2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU)

II. PHARMACOKINETICS

06-Nov-12 By: Takele B., CVMA, AAU 1

Learning Objectives
• Define PK
• Importance of PK
• The factors that modify the PK of drugs


PHARMACOKINETIC IMPORTANCE
• To know the dose
• To know the suitable route of adm
• To know the dosage interval
• To know the period of medication


General Concepts
Drug Dose
Administration

Absorption/distribution
Pharmacokinetics metabolism/excretion

Drug/Receptor
Pharmacodynamics Interaction

Pharmacotherapeutics Drug Effect
or Response


Pharmacokinetics
• The changes that occur to the drug when it is
inside the body.

• The ways in which the body processes drugs:
 Absorption
 Distribution
 Metabolism
 Excretion


Pharmacokinetics
Fate of drugs in the animal body


I. Absorption
 The transfer of a drug from its site of administration to its site
of action (or measurement)

Dose

Administration Site of
Site Action

Absorption
Barriers

Barriers to Drug Delivery
Effect
Cellular delivery Target
Tissue distribution

Liver metabolism
Gut metabolism
Intestinal absorption

Ingestion
Systemic
Circulation


Major Sites of Administration
Lungs
Mouth
Nose
GI
Skin
Muscle


Absorption from the Small Intestine
The small intestine is the major drug absorbing site due to the greatly
enhanced available surface area.

Luminal Folds (3 fold increase)

Villi (10-fold increase)

Microvilli (20-fold increase)

Overall, a 600-fold increase in surface area vs. a cylinder


Requirements for Oral Absorption

Dissolution

Transfer across the Gut Wall
Paracellular
Transcellular


Dissolution
The process by which a drug moves from the solid state into solution
Dosage
form
Dissolution

Granules Dissolution Solution Absorption

Deaggregation
Dissolution

The drug must be in solution to be absorbed


Microvilli
Microvilli

Brush Border
Membrane

Epithelial
Cell

Intestinal wall epithelial cells have many finger-like
projections on their luminal surface called microvilli
which form the brush border membrane


Routes of Passage across the
Small Intestinal Epithelial Cell
Gut Lumen
ParacellularActive Efflux
Transcellular Transport

Serosal Side

Transcellular Absorption -
Membrane Structure
 The major route of drug absorption
 The compound passes through the cell membrane
 Requirement for adequate lipophilicity

Phospholipid Head

Lipophilic Tail
Protein

06-Nov-12
StructureB., CVMA, AAUCell Membrane
By: Takele
of the 15

Membrane Partition- Ionizable
compounds
Administration Site Membrane Systemic Circulation

BH+

B B

BH+
 Only unionized drug typically cross membranes
 Ionized drug must first lose charge
 Dependent upon pKa and permeation rate of unionized
form

Movement of Drugs Across the Cell
Membrane
• Pharmacokinetics includes the movement of
substances across cell membranes

• Basic mechanisms:
– Passive diffusion
– Facilitated diffusion
– Active transport
– Pinocytosis/phagocytosis


Movement of Drugs…cont’d
• Passive diffusion:
 movement of particles from an area of high concentration
to an area of low concentration
– good for small, lipophilic, nonionic particles

• Facilitated diffusion:
 passive diffusion that uses a special carrier molecule
– good for bigger molecules that are not lipid
soluble


• Active transport:
– molecules move against the concentration
gradient from areas of low concentration of
molecules to areas of high concentration of
molecules;
– involves both a carrier molecule (transporter) and
energy
– SAR very specific=Not many drugs absorbed by
this route
– Many types for nutrient molecules

– Can be saturated by high concentration good for
accumulation of drugs within a part of the body

• Pinocytosis/phagocytosis:
– Molecules are physically taken in or engulfed.

– Pinocytosis is engulfing liquid;

– Phagocytosis is engulfing solid particles

–Good for bigger molecules or liquids


Barriers to Drug Absorption

 P-glycoprotein

 First Pass Extraction:
– gut wall
– liver


First-Pass Extraction

Gut wall

Portal Liver
vein

To site of
measurement

Metabolism Metabolism

To Feces

• Gut wall and liver are major drug metabolizing organs
Oral Bioavailability = % absorbed - % extracted

Gut Wall Metabolism
• The major isoform present in gut is CYP3A4

• In the small intestine this approaches 50% of
hepatic level

• Gut wall metabolism contributes extensively to the
first pass extraction of:
Midazolam, Verapamil, Cyclosporin, Felodipine
e.t.c!!


Absorption Parameters
Bioavailability:

• The extent to which a drug can overcome
the barriers to absorption (including first
pass metabolism)


Oral Bioavailability

Oral Bioavailability (%)= AUCoral x ivDose x 100
AUCiv poDose

Where AUC is the area under the plasma
concentration versus time course


Factors that affect Absorption
 The factors that modify the absorption of drugs is either
related
 to the drug or
 to the patients

A. Factors related to the drugs

1-Drug solubility
Insoluble drugs are not absorbed
e.g. barium sulphate


Absorption….

2-Degree of ionization
The greater the degree of ionization the lesser the
absorption because the lesser Lipophilic properties of the
drug ions.

• Ionized drug ------ polar ---- less lipid solubility ---Less
absorption.

• Unionized drug --- non-polar --- more lipid soluble ---More
absorption


Absorption
3-Valency

 Ferrous salt are better absorbed from the alimentary canal
than ferric salt

4-Pharmaceutical form

 Drugs in aqueous solution are more rapidly absorbed than
those given in oily solutions or suspension and

 the smaller the particle size of the powder the more
efficient is their absorption.


Absorption

B. Factors related to the patients

a)Routes of administration:
 Excellent from pulmonary alveoli,
 very good from sublingual mucosa.
 best from parenteral sites

 For oral drug, it is absorbed first from GIT either through
passive diffusion or active transport


b) Sites of absorption

GIT
Characters:
1) Very large surface area
2) Good blood supply
3) Internal environment (pH) is vary
throughout the GIT
4) Presence of gut contents
5) Gut flora


Sites of absorption…..
SKIN
Characters:
1) Large surface area
2) Out layer of dead cells
3) Poor blood supply
4) Epidermis is packed with keratin
N.B: Absorption through skin is limited to lipid soluble
compounds

LUNGS
Characters:
1) Large surface area
2) Blood flow
3) Both lipid soluble and water soluble compounds can be
absorbed

Absorption…

c)Area and vascularity of the absorbing surface:
Absorption is directly proportion to both area and
vascularity

d)State of health absorbing surface


Drug Absorption Terms
• Bioavailability: percent of drug administered that actually
enters the systemic circulation

• Ionization: the property of being charged
– Hydrophilic = ionized
– Lipophilic = nonionized
• Nature of the drug: pH of drug
– Weakly acid drugs = hydrophilic form in alkaline
environment
– Weakly alkaline drugs = hydrophilic form in acid
environment
• Ion trapping: when drugs change body compartments, they
may become ionized and trapped in the new environment
• Drug form is important; oral drugs must have different
properties than parenteral drugs AAU
06-Nov-12 By: Takele B., CVMA, 33

06-Nov-12
XX By: Takele B., CVMA, AAU 36

Factors affecting BA
1. Hepatic 1st pass metabolism
2. Solubility of a drug:
e.g. lipophilic better orally than
3. Chemical instability: e.g. insulin and penicillin G in
GIT
4. Nature of drug formulation
e.g. particle size, salt form

II.Distribution
 Is the process by which the drug reversibly leaves the
bloodstream and enters to interstitial (ECF) and/or cells or
tissues/its site of action

 After absorption of a drug, it is usually distributed through the
different tissues and the body fluid compartment including:
A-The plasma.
B-the ECF and
C- the ICF.


Binding of drugs to proteins
 Drugs are distributed and bind to α-acid glycoprotein and
proteins (albumin &globulin)

 bound drugs are pharmacologically inactive.

 only the free, unbound can act its target sites in the tissue ,
elicit biologic response, and be available to process of
elimination.

 Acidic drugs- albumin
 Basic drugs- globulin & α-acid glycoprotiens

• NB. Hypoalbuminemia can affect the level of free drug

Volume of distributions, Vd
Is a hypothetical volume of fluid into which the drug
is disseminated.

Vd= D/C : is drug specific

C- plasma drug conc.
D- total amount of drug in the body


III. Biotransformation
• Refers to the chemical alterations that drug
undergoes within living organism.

 The main purpose is
 to convert lipid soluble drug into more polar (water soluble) or
greater hydrophilic properties
 thus facilitating their renal excretion.

• The liver is the major site for drug metabolism.


Biotransformation---
Biotransformation reaction are classified into
A.Phase I or non-synthetic reactions:
These involve:
1.Oxidation
e.g. ethyl alcohol ----- acetaldehyde -----acetic acid -------
CO2 +H2O+energy
2.Reduction
e.g.chlorahydrate ------- trichloroethanol
3.Hydrolysis
e.g. Acetylcholine ----- Choline+Acetate

All the above reaction may result in:

1. Activation of pharmacologically inactive cpds to active ones
Imipramine (inactive) ------Despiramine (active)

2.Conversion of an active drug to metabolite that is also active
 Phencetin (active ---- Acetaminophen (paracetamol) (more
active).

3.Inactivation
 Acetylcholine (active) ------- choline +acetic acid (inactive)

4.Conversion to a toxic compound
 Methanol ----------- Formaldhyde (retinotoxic)

B-Phase II or synthetic reaction

• It involves the conjugation of the parent compound
or its metabolites with certain acid radicals or
amino acids.

• Synthetic reaction often result in inactivation of
drug and convert the drug to water soluble state.

• Example of synthetic(conjugation) reactions
include:

1. Conjugation of CAF with glucuronic acid

2. Conjugation of phenol with sulphate

3. Conjugation of sulphonamide with acetic acid

4. Conjugation of salcylate with glycine.


The biotransformation of drugs

Kinetics of Metabolism
1. First order kinetics:
• The metabolic transformation of drugs is catalyzed by
enzymes, and most of the reactions obey Michaelis-
Menten kinetics.
– The rate of drug metabolism is directly proportional
to the conc of free drug, and 1st order kinetics are
observed.
– This means that a constant fraction of drug is
metabolized per unit time.


• Effect of drug dose on the rate of drug metabolism

2-zero order kinetics

• The enzyme is saturated by a high free-drug conc, and
the rate of metabolism constant over time.
• Sometimes referred to clinically as nonlinear kinetics.
• A constant amount of drug is metabolized per unit of
time.


Effect of drugs on hepatic microsomal
enzyme
A-Activators or inducers

e.g.phenobarbitone, phenylbutazone, phenytoin,
Rifampin, tobacco smoking, androgen

 These drugs induce or stimulate the microsomal
enzyme so increase degradation of other drugs or
their own degradation


Effect of drugs on hepatic microsomal enzyme

B-Inhibitors

 e.g. Cimetidine,chloramphenicol,allopurinol,estrogen
and progesterone.

 These drugs inhibit the microsomal enzymes, so
 delay the rate of degradation of the drugs and prolong
their effects.


The biotransformation can lead to:
• 1) Transformation of molecules into more polar
metabolite
• 2) Change molecular weight and size of drug
• 3) Facilitate excretion and elimination drug from the
organism
Consequences
• - Decrease the half-life of drugs
• - Exposure to drug is shorten
• - Accumulation of drug is reduced
• - Probable reduce biological activity (toxicological
effects)

IV. Drug Elimination
• Removal of drugs from the body occurs via a
number of routes:
 major: through a kidney into the urine.
Others: bile, intestine, lung, milk in nursing dams,

Renal excretion
• Factors affecting excretion via kidney:
– • size (< 300)
– • Ionization (ionized)
– • Solubility (water soluble)

Biliary excretion
 Large and polar substances can be excreted via this route.
 Bile is excreted by hepatocytes into the canaliculi and flows
into the bile duct to the intestine.
 Gut microflora can convert some drugs to more lipid soluble
products, which can be reabsorbed into the portal venous
blood supply. This is called intrahepatic recirculation.

• Billiary excretion can leads to:
– 1- increasing half-life of drug
– 2- increasing hepatic exposure to drug
– 3- may cause hepatic damage

2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU)

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Ähnlich wie 2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU)

Ähnlich wie 2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU) (20)

2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU)