Instructions : Do read up on these topics, then give yourselves 20 minutes to answer each question. It is very useful to be able to practice answering within a limited time period -- so that your answers are concise and you don't run out of time before answering all questions.
Bioavailability
a. What is bioavailablity and how is it measured? (4 marks)
b. What are the factors that influence bioavailability of an orally administered drug? (6 marks)
a.
Bioavailability – the fraction of administered dose that reaches the systemic circulation unchanged.
Bioavalability = fraction absorbed x (1 – extraction ratio)
b.
Uptake – depends on the unionised, lipid soluble portion moving down a concentration gradient.
Ficks law of diffusion
Diffusion rate is proportional to the area, but inversely proportional to the thickness.
Diffusion rate is proportional to concentration gradient.
Diffusion rate is proportional to the solubility of the drug in the tissue, but inversely proportional to the square root of the molecular weight.
Drug factors
1. Formulation & dissolution – particle size & form (liquid, solid, sustained release, enteric coated)
2. PKa & ionisation - changes that favour the presence of the drug in its nonionized (lipid soluble) form increase absorption. Weak acids (aspirin) become highly ionized in the alkaline environment of the small intestine, but absorption is still good due to the large SA.
3. Ability to resist degradation – stability at different pHs, chemical or microbiological contents of GIT
Patient factors – position, age, pregnancy, gender, size.
1. Surface area - principle site of absorption is the small intestine, due to large SA. ↓bowel resections/disease.
2. Blood flow to mucosa
3. Gastric motility - gastric emptying rate, intestinal motility + transit time – affected by food, drugs & disease
4. Effects of disease
5. Drug interactions in the GIT lumen – food interactions, complexation (tetracyclines with divalent metal cations)
6. Passage through the GIT wall – metabolism by enzymes in intestinal endothelium
7. Compliance
Carrier mediated – levodopa, iron, calcium
Systemic availability post uptake
First Pass Hepatic Effect – drugs absorbed from the GIT enter the portal venous blood and pass through the liver before entering the systemic circulation. Hepatic extraction & metabolism can greatly diminish the systemic effect (e.g. propranolol, lignocaine).
Clearance
a. Define clearance. (2 marks)
b. Describe the clearance of drugs by the kidney and the factors that influence renal clearance of drugs. (8 marks)
a.
Clearance – the volume of
plasma completely cleared of drug per unit time (L/hr or mL/min)
Clearance = rate of
elimination from plasma / plasma [drug]
b.
Renal Clearance = rate of elimination urine / plasma drug
concentration
= [urine] x urine volume
/ [plasma]
The kidneys are the most important organs
for elimination of unchanged drugs or metabolites.
Water soluble compounds are
excreted more efficiently than lipid soluble compounds. \metabolism to convert highly
lipid soluble compounds to water soluble metabolites is important.
Drugs eliminated by the
kidneys are correlated with endogenous creatinine clearance or serum creatinine
concentration. The increase in these indices allows for an estimate of dosage
reduction.
Renal excretion involves…
- Glomerular
filtration – depends on protein binding, water/lipid solubility &
glomerular filtration rate.
- Active
tubular secretion – involves selective active transport
processes. E.g. organic anions (PAH, urate, thiazides) & cations
(A/NA, creatinine, morphine, atropine, LA).
- Passive
tubular reabsorption – removes drugs from the lumen that has
entered by the above 2 methods. Most predominant in lipid soluble drugs
that can readily cross renal tubular cell membranes e.g. thiopental. Water
solubility facilitates excretion. Influenced by rate of urine flow &
pH (weak acids are excreted more rapidly in alkaline urine – more crosses,
is ionized & \less able to
be reabsorbed).
Context Sensitive Half Time
a. Define context sensitive half time. (2 marks)
b. Compare the CSHT of Propofol, Thiopentone, Fentanyl and Remifentanil. How does their CSHT differ and what are the factors that influence their CSHT? Illustrate and explain. (8 marks)
a.
Context-Sensitive
Half Time – the time necessary for the plasma drug concentration to decrease
by 50% after discontinuing a continuous infusion designed to maintain constant
plasma concentration
b.
Context sensitive t½ - is a
function of elimination t½ but also considers the combined effects of…
- Distribution - peripheral tissue uptake will
decrease with infusion duration as the tissues reach equilibrium with plasma
- Rate of equilibration between plasma &
effector site
- Elimination
- Duration of drug infusion
- Method of administration – bolus or infusion
Notes:
When drawing these diagrams - make sure some key-points are accurate
- propofol CSHT at 8 hours is 40 minutes
- fentanyl shoots up after 2 hours
- remifentanil remains at 4 minutes no matter how long the infusion time is
Thiopentone – highly protein bound & lipid soluble. Offset of action is by
redistribution to inactive tissue sites. Context sensitive t½ becomes prolonged
after »15mins due to return from peripheral
compartments on infusion cessation, which slows the rate of plasma
[thiopentone] decline. \poorly suitable for infusions. (t½ 11.6 hrs)
Propofol – rapid ESET
& short context sensitive T½. Context sensitive T½ - for infusions up to 8hrs <40mins. The
rapid metabolic clearance is so great that when infusions are ceased drug
returning from tissue storage sites is not able to retard the decrease in
plasma concentration. Excellent for infusions. (t½ 0.5-1.5hrs)
Fentanyl – fentanyl's context sensitive t½ is larger than other
(al/su/remi-fentanils) if continuous infusion occurs beyond 2hours. This
reflects large Vd, fat solubility & saturation of inactive
tissue sites & return of opioid from peripheral compartments on infusion
cessation, which slows the rate of plasma [fentanyl] decline. (t½ »3-6hrs).
Remifentanyl – ~4mins & independent of infusion duration because
of small Vd & extremely rapid clearance. (t½ 99.8% cleared in 6mins or
less). Ideal drug for infusions.
Alfentanyl – some accumulation occurs, but is more predictable than fentanyl
because it levels off at about 60mins after a 3+hr infusion \longer infusions make little difference. Vd is low & is not widely
distributed \less is required to produce an adequate
effective concentration, hence its rapid excretion. (t½ 96% cleared in 60mins).
With prolonged infusions the context
sensitive t½ approaches the elimination
t½.
