Pharmacokinetics Flashcards
Define pharmacokinetics
Study of the movement of a drug into and out of the body
“What the body does to the drug”
Define pharmacodynamics
Study of the drug effect and mechanisms of action
“what the drug does to the body
Define pharmacogenetics
The effect of the genetic variability on the pharmacokinetics or dynamics of a drug on an individual
Why is the study of pharmacokinetics important?
Essential part of drug regulation (MHRA/FDA)
Elucidates the mechanisms of drug interactions
What are the key factors of pharmacokinetics?
Bioavailability Half-life Drug elimination Intra-subject variability Drug-drug interactions
How does understanding pharmacokinetics translate into clinical practice?
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
What are the 4 steps to the pharmacokinetic process?
ADME Absorption Distribution Metabolism Elimination
What is the therapeutic window?
The plasma concentration of a drug in which there is enough drug for an effect but not too much for risk of toxicity
What is bioavailability (F)?
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.
What factors affect bioavailability?
Absorption:
- Drug formulation
- Age
- Food: lipid soluble >water soluble
- Vomiting/malabsorption etc
First pass metabolism (extraction ratio)
What is meant by first pass metabolism?
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)
What is meant by drug distribution?
It refers to its ability to dissolve in the body
What are the two key factors of drug distribution?
Protein binding
Volume of distribution
Describe protein binding in reference to pharmacokinetics.
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
What are some factors that affect protein binding?
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
When are changes in protein binding important?
When there is :
High protein binding
Low Vd
Has narrow therapeutic ratio
What is volume of distribution (Vd)?
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)
How can tissue distribution be affected?
Specific receptor sites in tissues Regional blood flow Lipid solubility Active transport Disease states Drug interactions
Describe the metabolism part of pharmacokinetics.
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
Describe phase 1 of drug metabolism.
Oxidation and Reduction which are in part dependant on the cytochrome p450 family enzymes
Describe cytochrome P450 (CYP450) isoenzymes.
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
What is the most common form of CYP450 in humans?
3A4
What does CYP450 3A metabolise?
Calcium channel blockers Benzodiazepines HIV protease inhibitors Most statins Cyclosporin Most non-sedating antihistamines
What are some inhibitors of CYP450 3A?
Anti-fungals
- Ketoconazole
- Fluconazole
- Itraconazole
Cimetidine
Macrolides
- Erythromycin
Grapefruit juice
