Session 11 - Pharmacokinetics 02 Flashcards
What is the role of drug metabolism?
- Metabolism mainly take place in the liver via phase 1 and 2 enzymes
- Metabolise drugs by increasing their ionic charge and enhancing renal elimination
- Once metabolised - drugs are usually (not in all cases like prodrugs) incativated
Give an example of a drug that is infact activated when metabolised by phase 1 and 2 enzymes
- Codeine is infact activated when metabolised as it is converted to morphine. This is why codeine’s effect can vary so much as it depends on the variable expression of cytochrome P450s (CYP2D6 polymorphism)
What occurs during drug metabolism by phase 1 enzymes?
- Phase 1 enzymes are cytochrome P450s (CYP450s)
- CYP450s are “versatile generalists” they are not very specific enzymes with a low affinity but large capacity as there are so many
- Metabolised drugs eliminated directly or go to phase 2
- Catalyse redox, dealkylation, hydroxylation reactions
- increase ionic charge
What occurs during phase 2 drug metabolism?
- This is carries out by hepatic enzymes
- They are still generalists but exhibit more rapid kinetics then CYP450s
- Further increase ionic charge
- enhances renal elimination
What are some of the main factors affecting drug metabolism? (mnemonic)
- Age
- Sex
- General health “HRH” Heart, Renal, Hepatic
- Also genetic factors which affect CYP450 expression
- Other drugs can induce/inhibit CYP450 action
What is CYP450 induction and give an example of a drug that does this.
- This is where administration of a drug can induce the action of specific CYP450 isoenzyme by increasing transcription and translation or slower degradation. This means the enzyme has an increased rate of elimination and plasma levels will fall
- Such as carbamazepine (CBZ - an epileptic drug) that induces CYP3A4, which metabolises CBZ. This reduces CBZs own blood plasma levels and as such reduces it own potency
Give an example of CYP450 inhibition
- Grapefruit juice inhibits CYP3A4
- CYP3A4 metabolises Verapamil to treat high blood pressure
- as such Verapamil has reduces metabolism so is more potent and can reduce BP too far and cause fainting
CYP2D6 (activate codeine) is not expressed in 7% of Caucasians and hyperactive in 30% of east Africans what effect can this have?
If not expressed codeine will not be activated and they will not experience the pain relief.
On the other hand hyperactivity can result in too much morphine conversion and there is a rick of over dose (respiratory depression)
What is the main route of drug elimination?
- The kidney (other routes, bile, sweat, tears, genital secretion, saliva, breast milk - could be passed onto infant)
- This occurs in 3 processes:
- Glomerular filtration
- Active tubular secretion (OATs and OCTs)
- Passive tubular reabsorption (if drug metabolites are lipophilic they pass back into the blood)
Define clearance (Cl)
Formally defined as:
The volume of plasma that is completely cleared of the drug per unit time (measured in ml/min or ml.min^-1)
- Clearance is defined as the rate of elimination of a drug from the body.
Total body clearance = hepatic clearance + renal clearance
What is drug half life (t1/2)?
The amount of time over which the concentration of a drug in plasma decreases to 1/2 of that concentration
t1/2 = (0.693xVd)/Clearance
What is linear elimination kinetics?
- This is where a log[Plasma] vs time graph becomes linear (otherwise exponential in a normal plot)
- This only occurs is there is no rate limitation i.e. There are plenty enzymes and plenty OAT/OCT transporters. They are not saturated
What happens when elimination becomes saturated?
- The elimination kinetics follow ZERO ORDER kinetics. A standard plot is linear (not exponential).
- The removal process is not effected by [drug] the enzymes/carriers can’t function any faster
What is the clinical importance of zero order elimination kinetics?
If a drug starts to follow zero order kinetics the therapeutic response can suddenly escalate as the elimination mechanisms saturate.
If it followed first order elimination the effect would be la linear increase. As the rate of elimination would also increase.
This can occur with Alcohol if inordinate amounts are drank. Elimination would overload
Zero order kinetics occurs in relatively few drugs (at therapeutic doses). However, certain patients groups may be more at risk. Who are they?
- Elderly/infants - Renal and Hepatic function is reduced so elimination more easily saturated
- Polymorphism - If drugs are competing for the same elimination process the concentration of the drugs can rapidly build up.
- MDMA shows zero order kinetics
- Paracetamol shows zero order kinetics at very high doses.
