Pharmacokinetics 2

Question 1

Describe how it is easy to poison with digoxin.

Answer 1

Digoxin has a large Volume of Distribution (Vd)
Predominantly excreted by kidneys
Relatively long half life (as proportional to Vd) =40 hours
Thus 5 half lives to steady state will be > 1 week

Therefore:
- Needs loading doses to achieve a rapid therapeutic
effect
- Maintenance doses need reducing if renal failure is
present
- Loading dose can remain much the same in renal failure

So:
- If patient becomes digitoxic (bradycardia, xanthopsia,
vomiting….) (normally in old people)
- If normal GFR: 40 hours to reduces the [drug] to 50%
- BUT if renal failure is present, then clearance is
reduced - t1/2 will be increased and thus longer for
[drug] to return to therapeutic values

Question 2

What can be done if someone has become digitoxic?

Answer 2

Give an antidote

digiband

Question 3

Describe paracetamol poisoning.

Answer 3

90% of paracetamol is metabolised into sulphate (30%0 and glucuronide (60%)
The other 10% is metabolised via P450 oxidation into NAPQI (a highly toxic substance to the liver) which is then conjugated with glutathione to inactive metabolites cysteine/ mercapturic acid.

If too much paracetamol is taken then the sulphate and glucuronide pathways are saturated so more paracetamol gets oxidised into NAPQI
The conjugation of NAPQI then gets saturated, thus leading to toxic levels of NAPQI (not enough glutathione)

Question 4

What is the treatment of a paracetamol overdose?

Answer 4

Treatment is to replace glutathione i.e. N-acetylcysteine (Parvolex)

Question 5

What is the equation for working out the loading dose?

Answer 5

Loading dose = Vd x [drug]target

We get this from Vd =~ Dose/[Drug]t0

Question 6

How do we work out the elimination half-lives of drugs?

Answer 6

k=Ratio of clearance (Cl) / volume of distribution (Vd)

t1/2 = loge 0.5 / k
       = 0.693 / k
Therefore 
t1/2 is proportional to Vd
And
t1/2 is inversely proportional to Cl

Question 7

How do you account for someone with chronic kidney disease in working out the half life of a drug?
(With example)

Answer 7

Clearance = Renal function (GFR)
t1/2 = Vd / Clearance (GFR)

E.g.
- Assuming a half life of 4 hours with GFR of 90 (normal)
for a drug exclusively excreted by the kidneys
- The half life of this drug in a patient with CKD stage 3
and GFR of 45 would be 1/(1/2) = double. so 8 hours

Question 8

What is the multi compartment model?

Answer 8

Most drugs do not remain in one compartment (the plasma)
Therefore distribution occurs in 2 or
more ‘compartments’
The equilibrium between these compartments are not equal
Therefore rate of elimination can be different