1000 Drug Interactions That You Didnt Know You Knew

Paul Starr, M.D.

Department of Family Medicine Louisiana State University

Introduction
Drug interactions were once
thought to represent an insidious threat to public health. Although initial estimates predicted huge numbers of dangerous drug interactions, in practice they do not appear to be as menacing as they once appeared

Epidemiology
Unknown incidence Still a preventable cause of
morbidity

Pivot Table
war tet ter pro phe nif iro flu ery dig cim asp
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

Propranolol
Terfenadine Tetracycline Warfarin

Pivot Table
war tet ter pro phe nif iro flu ery dig cim asp
Aspirin
Cimetidine Digoxin Erythromycin

Fluconazole
Iron Nifedipine Phenytoin

Propranolol
Terfenadine Tetracycline Warfarin

Pivot Table
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

Propranolol
Terfenadine Tetracycline

(Dont forget to turn the corner!)

Learning objectives for improving awareness of drug interactions

A. B. C. D. Evaluate medications Famous interactions Group medications Hear your patient

Medications for this lecture

Aspirin Nifedipine

Cimetidine
Digoxin Erythromycin

Phenytoin
Propranolol Terfenadine Tetracycline Warfarin

Fluconazole
Iron

Consider the Medications passage through the body

Consider the Medications passage through the body

Absorption
a. Chelation : Divalent cations such as calcium or iron can bind to certain medications and prevent their absorption I. iron with tetracycline (H.C. Heinrich and KH Oppitz, Tetracycline inhibits iron absorption in man. Naturwissenschaften, 60:524, 1973)

Absorption
b.
Absorption pH: Weak acids need to be absorbed at a low pH. Raising the pH with antacid medication considerably hinders absorption. I. iron with cimetidine (R Esposito, Cimetidine and iron-deficiency anaemia. Lancet, 2:1132, 1977) II. cimetidine with aspirin (W Khoury, et.al., The effect of cimetidine on aspirin absorption. Gastroenterology, 76:1169, 1979.

Absorption
Drug
Acids:
Salicylic Acid 61% 13%

Absorption @ pH=1

@ pH=8

Thiopental

46%

34%

Bases:
Aniline
Quinine

6%
0%

56%
18%

Pivot Table
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

A
A

Propranolol
Terfenadine Tetracycline

Phase 1 (usually inactivated) CYP Enzymes Oxidation Reduction Dealkylation Hydrolysis Phase 2 (ear-marked for destruction) Conjugation Glucuronidation Sulfation Methylation Acetylation Protein Binding

CYP Enzymes in drug metabolism

Substrates Inhibitors
Cyp1A2 Coumadin Cyp2B6 Bupropion Cyp2C9 Phenytoin Cyp2C19 Diazepam Cyp2D6 Metoprolol Cyp2E1 Ethanol Cyp3A4,5,7 Terfenadine Cimetidine Thiotepa Isoniazid Ketoconazole Cimetidine Disulfiram Erythromycin

Inducers
Phenytoin Rifampin Rifampin N/A N/A INH Phenytoin

(and everything!)

CYP Enzyme Table

Three Kinds of Metabolic Interactions Substrate (a cyp enzyme simply

performs a reaction on a medication Inhibition (a medication binds so strongly to a cyp enzyme that it prevents the enzyme from metabolizing other medications) Induction (the medication interacts with the enzyme in a way that leads to new production of the enzyme; this takes time!)

Metabolism
Amitriptylline is metabolized
by CYP1A2 Cimetidine inhibits CYP1A2 Coadministration results in elevated Amitriptylline levels

Michaelis-Menten Model
(Pertinent to Substrate and Inhibition)
Enzyme Plus Substrate EnzymeSubstrate Complex K1 K2 Enzyme Plus Product

E+S

ES K-1

E+P

K1= forward reaction K2= completed reaction K-1= aborted reaction

Michaelis-Menten Model
(Pertinent to Substrate and Inhibition)
Enzyme Plus Substrate

E+S
Km
A derivation that describes the completed reaction

EnzymeSubstrate Complex K1 K2
K-1

Enzyme Plus Product

ES

E+P
Ki

A derivation that K1= forward reaction describes an K2= completed reaction inhibited K-1= aborted reaction reaction

Ki
_[Inhibitor]_ Ki = Km,obs - 1.0 Km (k2+k-1) Km= k1

Inhibition
Substrates Inhibitors Inducers
Phenytoin Rifampin Rifampin N/A N/A INH Phenytoin Cyp1A2 Warfarin Cimetidine Cyp2B6 Bupropion Thiotepa Cyp2C9 Phenytoin Isoniazid Cyp2C19 Diazepam Ketoconazole Cyp2D6 Metoprolol Cimetidine Cyp2E1 Ethanol Disulfiram Cyp3A4,5,7 Terfenadine Erythromycin (and everything!)

Induction
Endoplasmic Reticulum Nucleus

CYP1A

Up-regulation AhR + Arnt

Activation

Induction
Substrates Inhibitors Inducers Cyp1A2 Warfarin Cimetidine Phenytoin Cyp2B6 Bupropion Thiotepa Rifampin Cyp2C9 Phenytoin Isoniazid Rifampin Cyp2C19 Diazepam Ketoconazole N/A Cyp2D6 Metoprolol Cimetidine N/A Cyp2E1 Ethanol Disulfiram INH Cyp3A4,5,7 Terfenadine Erythromycin Phenytoin (and everything!)

Metabolism
Amitriptylline is metabolized by
CYP1A2 Cimetidine inhibits CYP1A2 Coadministration results in elevated Amitriptylline levels Ranitidine inhibits CYP1A2 BUT to a much lesser degree (lower Ki)

Metabolism
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

A
M M M A AM

Propranolol
Terfenadine Tetracycline

Target
1. If two medications make it past the hepatic enzymes, there is potential for interaction at the site of action, or at sites of major side effects. Propranolol with nifedipine (A-V conduction disturbances and sinus bradycardia U Elkayam et al, Effects of nifedipine on hemodynamics and cardiac function in patients with normal left ventricular ejection fraction already treated with propranolol. Am J Cardiol, 58:536, 1986 Warfarin with aspirin (RA OReilly et al, Impact of aspirin and chlorthalidone on the pharmacodynamics of oral anticoagulants in man. Ann NY Acad Sci, 179:173, 1971.)

Target
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

T M
M M A T

A
AM

Propranolol
Terfenadine Tetracycline

Elimination
Certain medications can compete for excretion Digoxin with erythromycin (H Wakasugi et al, Effect of clarithromycin on renal excretion of digoxin; interaction with P-glycoprotein. Clin Pharmacol Ther, 64:123, 1998) Although this report was regarding clarithromycin, the caution was extended to all macrolides. Interestingly, there are other digoxin/macrolide interactions including hepatic metabolism, and a unique mechanism in which gut flora which inactivate digoxin can be eliminated with oral antibiotics!

Elimination
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin

T M
M M A T

A
AM E

Propranolol
Terfenadine Tetracycline

Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
Aspirin
Cimetidine Digoxin Erythromycin

T M
M A T M

A
AM E

Fluconazole
Iron Nifedipine Phenytoin

Propranolol
Terfenadine Tetracycline

Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
Aspirin
Cimetidine Digoxin Erythromycin

T M
A M M A M M

?
MM AMM? M ? E M MM

Fluconazole
Iron Nifedipine Phenytoin

? T ? MM ? M

Propranolol
Terfenadine Tetracycline

Grouping Medications
Having memorized the above famous interactions, you can expand your knowledge dramatically by remembering a few rules regarding the drug families to which the medications belong. They can be grouped by:

Metabolic effects Chemical family

Potent Inhibitors
Fluoroquinolones (ie: ciprofloxacin) H2Blockers (ie: most notably cimetidine) Imidazoles (ie fluconazole) INH Ritonavir

Mnemonic: cip, cim, con, INH, and rit

Potent Inducers
Neuroleptics: Carbamazepine Phenobarbital Phenytoin AND: Rifampin
Mnemonic: carb, barb, pheny, and rif

H1 Blockers
war tet ter ast lor pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazole

T M A M MM M M A MM ? MM

Iron
Nifedipine Phenytoin Propranolol

M MA M M ? M? E M MM
T?

Terfenadine
Astemizole Loratadine Tetracycline

Divalent Cations
war tet ter pro phe nif iro ca ma flu ery dig cim
Aspirin

Cimetidine
Digoxin Erythromycin Fluconazole

T M A M M M M

MM A M? M MM

MM? E

Iron
Calcium Magnesium Nifedipine Phenytoin Propranolol Terfenadine Tetracycline

A
M M ?

? T ?

H2 Blockers
H2Blockers follow the same
rules as H1Blockers; Cimetidine is the most potent inhibitor, ranitidine to a lesser degree, and famotidine slightly lesser. Mnemonic: cim>ran>fam

Beta Blockers
BetaBlockers knowing that
propranolol contributes significantly to heart block in the presence of nifedipine, it is interesting to note that metoprolol and atenolol appear to be relatively safe. Mnemonic: pro>aten>meto

 Macrolide antibiotics are aggressively

metabolized by cyp3A4 with the exception of azithromycin which is metabolized by a different mechanism. Clarithromycin is one of the most potent utilizers of Cyp3A4 and entertains vast potential for competitive inhibition with many other medications. Mnemonic: clar>ery>azith

Macrolides

Antifungals
Antifungals of the imidazole class
are metabolized with varying affinities for the cyp enzymes. Fluconazole turns out to be one of the more benign medications whereas ketoconazole is a very potent inhibitor of cyp3A4. Mnemonic: keto>itra>flu

Calcium Channel Blockers

Calcium channel blockers
like betablockers vary in their ability to cause heart block. Mnemonic: ver>nif>car

 Examining medications encourages careful

review of medications Famous interactions should be memorized and form the basis of a broader understanding of drug interactions in general Grouping medications allows one to extrapolate known data to a certain extent across a drug groups Hearing patients complaints can help alert the physician to identifying previously unreported reactions

Conclusion