a clinical pharmacology perspective

A Clinical Pharmacology Perspective

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Drug Interactions

Matt DoogueChristchurch, NZ

n When one drug alters the effect of another drugn Interactions between current medsn Starting new medicinesn Tools for DDIs Ln My clinical approach to DDIs

Drug-Drug Interaction (DDI)

Drug-Drug Interaction (DDI)

n When one drug alters the effect of another drugn Increase effectn Decrease effect

n Can be beneficial or harmful.

Assessing Drug Drug Interactions1. Interactions between existing drugs in a given patient

have already occurred -relevant to diagnoses

2. Potential pharmacodynamic DDIs can be recognised by knowledge of the pharmacological effects of drugs and of patient physiology together

3. Drugs with a narrow therapeutic index are more likely to be ‘objects’ of PK-DDIs.

4. A small number of drugs are important ‘perpetrators’ of PK-DDIs.

5. Stopping a drug is a prescribing decision that may cause a DDI.

100%

10

Number of drugs

50%

5

Chance of DDI

Clinical Relevance

n Common, often ‘mild’, often missedn May be

n beneficial or harmful,

n increase or decrease effect

n Interindividual variabilityn eg. frailty, organ function,

Actions1. Change drug

2. Change dose

3. Change monitoring

Drug Drug Interactions

• Common

• Cause harm

• Poorly anticipated

• Current predictive tools are of limited utility

Potential DDIsA

B

C

D

E

F

G

A B C D E F GABCDEFG

21 combinations

Existing Drugs New Drugs

Potential DDIs

A

B

C

D

E

F

G

Premise 1: Interactions between existing drugshave already happened

n Relevant to differential diagnosisIs this patient presenting because of…

n Adverse effect?n Treatment failure?

Interactions between existing drugshave already happened

Existing Drugs

Actual DDIs

Two questionsn Is there harm?n Is there benefit?

A

B

C

D

E

Existing Drugs

Actual DDIs

Is there harm?n Is the presentation due to

(or contributed to by) their medicines?

n Are there any ADRs I should look for?

n If yes, is this because of an interaction?

A

B

C

D

E

Existing Drugs

Actual DDIs

Is there benefit?n Is the presentation due to

(or contributed to by) treatment failure?

n If yes, is this because of an interaction?

A

B

C

D

E

Existing Drugs New Drugs

Potential DDIs

A

B

C

D

E

F

G

21 11 combinations

Potential DDIsA B C D E F G

ABCDEFG

Classifying DDIs

Black Box

Clinical Pharmacology

Prescription

Concentration

PatientHealth

concentration at target

affinity to target

molecular effect/s

physiological effect/s

Dose

Effect/s

Pharmacokinetics

Pharmacodynamics

absorptionfirst pass metabolism

± activation

Bioavailability

metabolismexcretion

Clearance

Administrationadherence route

Distributiondiffusiontransport

Classifying DDIsPharmacokinetic

- bioavailability: absorption, first pass metabolism- clearance: metabolic, renal, other- distribution: trans-membrane transport

Pharmacodynamic- mode: physiological effect- mechanism: molecular target

Other- pharmaceutic - behavioural

Potential Pharmacodyamic Interactions?

• Potential pharmacodynamic DDIs can be recognised based on knowledge of the pharmacological effects of drugs andpatient physiology together

• Consider the drugs’ effects - additive or opposing

Additive EffectsMay be beneficialn ACE inhibitor + thiazide in hypertensionn Metformin + SGLT2 inhibitor in diabetes

n mycophenolate + prednisone + tacrolimus in renal transplant

May be harmfuln CNS depression e.g. alcohol + benzodiazepines

n Serotonin toxicity e.g. SSRIs + tramadol

n QTc prolongation e.g. erythromycin + antipsychotics

Opposing Effects

Molecularn b-blocker + b-agonist

n morphine + naloxone

Physiologicaln NSAIDs + antihypertensivesÞ ¯ antihypertensive effects

n Immunosuppressants + vaccines

Þ failure to seroconvert

Pharmaceutic InteractionsHappen outside the body - drugs/solutions/equipment � inactivation or

precipitation

Only admix when interactions are known to be absentask the pharmacist

Examples:• ciprofloxacin IV + amoxicillin IV = INCOMPATIBLE• insulin adsorbs to plastic IV lines/bags• phenytoin precipitates in solutions pH<7 e.g. D5W

Pharmacokinetic DDIs (PKDDIs)

A “perpetrator” drug causes a change in concentration of a “object” drug with clinical consequences.

Premise 2: If clinical consequences are unlikely PKDDIs are not important

2 - fold concentration change

Concentration mg/L = Dose mg/24hr Clearance x F L/hr

time

conc

entra

tion

narrow therapeutic index

time

conc

entra

tion

NarrowPerpetrator

WideNon perpetrator

Object drugtherapeutic Index?

Perpetrator druginducer or inhibitor?

Probable

Unlikely

Drug Interaction?

Possible

Are there important

perpetrators or objects of

PKDDIs?

IdentifyNEW DRUG PAIRS

that include perpetratorOR object drugs(s)

EstimatePK change

to the object drugof each pair

Considerlikely clinical consequences

of the PK changesfor that patient

PK-interactionunlikely

yes

no

www.pkis.org

Narrow Therapeutic Index Drug Classes

Drug class ExampleAnticoagulants warfarinImmunosuppressants tacrolimusAntiepileptics phenytoinAntiarrhythmics amiodaroneAntineoplastics docetaxel, imatinib

Therapeutic index: • easier to recognise than define,• would doubling or halving the dose of this drug

have a major effect on this patient?• the vulnerability of the patient

- affects the dose–response relationship.

Example 1: X = warfarin, i.e. narrow therapeutic index Current New

A

B X

C

D

E Y

F

Seven potential interactions to consider. Clinical solution, start warfarin as usual and adjust dose to INR.

Are any of the drugs important perpetrator or object drugs?

Example 2: B = warfarin, i.e. narrow therapeutic index Current New

A

B X

C

D

E Y

F

Two potential interactions to consider. Clinical solution, start new drugs, adjust warfarin dose to INR.



Example 3: X = rifampacin an important enzyme inducer. Current New

A

B X

C

D

E Y

F

Need to consider 7 potential DDIs1. High risk - ?alternative drug2. Consider each pair and select doses and monitoring


Example 4: B = rifampacin an important enzyme inducer. Current New

A

B X

C

D

E Y

F

Two potential interactions to consider. Clinical solution, consider potential effect of rifampacin on X & Y

(e.g. if renal clearance no problem). Select initial doses,

review and adjust doses based on appropriate biomarkers.

What I do

• How is the patient?– Any adverse effects or treatment failure?

• Group medicines by effects– What are the PD interactions?

• Are there any major inducers or inhibitors?• For medicines I start, which of the patients

medicines might they interact with?• Monitor, monitor, monitor

Assessing Drug Drug Interactions1. Interactions between existing drugs in a given patient

have already occurred -relevant to diagnoses

2. Potential pharmacodynamic DDIs can be recognised by knowledge of the pharmacological effects of drugs and of patient physiology together

3. Drugs with a narrow therapeutic index are more likely to be ‘objects’ of PK-DDIs.

4. A small number of drugs are important ‘perpetrators’ of PK-DDIs.

5. Stopping a drug is a prescribing decision that may cause a DDI.

We are all individuals

a clinical pharmacology perspective

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