kuliah

1. Dr. dr. Mgs. Irsan Saleh, M.Biomed
Bagian Farmakologi
Fakultas Kedokteran Universitas Sriwijaya
Drugs Interaction

2. Drug interactions:
Are they really important?
 Metaanalysis of 39
prospective clinical
trials has proved:
 Adverse Drug
Reactions are 4th
most frequent cause
of death
 Lazarou et al: JAMA
1998
 Analysis of USA
National Drug
Register has proved:
 The cause of 2/3 of
ADRs are drug
interactions
 Phillips et al: JAMA
2001

3.  The pharmacologic or clinical response to the
administration of a drug combination different
from that anticipated from the known effects of the
two agents when given alone
 May be harmful: toxicity, reduced efficacy
 May be beneficial: synergistic combinations,
pharmacokinetic boosting, increased
convenience, reduced toxicity, cost reduction
Drugs Interactions

4.  True incidence difficult to determine
– Data for drug-related hospital admissions do not separate out drug
interactions, focus on ADRs
 Most data are in the form of case reports
– Missing or incomplete information
 Patients receiving polypharmacy are at risk
– 77% of HIV patients on protease inhibitors experience drug
interactions
 Difficulty in assessing role of OTC and herbal drugs in drug
interactions
– Questions regarding “active” ingredient in herbal meds
Epidemiology of Drug-Drug Interactions

5. Epidemiology of Drug-Drug Interactions
 Incidence of potential drug-drug interactions ranges from 2-
17% of all Rx's and up to 6-42% of elderly patients
 Incidence of potentially clinically significant drug
interactions is high in the elderly (usually must involve
narrow therapeutic range drug and inhibitor/inducer of drug
metabolism or renal excretion)
 There is evidence suggesting that adverse health
outcomes associated with drug-drug interactions is
frequent

6. Drug Interactions Are Avoidable
Gosney et al. Lancet 1984;2:564
Previous
adverse
reactions
Contraindicated
drugs
Drug
interactions Totals
Avoidable 7 57 67 131
Probably
avoidable
---- ---- 37 37
Uncertain ---- 3 29 32
Total 7 60 133 200

7. Different kinds of drug interactions
PHARMACOKINETIC
Drug interactions:
PHARMACODYNAMIC
 Interaction drug - drug
 Interaction drug - alcohol
 Interaction drug - foods (and soft drinks)
 Interaction drug – food supplements
All these kinds are divided into:
Drug interactions:
– clinically relevant
– not clinically relevant

8. Why worry……Who cares……………
Most of the time its not a problem even if there are drug
interactions (High Therapeutic Index)
But
Combination of particular drugs is dangerous
Commonly occurs in drugs with a Low Therapeutic Index
Anti coagulants
Anti dysrhythmics
Anti convulsants
Immunosuppressants
Mood Stabilizers

9. Drug Interactions
Outside Body
Pharmacodynamic
Pharmacokinetic

10. Drug Interactions: Outside Body
Storage conditions:
Main offenders :
- light (sodium nitroprusside)
- water (aspirin)
- air (oxidation of drug)
Mixing
Precipitation reactions

11. Pharmacodynamic Interaction
Drug A alters the effect of Drug B
without a change in the concentration
of Drug B
Pharmacodynamic
Related to the drug’s effects in the body
One drug modulates the pharmacologic effect of another:
additive, synergistic, or antagonistic

12. Pharmacodynamic interactions
Often take a 2 -
agonist (salbutamol) to
induce
bronchodilatation
Often take  blockers
(propanolol) to reduce
heart rate force of
contraction
Asthmatics Hypertension
Diminished effect of 2 - agonist

13. Pharmacodynamic interactions
Antidepressants Sympathomimetics
Monoamine Oxidase
Inhibitors (MAOI’s) Inhibit
breakdown of
Noradrenaline Dopamine
Decongestants
(pseudoephidrine)
Asthma (salbutamol)
Foods rich in tyramine
(Beer, Wine, Beans)
MAOI’s enhance effects of these drugs
(pseudoephidrine and salbutamol)
And enhance the action of tyramine

14. Pharmacodynamic Interactions
NSAIDs Antihypertensives
For inflammation/
headache.
Most block Prostaglandin
synthesis. PGE2 and PGI2
cause renal arteriolar
dilation
1 Antagonist
1 Antagonist
Angiotensin Converting
Enzyme (ACE)
Inhibitors
Diuretics
Loss of ability to dilate renal arterioles (via PGE2 and PG2)
can lead to hypertensive crisis in people taking
antihypertensives

15. Pharmacodynamic Interactions
Benzodiazepines
(and antihistamines,
anticonvulsants, barbiturates)
Alcohol
CNS depressant CNS depressant
‘Additive’ CNS depression
Respiratory depression, hypotension, coma

16. Pharmacokinetic Interaction
Drug A alters the effect of Drug B by changing
the plasma concentration of Drug B
Pharmacokinetic
What the body does with the drug
One drug alters the concentration of another
Usually mediated by cytochrome P450 (CYP)

17. Drug enter to body
Metabolite drugs in
urine, feces, and bile
What the body does with drugs
Drugs in plasma
1 Absorption (input)
Drug in tissue
Metabolite
2 Distribution
3 Metabolism
4 Elimination (output)

18.  Absorption: food, chelation, GI motility, pH
 Distribution: transport, protein binding
 Metabolism: Phase I (CYP450), Phase II
(conjugation)
 Elimination: Renal (glomerular filtration); transport
Drug Interactions: pharmacokinetics

19. Drug
absorption
Drug
excretion
Drug
metabolism
(biotransformation)
CYP3A4, CYP2D6,
CYP2C9…
Pharmacokinetic drug
interactions
Drug
displacement
(protein-binding)
Transport
of the drug
inside the
body

20.  Decreased rate of absorption; not extent (↔ AUC):
– Common for many drugs; take without meals
 Decreased extent of absorption (↓ AUC):
– Indinavir AUC decreased by 77% with high calorie meal;
take on an empty stomach
 Increased extent of absorption (↑ AUC):
– Itraconazole (capsules) AUC increased by 66% with
standard meal
Alterations with food

21. Pharm Res 1999, 16(5): 718-24 Antimicrob Agent Chemother 1993,
37(4): 778-84
Alterations in absorption: food effects

22.  Irreversible binding of drugs
in the GI tract
 Tetracyclines, quinolone
antibiotics - ferrous sulfate
(Fe+2), antacids (Al+3,
Ca+2, Mg+2), dairy products
(Ca+2)
 Usually separating
administration of chelating
drugs by 2+ hours decreases
interaction effect Antimicrob Agent Chemother 1997,
39(suppl b): 93-7
Alterations in absorption: chelation

23. ALTERATIONS IN ABSORPTION
Complexation/Chelation
Example: antacids + tetracycline
Impact: tetracycline complexes with
divalent cations forming an insoluble
complex

24. ↑ GI motility: cisapride, metoclopramide
↓ motility: narcotics, antidiarrheals, high calorie meal /
viscosity (delayed gastric emptying)
Alterations in absorption: GI Motility
J Acquir Immune Defic Syndr.
2000 Jul 1;24(3):241-8.

25. ALTERATIONS IN ABSORPTION
Altered GI Transit
Example: anticholinergics + acetaminophen
Impact: delay in absorption of acetaminophen

26. ALTERATIONS IN ABSORPTION
Altered Gastric pH
Example: H-2 blockers + ketoconazole
Impact: dissolution of ketoconazole
is decreased, resulting in reduced
absorption

27. Alterations in absorption
Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771
Ketoconazole
Conc.
(mcg/mL)
Time (hrs)

28. Drugs Interaction: transport protein
Ayrton A, Morgan P. Role of transport proteins in drug absorption,
distribution and excretion. Xenobiotica. 2001;31:469-97

29. Drugs Interaction: transport protein
 Efflux proteins
– P-glycoprotein, MRP1, MRP2, OAT3 (transporter)
– Push out drug from gut back into lumen limiting drug
absorption
– Transporter induction may result in ↓ absorption
– Transporter inhibition may result in ↑ absorption
– Effects often difficult to assess
– Inhibition may be of clinical significance for drugs that
are large molecules, have low bioavailability, dissolve
slowly and/or incompletely

30. Simplified example of P-gp function

31. Drugs Interaction: transport protein
CLINICAL APPLICATION: HEALTHY HUMAN VOLUNTEERS
Rengelshausen et al. Brit J Clin Pharmacol 2003;56:32-8.

32.  Uptake proteins (Organic Anion Transp Prot)
– OATP: located on the luminal border of enterocytes
– Transport drug across lumen and promote absorption
– Transporter inhibition may result in ↓ absorption and
reduced bioavailability
– OATP substrates
• Pravastatin, digoxin, fexofenadine, benzylpenicillin
– OATP inhibitors
• Fruit juices, ritonavir, saquinavir, lovastatin
– In the intestine, OATP functions OPPOSITE of P-gp (i.e.
Pgp inhibition INCREASES drug absorption while OATP
DECREASES drug absorption for compounds that are
substrates of both proteins
Drugs Interaction: transport protein

33. OATP function: Intestine

34. Drugs Interaction: transport protein
Clin Pharmacol Ther. 2002 Jan;71(1):11-20.

35.  Drug metabolism
– Chemical modification of a xenobiotic
– Phase I (functionalization RX)
• Cytochrome P450 (CYP): i.e. CYP3A4, CYP2D6, CYP1A2 etc.
– Phase II (synthetic RX)
• Conjugation: i.e. glucuronidation (UGT1A1 etc.)
– Purpose: detoxification of foreign compounds
– Anatomic sites: Liver*, Gut*, kidney, lung, brain etc.
Drug Metabolism Interactions

36. Drug Metabolism Interactions

37.  Drugs may be metabolized by a single isoenzyme
– Desipramine/CYP2D6; indinavir/3A4; midazolam/3A,
caffeine/CYP1A2; omeprazole/CYP2C19
 Drugs may be metabolized by multiple isoenzymes
– Most drugs metabolized by more than one isozyme
• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
 Extensive listing + references:
– http://medicine.iupui.edu/flockhart/table.htm
CYP 450 Substrates

38.  Usually by competitive binding to enzyme site
 Onset and offset dependent on the half-life and
time to steady-state of the inhibitor
– Fluoxetine & CYP2D6; ritonavir and CYP3A4
 Time to maximum interaction effect dependent on
time required for substrate drug to reach new
steady-state
 Mechanism-based enzyme inactivation
– Grapefruit juice and intestinal CYP3A content
CYP 450 Enzyme Inhibition

39. Enzyme Inhibition

40.  The “usual suspects”
– Cimetidine (various)
– Erythromycin, clarithromycin (3A4)
– Ketoconazole, itraconazole (3A4)
– HIV protease inhibitors (esp. ritonavir)
– Fluoxetine, paroxetine (CYP2D6)
– Nefazodone (CYP3A4)
– Grapefruit Juice (intestinal CYP3A4 only)
Extensive listing with references:
– http://medicine.iupui.edu/flockhart/table.htm
CYP 450 Inhibitors

41. Sildenafil (Viagra®) + Grapefruit Juice
Jeter A et al. Clin Pharmacol Ther. 2002 Jan;71(1):21-9.

42. ALTERATIONS IN HEPATIC METABOLISM
Inhibition of Metabolism
Example: cimetidine + theophylline
Impact: cimetidine reduces the clearance
of theophylline causing an increase in
adverse effects

43.  The “usual suspects”
– Rifampin
– Rifabutin
– Carbamazepine
– Phenobarbital
– Phenytoin
– Nevirapine, efavirenz
– St. John’s wort
– Troglitazone, pioglitazone
 http://medicine.iupui.edu/flockhart/table.htm
CYP 450 Induction

44.  Results in reduction of plasma concentration of
substrate drugs
– Risk of therapeutic failure
– Removal of inducer may lead to toxic concentrations of
substrate
– Induction may lead to formation of toxic metabolite
CYP 450 Induction

45. Enzyme Induction

46. Induction: Influence of Ritonavir on
Olanzapine Disposition in Healthy Volunteers

47. ALTERATIONS IN HEPATIC METABOLISM
Induction of Metabolism
Example: phenobarbital + warfarin
Impact: phenobarbital increases the
metabolism of warfarin, resulting in
reduced anticoagulation

48. Representative substrates, inducers and inhibitors of cytochrome P450 (CYP)
enzymes
Enzyme Substrate Inducer Inhibitor
CYP2C19 Diazepam Rifampicin
CYP2D6 Amitriptyline
Haloperidol
Imipramine
Nortriptyline
Rifampicin

49. Table . Representative substrates, inducers andinhibitorsof
cytochrome P450 (CYP) enzymes
Enzyme Substrate Inducer Inhibitor
CYP3A3/4 Rifampicin
Alprazolam
Midazolam
CYP2D6 Haloperidol Phenobarbital
CYP2C9/10 Diazepam Isoniazid

50. ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow
Example: hydralazine + digoxin
Impact: hydralazine increases the renal
clearance of digoxin

51. ALTERATIONS IN RENAL CLEARANCE
Inhibition of Active Tubular Secretion
Example: probenecid + penicillin
Impact: probenecid prolongs the half-life
of penicillin, allowing single dose therapy

52. ALTERATIONS IN RENAL CLEARANCE
Alterations in Tubular Reabsorption
Example: antacids + aspirin
Impact: antacids reduce the tubular
reabsorption of salicylate via an increase
in urine pH

53. ALTERATIONS IN PLASMA PROTEIN
BINDING
Example: phenytoin + valproic acid
Impact: protein binding of valproic acid is
reduced and total Css decreased

54.  What is the time-course of the interaction?
– Immediately or over a period of time
 Is it a drug class effect?
– omeprazole vs. lansoprazole
 Is the interaction clinically significant?
– Therapeutic index of drugs
• Narrow or wide?
 How should the interaction be managed?
– DC drug? Switch to another drug? Change dose?
Evaluation of Specific Drug Interactions

55. General Considerations in Drug Interactions
 Drug interactions are usually considered clinically significant when precipitation
of toxicity ora change oftherapeutic activity
 Pharmacokinetic interactions refer to those pertinent to derangementin the
movementordisposition ofthe drugs.
 Disease states can also enhance the drug interactions.
Mechanisms of DrugInteractions and Patients at Risk

56. GeneralConsiderations in Drug Interactions
 Changes in drug binding by proteins do not usually produce clinically significant
effects
 Biotransformation in the liver is modulated by age andintrinsic liver disease
 Malnutrition might have a putative negative effect on drugoxidation.
 Alcohol and cigarette smoke arepotent hepatic enzyme inducers
Mechanisms of Drug Interactions and
Patients at Risk

57. General Considerations in Drug Interactions
 Pharmacodynamic interactions refer to those
resulting from the enhanced competition or inhibition
of binding of receptors at the target site of drug action
 Consequential additive/synergistic or antagonistic
effects.
Mechanisms of Drug Interactions and Patients at Risk

58.  Familiarity with metabolic pathways
 Know where to locate information on interactions
 Maintain high index of suspicion when:
– Therapeutic response is less than expected
– Toxic effects are present
 Choose drugs that are less likely to interact
 Consider TDM in certain situations (anti-TB TX)
– Anti-TB and anti-HIV therapy
Drug Interactions: General Tools for
Evaluation and Management

59. DRUG INTERACTION
INH - rifampicin
Possible additive
hepatotoxicity
Patients with
previous liver
disease
Monitor patients
for evidence of
hepatotoxicity
Elderly
Mean incidence of drug related toxic hepatitis were found to be
1.6% (isoniazid), 1.1% (rifampicin) and 2.6% (isoniazid +
rifampicin)

60. DRUG INTERACTION
INH-food
All food reduce absorption of
isoniazid
Food affects the oral absorption of
rifampicin

61. Proposed algorithm for the management of drug interactions
during antituberculous chemotherapy.
Alert of interaction
· Literature database
· Background knowledge to possible predict
· Therapeutic drug monitoring
Confirmation of interaction
· Correlation with literature database
· Clinical situation compatibility
· Therapeutic drug monitoring

62. Proposed algorithm
Assessment of clinical significance
· Clinical/ pharmacodynamic consequences?
· Severity?
· Therapeutic failure/resistance?
· Toxicity to organs?
Evaluation and/or implementation of therapeutic
alternatives
· Monitor pharmacodynamic consequences drug
concentrations
· Dosage, schedule manipulation
· Withdrawal of drug
· Substitution of drug
· Antidote' maneuver
· No active measure except diligent monitoring

63. Strategies to Prevent/Manage
Drug Interactions
1. Encourage patients to report all prescription, over-the-
counter and complementary and alternative drugs at every
health care encounter.
2. Support the implementation of electronic prescribing and/or
the use by patients of one pharmacy with updated drug
interaction software.
3. Work with pharmacists and be familiar with drug interaction
information sources
4. Consider whether drug therapy is necessary
5. When adding a new drug to regimen, screen for potential
drug-drug interactions.

64. 6. When adding a new drug to regimen in a patient,
screen for potential drug-disease interaction.
7. If drug interaction can not be avoided, adjust doses
and or/dosage intervals for affected medication and
monitor the patient closely.
8. Carefully monitor other drug therapy when
withdrawing a drug that can inhibit or induce hepatic
metabolism.
9. Regularly review the need for chronic medications-
reduce polypharmacy
Strategies to Prevent/Manage
Drug Interactions