Pharmacokinetics Flashcards
What is pharmacokinetics?
What the body does to a drug.
What are the main components of pharmacokinetics?
Absorption
Distribution
Metabolism
Elimination
What are the key factors of pharmacokinetics?
Bioavailability Half-life Drug elimination Intra-subject variability Drug-drug interactions
What things should you consider then thinking about PK?
Renal function Stress Pyrexia Alcohol Smoking Age Sex Exercise Infection Diet Occupational exposure Lactation Liver function Albumin conc. CV function Carcadian and seasonal variations Immunisation Barometric pressure GI function Pregnancy Infection
What are the four parts of drug therapy?
Pharmaceutical prep
Pharmacokinetic process
Pharmacodynamic process
Therapeutic process
What is bioavailability (F)?
Measure of drug absorption into body compartment where it can used - typically circulation
Drug administered via IV bolus is said to have 100% bioavailability.
Other routes of administration referenced as a fraction of i.v
What factors affect bioavailability?
Absorption: Formulation Age (luminal changes) Food (chelation, gastric emptying) Vomiting / malabsorption
First pass metabolism:
Metabolism before reaching systemic circulation (gut lumen, gut wall, liver)
What are modified release preparation?
Those which release the drug slowly and so, remain within the therapeutic range for longer.
What factors affect how well the drug dissolved and distributes through the interstitium?
Blood flow, capillary structure
Lipophilicity vs hydrophilicity
Protein binding (albumin)
Volume of Distribution
Displacement of a drug from binding site can result in protein bringing drug interactions. When is this clinically important?
Highly protein bound
Narrow therapeutic index
Low Vd
What effect does increasing free drug have on drug-protein binding and distribution?
Will be able to afford response and / or be eliminated.
Second drug displaced first drug from binding proteins.
More free first drug to elicit a response through receptor.
Potentially causing harm - entering toxic dose concentration.
Pregnancy (fluid balance), renal failure, hypoalbuminemia (malnutrition) among others.
what is the volume of distribution?
Vd is typically hypothetical measure of how widely a drug is distributed in the body (apparent Vd)
Vd = dose / [drug]plasma
When is Vd useful?
Estimating dishing regiments.
What does a Vd mean?
Small Vd - drug confined to plasma and ecf
Larger Vd - drug is distributed throughout the tissues.
What is Vd proportional to?
Half life
Describe the phases of metabolism in the liver?
Drug
Phase I enzymes + CYPs - oxidation, dealkylation, reduction hydrolysis
Phase II enzymes - Glucuronide, sulphate glutathione, N-acetyl
Conjugates
Then go to other sites (kidney to urine or gall bladder to bile)
What things affect the route and mechanism of metabolism of a drug?
Size
Lipophilicity
Hydrophobicity
Structural complexity
What things inhibit CYP3A4?
Grapefruit juice and statin therapy.
What is CYP 2D6?
Absent in 7% of Caucasians.
Hyperactivity / increased induction in 30% East Africans
Substrates include some anti arrhythmias, antidepressants and opioids.
Inhibited by some SSRIs, other anti arrhythmias and other antidepressants.
What is the clinical importance of having different CYPs?
Important for drug prescribing
Need to consider OTC and food as drug-drug interactions.
Also consider: Race Age Sex Species Clinical or physiological condition
How are drugs removed from the body?
Mostly via the kidney (25% of systemic blood flow)
Other possible routes: pulmonary, biliary, faecal, sweat, genital, secretions, saliva, breast milk
What affects drug elimination?
GFR and protein binding (gentamicin)
Competition for transporters (penicillin)
Lipid solubility, pH, flow rate (aspirin)
What is clearance?
Clearance of drug from the body is the rate of clearance from all routes - both metabolism and excretion taken together. (Mostly GFR)
What is half life?
Time is which concentration of a drug in plasma decreases by half
When will half life increase?
If GFR is reduced then clearance is compromised and half life increased. (half time is inversely proportional to clearance).
Also increased in: Renal or hepatic stenosis Haemorrhage Reduced metabolism Reduced plasma drug extraction Drug-drug interactions.
What is 1st and 0 order kinetics?
1st order - rate of elimination is proportional to drug concentration
0 order - rate of elimination is a constant
What is Half life proportional to?
Vd (volume of distribution)
What is half life inversely proportional to?
Cl (clearance)
What order kinetics do most dugs exhibit?
First order kinetics
What drugs do not exhibit first order Kinetics and what effect does this have?
Ethanol. Aspirin, phenytoin (unpredictable).
This is important as the dose change can produce unpredictable change in plasma so half life in not calculable.
What particular characteristics mean the drug needs careful monitoring.
PK Zero order kinetics Long half-life Narrow therapeutics window Drug-drug interaction Reported or expected toxic effects Therapeutic effect
When is the steady state plasma conc reached?
5 half lives
Same amount of half lives to eliminate dugs.
The therapeutic benefit is optimal at a steady state.
What things do you have to consider when doing half life?
Dosing schedule
Other than half life, what other things do you need to know to work out the dosing schedule?
Age (muscle mass)
Adipose tissue (Vd changes)
Pathological fluid spaces among others
