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84 Cards in this Set

  • Front
  • Back
Systemic Absorption depends on?
1. Physicochemical properties of the drug
2. Nature of the drug product
3. Anatomy and physiologic functions at the site of drug
absorption
Define:

Oxidation
Oxidizing Agent
Reduction
Reducing Agent
Antioxidant
• Oxidation Loss of electron
• Oxidizing agents Accepts electron
• Reduction Gain of electron
• Reducing agents Loses electron
• Antioxidant Supplies electron (gets oxidized itself)
What are Chelating Agents?

Example?
• Complexation using more than one bond
• EDTA (ethylene diamine tetraacetic acid)
What is Photolysis?
• Oxidation or hydrolysis could be catalyzed by light
• Lower the wavelength of light, higher the energy of radiation (in
terms of energy: UV>visible>IR)
What is Hygroscopicity?
• Deliquescent – absorbs water and dissolves itself
• Efflorescent – loses water to become lower hydrate or
anhydrate
• % of relative humidity is very important
Noyes-Whitney Equation
Measures dissolution rate

dc/dt = DAK (Cs – C) / h

where dc/dt = dissolution rate
D = diffusion rate constant
A = surface area of particle
K = oil/water partition coefficient
h = thickness of stagnant layer
Cs = conc of drug in stagnant layer
C = conc of drug in bulk solvent
dc/dt is _________ proportional to h

h changes constantly because of peristalsis movement
inversely proportional
Factors affecting dissolution
• Surface area
• Solubility
• pH
• Stirring
• Temperature
The peripheral compartment offers higher resistance to drug passage than the central compartment b/c?
1- Membrane restrictions (ie, blood brain barrier).
2- Poor blood perfusion
Disease state that can alter membrane restriction of a drug?
During meningitis inflamed brain cells may allow for higher drug uptake. Possible explanation: disease increased the BBB cell membranes permeability.
When does Perfusion occur?
Occurs when drug molecules cross the cell membranes as fast as they are brought to the transfer site. The transfer limit is the blood flow to the site or organ, i.e., a drug cannot flow faster than the speed at which it arrives at the transfer site. The permeability of cell membranes is quite high.
drug with large O/W partition coefficient tends to have a low or high R value in vivo?
high
protein binding or favorable solubility in the tissue site leads to longer or shorter distribution times?
longer
Restrictively eliminated
vs
Nonrestrictively eliminated
Restrictive- only free drug metabolized

Nonrestrictive- free drugs and protein bound drugs are eliminated
Ka indicates what?
Strength of protein binding

association constant relating the equilibrium concentrations of free drug, protein, and protein bound drug

The higher the Ka, the more the drug stays as a drug-protein complex
Drug parameters influencing V include
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
The macromolecules that are most involved in plasma protein binding
Albumin- reversible; binds to weak acidic (anionic) drugs; some cationic also bind

ᾀ1 acid glycoprotein-bind primarily basic (cationic) drugs like propanolol, imipramin;e, and lidocaine

Lipoproteins- bind plasma lipids, very lipophilic drugs and/or compounds
Scatchard Plot

What do these represent?

r
n
y-intercept
x-intercept
slope
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
Time when Drug concentration in the tissue compartment increases up to a maximum value at which time the drug levels in the tissue and the central compartments are in equilibrium.
Equilibrium
elimination half life
vs/2
distribution half life
elimination t 1/2 alpha= 0.693/alpha

distribution t 1/2 beta= 0.693/ beta
What is Vss?
Volume of distribution at steady state; sum of the volumes of the central and tissue compartments at steady state
What is Vexp?
Volume of distribution extrapolated; calculated by using B intercept of the general equation for two compartment model
Equation Recognition:

C= 32.9 e ^(-0.32t)

C= 10e^ (-2t) + 10e^ (-0.1t)

C= 95e^(-t) - 95e^(-6t)
one compartment IV

two compartment IV

one compartment oral
Equation recognition:

C= 40e^(-0.53t) + 20e^(-2.5t)

C=20e^ (-2t) + 10e^ (-0.1t)

C= 9.5e^ (-2t) - 9.5e^ (-16t)
two compartment IV(flip flop)

two compartment IV

one compartment oral
Typical value for Vc
3-20 L
What is Vss?
Volume of distribution at steady state; sum of the volumes of the central and tissue compartments at steady state
What is Vexp?
Volume of distribution extrapolated; calculated by using B intercept of the general equation for two compartment model
What is Vbeta?
Volume of distribution by area
compare Vss, Vexp, Vbeta, and Vc
Vexp> Vbeta~Vss>Vc
Compartmental approach
vs
Noncompartmental approach

for finding clearance in two-compartment model
compartmental:

CL=kVc or CL= bete* Vbeta

Noncompartmental:

CL= FD/ AUC
i. Cp = 30 exp (-0.3t) + 22 exp (-0.25t) + 10 exp (-0.1t)

ii. Cp = 6 exp (-2.2t) + 3 exp (-0.7t) –9 exp (-2.5t)

iii. Cp = 120 exp (-4.1t) + 91 exp (-0.41t)
i. Three compartment model IV bolus
ii. Two compartment model oral absorption
iii. Two compartment model IV bolus
iv. Cp = 100 exp (-0.13t) –100 exp (-3.46t)

v. Cp = 100 exp (-3.46t) –100 exp (-0.13t)

vi. Cp = 100 exp (-0.13[t-0.4]) –100 exp (-3.46[t-0.4])
iv. One compartment model oral absorption
v. One compartment model oral absorption, flip-flop
vi. One compartment model oral absorption with a lag time
vii. Cp = 75 exp (-0.13t) –89 exp (-1.2t)

viii. Cp = 45 exp (-0.35t)
vii- one compartment oral absorption with a lag time

viii- one compartment model IV bolus
Diffusion
vs
Perfusion
Slow Diffusion

Rapid Diffusion
Partition Coefficient
Oil/Water
affect on Vapp

High Protein binding
Low Protein binding
High Tissue Binding
Low Tissue Binding
High Protein binding-low Vapp
Low Protein binding- high Vapp
High Tissue Binding- high Vapp
Low Tissue Binding- low Vapp
VD is constant only when what?
drug conc are in equilibrium between plasma and tissue
When no binding occurs in tissue and plasma, the volume of the distribution will not exceed the real anatomic volume
Remember
if no points lie above the extrapolated line, then _____

if peak is above extrapolated line, then _____
one compartment

plot is two or higher compartment model
Study of size
Allometry

y=bWa
Most important Liver Functions
- 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
Bioavailability factor (F) depends on what two factors?
Fa- absorption factor

Ff-first pass effect factor
Drugs that have extensive first pass effects
1. Propanolol
2. Nitroglycerin
3. Morphine
High calorie diet defined by FDA
containing at least 50% of the calories derived from food
exact copies of brand product in appearance and performance
Generics
same performance characteristics as the brand product; not exact copies
bioequivalent products

pharmaceutically equivalent drug products having similar rate and extent of absorption when given in the same dose and route of administration
Purpose of the BCS Guidance
• Expands the regulatory application of the BCS and recommends methods for classifying drugs.
• Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.
Goals of the BCS Guidance:
• To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests.
• To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests.
• To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance.
Define:

Class 1
Class 2
Class 3
Class 4
Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
When is a drug considered HIGHLY SOLUBLE?
• A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.
When is a drug considered HIGHLY PERMEABLE?
• A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
When is a drug considered RAPIDLY DISSOLVING?
• 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.
Drug dissolves rapidly and is well absorbed. BA problem not expected for immediate release products.
CLASS 1
Drug dissolution is limited and well absorbed. BA is controlled by the dosage form and rate of release of the drug substance.
CLASS 2
Drug permeability is limited. BA may be incomplete if drug is not released and dissolved within absorption window
CLASS 3
Difficulty in formulating drug product that will deliver consistent drug bioavailability. An alternate route of administration may be needed.
CLASS 4
Drug product that contains same active drug substance in the same dosage form and is marketed by more than one pharmaceutical maunfacturer.
Multisource Products
Drug products for which the patent has not expired or has certain exclusivities so that only one manufacturer can make it.
Single Source Product
A book published annually by the FDA that lists drugs approved for multisource prescription.
The book facilitates the decisions on drug product selection for drug substitution to physicians and pharmacists.
Orange Book
For Systemic Drugs: Rate and extent to which the active ingredient or active moiety is absorbed from a drug product and reaches the blood.

For non-systemic drugs: rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability
Are pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.
May contain different inactive ingredients, provided the manufacturer identifies the differences and proved information that the differences do not affect safety and efficacy of the product.
Bioequivalent Drug Products
Document required by FDA to market a generic drug.

Pharmacodynamic or toxicology studies are not required.

Bioavailability studies are required.
Abbreviated New Drug Application

ANDA
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.
Drug Product
The Active Pharmaceutical Ingredient (API). Component of the drug that furnishes the pharmacological activity
Drug Substance
Relationship in terms of bioavailability, therapeutic response, or a set of established standards of one drug product to another
Equivalence
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
Pharmaceutical Alternatives
May differ in shape, release mechanism, excipients, expiration time, packaging.

Identical to other drug products in: same API, salt ,ester,same dodage form, same route of administration, same strength or concentration.
Pharmaceutical Equivalents
Requires physicians approval as the dosage form (tablet vs. capsule , vs. suspension) or salt of the API (ie., tetracycline hydrochloride vs tetracycline phosphate) changes.
The process of dispensing a pharmaceutical alternative.
Pharmaceutical Substitution
Usually pre-approved by the physician if specified in the prescription.
The pharmacist cannot substitute without physicians approval.
Generic Substitution
Drugs from same therapeutic class. Contain different API but are indicated for the same therapeutic objective.
Therapeutic Alternatives
Bioavailability Studies are needed when...
- the formula of a drug product changes
- the API changes (the salt), particle size
- dosage form changes
- performance changes (i.e. dissolution performance changes of tablets or capsules due to process or equipment changes)
- product design changes (i.e. from immediate to sustained release tablets).
When is it Flip Flop?
1. Negative (2nd exponent is smaller)
2. exponents are same
3. when Kb >>Ka

only occurs in oral absorption
Vss has similar value as ?
V beta
Vss is smaller than?
Vexp
Vss is larger than?
Vc
time elapsed from the drug intake to the beginning of the absorption process
Lag Time

Can have both positive and negative lag time
Lag time may be due to what?
1. Stomach emptying rate
2. intestinal motility
3. dosage form factors
Flip Flop occurs when?
Ke>> Ka

when experimental dosage forms delay absorption

Flip Flop effect cannot be determined without IV data
Peak time can be used to?
1. determine comparative bioavailability and bioequivanlence
2. Determine the preferred route of drug administration and the desired dosage form for the patient
3. to assess the onset of action
Flip flop does not usually occur in what?
two compartment oral models
Drugs with _____ ka are not suitable for oral dosage
Low
absorption process starts when?
when blood levels are observed
What is MRT?

How can you find it?
MRT= Total resistance time per amount of particles; time required for 63.2% of an intravenous dose to be eliminated from the body

MRT= AUMC/AUC = 1/k