2 - PharmacoKINETICS Flashcards
what key variable affects the pharmacoKINETICS of a patient?
STATE OF THE PATIENT;
need a thorough case history
how to determine standard dose?
- animal studies –> define kinetic parameters
-
clinical trials –> determine effect in humans
- may need to be halted due to adverse rxns/ or negative results
what are the key pharmacokinetic parameters
- metrics
- fraction absorbed
- volume of distribution
- clearance
- half-life
- therapeutic index
- overall measurements
- “macro” quantitations
- classical pharmacology (blood/urine samples)
- mathematical determinations
fraction absorbed: define
- “F”
- aka oral bioavailability (the fraction of an administered dose of unchanged drug that reaches the systemic circulation
apparent volume of distribution: define
- measures volume necessary toc ontain the drug homogenously at the concrentration found in blood, plasma, or water
- “apparent” bc it’s not real; can vastly exceed any physical volume in the body
- can be defined w/ respect to concentration in blood, plasma, or water
what does it mean if a substance has a high volume distribution (Vd)?
high concentration in EXTRAVASCULAR versus vascular compartment
(a low vol dist –> means higher conc in vascular compartment)
clearance: define and factors affecting this
- rate at which active drug is removed from the body
- (rate of elimination / concentration)
- affected by:
- dose
- organ BF
- liver/kidney fxn
- plasma protein binding (incl. albumin conc, alpha-acid glycoprotein conc, and capacity-lmtd protein binding)
half-life: define, and rate
- indicates how long the drug is going to be present in the body
- rate: exponential decay
when is the dose/conc. considered to be zero (w/ regards to half-life)?
at 4.3 half-lives
loading dose: define
an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose
maintenance dose: define
maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state
how do you calculate steady state plasma concentrations?
how do you achieve this?
- It’s an average of the doses –> black line is “idealized” plasma conc of the dose
- achieved thru a dynamic process involving many diff variables
what are the differences b/w the 3 drugs w/ regards to BIOAVAILABILITY
REMEMBER: bioavailability is the fraction of unchanged drug reaching the systemic circulation following administration by any route
Key concept of bioavailability and route:
- IV
- oral
- transdermal
- IV –> most rapid onset; & 100% bioavailability
- oral –> best for compliance, 5-100% bioavailability (due to variable first pass effect)
- transdermal –> 80-100% (pretty good bioavailability %)
since bioavailability does not consider metabolism, what factors are not affected?
- activation
- inactivation
- drug-drug interactions
- serum protein interactions
what are the immediate effects of drug administration?
(re: pharmacoDYNAMICS and pharmacoKINETICS)
pharmacokinetics drop rapidly,
and pharmacoDYNAMICs gradually decreas and last longer than pharmacodynamics
enalapril: fxn, half-life, effect
- inhibits angiotensin converting enzyme (ACE inhibitor)
- half-life: 3 hour
- effects after oral dose:
- peak plasma conc after 3 hr is 64 ng/mL
- plasma conc changes by factor of 16 over 1st 12 hours
- at same time –> ACE inhibition reduced by 20%
- common effect of enzyme inhibitors or drugs that compete w/ receptors
what are the delayed effects of drug administration?
(course of minutes, hours/days)
- minutes
- time required for its distribution from plasma to site of action
- common w/ most drugs
- hours/days
- slow turnover of a physiological substance involv. in drug effect
- hormone replacement therapy
what are the general equations for pharmacoKINETICS and pharmacoDYNAMICS
graded-dose response curve: define
- Effects increase on a continuous scale.
- The dose that gives effect = ½ Emax is D50 (or EC50 when concentration is plotted instead of dose).
- The efficacy of a drug is indicated by its own maximum effect.
- The potency is indicated by D50 (or) EC50
efficacy: define, relationship
- the maximum response a drug can produce
- due to intrinsic activity
- the greater the response, the greater the efficacy
intrinsic activity: define, &relationship w/ efficacy
- the inherent ability of a drug to elicit a response
- drug w/ high intrinsic activity –> high efficacy
potency: define
- The concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect (a measure of the dose required to produce a response)
- measured as D50 dose of the dose response curve
- The less drug required to reach EC50 or ED50, the greater the drug potency
- so small D50 means high potency
what is the POTENCY and EFFICACY of the dose-response curve?
how do the potency/ efficacy of the drugs compare?
therapeutic index: define, equation, how is it determined?
- A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective.
- ratio = LD50 / ED50
- lethal curve (determined in animals) gives the LD50
what is therapeutic index of an EFFECTIVE DRUG?
(w/ regards to effective dose and lethal dose?)
High LD50, Low ED50
(non-effective drug is LOW LD50, HIGH ED50)
which is preferable?
drug with (HIGH/LOW) therapeutic index
a drug with a HIGH therapeutic index is PREFERABLE because it has a larger therapeutic window
(for example: digitalis is used in heart failure and has a low therapeutic index of 2:1 –> very dangerous drug)
arousal scale: barbituates vs benzodiazepine
- barbituates: can induce anesthesia, coma, or death
- benzodiazepine: typically only sedation/sleep
therapeutic index caution?
combination w/ other drugs of abuse can be lethal
(e.g. diazepam is very safe bc it has 100:1 ratio, BUT w/ alcohol –> can be lethal)
what factors affect pharmacoKINETICS?
- diseases of the liver (hepatitis, cirrhosis)
- cardiac disease –> effects BF
- pulm disease –> pulm insufficiency can affect half-life
- genetic polymorphism –> individual variation in enzyme levels
- age
- nutrition
