum perforatum ) Ginseng ( Panax ginseng )
Antibiotics 400 A 55 yo male with ALL, on methotrexate, becomes neutropenic when treated for a GAS pharyngitis. Why?
Antibiotics 400 • Penicillins block the tubular secretion of methotrexate and can lead to a significant increase in plasma MTX levels, leading to greater hepatic, renal and bone marrow toxicity of MTX • NSAIDs cause renal efferent arteriolar vasoconstriction and relative renal hypoperfusion. This can lead to MTX bio-accumulation and toxicity.
Antibiotics 500 What happens when you mix meropenem and valproic acid?
Antibiotics 500 • Valproic acid levels plummet – The nature of the interaction is uncertain – Increasing valproic acid doses will frequently not overcome the reaction and puts the patient at risk of toxicity when the meropenem is stopped
HIV Meds 100 • Which two HIV antiretroviral components are potent P4503A4 inhibitors?
HIV Meds 100 • Ritonavir and cobicistat – Ritonavir in Norvir, Kaletra – Cobicistat in Stribild, Genvoya, Prezcobix
HIV Meds 100
HIV Meds 200 • Which inhaled corticosteroid is safest for someone on ritonavir
HIV Meds 200 • The safest ICS is Qvar (beclomethasone) – Virtually all other inhaled (oral and nasal) CS are P450-metabolized – Many case reports of hypercortisolism when taken with potent P450 inhibitors
HIV Meds 300 Which calcium channel blocker is safest in someone taking Genvoya?
HIV Meds 300 • None. . – All CCBs are CYP450 3A4 metabolized, and their bioavailability dramatically increased when used with ritonavir (Norvir, Kaletra) or cobicistat (Prezcobix, Stribild, Genvoya)
HIV Meds 400 • Which is the safest statin with ritonavir? – Atorvastatin – Simvastatin – Lovastatin – Pravastatin – Rosuvastatin
HIV Meds 400 • Which is the safest statin with ritonavir? – Atorvastatin – limit to 20 mg/day – Simvastatin – DO NOT USE – Lovastatin – DO NOT USE – Pravastatin – no concerns – Rosuvastatin - limit to 10 mg/day
HIV Meds 500 • Which of these significantly interacts with ritonavir/cobicistat? – Diazepam – Sildenafil – Ergotamine – Ticagrelor
HIV Meds 500 • All do – Diazepam (only safe BDZs are lorazepam, temazepam and oxazepam) – Sildenafil (AUC increases 4x; same with other PDE 5 inhibitors) – Ergotamine (absolute CI) – Ticagrelor (AUC increase 7x)
Warfarin 100 • Is warfarin pharmacology straightforward?
. Warfarin 100 • Not a chance – Warfarin is a racemic mixture of its R-isomer (less potent) and S-isomer (more potent). S-warfarin is metabolized primarily by the CYP 2C9 isoenzyme whereas R-warfarin is metabolized by CYP 1A2 and 3A4. Depending on the dominant isoenzyme inhibited by the interacting drug, the effect on warfarin may or may not be clinically significant. Consequently, drugs that impact CYP 2C9 metabolism can be expected to have a disproportionate effect on the INR – There are numerous agents, such as metronidazole, trimethoprim/sulfamethoxazole (TMP/SMX), and amiodarone, that are commonly prescribed to older individuals that inhibit the CYP 2C9 pathway These medications, when used in conjunction with warfarin have significant effects on the INR and bleeding risk. In addition, while warfarin clearance is not affected by renal dysfunction, serum levels of interacting drugs (such as ciprofloxacin or TMP/SMX) may increase with renal dysfunction, enhancing the interaction. – Absorption is affected by gut flora, whih is affected by antoibiotics
Warfarin 200 Is there an oral antibiotic that is free of the potential to alter warfarin absorption or metabolism?
Warfarin 200 • No – Almost all antibiotics can potentiate the effects of warfarin by: • Alteration of intestinal flora that produce vitamin K • Inhibition or induction of cytochrome P450 – Unless the INR can be monitored every other day, ciprofloxacin, macrolides, metronidazole and TMP-SMX generally should not be prescribed to patients who are taking warfarin
Warfarin 300 Is acetaminophem safe with warfarin?
Warfarin 300 • No – As few as seven 325-mg tablets of acetaminophen can lead to increased warfarn effect. – The proposed mechanism is the inhibition of CYP450 by acetaminophen resulting in decreased metabolism of warfarin.
Warfarin 400 Do statins affect warfarin-related anticoagulation?
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