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Definitions |
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Physiologic Model
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Flow Model
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semibatch or unsteady CSTR:
dT/dt
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[Q-Ws-sum(Fio(Cpi(T-Tio)+[(-deltaHrx(T)(-rV)]/sum(NiCpi)
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Integrated 1st Order Rate Law
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ln[A]=-kt+ln[A]
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Two principal organs of elimination
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Liver
Kidneys
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Equation for Rate Law
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Rate=-(delta [A])/(delta t)=k[A]
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Intrinsic clearance
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represents the liver’s innate ability to clear unbound drug from intracellular water via metabolism or biliary excretion
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multiple reactions in a PFR
dT/dV
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[sum(rDelaH) -Ua(T-Ta)]/[sum(FjCpj]
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Restrictively eliminated
vs
Nonrestrictively eliminated
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Restrictive- only free drug metabolized
Nonrestrictive- free drugs and protein bound drugs are eliminated
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Bimolecular
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2 reactants are involved in an elementary step
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Bioavailability
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The “rate and extent” to which an active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action (true definition)
Bioavailability refers the fraction (extent) of the drug dose that reaches the systemic circulation.
Bioavailability is commonly referred to as “F” where F stands for “Fraction reaching systemic circulation”.
Disintegration, Dissolution, Diffusion, Metabolism in intestinal wall, metabolism in liver are all rate determining steps of bioavailability.
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Distribution phase
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- distribution into tissues primarily determines the early rapid decline in plasma concentration.
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What is E related to?
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ffb, CLint, LBF
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Difficulty in formulating drug product that will deliver consistent drug bioavailability. An alternate route of administration may be needed.
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CLASS 4
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Define:
Oxidation
Oxidizing Agent
Reduction
Reducing Agent
Antioxidant
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• Oxidation Loss of electron
• Oxidizing agents Accepts electron
• Reduction Gain of electron
• Reducing agents Loses electron
• Antioxidant Supplies electron (gets oxidized itself)
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Reaction Mechanism
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a series of elementary reactions that take place during the course of a complex reaction
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Reaction Rate
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A change in concentration of a reactant or product
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Renal Clearance
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Renal clearance (ClR) is defined as the proportionality term between urinary excretion rate and plasma concentration:
Rate of excretion = ClR*C
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semi-batch reactor mass balance
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raV = dN/adt
Fbo = dNb/dt
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The finished dosage form including the primary packaging (ie. tablet, capsule, solution in bottles) that contains the active ingredient usually in association with inactive ingredients.
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Drug Product
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Drug product that contains the same therapeutic moiety but as different salts, esters, or complexes.
Example: tetracycline HCL or tetracycline phosphate, equivalent to 250mg of tetracycline base
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Pharmaceutical Alternatives
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First order Reaction
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reaction whose rate depends on the concentrations of a single reactant raised to the first power. Use integrated rate law of ln[At] / ln[A0] = -kt
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Drug Transport and Absorption
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1. Transcellular - (passive diffusion, carrier mediated, and vesicular)
2. Paracellular - (passive diffusion)
3. Carrier Mediated - (active transport, facilitated diffusion)
4. Cellular Efflux
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2 Types of Carrier Mediated Transcellular Transport
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1. Active
2. Facilitated Diffusion
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Unbound Drug Concentration
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Only unbound drug passes through cell membranes to reach sites of storage, metabolism, or activity
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PBR heat exchanger in terms of molar flow rates
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r'*deltaHrx(T)-Ua](bulk density)(T-Ta)/[Fao(sum(Ni/Na)*Cpi + DeltaCpX)]\
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acid labile r...
example of acid labile drugs r...
how do u adjust it in pediatric...
What about weak acid?
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destroyed in acid environment
Penicillin, amoxicillin
increase dose in premature since higher acid level
But decrease dose in full term
W.A. absorbs more in acidic env. so less is needed
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Drug parameters influencing V include
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1- Lipophilicity
2- Plasma Protein Binding
3- Tissue Binding
higher the lipophilicity= higher V
higher plasma protein binding= lower V
higher tissue affinity= higher V
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Second Order Rate Reaction
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Rate of the reaction is directly proportional to the square of the concent ratio of one of the reactants
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First-Order Reactions
what does it look like?
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Amount or concentration of drug decreases at a rate that is proportional to the amount of drug remaining
da/dt = -KA
looks like a downward curved line (top left to bottom right conc. vs. time)
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GastroIntestinal enzymes r not developed fully, expect...
exception is
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higher F, less drug needed
Digoxin, need flora to become to active form
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Most important Liver Functions
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- Removing and excreting body wastes and hormones as well as drugs and other foreign substances
-Synthesizing plasma proteins, including those necessary for blood clotting
-Producing immune factors and removing bacteria, helping the body fight infection
-Produce bile, excrete bilirubin, store vitamins, minerals, and sugars, processes nutrients
Liver can self-repair and regenerate
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Systemic exposure of drugs-time profile
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Tmax happens at Cmax (peak of curve)
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Explain the advantage and disadvantage of MDRD
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Good for finding kidney disease
Not good for patients on drug, false result, Over estimate CrCL
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Document required by FDA to market a generic drug.
Pharmacodynamic or toxicology studies are not required.
Bioavailability studies are required.
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Abbreviated New Drug Application
ANDA
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Extraction Ratio (E or ER)
Ex: Cin = 10 mg/L and Cout = 1 mg/L
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(E)ER = (Cin - Cout)/Cin
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gastric emptying in neonates is responsible for drug...
Absorption depend on ...
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delaying, more time to reach Cmax
age and physical development
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Scatchard Plot
What do these represent?
r
n
y-intercept
x-intercept
slope
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r= moles of drug bound/total moles of protein
n= number of independent binding sites per protein molecule
y-intercept= nKa
x-intercept= n
slope= -Ka
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In a gas reactor, what is v (volumetric flow rate)
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v = vo(Ft/Fto)(Po/P)(P/To):
v = vo(1+ epilson*X)(Po/P)(P/To)
derived from:
Ct = Ft/v = P/(ZRT)
Cto = Fto/vo = Po/(ZoRTo)
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T or F
a)Clearance is not always additive
b) negative clearance denotes Cl filtered
c)Tubular secretion is passive and no need for carriers
d) all drugs r filtered to some extent
e) Bound drug is filtered
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a) F, always
b) F, Reabsorption
c) F, active
d) T
e)F, only unbound
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How would you create a dosage form that has the highest possible dissolution?
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You’d give it as an oral liquid. That way it’s already dissolved. Even then, much of the drug may not make it all the way into the blood.
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When is a drug considered RAPIDLY DISSOLVING?
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• A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.
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What model of administration shoud be avoided in neonates? Why
What is a neonate TBW?
ECW is a clue for...
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IM, they r bags of H2O, no muscle tone, no friction in the area/ contractility
Rectal admin., they poop it out but F may increase
Transdermal absor is higher, may be dangerous
lowest amount on face and groin area
92%
aminoglycosides, important becoz they have 50% ECW
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For IV, what is Css?
What is Co for IV?
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Css = ko / CL
Co = C e -(ke*t)
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