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Basic Principle of Pharmacokinetik

Dept. Pharmacology & TherapeuticSchool of Medicine

Universitas Sumatera Utara

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Content

Defenit ion The movement o f Drugs in the body :

1. Permeation : a . Aq ueous d i ffus ion b . Lip id d i ffus ion c. Transpo rt by sp ecial carr ier d . Endocy tos is /p inocytos is

2. Ficks Law of Diffusion 3. water & lipid solubility of drugs:

a. Aqueous diffusionb. Lipid diffusion

c. Ionization of weak acids and bases4. Hands-Hasselbach relationship

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Defenition

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Pharmacokinetic

The actions of the body on the drug,including absorption, distribution,metabolism, and excretion.

Elimination of a drug may be achieved bymetabolism or by excretion.

Biodisposition is a term sometimes used todescribe the processes of metabolism andexcretion.

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Pharmacokinetic Principle In practical therapeutics, a

drug should be able to reachits intended site of action after administration by someconvenient route

In some cases, a chemicalthat is readily absorbed anddistributed is administered andthen converted to the activedrug by biologic processes inside the body PRODRUG

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Most often, a drug is administeredinto one body compartment, eg, thegut, and must move to its site of action in another compartment, eg,the brain

Requires that the drug be absorbed into the blood from its site of administration and distributed to itssite of action, permeating throughthe various barriers that separatethese compartments

A drug given orally to produce aneffect in the central nervous system,these barriers include the tissuesthat comprise the wall of theintestine, the wall of the capillariesthat perfuse the gut and the blood -brain barrier, the walls of thecapillaries that perfuse the brain

Finally, after bringing about itseffect, a drug should be eliminatedat a reasonable rate by metabolicinactivation, by excretion from thebody, or by a combination of theseprocesses

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Physiologic Barriers

A drug must overcome physical, chemical, andbiological barriers to reach its molecular andcellular sites of action

Most drugs must distribute from the bloodstream into local tissues, a process that may beimpeded by such stuctures as the blood brainbarrier.

Drug distribution occurs mainly through passivediffusion, the rate of which is affected by localionic and cellular conditions

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Drug Absorption, Distribution, Metabolism, and Exretion

Free drug

Protein bounddrug

Systemiccirculation

Metabolites

(active andinactive)

Metabolism

Absorption Excretion

Receptors

Tissue reservoirsFree Bound

Free Bound

The basic principle of pharmacokinetic affect the amount of free drug that ultimately reaches the targetsite

To elicit an effect on its target, a drug must be absorbed and then distributed to its target beforebeing metabolized and excreted

Free drug in the systemic circulation is in equilibrium with tissue reservoir, plasma proteins, and the targetsite (which usually consists of receptors); only the fraction of drug that succcessfully binds to specific

receptors will have a pharmacologic effectMetabolism of drug can result in both inactive and active metabolits

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Permeation The movement of drug molecules into and within the

biologic environment. Four primary mechanism :

1. Aqueous diffusion

2. Lipid diffusion3. Transport by special carriers4. Endocytosis, pinocytosis

Passive diffusion in aqueous or lipid medium is common,but active processes play a role in the movement of many drugs, especially those whose molecules are toolarge to diffuse readily

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Drug Transport Mechanisms

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Aqueous diffusion The movement of molecules through the watery

extracellular and intracellular spaces The membranes of most capillaries have small water-

filled pores that permit the aqueous diffusion of

molecules up to the size of small proteins between theblood and the extravascular space. Aqueous diffusion of drug molecules is usually driven by

the concentration gradient of the permeating drug, adownhill movement

Passive process governed by Ficks law. Drug molecules that are bound to large plasma protein

(eg. Albumin) will not permeate these aqueous pores

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Lipid diffusion The movement of molecules through membranes and other lipid

structures The most important limiting factor for drug permeation, because of the large number of lipid barriers that separate the compartment of the body

Passive process governed by Ficks law

The lipid : aqueous partition coeffitient of a drug determines howreadily the molecules moves between aqueous and lipid media

In the case of weak acids and weak bases, the ability to move fromaqueous to lipid varies with the pH of the medium

The ratio of lipid soluble form to water-soluble form for a weak acid

or weak base is expressed by the Henderson-Hasselbach

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Transport by special carriers

Exist for certain substances that are important for cell function andtoo large or too insoluble in lipid to diffuse passively throughmembrane, eg, peptides, amino acids, glucose

Saturable and inhibitable

The carriers bring about movement by active transport or facilitateddiffusion Not governed by Ficks law Selective inhibitors for these carrier probenecid, which inhibits

transport of uric acid, penicillin, and other weak acids, is used to

increase the excretion of uric acid in gout The family of P-glycoprotein transport molecule responsible for

expulsion of certain drugs into the intestinal lumen

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Transport by special carriers

Facilitated diffusion

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Endocytosis, pinocytosis

Endocytosis :- the cell membrane involutes around the molecule toform a closed cavity or vesicle from which the drug issubsequently released into the interior of the cell- permits very large or very lipid insoluble chemicals toenter cells- B12 with intrinsic factor and iron with transferrin, and thecomplexes enter cells by this mechanism- Spesific receptors for the transport proteins must bepresent

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Endocytosis, exocytosis

Exocytosis :- the reverse process, ie, the expulsion of membrane-encapsulated material from cells.- responsible for the secretion of many substances fromcells- examples :

- many neurotransmitter substances are stored inmembrane-bound vesicles in nerve endings to protectthem from metabolic destruction in the cytoplasm

- appropriate activation of the nerve ending causesfusion of the storage vesicle with the cell membraneand expulsion of its contens into the extracellular

space