Pharmacokinetics : Drug distribution, metabolism & excretion

Question 1

What does distribution mean? (3)

Answer 1

The movement of a drug from the bloodstream to tissues & organs
Allows drug to reach “target tissue”
Main distribution fluid: blood (plasma)

Question 2

What are the body fluid compartments? (5)

Answer 2

Intracellular fluid

Extracellular fluid
- interstitial fluid
- plasma
- transcellular fluid

Question 3

How does distribution occur? (3)

Answer 3

Distribution around the body occurs when the drug reaches the circulation
Must then penetrate tissues to act
Drugs that are sufficiently lipid soluble to be readily absorbed orally are rapidly distributed throughout the body water compartments

Question 4

How are lipid soluble, highly ionised and high protein bound drugs distributed? (3)

Answer 4

Lipid soluble drugs enter cells
Highly ionised drugs are confined to ECF
Drugs that are highly protein bound or have a high molecular weight are retained in circulation

Question 5

What are free drugs? (2)

Answer 5

Drugs not bound to plasma proteins

Move from bloodstream into tissues quickly

Question 6

What are protein bound drugs?
Where are they confined to?
(3)

Answer 6

Many drugs are loosely bound to a plasma protein called albumen.
Confined to the vascular system
An equilibrium forms between the protein bound and free drug

Question 7

Which factors affect distribution (4)

Answer 7

Factors affecting distribution:

• diseases which affect protein levels
• competition between different drugs
• natural barriers e.g. blood brain barrier
• tissue perfusion

Question 8

Give 4 natural barriers to distribution

Answer 8

Capillaries and cell membranes
Blood-brain barrier
Blood-placenta barrier
Blood-retina barrier

Question 9

Explain the Blood-brain barrier (5)

Answer 9

Lack pores, capillary cells tightly joined to each other.
Covered with lipid sheaths
Allows some lipid-soluble drugs to pass across
Prevents/reduces water-soluble drugs crossing
Highly protein-bound drugs penetrate slowly.

Question 10

Explain the blood-placenta barrier (4)

Answer 10

Dam and foetus blood vessels separated by several dense layers of tissue
Few pores
Only allows selective transportation
Small and lipophilic molecules pass across

Question 11

Where does metaboliosm occur?
What are two important effects?
What are two types of reactions?

Answer 11

The liver is the main organ of drug metabolism

2 important effects
- drug is made more hydrophilic
- metabolites are usually less active

2 types of reactions
- phase I & phase II

Question 12

What is a Phase I reaction (4)

Answer 12

Biotransformation of a drug to a more polar metabolite
Oxidation (catalysed by the cytochrome P450 enzymes)
Reduction
Hydrolysis

Question 13

What are Cytochrome P450 enzymes (CYP450)?

Answer 13

substrate specificity of this enzyme complex is very low, and many different drugs can be oxidised (oxidase)
Numerous isoforms of P-450 exist
About 6 isoforms account for most hepatic drug metabolism
Can be induced / inhibited by drugs

Question 14

Different types of conjugation (transferases) (6)

Answer 14

• glucuronide, acetyl, glutathione, glycine, sulphate, methyl

Question 15

What are phase II reactions?

Answer 15

made more hydrophilic by conjugation with endogenous compounds in the liver.
The resulting conjugates are almost always less active.
Different types of conjugation (transferases)

Toxic metabolites ! Paracetamol toxicity in cats.

Question 16

What factors affect drug metabolism? (6)

Answer 16

Enzyme induction
Enzyme inhibition
Genetics
Age
Species variation
Health status – liver disease

Question 17

What is the process of excretion? (4)

Answer 17

Renal excretion into urine (elimination of most drugs)
Biliary excretion into intestines (enterohepatic circulation)
Volatile agents may be excreted through lungs
Via skin, saliva, mammary glands (small amounts)

Question 18

Explain renal excretion (4)

Answer 18

Hydrophilic, ionised metabolites excreted easily in urine
Small, non-protein bound drugs filtered through glomerulus
Larger protein bound molecules secreted into tubules via a carriers
Glomerular filtration rate can affect drug elimination

Question 19

Explain what is meant by the rate of drug elimination (5)

Answer 19

Fall in plasma concentration with time
Follows exponential curve
A constant fraction of the drug present is eliminated per unit time
(e.g. 2% of the drug present is eliminated in 1 minute)
Rate of elimination is proportional to the amount of drug remaining
First order elimination kinetics

Question 20

Explain the concept of Drug Half-Life (4)

Answer 20

Time taken for the concentration of a drug in the bloodstream to fall by HALF its value
Drugs with very short half-lives don’t maintain their therapeutic effect for long
Determines when repeat dosing required
Can range from minutes to hours to days

Question 21

Explain the concept of drug clearance (4)

Answer 21

the volume of blood or plasma cleared of a drug in unit time.
It is clearance, not the half-life of a drug, that provides an indication of the ability of the liver and kidney to dispose of the drugs.
Measured in L/hr or ml/min
Can be used to plan dosing regimens