Two-compartment model and zero-order kinetics

Question 1

Kinetics of may drug is more accurately fit using ?

Answer 1

A two-compartment

Question 2

Assumes two compartments:

Answer 2

Central (plasma) and peripheral (tissues, fat etc.)

Question 3

Why does Cp initially drop quickly ?

Answer 3

Due to distribution into tissues

Question 4

This is followed by a slower decrease in Cp due ?

Answer 4

Due to elimination

Question 5

What does the two-compartment model assume?

Answer 5

That after administered into the central compartment, drug distributes between the central and the peripheral compartment

Question 6

At a time interval a distribution equilibrium ?

Answer 6

Is achieved and elimination of the drug occurs from the central compartment

Question 7

Central compartment =

Answer 7

Highly perfused (high blood flow) tissues, e.g. heart, lungs, kidney, liver and brain

Question 8

Peripheral compartment =

Answer 8

Poor blood flow tissues, e.g. muscle, fat and skin

Question 9

Decrease in Cp occurs in two phases:

Answer 9

1. Fast phase (α) - distribution to peripheral compartment

2. Slow phase (β) - elimination by excretion and metabolism

Question 10

Some drugs, such as ethanol and phenytoin, do not show?

Answer 10

Exponential decrease in Cp

Question 11

Decrease in Cp is ? what is this called ?

Answer 11

Linear. Called zero order or saturating kinetics

Question 12

How is alcohol mainly eliminated by ?

Answer 12

Metabolism

Question 13

What is the first step ?

Answer 13

Oxidation to aldehyde by alcohol dehydrogenase (ADH)

Question 14

Ethanol + NAD+ ⇌

Answer 14

Acetaldehyde + NADH + H+

Question 15

ADH enzyme has ?

Answer 15

A very low Km

Question 16

Why do we need to understand dose-response relationships ?

Answer 16

1. Deduce mechanism of drug actions:
   - Dose response curves can help us deduce whether a drug acts on a particular receptor and whether it is competitive or non-competitive antagonist or neither
2. Determination of dosage:
   - Help to determine the appropriate dose of a given that produces the desired therapeutic effect while limiting harmful side effects
3. Facilitate therapeutic choices:
   - Understanding of efficacy and potency enable better choices of therapeutic agents

Question 17

What is potency ?

Answer 17

This is a measure of the amount or concentration of a drug required to produce a response and can be determined by a drug’s EC50

Question 18

What makes a drug more potent ?

Answer 18

Drugs that are able to produce responses at lower doses than others are said to be more potent

Question 19

What is Efficacy ?

Answer 19

This is a measure of the maximum effect a drug can produce, it can thus be determined by a drug’s Emax

Question 20

A drug with a higher Emax is thus said to ?

Answer 20

Be more efficacious

Question 21

Explain Quantal dose-response relationships ?

Answer 21

• All or none dose response
• Commonly used for assessing safety (therapeutic index)
• E.g. Effectiveness of an oral contraceptive, percentage of rodent death at a given dose of phenorbarbitone

Question 22

What is meant by ED50 ?

Answer 22

The dose of a drug that produces an effect in 50% of the test population

Question 23

What are some examples of drugs with narrow therapeutic index ?

Answer 23

• Digoxin (1.0-2.0μg/L)
• Theophylline (10-20mg/L)
• Phenytoin (10-20mg/L)
• Lithium (0.4-1.0mmol/L)
• Aminoglycosides such as Gentamicin
• Warfarin
• Etc…