Lecture 17: Drug Interactions

drug interaction

occurs when the pharmacological activity of one drug is altered by concomitant use of another drug or by presence of some other substance

3-7%

__ of hospitalizations are due to drug interations

factors that contribute to drug interactions

• polypharmacy

• multiple prescribers

• multiple pharmacological effects of medications

• disease states

• advancing age

• narrow therapeutic index drugsvit

victim drug

drug affected by interaction

perpetrator drug

drug that causes the interaction

quantitative

most interactions are __ leading to increased or decreased effect

qualitative

rarely interactions are __ leading to a rapid or slower effect

inhibition of CYP3A4-mediated metabolism of protease inihibitors

desired drug interaction of ritonavir

prevent renal secretion of penicillin (WWII)

desired drug interaction of probenecid

reduce

if medications require acidic environment for absorption, increasing pH to neutral or alkaline will ___ absorption

antineoplastic drugs

will directly kill proliferating enterocytes needed for drug absorption

cyclophosphamide, vincirstine

examples of antineoplastic drugs

victim: tetracycline and quinolone antibiotics

perpetrator: trivalent ions

victim: anionic drugs

perpetrator: cholestramine

metoclopramide, cisapride, domperidone

perpetrator example that increases gastric emptying and GI motility

anticholinergic drug (diphenhydramine)

perpetrator example that decreases gastric emptying and Gi motility

victim: anticoagulant drugs (warfarin)

perpetrator: phenylbutazone

increased clotting time, risk of hemorrage

outcome of phenylbutazone acting on anticoagulant drugs

victim: diabetic drug (tolbutamide)

perpetrator: sulfoamides

enhanced hypoglycemia

outcome of sulfonamides acting on diabetic drugs

decrease plasma levels and efficacy

outcome of phenobarbital or rifampin acting on corticosteroids, oral contraceptives, warfarin, phenytoin

victim: corticosteroids, oral contraceptives, warfarin, phenytoin

perpetrator: phenobarbital, rifampin

benzo(a)pyrene, omeprazole, phenobarbital, rifampin

P450 1A2 inducers

phenobarbital, rifampin, phenytoin

P450 2C19 inducers

phenobarbital, rifampin, phenytoin

P450 2C9 inducers

chronic ethanol

P450 2E1 inducer

St. John’s Wort, phenobarbital, rifampin, phenytoin

P450 3A4 inducers

days to weeks

enzyme induction typically lasts __

2-3 days

enzyme inhibition typically observed in __

victim: tyramine-rich food

perpetrator: MAO inhibitor

enhanced absorption of tyramine

outcome of MAO inhibitor acting on tyramine-rich foods

victim: warfarin

perpetrator: metronidazole

increase anticoagulant activity

outcome of metronidazole acting on warfarin

victim: alcohol

perpetrator: disulfiram, metronidazole

increase acetaldehyde levels (flushing reaction)

outcome of disulfiram and metronidazole acting on alcohol

monoamine oxidase inhibitor (MAOIs)

treat depression by preventing breakdown of neurotransmitters

Nardil, Parnate, Marplan

examples of monoamine oxidase inhibitors

hypertensive crises

__ precipitated by drugs and food rich in tyramine (cheese, wine, preserved meats)

flushing reactions

occur when aldehyde dehydrogenase is inhibiting (due to genetics or antagonists)

flushing, erythema, throbbing, breathing difficulty, vomiting, hypotension

symptoms of flushing reactions

disulfiram

medication with intended effect to discourage drinking

cephalosporins, isoniazid, metronidazole, nitrofuratoin

antibiotics that can cause flushing reactions with alcohol

glyburide, tolbutamide

diabetic drugs that can cause flushing reactions with alcohol

allergic rhinitis

terfenadine was used to treat __

inactive prodrug

terfenadine is a __ that is converted to active fexofenadine

QT prolongation, Torsades de Pointes, and ventricular tachycardia

inhibition of CYP metabolism by erythromycin increased terfenadine levels which led to __

macrolides (clarithromycin, erthromycin)

P450 1A2 inhibitors

cimetidine, ritonavir, antidepressants (SSRIs - fluoxetine, fluvoxamine, sertraline)

P450 2C19 inhibitors

cimetidine, amiodarone, ritonavir, azole antifungals (fluconazole, itraconazole, ketoconazole), antidepressants (SSRIs - fluoxetine, fluvoxamine, sertraline)

P450 2C9 inhibitors

cimetidine, amiodarone, antidepressants (SSRIs - clomipramine, desipramine, fluoxetine, fluvoxamine, sertraline, paroxetine, amitriptyline, buproprion)

P450 2D6 inhibitors

cimetidine, amiodarone, ritonavir, azole antifungals (fluconazole, itraconazole, ketoconazole), antidepressants (SSRIs - fluoxetine, fluvoxamine), macrolides (erythromycin), grapefruit juice

P450 3A4 inhibitors

omeprazole, burnt meats

induce enzymes

erythromycin

inhibit enzymes

enterohepatic recirculation

interference between liver and intestines

bacterial flora

__ in intestines modify drugs that allow for reabsorption

victim: oral contraceptive

perpetrator: penicillin

risk of pregnancy

outcome of penicillin acting on oral contraceptive

cyclosporine, digoxin, doxorubicin, paclitaxel

substrates for P-glycoprotein

amiloride, amiodarone, atorvastatin, verapamil

inhibitors for P-glycoprotein

paclitaxel, rifampin (PXR), st. john’s wort (PXR)

inducers for P-glycoprotein

sulfonamides and trimethoprim

desired outcome of synergistic interactions is that ___ antibacterial drugs that work better together

victim: potassium-sparing drugs, perpetrator: potassium supplements

adverse outcome of synergistic interactions that leads to hyperkalemia

antagonistic interactions

occurs when the two chemicals have opposing effects

victim: warfarin

perpetrator: vitamin K

Glycyrrhizin

found in black licorice

11 beta - hydroxysteroid dehydrogenase

glycyrrhizin hydrolyzed in the intestine to glycyrrhetinic acid which inhibits __ and increases cortisol in the kidneys leading to fluid retention, hypokalemia, hypertension

victim: antihypertensive drugs

perpetrator: licorice

furanocoumarins (bergamottin, naringin)

components of grapefruit juice

victims: calcium channel blockers (felodipine), psychiatric medications (sertraline), cholesterol inhibitors (statins), erectile dysfunction (sildenafil)

perpetrator: grapefruit juice

CYP3A4/5

furanocoumarins decreases ___ in intestines

OATP1B1, 1B3, and 2B1

furanocoumarins inhibits OATP1A2 in intestine and ___ in liver

smoking and charcoal-broiled meats

__ containing polyaromatic hydrocarbons can induce CYP1A2 expression

theophylline, olanzapine, diazepam, phenacetin

increased CYP1A2 expression increases metabolism of __

CYP2E1

chronic alcohol consumption can increase the protein stability of ___

enhance CNS depressive effects

ethanol can __ of medications and reduce anesthetic effects