Pharmacodynamics

Question 1

List the targets of which drugs can work on

Answer 1

• Receptors - KING
  
  • Kinase receptors
  • Ion channels
  • Nuclear receptors
  • G-protein receptors
• Ion channels
• Transporters
• Enzymes

Question 2

Define potency and what it depends on

Answer 2

• Effective concentration giving 50% of the maximal response
• Depends on both affinity and intrinsic efficacy plus cell/tissue-specific components (eg. Number of receptors)
• Potency requires: ligand binding to the receptor (affinity), receptor activation (intrinsic activation), things to happen to generate a measurable response (efficacy)
• Potency = affinity + efficacy (used loosely)

Question 3

Define affinity

Answer 3

• Tendency of a drug to bind to a specific receptor type
• The lower Kd (dissociation constant), the higher the affinity
• Graph of proportion of bound receptors over log drug concentration

Question 4

Define efficacy

Answer 4

• Ability of a ligand to cause a response

- Describe the maximum effect of a drug

Question 5

Define therapeutic window

Answer 5

• Range of dosages that can effectively treat a condition while still remaining safe
• Range between the lowest dose that has a positive effect and the highest dose before the negative effects outweigh the positive effects

Question 6

Describe using an example the effect of inhibiting CYP450

Answer 6

• Inhibition via competitive or non-competitive inhibition lowers rate of elimination and plasma levels of drug will increase
• CYP450 inhibition by cimetidine increases warfarin concentration and activity

Question 7

Describe using an example the effect of stimulating CYP450

Answer 7

• Increases the amount of enzyme present

- Eg. Carbamazepine induces CYP3A4 - increases metabolism of warfarin and therefore decreases its effect

Question 8

Describe how renal disease affects drug interactions

Answer 8

• Reduced clearance of renally excreted drugs
• Disturbances of electrolytes may predispose to toxicity - especially potassium
• Nephrotoxins will further damage kidney function
• Changes in proportion of free/bound drugs

Question 9

Describe how hepatic disease affects drug interactions

Answer 9

• Reduced clearance of hepatic metabolised drugs
• Reduced CYP450 activity
• Much longer half lives
• Toxicity
• Eg. opiates in cirrhosis - small doses accumulating leading to coma

Question 10

Describe how cardiac disease affects drug interactions

Answer 10

• Excessive response to hypotensive agents

- Reduced organ perfusion - reduced hepatic and renal blood flow and clearance

Question 11

List factors leading to high risk of ADRs

Answer 11

• Ignorant, inappropriate or reckless prescribing
• Polypharmacy
• Patients at the extremes of age
• Multiple medical problems
• Use of drugs with narrow therapeutic indexes - increased risk of toxicity
• Drugs are being used near their minimum effective concentration - increased risk of treatment failure if metabolism increased

Question 12

Describe the effect of grapefruit juice on drug metabolism

Answer 12

• Grapefruit juice inhibits several CYP450 isoenzymes
• Reduce clearance of simvastatin, amiodarone, terfenadine
• May lead to increased exposures of drug up to 15 fold