Session 2 Pharmacokinetics and Pharmacodynamics Flashcards
What are 2 reasons why PK are important?
- Population and individual tailoring
2. Predicting toxicity
Key factors influencing PK?
bioavailability half-life drug elimination inter-subject variability drug-drug interactions
Define bioavailability (F)
the measure of drug absorption where it can be used
What is the bioavailability of a drug administered via IV bolus?
100%
other routes are referenced as a fraction of IV
What 2 things is bioavailability affected by?
- Absorption
2. First Pass Metabolism
What influences absorption of a drug?
formulation
age (luminal changes)
food (chelation, gastric emptying)
vomiting/malabsorption (Crohn’s)
Define first pass metabolism
metabolism before reaching systemic circulation (gut lumen, gut wall, liver)
What is the formula for calculating bioavailability?
AUC oral / AUC IV then x answer by 100%
AUC = area under curve
what does the rate of absorption dictate? (normally seen on plasma concentration-time graph)
visibility of distribution and elimination phases
plasma concentration-time graph with a steep upward slope indicates what?
rate of absorption > rate of distribution
plasma concentration-time graph with a slow upward slope indicates what?
rate of absorption < rate of distribution
won’t see an obvious distribution phase
What is modified release preparation? what are the advantages and disadvantages?
form of taking tablets that dissolve over time (extended release)
concentration of the drug stays within the therapeutic window (between maximum safe concentration and minimum effective concentration)
- adherence is better
- but these are more expensive
What are some factors that affect drug distribution?
blood flow and capillary structure lipophilicity and hydrophilicity protein binding: * albumin = acidic drugs * globulins = hormones * lipoproteins = basic drugs * glycoproteins = basic drugs
what ‘model’ does rate of distribution and equilibration from IV administration typically follow?
multiple compartment model
explain protein binding drug interaction
why is this clinically important?
- normally, only FREE drug will be able to afford a response and/or be eliminated
- displacement of a drug from a binding site can result in protein binding drug interaction
This is clinically important if;
- the drug is highly protein bound
- narrow therapeutic index
- low volume of distribution
in terms of protein binding drug interaction, what happens if there is increased free drug?
why is this relevant?
- the increased free drug will be able to afford a response and/or be eliminated
- a second drug can displace first drug from binding site
= more free drug to elicit a response
relevant as this can potentially cause harm
e.g. in pregnancy (fluid balance), renal failure or hypoalbuminemia (change in amount of protein will change amount of free drug!)
What is volume of distribution and what is the equation?
= a proportionality factor
Vd = Dose/[Drug]plasma
Vd calculation:
- dose = 100mg
- Cp (plasma conc.) = 20mg/L
what is Vd?
Vd = 5L
100mg / 20mg/L
Vd calculation:
- dose = 100mg
- Cp = 10 ug/mL
what is Vd?
Vd = 10L
Calculation to find out dose?
Vd x [Drug]plasma = Dose
What does a smaller apparent Vd suggest?
drug is confined to plasma and extracellular fluid (i.e. less spread out)
What does a larger apparent Vd suggest?
drug is distributed throughout tissues (i.e. very dispersed)
What site in the body has the most numerous and diverse metabolic enzymes?
the liver!
What factors affect the drugs route and mechanism?
size, lipophilicty, hydrophilicity and structural complexity
What do phase I enzymes do?
convert drugs into lipophilic metabolites
Outline the general principles of metabolism of a drug
drug > phase I enzymes > CYPs: oxidation, dealkylation, reduction and hydrolysis (then kidney or gall bladder or keep going) > phase II enzymes > glucuronide, sulphate, glutathione, N-acetyl > conjugates > then kidney or gall bladder (urine and bile respectively)
what system do the majority of phase I catalysed reactions utilise?
Cytochrome P450 system
there are numerous genes that encode these enzymes
and few CYP families deal with most reactions
Isoenzyme and Action
- CYP1A
- CYP2C
- CYP2D
- CYP2E
- CYP3A
- Induced by smoking
- many inhibitors
- matabolises many drugs
- alcohol metabolism
- 50% therapeutics
importance of CYP250 enzymes?
they can be induced or inhibited by endogenous or exogenous compounds affecting phase I metabolism
What causes CYP3A4 inhibition?
grapefruit/juice and statin therapy
what causes CYP2D6 inhibition? what are some substrates? absent where and hyperactive where?
inhibited by: some SSRI’s
substrates: beta blockers, many SSRI’s, some opioids
absent in 7% caucasians
hyperactive in 30% east africans
what is primarily responsible for drug elimination?
kidneys (25% of systemic blood flow)
possible routes of elimination?
kidneys
fluids = sweat, tears, genital secretions, salvia and breast milk
solids = faeces, hair
gases = volatile compounds (alcohol breath test)
Renal elimination metabolites are typically?
low molecular weight polar metabolites
what is renal elimination affected by? give drug examples
- GFR and protein binding (gentamicin)
- Competition for transporters (penicillin)
- Lipid solubility, pH and flow rate (aspirin)
Hepatic elimination metabolites are typically?
high molecular weight and conjugated with glucuronic acid
- bile = important route for conjugates
- elimination in faces or reabsorbed
What is zero order kinetics?
constant amount of drug eliminated per unit time
= straight descending line on graph
set amount / time
What is first order kinetics?
constant proportion of the drug is eliminated per unit time
= initial decreasing steepness of graph due to great drop in concentration
- half-life
define clearance and give formula
1000 ml/min in through kidneys and 100 ml/min out = 10% clearance
volume of blood cleared of a substance per minute
rate of elimination from body / drug concentration in plasma
if drug concentration is high, what happens with elimination?
more drug in the same volume is cleared so elimination rate is increased
clinical significance of relationship between half-life, volume of distribution and clearance?
Vd is the theoretical volume that needs to be cleared.
plus with clearance rate, we can determine the overall rate of elimination. from this we can dictate the half life.
elimination determines drug to maintain the steady state concentration (Css) plus half life is useful for one-off dose
helpful for chronic treatment dosing
what type of kinetics do most drugs exhibit?
first order kinetics at therapeutic doses where half life is constant
what things exhibit zero order kinetics? relevance of this?
high drug doses, alcohol, salicyclic acid and phenytoin
dose change can produce unpredictable change in plasma concentration so we can’t calculate half life
how many half life’s to reach a steady state?
relevance of steady state?
how many half life’s for almost complete elimination?
5
therapeutic benefit is optimal at steady state
5
half life calculation
(0.693 x Vd) / clearance = half life
clearance calculation (there are 2)
rate of elimination from body / drug concentration in plasma = clearance
rate of infusion / steady state plasma concentration = clearance
rate of elimination calculation (there are 2)
clearance x plasma concentration = elimination
clearance x steady state plasma concentration = elimination
rate of infusion calculation
clearance x steady state plasma concentration = rate of infusion
steady state plasma concentration calculation (there are 2)
rate of infusion / clearance = Css
(maintenance dose x oral bioavailability) / (dose interval x clearance) = Css
rate of administration calculation
(dose x oral bioavailability) / dose interval = rate of administration
loading dose calculation
when would you use a loading dose?
loading dose = Css x Vd
use if rapid onset required or if drug has a long half life
why would you perform dosing schedules?
to maintain a dose within the therapeutic range
safe and achieves adherence
