L65: Dose Response Relationship

Question 1

Pharmacodynamics vs Pharmacokinetics

Answer 1

Pharmacodynamics:
- Onset, Intensity, Duration of drug response according to concentration of drug

Pharmacokinetics:
- Explore factors determining relationship between Drug Dosage and Time-varying Concentration of drug

Question 2

Types of drug action

Answer 2

1. Stimulation (Pilocarpine)
2. Repression (Barbituates)
3. Irritation (Bitter)
   - non-selective
4. Replacement (Levodopa)
5. Cytotoxic (Penicillin)

Question 3

How to calculate efficacy of drug

Answer 3

Response (total receptor-mediated stimulus) = Total Receptor Occupancy x Efficacy x Receptor concentration

Total Receptor occupancy = Langmuir adsorption isotherm = [drug]/[drug]+Kd
Kd = equilibrium dissociation constant = affinity
Intrinsic efficacy = power of drug to induce response, Amplifies the stimulus

Shift left of receptor occupancy curve

Question 4

Potency and Efficacy

Answer 4

Efficacy:
maximum effect that a drug can produce regardless of dose

Potency:
amount of a drug that is needed to produce a given effect
- Receptor density and efficiency of stimulus-response mechanism
- Affinity and Efficacy

Question 5

Affinity

Answer 5

Attraction of drug for receptor

Both agonist and antagonist have affinity

Question 6

Efficacy

Answer 6

Intrinsic activity (0-1)

Antagonist has no efficacy

Question 7

Agonists, antagonists, inverse agonist, partial agonist, ligand
Competitive vs non-competitive

Answer 7

Partial agonist: Activates receptor to produce submaximal effect but antagonise action of full agonist

Non-competitive antagonist: ~ partial antagonist (do not occupy receptor but block receptor activity)

Question 8

Classifications of inhibitor

Answer 8

1. Specific (act on specific receptor)

—> Reversible

• competitive (reducing the proportion of enzyme binding to substrate —> relieved by increasing substrate concentration —> curve shift RIGHT e.g. Methotrexate)
• non-competitive (bind to different binding site and decrease turnover number, cannot overcome by increasing substrate concentration —> curve shift DOWNWARDS e.g. Acetazolamide)

—> Irreversible (bind tightly, dissociate very slow, e.g. penicillin, Sarin gas)

2. Non-specific (ultimately denature protein portion of enzyme —> irreversible e.g. heavy metal, alcohol, oxidising and reducing agents)

Question 9

1. Uncompetitive (different site)
2. Noncompetitive (different site)
3. Nonclassical competitive (different site)
4. Pseudo-irreversible competitive (same site)
5. Potentiation (different site)

Answer 9

Uncompetitive: only bind to ES complex

Non-competitive: bind to enzyme with/without substrate

Nonclassical competitive: bind to allosteric site but block substrate from binding to active site

Pseudo-irreversible competitive: bind to active site very tightly and prevent substrate binding —> cannot overcome by increasing substrate concentration —> curve shift DOWNWARDS

Potentiation: binds different site on enzyme and increase efficacy/affinity of other ligand

Question 10

Desensitisation

Answer 10

1. Homologous: only limited to output from stimulated receptor
2. Heterologous: attenuation extend to action of all receptor that share common signalling pathway

Question 11

Therapeutic index

Answer 11

Ratio of toxicity-producing dose to effective response dose

TD50/ED50 (toxic response in 50% of population / therapeutic response in 50% of population)
—> represented by quantal dose response curve (% population against dosage —> each curve represent a specific response)

Question 12

Narrow therapeutic index drugs

Answer 12

Warfarin
Lithium
Digoxin
Phenytoin
Gentamicin

Question 13

Drug synergism

Answer 13

1. Additive effect: A+B=AB
2. Supraadditive effect: A+B>AB
3. Potentiation effect