Pharmacokinetics

Question 1

Define pharmacokinetics

Answer 1

Study of the movement of a drug into and out of the body

“What the body does to the drug”

Question 2

Define pharmacodynamics

Answer 2

Study of the drug effect and mechanisms of action

“what the drug does to the body

Question 3

Define pharmacogenetics

Answer 3

The effect of the genetic variability on the pharmacokinetics or dynamics of a drug on an individual

Question 4

Why is the study of pharmacokinetics important?

Answer 4

Essential part of drug regulation (MHRA/FDA)

Elucidates the mechanisms of drug interactions

Question 5

What are the key factors of pharmacokinetics?

Answer 5

Bioavailability
Half-life
Drug elimination
Intra-subject variability
Drug-drug interactions

Question 6

How does understanding pharmacokinetics translate into clinical practice?

Answer 6

Understanding bioavailability leads to correct formulation

Estimating half-lives allows dosing regimens to be devised

Understanding intra-subject variability allows appropriate dosing regimens for special patient groups

Helps determine why a patient may fail to respond to a treatment
Or… why a drug has caused toxicity

Question 7

What are the 4 steps to the pharmacokinetic process?

Answer 7

ADME
Absorption
Distribution
Metabolism
Elimination

Question 8

What is the therapeutic window?

Answer 8

The plasma concentration of a drug in which there is enough drug for an effect but not too much for risk of toxicity

Question 9

What is bioavailability (F)?

Answer 9

The fraction of a dose which finds its way into a body compartment, usually the circulation
For an intravenous bolus, bioavailability is 100%
For other routes, compare amount reaching the body compartment by that route with intravenous bioavailability.

Question 10

What factors affect bioavailability?

Answer 10

Absorption:

• Drug formulation
• Age
• Food: lipid soluble >water soluble
• Vomiting/malabsorption etc

First pass metabolism (extraction ratio)

Question 11

What is meant by first pass metabolism?

Answer 11

Any metabolism occurring before the drug enters the systemic circulation. (the ‘first pass’ effect)

Can occur in:
- The Gut Lumen (gastric acid, proteolytic enzymes,
grapefruit juice)
E.g. Benzylpenicillin, insulin, ciclosporin
- The Gut Wall (P-glycoprotein efflux pumps drugs out of
the intestinal enterocytes back into the lumen)
E.g. ciclosporin
- The Liver ( E.g. propranolol is extensively metabolised)

Question 12

What is meant by drug distribution?

Answer 12

It refers to its ability to dissolve in the body

Question 13

What are the two key factors of drug distribution?

Answer 13

Protein binding

Volume of distribution

Question 14

Describe protein binding in reference to pharmacokinetics.

Answer 14

Once in the systemic circulation, many drugs are bound to circulating proteins

• Albumin (acidic drugs)
• Globulins (hormones)
• Lipoproteins (basic drugs)
• Acid glycoproteins (basic drugs)

Most drugs must be unbound (free) to have a pharmacological effect

Only the fraction of the drug that is not protein bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc

Question 15

What are some factors that affect protein binding?

Answer 15

Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
- If another drug is giving with the target drug that binds
to protein more easily then it will displace the target
drug increasing the amount of ‘free’ target drug
increasing the target drugs effects

Question 16

When are changes in protein binding important?

Answer 16

When there is :
High protein binding
Low Vd
Has narrow therapeutic ratio

Question 17

What is volume of distribution (Vd)?

Answer 17

A measure of how widely a drug is distributed in body tissues
Vd~Dose/[Drug]t0
It is a hypothetical measure, but it can be useful in understanding dosing regimens
t1/2 is proportional to Vd (and clearance)

Question 18

How can tissue distribution be affected?

Answer 18

Specific receptor sites in tissues
Regional blood flow
Lipid solubility
Active transport
Disease states
Drug interactions

Question 19

Describe the metabolism part of pharmacokinetics.

Answer 19

Metabolism of a pharmacologically inactive compound to one with pharmacological activity (‘Pro-drugs’):
- Inactive enalaprilat to active enalapril
- L-Dopa is metabolised to a more active metabolite to
improve distribution (crosses brain blood-barrier)

Metabolism of a pharmacologically active compound to other active compounds
E.g. codeine to morphine

Question 20

Describe phase 1 of drug metabolism.

Answer 20

Oxidation and Reduction which are in part dependant on the cytochrome p450 family enzymes

Question 21

Describe cytochrome P450 (CYP450) isoenzymes.

Answer 21

Present mainly in liver (some gut and lung)

Big ones: CYP2D6, 2C9, 2C19, 3A4

Super family of isoforms responsible for approximately 90% human drug metabolism through oxidative reactions

Metabolise toxins such as carcinogens and pesticides

Genetic differences in metabolism

Question 22

What is the most common form of CYP450 in humans?

Answer 22

3A4

Question 23

What does CYP450 3A metabolise?

Answer 23

Calcium channel blockers
Benzodiazepines
HIV protease inhibitors
Most statins
Cyclosporin
Most non-sedating antihistamines

Question 24

What are some inhibitors of CYP450 3A?

Answer 24

Anti-fungals

• Ketoconazole
• Fluconazole
• Itraconazole

Cimetidine

Macrolides
- Erythromycin

Grapefruit juice

Question 25

What are some CYP 3A inducers?

Answer 25

Carbamazepine
Phenytoin
Rifampicin
Ritonavir
St. John's Wort

Question 26

What is the importance of CYP450 variability in different humans?

Answer 26

Some people have certain CYP450s absent or have them hyperactive
If they have them absent then:
They feel the effects of drugs normally metabolised by that CYP450 even more, they don’t need as much of that drug.

If they have them hyperactive then:
The drug is metabolised faster and doesn’t have as big an effect on the person, they need more for it to have an effect.
And if the CYP450 is induced by something, this has an even greater effect of reducing the effect of the drug

E.g. CYP 2D6:

• Absent in 7% Caucasians
• Hyper active in 30% of East Africans

Question 27

What is the main route for drug elimination?

Answer 27

The kidney

Other routes include the lungs, breast milk, sweat, tears, genital secretions, bile, saliva

Question 28

Which three processes determine the renal excretion of drugs?

Answer 28

Glomerular filtration - Unbound drugs e.g. gentamicin
Passive tubular reabsorption - Affected by urine flow rate and pH - e.g. aspirin
Active tubular secretion - Penicillin

Question 29

What is meant by clearance?

Answer 29

Ability of body to excrete drug

mostly = GFR

Question 30

What are the two different ways rate of elimination can be for a drug?

Answer 30

1st Order kinetics - Linear
Rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. Half life can be defined.

Zero Order kinetics - Non-linear
Rate of elimination is a constant

Question 31

Why do we need to be careful when dealing with Zero Order kinetics?

Answer 31

Zero order drugs are more likely to result in toxicity
Fixed rate of elimination per unit time
"Small" dose changes may:
- Produce large increments in dose
- Lead to toxicity
No half life is calculable
Drug monitoring is essential

Question 32

When do we use drug monitoring?

Answer 32

PK reasons:

• Zero order kinetics
• Long half-life
• Narrow therapeutic window
• At greater risk of drug-drug interactions

Others include:
- Known toxic effects (e.g. bone marrow suppression or
alteration in U+Es)
- Monitoring therapeutic effect (e.g. BP, glucose, etc.)

Question 33

What is multiple dosing?

Answer 33

During repeated drug administration, a new steady state is achieved in 3-5 half-lives
Generally this is irrespective of dose or frequency of administration..