1. New Zealand College of Pharmacists
Drug Interactions
New Zealand College of Pharmacists

2. Purpose of Presentation
This presentation supplements the course materials

3. Risk Factors for Drug Interactions
High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy
Renal, liver impairment
High Risk Drugs
Narrow therapeutic index drugs
Recognised enzyme inhibitors or inducers

4. Some drugs with a low therapeutic index
Lithium
Digoxin
Carbamazepine
Cyclosporin
Phenytoin
Phenobarbitone
Theophylline (Aminophylline)
Warfarin

5. Pharmacodynamic Drug Interactions
One drug causes a change in patient response to another drug without altering that drug’s pharmacokinetics
Eg increase toxicity of digoxin caused by diuretic induced hypokalaemia
Additive effects of alcohol and benzodiazepines
Beta-blocker given with beta-agonist

6. Pharmaceutical Interactions
Interactions that occur prior to systemic administration.
For example incompatibility between two drugs mixed in an IV fluid. These interactions can be physical (e.g. with a visible precipitate) or chemical with no visible sign of a problem

7. Pharmacokinetic Drug Interactions
One drug alters the rate or extent of absorption, distribution, metabolism or excretion of another drug.
A change in blood concentration causes a change in the drug’s effect.

8. Altered Absorption (Availability)
Change in gastrointestinal pH
Ketoconazole needs acidic conditions in gut
Drug binding in GI tract
E.g. tetracycline and calcium
Change in gastrointestinal flora
Antibiotics with OCs         
Change in gastrointestinal motility
Metoclopramide and digoxin
Malabsorption caused by other drugs
Orlistat (Xenical) and fat soluble vitamins

9. CYP450 Nomenclature
Family
CYP2D6
Individual Gene
Sub-Family

11. CYP 450 System Definitions
Substrate: Drug is metabolised by the enzyme system
Inducer: Drug that will increase the synthesis of CYP450 enzymes
Inhibitor Drug that will decrease the metabolism of a substrate

12. Enzyme Induction 1
Leads to production of more enzyme, usually after 3-4 days of exposure to inducer
Most CYPs are inducible but not CYP2D6
Time course of interaction depends on half-life of inducer.

13. Enzyme Induction 2
Rifampicin has short half-life and induction apparent with 24 hours
Phenobarbitone has longer half life so time to complete induction takes longer

14. Enzyme Inducers Examples
Rifampicin
Phenobarbitone
Carbamazepine
Cigarette smoke

15. Enzyme Inhibition
Often rapid, reversible and relatively short acting. E.g. erythromycin and cyclosporin NB erythromycin is a substrate and an inhibitor of CYP 3A4
May be prolonged due to long half- life of drug. E.g. amiodarone and S-Warfarin NB amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

16. Enzyme characteristics % drugs metabolised by enzyme
2C Small no. but significant interactions
2C Small no. but significant interactions
2E ?

17. EXCRETION Drug A increases or reduces the excretion
(usually renal) of Drug B.
Blood levels of B fall below or rise above
normal therapeutic range.
Becomes either ineffective or toxic.

18. Excretion Interactions
Mechanisms of urinary excretion:
- Simple filtration
- Active secretion
Mechanisms for active secretion
- Acids
- Bases

19. Excretion interactions
Active secretion mechanisms have limited capacity.
e.g. One acid drug may saturate the acid drug
active secretion mechanism. Another acid drug
will then be secreted less efficiently

20. Excretion Interaction Lithium + Thiazides
Probable mechanism:
Thiazides cause diuresis and initial sodium loss.
Compensatory sodium retention in proximal
tubules.
Proximal tubules do not distinguish sodium
from lithium.
Lithium also retained and accumulates.

21. Excretion Interaction Change in renal blood flow
Methotrexate and NSAIDs
NSAIDS can decrease renal blood flow by inhibition of renal prostaglandins.
Reduced clearance of MTX and active (toxic) metabolite

22. Protein Binding Drug Displacement
Plasma
Tissue
Drug B
Drug A
protein bound
Drug A
free
Drug A
free
Drugs A and B both bind to the same plasma protein

23. Protein Binding Interactions
Importance has been over emphasised
Protein binding is a dynamic state
Increased availability of free drug displaced from plasma proteins
……….. But compensatory mechanisms maintain free drug concentration
Only important in interpretation of total drug concentrations e.g. phenytoin/VPA

25. Some enzyme Inducers Barbiturates (3A) Carbamazepine (2C19, 3A)
Phenytoin (3A)
Rifampicin (2C19, 2C9, 3A)
St Johns Wort (3A)
Ethanol (2E1)
Troglitazone (3A)
Tobacco (1A2)
Omeprazole (1A2)
Nevirapine (3A)

26. Where are these enzymes ?
Most cells
Predominantly in endoplasmic reticulum of hepatocytes
Also present in gut wall
Kidney lungs and brain
Liver is main site of drug metabolism

27. Significance of Gut CYPs
CYP3A4 most important. Quite high concentrations in mucosa of small intestine
Activity is fold less than in whole liver
Quantitatively significant if oral dose is small or rate of absorption very slow.

28. Enzyme characteristics Genetic Polymorphism
CY2D6 PM- 5-10% Caucasians, <1% Asians (Also “super-fast metabolisers)
CYP2C9 PM 1-3% Caucasians
CY2C19 PM- 3-5% Caucasians, 15-20% Asians

29. Enzyme Characteristics Interindividual Enzyme Content
CYP3A x 5
CYP2D > 50
CYP1A x 20
CYP2C x 5
CYP2C ?
CYP2E x 12

30. Interactions via Enterohepatic Circulation (EHC)
Free drug
Conjugate
Liver
Gut
Bile
Bacteria

31. Case 1 SSRI/TCA
What is the mechanism of the pharmacokinetic interaction ?
What possible pharmacodynamic interactions are there ?
What would be the most hazardous combination ?
What would be the safest combination ?
How would the interaction be managed ?

32. Case 2 SSRI/Tramadol
What CYP enzyme is involved in the metabolism of both these drugs ?
What possible interactions are there ?
Where can you find information on this interaction ?
Are there any case reports in the literature ?
How would you find these case reports ?

33. Case 3
Patient taking timolol eye drops (for more than six months).Complains of slow heart rate and dizziness shortly after taking cimetidine tablets which he had bought OTC.
What is the mechanism of this interaction ?
How could the interaction be managed ?

34. ACE/Diuretics/NSAIDS
Prescriber Update July 2002
Diuretics (hypovolaemia)
ACE Inhibition of RAA system therefore less constriction of efferent arteioles from glomerulus
NSAIDS/COX-2 inhibition of renal prostaglandins, therefore less dilataion of afferent arterioles.