Drug-drug interactions

What are drug-drug interactions?

A change in one drugs effect when administered with another drug, food or other susbstance

What drugs worsen renal impairment?

Diuretics and NSAIDs

What drug reduces warfarins blood thinning effect?

Carbamazepine

Where can drug interactions have an affect?

• At the stomach or small intestine - absorption

• At the tissues - distribution

• At the liver - metabolism

• At the kidneys - elimination

What drugs change the gastric pH and can effect dissolution and ionisation?

Ketoconazole

• PPI

• H2 antagonists

• Antacids

What drugs change the drug binding and can effect bioavailability?

Tetracyclines and milk

• Forms insoluble complex together

• Reduces absorption

What drugs change the gastric motility and can effect gastric emptying time?

Metoclopramide and domperidone - given for IBS

• Increases the time of emptying into the small intestine

• Reduces rate and extent of absorption

What happens when you give a patient a higher binding affinity drug than a drug in the body?

Displacement from binding site

• Volume of distribution changes

• Half life changes

• Low unbound fraction drugs

• ‘Victim’ drug levels increase in the body

What happens when a drug is an inhibitor to a CYP enzyme?

• Macrolide - -mycins

• Ca²⁺ blockers - verapamil, diltiazem

• HIV antivirals

• Azoles - keto-/itra

What happens when a drug is an inducer to a CYP enzyme?

• Anti epileptics - carba, pheny

• St Johns Wort

• Rifampicin

List some inducers and inhibitors of CYP3A4

Why do people who smoke need a higher dose of clozapine (antipsychotic)?

They have a C_max that is 20% lower than non-smokers

• Tobacco induces the expression of CYP1A2

• Metabolism is more than non smokers

• Dose should be lowered eventually as they cannot smoke in hospital

• Also affects theophylline, imipramine, propranolol

What fruit inhibits the function of CYP3A4 and what meds does this affect?

Grapefruit

• Statins - simvastatin, atorvastatin and lovastatin

• High bp & heart meds - nifedipine, felodipine, verapamil and amiodarone

• Anxiety & psychiatric drugs - buspirone, carbamazepine and sertraline.

• Organ transplant & immunosuppressants - cyclosporine and tacrolimus.

• Migraine treatments - atogepant and ubrogepant

• Erectile dysfunction drugs - sildenafil and tadalafil

• Corticosteroids - budesonide

• Antihistamines - fexofenadine can block absorption and decrease the effectiveness

• Pain & other specialty drugs - suzetrigine and certain cancer therapies

What condition and drug interaction should you be aware of if a patient is addicted to heroin?

More likely to contract tuberculosis - 4 meds for 6 months

• Rifampicin (TB) + Methadone (opioid substitution)

• R is an inducer of CYP3A4, reducing M plasma conc

• Dose of M needs to be increased (90→160mg) and then lowered when TB course is finished (160→90mg)

What other CYP enzyme does rifampicin effect and how can we fix it when treating heroin patient?

CYP2B6

• Start 1 week prior to ending R and reduce M by 10mg in 2 day intervals

What happens when you give a patient midazolam with ritovavir?

• R inhibits CYP3A4

• Clearance decreases and M concentration increases

What happens when you give a patient midazolam with carbamazepine?

• C induces CYP3A4

• Clearance increases and M concentration decreases

Equation for half life

t_1/2 = 0.693 x V_d / CL

Equation for average steady state concs

C_ss = F x dose / CL x t