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1000 Drug 1000 Drug Interactions That Interactions That You Didn’t Know You Didn’t Know You Knew You Knew Paul Starr, M.D. Paul Starr, M.D. Department of Family Department of Family Medicine Medicine Louisiana State University Louisiana State University
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1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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Page 1: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 2: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana 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

Page 3: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

EpidemiologyEpidemiology

• Unknown incidence

• Still a preventable cause of morbidity

Page 4: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 5: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 6: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!)

Page 7: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 8: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Medications for this lectureMedications for this lectureAspirin

Cimetidine

Digoxin

Erythromycin

Fluconazole

Iron

Nifedipine

Phenytoin

Propranolol

Terfenadine

Tetracycline

Warfarin

Page 9: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 10: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Consider the Medication’s passage through the body

Page 11: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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)

Page 12: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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.

Page 13: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

AbsorptionAbsorptionDrug Absorption @ pH=1 @ pH=8

Acids:

Salicylic Acid 61% 13%

Thiopental 46% 34%

Bases:

Aniline 6% 56%

Quinine 0% 18%

Page 14: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 15: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Phase 1 (usually inactivated)

CYP EnzymesOxidationReductionDealkylationHydrolysis

Phase 2 (“ear-marked for destruction”)

ConjugationGlucuronidationSulfationMethylationAcetylation

Protein Binding

Page 16: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!)

 

Page 17: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

CYP Enzyme TableCYP Enzyme Table

Page 18: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!)

Page 19: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

MetabolismMetabolism

• Amitriptylline is metabolized by CYP1A2

• Cimetidine inhibits CYP1A2

• Coadministration results in elevated Amitriptylline levels

Page 20: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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)

Page 21: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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)

Page 22: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Ki

Ki = _[Inhibitor]_Km,obs - 1.0

Km

Km= (k2+k-1)k1

Page 23: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!)

Page 24: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

InductionInduction

Endoplasmic Reticulum

Nucleus

CYP1A

AhRActivation

Arnt+

Up-regulation

Page 25: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!)

Page 26: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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)

Page 27: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 28: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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.)

Page 29: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 30: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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!

Page 31: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 32: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 33: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

?

Page 34: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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:

Page 35: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Potent InhibitorsPotent Inhibitors• Fluoroquinolones (ie: ciprofloxacin)

• H2Blockers (ie: most notably cimetidine)

• Imidazoles (ie fluconazole)

• INH

• Ritonavir

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

Page 36: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Potent InducersPotent InducersNeuroleptics:

• Carbamazepine

• Phenobarbital

• Phenytoin

AND:

• Rifampin

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

Page 37: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 38: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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

Page 39: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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”

Page 40: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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”

Page 41: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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”

Page 42: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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”

Page 43: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

Calcium Channel BlockersCalcium Channel Blockers

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

Page 44: 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University.

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