Session 2- PK and PD

Question 1

Why is digoxin given as a loading dose then a maintenance dose?

Answer 1

Has a half life of 40hrs - to get to a steady state would take a week and the drug is often given in emergency scenarios.

Question 2

How would prescription of digoxin change in those with renal failure?

Answer 2

Digoxin is secreted by the kidneys.
Loading dose would stay the same.
Maintenance dose will need to be reduced.

Question 3

Describe metabolisms of paracetamol in overdose:

Answer 3

Paracetamol is normally metabolised 90% direct to the phase II pathway and 10% via phase I.
In overdose the conjugation of paracetamol with glucuronide and sulfate becomes saturated. This means that the phase I pathway becomes used.
The phase I pathway produces a harmful metabolite NAPQI. This then leads to the depleted of glutathione and the liver is subject to oxidative damage.

Question 4

How would yo go about managing paracetamol overdose?

Answer 4

Take a timed paracetamol and plot on the chart. If above the line N-acetyl cysteine treatment is advise. If timing of ingestion is unknown or staggered then N-Acetyl cysteine is indicated.

Question 5

How would you calculate the loading dose?

Answer 5

Loading dose = Volume of distribution x target [drug]
Example:

Phenytoin = 0.7L per kg body weight

100kg man

Vd = 70L

Cpss = plamsa concentration at steady state
Cpss phenytoin = 20mg/L

70L x 20mg/L = 1400mg or 1.4g

Question 6

What is the elimination constant and how is it calculated?

Answer 6

The slope of the curve (plasma concentration vs time)
Calculation =
k = clearance/volume of distribution

Question 7

How could you calculate half life from k?

Answer 7

Half life = log(0.5)/k

Question 8

Define affinity:

Answer 8

The tendency of a drug to bind to a specific receptor type.

Question 9

How do we measure affinity?

Answer 9

Kd is the disassociation constant the lower the value the higher the affinity . Kd is the concentration required to fill half the available receptors.

Question 10

Define efficacy:

Answer 10

The ability of a drug to produce a response as a result of the receptor or receptors being occupied - describes the maximum effect of a drug.

Question 11

Define potency:

Answer 11

Dose required to produce the desired biological response - e.g. describes the different doses of two drugs required to exert the same effect. Measure of both affinity and efficacy.

Question 12

What are common enzymes inducers?

Answer 12

Phenytoin
Carbamazepine 
Barbiturates
Rifampicin
Alcohol (chronic)
Sulphonylureas and St. Johns Wort

Question 13

What are common enzyme inhibitors?

Answer 13

Omeprazole
Disulfiram
Erythromycin
Valporate
Isoniazid
Cimetidine/ciprofloxacin
Ethanaol (acute)
Sulphonamides 

Grapefruit juice!
Cranberry juice!

Question 14

Describe the different classes of ADR’s:

Answer 14

Augmented pharmacological effects - usually dose related - know to occur from pharmacology of the drug e.g. hypoglycaemia from Insulin.
Bizarre effects - unpredictable yet uncommon e.g. anaphylaxis in penicillin
Chronic effects - adverse effects that only occur after prolonged exposure e.g. iatrogenic Cushing’s with prednisolone, colonic dysfunction with laxatives.
Delayed effects - adverse effects that occur remote from treatment either in children of patients or patients themselves. E.g. 2ndry cancers in those treated with alkylating agents in Hodgkins.
End of treatment effects - effects that occur when a drug is suddenly stopped - unstable angina after B antagonists suddenly stopped.

Question 15

What factors increase the risk of ADR’s occurring?

Answer 15

Ignorant, inappropriate or reckless prescribing.
Polypharmacy
Patients at extremes of age (renal and hepatic) or co-morbidities.
Multiple medical problems
Use of drugs with narrow therapeutic indexes.