Flashcards in 2- Pharmacokinetics Deck (41):
Study of what body does to drug
What drug does to body
What genetic variability does to pharmacokinetics on a individual
How does pharmacokinetics impact on clinical practice?
Understanding bioavailability to give correct formulation
Estimates of half lives enable dosing regimens to be created
Helps to understand why a drug fails to work/causes toxicity
Fraction of a dose which finds its way into a body compartment, usually the circulation
What is the bioavailability of a drug given intravenously?
How is bioavailability calculated?
Method of dosage (eg oral) / IV
If on a graph, area under curve = total drug exposure
What are the factors affecting absorption?
Drug formulation - immediate or modified release
Food - water or lipid soluble
First pass metabolism
What is first pass metabolism?
Metabolism that occurs before drug enters systemic circulation in gut lumen (via gastric acid/ proteolytic enzymes), gut wall (drug effluxed out of enterocytes back into lumen by p-glycoprotein) and liver (propanolol metabolised extensively)
Which plasma proteins bind which type of drug?
Albumin - acidic drugs
Globulins - hormones
Lipoprotein and acidic glycoproteins- basic drugs
What causes protein binding drug interactions?
Displacement of a drug from its binding site
What alters protein binding and what causes this?
Altered fluid balance caused by:
When will altered protein binding cause distribution changes?
If drug in question:
Is highly protein bound
Has a low volume of distribution
Has a narrow therapeutic window
What is the effect of adding an additional highly bound drug?
Additional drug will steal protein binding sites from first drug, meaning more of the first drug is free in plasma, increasing its effect
Define volume of distribution
Measure of how widely a drug is distributed in body tissues
What is the formula for volume of distribution?
Vd =Dose / [Drug]t0 (plasma conc of drug)
What are the units of volume of distribution and how does this effect prescribing?
Units are L/kg
Means the larger the patient, the higher the dose needed to create the same effect as in a smaller patient
What effect does a large volume of distribution have on half life?
The larger the volume of distribution, the longer the half life
What factors affect distribution?
Specific receptor sites in tissues
Blood flow to region
What is phase I of metabolism?
Oxidation and reduction reactions in the liver, via cytochrome p450 enzymes
What are the main cytochrome enzymes?
What does CYP2D6 metabolises and what is it inhibited by? Why is this important?
Metabolises: Codeine, beta blockers and tricyclics (antidepressants)
Inhibited by: fluoxetine (Prozac), halaperidol (anti-psychotic) and quinidine (anti arrhythmic)
Important as CYP2D6 is absent in some Caucasians and hyperactive in some East Africans
What is metabolism affected by?
How are drugs excreted from the body and give examples
Glomerular filtration - unbound drugs eg gentamicin, proportional to GFR
Passive tubular reabsorption - aspirin, affected by urine flow rate and pH
Active tubular secretion - penicillin
Ability of the body to excrete drugs
What is the relationship between half life and clearance rate?
Half life inversely proportional to clearance, so low GFR, longer half life
What is the equation for elimination?
K= clearance / Vd
Define first order/ linear kinetics
Rate of elimination is proportional to drug level, so half life can be defined
Define zero order / non linear kinetics
Rate of elimination is constant
At high concentrations, what type of kinetics do most drugs display?
At high concentrations, as enzymes or receptors become saturated
Why are zero order drugs more likely to causes toxicity?
Have a fixed rate of elimination per unit time
Small dose increases cause large increments in plasma concentrations
Half life not calculable
What qualifies a drug for careful monitoring?
Zero order kinetics
Long half life
Narrow therapeutic window
High risk of drug - drug interactions
Known toxic effects
Define steady state
Where the intake of a drug is in equilibrium with its excretion, takes 3 - 5 half lives to achieve and 4-5 half lives go eliminate
What is a loading dose and when is it given?
A larger dose of drug given to achieve therapeutic levels quickly, given if rapid therapeutic effect is needed and drug has long half life
Define maintenance dose
Dose given to maintain a therapeutic level of drug in blood stream
What is the equation for a loading dose?
Loading dose = Vd x [drug] target
Where Vd = dose / [drug] t0
On a [plasma] / time graph, what does the slope of the curve represent?
The elimination rate = k = clearance:volume of distribution
How half life related to clearance and volume of distribution?
Half life is proportional to volume of distribution
Inversely proportional to clearance
What is the formula for half lives (with respect to k) ?
T= 0.693 / k
How does renal function impact on half life?
Half life inversely proportionate to 1 / GFR
In CKD, half life is extended