2.1 Pharamacokinetics 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 drug effect and mechanisms of action
What the drug does to the body
Define pharmacogenetics
The effect of genetic variability on the pharmacokinetics or dynamics of a drug on an individual
How does bioavailability translate or clinical practice?
Calculate correct formulation
How does estimating half life translate into clinical practice?
Allows dosing regimes to be devised
What processes occur as part of pharmacokinetics?
Absorption
Distribution
Metabolism
Elimination
What is the therapeutic window?
Range of plasma concentration in which the drug has the desired effect
Define bioavailability (F)
The FRACTION of a dose which finds its way into a body compartment, usually the circulation
What is the bioavailability for an IV bolus?
100%
What are the axis for a bioavailability curve?
X time post dose
Y plasma concentration
What does the area under a bioavailability curve represent?
Total drug exposure
How can oral bioavailability be calculated?
F = AUC oral / AUC IV
What factors affect bioavailability?
Absorption
- drug formulation, age, food, vomiting, malabsorption
First pass metabolism
What sort of drug formulation is preferable and why?
Modified release once a day
Short half life needs to be given many times a day. Immediate release may dip out of the therapeutic window
What is first pass metabolism?
Any metabolism occurring before the drug enters the systemic circulation
Name three areas where first pass metabolism can occur
Gut lumen
Gut wall
Liver
Describe the effect of first pass metabolism in the gut lumen
Affect3 by gastric acid, proteolytic enzymes, grapefruit juice
Affects benzylpenicillin, insulin, cyclosporin
Describe the action of first pass metabolism in the gut wall
P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen
Eg ciclosporin
Name a drug that is extensively metabolised in the liver
Propranolol
What are two key factors in drug distribution?
Protein binding
Volume of distribution
Which state should drugs be in to have a therapeutic effect normally?
Unbound
What causes protein binding drug interactions?
Displacement of drugs from binding sites
What factors affect protein binding?
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
In what circumstances will changes in protein binding causing changes in drug distribution be important?
High protein binding
Low Vd
Narrow therapeutic window
Describe what happens when you add a highly bound precipitant drug (B) to drug A
More highly protein bound drug b will steal binding sites
Increase free drug a
(Increases effects of a)
What is volume of distribution a measure of?
How widely a drug is distributed in body tissues
How can Vd be calculated?
Dose/ concentration of drug at time 0
What is half life proportional to?
Vd and clearance
What can Tissue distribution be affected by?
Specific receptor sites in tissues Regional blood flow Lipid solubility Active transport Disease states Drug interactions
Where does the majority of drug metabolism occur?
Liver
What should the end products of conjugation be soluble in after metabolism?
Water to allow rapid elimination from the body
What are the two ways active metabolites can be formed in metabolism?
Metabolism of an inactive compound to active one (pro-drug)
Metabolism of an active compound to another active compound
Give an example of a pro drug
L dopa
Give an example of an active drug that is metabolised by liver to another active drug
Codeine to morphine
What factors can influence the activity of p450 enzymes?
Enzyme inducing/inhibiting drugs Age Liver disease Hepatic blood flow Cigarette and alcohol consumption
Where can CYP450s be found?
Mainly liver
Some gut and lung
Give an example of drug interaction due to enzyme inhibition
Cimetidine inhibits CYP causing there to be higher concentrations of warfarin in the plasma
Higher risk of bleeding
Describe the genetic distribution of CYP 2D6
Absent in 7% of Caucasians
Hyperactive in 30% of east Africans
What drugs are metabolised by CYP 2D6?
Codeine
Beta blockers
Tricyclics
What drugs are inhibited by CYP 2D6?
Fluoxetine
Paroxetine
Haloperidol
Quinidine
What is the main route of drug elimination?
Kidney
What are some other routes of drug elimination? (Other than kidney)
Lungs, breast milk, sweat, tears, genital secretions, bile, saliva
What three processes determine the renal excretion of Drugs?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
What drugs are excreted through glomerular filtration?
Unbound drugs like gentamicin
What drugs are actively secreted in nephron excretion?
Penicillin
Which drugs are removed by passive reabsorption and what are they affected by?
Aspirin
Affected by urine flow rate and pH
What is clearance and what is it dependent on?
Ability of body to excrete a drug
Dependent on GFR (renal function)
What is the relationship between half life and clearance?
Half life is inversely proportional to clearance
What effect will a reduced GFR have on clearance and half life p?
Reduced clearance
Increased half life
Describe the rate of elimination in first order kinetics (linear)
Rate if elimination proportional to drug level
Constant fraction of drug eliminated in unit time
Half life can be defined
Describe the rate of elimination in zero order kinetics (non linear)
Rate of elimination is constant
In which type of kinetics can half life be defined?
First order/linear
What is the equation for half life?
Half life = 0.693 x Vd/CL
What type of kinetics do most drugs exhibit at high dose and why?
Zero order
Because the receptors/enzymes become saturated
Why are zero order drugs more likely to produce toxicity?
Fixed rate of elimination per unit time
Small dose changes may produce large increments in plasma concentration
What qualities of a drug may mean they require more monitoring?
Zero order kinetics Long half life Narrow therapeutic window Greater risk of interactions with other drugs Known toxic effects
In how many half lives will steady state of a drug be achieved?
3-5
(Irrespective of dose of frequency of administration)
Drugs with larger half lives take longer to reach steady state
How many half lives will it take to eliminate a drug from steady state?
4 to 5
What can affect the maintenance dose of a drug?
Age and renal function
True or false : loading dose can remain much the same in renal failure
True
True or false: maintenance dose can remain much the same in renal failure
False
Should be reduced
How can loading dose be calculated?
Loading dose = VD x target drug concentration
How can you work out elimination rate constant (k)?
K = clearance / Vd
How can drug elimination be improved in someone with renal failure?
Give a drug that will bind the drug in the plasma to inactivate it
