Pharmacokinetics

Question 1

What is first pass metabolism?

Answer 1

Oral drugs are absorbed in the gut (mainly small intestine) and transported to the liver via the portal system.
- they are metabolised in the liver but also at the gut wall

Question 2

What are the two types of metabolic reactions in the liver

Answer 2

Phase 1 reactions

Phase 2 reactions

Question 3

What are phase 1 reactions?

Answer 3

Oxidation via CYP450

reduction and hydrolysis

Question 4

What are phase 2 reactions?

Answer 4

Conjugation of drug or its phase 1 metabolite

• glucuronidation is most important reaction
• drugs that are predominantly metabolised via phase 2 reactions include Lorazepam, Diazepam

Question 5

What is the purpose of drug metabolisation?

Answer 5

1. Makes drugs more polar so they can be excreted in the urine
2. Activates pro-drugs

Question 6

What is enzymes induction and what effect does it have?

Answer 6

Some drugs induce the action of CYP450 enzymes, increasing their activity. This occurs either by binding to the enzyme or increasing the expression of the gene coding for the enzyme.

• increased metabolism of active drug so reduced therapeutic effect
• increased metabolism of prodrug so toxicity develops

Question 7

Name some common enzyme inducers?

Answer 7

Carbamazepine - 3A4
Phenytoin - 3A4 and C19
Barbiturates
ETOH - 2E1
Rifampicin - many including 3A4
St John's Wort - 3A4

Question 8

What is enzyme inhibition and what effect does it have?

Answer 8

Some drugs reduce the action of CYP450 enzymes causing decreased metabolism

• reduced therapeutic effect of prodrugs
• toxicity of active drugs

Question 9

Define half life

Answer 9

the time taken for the concentration of a drug to fall by half its original value

Question 10

What is T1/2 important for calculating?

Answer 10

Dosing interval

T1/2 = Vd x 0.693 / Cl

A long T1/2 can be due to a high Vd or low clearance rate

Question 11

Define clearance

Answer 11

The volume of plasma cleared of a drug in a unit time

• units are always volume/time e.g. ml/min or L/hr
• Cl = Clm (metabolic/liver) + Clr (renal)

Question 12

What is clearance important for when it comes to drug dosing?

Answer 12

Calculating the maintenance dose (elimination rate)
elimation rate (at steady state) = Cl x Cp
Cp (plasma conc)

Question 13

How do you calculate clearance?

Answer 13

Cl = F x dose / AUC

F = bioavailability

Question 14

How can you calculate AUC for a drug?

Answer 14

Knowing two T1/2 of the drug you can draw a graph and use the trapezoid method

Question 15

What is steady state and why is it important?

Answer 15

5 x T1/2

therapeutic drug monitoring must be done at steady state

Question 16

What are the feature of renal clearance of a drug?

Answer 16

= filtration + secretion - reabsorption

• Drug must be water soluble (polar)
• Only free drug (not protein bound) can be excreted
• competitive transporters
• saturable transporters

Question 17

What components are important for hepatic clearance?

Answer 17

HC = HBF x ER

HBF = hepatic blood flow
- decreases with age and cirrhosis
ER - extraction ratio

Question 18

What effect does cirrhosis have on drug pharmacokinetics?

Answer 18

Drug bypasses first pass metabolism due to portal shunting via collaterals
- results in increased bioavailability

Question 19

Define volume of distribution

Answer 19

the apparent volume into which the drug is distributed

- 15L suggests the drug distributes through the total body water - often lipophilic

Question 20

Why is Vd important?

Answer 20

Loading dose is required if there is a large Vd in order to get plasma concentration into therapeutic range quickly

Question 21

Name some important enzyme inhibitors

Answer 21

SSRIs - CYP2D6 (metabolises Tamoxifen to active metabolite)
Omeprazole - CYP2C19 (metabolises Clopidogrel to active metabolite)
Macrolide’s, azaleas, protease inhibitors
- in combination with statins cause increased levels and rhabdo
- increase levels of Tacrolimus/Cyclosporin leading to toxicity

Question 22

Define bioavailability (F)

Answer 22

the proportion of administered drug reaching the systemic circulation

• IV drugs F = 100%
• drugs with high first pass metabolism have low F, e.g. insulin

Question 23

How do you caculate bioavailability (F)?

Answer 23

F = 100 x AUC po x Dose IV / AUC IV = Dose po

Question 24

Define zero order (non-linear) kinetics and give examples.

Answer 24

rate of elimination of the drug is constant and unaffected by the plasma concentration

• ethanol
• phenytoin
• salicylates

Question 25

Why are zero order kinetics important?

Answer 25

• ## when any enzyme system responsible for metabolising a drug is saturated, the elimination kinetics of that drug will change from 1st to 0 order kinetics

Question 26

What is 1st order (linear) kinetics?

Answer 26

the rate of drug elimination is proportional to the plasma concentration
- 95% of drugs follow 1st order kinetics at therapeutic levels

Question 27

What is the action of P-glycoprotein?

Answer 27

transmembrane efflux transporters (active transport system)

Protects body from harmful substances by:

1. Removing drugs absorbed in the intestines back into the gut lumen.
2. Maintaining the integrity of the blood brain barrier.
3. Removing drugs from the kidneys and liver into the urine and bile respectively.

Question 28

What are the clinical implications of P-glycoprotein and drugs?

Answer 28

• reason for multi drug resistance in cancer cells
• partly responsible for the clearance of medicines via the renal and hepatic systems
• the system is saturable and can be inhibited or induced. This can lead to drug interactions

Question 29

What are the drug substrates for P-glycoprotein?

Answer 29

Digoxin
Loperamide
Colchicine
Dabigatran

Question 30

What drugs are inducers of P-glycoprotein?

Answer 30

Phenytoin
Rifampicin
Carbamazepine
St John’s Wort

Question 31

What drugs inhibit P-glycoprotein?

Answer 31

Amiodarone
Ketakonazole/Itrakonazole
Erythrmoycin/Clarithromycin
Ciclosporin
Verapamil
Diltiazem
Quinidine
Protease inhibitors
Tacrolimus/Sirolimus
Grapefruit juice

Question 32

Name some important P-glycoprotein mediated drug interactions

Answer 32

P-glycoprotein interactions do not routinely change plasma concentrations nearly as much as CYP450 interactions
- Digoxin metabolism inhibited by Verapamil, Amiodarone, Quinidine, Ciclosporin -> toxicity

note Dabigatran etexilate (pro-drug) is a substrate for P-glycoprotein but not Dabigatran therefore if co-administered with a portent P-glycoprotein inhibitor, will get reduced plasma conc of active drug. This is only relevant to the component of Dabigatran metabolised at the gut wall by P-glycoprotein (not at the liver by liver esterases) so real life interactions are variable.