pharm 1 Flashcards
volume of distribution describes relationship between
drugs plasma concentration following a specific dose. it is a theoretical measure of how a drug distributes throughout the body.
what 2 things does vD assume
-drug distributes instantaneously
-drug is not subjected to biotransformation or elimination before it fully distributes
what are the implications when a drugs vd exceeds TBW?
vd > TBW it is assumed to be lipophilic
distributes into TBW and fat
need a HIGHER dose to achieve a given plasma concentration
ex: propofol and fentanyl
if vd < tbw the drug is assumed to be
hydrophiilic
hydrophilic distributes into where
some or all of the body water. but it does not distribute into fat.
requires a lower dose to achieve a given plasma concentration
examples of hydrophilic drugs
NMB, albumin
for an IV drug what is the bioavaliability
always 1- b/c the drug enters the blood stream
what is the bioavaliability of drugs via routes other than IV
drug administered by any other route may not be absorbed completely- may be subject to first pass metabolism in the liver- reduces bioavaliability and explains why the dose achieves a given plasma concentrration- dependent on route of administration
bioavaliability less than 1
what is clearance
volume of plasma that is cleared of a drug per unit of time
clearance is directly proportional to
blood flow to cleansing organ, extraction ratio, drug dose
clearance is indirectly proportional to
half life, drug concentration in central compartment
how many half times until steady state is achieved
5
what is steady state
occurs when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body
- a stable plasma concentration
is the drug in each compartment = during steady state
no- each compartments equilibrated although total amount of drug may be different in each
what are the phases of distribution
alpha and beat
alpha distribution phase
drug distribution from plasma to tissues
beta distribution phase
begins as plasma concentration falls below tissue concentration. concentration gradient reverses, causes drug to re-enter the plasma. beta phase describes drug elimination from central compartment
how do you figure out how much of a drug is left after a certain amount of half times
50% for each half time - picture on phone
what is context sensitive half time
half times DO NOT consider time
context sensitive half time does! - time required for plasma concentration to decline by 50% after d/c the drug
what is the difference bwteen a strong and weak acid or base
if you put a strong acid or strong base in water- it will ionize completely
if you put a weak acid or weak base in water- a fraction of it will be ionized, the remaining fraction will be unionized
acid vs base
acid donates a proton
HA - H+ + A
base accepts proton
B + H+ - BH
what is ionization
the process where a molecule gains a pos or neg charge
what is ionization dependent on
ph of the solution and ph of the drug
when pka and ph are the same
50% of the drug is ionized and 50% is non ionized
solubility of ionized drug
hydrophilic and lipophobic
non ionized solubility
lipophillic and hydrophobic
is ionized or non ionized pharmacologically effective
non ionized
is ionized or non ionized more likely to go through hepatic biotransformation
non ionized
is ionized or non ionized more likely to go through renal elimination
ionized
does ionized or non ionized diffuse across lipid bilayer
non ionized
can go through: blood brain barrier, Gi tract, placenta
what happens with weak bases in an acidic solution or in a basic solution
in acidic solution: weak bases are more ionized and water soluble
in basic solution: weak bases are more non ionized and lipid soluble
what happens to weak acids in acidic and basic solutions
in acidic solution: weak acids are more non ionized and lipid soluble
in basic solution: weak acids are more non ionized and water soluble
how to tell by the name if a drug is weak acid or weak base
weak acid is paired with pos ion (sodium, calcium or mag)
ex: sodium thiopental
weak base is prepared with neg ion: chloride or sulfate
(lidocaine hydrochloride, morphine sulfate)
what are the 3 key plasma proteins
albumin, a1 acid glycoprotein, beta globulin
what plasma protein primarily binds to acidic drugs but can also bind to some neutral and basic drugs
albumin
what plasma protein binds to basic drugs
a1 acid glycoprotein and beta globulin
what conditions will reduce serum albumin concentration
liver dz, renal dz, old age, malnutrition, pregnancy
what will increase or decrease a1 acid glycoprotein concentration
increase: surgical stress, MI, chronic pain, RA, old age
decrease: neonates, pregancy
decreased plasma protein binding-> __ cp (plasma drug concentration)
increased
what is first order kinetics
constant fraction of drug is eliminated per unit of time
what is zero order kinetics
-more drug than enzyme
-constant amount of drug is eliminated per unit of time
-rate of elimination is independent of plasma drug concentration
-ex: aspirin, phenytoin, warfarin, heparin, theophylline
phase 1 reactions result in
small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for phase 2
most phase 1 biotransformations are carried out by what system
p450
what are the 3 main phase 1 reactions
oxidation, reduction and hydrolysis
this removes electrons from a compound
oxidation
this adds electrons to a compound
reduction
this adds water to a compound to split it apart (usually an ester)
hydrolysis
function of phase 2 rxn
conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule
results in water soluble, biologically inactive molecule ready for excretion
typical substrates for conjugation reactions include
glucuronic acid, glycine, acetic acid, sulfuronic acid, methyl group
do all drugs need to do phase 1 rxn before phase 2
no can go right to p2
enterohepatic circulation
some conjugated compounds are excreted in the bile, reactivated in the intestine and then reabsorbed into systemic circulation
what are some examples of durgs that undergo enterohepatic circulation
diazepam and warfarin
extraction ratio
a measure of how much of a drug is delivered to clearing organ vs how much of a drug is removed by that organ
ER of 1 means that clearing organ removes 100% of the delivered drug
ER of 0.5 means that the clearning organ removes 50% of the delivered drug
increased liver blood flow -> __ clearance
increased
called perfusion dependent elimination
a drug with a high hepatic extraction ratio means what
> 0.7
clearance is dependent on liver blood flow! not hepatic enzyme activity
what is low hepatic extration ratio
<0.3
what is clearance dependent on if drug has low hepatic extraction ratio
dependent on the ability of the liver to extract the drug from the blood
enzyme induction ->
increases clearancee
enzyme inhibition->
decreases clearance
what is the most important mechanism of drug biotransformation in the body
p450 system
where do the enzymes for p450 reside
in the liver in smooth endoplasmic reticulum
2 drug classes and 7 drugs that are metabolized by pseudocholinesterase
nmb: succinylcholine, mivacurium
ester type local anesthetics: chloroproacine, tetracaine, procaine, benzocaine, cocaine
6 drugs metabolized by plasma esterases
esmolol
remifentanil
remimidazolam
clevidipine
atracurium
etomidate
drug biotransormed by alkaline phosphatase hydrolysis
fospropofol
pharmacokinetics
what the body does to the drug. absorption, distribution, metabolism, elimination
phamacobiophysics
drugs concentration in the plasma and the effect side (biophase)
pharmacodynamics
what the drug does to the body. relationship between effect site concentration and clinical effect
how is potency measured
potency- dose required to achieve a given clinical effect
ed50 and ed90 are measures of potency. represent dose required to achieve a given effect in 50% and 90% of the population respectively
what is an inverse agonist vs antagonist
inverse: binds to receptor and causes opposite effect of full agonist. negaive efficacy
antagonist: occupies receptor and prevents agonist from binding to it. does not tell the cell to do anything. does not have efficacy
competitive antagonism
is REVERSIBLE. increasing concentration of agonist can overcome competitive antagonism
ex: atropine, vecuronium, rocuronium
noncompetitive antagonism
NOT REVERSIBLE. drug binds to receptor- through covalent bonds.
effect cannot be overcome by increasing concentration of an agonist.
only by creating new receptors can the effect of a noncompetitive agonist be reversed. explains why these drugs have a long duration of action
examples of noncompetitive antagonism
aspirin and phenoxybenzamine
ed50
effective dose 50
dose that produces expected clinical response in 50% of population
measure of potency
td50
toxic dose 50- dose that produces toxicity in 50% of the population
therapeutic index
helps us determine safety margin for desired clinical effect
wide vs narrow therapeutic index
narrow TI- narrow margin of safety
wide TI- wide margin of safety
chirality
division of sterochemistry. deals with molecules that have a center of 3- dimensional asymetry
where does the asymmetry in chirality usually stem from
tetrahedral bonding of carbon- carbon binds to 4 different atoms
a molecule with 1 chiral carbon will exist as
2 enantiomers- the more chiral carbons in a molecule, the more entantiomers created
enantiomers
chiral molecules that are non superimposable mirror images of one another.
different entantiomers can produce other clinical effects
racemic mixture
contains 2 enantiomers in = amounts
about 1/3 of the drugs we give are entantiomers- most are racemic mixtures
ex of racemic mixtures
bupivicaine, ketamine, iso, des (not sevo)
