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56 Cards in this Set
- Front
- Back
maximum concentration
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absorption rate = elimination rate
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AUC = area under the curve
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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 |
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Advantages of Oral Administration
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common, safe, convenient, economical, amenable to self-administration, quick onset, duration of effect is flexible
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Disadvantages of oral administration
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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 |
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ADME
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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) |
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What are the 6 types of entero movement of drugs relevant to the drug absorption and distribution model?
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1) paracellular
2) carrier-mediated 3) limited carrier-mediated 4) reverse carrier-mediated 5) metabolizing enzymes 6) combined movement |
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paracellular
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drug is transported between cells
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carrier-mediated
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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.
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limited carrier-mediated
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some fraction is moved into blood stream, some fraction is moved back into the gut limen
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reverse carrier-mediated
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drug is removed from the blood stream and delivered back to the lumen. P-gp is an example in enterocytes.
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metabolizing enzymes
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the drug is metabolized before it hits the blood stream. CYP3A is an example in enterocytes.
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combined movement
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any combination of paracellular, carrier-mediated, limited carrier-mediated, reverse carrier-mediated or metabolizing enzyme entero movement of drugs
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passive diffusion
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net movement of drug from high concentration to low concentration in order to move toward concentration equilibrium
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partition coefficient
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Oil:water, higher partition coefficient means higher lipophilicity
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what three factors affect permeability
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size, lipophilicity, charge
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how do changes in lipophilicity change permeability?
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increased lipophilicity, increased permeability
decreased lipophilicity, decreased permeability |
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how do changes in size change permeability?
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smaller molecular weight higher permeability
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how does changes in charge change permeability?
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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 |
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What is the gastric pH?
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1.5 - 7
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What is the intestinal pH?
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6.2 - 7.5
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What is the urine pH?
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4.5 - 7.5
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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?
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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. |
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What are the three types of barriers most relevant to Pharmacokinetics?
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1) BBB
2) Renal tubules 3) blood capillaries & renal glomerular membranes 4) hepatic blood vessels |
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what types of molecules may pass through the BBB?
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since there are very tight junctions, only small, lipophilic molecules can pass
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what types of molecules may pass through renal tubules?
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relatively non-ionized, lipophilic drugs can be reabsorbed
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what types of molecules may pass through blood capillaries & renal glomerular membranes?
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porous membranes allow non-polar and polar molecules as well as MW up to albumin to pass
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what types of molecules may pass through hepatic blood vessels?
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basement membranes and tight junctions restrict movement
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P-gp
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P-glycoprotein is an efflux transport protein that is used in reverse carrier-mediated transport. that pushes drugs back out into the gut lumen.
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CYP3A
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drug metabolizing enzyme in the gut wall enterocytes
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What is the clearance of any organ?
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CL = Q*E
CL = clearance Q = blood flow E = extraction ratio |
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What is the half-life t1/2 of a drug?
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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.
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perfusion-rate limited
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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.
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permeability-rate limited
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membranes resist the drug, so movement is limited by movement of drug into the tissue
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protein binding on volume
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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.
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how can volume of distribution (V) be larger than the total body water of an individual?
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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 |
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Cytochrome P450 enzymes = CYP P450
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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)
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What is involved in phase I CYP P450 reactions?
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these involve the most common routes of oxidation, reduction, and hydrolysis
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What is involved in phase 2 CYP P450
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conjugation reactions, glucuronidation and sulfation are the primary pathways
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does all metabolism produce inactive drug?
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nope. some metabolism (aspirin, among others) produces active metabolites.
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What's the story on Alcohol and Acetaminophen?
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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.
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What is the renal basis for the liver producing water soluble compounds?
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increases hydrophilicity increases excretion and simultaneously slows reabsorption since excretion favors hydrophilicity and reabsorption favors lipophilicity
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CLtotal
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this represents total clearance and it depends on CLh and CLr, which are renal clearance and hepatic clearance
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what is the rate limiting step in intestinal absorption?
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gastric emptying
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what does a high fat meal do to absorption?
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high fat will slow gastric emptying time which in turn will slow absorption and delay the onset of action
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what three processes is F dependent on?
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Fa = fraction of drug absorbed
Fg = fraction of drug escaping gut metabolism Fh = fraction of drug escaping hepatic metabolism F = Fa*Fg*Fh |
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what makes a generic completely exchangeable with a name brand drug?
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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) |
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enterohepatic recirculation
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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
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E = ER = extraction ratio
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ER = (Cin - Cout)/Cin
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F*
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F* is the fraction of drug escaping first pass metabolism and F* = 1 - ER
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factors that affect hepatic blood flow (Q)
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1) CHF
2) shock 3) food intake 4) drugs 5) cirrhosis |
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What are the determinants of Hepatic Clearance (CLh)?
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1) hepatic blood flow (Q)
2) protein binding (fup) 3) intrinsic clearance (CLint) |
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what is intrinsic clearance?
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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) |
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when drugs overwhelm the enzymatic capacity of the body, what happens?
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you can have so much drug that you have reduced metabolism.
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what factors affect CLint?
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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 |
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What is significant about drug interaction and CLint?
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drugs will interact and change CLint to alter its effect. be careful and be cognizant
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pediatric patients have an exaggerated response to some drugs. why?
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because of CYP2D6 reduced ability to metabolize drugs, which provides a higher level of unbound, unmetabolized drug... larger effect
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