- drug absorption - fev 2010

7/29/2019 - Drug Absorption - Fev 2010

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Drug Absorption

PHCL 2XX

Dr VN NDIKUM


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Pharmacokinetic Overview (PK)


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Pharmacokinetic Overview .

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Pharmacokinetic Overview .

Definition of PK: The study of the movement of drugs in the body, including

the processes of absorption, distribution, localization intissues, biotransformation and excretion. The actions of thebody on the drug are called pharmacokinetic processes

Pharmacokinetic processes govern the absorption,distribution, metabolism and elimination of drugs

Learning pharmacokinetics is of great practicalimportance in the choice and administration of a

particular drug for a particular patient, e.g., onewith impaired cardiac, hepatic or renal function


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Drug Absorption

Absorption is the process by which a drug entersthe bloodstream without being chemically altered,

Or

The movement of a drug from its site ofapplication into the blood or lymphatic system.

NB:

Absorption is instantaneous for bolus intravenousadministration. Drugs taken by mouth pass to the stomach & then

the intestine they are absorbed from the GItractinto the circulatory system


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Most drugs cross biomembranes by passive diffusion where the

rate of absorption is proportional to the drug concentration

gradient. In which case will the rate be larger?

Out In

A B

Out In


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The Movement of Drug MoleculesAcross Cell Barriers

Cell membranes form the barriers betweenaqueous compartments in the body.

The most universal function of cellmembrane is to act as a selective barrier to

the passage of molecules, allowing somemolecules to cross while excluding others. The cell membrane consists of a bimolecular

lipid sheet (hydrophobic) interspersed withprotein molecules (hydrophilic), and contains

minute aqueous pores which allow passageof small hydrophilic substances.


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The Movement of Drug MoleculesAcross Cell Barriers

Cell membranes form the barriersbetween aqueous compartments inthe body.

The most universal function of cellmembrane is to act as a selective

barrier to the passage of molecules,allowing some molecules to crosswhile excluding others.

The cell membrane consists of abimolecular lipid sheet

(hydrophobic) interspersed withprotein molecules (hydrophilic), andcontains minute aqueous poreswhich allow passage of smallhydrophilic substances


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Factors which influence the rate ofabsorption

1. Mechanism of transportation acrossmembrane

2. the physicochemical properties of the

drug3. routes of administration

4. dosage forms

5. circulation at the site of absorption6. concentration of the drug


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Mechanisms of solute transport acrossmembranes

passive diffusion

filtration and bulk flow

endocytosis

active transport


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Mechanism of transport-Passive diffusion

Passive diffusion is the direct movement of asolute through a biologic barrier from the phasesof higher concentration to a phase of lowerconcentration.

This is the most common mechanism oftransport.

The rate of diffusion is related to lipid solubility

and polarity, pH, etc. The concentration gradient is the most important

factor in determining rate.

Example include phenobarbital


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Mechanism of transport- Filtration

Involves the bulk flow of water related toosmotic and hydrostatic pressures.

Small water soluble, polar and non-polar,substances are transported by this process.

It is most probable that these substance passthrough spaces between cells rather than acrossthe cell membrane.

It is a purely physical process and the mostimportant force is a pressure gradient.

Examples include water and urea.


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Passive diffusion

Aqueous diffusion

Drug passes through

aqueous pores in

biomembranes BUT

these pores limited to

molecular wts of


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Mechanism of transport - SpecializedTransport Mechanisms

1. Facilitated diffusion or transport: This is a carrier mediated transport system

It is characterized by: Selectivity, Competitiveness,Saturability, Concentration gradient

2. Active transport is a carrier mediated transport system,

energy is required and the transport is against a concentrationgradient.

is characterized by saturability, selectivity, andcompetitiveness.

3. Pinocytosis requires energy.

The transport mechanism is by invagination of the cellmembrane to form a vesicle and the engulfing of theinvagination


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Mechanism Direction Energyrequired

Carrier Saturable

Passive

diffusion

Along gradient No No No

Facilitateddiffusion

Along gradient No Yes Yes

Active transport Againstgradient

Yes Yes Yes


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Drug Absorption:Factors which influence the rate of absorption

1. types of transport

2. the physicochemical propertiesof the drug

3. routes of administration

4. dosage forms

5. circulation at the site of absorption

6. concentration of the drug


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physicochemical factors of a drug thatcould influence transport

Following drug administration, thererelease of active drug from dosage form

Disintegration and dissolution as critical

steps in oral absorption Characteristics of the drug (solute) and the

physicochemical factors influencing transport:

Molecular size and shape

Lipid solubility

Partition coefficient - relation to lipid solubility

Weak acids - weak bases


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Lipid-Water Partition Coefficient (P.C

The ratio of the concentration of

the drug in two immiscible phases: Phase 1: a nonpolar liquid or organic

solvent (representing the membrane);

and Phase 2: an aqueous buffer, pH 7.4

(representing the plasma)

The higher the lipid/water p.c. the

greater the rate of transfer acrossthe membrane


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2. the physicochemical properties of thedrug

3. routes of administration

4. dosage forms

5. circulation at the site of absorption

6. concentration of the drug


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Routes of Drug Administration

The route of administration (ROA) that ischosen may have a profound effect upon thespeed and efficiency with which the drug acts(see lecture on routes of administration)


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4. dosage forms



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Factors which influence the rate of absorption:concentration of the drug

The concentration of a drug at the site ofabsorption could influence the rate of absorption

The higher the concentration, the higher the rateof absorption

Example: Time-release preparations

Oral - controlled-release, timed-release, sustained-release designed to produce slow,uniform absorption for 8 hours

or longer

better compliance, maintain effect over night, eliminateextreme peaks and troughs

Depot or reservoir preparations parental administration (except IV), may be prolonged by

using insoluble salts or suspensions in non-aqueous vehicles.


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4. dosage forms



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Factors which influence the rate of absorption:Dosage Form -

Form of preparation of administereddrug could also determine the rate ofabsorption.

The rate of absorption will depend onthe solubility and ease of dissolutionof the drug


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4. dosage forms



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Factors which influence the rate of absorption:Blood circulation at various organs

The rate of absorption will also depend onthe rate of blood flow in the organ wherethe drug is absorbed.


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Factors which influence the rate of absorption:Blood circulation at various organs

Tissue Mass (kg) Blood Flow(mL/min)

Flow (percentof Cardiac

Output)

Brain 1.4 750 13.9

Heart 0.3 250 4.9

Liver 2.9 1500 27.8

Kidneys 0.3 1260 23.3

Skeletal muscle 34.4 840 15.6

Skin 4.0 462 8.6

Placenta andfetal

(term)3.8 500 9

Whole body 70 5400 100


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In summary

TheRate of Absorptionis determinedby the physical characteristics of thedrug, the speed which the drug is

absorbed and/ or released, as wellas the need to bypass hepaticmetabolism and achieve high conc. at

particular sites


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Absorption of Oral drugs

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

to

systemic

circulation


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Absorption

of inhaledproducts


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Absorption from the Skin

Must cross several cell layers (stratumcorneum, epidermis, dermis) to reachblood vessels.

Factors important here are:lipid solubility

hydration of skin

site (e.g. sole of feet vs. scrotum)


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Other Routes of Exposure

Intraperitoneal large surface area, vascularized, first pass

effect.

Intramuscular, subcutaneous, intradermal: absorption through endothelial pores into the

circulation; blood flow is most important +other factors

Intravenous

Ph ki i P h


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Pharmacokinetic Parameters that areused to describe absorption

1. Bioavailability ( la biodisponibilit) F Describes Measures Rate and Extent of Drug

Absorption into the Systemic Circulation

2. Tmax

3. Cmax


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Bioavailability (F):

Bioavailability (F): the fraction of the dose that reaches the

systemic circulation. (F=1 for IVadministration.)

Absolute Bioavailability: Estimation of F for any other route in

comparison to intravenous administration.

Relative Bioavailability: Estimation of F for a dosage form to another

given by anextravascular (non-intravenous)route of administration.


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Determinants ofBIOAVAILABIITY

Affected by: 1st pass metabolism

(eg: Lidocaine,propranolol)

Solubility Instability

(eg: Penicillin G, insulin)

Seru

mC

oncen

tration

Time

Injected Dose

Oral Dose


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Area under the Curve (AUC)

AUC is a quantitative measurement ofBioavailability


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Bioavailability

The fraction of the dose of a drug (F) thatenters the general circulatory system,

F= amt. Of drug that enters systemic circul.

Dose administered

F = AUC/Dose


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Examples: If the drugs bioavailability is 50%, the body

will only absorb 250 mg of a 500 mg dose.


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Time to Peak Concentration (Tmax)

0

10

20

3040

50

60

70

80

90

100

0 min 5 min 10 min 20 min 30 min 60 min 120

min

180

min

IV

Oral

Rectal

Question: Which route has the lowest Tmax?


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Maximum Concentration (Cmax)

0

10

20

3040

50

60

70

80

90

100

0 min 5 min 10 min 20 min 30 min 60 min 120

min

180

min

IV

Oral

Rectal

Question: Which route has the Highest Cmax?


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Plasma levelcurve

Cmax= maximal druglevel obtained with thedose.

Tmax = time at whichCmax occurs.

Lag time = time fromadministration to

appearance in blood. Onset of activity = time

from administration toblood level reachingminimal effective

concentration (MEC). Duration of action = time

plasma concentrationremains greater than MEC.


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- drug absorption - fev 2010

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