distribution Flashcards
drug factors affecting distribution
physiochemical properties
- solubility
- size of the molecule
- ionization
- when an ionized species of drug accumulates in a particular tissue or organ because it cannot easily leave cells - ion trapping - ions can’t cross cell membranes without a transporter
physiologic factors affecting distribution
- protein binding of the drug
- lean to fat ratio of the patient
- blood flow to tissue (perfusion)
most well perfused tissues
kidney, heart, liver, brain. high rate of flow and extensive network of capillaries
why protien-bound drugs can’t leave capillaries
- paracellularly; too large (except liver)
2. transcellularly: too polar
2 main plasma binding protiens
- albumin: constant, hydrophobic and acidic drugs
2. alpha 1 acid glycoprotein: concentration can change due to stress (increase due to injury); basic drugs
high protein bound drugs
- won’t be able to cross filtration barrier in the kidneys (less excretion via urine)
- less free (unbound) drug in circulation and less to enter tissues
the amount of drug bound to a plasma protein is determined by (3)
- drug concentration
- number of available binding sites
- affinity of the drug for the protien
number of available binding sites
- protein binding reversible and saturable
- drugs compete for the same binding sites (results in more free molecules of both drugs)
- greatest effect observed with 90% protein bound or greater
hypoalbuminemia
low plasma levels, less drug bound to proteins. results in a higher free drug concentration in the plasma and possible toxic effects as more drug would be able to leave the plasma
TBW
total body water, 0.6 X kg = L
ECF
extracellular fluid, 0.2 x kg = L
ISF
interstitial fluid, 0.75 x .2 x kg = L (.15)
Plasma
.25 x .2 (0.05) x kg = L
ICF
intracellular fluid, .40 x kg = ICF
vd
dose/C- zero
C-Zero
theoretic drug concentration at the instant the dose is administered. often extrapolated value
Vd > 0.6 L/kg
indicates there is tissue binding of the drug. higher the number, greater degree of tissue binding
Vd between 0.2- 0.6
drug distributes in ECF and some in ICF. higher the number the more in the ICF
Vd 0.05-0.2
drug is freely distributed in ECF (plasma and interstitial)
Vd0.05 or less
drug confined to the plasma
why some only in plasma
big molecules, vascular, high protein bound, hydrophilic
why not in plasma
small, high lipophilicity
blood brain barrier
bain capillaries that protects the brain from dangerous molecules from entering into CNS
BBB capillaries
lined with a continuous layer of thin epithelial cells with tight junctions - lowest paracellular permeability in the body
astrocyte
in the brain. must cross astrocyte and the capillary endothelium before entering the brain
PgP
P-glycoprotein - present to help actively pump out drugs and other toxins from the brain
How do solutes distribute in the brain?
paracellular is impossible even for small solutes in BBB. transcellular transport and transcytosis are the only mechanisms for distribution of solutes in the brain. transcellular slowed from astrocyte sheath
what type of molecules can’t pass into the brain?
hydrophillic, polar, ionized, larger than 300 daltons
metabolism
collection of processes that alter a drug to produce a metabolite. metabolites usually have little to no biological activity except in prodrugs
excretion
removal of unchanged parent drug.
primary excretory organ
kidneys. can be eliminated through bile or pulmonary route
% undergoes metabolism. % undergoes elimination as unchanged molecules through bile and kidney
75, 25
most important metabolic organ
liver (100) ! then lungs (20), kidney (8), intestines (6)
biotransformation/metabolism serves to make drug molecules more_____
hydrophillic/polar and/or larger. makes them easier to eliminate from the body through the urine.
phase 1
reactions which a reactive functional group is introduced or exposed in the drug molecule. increases polarity and preparation for phase 2. product is a “derivative”
common phase 1 reactions
oxidation, reduction, hydrolysis, dealkylation, hydroxylaton. -OH, NH2, -COOH, -SH
sometimes it is polar enough to be excreted without subsequent phase 2 action. may undergo more than one phase 1 reactions.
primary reactions in CYP450 enzymes
phase 1
phase 2
reactions in which a molecule or large functional group provided by the body is added to the drug or a derivative to form a conjugate. increase water solubility for easier elimination out of the body.
drug may undergo more than 1 phase 2 reaction. doesn’t need to undergo phase 1 if already has a reactive roup
6 types of phase 2 reactions
- glucuronidation: derivative of glucose is added to the molecule, large molecular weight, polar weak acids, ionized at pH. morphine, valproic acid, UGT enzymes catalyze glucuronidation
- sulfation: addition of a sulfate group
- glutathione conjugation: addition of glutathione, cysteine, glycene, tripeptide of glutamic acid (acetaminophen)
- amino acid conjugation: addition of glycine, glutamine, aspartate, serine
- acylation: primary alkyl and aromatic amines are conjugated with acetic acid to form an acetyl conjugate (CH3COO-) hydralazine, isoniazid
- methylation: addition of a CH3 group
phase 2 reactions usually make it more water soluble except in _______
acetylation and methylation
cytochrome P450 enzymes
superfamily of mixed-function, heme-containing oxidases for oxidation reactions and hydrolysis. involved in endogenous substrates, steroids, fatty acids prostaglandins, and bile acids. remove drugs, carcinogens, plant toxins, enviromental pollutants
first number following CYP
family in which the enzymes share 40% amino acid homology
first letter following CYP
subfamily which the enzymes share 55% or greater homology
last number following CYP
gene product
- and number following the CYP
enzyme is in a different isoform
CYP families 1, 2, 3
act upon drugs and other xenobiotics (substances outside the body)
major enzymes in drug metabolism
CYP3A4,5
major enzyme in alcohol metabolism
CYP2E1
CYP families 4, 5, 8
fatty acids, prostaglandins, thromboxanes
CYP families 7, 11, 17, 21, 24, 27
steroid hormones
enterohepatic recycling and glucuronidation
drug gluceronides excreted in the bile and in the gut. hreabsorbed and go through cycle instead of being eliminated so it prolongs its action
exposure induces CYP enzyme
metabolism by that enzyme will increase and the patient will need a higher dose
smoking induces ____ so patients taking Zyprexa who are smokers will_____
CYP1A2, need a higher dose
if exposure inhibits CYP enzyme
patient will have higher than normal plasma concentration due to less metabolism of a drug
grapefruit juice inhibits ___. patient taking statin with grapefruit juice will need ____
CYP3A4, lower dose
Paxil inhibits ____.
CYP2D6. metabolizes the prodrug codeine into active drug morphine. Tylenol-3 will not be an effective pain reliever for patients taking Paxil
if a patient is taking more than one drug that is metabolized by the same enzyme
there will be a competition for that enzyme. translates into less of both drugs being metabolized and a higher plasma concentration
amount of drug excreted from the body is determined by three processes
- filtration (sends blood to urine)
- reabsorption (sends drug back to the blood)
- secretion (sends drug back into the body)
filtration
occurs at the glomerular capillary
larger the molecule, less of it that will be filtered out. anything larger than 5,000 daltons will not be filtered, protien-bound drugs will not be filtered (albumin is 67,000 daltons), hydrophillic polar and ionized drugs remain in the urine
reabsorption
sends drug back to the blood
drug returns to the blood from the filtrate in the tubule via the paratubular capillaries
non-ionized, lipophilic molecules do this
secretion
sends drug back to the body
drug leaves the paratubular capillaries and enters the tubular space
lipophillic molecules more likely as the process involves crossing multiple cell membranes
amount excreted =
amount filtered - (amount reabsorbed + amount secreted)
zero order equations
Ct = C-zero - Kt half-life = A / 2K (zero order is dose dependent)
First order equations
Ct= C-zero e ^ -Kt half-life = 0.693 / k (independent of dose)
volume of distribution equation
vd = dose/ c-zero (to normalize vd divide by the kg of the patients weight)
decrease in plasma conc same from one hour to next
zero order
decrease in plasma conc increases from one hour to next
first order
zero order k units
amount per time, mg/h
first order k units
inverse time, h^-1
if you are given half-life with no description of it being related to the dose administered
first order
the half life of a 300 mg dose of drug Y is 3 hours
zero order
the half life of drug X is 3 hours
first order
first order on graph paper
cartesian: curved line
log : straight line
zero order on graph paper
cartesian: straight line
nutrition factors influencing Activity and level of CYP enzymes
3A3,4 - grapefruit juice inhibits
smoking factors influencing Activity and level of CYP enzymes
1A2 - smoking induces, olanzapine
alcohol factors influencing Activity and level of CYP enzymes
2E1 - chronic alcohol induces
Drug factors influencing Activity and level of CYP enzymes
2C, 2D6, 3A3,4,5 affects lots
enviiroment factors influencing Activity and level of CYP enzymes
1A2, 2E1, 3A3, 4, 5
genetic polymorphism factors influencing Activity and level of CYP enzymes
2C9, 19, 2D6
what does the elimination rate constant tell us correlated to concentration
if K= 0.215 hr -1 then 20% of whatever the drug conc that’s how much is eliminated in one hour
factors regarding the ability of a drug to undergo ion trapping (4)
- degree of plasma protein binding of the drug
- pKa of the drug
- whether the drug is an acid or a base
- pH of the environment in the tissue or the organ
patients who express a non-functional allele of CyP2D6
should have a dose reduction on drugs that are metabolized by 2D6 or even avoid them completely
if you solve for Ct of the first dose. What would be the C-zero of the second dose?
first dose Ct + C-zero of the first dose = C-zero of second dose
