Unit 4 Pharmacology: Pharmacokinetics Flashcards
What relationship does Vd describe
the one between an administered dose of a drug and the plasma concentration that results
Vd assumes two things
the drug distributes instantaneously (full equilibration occurs at time =0) and that the drug is not subject to biotransformation or elimination before it fully distributes
what is the equation for Vd in relation to amount of drug and desired plasma concentration
Vd= (amount of drug/desired plasma concentration)
Distribution of total body water in 70kg patient:
ICF 28L, ECF 14L (Plasma volume 4L, ISF 10L)
what makes up ECF
plasma volume and ISF
when is a drug assumed to be lipophilic
when Vd exceeds TBW >.6L/kg (or >42L in 70k person)
when is a drug assumed to be hydrophillic
when Vd is less than TBW <.6L/kg (or <42L in 70kg person)
Vd is affected by which drug characteristics
molecular size, ionization, protein binding
Vd is affected by which patient characteristics
pregnancy and burns (among other things)
what is the relationship between Vd and loading dose
the higher the Vd, the higher the loading dose that must be given to achieve predetermined plasma concentration
formula for calculation of loading dose
Vd*(desired plasma concentration/bioavailability)
what is the bioavailability of an IV med
1, since it is injected directly into the bloodstream
drug clearance
volume of plasma that is cleared of drug per unit of time
clearance is directly proportional to
blood flow clearing organ, drug dose and extraction ratio
clearance is inversely proportional to
half life and drug concentration in the central compartment
most important organs involved in clearance
liver, kidney, organ independent (hofmann elimination and ester hydrolysis in the plasma)
to maintain a steady state concentration or “stable concentration” in the plasma, the infusion rate or dosing interval must equal
the rate of drug clearance by metabolism and elimination
(rate of administration=rate of elimination)
steady state is achieved after how many half lives
five (96.9% eliminated)
if a drug has a long half life, you can achieve steady state faster by
administering a loading dose
what does the plasma concentration curve illustrate
biphasic decrease of a drugs plasma concentration after a rapid IV bolus
what does the alpha phase of the plasma concentration curve illustrate
distribution
what does the beta phase of the plasma concentration curve illustrate
elimination
what is the steepness of the plasma concentration slope influenced by
the lipophilicity. the more lipophilic the drug, the larger the Vd, and the greater the slope
what is redistribution of a drug based on
concentration gradient between plasma and tissues (influenced by degree of lipophilicity)
as the plasma concentration (Cp) continues to decline as a result of continued elimination, what happens to the concentration gradient
it reverses and the drug redistributes back from the peripheral compartment into the central compartment
define rate constant
speed at which reaction occurs (how fast a molecule moves between compartments)
define K12
rate constant for drug transfer from central to peripheral compartment
define K21
rate constant for drug transfer from peripheral to central compartment
define ke
rate constant for drug elimination from the body
what is the big takeaway from a three compartment model (as compared to the two compartment model we use at baseline)
there are different rate constants to and from each compartment and from the central compartment. and some compartments may saturate before others. so different rates of compartment saturation impact how the drug is eliminated from the body
after administering an IV drug that distributes into a one compartment model, the patients serum contains 6.25% of the original dose. how many half lives have elapsed?
4
elimination half life
the time it takes for 50% of the drug to be removed from the body after rapid IV injection
elimination half time
the time it takes for 50% of the drug to be removed from the plasma during the elimination phase
when will the elimination half life and elimination half time be different
when the rate of drug removal from the plasma is not the same as the rate of drug removal from the body
does half life measure a constant fraction or a constant amount?
constant fraction. ex) it takes the same time for the plasma concentration of a drug to fall from 200mg/L to 100mg/L as it takes for the same drug to fall from 50mg/L to 25mg/L
define context sensitive half time
time required for plasma concentration to decline by 50% after the infusion has stopped. it takes the duration of drug administration into account
context sensitive half time of phenylpiperdines from highest to lowest
fentanyl (by far), alfentanil, sufentanil, remifentanil
define an acid
substance that donates a proton HA+<–>H+ + A
(a drug that is a weak acid will donate a proton to water)
define a base
substance that accepts a proton B- + H+ <–> BH
(a drug that is a weak base will accept a proton from water)
what’s the difference between a strong base or acid and a weak base or acid?
if you put a strong acid or a strong base in water, it will dissociate completely. if you put a weak acid or a weak base in water, a fraction will ionize, and the remaining fraction will be non ionized.
ionization is dependent on two factors
the pH of the solution and the pKa of the drug
the pKa (a constant value) tells us how much the drug wants to behave like _______
an acid. low pKa = amazing acid. high pKa= terrible acid.
a drugs pKa equals the pH where
50% of the drug is ionized and the other 50% of the drug is non ionized
Henderson Hasslebach equation
pH = pKa + log ((base)/(conjugate acid))
the bottom line about weak bases in an acidic or basic solution
in an acidic solution, weak bases are more ionized and water soluble
in a basic solution, weak bases are more non ionized and lipid soluble
the bottom line about weak acids an an acidic or basic solution
in an acidic solution, weak acids are more non ionized and lipid soluble
in a basic solution, weak acids are more ionized and water soluble
drug formulations: a drug that is a weak acid is usually paired with
a positive ion such as sodium, calcium, or magnesium
ex) sodium thiopental
drug formulations: a drug that is a weak base is usually paired with
a negative ion, such as chloride or sulfate
ex) lidocaine hydrochloride
solubility of an ionized solution
hydrophilic, lipophobic
pharmacologic effect of an ionized solution
not active
hepatic biotransformation of an ionized solution
more likely
diffusion across lipid bilayers (BBB, GI, placenta) of an ionized solution
NO diffusion
solubility of a non ionized solution
lipophilic, hydrophobic
pharmacologic effect of a non ionized solution
active
hepatic biotransformation of a non ionized solution
more likely
renal elimination of a non ionized solution
less likely
diffusion across lipid bilayer of a non ionized solution (BBB, GI, placenta)
yes, diffusion occurs
when does the ionized fraction predominate
the molecule is a weak base and the pH of the solution <the pKa of the drug (a base is added to an acidic solution)
the molecule is a weak acid and the pH of the solution > the pKa of the drug (an acid is added to a basic solution)
when does the non ionized fraction predominate
the molecule is a weak base, and the pH of the solution is > the pKa of the drug (a base is added to a basic solution)
the molecule is a weak acid, and the pH of the solution is < the pKa of the drug (an acid is added to an acidic solution)
why does maternal alkalosis and fetal acidosis create the strongest gradient for passage of local anesthetic from the mother to the fetus?
maternal alkalosis increases the non ionized fraction in the maternal circulation; more LA is available to diffuse across the placenta. fetal acidosis increases the ionized fraction in side the fetus. this prevents the LA from crossing the placenta back to the mother, thus trapping it in the fetus.
which LA is most likely to undergo fetal ion trapping
lidocaine
which LA is least likely to undergo fetal ion trapping
chlorpromazine (due to high pKa and rapid metabolism in the mothers blood)
how does fetal pH compare to maternal pH
fetal pH is a little lower
how to calculate free fraction perfect change based on bound fraction (originally 98% bound, decreased to 96% bound)
percent change = [(new value of unbound - old value of unbound drug) / (old value of unbound drug)] * 100
ex) [(4-2) / 2] x 100 = 100%
which organ synthesizes plasma proteins
liver
types of weak bonds drug and protein can form (3)
ionic(-), hydrogen(-) or van der waals
what does plasma protein effect (2)
intensity of drug effect and drug DOA
plasma concentration of albumin can be decreased by (5)
liver disease, renal disease, old age, malnutrition, pregnancy
what charge does albumin carry
negative
what drugs does albumin primarily bind do
acidic primarily (but can sometimes bind with neutral and basic drugs)
what drugs does a1 acid glycoprotein bind to
basic drugs
plasma concentration of a1 glycoprotein is increased by (5)
surgical stress, MI, chronic pain, RA, advanced age
plasma concentration of a1 acid glycoprotein is decreased by
neonates, pregnancy
what drugs does the beta globulin protein bind to primarily
basic drugs
why does renal disease decrease plasma protein
increase in protein extraction
relationship between unbound fraction of drug and potency
increase in unbound fraction of drug means increase in potency
relationship between Vd and degree of plasma protein binding
the volume of distribution is inversely related to the degree of plasma protein binding
highly protein bound drugs’ metabolism and elimination rates are usually
slower
zero order kinetics
process that metabolizes constant amount of drug per unit of time (theres not enough enzyme available to metabolize all the drug that is delivered to it aka the process is saturated. therefore, the enzyme will metabolize a constant amount per unit time.)
first order kinetics
constant fraction of the drug is metabolized per unit of time (less drug than enzyme aka no saturation. most drugs we administer follow this)
rate of metabolism depends on two factors
concentration of drug at site of metabolism and intrinsic rate of metabolic process
what is concentration of a drug at the site of metabolism influenced by
blood flow to the site of metabolism
what is the intrinsic rate of the metabolic process influenced by
genetics, enzyme induction, enzyme inhibition
examples of drugs that utilize zero order kinetics (6)
ASA, phenytoin, alcohol, warfarin, heparin, theophylline
three phases of drug metabolism
phase 1: modification (oxidation, reduction, hydrolysis)
phase 2: conjugation
phase 3: excretion
types of metabolism that occur in the plasma include
hofmann elimination (pH and temperature dependent)
hydrolysis reactions catalyzed by non specific plasma esterase’s and pseudocholinesterases
primary role of metabolism
change a lipid soluble, pharmacologically active compound into a water soluble, pharmacologically inactive byproduct
what happens during phase 1 of metabolism
increase in water solubility or polarity, usually by P450 system
what are the three types of phase 1 reactions
oxidation, reduction, hydrolysis
what happens during oxidation
removes electrons from a compound
what happens during reduction
adds electrons to a compound
what happens during hydrolysis
adds water to a compound to split it apart
what happens during phase 2 of metabolism (conjugation)
adds endogenous, highly polar, water soluble substrate to the molecule. produces a water soluble biologically inactive molecule ready for excretion
common substrates for conjugation reactions (5)
glucoronic acid, glyceine, acetic acid, sulfuric acid, or a methyl group.
what happens during phase 3 of metabolism (elimination)
involves ATP dependent carrier proteins that transport drugs across cell membranes. these are present in kidneys, liver, and GI tract
drugs that undergo perfusion dependent hepatic elimination include
fentanyl, lidocaine, propofol
drugs that undergo capacity dependent elimination include
diazepam and rocuronium
hepatic clearance is dependent on
liver blood flow and hepatic extraction ratio
define hepatic extraction ratio
how much drug is delivered to the clearing organ versus how much drug is eliminated by that organ
hepatic extraction ratio equation
extraction ratio= (arterial concentration-venous concentration)/(arterial concentration)
