1000 Drug Interactions 1000 Drug Interactions That You Didn’t Know That You Didn’t Know

You KnewYou Knew

Paul Starr, M.D.Paul Starr, M.D.Department of Family MedicineDepartment of Family Medicine

Louisiana State UniversityLouisiana State University

IntroductionIntroduction• 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

EpidemiologyEpidemiology

• Unknown incidence

• Still a preventable cause of morbidity

Pivot TablePivot Table

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

Warfarin

war tet ter pro phe nif iro flu ery dig cim asp

Pivot TablePivot Table

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

Warfarin

war tet ter pro phe nif iro flu ery dig cim asp

Pivot TablePivot Table

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

(Don’t forget to turn the corner!)

Learning objectives for Learning objectives for improving awareness of improving awareness of

drug interactionsdrug interactions

A.     Evaluate medications

B.      Famous interactions

C.      Group medications

D.      Hear your patient

Medications for this lectureMedications for this lectureAspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

Warfarin

Consider the Medication’s Consider the Medication’s passage through the bodypassage through the body

Consider the Medication’s passage through the body

AbsorptionAbsorption

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)

AbsorptionAbsorption• 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.

AbsorptionAbsorptionDrug Absorption @ pH=1 @ pH=8

Acids:

Salicylic Acid 61% 13%

Thiopental 46% 34%

Bases:

Aniline 6% 56%

Quinine 0% 18%

Pivot TablePivot Table

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AAAA

AA

Phase 1 (usually inactivated)

CYP EnzymesOxidationReductionDealkylationHydrolysis

Phase 2 (“ear-marked for destruction”)

ConjugationGlucuronidationSulfationMethylationAcetylation

Protein Binding

CYP Enzymes in drug CYP Enzymes in drug metabolismmetabolism

 

Substrates Inhibitors InducersCyp1A2 Coumadin Cimetidine PhenytoinCyp2B6 Bupropion Thiotepa RifampinCyp2C9 Phenytoin Isoniazid RifampinCyp2C19 Diazepam Ketoconazole N/ACyp2D6 Metoprolol Cimetidine N/ACyp2E1 Ethanol Disulfiram INHCyp3A4,5,7 Terfenadine Erythromycin Phenytoin (and everything!)

 

CYP Enzyme TableCYP Enzyme Table

Three Kinds of Metabolic Three Kinds of Metabolic InteractionsInteractions

• 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!)

MetabolismMetabolism

• Amitriptylline is metabolized by CYP1A2

• Cimetidine inhibits CYP1A2

• Coadministration results in elevated Amitriptylline levels

Michaelis-Menten ModelMichaelis-Menten Model

E + S ES E + P

EnzymePlus

Substrate

Enzyme-SubstrateComplex

EnzymePlus

ProductK1 K2

K-1

K1= forward reactionK2= completed reactionK-1= aborted reaction

(Pertinent to Substrate and Inhibition)

Michaelis-Menten ModelMichaelis-Menten Model

E + S ES E + P

EnzymePlus

Substrate

Enzyme-SubstrateComplex

EnzymePlus

ProductK1 K2

K-1

K1= forward reactionK2= completed reactionK-1= aborted reaction

KmA derivation

that describes the completed

reaction

KiA derivation that

describes an inhibited reaction

(Pertinent to Substrate and Inhibition)

Ki

Ki = _[Inhibitor]_Km,obs - 1.0

Km

Km= (k2+k-1)k1

InhibitionInhibition 

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 INHCyp3A4,5,7 Terfenadine Erythromycin Phenytoin (and everything!)

InductionInduction

Endoplasmic Reticulum

Nucleus

CYP1A

AhRActivation

Arnt+

Up-regulation

InductionInduction 

Substrates Inhibitors InducersCyp1A2 Warfarin Cimetidine PhenytoinCyp2B6 Bupropion Thiotepa RifampinCyp2C9 Phenytoin Isoniazid RifampinCyp2C19 Diazepam Ketoconazole N/ACyp2D6 Metoprolol Cimetidine N/ACyp2E1 Ethanol Disulfiram INHCyp3A4,5,7 Terfenadine Erythromycin Phenytoin (and everything!)

MetabolismMetabolism

• 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)

MetabolismMetabolism

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AAAA

AA

MM

MMMM

MM

TargetTarget1.  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 O’Reilly et al, Impact of aspirin and chlorthalidone on the pharmacodynamics of oral anticoagulants in man. Ann NY Acad Sci, 179:173, 1971.)

TargetTarget

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AAAA

AA

MM

MMMM

MMTT

TT

EliminationEliminationCertain medications can compete for excretionDigoxin 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!

EliminationElimination

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AAAA

AA

MM

MMMM

MMTT

TT

EE

Famous Interactions

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AA

A

M

MM

MT

T

E

Famous Interactions

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

war tet ter pro phe nif iro flu ery dig cim

AA

A

M

M M

MT

T

EM M ?

A MMM M M M

?

M?

?MM

? M

?

Grouping MedicationsGrouping Medications

• Metabolic effects

• Chemical family

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:

Potent InhibitorsPotent Inhibitors• Fluoroquinolones (ie: ciprofloxacin)

• H2Blockers (ie: most notably cimetidine)

• Imidazoles (ie fluconazole)

• INH

• Ritonavir

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

Potent InducersPotent InducersNeuroleptics:

• Carbamazepine

• Phenobarbital

• Phenytoin

AND:

• Rifampin

Mnemonic: “carb, barb, pheny, and rif”

H1 BlockersH1 BlockersAspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Astemizole

Loratadine

Tetracycline

war tet ter ast lor pro phe nif iro flu ery dig cim

AAAA

AA

MM

M M

MMTT

TT

EEMM MM ??

AA MMMMMM MMMM

MM??

??MMMM

??

??

MMMM

MM

MM

MM

Divalent CationsDivalent Cations

Aspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Calcium

Magnesium

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

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

AM

M M

MT

T

EM M ?

A MMM M M M

?

M?

?

MM

? M

?

A

A

H2 BlockersH2 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 BlockersBeta 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”

MacrolidesMacrolides• 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”

AntifungalsAntifungals• 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 BlockersCalcium Channel Blockers

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

ConclusionConclusion• 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 patient’s complaints can help alert the physician to identifying previously unreported reactions