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Drug Interactions
New Zealand College of
Pharmacists
Purpose of Presentation
• This presentation supplements the
course materials
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
Some drugs with a low therapeutic index
Lithium
Digoxin
Carbamazepine
Cyclosporin
Phenytoin
Phenobarbitone
Theophylline
(Aminophylline)
Warfarin
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
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
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.
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
CYP450 Nomenclature
Family
CYP2D6
Sub-Family
Individual Gene
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
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.
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
Enzyme Inducers
Examples
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•
Rifampicin
Phenobarbitone
Carbamazepine
Cigarette smoke
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
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•
•
•
Enzyme characteristics
% drugs metabolised by
enzyme
3A4
2D6
1A2
2C9
60%
25%
15%
Small no. but significant
interactions
• 2C19
Small no. but significant
interactions
• 2E1
?
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.
Excretion Interactions
Mechanisms of urinary excretion:
- Simple filtration
- Active secretion
Mechanisms for active secretion
- Acids
- Bases
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
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.
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
Protein Binding
Drug Displacement
Drug B
Plasma
Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drugs A and B both bind to the same plasma protein
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
Some enzyme Inducers
• Barbiturates (3A)
• Carbamazepine
(2C19, 3A)
• Phenytoin (3A)
• Rifampicin
(2C19, 2C9, 3A)
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•
•
•
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•
St Johns Wort (3A)
Ethanol (2E1)
Troglitazone (3A)
Tobacco (1A2)
Omeprazole (1A2)
Nevirapine (3A)
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
Significance of Gut CYPs
• CYP3A4 most important. Quite high
concentrations in mucosa of small
intestine
• Activity is 20-300 fold less than in whole
liver
• Quantitatively significant if oral dose is
small or rate of absorption very slow.
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
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Enzyme Characteristics
Interindividual Enzyme
Content
CYP3A4
CYP2D6
CYP1A2
CYP2C9
CYP2C19
CYP2E1
x5
> 50
x 20
x5
?
x 12
Interactions via Enterohepatic
Circulation (EHC)
Free drug
Liver
Conjugate
Bile
Free drug
Bacteria
Conjugate
Gut
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 ?
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 ?
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 ?
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.