Pharmacokinetics in practice and pharmacogenomics

Question 1

First order kinetics

Answer 1

Rate of elimination is proportional to the plasma drug concentration (does not become saturated).

A constant % of the plasma drug is eliminated over a unit of time.

Question 2

Zero order kinetics

Answer 2

Rate of elimination is NOT proportional to the plasma drug concentration (metabolism processes become saturated).

A constant amount of plasma drug is eliminated over a unit of time.

Question 3

Cmax

Answer 3

Maximum plasma concentration

Question 4

Tmax

Answer 4

time taken to reach cmax

Question 5

Clearance (CL)

Answer 5

removal of drug by all eliminating organs

Question 6

Slower absorption

Answer 6

Increased tmax

Question 7

MR formulation caused less complete absorption from GI tract

Answer 7

reduced Cmax

Question 8

Modified release formulations usually require…

Answer 8

Less frequent dosing

Question 9

In IV drugs bioavailability is 100%

Answer 9

Therefore absorption and tmax are NOT relevant

Question 10

t1/2

Answer 10

Time taken for plasma drug concentration to fall 50%

Question 11

Half life t1/2 depends on

Answer 11

Clearance and volume distribution .

Question 12

A drug with large Vd

Answer 12

Cleared more slowly

Question 13

A drug with small Vd

Answer 13

Cleared rapidly

Question 14

t1/2 is NOT dependent on

Answer 14

Dose or formulation

Question 15

A drug will be 97% cleared from the body after

Answer 15

5 half lives

Question 16

Gentamicin

Answer 16

Small molecule, hydrophilic, small distribution - t1/2= 2-3 hours

Question 17

Digoxin

Answer 17

Small molecule, lipophilic, t1/2= 30-40 hours.

Question 18

If a drug has short 1/2 life it needs

Answer 18

More frequent dosing

Question 19

If there is an organ dysfunction

Answer 19

t1/2 may be increased

Question 20

How is t1/2 relevant in clinical practice?

Answer 20

ADR and management of toxicity (how long it takes for the symptoms to revolve)

Question 21

Short t1/2 increases the risk of what?

Answer 21

Discontinuation/withdrawal symptoms - weaning dose on cessation.

Question 22

STAT doses are useful in

Answer 22

Treating acute conditions.
Effect wears off after a few minutes/hours.

*Most drugs require repeated dosing for a more prolonged therapeutic effect.

Question 23

Steady state

Answer 23

Rate of drug input is equal to rate of drug elimination.

Question 24

Css

Answer 24

Drug plasma concentration at steady state

Question 25

Time to Css

Answer 25

5x t1/2 (after initiation and dose increase)

Question 26

Continuous IV infusion

Answer 26

Infusion rate can be titrated up and down to achieve desired therapeutic effect: - critical care patients - abx - unfractionated heparin - GA

Question 27

Does a dose reduction affect Css in continuous infusion?

Answer 27

No - t1/2 remains the same

Question 28

A 50% dose reduction in continuous IV leads to

Answer 28

50% reduction in Css

Question 29

A reduced clearance rate...

Answer 29

- Increases t1/2 - Time to Css increases (5x t1/2) - Css increases ***Dose reduction is required

Question 30

Repeat IV dosing

Answer 30

Peaks and troughs in plasma concentration causing oscillation around the mean. Time to Css does not change.

Question 31

What can be done to reduce time to steady state?

Answer 31

A loading dose can be administered. Digoxin Vancomycin Teicoplanin Amiodarone Heparin

Question 32

Why is steady state important?

Answer 32

Aims for Css which is between maximum safe concentration MSC and minimum effection concentration MEC. Between the two is the therapeutic window.

Question 33

Zero order kinetics

Answer 33

Drugs are metabolised by an amount (e.g in mg) in a unit of time Metabolism is dependent on mechanisms that become saturated Elimination is irrespective of plasma concentration Small increases in dose may cause large increases in plasma concentration There caution needed when adjusting doses Ethanol and pehnytoin.

Question 34

Drugs with narrow therapeutic window

Answer 34

Drugs with a narrow window between MEC and MSC Can have first order or zero order kinetics Monitor drug plasma levels to ensure efficacy and avoid toxicity (therapeutic drug monitoring - TDM) Levels are taken pre-dose (trough)/post dose (peak) or occasionally both Levels may be affected by: organ dysfunction, albumin levels, disease states, drug interactions, patient compliance

Question 35

What are examples of narrow therapeutic window drugs?

Answer 35

Vancomycin, gentamicin, pehnytoin, digoxin, theophylline, lithium

Question 36

Pharmacogenomics

Answer 36

‘The use of genetic and genomic information to tailor pharmaceutical treatment to an individual.’

Question 37

Why is pharmacogenomics useful to prescribe drugs?

Answer 37

Patient's genome is used to identify most appropriate treatment and dose.

Question 38

Genomic variations can results in differences in drug

Answer 38

Pharmacodynamics: variations in drug receptor (efficacy variations and increased ADR) Pharmacokinetics: variations in drug metabolism.

Question 39

Example of application of pharmacogenomics?

Answer 39

Abacavir - variant HLA-B Tested - swapped if needed