4 Pharmacodynamics, Drug Interactions and Toxicology

Question 1

Identify 5 locations where drugs work (at a cellular level)

Answer 1

• Cell surface receptors
• Nuclear receptors
• Enzyme inhibitors
• Ion channel blockers
• Transport inhibitors

Question 2

Identify 5 unconventional mechanisms of drug action

Answer 2

• Disrupting structural proteins
• Acting as enzymes
• Covalently linking to macromolecules
• Reacting chemically with small molecules
• Binding free molecules/atoms

Question 3

What is drug selectivity?

Answer 3

Drug selectivity refers to a drug’s ability to preferentially act at its target, reducing the chances of its interaction with different targets

Question 4

What is drug specificity?

Answer 4

Drug specificity refers to a drug’s ability to bind to specific receptor subtypes, often allowing drugs to be targeted against specific organ

Question 5

What is affinity?

Answer 5

Affinity is the tendency of a drug to bind to a specific receptor type

Question 6

What is efficacy?

Answer 6

• Efficacy is the ability of a drug to produce a response as a result of the receptor or receptors being occupied
• It describes the maximum effect of a drug

Question 7

What is potency?

Answer 7

Potency is the dose required to produce the desired biological response of a drug

Question 8

What is the therapeutic index? How is it calculated?

Answer 8

The therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects

Therapeutic index = Toxic Dose (TD50) / Effective dose (ED50)

Question 9

What is the therapeutic window?

Answer 9

• The therapeutic window is the range of dosages that can effectively treat a condition while still remaining safe
• It is the range between the lowest dose that has a positive effect, and the highest dose before the negative effects > positive effects

Question 10

In terms of the therapeutic window, what do the following mean:

• MEC
• MTC

Answer 10

• MTC = Minimum toxic concentration
• MEC = Minimum effective concentration

Question 11

What are the effects of pharmacodynamic drug-drug interactions?

Answer 11

Interactions either enhance or reduce therapeutic outcome through actions on the receptors

Question 12

Describe two types of pharmacodynamic drug-drug interactions and how they occur

Answer 12

• Agonism/antagonism at same receptor e.g. beta blockers and β₂ agonists
• Agonism/antagonism at different receptors e.g. warfarin and aspirin

Question 13

Which drugs commonly produce pharmacodynamic drug interactions? (5 As)

Answer 13

• Anticonvulsants
• Antibiotics
• Anticoagulants
• Antidepressants/Antipsychotics
• Antiarrhythmics

Question 14

In three steps, explain how the falling GFR in renal disease leads to drug interactions

Answer 14

⇒ Reduced clearance of renally excreted drugs

⇒ Disturbances of electrolytes may predispose to toxicity

⇒ Nephrotoxins will further damage kidney function

Question 15

In four steps, explain how hepatic disease leads to drug interactions

Answer 15

⇒ Reduced clearance of hepatic metabolised drugs

⇒ Reduced CYP 450 activity

⇒ Much longer half lives

⇒ Toxicity

Question 16

In four steps, explain how the falling cardiac output in cardiac disease leads to drug interactions

Answer 16

⇒ Excessive response to hypotensive agents

⇒ Reduced organ perfusion

⇒ Reduced hepatic blood flow and clearance

⇒ Reduced renal blood flow and clearance

Question 17

In three steps, explain how grapefruit juice leads to drug interactions

Answer 17

⇒ Inhibits several CYP450 isoenzymes

⇒ Decreases clearance of many drugs

⇒ May lead to increased exposures to drug of up to 16 fold

Question 18

In four steps, explain how cranberry juice leads to drug interactions

Answer 18

⇒ Inhibits CYP2C9 isoform

⇒ Decreases clearance of warfarin

⇒ Enhanced anticoagulant effect

⇒ Increased risk of haemorrhage

Question 19

How can the inter-patient variability in drug response be explained?

Answer 19

Pharmacogenetics – the variation in CYP450 expression accounts for a great deal of inter-patient variability in drug response

Question 20

Provide two examples of drugs showing variations in CYP450 pharmacogenetics

Answer 20

• Warfarin response (CYP2C9)
• Codeine response (CYP2D6)

Question 21

What is an adverse drug reaction (ADR)?

Answer 21

An adverse drug reaction is an unwanted or harmful reaction which occurs after the administration of a drug(s) and is suspected or known to be due to the drug(s)

Question 22

What is an ADR? Identify and describe the three types of ADRs

Answer 22

An adverse drug reaction is an unwanted or harmful reaction which occurs after the administration of a drug(s) and is suspected or known to be due to the drug(s)

• Major – permanent / life threatening
• Moderate – requiring additional treatment
• Mild – trivial or unnoticeable

Question 23

Identify 5 causes of variability in the drug response related to the biological system

Answer 23

• Body weight and size
• Age and sex
• Pharmacogenetics
• Condition of health
• Placebo effect

Question 24

Describe 3 causes of variability in drug response related to conditions of administration

Answer 24

1. • Dose, formulation, route of administration
2. • Repeated administration of drug – drug resistance; drug tolerance-tachyphylaxis; drug allergy
3. • Drug interactions – GI absorption, protein binding / distribution, metabolism (stimulation/inhibition), excretion (pH/transport processes)

Tachphylaxis= rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system