BIOPHARMACEUTICS

Biopharmaceutics It is defined as the study of various factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimize the therapeutic efficacy of drug products. Biopharmaceutics aspect involves the pharmacokinetic and pharmacodynamic studies of drug. Pharmacokinetic deals with absorption , distribution , metabolism and elimination of drug and thus determines the effective drug level in body fluid and tissues. Pharmacokinetics deals with induction of drug action as a function of 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

PROCESS INVOLVED IN DRUG THERAPY

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 its mechanism of action It is characterized by the concentration of drug at the site of action & its relation 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

SCHEMATIC REPRESENTATION OF PHARMACOKINETIC PROCESS

ADME

ABSORPTION: The process of movement of unchanged drug from its site of administration to the 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 plasma and hence its onset of action ,intensity and duration of response depends upon the bioavailability of drug from its dosage form. DISTRIBUTION The movement of drug between one compartment to other( generally blood and the extravascular tissue) is referred as distribution. ELIMINATION The process that tends to remove the drug from the body and terminate its action is known as elimination Metabolism (Biotransformation) Inactivation of drug due to its conversion from one chemical form to another is called metabolism Excretion The process of the removal of the drug or its metabolite from the body by different routes is excretion.

IMPORTANT DEFINITIONS

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Biological Half Life: It is the time required for the drug concentration in the blood or plasma to reduce by half its original concentration. Bioequivalence: It is the comparison of bioavailability of different formulations or drug products of different manufacturers or different batches of the same drug product of same strength. Bioavailable Dose: The fraction of the administered dose of the drug that reaches the systemic circulation in unchanged form is known as bioavailable dose. (Exception prodrug) An administered dose will be 100% bioavailable only if the drug is completely released from the dosage form into GI fluids.

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 or chemically 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.

SIGNIFICANCE OF RATE AND EXTENT OF ABSORPTION IN DRUG

THERAPY

Drug completely but slowly absorbed may fail to show therapeutic response as the plasma conc. for desired effect never achieved. Rapidly absorbed drug attains the therapeutic level easily to elicit pharmacological effect.

MECHANISM OF DRUG ABSORPTION

1. Active transport 2. Passive transport 3. Facilitated diffusion 4. Pinocytosis / Endocytosis 5. Ion-Pair absorption 6. Convective pore transport

MECHANISM OF DRUG ABSORPTION

1.

Passive diffusion: It involves the transport of drug from region of higher concentration in the GI tract to lower concentration in the blood. When drug reaches to blood circulation , it is continuously removed from the site of absorption, maintaining the high concentration gradient. No energy is utilized so called as passive diffusion. Small lipid soluble drug can easily cross the membrane than big polar molecules. Low molecular weight polar molecule can pass GI membrane through 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

ACTIVE TRANSPORT When the concentration of drug on both the sides of membrane becomes same it leads to the state of the equilibrium , which is a limitation of the passive diffusion It brings transportation against concentration gradient & requires energy. It requires a carrier which 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

FACILITATED DIFFUSION

This is also carrier mediated transport system which differs from active transport that it can not transport a substance against a conc. gradient and so occur fro higher to lower concentration but does not require an expenditure 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

ION PAIR ABSORPTION

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 or channel 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.

FACTORS AFFECTING 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

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

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.

ROUTES OF ADMINISTRATIONS
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.

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 in blood 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

METABOLISM OR 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 of protein binding Less toxic Less capability of being stored in fats. Less penetrability through the biological membrane so less pharmacological active

CONT..
Phase I reaction: non synthetic like hydrolysis , reduction or oxidation which form polar functional 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

EXCRETION
Excretion terminates the drugs activity Majority of drug excreted through urine, some of them through bile, saliva, sweat. Poorly absorbing drugs are excreted through feaces. Volatile substance can be detected in breath. Oil soluble drug have comparatively more residence than polar drug which excretes fast.

PLASMA CONCENTRATION TIME PROFILE DRUG EFFICIENCY & DOSE RESPONSE CONCEPT
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 .

PHARMACOKINETIC PARAMETERS
Absorption phase : initial rise in plasma conc. is rapid due 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 to achieve Cmax. Area Under Curve: (AUC) It is the total integral area under plasma concetration time profile and is related to the total amount of drug absorbed into systemic circulation after administration of single drug.

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 pharmacological response. Onset of action: begining of action
Duration of action: time period for which the plasma conc of

drug remains above MEC