1000 Drug Interactions That You Didn

1
1000 Drug Interactions That You Didnt Know You
Knew

• Paul Starr, M.D.
• Department of Family Medicine
• Louisiana State University

2
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

3
Epidemiology

• Unknown incidence
• Still a preventable cause of morbidity

4
Pivot Table
war tet ter pro phe nif iro flu ery dig cim asp
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline Warfarin
5
Pivot Table
war tet ter pro phe nif iro flu ery dig cim asp
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline Warfarin
6
Pivot Table
war tet ter pro phe nif iro flu ery dig cim
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
(Dont forget to turn the corner!)
7
Learning objectives for improving awareness of
drug interactions

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

8
Medications for this lecture
Nifedipine Phenytoin Propranolol Terfenadine Tetra
cycline Warfarin

• Aspirin
• Cimetidine
• Digoxin
• Erythromycin
• Fluconazole
• Iron

9
Consider the Medications passage through the body
10
Consider the Medications passage through the body
11
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, 60524, 1973)

12
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, 21132,
  1977)
• II. cimetidine with aspirin (W Khoury, et.al.,
  The effect of cimetidine on aspirin absorption.
  Gastroenterology, 761169, 1979.

13
Absorption
Drug Absorption _at_ pH1 _at_ pH8 Acids
Salicylic Acid 61 13 Thiopental
46 34 Bases Aniline
6 56 Quinine
0 18
14
Pivot Table
war tet ter pro phe nif iro flu ery dig cim
A
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
A
A
15

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

16
CYP Enzymes in drug metabolism
  Substrates Inhibitors Inducers Cyp1A2 Cou
madin Cimetidine Phenytoin Cyp2B6 Bupropio
n Thiotepa Rifampin Cyp2C9 Pheny
toin Isoniazid
Rifampin Cyp2C19 Diazepam Ketoconazole
N/A Cyp2D6 Metoprolol Cimetidine
N/A Cyp2E1 Ethanol Disulfiram
INH Cyp3A4,5,7 Terfenadine Erythromycin
Phenytoin (and everything!)  
17
CYP Enzyme Table
18
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!)

19
Metabolism

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

20
Michaelis-Menten Model
(Pertinent to Substrate and Inhibition)
Enzyme Plus Substrate
Enzyme- Substrate Complex
Enzyme Plus Product
K1
E S
ES
E P
K2
K-1
K1 forward reaction K2 completed reaction K-1
aborted reaction
21
Michaelis-Menten Model
(Pertinent to Substrate and Inhibition)
Enzyme Plus Substrate
Enzyme- Substrate Complex
Enzyme Plus Product
K1
K2
E S
ES
E P
K-1
Ki A derivation that describes an inhibited
reaction
Km A derivation that describes the completed
reaction
K1 forward reaction K2 completed reaction K-1
aborted reaction
22
Ki
_Inhibitor_
Ki
Km,obs
- 1.0
Km
(k2k-1)
Km
k1
23
Inhibition

•  
• 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!)

24
Induction
Endoplasmic Reticulum
Nucleus
CYP1A
Up-regulation
AhR Activation

Arnt
25
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!)

26
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)

27
Metabolism
war tet ter pro phe nif iro flu ery dig cim
A
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
M
A
M
M
M
A
28
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, 58536, 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, 179173, 1971.)

29
Target
war tet ter pro phe nif iro flu ery dig cim
A
T
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
A
M
M
M
M
A
T
30
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, 64123, 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!

31
Elimination
war tet ter pro phe nif iro flu ery dig cim
A
T
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
A
M
M
E
M
M
A
T
32
Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
A
T
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
A
M
M
E
M
M
A
T
33
Famous Interactions
war tet ter pro phe nif iro flu ery dig cim
A
T
?
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Tetracycline
A
M
M
M
M
?
M
E
A
M
?
M
M
M
M
M
M
M
A
T
?
?
M
M
?
M
34
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

35
Potent Inhibitors

• Fluoroquinolones (ie ciprofloxacin)
• H2Blockers (ie most notably cimetidine)
• Imidazoles (ie fluconazole)
• INH
• Ritonavir

Memorize!
Mnemonic cip, cim, con, INH, and rit
36
Potent Inducers

• Neuroleptics
• Carbamazepine
• Phenobarbital
• Phenytoin
• AND
• Rifampin

Memorize!
Mnemonic carb, barb, pheny, and rif
37
H1 Blockers
war tet ter ast lor pro phe nif iro flu ery dig
cim
T
A
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Nifedipine Phenytoin Propranolol Terfenadin
e Astemizole Loratadine Tetracycline
?
M
A
M
M
?
M
M
A
E
M
?
M
M
M
M
M
M
M
M
A
T
?
M
M
?
M
M
38
Divalent Cations
war tet ter pro phe nif iro ca ma flu ery dig
cim
A
T
?
Aspirin Cimetidine Digoxin Erythromycin Fluconazol
e Iron Calcium Magnesium Nifedipine Phenytoin Prop
ranolol Terfenadine Tetracycline
A
M
M
M
M
?
M
E
A
M
?
M
M
M
M
M
M
M
A
T
?
?
M
M
?
M
39
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 cimgtrangtfam

40
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 progtatengtmeto

41
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 clargterygtazith

42
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
  ketogtitragtflu

43
Calcium Channel Blockers

• Calcium channel blockers like betablockers vary
  in their ability to cause heart block. Mnemonic
  vergtnifgtcar

44
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 patients complaints can help alert the
  physician to identifying previously unreported
  reactions