S2) Pharmacodynamics, Drug Interactions and Toxicology

Question 1

What is pharmacokinetics?

Answer 1

Pharmacokinetics is the study of the movement of a drug into and out of the body

“What the body does to the drug”

Question 2

What is pharmacodynamics?

Answer 2

Pharmacodynamics is the study of drug effect and mechanisms of action

“What the drug does to the body”

Question 3

What is pharmacogenetics?

Answer 3

Pharmacogenetics is the effect of genetic variability on the pharmaco- kinetics/dynamics of a drug on an individual

Question 4

What are agonists?

Answer 4

Agonists are drugs which activate endogenous proteins

Question 5

What are antagonists?

Answer 5

Antagonists are drugs which antagonise, block or inhibit endogenous proteins

Question 6

What are competitive antagonists?

Answer 6

• Competitive antagonists are drugs which compete with the substrate to antagonise, block or inhibit endogenous proteins
• They bind at the same site as the substrate and are surmountable

Question 7

What are non-competitive antagonists?

Answer 7

• Non-competitive antagonists are drugs which bind irreversibly to endogenous proteins to antagonise, block or inhibit their actions
• They bind at the allosteric site and are non-surmountable

Question 8

Identify 5 locations where drugs work

Answer 8

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

Question 9

Identify 5 unconventional mechanisms of drug action

Answer 9

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

Question 10

What is drug selectivity?

Answer 10

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

Question 11

What is drug specificity?

Answer 11

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

Question 12

What is affinity?

Answer 12

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

Question 13

What is efficacy?

Answer 13

• 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 14

What is potency?

Answer 14

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

Question 15

What is the therapeutic index?

Answer 15

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

Question 16

How does one calculate the therapeutic index?

Answer 16

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

Question 17

What is the therapeutic window?

Answer 17

• 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 18

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

• MEC
• MTC

Answer 18

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

Question 19

What is the probability of drug interaction?

Answer 19

The probability of drug interaction rises with the number of drugs a patient uses

Question 20

In terms of absorption, explain how pharmacokinetic drug-drug interactions can occur

Answer 20

⇒ Altered P-Glycoprotein activity

⇒ Inducable/inhibitable active transporter

Question 21

In terms of distribution, explain how pharmacokinetic drug-drug interactions can occur

Answer 21

Protein-binding interactions, important for:

• IV drugs
• Drugs with short half-life (rapidly cleared)
• Drugs with narrow therapeutic index

Question 22

In terms of metabolism, explain how pharmacokinetic drug-drug interactions can occur

Answer 22

Changes in blood flow (first pass metabolism)

Question 23

Explain how CYP450 inhibition occurs

Answer 23

• Related to:

I. Half life and clearance of affected drug

II. Plasma concentration at time of interaction

• Relatively quick onset (several hours to days)

Question 24

Explain how CYP450 induction occurs

Answer 24

• Increase the amount of enzyme present for a specific action
• Usually phase 1 processes
• Rate depends on drug and enzyme (takes days/weeks)

Question 25

What are the effects of pharmacodynamic drug-drug interactions?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

Which drugs commonly produce pharmacodynamic drug interactions?

Answer 27

- Anticonvulsants - Antibiotics - Anticoagulants - Antidepressants/Antipsychotics - Antiarrhythmics

Question 28

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

Answer 28

⇒ **Reduced clearance** of renally excreted drugs ⇒ **Disturbances of electrolytes** may predispose to toxicity ⇒ **Nephrotoxins** will further damage kidney function

Question 29

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

Answer 29

⇒ Reduced clearance of hepatic metabolised drugs ⇒ Reduced CYP 450 activity ⇒ Much longer half lives ⇒ Toxicity

Question 30

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

Answer 30

⇒ Excessive response to hypotensive agents ⇒ Reduced organ perfusion ⇒ Reduced hepatic blood flow and clearance ⇒ Reduced renal blood flow and clearance

Question 31

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

Answer 31

⇒ Inhibits several CYP450 isoenzymes ⇒ Decreases clearance of many drugs ⇒ May lead to increased exposures to drug of up to 16 fold

Question 32

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

Answer 32

⇒ Inhibits CYP2C9 isoform ⇒ Decreases clearance of warfarin ⇒ Enhanced anticoagulant effect ⇒ Increased risk of haemorrhage

Question 33

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

Answer 33

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

Question 34

Provide two examples of drugs showing variations in CYP450 pharmacogenetics

Answer 34

- Warfarin response (CYP2C9) - Codeine response (CYP2D6)

Question 35

What is an adverse drug reaction (ADR)?

Answer 35

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 36

Identify and describe the three types of ADRs

Answer 36

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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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