Drug Interactions Flashcards
Pharmacodynamics
what the drug does to the body
A pharmacodynamic (PD) drug interaction happens when 2 or more drugs are…
given together and their end effects impact each other
First-pass metabolism results in…
the inactivation of some % of ~75% of oral drugs
With most drugs, inducers make more enzymes, which…
decrease the active drug
With prodrugs, more enzymes due to an inducer will…
increase the active drug
With most drugs, inhibitors make enzymes inactive, which will…
increase the active drug
With prodrugs, less enzymes due to an inhibitor will…
decrease the active drug
With inducers, there is…
a lag time to see effect (full effect on drug levels may not be seen for up to 4 weeks); effects remain after the drug is d/c’d (until the enzyme degrades; can take 2-4 weeks)
With inhibitors, there is…
quick onset and the effect stops when the drug is d/c’d
Major CYP Inducers: “PS PORCS”
Phenytoin
Smoking
Phenobarbital & primidine Oxcarbazepine (and eslicarbazepine) Rifampin (and rifabutin, rifapentine) Carbamazepine (also an auto-inducer) St. John's wort
Major CYP inhibitors: “G <3 Pacman”
Grapefruit
<3
Protease Inhibitors- especially ritonavir, but many PIs are potent inhibitors
Azole antifungals- fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, and isavuconazonium
C- cyclosporine, cimetidine, cobicistat
Macrolides (clarithromycin and erythromycin, but not azithromycin)
Amiodarone (and dronedarone)
Non-DHP CCBs- diltiazem and verapamil
P-glycoprotein (P-gp) efflux pump substrates
- anticoagulants (apixaban, edoxaban, dabigatran, rivaroxaban)
- CV drugs (digoxin, diltiazem, carvedilol, ranolazine, verapamil)
- Immunosuppressants (cyclosporine, sirolimus, tacrolimus)
- HCV drugs (ombitasvir, paritaprevir, dasabuvir, sofosbuvir)
- Others (atazanavir, colchicine, dolutegravir, posaconazole, raltegravir, saxagliptin)
P-gp inducers
- carbamazepine
- dexamethasone
- phenobarbital
- phenytoin
- rifampin
- St. John’s Wort
- tipranavir
P-gp inhibitors
- Anti-infectives (clarithromycin, itraconazole, posaconazole)
- CV drugs (amiodarone, carvedilol, conivaptan, diltiazem, dronedarone, quinidine, verapamil)
- HIV drugs (cobicistat, ritonavir)
- HCV drugs (ledipasvir, paritaprevir)
- Others (cyclosporine, flibanserin, ticagrelor)
The recycling of an already-metabolized drug is called…
enterohepatic recycling (which increases the duration of action of many drugs, including some antibiotics, some NSAIDs, and ezetimibe)
amiodarone/dronedarone + warfarin
Amiodarone inhibits multiple enzymes, including CYP2C9, which metabolizes the major warfarin isomer. If using amiodarone and adding warfarin (start warfarin at a lower dose of ≤ 5 mg). If using warfarin 1st and adding amiodarone, decrease warfarin dose 30-50% based on INR (monitor and adjust)
amiodarone + digoxin (monitor for s/s of toxicity such as nausea, and HR)
Amiodarone inhibits P-gp; digoxin is a P-gp substrate (decreased digoxin excretion, more ADRs). If using amiodarone and adding digoxin (start oral digoxin at a low dose, such as 0.125 mg daily instead of 0.25 mg daily). If using digoxin and adding amiodarone (decrease oral digoxin dose by 50%).
Digoxin and loop diuretic (monitor electrolytes & correct if abnormal). Kideny impairment, decrease digoxin dose or frequency, or d/c.
Digoxin is cleared by P-gp and excreted by the kidneys. Loops decrease K, Mg, Ca, and Na. Digoxin toxicity risk is increased with decreased K and Mg, and increased Ca.
Drugs that decrease HR (additive effects when combined such as amiodarone, digoxin, BBs, clonidine, and dexmedetomidine)
Monitor HR; normal range 60-100 bpm
Statins + Strong CYP3A4 inhibitors
Increased levels of CYP3A4 substrates (lovastatin, simvastatin, atorvastatin). Increased myopathy risk. Simvastatin and lovastatin are C/I. Recommend a statin not metabolized by CYP450 enzymes (pitavastatin, pravastatin, rosuvastatin)
Warfarin + CYP2C9 inhibitors and inducers
- Increased INR and bleeding risk with inhibitors
- Decreased INR and clotting risk with inducers
- Monitor INR
CYP2C9 inducers
rifampin, St. John’s Wort
CYP3A4 inhibitors + CYP3A4 substrates (many)
Do not use a CYP3A4 inhibitor with an opioid metabolized by CYP3A4 (fentanyl, hydrocodone, oxycodone, methadone). Can increase ADRs and cause fatal sedation.
Grapefruit juice
Do not take with CYP3A4 substrates. Drugs include amiodarone, simvastatin, lovastatin, nifedipine, and tacrolimus
Valproate + lamotrigine.
VPA is an inhibitor of lamotrigine metabolism. Increased lamotrigine levels increase risk of serious skin reactions (SJS/TEN). Start lamotrigine using the starter kit that starts with lower doses. Titrate carefully every 2 weeks.
Valproate + lamotrigine.
VPA is an inhibitor of lamotrigine metabolism. Increased lamotrigine levels increase the risk of serious skin reactions (SJS/TEN). Start lamotrigine using the starter kit that starts with lower doses. Titrate carefully every 2 weeks.
Monoamine oxidase (MAO) inhibitors (isocarboxazid, phenelzine, tranylcypromine, linezolid, methylene blue)
Blocking MAO with an inhibitor will increase Epi, NE, DA, and serotonin. High levels can cause hypertensive crisis and high serotonin can use serotonin syndrome.
Monoamine oxidase (MAO) inhibitors + drugs that raise Epi, Ne, and DA
Do not use together. These drugs include: pseudoephedrine, phenylephrine, epinephrine, norepinephrine, dobutamine, SNRIs, bupropion, stimulants (including amphetamines)
Monoamine oxidase (MAO) inhibitors + drugs that raise serotonin
High serotonin can cause serotonin syndrome. Use a 2-week washout period between serotonergic drugs and another antidepressant; if changing fluoxetine to an MAO inhibitor, wait 5 weeks.
drugs that raise serotonin
- Antidepressants: SSRIs, SNRIs, TCAs, MAO inhibitors, mirtazapine, trazodone
- Opioids: fentanyl, methadone, tramadol
- Others: buspirone, dextromethorphan (high doses), lithium, St. John’s Wort
MAO inhibitors (non-selective and selective MAO-B inhibitors) + tyramine-rich foods/drinks
- Selective MAO-B inhibitors: rasagiline, selegiline
- MAO metabolizes tyramine; if blocked, tyramine causes increased NE, with risk of hypertensive crisis.
tyramine-rich foods/drinks
Avoid these foods: aged cheeses, air-dried meats, sauerkraut, some wines and beers
CYP2D6 inhibitors (amiodarone, fluoxetine, paroxetine, fluvoxamine) + CYP2D6 substrates (many)
Avoid using together or decrease the dose of the substrate (increased risk of ADRs)
CYP3A4, P-gp inhibitors + calcineurin inhibitors (CNIs) or mTOR kinase inhibitors
Decreased drug metabolism, increased toxicity such as increased BP, kidney toxicity, metabolic syndrome, and other ADRs. Avoid using together or decrease the dose of CNI or mTOR kinase inhibitor cautiously. Monitor transplant drug level/trough.
Phenytoin, phenobarbital, primidone, carbamazepine (auto-inducer), oxcarbazepine + other drugs metabolized by CYP enzymes
Will increase drug metabolism and decrease levels (loss of seizure control). Monitor drug levels: induction takes up to 4 weeks for the full effect. Consider increasing the dose of the substrate drug. If the substrate is lamotrigine, use the starter kit with higher doses.
rifampin + CYP and P-gp substrates
The concentration of substrate drugs will greatly decrease. Monitor drug levels (such as the INR with warfarin)
CYP3A4 inducers + opioids that are CYP3A4 substrates (fentanyl, hydrocodone, oxycodone, methadone)
Increased metabolism, decreased opioid concentration. Assess the patient’s pain to determine if an increased maintenance dose is ndded. Use caution.
CYP2D6 UMs + prodrugs (codeine, tramadol)
There are no CYP2D6 inducers. 2D6 UMs will produce more active drug. DO not use codeine or tramadol in patients <12 years and in children <18 years after tonsillectomy +/ adenoidectomy (C/I). Do not use codeine or tramadol in a breastfeeding mother unless it is known that she is not a 2D6 UM (PGx testing)
CYP3A4, P-gp inducers + calcineurin inhibitors or mTOR kinase inhibitors
Increase drug metabolism, decrease transplant drug level and increase risk of transplant (organ) rejection. Avoid using together or increase CNI or mTOR kinase inhibitor carefully. Monitor transplant drug level/trough for efficacy.
Smoking (tobacco and marijuana) + some CYP1A2 substrates
- Smoking primarily induces CYP1A2.
- Current smokers: the substrate drug will have lower levels. A higher dose may be required.
- Smokers who quit: when the inducer (smoking) is stopped, drug concentrations will increase and cause toxicity. Counsel for smoking cessation. Monitor INR if taking warfarin.
CYP1A2 substrates
some antipsychotics, antidepressants, hypnotics, anxiolytics, caffeine, theophylline, warfarin (less potent R-isomer)
Nicotine replacement (NRT) products do not…
induce CYP enzymes
Serotonin syndrome risk increases when 2 or more drugs that affect serotonin are used together. s/s include autonomic dysfunction, AMS, and neuromuscular excitation. These drugs include:
- antidepressants (SSRIs, SNRIs, TCAs, mirtazapine, trazadone)
- MAO inhibitors
- buspirone
- dextromethorphan (in excess)
- dihydroergotamine
- lithium
- lorcaserin (selective serotonin 2C agonist)
- opioids
- metoclopramide
- triptans (PRN use may be safe)
- natural products (St. John’s wort)
- tegaserod (for IBS- constipation)
Increased bleeding risk when combined
- anticoagulants
- antiplatelets (salicylates- aspirin, dipyridamole, clopidogrel, prasugrel, ticagrelor)
- NSAIDs
- SSRIs, SNRIs
- Natural products (5 G’s: garlic, ginger, ginkgo biloba, ginseng and glucosamine, vitamin E, willow bark, fish oils (high doses)
Hyperkalemia risk Counsel patients to avoid salt substitutes that contain KCl. Monitor K. (s/s include weakness, heart palpitations, arrhythmia) Drugs that increase risk include:
- spironolactone, eplerenone (highest risk)
- renin-angiotensin-aldosterone drugs (ACE inhibitors, ARBs, aliskiren, sacubitril/valsartan)
- amiloride
- triamterene
- salt substitutes (KCl)
- calcineurin inhibitors (tacrolimus, cyclosporine)
- canagliflozin
- SMX/TMP
- drospirenone-containing oral contraceptives (drospirenone is a progestin and K-sparing diuretic)
QT prolongation increases the risk of torsades de pointes (TdP). Risk increases with:
- higher doses
- higher drug levels due to concurrent enzyme inhibitors
- higher levels due to reduced drug Cl
- Multiple QT-prolongation drugs
- Elderly (60+)
- Patients with CVD, including arrhythmias, HF, MI
Multiple QT-prolongation drugs
- Antiarrhythmics (including amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
- Antibiotics/antifungals (quinolones and macrolides)
- Azole antifungals (except isavuconazonium)
- Antidepressants (tricyclics, SSRIs, mirtazapine, trazodone, SNRIs)
- Antipsychotics (including phenothiazines, haloperidol, ziprasidone)
- Antiemetics (5-HT3 receptor antagonists ex. ondansetron, droperidol, and phenothiazines)
- Others (donepezil, fingolimod, methadone)
QT-prolongation drug safety
- Carefully dose. Use lower doses/caution in the elderly.
- Amiodarone is DOC to treat arrhythmia in patients with HF
- Do not exceed citalopram 40 mg/day or 20 mg/day in elderly (>60 years), liver disease or with enzyme inhibitors that decrease the clearance
- Do not exceed escitalopram 20 mg/day or 10 mg/day in the elderly. Among SSRIs, sertraline is considered safer with CVD.
- Do not use droperidol for inpatient N/V (injection only; restricted use)
CYP2C19 substrates
clopidogrel, phenytoin, thioridazine, voriconazole
Example of chelation
Quinolone antibiotics binds to calcium-containing drugs and dairy products. When taken together, the antibiotic will not dissolve and the infection will not be adequately treated.
Drugs with polyvalent cations or other binding properties (antacids, multivitamins, sucralfate, bile acid resins, Al, Ca, Fe, Mg, Zn, phosphate binders) should be…
separated out from quinolones, tetracyclines, levothyroxine, and oral bisphosphonates
Some drugs require an acidic gut for adequate absorption. Acid-suppression drugs (PPIs) decrease the absorption of…
some antifungals (itraconazole)
Example of decreased excretion: giving probenecid with penicillin can be beneficial when high penicillin levels are needed to…
cross the BBB
Do not use codeine in ultra-metabolizers (UMs)…
of CYP2D6
Risk of poor analgesia with PMs of CYP2D6. Do not use codeine, use an…
alternative analgesic in patients identified as PMs of 2D6.
Risk of clopidogrel with CYP2C19 inhibitors, so avoid use. For example with:
omeprazole and esomeprazole
Risk with PMs of CYP2C19; low conversion to active form with reduced effect of drug on platelet activity. Use an…
alternative P2Y12 inhibitor (not clopidogrel) in patients identified as PMs.
G <3 PACMAN (Enzyme Inhibitors)
- Grapefruit
- Protease inhibitors (especially ritonavir)
- Azole antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole and isavuconazonium)
- C (cyclosporine, cimetidine, cobicistat)
- Macrolides (clarithromycin, erythromycin)
- Amiodarone (and dronedarone)
- Non-DHP CCBs (diltiazem and verapamil)
PS PORCS (Enzyme Inducers)
Phenytoin
Smoking
Phenobarbital and primidone
Oxcarbazepine (and eslicarbazepine)
Rifampin (and rifabutin, rifapentine)
Carbamazepine (also auto-inducer)
St. John’s Wort
