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

PharmacokineticDrug 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

CYP2D6

Family

Sub-Family Individual Gene

CYP 450 SystemDefinitions

• Substrate:Drug is metabolised by the enzyme system

• Inducer:Drug that will increase the synthesis of CYP450 enzymes

• InhibitorDrug 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 InducersExamples

• Rifampicin

• Phenobarbitone

• Carbamazepine

• Cigarette smoke

Enzyme Inhibition

• Often rapid, reversible and relatively short acting.E.g. erythromycin and cyclosporinNB erythromycin is a substrate and an inhibitor ofCYP 3A4

• May be prolonged due to long half- life of drug.E.g. amiodarone and S-WarfarinNB amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

Enzyme characteristics% drugs metabolised by

enzyme• 3A4 60%• 2D6 25%• 1A2 15%• 2C9 Small no. but significant

interactions

• 2C19 Small no. but significant interactions

• 2E1 ?

EXCRETIONDrug A increases or reduces the excretion (usually renal) of Drug B.

Blood levels of B fall below or rise abovenormal 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 drugactive secretion mechanism. Another acid drug will then be secreted less efficiently

Excretion InteractionLithium + 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 InteractionChange 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 BindingDrug Displacement

Plasma Tissue

Drug Aprotein bound

Drug Afree

Drug Afree

Drug B

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)

• 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 characteristicsGenetic Polymorphism

• CY2D6PM- 5-10% Caucasians, <1% Asians(Also “super-fast metabolisers)

• CYP2C9PM 1-3% Caucasians

• CY2C19PM- 3-5% Caucasians, 15-20% Asians

Enzyme CharacteristicsInterindividual Enzyme

Content• CYP3A4 x 5

• CYP2D6 > 50

• CYP1A2 x 20

• CYP2C9 x 5

• CYP2C19 ?

• CYP2E1 x 12

Interactions via Enterohepatic Circulation (EHC)

Free drug

Conjugate

Free drug Conjugate

Liver

Gut

Bile

Bacteria

Case 1SSRI/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 2SSRI/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.