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56 Cards in this Set

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maximum concentration
absorption rate = elimination rate
AUC = area under the curve
the curve is a dose response curve and the area under the curve is proportional to the response intensity and duration

AUC = F*D/CL

F = bioavailability = fraction of drug that reaches systemic circulation
CL = clearance
D = dose
Advantages of Oral Administration
common, safe, convenient, economical, amenable to self-administration, quick onset, duration of effect is flexible
Disadvantages of oral administration
1) Emesis: GI mucosal irritation
2) degredation: digestive enzymes or low gastric pH, mucosal enzymes may metabolize before absorption -> reduced F
3) easily alterable absorption profile: presence of food or other drugs affect absorption
4) Compliance: efficacy relies on patients compliance
ADME
Absorption: movement of unchanged drug from site of administration to site of measurement (plasma)
Distribution: reversible transfer of drug from site of measurement and tissue to terminal site (intended or unintended)
Metabolism: conversion of one chemical entity to another (liver)
Excretion: irreversible loss of chemically unchanged or parent drug (kidney)
What are the 6 types of entero movement of drugs relevant to the drug absorption and distribution model?
1) paracellular
2) carrier-mediated
3) limited carrier-mediated
4) reverse carrier-mediated
5) metabolizing enzymes
6) combined movement
paracellular
drug is transported between cells
carrier-mediated
drug is carried by proteins through enterocyte into the blood stream. because rate of transfer is limited to the carrier protein, the system can become saturated and the rate has a limited rate capacity.
limited carrier-mediated
some fraction is moved into blood stream, some fraction is moved back into the gut limen
reverse carrier-mediated
drug is removed from the blood stream and delivered back to the lumen. P-gp is an example in enterocytes.
metabolizing enzymes
the drug is metabolized before it hits the blood stream. CYP3A is an example in enterocytes.
combined movement
any combination of paracellular, carrier-mediated, limited carrier-mediated, reverse carrier-mediated or metabolizing enzyme entero movement of drugs
passive diffusion
net movement of drug from high concentration to low concentration in order to move toward concentration equilibrium
partition coefficient
Oil:water, higher partition coefficient means higher lipophilicity
what three factors affect permeability
size, lipophilicity, charge
how do changes in lipophilicity change permeability?
increased lipophilicity, increased permeability

decreased lipophilicity, decreased permeability
how do changes in size change permeability?
smaller molecular weight higher permeability
how does changes in charge change permeability?
weak acids w/ low pH = less ionized = more absorption

weak acids w/ high pH = more ionized = less absorption

weak bases w/ low pH = more ionized = less absorption

weak bases w/ high pH = less ionized = more absorption
What is the gastric pH?
1.5 - 7
What is the intestinal pH?
6.2 - 7.5
What is the urine pH?
4.5 - 7.5
Charge is relative, so how does the pKa of a drug as it interacts with the pH of the environment change its permeability based on the pH partition hypothesis?
before a drug is introduced in a system, there is an equilibrium. When you introduce a drug into once side of a membrane, it has a pKa that is either higher or lower than the system pH.

If the drug's pKa is lower than the pH and the drug is a weak base, then it is less ionized, which means there is more absorption

Once the drug passes the membrane, if the pKa of this weak base is then above the pH value, then it is relatively ionized and cannot be reabsorbed.
What are the three types of barriers most relevant to Pharmacokinetics?
1) BBB
2) Renal tubules
3) blood capillaries & renal glomerular membranes
4) hepatic blood vessels
what types of molecules may pass through the BBB?
since there are very tight junctions, only small, lipophilic molecules can pass
what types of molecules may pass through renal tubules?
relatively non-ionized, lipophilic drugs can be reabsorbed
what types of molecules may pass through blood capillaries & renal glomerular membranes?
porous membranes allow non-polar and polar molecules as well as MW up to albumin to pass
what types of molecules may pass through hepatic blood vessels?
basement membranes and tight junctions restrict movement
P-gp
P-glycoprotein is an efflux transport protein that is used in reverse carrier-mediated transport. that pushes drugs back out into the gut lumen.
CYP3A
drug metabolizing enzyme in the gut wall enterocytes
What is the clearance of any organ?
CL = Q*E

CL = clearance
Q = blood flow
E = extraction ratio
What is the half-life t1/2 of a drug?
t1/2 is proportional to V/CL, which means that it's proportional to volume of distribution and inversely proportional to the extend to which it moves outside the vascular space. also, since k = rate constant = CL/V, t1/2 is inversely proportional to the rate of elimination. higher rate of elimination mean shorter half life.
perfusion-rate limited
where there is no distinction between blood and tissue as far as where the drug moves freely. the limitation of the drug getting to target is movement through the tissue perfusion.
permeability-rate limited
membranes resist the drug, so movement is limited by movement of drug into the tissue
protein binding on volume
ratio of bound to unbound drug in plasma. drug can be bound or unbound in blood and can be bound or unbound in tissue. only unbound drug in blood can move into tissue.
how can volume of distribution (V) be larger than the total body water of an individual?
V = Vp + (fup/fut)*Vt

volume depends on that fup/fut ratio. which is directly related to the affinity of plasma proteins for binding and for tissue proteins for binding.

Vp = volume of plasma
fup = fraction unbound in plasma
fut = fraction unbound in tissue
Vt = volume of tissue
Cytochrome P450 enzymes = CYP P450
enzymes in the liver that are responsible for metabolizing that makes it more water soluble (to release in urine) and big (to release in the bile)
What is involved in phase I CYP P450 reactions?
these involve the most common routes of oxidation, reduction, and hydrolysis
What is involved in phase 2 CYP P450
conjugation reactions, glucuronidation and sulfation are the primary pathways
does all metabolism produce inactive drug?
nope. some metabolism (aspirin, among others) produces active metabolites.
What's the story on Alcohol and Acetaminophen?
When you drink alcohol regularly, you up regulate CYP2E1, if you remove ethanol, then there is excessive CYP2E1 and without time to down regular, they will metabolize acetaminophen which produces NAPQI, which is a toxic metobolite.
What is the renal basis for the liver producing water soluble compounds?
increases hydrophilicity increases excretion and simultaneously slows reabsorption since excretion favors hydrophilicity and reabsorption favors lipophilicity
CLtotal
this represents total clearance and it depends on CLh and CLr, which are renal clearance and hepatic clearance
what is the rate limiting step in intestinal absorption?
gastric emptying
what does a high fat meal do to absorption?
high fat will slow gastric emptying time which in turn will slow absorption and delay the onset of action
what three processes is F dependent on?
Fa = fraction of drug absorbed
Fg = fraction of drug escaping gut metabolism
Fh = fraction of drug escaping hepatic metabolism

F = Fa*Fg*Fh
what makes a generic completely exchangeable with a name brand drug?
they must be bio-equivalent
1) same drug
2) same strength
3) same route of administration
4) same bio-availability

must be same therapeutic equivalent
1) bio-equivalent
2) pharmaceutical equivalent (same dosage form, same salt form)
enterohepatic recirculation
a drug that is reabsorbed after it hits the small instestine in the bile and if unmetabolized can alter the time concentration profile with a secondary increase in systemic circulation
E = ER = extraction ratio
ER = (Cin - Cout)/Cin
F*
F* is the fraction of drug escaping first pass metabolism and F* = 1 - ER
factors that affect hepatic blood flow (Q)
1) CHF
2) shock
3) food intake
4) drugs
5) cirrhosis
What are the determinants of Hepatic Clearance (CLh)?
1) hepatic blood flow (Q)
2) protein binding (fup)
3) intrinsic clearance (CLint)
what is intrinsic clearance?
the intrinsic ability of hepatic enzymes to eliminate drug when there are no limitations due to blood flow or protein binding. it is measured by volume over time.

CLint = Vmax/(Km + C)
when drugs overwhelm the enzymatic capacity of the body, what happens?
you can have so much drug that you have reduced metabolism.
what factors affect CLint?
1) inducing metabolism by increasing Vmax will increase CLint
2) increasing Km will decrease CLint because increasing Km is essentially increasing enzyme inhibition
3) liver disease decreases CLint because drug metabolism enzymes decrease
What is significant about drug interaction and CLint?
drugs will interact and change CLint to alter its effect. be careful and be cognizant
pediatric patients have an exaggerated response to some drugs. why?
because of CYP2D6 reduced ability to metabolize drugs, which provides a higher level of unbound, unmetabolized drug... larger effect