drug distribution

Question 1

Discuss factors that determine bioavailability.

Answer 1

-Volume of distribution: The volume of plasma which the drug would need to be dissolved in plasma for it to be within therapeutic range. Should be 42L. The greater the Vd, the greater the ability of the drug to pass across membrane as more plasma is required to maintain the drug within the therapeutic range
-Half-life: Half the amount of time it takes the drug to leave the circulation t1/2= 0.639 Vd/Ci
-Clearance: Theoretical volume from which plasma is removed
-Chronic administration: dosage which allows effectiveness- usually equivalent to 4/5 half lives.
-Elimination:
metabolism in the liver
excretion in the kidneys and the bile duct

Question 2

Discuss factors that determine drug distribution.

Answer 2

Distribution: the reversible movement of an unchanged drug from the circulation to tissues and extra-vascular fluids.

• Protein binding: Only unbound drug can have any effect. Can be reversed during pregnancy, renal failure, using other drugs… only important when more than 90% of drug is bound.
• Tissue perfusion
• Drug properties e.g. lipophilic, ionised
• Membrane properties
• Disease
• Tissue mechanism

Question 3

Discuss the importance of selective accumulation and physiological barriers to distribution.

Answer 3

Chronic administration:
-In order for maximal effect, the drug must be administered usually 4-5 times its half-life.
-Allows therapeutic range to be achieved i.e. range at which drug has maximal efficacy.
Conjugation:
-cannot be reabsorbed from intestine- can lead to drug toxicity

Question 4

Discuss the mechanism of renal drug excretion and the relevance to renal disease states.

Answer 4

Excretion: removal of drug via the kidneys and bile duct.
Glomerular filtration:
-The glomerulus filter about 190litres of blood a day.
-They filter the unbound drugs- unless too big, odd charge
Active tubular secretion :
-eliminates anionic and catatonic protein-bound drugs
Passive tubular reabsorption:
-prevents the build up of drugs in the renal tubule
-passive diffusion réabsorbes it back into circulation
-only filters un-ionised drugs.

Bile secretion:

• Some drugs can be eliminated through bile.
• Drugs can then be reabsorbed through bile into circulation-enters-hepatic circulation
• Metabolised by liver

Question 5

what is drug metabolism and what does it cause.

Answer 5

Drug metabolism: the biochemical modification of drugs through enzymatic activity:

• makes lipid-soluble molecules- water soluble and non-polar so they can be excreted
• deactivates drugs
• activates prodrugs
• produces toxic metabolites: Direct, teratogenesis, carcinogenesis.

Question 6

Describe the process of metabolism:

Answer 6

Phase 1:

• Drugs are made polar through attachment or insertion of an endogenous particle.
• oxidation/reduction/hydrolysis
• Allows active site for phase 2
• cytochrome P-450 enzymes are the largest family of enzymes involved in metabolism

Phase 2: GLUCORONIDATION
-conjugation: process by which lipid-soluble molecule are made water-soluble.

Question 7

What affects metabolism

Answer 7

Induction:enzyme activity is increased- metabolism increases-effect of drug decreases
-Inhibition: enzyme activity is decreased- metabolism decreases- potential toxicity
-Age:
children- unable to produce enzymes and have reduced renal activity- metabolism in puberty is greater than in adults
elderly- chronic disease(multiple drug therapy) and reduce liver weight
-Sex- pregnancy hormones
-Ethnicity
-enzyme polymorphism:
70 common nucleotide polymorphisms of enzymes (poor metabolisers, intermediate metabolisers, extensive metabolisers, ultra rapid metabolisers)

Question 8

where are drugs secreted into in active tubular secretion

Answer 8

proximal tubule

Question 9

where does passive tubular reabsorption occur?

Answer 9

In the distal tubule and collecting duct

Question 10

where is bile secreted and how much is secreted per day

Answer 10

Liver

1 litre

Question 11

Phase 1 metabolism

Answer 11

CYP3A4 - in liver and gut- diazepam, methadone
CYP2D6- antidepressants/antipsycotics/ codeine to morphine.
5-10% of population has reduced expression- immune
Cigarette smoke is an inducer
Shows 70 different nucleotide polymorphisms- poor,intermediate, extensive and ultra rapid metabolisers
CYP1A2- theophylline- induced by smoking

Question 12

CYP2C9

Answer 12

metabolises around 16 known drugs
Including Warfarin
Presents about 8 allelic variants- all non-functional proteins