Session 9

Question 0

Define the term oral bioavailability

Answer 0

Oral bioavailability - the proportion of a dose given orally that reaches the systemic circulation in an unchanged form.
Can be expressed as amount or rate.
Amount - measured by area under curve of. Look drug level vs. time plot
Rate - measured by peak height and rate of rise of drug level in blood

Question 1

Describe the principles of drug formulation and administration, including use of different sites of administration

Answer 1

Formulation - solid (tablets), liquid - compliance
Administration - focal (eye, skin, inhalation), systemic enteral (sublingual, oral, rectal), systemic parenteral (IV, IM, SC, inhalation, transdermal)

Question 2

Explain the therapeutic ratio

Answer 2

Maximum tolerated dose/minimum effective dose

LD50 (lethal dose to 50% people)/ED50 (effective dose in 50% people)

Question 3

Describe the first pass effect

Answer 3

Substances absorbed from the lumen of the ileum enter the venous blood which drains into the hepatic portal vein and is transported directly to the liver. The liver is the main site of drug metabolism as it contains all the necessary enzymes, so any drug may be extensively metabolised during this first pass through the liver. The parenteral, sublingual and rectal routes avoid it.

Question 4

Explain drug distribution

Answer 4

Drug distribution - the theoretical volume into which a drug has distributed assuming that this is occurring instantaneously
Amount given/plasma concentration (at time 0)
It is the free level of the drug that exerts an effect

Question 5

Explain protein binding interactions

Answer 5

Object Drug (class I) - used at a dose much lower than the number of albumin binding sites
Precipitate Drug (class II) - used at a dose much higher than the number of albumin binding sites 
When the drugs are administered simultaneously, class I drugs are displaced by class II drugs, raising the free level of object drugs and increasing risk of toxicity. 
E.g. Warfarin (object) vs. Sulphonamides/Aspirin (precipitate)

Question 6

Discuss first and zero order kinetics

Answer 6

First order - drug is used at concentration lower than Km, metabolism is proportional to drug concentration, straight line (log vs time), half life can be defined, predictable therapeutic response
Zero order - drug is used at concentration greater than Km, enzyme is saturated, rate of decline of plasma drug level is constant regardless of concentration, straight line (plasma conc vs time), therapeutic response can suddenly escalate
During drug administration, a steady state will be reached within 5 half-lives of that drug. If an immediate effect is required, a loading dose is necessary.

Question 7

Discuss the metabolism of drugs by the liver

Answer 7

Phase 1 - reactive group exposed or added (oxidation, reduction, hydrolysis), requires the cytochrome P450 enzyme system and NADPH, enzymes are inducible and inhibitable
Phase 2 - reactive group conjugated with a water soluble molecule (glucoronic acid, glutathione sulphate ions) to form a water soluble complex, requires specific enzymes and a high energy cofactor (UDPGA)

Question 8

Discuss the excretion of drugs by the kidneys

Answer 8

Only the free unbound drug is filtered through the glomerular tuft, drugs can be actively secreted by the tubule, urine pH can determine how much of the drug is excreted.
For weak acids (aspirin), making the urine alkaline will make the drug ionised –> less tubular absorption (charged drugs stay in lumen)
For weak bases (amphetamine), making the urine acidic will make the drug ionised –> less tubular absorption