P1- Kinetics Exam 2

Front 1

Systemic Absorption depends on?

Back 1

1. Physicochemical properties of the drug
2. Nature of the drug product
3. Anatomy and physiologic functions at the site of drug
absorption

Front 2

Define:

Oxidation
Oxidizing Agent
Reduction
Reducing Agent
Antioxidant

Back 2

• Oxidation Loss of electron
• Oxidizing agents Accepts electron
• Reduction Gain of electron
• Reducing agents Loses electron
• Antioxidant Supplies electron (gets oxidized itself)

Front 3

What are Chelating Agents?

Example?

Back 3

• Complexation using more than one bond
• EDTA (ethylene diamine tetraacetic acid)

Front 4

What is Photolysis?

Back 4

• 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)

Front 5

What is Hygroscopicity?

Back 5

• Deliquescent – absorbs water and dissolves itself
• Efflorescent – loses water to become lower hydrate or
anhydrate
• % of relative humidity is very important

Front 6

Noyes-Whitney Equation

Back 6

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

Front 7

dc/dt is _________ proportional to h

h changes constantly because of peristalsis movement

Back 7

inversely proportional

Front 8

Factors affecting dissolution

Back 8

• Surface area
• Solubility
• pH
• Stirring
• Temperature

Front 9

The peripheral compartment offers higher resistance to drug passage than the central compartment b/c?

Back 9

1- Membrane restrictions (ie, blood brain barrier).
2- Poor blood perfusion

Front 10

Disease state that can alter membrane restriction of a drug?

Back 10

During meningitis inflamed brain cells may allow for higher drug uptake. Possible explanation: disease increased the BBB cell membranes permeability.

Front 11

When does Perfusion occur?

Back 11

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.

Front 12

drug with large O/W partition coefficient tends to have a low or high R value in vivo?

Back 12

high

Front 13

protein binding or favorable solubility in the tissue site leads to longer or shorter distribution times?

Back 13

longer

Front 14

Restrictively eliminated
vs
Nonrestrictively eliminated

Back 14

Restrictive- only free drug metabolized

Nonrestrictive- free drugs and protein bound drugs are eliminated

Front 15

Ka indicates what?

Back 15

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

Front 16

Drug parameters influencing V include

Back 16

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

Front 17

The macromolecules that are most involved in plasma protein binding

Back 17

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

Front 18

Scatchard Plot

What do these represent?

r
n
y-intercept
x-intercept
slope

Back 18

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

Front 19

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.

Back 19

Equilibrium

Front 20

elimination half life
vs/2
distribution half life

Back 20

elimination t 1/2 alpha= 0.693/alpha

distribution t 1/2 beta= 0.693/ beta

Front 22

What is Vss?

Back 22

Volume of distribution at steady state; sum of the volumes of the central and tissue compartments at steady state

Front 23

What is Vexp?

Back 23

Volume of distribution extrapolated; calculated by using B intercept of the general equation for two compartment model

Front 24

Equation Recognition:

C= 32.9 e ^(-0.32t)

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

C= 95e^(-t) - 95e^(-6t)

Back 24

one compartment IV

two compartment IV

one compartment oral

Front 25

Equation recognition:

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

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

C= 9.5e^ (-2t) - 9.5e^ (-16t)

Back 25

two compartment IV(flip flop)

two compartment IV

one compartment oral

Front 26

Typical value for Vc

Back 26

3-20 L

Front 27

What is Vss?

Back 27

Volume of distribution at steady state; sum of the volumes of the central and tissue compartments at steady state

Front 28

What is Vexp?

Back 28

Volume of distribution extrapolated; calculated by using B intercept of the general equation for two compartment model

Front 29

What is Vbeta?

Back 29

Volume of distribution by area

Front 30

compare Vss, Vexp, Vbeta, and Vc

Back 30

Vexp> Vbeta~Vss>Vc

Front 31

Compartmental approach
vs
Noncompartmental approach

for finding clearance in two-compartment model

Back 31

compartmental:

CL=kVc or CL= bete* Vbeta

Noncompartmental:

CL= FD/ AUC

Front 32

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)

Back 32

i. Three compartment model IV bolus
ii. Two compartment model oral absorption
iii. Two compartment model IV bolus

Front 33

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])

Back 33

iv. One compartment model oral absorption
v. One compartment model oral absorption, flip-flop
vi. One compartment model oral absorption with a lag time

Front 34

vii. Cp = 75 exp (-0.13t) –89 exp (-1.2t)

viii. Cp = 45 exp (-0.35t)

Back 34

vii- one compartment oral absorption with a lag time

viii- one compartment model IV bolus

Front 35

Diffusion
vs
Perfusion

Back 35

Slow Diffusion

Rapid Diffusion

Front 36

Partition Coefficient

Back 36

Oil/Water

Front 37

affect on Vapp

High Protein binding
Low Protein binding
High Tissue Binding
Low Tissue Binding

Back 37

High Protein binding-low Vapp
Low Protein binding- high Vapp
High Tissue Binding- high Vapp
Low Tissue Binding- low Vapp

Front 38

VD is constant only when what?

Back 38

drug conc are in equilibrium between plasma and tissue

Front 39

When no binding occurs in tissue and plasma, the volume of the distribution will not exceed the real anatomic volume

Back 39

Remember

Front 40

if no points lie above the extrapolated line, then _____

if peak is above extrapolated line, then _____

Back 40

one compartment

plot is two or higher compartment model

Front 41

Study of size

Back 41

Allometry

y=bWa

Front 42

Most important Liver Functions

Back 42

- 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

Front 43

Bioavailability factor (F) depends on what two factors?

Back 43

Fa- absorption factor

Ff-first pass effect factor

Front 44

Drugs that have extensive first pass effects

Back 44

1. Propanolol
2. Nitroglycerin
3. Morphine

Front 45

High calorie diet defined by FDA

Back 45

containing at least 50% of the calories derived from food

Front 46

exact copies of brand product in appearance and performance

Back 46

Generics

Front 47

same performance characteristics as the brand product; not exact copies

Back 47

bioequivalent products

pharmaceutically equivalent drug products having similar rate and extent of absorption when given in the same dose and route of administration

Front 48

Purpose of the BCS Guidance

Back 48

• 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.

Front 49

Goals of the BCS Guidance:

Back 49

• 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.

Front 50

Define:

Class 1
Class 2
Class 3
Class 4

Back 50

Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility

Front 51

When is a drug considered HIGHLY SOLUBLE?

Back 51

• 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.

Front 52

When is a drug considered HIGHLY PERMEABLE?

Back 52

• 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.

Front 53

When is a drug considered RAPIDLY DISSOLVING?

Back 53

• 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.

Front 54

Drug dissolves rapidly and is well absorbed. BA problem not expected for immediate release products.

Back 54

CLASS 1

Front 55

Drug dissolution is limited and well absorbed. BA is controlled by the dosage form and rate of release of the drug substance.

Back 55

CLASS 2

Front 56

Drug permeability is limited. BA may be incomplete if drug is not released and dissolved within absorption window

Back 56

CLASS 3

Front 57

Difficulty in formulating drug product that will deliver consistent drug bioavailability. An alternate route of administration may be needed.

Back 57

CLASS 4

Front 58

Drug product that contains same active drug substance in the same dosage form and is marketed by more than one pharmaceutical maunfacturer.

Back 58

Multisource Products

Front 59

Drug products for which the patent has not expired or has certain exclusivities so that only one manufacturer can make it.

Back 59

Single Source Product

Front 60

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.

Back 60

Orange Book

Front 61

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.

Back 61

Bioavailability

Front 62

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.

Back 62

Bioequivalent Drug Products

Front 63

Document required by FDA to market a generic drug.

Pharmacodynamic or toxicology studies are not required.

Bioavailability studies are required.

Back 63

Abbreviated New Drug Application

ANDA

Front 64

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.

Back 64

Drug Product

Front 65

The Active Pharmaceutical Ingredient (API). Component of the drug that furnishes the pharmacological activity

Back 65

Drug Substance

Front 66

Relationship in terms of bioavailability, therapeutic response, or a set of established standards of one drug product to another

Back 66

Equivalence

Front 67

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

Back 67

Pharmaceutical Alternatives

Front 68

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.

Back 68

Pharmaceutical Equivalents

Front 69

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.

Back 69

Pharmaceutical Substitution

Front 70

Usually pre-approved by the physician if specified in the prescription.
The pharmacist cannot substitute without physicians approval.

Back 70

Generic Substitution

Front 71

Drugs from same therapeutic class. Contain different API but are indicated for the same therapeutic objective.

Back 71

Therapeutic Alternatives

Front 72

Bioavailability Studies are needed when...

Back 72

- 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).

Front 73

When is it Flip Flop?

Back 73

1. Negative (2nd exponent is smaller)
2. exponents are same
3. when Kb >>Ka

only occurs in oral absorption

Front 74

Vss has similar value as ?

Back 74

V beta

Front 75

Vss is smaller than?

Back 75

Vexp

Front 76

Vss is larger than?

Back 76

Vc

Front 77

time elapsed from the drug intake to the beginning of the absorption process

Back 77

Lag Time

Can have both positive and negative lag time

Front 78

Lag time may be due to what?

Back 78

1. Stomach emptying rate
2. intestinal motility
3. dosage form factors

Front 79

Flip Flop occurs when?

Back 79

Ke>> Ka

when experimental dosage forms delay absorption

Flip Flop effect cannot be determined without IV data

Front 80

Peak time can be used to?

Back 80

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

Front 81

Flip flop does not usually occur in what?

Back 81

two compartment oral models

Front 82

Drugs with _____ ka are not suitable for oral dosage

Back 82

Low

Front 83

absorption process starts when?

Back 83

when blood levels are observed

Front 84

What is MRT?

How can you find it?

Back 84

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