Pharmacokinetics Flashcards
Clearance
Rate of elimination / [Drug] plasma
First order elimination
Usual for dosage at which drugs are given
when the rate of elimination is proportional to the concentration of drug
Zero order elimination is when there is not a dependance of rate of concentration on clearance and you get drug buildup and potential severe toxicity
T1/2
0.693 * Vd / Cl
Bioavailability
fraction of unchanged drug reaching the systemic circulation by any route
not changed by percent bound to transport protein
IV= 100%
Oral = 100- stuff that is not absorped - stuff that is metabolized in first pass to liver (because ab into portal circulation) = can bypass this sublingually or partially sub-rectally (practically get about 50% to bypass and 50% ab into veins that go into portal system), or transdermally
Henderson Hasselbach equation
pH= pKa + log [U]/[P]
Weak acid = H+ + A- –> HA
Weak base = H+ + B –> HB+
C50
concentration of a drug that produces 50% of the max effect
want the initial concentration to key high in relationship to the C50
Peak drug concentration
= dose/ Vd
Steady state concentration
Rate of drug in / clearance
Concentration max drug
[steady state] + 1/2[bolus]
min = [steady state] - 1/2[bolus]
Vd
Hypothetical volume to take up drug dose at plasma concentration
Vd = dose / [Drug]plasma
Where does drug metabolism occur?
Mostly in the SER of the liver (duel blood supply)
First pass - oral or 50% rectal (superior rectal veins to IMA to Portal)
Drug absorbed = drug does * bioavailability
What are the most common phase I enzymes?
cytochrome p450 oxidases (CYP 450)
more than 50% are CYP 3A4
CYP 2D6 (polymorphisms which can result in rapid conversion of codeine to morphine)
What is the basic phase I rxn?
Drug + Fe –> + oxidized flavoprotein (oxidized by NADPH) –> Drug-Fe-O2 –> Drug-O + H20
What are the most common phase II enzymes?
UGT (UDP glucuronosyl transferase)
NAT (N-acetyl transferase)
GST (glutathione-s transferase)
SULT (sulfotransferase)
What drug is heavily metabolized by phase II enzymes?
Tylenol/ acetamenaphine - 95% excreted
BUT if you have altered hepatic fn or other drugs that compete for detox you can get toxic problem
treat with N-acetylcysteine
What is gray baby syndrome and how is it caused?
Infants lack some of the liver enzymes that adults do (UGT) and so can’t metabolize chloramphenicol (anti-bacterial) the way adults do and so get toxicity (cyanosis, ashy skin, floppy, hyothermia, cardiovascular collapse, hypotension)
What metabolism enzymes do the elderly loose?
Preferentially loose phase I enzymes unless they are malnurished /cachetic and then they don’t have the substrates for phase II rxns
What are some co-morbidities that can effect drug metabolism?
Altered hepatic function (has to be very severe to decrease metabolism)
Altered hepatic perfusion
Nutritional status
Cancer/cachexia
Competitive antagonist
no change in Emax at high enough agonist concentrations
right shift in the curve, but same Emax
C’ = C(1+ [I]/K) where [I] is a fixed concentration of antagonist and K is the dissociation constant of the antagonist
Ex: propranolol (beta antagonist, cleared differently with different people) so [I] will vary and so effect of C does of epi/ne will have a different C’ effect depending on the person ; also depends on C so if you give propranolol for a resting dose of epi and then you exercise, can see you overcome the effect of the anatgonist (reach the same pt on the y axis by moving across to the right enough on the x)
Non competitive antagonists
irreversible so agonists cannot increase [ ] to surmount inhibition ; so lower Emax unless a huge no of spare receptors, but can have the same Ec50
ex: phenoxybenzamine (a adrenergic receptor antagonist) to control HT of a pheo so will control HT even in face of large doses of epi from the tumor, but can’t overcome the block either if something goes wrong
Nicotinic receptor
5 subunits, ach binds to two a units (beta, gamma, and delta are other)
Non specific cation receptor, Enernst = 0, membrane potential -70 so cations (Na) physiologically flow in
Therapeutic window
TD50/ ED50
50% toxic/ 50% effective (want toxic dose to be much higher), want a large therapeutic window
4 beta lactam antibiotic families
- ) PCN
- ) cephalosporin
- ) carabepenems
- ) monobactam
What is the effect of a beta lactamase on PCN
penicilloic acid which is not antibacterial
