Pharmacokinetics Flashcards
What is drug elimination and why does it occur?
The removal of a drug from the body - it is a term covering metabolism and excretion of the drug.
It occurs to maintain homeostasis within the body and as a protective function.
How do phase I and phase II enzymes increase the ionic charge?
Phase I modify existing functional groups, increasing the nett charge.
Phase II add charged molecules, increasing the nett charge.
What factors affect drug metabolism?
Age - paediatric and elderly both metabolise drugs at different rates.
Sex.
Liver, renal and heart function.
Other drugs - can induce or inhibit CYP450s.
Genetic variability.
How can genetic variability affect drug metabolism?
Polymorphism - there is a difference in ability between different people’s CYP450s to metabolise: they can be poor, intermediate, extensive or ultrarapid metabolisers.
Non-expression - certain groups of people cannot express certain CYP450s.
What is the time taken for induction and inhibition of CYP450s to occur, and what are some examples?
Induction typically takes around 1-2 weeks, through transcription and translation; such as carbamazepine.
Inhibition typically takes between one and a few days, through competitive and non-competitive inhibition; such as grapefruit juice.
Both affecting CYP3A4.
Give an example of a CYP450 that is not expressed in a certain population and what this means.
CYP2C19 is not expressed in 5% of Caucasians or 30% of Asians, which means that Valium or phenytoin cannot be metabolised properly.
This means that the concentration of these drugs may be much higher than expected and cause adverse drug reactions
CYP2D6 can display genetic polymorphism and acts on codeine, what may be the affects of different isoenzymes?
If it is a poor metaboliser, then codeine will be converted to morphine at a slower rate and so less pain relief will be experienced.
If it is an ultrarapid metaboliser, then codeine will be converted to morphine rapidly and they may experience morphine intoxication/ ADRs.
Outline the different routes of drug elimination.
Excretion via the kidney.
Or through:
- Exhalation.
- Saliva.
- Lacrimation.
- Breast milk - can affect the infant.
Outline the 3 processes of renal excretion.
Glomerular filtration - 20% of blood passes through and the drug can pass through fenestrated capillaries.
Active tubular secretion - 80% of the blood passes through and OATs and OCTs can use secondary active transport to transport the drug out of the proximal tubules.
Passive tubular reabsorption - only lipophilic drugs can be reabsorbed.
What is the definition of clearance?
The volume of plasma that is completely cleared of the drug per unit time.
What is the definition of drug half life?
The time taken for the concentration of the drug in plasma to half, from the time when it was first measured.
What is the difference between first and zero order kinetics?
First order: the rate of metabolism/ transport is proportional to the concentration of drug. This is because there is an excess of enzyme or transporter, and so by increasing the concentration, more enzymes/ transporters are becoming saturated.
Zero order: the rate at which metabolism/ transport is independent of the concentration, the rate does not change. This is because the transporters/ enzymes are saturated and increasing the concentration can not further saturate them.
When can zero order kinetics be seen clinically?
In the elderly with polypharmacy - multiple drugs are taking up the transporters/ enzymes and so they are limited.
Infants - the liver enzymes do not fully develop until they are around the age of 5, and so they are deficient at this age.
Those with reduced hepatic/ liver function - cancer or alcoholics.
Where are phase II enzymes mostly found in the liver?
In the cytosol of hepatocytes.
What is total body clearance made up of?
Hepatic clearance and renal clearance.
