02 PK Absorption Eng

713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

Dr. Korawuth Punareewattana

Pharmacokinetics: Drug Absorption

Faculty of Veterinary Medicine, Khon Kaen University

Topic 2

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Topic Contents

Foundation of Pharmacokinetics Definition and Processes Passage of drug across biological membranes Mechanisms of drug transport

Pharmacokinetics: Drug absorption (1st step of PK) Definition Bioavailability and first pass effect Route of drug administration and Drug absoption

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Pharmacokinetics conceptsPharmacology consists of 2 process Pharmacokinetics (PK) - PK describes how the body affects a specific drug after

administration Or What body does to a drug

Pharmacodynamics (PD) PD describes how a drug affects the body system after

administration Or What drug does to the body Or drug action

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Pharmacokinetics or Drug disposition Processes of Pharmacokinetics The ADME scheme A - Absorption D - Distribution M - Metabolism

or Biotransformation E - Excretion

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Pharmacokinetics

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Passage of Drugs across Biological membrane Drug transport is a foundation to all ADME processes

Physicochemical determinants Membrane characteristics Drug properties

Mechanism of drug transport Passive diffusion Carrier-mediated transport Bulk flow Filtration etc

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Membrane characteristics Bilayer of amphipathic lipids barriers

Embedded proteins

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Drug properties

Molecular weight, shape and size Lipid solubility Ionization

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Molecular weight, shape and size Small molecules more chance of crossing membrane

Selectivepermeability

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Lipid Solubility

Partition coefficient (Kp) = solubility in lipid / solubility in water

Increase lipid solubility causes increased partition coefficient Increase in partition coefficient causes increased permeability.

Permeability

Kp

Movement directly through the lipid bilayer requires that the substancedissolve into the lipid bilayer

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IonizationGeneral rules A drug usually exists in 2 forms unionized and ionized forms Unionized drug can passively diffuse across membrane The ratio of unionized drug will indicate direction of passive diffusion

Factors affecting ionization are pH of the medium pKa (acid dissociation constant) of the drug

Acidic drug tend to ionize in more basic medium pH pKa = log (ionized / nonionzized)

Basic drug tend to ionize in more acidic medium pH pKa = log (nonionized / ionized)

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Ionization Henderson-Hasselbach Equations for calculations

Equation for Acids: Equation for Bases:

K =[CH3COO

-] [H+]

[CH3COOH]

pH = pK + log[CH3COO

-]

[CH3COOH]

K =[NH3] [H

+]

[NH4+]

pH = pK + log[NH3]

[NH4+]

pH = pK + log[H+ acceptor]

[H+ donor]

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Stomach fluidpH 2

PlasmapH 7

More non-ionized Ionized

Less non-ionized Ionized

ExampleAcidic drug pKa 6 pH pKa = log (ionized / non-ionized)

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Some data for practice calculation

Plasma pH 7.4CSF 7.4Stomach 1.4Small Intestine 8.0Rumen 6.7

Acidic drug pKa Basic drug pKa

Ampicillin 2.5 Strychnine 8.0

Sulfadiazine 6.5 Aminopyrine 5.0

Aspirin 3.4 Procaine 9.014

Mechanisms of Drug TransportTranscellular transport Passive diffusion Carrier-mediated transport Facilitated diffusion Active transport

Ion-pair transport Endocytosis or

PinocytosisParacellular transport Bulk flow Filtration

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Passive diffusion Drugs that can passively diffuse through cell membrane

must be Lipid soluble Unionized form Move according to concentration gradient

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Carrier-mediated transport Facilitated diffusion Carrier needed Can be saturated

No energy required Move along conc. gradient

Active transport Carrier needed Can be saturated

Energy required Move against conc. gradient

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Ion-pair transport and endocytosis

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Bulk flow and Filtration Bulk flow is an important way of a drug to move out of blood vessel

Filtration is an important way to excrete drug

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Pharmacokinetics: Drug AbsorptionAbsorption

describes the rate and extent at which a drug leaves its site of administration.Bioavailability

is the extent to which a drug reaches its site of action, or to a biological fluid (such as plasma) from which the drug has access to its site of action.

Note % Absorption = % first pass effect + % bioavailability So bioavailability is not the same as absorption

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Factors Affecting Drug Absorption

Dose, Concentration, and Rate of administration

Dosage forms

Physical and chemical properties of drugs

Physiological Factors

Routes of drug administration

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Factors Affecting Drug Absorption:

Dosage forms Dosage forms with different formulations Clearly affect drug absorption Depend on how well they can be dissolved Liberation process

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Physicochemical Properties of Drug

Acid or Base

Degree of ionization

Polarity

Molecular weight

Lipid solubility or...

Partition coefficient (Kp)

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Physicochemical Properties of Drug Lipid solubility and Absorption

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Barbiturate Kp % Absorbed from rat colon

barbitalphenobarbitalpentobarbitalsecobarbital

0.74.82851

12203040

Data from: Schanker LS. J Pharmacol Exp Ther 123:81, 1958.


Physiological Factors

Gastric motility

Gastric emptying time

pH at the absorption site

Area of absorbing surface

Blood flow

Presystemic elimination

Ingestion with or without food

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Physiological Factors pH at the absorption site

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Acids5-nitrosalicylicsalicylicacetylsalicylicbenzoic

pKa

2.33.03.54.2

% absorbed at

pH 4

40644162

pH 5

27352736

pH 7

030---35

pH 8

010---5

Basesaniline 4.6 40 48 58 61aminopyrine 5.0 21 35 48 52quinine 8.4 9 11 41 54

Data from: Schanker LS, J Pharmacol Exp Ther 123:81, 1958.


Physiological Factors Area of absorbing surface

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% absorbed in 1 hr % absorbed in 10 minDrug from stomach from small intestine

phenobarbital 17 52pentobarbital 24 55promethazine 0 38ehtanol 38 64

Data from: Magnussen MP. Acta Pharmacol Toxicol 26:130, 1968.


Routes of Drug Administration

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Routes: Oral Ingestion (PO)Several factors affect absorption by this route

- So absorption may change drastically based on these factors

Dosage forms (physical state of drug)

Drug concentration

Surface area of absorption

Blood flow to GI

GI activity

Food

Bacteria in GI

First past effect (hepatic metabolism)

Entero-hepatic cycle29


Routes: Oral Ingestion (PO) Enterohepetic cycle & First pass effect

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Routes: Sublingual administration

Absorption from the oral mucosa has special significance for certain drugs despite small surface area.

Nitroglycerin - nonionic, very lipid soluble.Because of venous drainage into the superior vena cava, this route protects it from first-pass liver metabolism.

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Routes: Rectal administration Useful when oral administration is precluded by vomiting or when the patient is unconscious. Approximately 50% of the drug that is absorbed from the

rectum will bypass the liver, thus reducing the influence of first-pass hepatic metabolism.

Disadvantages irregular and incomplete irritation.

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Routes: Parenteral administration Subcutaneous Slow absorption

Intramuscular Fast absorption

Intra-peritoneal Rapid absorption Large absorbing area

Intravenous, Intra-arterial No absorption

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Routes: Pulmonary absorption Gaseous and volatile drugs may be inhaled and absorbed by the

pulmonary epithelium and mucous membranes of respiratory tract.

-almost instantaneous absorption-avoids first-pass metabolism-local application

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Routes: Topical (Transdermal route) Few drugs readily penetrate the skin

- Absorption is proportional to surface area- More rapid through abraded, burned skin- Inflammation increases cutaneous blood flow and, therefore, absorption- Enhanced by suspension in oily vehicle and rubbing into skin

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Transdermal systemic effect Epicutaneous local effectabsorption no absorption

Bioavailability (F) The fraction of a dose that reaches the systemic circulation in a

chemically unaltered form

Fractional availability = F

Quote as percentage or decimal e.g. 25% or 0.25

Has no units

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Bioavailability (F)

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Incomplete oral bioavailability

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2. Chemical, enzymatic

or bacterial attack

3. Failure of

absorption &

pGP efflux

1. Failure of disintegration

or dissolution

4. First pass metabolism

in gut wall or liver

Liver


Failure of absorption

Binding to other molecules in the gut contents

Too polar to undergo passive diffusion

Efflux due to P-glycoproteins (P-gp, MDR1)

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First pass metabolism Minor-Metabolism in the gut wall Major-Hepatic metabolism

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02 PK Absorption Eng

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