F. Y. Biopharmaceutics

7/31/2019 F. Y. Biopharmaceutics

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BIOPHARMACEUTICS

Biopharmaceutics

It is defined as the study of various factors influencing the rate andamount of drug that reaches the systemic circulation and the use ofthis information to optimize the therapeutic efficacy of drug products.

Biopharmaceutics aspect involves the pharmacokinetic andpharmacodynamic studies of drug.

Pharmacokinetic deals with absorption , distribution , metabolismand elimination of drug and thus determines the effective drug level inbody fluid and tissues.

Pharmacokinetics deals with induction of drug action as a functionof concentration of drug in the body.

Following steps are involved to elicit the pharmacological action.

Drug release

Dissolution of drug

Absorption of drug in systemic circulation

Reaching the drug at site of action

Maintainace of adequate conc. at site of action


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PROCESSINVOLVEDINDRUGTHERAPY Drug therapy and administration can be divided into four processes.

1. Pharmaceutical Phase

Physiochemical properties of drug

Design & manufacturing of dosage form

2. Pharmacokinetic phase (what body does to drug)

Concerned with ADME of drug

Plasma drug concentration time profile

Its relationship with the dose , dosage form, dosing frequency and route of

administration Relates changes in concentration of drug within the body with time

after administration

3.Pharmacodynamics phase ( what drug does to body)

Concerned with biochemical & physiological effects of drug and itsmechanism of action

It is characterized by the concentration of drug at the site of action & itsrelation to the magnitude of effects observed.

Relates response to concentration of drug in the body

4. Therapeutic Phase :-

Concerned with the translation of pharmacological effect into clinical

benefit


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SCHEMATICREPRESENTATIONOF PHARMACOKINETICPROCESS


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ADME ABSORPTION:

The process of movement of unchanged drug from its site of administration tothe systemic circulation is called absorption.

BIOAVAILABILITY It is defined as the rate and extent (amount) of drug absorption and

availability from the site of action. The concentration of drug in the plasmaand hence its onset of action ,intensity and duration of response depends uponthe bioavailability of drug from its dosage form.

DISTRIBUTION

The movement of drug between one compartment to other( generally bloodand the extravascular tissue) is referred as distribution.

ELIMINATION

The process that tends to remove the drug from the body and terminate itsaction is known as elimination

Metabolism (Biotransformation)

Inactivation of drug due to its conversion from one chemical form to anotheris called metabolism

Excretion

The process of the removal of the drug or its metabolite from the body bydifferent routes is excretion.


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IMPORTANT DEFINITIONS

Biological Half Life:

It is the time required for the drug concentration in the blood or

plasma to reduce by half its original concentration.

o Bioequivalence:

o It is the comparison of bioavailability of differentformulations or drug products of different manufacturersor

different batches of the same drug product of same strength.o Bioavailable Dose:

o The fraction of the administered dose of the drug that reaches

the systemic circulation in unchanged form is known as

bioavailable dose. (Exception prodrug)o An administered dose will be 100% bioavailable only if the drug

is completely released from the dosage form into GI fluids.


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ABSORPTION

Drug absorption is defined as the process of movement of

unchanged drug from the site of administration to systemic

circulation. It excludes the drug that is metabolized orchemically changed at the site of application, at site of drug

release or in the membrane.

It is difficult to measure conc. of drug at site of administration.

So it can be measured in plasma more accurately.

Correlation between plasma concentration of drug and

therapeutic response. Thus

Absorption can be defined as the process of movement of

unchanged drug from the site of administration to the site of

measurement i.e. plasma.


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SIGNIFICANCEOFRATEANDEXTENTOFABSORPTIONINDRUGTHERAPY

Drug completely but slowly absorbed may fail to show

therapeutic response as the plasma conc. for desired effectnever achieved.

Rapidly absorbed drug attains the therapeutic level easily toelicit pharmacological effect.


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MECHANISMOF DRUG ABSORPTION

1. Active transport

2. Passive transport

3. Facilitated diffusion

4. Pinocytosis / Endocytosis 5. Ion-Pair absorption

6. Convective pore transport


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MECHANISMOF DRUG ABSORPTION

1. Passive diffusion: It involves the transport of drug from

region of higher concentration in the GI tract to lowerconcentration in the blood. When drug reaches to bloodcirculation , it is continuously removed from the site ofabsorption, maintaining the high concentration gradient.

No energy is utilized so called as passive diffusion.

Small lipid soluble drug can easily cross the membrane thanbig polar molecules.

Low molecular weight polar molecule can pass GI membranethrough water filled pores in the bilayer.

Passive diffusion is governed by Ficks law. -dC/ dt = Ka [C1-C2]

but C1>> C2

-dC/ dt = Ka. C1


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ACTIVE TRANSPORT

When the concentration of drug on both the sides ofmembrane becomes same it leads to the state of theequilibrium , which is a limitation of the passive diffusion

It brings transportation against concentration gradient &requires energy.

It requires a carrierwhich may be enzyme or some other

component of cell Carrier protein

Drugs having similar structure with amino acids ,essential nutrients, vitamins are absorbed by active

transport. Eg. Levodopa structurally similar to amino acids like

tyrosine is absorbed by active transport


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FACILITATED DIFFUSION

This is also carrier mediated transport system which

differs from active transport that it can not transport asubstance against a conc. gradient and so occur fro higher

to lower concentration but does not require anexpenditure of energy.

Pinocytosis / Endocytosis

Only mechanism here material does not have to be in

aqueous solution in order to be absorb. It involves the

engulfing of extracellular solids (phagocytosis ) or liquids

(pinocytosis) within a segment of the cell membrane to form

vacuoles containing the material which then cross the

membrane. Macromolecules like proteins are absorbed by

this method


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IONPAIRABSORPTION

Drug ion interact with organic ions of opposite charge to

form an absorbable neutral form which undergo passive

diffusion. Eg. Drugs like quaternary compounds, tetracycline

These are ionized over entire GIT range.

Are lipid insoluble

Water soluble drugs are too large to pass through pore orchannel so ions of these interact with organic ions of

opposite charge to form an absorbable neutral form which

undergo passive diffusion.

CONVECTIVE PORE TRANSPORT Very small molecules like water, urea, low molecular wt sugars & organic

electrolytes cross the cell membranes through aq. filled channels or pores

Pore radius 0.4 nm.


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FACTORSAFFECTING ABSORPTION

1. Physiological factors

2. Physicochemical factors

3. Dosage form consideration

1. Physiological factors

Anatomy of GIT or surface area GIT- pH

Gastric emptying rate

Gastro intestinal motility/ peristalsis

Interaction of drug within the component of GIT

Dietary factors


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CONT.

2. Physicochemical factors:

Lipid solubility & dissociation constant

Dissolution rate

Particle size and effective surface area

Salt forms

Drug stability and hydrolysis in GIT Surface active agents

Viscosity

Complexation and adsorption

Bulk solubility and solubility in diffusion layer

Crystal form


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CONT.

3. Dosage form consideration

A) Influence of type of dosage forms Solution>Suspension>Capsules>Compressed

tablet>Coated medicament

B) Influence of Excipient

Diluents, Surface active agents, viscosity enhancers etc.


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ROUTESOFADMINISTRATIONS

Three major routes of administration are

The Enteral Route:Includes peroral i.e. gastrointestinal , sublingual, buccal

and rectal route

The Parenteral Route

IV, Subcutaneous, IM etc

The Topical Route

skin, eyes or some specific membranes.


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DISTRIBUTION Fate of drug after absorption

It is reversible transfer of drug from one location to another

within the body and determines the extent of drug present inblood and tissue fluid.

The rate and extent of drug distribution determines the

onset of action.

Same time it undergoes protein binding and forms complex Distribution of drug varies from tissue to tissue

Drug distributes rapidly in tissues with high blood supply

kidney, liver , heart, lungs

Bound drug can not show pharmacological action Large polar molecules are difficult to distribute

Smaal lipophillic molecules can distribute easily


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METABOLISMOR BIOTRANSFORMATION

Drug is foreign substance to the body so body always

tries to eliminate it.

It can be eliminated either in unchanged form or

undergoing chemical changes. (insoluble lipid soluble or

non ionizable drug is converted into more polar , water

soluble form that can easily eliminated)

These changes are called as biotransformation or

metabolism.

Metabolites more water soluble and more ionized.

Less capable ofprotein binding

Less toxic

Less capability of being stored in fats.

Less penetrability through the biological membrane so

less pharmacological active

CO


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CONT..

Phase I reaction: non synthetic like hydrolysis , reduction or

oxidation which form polarfunctional group

Phase II reaction: involves conjugation gluconidation,acetylation, sulfation, etc.

Conjugation: eg. Acetaminophene forms acetaminophene

glucoronide

Oxidation: eg. Amoxaphine oxidation 8- hydroxy Amoxaphine

Hydrolysis:Aspirine Salicylic Acid

Reduction: Nitroglycerine forms dinitroglycerol


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EXCRETION

Excretion terminates the drugs activity

Majority of drug excreted through urine, some of themthrough bile, saliva, sweat.

Poorly absorbing drugs are excreted through feaces.

Volatile substance can be detected in breath.

Oilsoluble drug have comparatively more residencethan polardrug which excretes fast.

PLASMA CONCENTRATION TIME PROFILE


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PLASMA CONCENTRATION TIME PROFILEDRUGEFFICIENCY & DOSERESPONSECONCEPT

The therapeutic effect of drug is considered as function of

the concetration of drug in blood plasma. Plasma concentration time profile gives information about

attaining and maintaining the optimum concentration of the

drug at the site of action .

P P


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PHARMACOKINETIC PARAMETERS

Absorption phase : initial rise in plasma conc. is rapiddue to rate of absorption is fast than distribution and

elimination. Continue till achieve Cmax. Ka>Kd>Ke Peak plasma concentration(Cmax) : Highest

concentration of drug achieved in plasma after a single

dose of drug. Ka =Kd=Ke

Elimination phase: After Cmax conc of drug declines Ke> rate of entry of drug in blood

Time of peak concentration (tmax): time required toachieve Cmax.

Area Under Curve: (AUC) It is the total integral area underplasma concetration time profile and is related to the total

amount of drug absorbed into systemic circulation after

administration of single drug.

PHARMACODYNAMIC PARAMETERS


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PHARMACODYNAMIC PARAMETERS Minimum effective concentration: (MEC)

Minimum concentration of drug in plasma required to produce

the therapeutic effect

Maximum safe concentration: (MSC) minimum toxic conc. (MTC)

Above this concentration toxic effects are produced

Therapeutic Effect :

Concentration between MEC and MSC

Subtherapeutic level:

Concentration below MEC

Therapeutic window: (Therapeutic index)

Ratio of MEC and MSC

Onset of time: Time required to begin pharmacologicalresponse. Onset of action: begining of action

Duration of action: time period forwhich the plasma conc of

drug remains above MEC

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F. Y. Biopharmaceutics