Pharmacokinetics 4

Question 1

Phenytoin is a liver enzyme (cytochrome P450) inducer. what is an emzyme inducer?

Answer 1

1) An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme
2) therefore, significant interactions with other drugs e.g. OCs

Question 2

name some drugs used to treat Seizures

Answer 2

‘old style’ e.g.
1) phenytoin
2) carbamazepine
3) sodium valproate / valproic acid
‘new style’ e.g.
4) gabapentin,

Question 3

unlike most other drugs Phenytoin displays non-linear pharmacokinetics. explain why

Answer 3

non-linear behaviour is down to saturation.

1) does not follow the trend on the graph. as the dose goes up the plasma concentration does not go up in a linear pattern.
2) Cp rises sharply as the rate at which the body can clear phenytoin becomes saturated. the liver which is involved in phenytoins metabolism can only handle so much, eventually all the pathways dealing with it are saturated and so the drug goes straight into the blood stream and the plasma concentration of the drug just shoots up

Question 4

outline the distribution, metabolism and excretion of Phenytoin

Answer 4

1) Distribution: 90% protein binding; so highly protein bound
2) Metabolism: Significant metabolism by liver
3) excretion: Very little excreted unchanged

Question 5

what is Vmax and Km

Answer 5

1) Vmax: Cp rises sharply as the rate at which the body can clear phenytoin becomes saturated
2) Km: is the concentration of substrate which permits the enzyme to achieve half Vmax.

Question 6

what is the Michaelis-Menten equation for phenytoin?

Answer 6

1) Daily dose= Vmax x Cpˢˢ ÷ Km + Cpˢˢ (REMEMBER)

• Vmax comes from population data = 7mg/kg/day
• KM comes from population data = 5.7mg / L

Question 7

rearrange the Michaelis-Menten equation for phenytoin so you can work out the Cpˢˢ when given a dose.

Daily dose= Vmax x Cpˢˢ ÷ Km + Cpˢˢ (REMEMBER)

Answer 7

Cpˢˢ = Daily dose x Km ÷ Vmax - daily dose

Question 8

what is lithium used to treat and why is monitoring necessary?

Answer 8

1) Effective in acute mania, prophylaxis of manic depression
2) Very narrow therapeutic window. Important to determine effective levels for individuals, as these vary markedly from person to person
3) Toxic, dose-dependent side effects
blurred vision, drowsiness, confusion, palpipations
- Known teratogen

Question 9

what is lithium’s metabolism and excretion?

Answer 9

1) metabolism: none

2) excretion: Follows 1st order kinetics. Clearance approximates to 25% of creatinine clearance

Question 10

what is Theophylline used to treat and why is therapeutic motoring required?

Answer 10

1) therapy for respiratory diseases such as COPD and asthma. Less used now for COPD as longer-acting inhaled β-agonists are available
2) Narrow therapeutic index: Serious toxicity at > 20mg/L: arrhythmias / seizures, no warning signs!
- Significant inter-patient variability in p/kinetics
3) Therapeutic range 5-15mg/L

Question 11

what is the absorption, metabolism and excretion of Theophylline?

• Aminophylline- salt of Theophylline

Answer 11

1) absorptiopm: Oral bioavailability ~100% - Remember salt factor too (Aminophylline)
2) metabolism: Significant metabolism by liver; wide inter-patient variability;
3) excretion: <10% excreted unchanged
- REMEMBER: Overall, elimination is first order

Question 12

describe the clearance of Theophylline

Answer 12

1) Clearance variation with age and Clearance variation with some disease states
2) premature and full term babies clear it poorly but infants and kids clear it much better
3) adults clear it less well in comparison to infants and kids and the elderly clear it as poorly as babies.
- remember the graph will be a mountain shape

Question 13

the clearance of Theophylline varies with some disease states. For the following disease states, would they increase or decrease the clearance of theophylline?

1) Acute pulmonary oedema
2) Congestive heart failure
3) Liver cirrhosis
4) Mild smoking, Heavy smoking
5) Cystic fibrosis

Answer 13

1) Acute pulmonary oedema: decrease
2) Congestive heart failure: decrease
3) Liver cirrhosis: decrease
4) Mild smoking, Heavy smoking : increase and in heavy smoking a large increase
5) Cystic fibrosis : increase

Question 14

the clearance of Theophylline varies with some with some drug interactions. for the following drugs state if they increase or decrease the clearance of theophylline

1) Propranolol
2) Oral contraceptives
3) Cimetidine
4) Carbamazepine
5) Phenytoin
6) Rifampicin

Answer 14

1) Propranolol: Decreased
2) Oral contraceptives: Decreased
3) Cimetidine: Decreased
4) Carbamazepin: Increased
5) Phenytoin: Increased
6) Rfampicin: Increased