pharmacokinetics

Question 1

Define blood:gas partition coefficient (BGPC) and its’ significant in inhalational agents.

Answer 1

-The blood:gas partition coefficient is defined as the ratio of the amount of anaesthetic in blood and gas when the two phases are of equal volume and pressure and in equilibrium at 37°C.(2)
-BGPC indicate the solubility (0.5) of inhalational agent.
-The onset is inversely related to BGPC. (0.5) Or The rate of increase of the PA toward the PI (maintained constant by mechanical ventilation of the lungs) is inversely related to the solubility of the anesthetic in blood.
-Based on their BGPC, inhaled anesthetics are categorized (0.5) traditionally as soluble, intermediately soluble, and poorly soluble.
-examples- BGPC halothane 2.46, Isoflurane 1.46, desflurane 0.42
-BGPC- Reduce by anaemia, extreme age, increase by heavy fat meal (0.5)

Question 2

what is prodrug

Answer 2

-A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized into a pharmacologically active drug. (×1.0)
-It’s designed to overcome the disadvantages of pharmacological properties of active compound. (x0.5)
-Examples: ×0.5 per examples
Paracoxib and valdecoxib, tramadol and 0-desmethyl-tramadol, Plavix and 2-Oxoclapidogrel, fospropofol and propofol, cortisone and hydrocortisone, methyldopa and methylnoradrenaline, enalapril and enalaprilat, codeine and morphine, SN/GTN and nitric oxide

Question 3

Discuss the advantages and disadvantages of prodrug.

Answer 3

Advantages: (2.5)
-Increase bioavailability by avoid 1st pass metabolism
-Reduce toxicity (eg paracoxib)
-Facilitate administration (fospropofol, GTN/SNP)
-Increase delivery of drug to site of action
-Increase duration of action

Disadvantages: (1.5)
-slower onset
-Variable effect in genetic polymorphism of drug metabolism, eg CYP2D6 deficiency with reduce tramadol effect, CYP2D19 deficiency has increase thrombo-embolic event when use clopidogrel in IHD
-Effect of drugs may be affected by enzyme inducer or inhibitor when given with together with other drugs.

Question 4

With aid of diagram explain the pharmacodynamic interaction between drugs with example.

Answer 4

-Isobologram. (×1)
-Additive = combine effect = simple addition = 1+1 =2 (×1) (N20 + sevoflurane)
-Synergism = combine effect > simple addition = 1+1 = >2 (×1) (Remifentanil + Propofol)
-Antagonism = combine effect < simple addition = 1+1 < 2 (×1) (morphine + naloxone)
-Potentiation: drug effect augmented by another drug which has no effect on its own (0+1 >1) clavulanic acid with ampicillin, piperacillin with tazobactam

Question 5

hepatic metabolism

Answer 5

-Hepatic metabolism of drugs is influenced by -the saturability (i.e. capacity)
of the metabolizing enzymes
-and the delivery of the drug to the hepatocyte (hepatic blood flow).

• The rate of hepatic metabolism is referred to as the hepatic extraction ratio (ER).
• Metabolizing enzymes with a high Michaelis constant
  (the concentration of substrate at which the enzyme is working at 50% maximum rate) have a high capacity for metabolizing the drug, thus the hepatic ER will
  be influenced by the delivery of the drug to the liver in the hepatic blood flow.

-The metabolism of these drugs is therefore ‘flow dependent’.

-Flow-dependent drug metabolism (with high hepatic ER) is seen with propranolol, propofol, tricyclic antidepressants, opioids and lignocaine.

-Metabolizing enzymes with a low Michaelis constant have a low capacity for drug metabolism, resulting in a low hepatic ER.

-Any increase in the free unbound fraction of the drug reaching the hepatocyte will readily saturate the enzyme system.

-This has clinical implications if the drug is highly protein-bound (where
a small change in protein binding results in a largely proportional increase in
free drug) and if the drug has a low therapeutic window.

-The metabolism of these drugs is therefore ‘capacity limited’. Capacity-limited drug metabolism is seen with phenytoin, warfarin, barbiturates, NSAIDs and benzodiazepine

Question 6

list drugs can be removed by hemodialysis

Answer 6

SNP
Penicillin
ethanol,
methanol,
aspirin,
lithium,
barbiturates,
gentamicin
cephalosporins
ethylene glycol.

Question 7

List drugs not removed by dialysis

Answer 7

digoxin,
tricyclic antidepressants,
β-blockers,
sulphonylureas
phenytoin
morphine