CB - Distribution and Metabolism

Question 1

What is the blood brain barrier’s function? (2)

Answer 1

Homeostatic mechanism allowing a constant CNS environment

Brain is not exposed to polar components in the plasma

Question 2

What is the structure of the BBB? (3)

Answer 2

• Small membrane pores
• Tight junctions between cells
• Active transporters
  (IN - essential nutrients, OUT - waste products)

Question 3

What is more absorbed, lipid soluble or water soluble?

Answer 3

Lipid Soluble

Question 4

What is Parkinson’s disease caused by and why can it not be easily resolved?

Answer 4

Caused by a decrease of dopamine in the substantia nigra

Cannot add dopamine in the patient as:

• Dopamine is a very polar molecule and so cannot cross the BBB

Question 5

What is a method to treat Parkinson’s?

Answer 5

Give LEVODOPA (precursor of dopamine)

• Can be transported through the BBB via Amino acid cotransport

LEVODOPA (plasma) →BBB→ LEVODOPA (brain)

Question 6

What enzyme converts Levodopa to Dopamine in the plasma and brain?

Answer 6

Dopa decarboxylase

Question 7

What are some issues caused by dopa decarboxylase and how are they prevented?

Answer 7

A build-up of DOPAMINE in the plasma will have unwanted side effects

• A high dose of LEVODOPA is needed

A drug called CARBIDOPA cannot cross the BBB (too polar) and Inhibits DOPA decarboxylase

Question 8

What are the differences between RATE and EXTENT?

Answer 8

RATE - Time taken between dosing and equilibrium of plasma:tissues

EXTENT - Ratio of drug in tissues compared to plasma at equilibrium

Question 9

Where is the [DRUG] during injection, equilibrium and post-equilibrium?

Answer 9

At injection, [DRUG] is high in blood

At Equilibrium, [DRUG] is even in both blood and tissue

At post-equilibrium, [DRUG] moves back to blood and is eliminated

Question 10

What does the rate of distribution depend on? (2)

Answer 10

1. Diffusion rate of drug across membranes
2. Perfusion rate of tissues that take up the drug

Question 11

What are factors affecting RATE (2) and EXTENT (2) of drug distribution?

Answer 11

RATE

• Rate of partitioning into tissues
• Organ blood flow (affected by cardiac output)

EXTENT

• Plasma protein binding
• Tissue composition of body

Question 12

What does ELIMINATION of a drug involve?

Answer 12

Removal of the drug from the body and involves:

Metabolism

• Drug is transformed into a different molecule

Excretion

• Drug molecules is expelled in the body’s liquid, solid or gaseous waste

Question 13

What are 3 features of drug metabolism?

Answer 13

1. Required for the elimination of lipid-soluble drugs
2. Allows a lipid-soluble drug to be converted to a water-soluble molecule
3. Water-soluble molecules are much more readily eliminated from the body in the urine

Question 14

What are the 2 phases of drug metabolism?

Answer 14

PHASE 1 - oxidation , reduction, hydrolysis

• Introduces a functional side group into the drug molecule that serves as a site for the PHASE 2 metabolism

PHASE 2 - conjugation reactions

• Formation of covalent bonds between the PHASE 1 metabolite and an endogenous substrate

e.g. BENZENE (lipid soluble) —> PHENOL (lipid soluble) —> PHENYL SULPHATE (water soluble)