Pharmacokinetics lecture Flashcards
What is the most common CYP450 enzyme
CYP3A4
What CYP450 enzyme converts codeine to active opioid (morphine)
CYP2D6
What does grape juice do to liver enzyme and what impact does it have on drug’s plasma concentration?
it inhibits liver enzyme, thus increases plasma drug concentration
Clearance formula
Clearance=Q (liver blood flow) X E (extraction ratio)
What does high extraction ratio mean to clearnace?
The more blood flow I have, the more drug will be taken out of the system
Extraction ratio of perfusion dependent elimination
E>=0.7
Examples of high-clearance drugs
verapamil, morphine and lidocaine
Total volume of fluid in body
42L
volume of ISF
10L
volume of intracellular
28L
volume of plasma
5L
normal Vd
0.6L/kg (42L/70kg)
what are the 2 types of hepatic clearance?
perfusion dependent elimination & capacity dependent elimination
Extraction ratio of capacity dependent elimination
E<0.3
what does capacity dependent elimination depend on?
Protein binding and hepatic enzymes
examples of capacity dependent elimination drugs
diazepam and theophylline
how many half-lives does it take for a drug to be considered eliminated from the body
4-5 half-lives
drugs actively excreted by kidneys
furosemide, morphine, meperidine(demerol), penicillin, quaternary ammonium compounds
drugs excreted during passive glomerular filtration
amino glycoside antibiotics
drugs excreted by active secretion in proximal loop
penicillin
drugs reabsorbed in distal loop
propofol (lipophilic)
What factors does age affect drug PK?
liver fxn, renal fxn, increased fat, increased Vd
Women specific response to anesthetics
quicker emergence; sensitive to paralytics, adverse effects of opioids
Men specific response to anesthetics
more sensitive to propofol
common membrane transporters
P-gp, MDR1, ABCB1
what type of drug is dapagliflozin?
SGLT2 inhibitor
what adverse effect does SGLT2 have?
hypotension, dehydration
2 types of membrane transporters
Uptake and efflux
examples of uptake transporters
OATP family, OAT family (SLC22A), OCT family(SLC22A), glucose transporters (organic anion-transporter, transporters are more uptakers )
examples of efflux transporters
P-GP, MRP, BSEP, BCRP (the last P stands for pump, pumps are more effluxers)
what is efflux transporter also called
reverse transporter
factors influence PK activity
ionization and lipid solubility; ion trapping; protein binding; molecular size; drug transporters.
important compartments in the body are:
BBB; GI; placenta
what plays important role in ionization?
hepatocytes and renal absorptive membrane
locations ion trapping commonly happens
brain and placenta
ph of CSF
7.4
ph of stomach, small intestine and ileum + large intestine
1-3, 5-6, 7-8
max size of molecular to pass lipid barriers
100-200 amu
which patients have reduction in proteins?
Liver or kidney disease; malnutrition, pregnant woman
albumin likes to bind with what?
acids
alpha1-acid protein likes to bind with what
bases
rank the force of chemical bonds between molecules (intermolecule)
covalent>ionic>hydrogen>van der waals
what forces are intramolecular
covalent> ionic
what forces are intermolecular
hydrogen>dipole>van der waal
SLT, OST main site of action includes
BBB, GI tract, renal tubules, biliary tract, placenta
PGP aka
MDR1 (multidrug resistance protein 1), ABCB1 (ATP binding cassettes sub family b1)
PGP characteristics
membrane embedded protein; efflux transporter; non-selective; protective fxn (fetus, brain)
differentiate 1st order, zero order, 1st pass effect, phase 1 and phase 2. Perfusion dependent vs capacity dependent clearance.
1st order, zero order, phase 1, phase 2 describe metabolism. 1st pass effect is absorption, perfusion dependency vs capacity dependency are about clearance
IM bioavailability
75-100%
transdermal
80-100%
inhalation
5-100%
is liver the only organ having first pass effect?
lungs also have first pass effect
large Vd
>0.6L/kg
small Vd
<0.4L/kg
blood brain barrier characteristics
tight junction; P-GP, lipophilic, small molecules
metabolism aka
biotransformation
Other than liver, what other organs metabolize?
Lungs, plasma, GI, skin, kidneys, heart, brain
what happens during phase 1
oxidation, reduction and hydrolysis
what happens during phase 2. List one substance involved
conjugation.
Glucuronic
In which phase of metabolism is CYP450 involved?
phase I
where are CYP450 located?
smooth ER
CYP aka
mixed-function oxidase system
example of enzyme induction and effect
alcohol, reduced half life, subtherapeutic
example of enzyme inhibition and effect
grape fruit juice, overdose
example of enzyme inhibition and effect
grape fruit juice, overdose
example of zero order kinetics
alcohol
perfusion dependent elimination extraction ratio
>0.7
capacity dependent elimination extraction ratio
<0.3
perfusion dependent elimination drugs aka and examples
high clearance drugs; verapamil, lidocaine, morphine
what does capacity dependent elimination depend on
hepatic enzyme and protein binding
examples of capacity dependent elimination
diazepam and theophylline
examples of drugs actively secreted by liver
morphine, meperidine, quaternary ammonium, furosemide, penicillin
drug that is eliminated during glomerular filteration
aminoglycoside antibodies
drug eliminated during active secretion
penicillin
drug going through reabsorption
propofol
gender factors with drugs
female emerge quicker, more sensitive to paralytics, more PONV; Male sensitive to propofol
is sux affected by liver? why?
no, sux effect is at NMJ, does not get metabolized, just in vascular.
