Lec 9- Interactions

Question 1

How do we define an interaction

Answer 1

• A change in one drugs effect when administered with another drug, food or other substance
• FOOD = Milk
• HERBALS= St Johns Wort
• DRUGS= Any
• LIFESTYLE= Alcohol, smoking

Question 2

Will it be important

Answer 2

• Mostly No / Yes
• Depends on a number of factors
• High risk drugs: Narrow TI
• High risk Patients: pregnant, geriatric, liver/renal disease

Question 3

Polypharmacy: use of medicine in the preceding week

Answer 3

Question 4

Interactions- clinical presentation

Answer 4

• BENEFICIAL
  
  • POTENTIATE: Combination anti-biotics (Additive/Synergistic)
  • ANTAGONISM: ‘Antidote’ for overdose (Antagonistic =Lessened effects)
• Undesirable
  
  • TOXICITY: Diuretics and NSAIDs worsening renal impairment (Additive/Synergistic)
  • LOSS OF EFFECT: Carbamazepine reducing warfarin’s blood thinning effect (Antagonistic =Lessened effects)

Question 5

Interactions- Clinical presentation

Warfarin example

Answer 5

• An 87-year-old woman is brought to the A&E by ambulance.
• Her INR is 6 (Therapeutic range 2-3) and this is her CT scan
• Her daughter tells you she is usually on warfarin and has recently been taking some other tablets for a UTI
• This patient was prescribed erythromycin for her UTI
• It turns out that erythromycin is able to inhibit the metabolism of warfarin and thereby leading to a cranial haemorrhage
• Something as simple as erythromycin is potentially lethal as an interaction for those taking warfarin

Question 6

Interactions- ADME processes

Answer 6

• An interactions can occur at different points in the PK of a drugs, depending on the route of administration
• ABSORPTION: Often at the level of the stomach Or small-intestine
• DISTRIBUTION: At a tissue level
• METABOLISM: At the liver
• ELIMINATION: At the kidneys
• For example and orally dosed agent may have more of a clinical problem with an interaction compared to one which dosed through an IV bolus

Question 7

Interactions- Impact on absorption

Answer 7

• For orally dosed therapeutics, interactions at the level of the stomach and small-intestine are important and impact on the process of drug absorption

Question 8

Interactions- Impact on distribution

Answer 8

• For drugs to be able to distribute out of the circulation and into target tissues, diffusion across cellular membranes is important
• Interactions often occur at the level of plasma protein
• Albumin has two main drug binding sites, the bindings depends on the affinity of a drug towards the proteins
• Co-administer a drug with higher binding affinity than the victim drug leads to displacement from binding site

Question 9

What is the impact of this on the PK of a drug and does it impact on drugs with a low or high Fu

Question 10

Interactions- Impact on metabolism

Answer 10

• For orally dosed therapeutics, interactions at the level of the small intestine and liver can be clinically significant as they often impact upon drug metabolism
• The main target is often CYP450 enzymes
• The perpetrator drug will cause one of these

Question 11

Interactions- impact on metabolism

Answer 11

• The drug agent causing the change in metabolism (perpetrator) itself has to undergo ADME processes
• Less enzyme (function)=> Inhibitor => Time to see effect depends on the half-life of the drug and time it takes to reach a steady state
• More enzyme (amount) => Inducer => Can take a few weeks to see maximum effects and a few weeks to recover
• Manifests as changes in clearance or half-life and plasma concentrations

Question 12

Interactions- Impact on metabolism

Answer 12

• Inhibitor-
  
  • Macrolide AB (–mycins)
  • Ca²⁺ blockers (verapamil / Diltiazem)
  • HIV anti-virals
  • Azoles (Keto/itra)
• Inducer
  
  • Anti-epileptics (Carbamazepine, Phenytoin)
  • St Johns Wort
  • Rifampicin

Question 13

Interactions- impact on metabolism (examples)

What will happen?

Answer 13

• Increased elimination
• Reduced Half-life
• Reduction in immune-suppresion
• Organ rejection

Question 14

Interactions- impact on metabolism

Answer 14

Question 15

Interactions- impact on metabolism (examples)

Answer 15

• Inducers (rifampicin)- Note that the effect is NOT instantaneous
• Inducers require some time to manifest an effect on the metabolism of drugs

Question 16

Interactions- impact on metabolism (examples)

Answer 16

• INDUCER (CYP2C9)
  
  • Antiepileptics (carbamazepine, phenytoin)
  • Rifampicin
  • St Johns Wort
• INHIBITOR
  
  • Amiodarone
  • Fluoxetine
  • FLuconazole
• Narrow TI drug
• Control of PK important
• Increased or decrease in clotting
• Alters elimination
• Alters half-life

Question 17

Interactions- impact on metabolism (examples)

Clonzapine

Answer 17

• Food / Lifestlye interaction
• Smokers have a C_max that is 20% lower than non-smokers
• Tobacco INDUCES the expression of CYP1A2 (hence 20% reduction)
• Patients admitted or unable to smoke should get a dose reduction

Question 18

Interactions- impact on metabolism

Answer 18

• Food / Lifestyle interaction
• Grapefruit juice contains chemicals which strongly inhibit the function of CYP3A4
• This can have an effect on a wide range of drugs

Question 19

Interactions- impact on renal elimination

Answer 19

• The kidney play a major role in the elimination of drugs
• Patients with renal failure are more prone to presenting with more significant ADR as a result of an interaction
• NSAIDS- alter renal blood flow change GFR; Affects methotrexate (toxic) reduced elimination
• Thiazides diuretic- Alter fluid secretion/reabsorption; Affects lithium (depression) reduced elimination
• Bicarbonates- Alters urine pH; Encourages elimination of aspirin in OD cases

Question 20

Summary

Answer 20

• Describe the term interactions in the context of alterations in the ADMA of a victim drug
• Illustrate examples of interactions at the level of ADME
• Describe the consequence on the PK of the victim drug