Drug distribution

Question 1

What is drug distribution?

Answer 1

Reversible transfer of a drug between the blood and the extravascular fluids and tissues of the body (fat, muscle, brain tissue)

Question 2

Factors that determine distribution

Answer 2

• Plasma protein binding
• Tissue perfusion
• Membrane characteristics

Question 3

Plasma protein binding

Answer 3

• Many drugs bind to proteins in plasma
• Only unbound drugs are active
• Binding is reversible

Question 4

Plasma protein binding can be changed by

Answer 4

• Renal failure
• Hypoalbuminaemia
• Pregnancy
• Other drugs
• Saturability of binding

Question 5

Membrane characteristics

Answer 5

• Blood-brain barrier

- Blood-testes/ovary barrier: lipid soluble drugs, actively transported

Question 6

Therapeutic range is characterised by…

Answer 6

• Volume of distribution
• Clearance
• Half life

Question 7

Volume of distribution

Answer 7

• Volume in which amount of drug would be uniformly distributed to produce observed concentration
• ## Higher the Vd, the greater the ability of the drug to diffuse to and through membranes

Question 8

Volume distribution, if whole body fluid, if just ECF, if highly protein bound or if sequestered extravascular lipid compartment

Answer 8

• Body fluid: 42L
• ECF, cannot penetrate cells: 12L
• Protein bound: 3L
• Extravascular lipid compartment: >40L

Question 9

Clearance

Answer 9

• Measure of elimination: Theoretical volume of fluid from which a drug is completely removed over a period of time.
• Measure in units of time (ml/min)

Question 10

Clearance depends on

Answer 10

• Concentration
• Urine flow rate for renal clearance
• Metabolism
• Biliary excretion for hepatic clearance

Question 11

Half life

Answer 11

• Time taken for the drug concentration in the blood to decline to half of the current value

Question 12

Half life depends on

Answer 12

• Volume of distribution
• Rate of clearance
• Kidneys and/or liver working
• Prolongation of the half-life will increase the toxicity of the drug for these reasons
• Links chemical properties of the drug and ability of the body to metabolise and excrete drugs

Question 13

Chronic administration

Answer 13

• Best way to get therapeutic benefit

- Plasma levels need to be stabilised after 4-5 half lives

Question 14

Drug elimination definition

Answer 14

• Removal of active drug and metabolites from the body
• Determines length of action of the drug
• 2 parts: drug metabolism -> liver. Drug excretion -> kidney but also biliary system, lung, milk

Question 15

3 mechanisms of excretion

Answer 15

• Glomerular filtration
• Passive tubular reabsorption
• Active tubular secretion

Question 16

Glomerular function

Answer 16

• GFR is how you measure renal function
• All unbound drugs will be filtered at the glorulus as long as not too large
• If you lower GFR, you lower excretion

Question 17

Passive tubular resorption

Answer 17

• Concentration gradient created to allow drug to move back through tubule into circulation
• Occurs in distal tubule
• Unionised drugs are resorbed

Question 18

Active tubular secretion

Answer 18

• Actively secreted into proximal tubule

- Important system for cationic and anionic drugs

Question 19

Biliary secretion

Answer 19

• Drugs can be passively or actively secreted into bile
• Many drugs are reabsorbed from bile into the circulation -> entero-hepatic circulation
• Continues until drug is metabolised in the liver or excreted by the kidneys
• Damage to liver may reduce the rates of conjugation and biliary secretion -> build up or reabsorption of drug with resultant toxicity