1000 Drug Interactions
That You Didn’t 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
(Don’t 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
Phenytoin
Digoxin
Propranolol
Erythromycin
Terfenadine
Fluconazole
Tetracycline
Iron
Warfarin
Consider the Medication’s
passage through the body
Consider the Medication’s
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
Absorption @ pH=1
@ pH=8
Acids:
Salicylic Acid
61%
13%
Thiopental
46%
34%
Aniline
6%
56%
Quinine
0%
18%
Bases:
Pivot Table
war tet ter pro phe nif iro flu ery dig cim
A
Aspirin
A
Cimetidine
Digoxin
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
A
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
(and everything!)
Inducers
Phenytoin
Rifampin
Rifampin
N/A
N/A
INH
Phenytoin
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
E+S
EnzymeSubstrate
Complex
K1
K2
ES
K-1
Enzyme
Plus
Product
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
ES
Enzyme
Plus
Product
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
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!)
Phenytoin
Rifampin
Rifampin
N/A
N/A
INH
Phenytoin
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
A
Aspirin
Cimetidine
M
AM
Digoxin
M M
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
A
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 O’Reilly 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
A
T
M
AM
Digoxin
M M
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
A
T
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
A
T
M
AM
E
Digoxin
M M
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
A
T
Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
Aspirin
Cimetidine
T
M
A
AM
E
Digoxin
M
Erythromycin
M
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
A
T
Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
Aspirin
Cimetidine
T
M
A
Digoxin
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
?
M
M
M
M
A
MM AMM?
M ?
E
M
MM
A
? T ?
MM
?
M
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
Iron
T
M
A
M MM
M M
A
Nifedipine
Phenytoin
Propranolol
Terfenadine
Astemizole
Loratadine
Tetracycline
MM
? MM
A
?
M MA M M ?
M?
E
M
MM
T?
Divalent Cations
war tet ter pro phe nif iro ca ma flu ery dig cim
Aspirin
Cimetidine
T
M
A
Digoxin
Erythromycin
Fluconazole
?
M
M
M
M
A
Iron
Calcium
M
M
Phenytoin
Propranolol
Terfenadine
Tetracycline
?
MM A
M?
M
MM
? T ?
Magnesium
Nifedipine
A
M
MM?
E
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”
Macrolides
• 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”
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”
Conclusion
• 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