prelims

biopharmaceutics

The

science that examines the

interrelationship of the physicochemical

properties of the drug, the dosage form in

which the drug is given, and the route of

administration on the rate and extent of

systemic drug absorption

biopharmaceutics

The

study of the chemical and physical

properties of drugs, their components, and

their activities in living organisms

Bioavailability

A measurement of the rate and extent

of systemic absorption of

therapeutically active drug

Pharmacokinetics

The study of the time course of drug

movement in the body during

absorption, distribution, and elimination.

Clinical Pharmacokinetics

Application of pharmacokinetic

methods to drug therapy.

Clinical Pharmacokinetics

the study of the relationships

between drug dosage regimens

and concentration time profiles

Three fundamental parameters

• clearance

• volume of distribution

• elimination of half life

Clearance

volume of fluid completely cleared of drug

per unit time

Volume of distribution

apparent volume into which the drug has

distributed to produce the measured

concentration

Elimination half life

time taken for 50% of the drug to be

eliminated

Population Pharmacokinetics

Study of pharmacokinetics differences of drugs in

various population

TDM ( Therapeutic Drug Monitoring)

Employed for very potent drug to optimize efficacy and to prevent any adverse toxicity

CPKS ( Clinical Pharmacokinetic Service)

Provides pharmacokinetic and drug analysis services for safe drug monitoring drug monitoring

Digoxin

0.5 -2.1

Amiodarone

1.0 - 2.5

Salicylate

150 - 300

Theophylline

10 - 20

Phenytoin

10 - 20

Carbamazepine

5.0 - 12

Experimental Pharmacokinetics

Development of biologic sampling techniques ,

analytical methods for the measurement of

drugs and metabolites and procedure that

facilitates data collection and manipulation

Theoretical Pharmacokinetics

Development of pharmacokinetics models

that predict drug disposition after

administration

In vivo

involves human subjects/ laboratory

animals

In vitro

employs test apparatus and equipment

without involving human subjects/ laboratory

animals

Model

a hypothesis using

mathematical terms to describe

quantitative relationship concisely.

• Empirical

• physiological

• compartmentally based

types of model

Pharmacokinetic Models

• Catenary

• Mammillary

• Physiologic Pharmacokinetic

Pharmacodynamics

The study of the relation of the

drug concentration or amount at

the site of action and its

pharmacologic response

Clinical Toxicology

The study of the adverse effects of

drugs and toxic substances in the

body

Considerations in Drug Product Design

• Therapeutic objective

• Drug (API)

• Route of administration

• Drug dosage and dosage regimen

• Type of drug product

• Excipients

• Method of manufacture

Drug Disposition

The description of

drug distribution and

elimination.

Drug exposure

refers to the dose and

various measure of acute or integrated

drug concentrations in plasma and

other biological fluid.

Drug response

refers to the direct

measure of the pharmacologic effect

of the drug

Physicochemical Properties

A. Drug Dissolution

B. Drug Solubility

C. Particle Size and Surface Area

D. Partition Coefficient and Extent of Ionization

E. Salt Formation

F. Polymorphism

G. Chirality

H. Hydrates

I. Complex Formation

Drug Dissolution

the rate at which the solid drug enters

into solution is often the rate limiting

step in bioavailabilty

Noyes Whitney equation

describes the diffusion controlled rate of drug dissolution

Drug Solubility

in a saturated solution is a static

(equilibrium) property. The

dissolution rate of a drug is a dynamic

property related to the rate of

absorption.

Particle Size and Surface Area

inversely related

Particle Size and Surface Area

As solid drug particle size decreases,

particle surface area increases.

Partition Coefficient

The _____________________ of a drug is

the ratio of the solubility of the drug,

at equilibrium, in a non aqueous

solvent

Partition Coefficient

Inc in the no of carbon

Partition Coefficient

Decrease water solubility

Extent of Ionization

Drugs that are weak electrolytes (acids or

bases) exist in both an ionized form and a

nonionized form in solution.

extent of ionization

depends on the pKa

of the weak electrolyte and the pH of the

solution.

ionized form

The________________ is polar and

therefore more Water soluble than the

nonionized form

polar

The ionized form is ________________________, and

therefore more Water soluble than the

nonionized form

Water soluble

The ionized form is polar and

therefore more __________________________, than the nonionized form

Henderson Hasselbalch equation

describes the relation between the ionized

and the nonionized forms of a drug as a

function of pH and pKa

advantages of salt formation

• greater stability

• less local irritation at the

absorption site

• less systemic toxicity

disadvantages of salt formation

• provide slower dissolution

• slower bioavailability

• longer duration of action

chloramphenicol

Salt Formation drug

WEAKLY ACIDIC DRUGS

potassium and sodium salts

WEAKLY BASIC DRUGS

• Hydrochloride

• Sulfate

• Citrate

• gluconate

• salts

• estolate

• napsylate

• stearate salts

Polymorphism

the ability of a drug to exist in more than

one crystalline form

Polymorphism

Same CHEMICAL STRUCTURE, DIFFERENT

PHYSICAL PROPERTIES

Chirality

the ability of a drug to exist as optically active

stereoisomers or enantiomers

S enantiomer

For example, ibuprofen exists as the R and S

enantiomers; only the___________ is

pharmacologically active .

Hydrates

Drugs may exist in a hydrated, or solvated, form or

as an anhydrous molecule

Hydrates

Dissolution rates differ for hydrated and anhydrous forms.

Complex

is a species formed by the reversible

or irreversible association of two or more

interacting molecules or ions.

Chelates

are complexes that typically involve a

ring like structure formed by the interaction

between a partial ring of atoms and a metal

hemoglobin, insulin,

cyanocobalamin

examples of chelates

Complex formation

usually alters the physical and chemical characteristics of the drug.

Large drug complexes,

___________ such as drug protein

complexes, do not cross cell membranes

easily.

Liberation

delivery of the active

ingredient from a dosage

form into solution.

Liberation

the first step which determines onset of

action, rate of absorption, availability,

etc., which is true for all drug products

by all routes of administration (except

intravenous and the peroral use of true

solutions)

disintegration

a state in which any residue of the

tablet, except fragments of insoluble

coating, remaining on the screen of

the test apparatus in the soft mass

have no palpably firm core.

dissolution

the process by which a chemical or drug

becomes dissolved in a solvent.

Rate Limiting Step

the process with the slowest

rate constant in a system of

simultaneous kinetic

processes.

Absorption

The process of uptake of the compound

from the site of administration into the

systemic circulation

Absorption

The movement of the drug from the site of

application to the bloodstream.

Absorption

The amount of perfused blood in the site of

application affects the rate of absorption.

Distribution

transfer of the drug from the blood

to extravascular fluids and tissues

Distribution

The amount of blood perfusion in an

area of the body also affects the

rate at which the drug could be

distributed there.

Volume of distribution

Estimate the extent of drug distribution in

the body

Volume of distribution

theoretical volume in which the total amount of

drug would need to be uniformly distributed to

produce the desired blood concentration of a

drug

EXTRACELLULAR FLUID

10-20L

CIRCULATORY SYSTEM

5L

INTRACELLULAR FLUID

25-30L

WHOLE BODY FLUID

40L

Metabolism

enzymatic or biochemical transformation of the drug

substance to (usually less toxic) metabolic products,

which may be eliminated more readily from the body

Xenobiotics

foreign chemicals

MORE POLAR

goal of metabolism

Excretion

final loss of the drug of the drug substance or its metabolites substance or its metabolites from the body from the body

kidneys

polar metabolites through

the _____

bile

non polar drugs through the ____________

disposition

LADR

elimination

metabolism and excretion

Drug Administration

Often the goal is to attain a

therapeutic drug

concentration in plasma from

which drug enters the tissue

Drug Administration

Affect the ONSET,

INTENSITY and DURATION of

the drug in the body

• Parenteral

• Enteral

• Transdermal

• Inhalation and Intranasal

common routes of drug administration

100%

IV bolus BA

immediate effect

IV bolus ADV

Inc. chance of

adverse reaction

IV bolus DIS

100%

IV infusion BA

May inject

large fluid

volumes

IV infusion ADV

Plasma drug

levels

precisely

controlled

IV infusion ADV

Drugs with

poor lipid sol

and irritating

drugs

IV infusion ADV

Requires skill of

insertion

Tissue damage at

the site of

injection

IV infusion DIS

Rapid(aqueous soln)

IM BA

Slow (non aqueous soln)

SC BA