1. Drug Interactions

2. Overview
Definition
Mechanisms and Examples, but NOT all of drug interactions
Sources of information

3. Definition
Drug interaction is the alteration of Pharmacological effect (Duration or Magnitude or both) of a drug in the presence of another drug

5. Medication Errors
Mediction errors in the United States annually that result in death is between 44,000 & 98,000
Drug Interaction is an Important Source of Medication Errors

6. Increasing risk of death7 6 5 4 2 3
1 in 10
1 in 10
1 in 10
1 in 10
1 in 10
1 in 10
Lightning
Murder
Plane crash
Auto-cash
Fatal, unexpected
drug reaction

8. Drug Interactions 17% In surgical patients
22% In patients on medical wards
19% In nursing home patients
23% In outpatients

9. Drug Interactions Not all drug interactions are bad.
Interactions can occur between Drugs, Food, Chemicals or Laboratory tests
More than Two drugs can be involved.

10. Drug Interactions
Not only, the drugs themselves that interact, but also, their Metabolites too
Interaction correlates with the number of administered drugs
Risk fators: Low TI, Disease

11. Drug Interaction
Unidirectional
A B
Bidirectional
A B

12. Drug-Drug Interaction
Pharmacokinetic Interaction
Pharmacodynamic Interaction 12

13. Pharmacokinetic vs Pharmacodynamic Interactions
Pharmacokinetic: Amount of drug in blood is altered
Pharmacodynamic: Amount of drug in blood remains the same, but its effect is altered

14. Drug Interactions Synergism 2 + 2 > 4 Additive 2 + 2 = 4
Antagonism < 4

15. Drug Interactions

16. Synergism (Useful) Aminoglycosides + -lactam
Amphotricine B + Flucytozine
Drug therapy of TB
Cotrimoxazole
-Blocker + Diuretic + ACEIs
- agonists + Corticosteroids

17. Aminoglycosides + -lactam

18. Synergism (Useful) Aminoglycosides + -lactam
Amphotricine B + Flucytozine
Drug therapy of TB
Cotrimoxazole
-Blocker + Diuretic + ACEIs
- agonists + Corticosteroids

19. Trimethoprim + Sulfamethoxazole
Inhibited by
SULFONAMIDES
Inhibited by
TRIMETHOPRIM

20. Synergism (Useful) Aminoglycosides + -lactam
Amphotricine B + Flucytozine
Drug therapy of TB
Cotrimoxazole
-Blocker + Diuretic + ACEIs
- agonists + Corticosteroids
Coamoxyclav

21. Noradrenergic Synapse

23. Synergism or additive (Harmful)
Coadministration of sedative drugs
Two or more NSAIDs
Anticholinergic drugs
MAOIs & Sympathomimetic agents, food or antidepressants
CCBs & Beta blockers
Warfarin & NSAIDs

24. Coadministration of Sedative Drugs
BZDs + Sedatives
Death
Coma
Hypnosis
BZDs
Sedation

25. Synergism or additive (Harmful)
Co administration of sedative drugs
Two or more NSAIDs
Anticholinergic drugs
MAOIs & Sympathomimetic agents, food or antidepressants
CCBs & Beta blockers
Warfarin & NSAIDs

26. MAOIs & Sympathomimetic Agents or Antidepressants

27. MAO T
Tyramine
Inactive T
Tyramine is present in aged cheese

28. Synergism or additive (Harmful)
Co administration of sedative drugs
Two or more NSAIDs
Anticholinergic drugs
MAOIs & Sympathomimetic agents, food or antidepressants
CCBs & Beta blockers
Warfarin & NSAIDs

29. Antagonism Co administration of agonist & Antagonist
Bacteriocidal + Bacteriostatics Antibiotics
NSAIDs & Antihypertensives
TCA & Hypotensive drugs
Antidotes in poisoning

30. Antagonism Co administration of agonist & Antagonist
Bacteriocidal + Bacteriostatics Antibiotics
NSAIDs & Antihypertensives
TCA & Hypotensive drugs
Antidotes in poisoning

31. G
Imipramine G

32. Antagonism Co administration of agonist & Antagonist
Bacteriocidal + Bacteriostatics Antibiotics
NSAIDs & Antihypertensives
TCA & Hypotensive drugs
Antidotes in poisoning

33. Indirect Effect Digoxin & Diuretics ACEIs & Potassium sparing agents
Diuretics & Lithium

34. Pharmacokinetic
Absorption
Distribution
Elimination

35. Absorption Antacids: Tetracyclines, Iron, Ketoconazole, Ciprofloxacin
Antibiotics: Digoxin, OCP
Cholestyramine: Digoxin, Warfarin, Thyroid hormones
Sucralfate: Phenytoin
Anticholinergic & Morphine: Decreased GI motility
Antineoplastic drugs: Phenytoin, Digoxin
Food: Antibiotics, Captopril, Griseofulvin, Propranolol

36. Tetracyclines OH O R1 R2 R3 R4
CONH2

37. Ciprofloxacin

38. Absorption Antacids: Tetracyclines, Iron, Ketoconazole
Antibiotics: OCP, Digoxin
Cholestyramine: Digoxin, Warfarin, Thyroid hormones
Sucralfate: Phenytoin
Anticholinergic & Morphine: Decreased absorption
Antineoplastic drugs: Phenytoin, Digoxin
Food: Antibiotics, Captopril, Griseofulvin, Propranolol

39. Time-Course of the Antibiotics

40. Time-Course of the Antibiotics

41. Metabolism Drugs with high FPM show variable Cp
Enzyme induction: 1-3 weeks
Enzyme inhibition: 24 h

42. Drug Metabolism
Effect
Target
Drug
Cytochrome P450 enzymes
Metabolite

43. Enzyme/Substrate Interaction
Enzyme (e.g.) CYP3A4

44. Enzyme/Substrate Interaction

45. Enzyme Induction

46. Drug Metabolism +++ Target Less Drug Effect Metabolite +++
Enzyme Inducing Drug
Cytochrome P450 enzymes
+++
Metabolite
+++

47. Enzyme Inducers Phenobarbital: Warfarin, OCP, Vit D Phenytoin: Vit D
Carbamazepine
Rifampin: Warfarin, Methadone, OCP
Griseofulvin
Alcohol (chronic)
Smoking: Theophylline, TCA
14 case of death after Phenobarbital & warfarin

48. Effects of Enzyme Induction on plasma Cs. of drugs

49. Enzyme Inhibiting Drug
Drug Metabolism
Target
Drug
Greater
Effect
Enzyme Inhibiting Drug
Cytochrome P450 enzymes
- - -
Metabolite
- - -

50. Enzyme inhibitor (e.g. ritonavir)
Enzyme Inhibition
Enzyme inhibitor (e.g. ritonavir)

51. Enzyme inhibitors INH Ketoconazole Erythromycin: Terfenadine
Allopurinol: 6-MP
Cimetidine
Ciprofloxacin
Alcohol (Acute)
MAOIs
Disulfiram

52. Effects of Enzyme Inhibition on plasma Cs. of drugs

53. Enzyme inhibitor started
Plasma
concentration of
target drug
Time
Enzyme inhibitor started

54. Torsades de Pointes
The first case we will consider is that of the potentially lethal arrhythmia, torsades de pointes, occurring in association with terfenadine (Seldane®) use in a young woman. {Monahan}
This ECG is a classic example of torsades de pointes, which is French for “twisting of the points.” Torsades is a form of ventricular tachycardia that can most often be due to medications. The QRS complexes during this rhythm tend to show a series of “points up” followed by “points down” often with a narrow waist between. Recognition and reporting of this arrhythmia in association with terfenadine, astemizole (Hismanal®), cisapride (Propulsid®), grepafloxacin (Raxar®), and mibefradil (Posicor®), ultimately led to these medications’ removal from the market.
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR. Torsade de pointes occurring in association with terfenadine use. JAMA 1990; 264:
Monahan BP et al. JAMA 1990;264:2788–279090

55. Enzyme inhibitors INH Ketoconazole Erythromycin: Terfenadine
Allopurinol: 6-MP
Cimetidine
Ciprofloxacin
Alcohol (Acute)
MAOIs
Disulfiram

56. CYP2D6 PM fail to generate active metabolite
Morphine
Codeine
O-demethylation
CYP2D6
CYP2D6 PM fail to generate active metabolite
No analgesic effect

57. Overactive metabolism can cause adverse events
“Normal” Activity
Morphine
Enzyme
Pro-Drug
(Codeine)
Morphine
Enzyme
“Ultra-rapid” Activity
Pro-Drug
(Codeine)

58. Protein Binding D D X

59. Protein Binding
Salicylates: Methotrexate, Warfarin, Hypoglycemic agents
Sulfonamides: Warfarin, Bilirubin

60. Protein Binding W W
Phenylbutazone W
Inactive
Liver

61. Elimination Loop diuretics: Decrease Cl of Aminoglycosides
K+ sparing agents & Potassium
Quinidine, Verapamil & Amiodarone: Decrease Cl of Digoxin
Diuretics & NSAIDs: Decrease Cl of Lithium
Probencid: Decrease Cl of PNC
Alteration of pH

62. Interactions Before Administration
Phenytoin precipitates in dextrose solutions (e.g. D5W)
Amphotericin precipitates in saline
Gentamicin is chemically incompatible with most beta-lactams, resulting in loss of antibiotic effect
The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here.
When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longer available to control seizures.
Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder.(Personal Communication, David Flockhart, MD, PhD., University of Indiana, July 2001)
Lastly, aminoglycosides should not be co-mixed in IV fluids with beta-lactam antibiotics because covalent bonds are formed between the two drugs. This can markedly reduce antibiotic efficacy.

63. Drug-Food Interactions
Tetracycline and milk products
Warfarin and vitamin K-containing foods
Grapefruit juice
Several drugs are known to interact with foods,{Williams} some of which are listed here. One of the early observations was the reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients should be counseled to maintain a consistent diet during warfarin therapy.
Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs. This was first described for felodipine (Plendil®) {Bailey 1991} but has now been observed with several drugs.{Kane} This interaction can lead to reduced clearance and higher blood levels when the dugs are taken simultaneously with grapefruit juice. With regular consumption, grapefruit juice also reduces the expression of CYP3A in the GI tract.{Lown}
Williams L, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs. Med Clin N Am 1993; 77(4):
Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337(8736):
Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000; 75(9):
Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99(10):

64. Tetracycline Teeth

65. Drug-Herbal Interactions

66. Effect of Grapefruit Juice on Felodipine Plasma Concentration
5mg tablet
with juice
without

67. Effect of St. John’s wort on Indinavir Plasma Concentration

68. Low Therapeutic Index Drugs
Morphine
Warfarin
Digoxin
Lithium
Antineoplastics
Cyclosporin
Phenytoin
Theophylline

69. We should know the specific toxicity of drugs & their antidote
Morphine = Respiratory depression
Warfarin = Hemorrhage
Penicillne = Seizure
Digoxin = Arrhythmia

70. Physiologic Factors Age Sex: Diethylstilbestrol
Diet: Absorption & Metabolism
Genetic: INH, Succinylcholine
Pregnancy

71. Pathological Factors Hyper or Hypo-Thyroidism Burn CHF GI disorders
Renal & hepatic dysfunctions
Recreational drugs
Diabetes
....

72. Reducing the risk factors of DI
Patient risk factors
Drug history
OTC drugs
Mechanism of action
Therapeutic alternatives
Complex therapeutic regimens
Education of patients
Monitor therapy

74. Pharmacogenomics Today Future empirical prescription
“One drug fit all”
Drug A
Drug B
Drug C
Drug D
Individual physician experience
Cost: time, money & well-being
Future
Rational prescription
“individualized”
Patient genetic’s profiles
Drug A
Drug B
Drug C
Drug D
Informed physician diagnosis
Saving : time, money & patient’s life

75. Inhibit DNA & RNA synthesis
6-Mercaptopurine
TPMT is the only detoxifying enzyme of 6-MP in hematopoietic cells
TPMT deficiency lead to hematopoietic toxicity
Thioguanine
nucleotides
(TGN)
Inhibit DNA & RNA synthesis
HGPRT
6-Thiouric acid
TPMT
Azathioprine
6-Methylmercaptopurine XO