1. Pharmacokinetics and Pharmacodynamics Flashcards
pharmacokinetics
how the body handles the drug
pharmacodynamics
effect of the drug on the body
ADME components
Absorption
- extent/rate
Distribution
Metabolism
Excretion
A+D
drug IN
M+E
drug OUT
AUC
area under curve
reflects actual body exposure to drug after administration of a dose of drug
mg*h/L
factors that influence oral drug absorption
1)GI tract acidity
2)bowel disorder hx
factors that influence IM drug absorption
1)muscle mass
2)pain/necrosis complications
3)skin/muscle irritation
4)delayed/unpredictable onset
physiochemical properties that may influence ADME
- solubility
- partition coefficients
- ionization
- pKa
solubility
if a drug is lipophillic or lipophobic
the more aqueous the solution, the more rapidly it is absorbed
partition coefficients
ratio of drug split into oil phase vs aqueous concentration
higher partition coefficient
higher permeability
faster drug absorption
ionization
weak acid vs weak base
how quickly does it ionize in aqueous solution
charged molecules do not cross membranes by diffusion
pKa
the pH at which 50% of the drug is ionized and 50% of the drug is neutral
ration of
unionized:ionized
higher pKa
higher pKa = slower movement of compound into the tissue
prodrug
inactive precursors that are metabolized into active metabolites
why are prodrugs used
to improve how active drug is A, D, M, or E
to increase aqueous solubility
prodrug examples
Fospropofol
fosphenytoin
valacyclovir
Slide 26
bioavailabilioty
how much drug is actually available systemically after first pass/second pass of metabolism
first pass
metabolized by the liver
low first pass drug
bypass the liver
more drug available
IV drugs
high first pass drug
pass through liver
less drug available
Ca channel blockers
beta blockers
diuretics
lidocaine
“F”
Bioavailability (F) is defined as the rate and extent to which the active constituent or active moiety of a drug is absorbed from a drug product and reaches the circulation
F=1.0
both routes deliver the same amount of drug to target organ
For an IV drug, if F is close to 1.0
use a lower loading dose
almost all drug reaching circulation
For an Oral drug, if F is low («1.0)
use a higher loading dose
not enough drug reaching circulation
Phase 1
(nonsynthetic)
Drug metabolism
involve intramolecular modifications:
Hydrolysis
Oxidation
Reduction
Phase 2
(synthetic)
Drug metabolism
conjugation of the drug with an endogenous substance by
Glucuronidation
Methylation
Acetylation
Sulfation
Cytochrome P 450 system
CYP450 enzymes
- 1A2, 2C9, 2C19, etc
root of many drug interactions
if 2 drugs are taken together and they both are metabolized through the CYP450 system, they will take longer to metabolize.
hepatic enzyme induction
slow onset
long duration
prevents activation of drug metabolism in liver
expect increase in elimination rate (decrease 1/2 life)
drug does not stay in the body long
not many inducers
hepatic enzyme inhibition
rapid onset
short duration
stimulates activation of drug metabolism in liver
expect decrease in elimination rate
(increased 1/2 life)
drug stays in body longer
many inhibitors
more-protein bound drug
more narrow therapeutic range
protein binding range
0-99%
albumin
high capacity
low affinity
alpha 1 acid glycoprotein
low capacity
high affinity
affinity
affinity describes the strength of the interaction between (usually two) molecules that bind together
more protein bound drugs
penetrate tissues better than those that are highly protein bound
clearance of such drugs is also higher
therapeutic index (Ti)
ratio of toxic concentration to therapeutic concentration
Large TI
safer if does isnt accurate
Narrow TI
higher risk of toxicity if does isnt accurate
therapeutic range
dosage range or blood plasma or serum concentration usually expected to achieve the desired therapeutic effect
what factors influence renal clearance of drug
- filtration
- proximal tubular secretion
- distal tubular reabsorption
filtration
depends on molecule size
protein binding
integrity of glomerulus
proximal tubular secretion
can cause an increase in the size of elimination rate constant (shorter 1/2 life)
distal tubular reabsorption
ion trapping can occur for lipid soluble unionized drug
First Order Kinetics
amount of drug eliminated in a set amount of time is proportional to the amount present in the body
ex. aspirin
Zero Order Kinetics
amount of drug eleiminated in a set amount of time is independent of the amount present in the body
ex. alcohol/phenytoin
Loading Dose equation
LD = (CVd)/(FS)
LD
loading dose
mg
C
concentration
mg/L
Vd
volume of distribution
L
F
bioavailaibility
(between 0-1)
S
salt fraction
LD quick calc
Vd*C
How to estimate drug half life
look at drug concentration time plot and determine where drug concentration drops in half, then calc the time it took for that drop from the x axis
how to estimate volume of distribution
????
estimate the time required to reach steady-state for first order drugs
50% of drug is lost each half life
If 30 unites are present at the end of 3 half lives, how much drug did you start with?
240 units
end units*(2^(#half life))
30*(2^3)
receptor agonist
substances that mimic the effects of a compound already made in the body
stimulatory
increase normal effect
receptor antagonist
substances that block the effects of a compound already made in the body
inhibitory
decrease normal effect
partial agonist
stimulates some of the natural effect
partial antagonist
inhibits some of the natural effect
EC50
concentration of a drug that is necessary to cause half of the maximum possible effect
higher EC50
higher potency
lower EC50
lower potency
higher maximum effect
higher efficacy
lower maximum effect
lower efficacy
potency
measure of a drug’s biological activity expressed in terms of the dose required to produce a pharmacological effect of given intensity
efficacy
the ability of an intervention or drug to produce a desired effec
drug tolerance
occurs slowly over time
does not reverse rapidly after withdrawal of drug
CHRONIC tolerance
think opioids
drug tachyphylaxis
occurs rapidly
reverses rapidly after withdrawal of drug
ACCUTE tolerance
reversible
(competitive)
drugs bind to receptor but can be kicked off by other drugs w/higher affinity
used receptors can recycle
irreversible
(noncompetitive)
drugs bind to receptros and then receptor is degraded
new receptors must be created after drug binds
used receptors thrown away
