PHARMACOKINETICS

II.
PHARMACOKINETICS
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
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 process by which a drug moves from its sites of

administration into the venous or lymphatic
circulation.
 The factors that modify the absorption of drugs

is either related
 to the drug or
 to the patients
Absorption….
A. Factors related to the drugs
1-Drug solubility
Insoluble drugs are not absorbed
e.g. barium sulphate
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 parentral sites
 For oral drug, it is absorbed first from GIT either

through passive diffusion or active transport
Sites of absorption
GASTROINTESTINAL TRACT (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…
b)Area and vascularity of the absorbing surface:

 Absorption is directly proportion to both area and
vascularity
c)State of health absorbing surface

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
Membrane
 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
Membrane
 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 and energy
 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
Schematic representation of drugs
crossing a cell m/m of the GIT
Movement of Substances Across the Cell
Membrane
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
XX
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 interstitium (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
C-and the ICF.
Binding of drugs to
proteins
 Drugs are distributed and bind to α-acid glycoprotiens and
protiens (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 and 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
Any question??
III. Biotransformation
 Refers to the chemical alterations which drug
undergoes within living organism.
 The main aim of drug biotransformation is to

convert lipid soluble drug into more polar (water
soluble) of 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 i

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 ----------- Formadhyde (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 chloramphenicol with glucuronic
acid
2. conjugation of phenol with sulphate
3. conjugation of sulphonamide with acetic acid
4. conjugation of sailcylate with glycine.

Site of transformation
 The majority of drugs are metabolized by the
hepatic microsomal enzyme located in the
hepatic endoplasmic reticulum.
2-zero order kinetics
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)
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
How to prolong duration of action of the drug
1-Delay drug absorption by

a. reduction of solubility of the drug by formation
of sparingly soluble complexes e.g.protamine
zinc insulin and procaine pencillin
b. reduction of vascularity of absorping area by
administration of vasoconstrictor drug with the
drug e.g. adrenaline with local anaethetic
c. administration of drug in oily solution
e.g.vasopressin tannate in oil
How to prolong…..
d. Implantation of drug pellets S.C.e.g.
desoxycorticosterone acetate (DOCA)) in Addison
disease
e. the use of sustained released tablets
2-Delay drug distribution by

 The use of highly protein bound drug.
e.g. Long acting sulphonamide like sulfadiethoxine have
been designed.
How to prolong….
3-Delay drug metabolism in the liver By
 depression of microsomal enzymes by certain
drugs e.g.SKF-525A ( Not used now)
4-Delay drug excretion in the kidney

 Probencid delay the excretion of pencillin by
blocking its renal tubular secretion
THANK YOU
Any question??

PHARMACOKINETICS

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II.

 To know the dose

 The changes that occur to the drug when it is

 The ways in which the body processes drugs.

 The process by which a drug moves from its sites of

 The factors that modify the absorption of drugs

 Ionized drug ------ polar ---- less lipid solubility ---Less

 Unionized drug --- non-polar --- more lipid soluble ---More

 Ferrous salt are better absorbed from the

 Drugs in aqueous solution are more rapidly

 the smaller the particle size of the powder the

 For oral drug, it is absorbed first from GIT either

GASTROINTESTINAL TRACT (GIT)

b)Area and vascularity of the absorbing surface:

c)State of health absorbing surface

 Pharmacokinetics includes the movement of

 Is the process by which the drug reversibly leaves

 After absorption of a drug, it is usually

 Acidic drugs- albumin

 NB. Hypoalbuminemia can affect the level of free drug

 Is a hypothetical volume of fluid into which the

 Vd= D/C : is drug specific

C- plasma drug conc.

 The main aim of drug biotransformation is to

 The liver is the major site for drug metabolism.

A.Phase I or non-synthetic reactions:

1. Activation of pharmacologically inactive cpds to active ones i

2.Conversion of an active drug to metabolite that is also active

4.Conversion to a toxic compound

B-Phase II or synthetic reaction

 It involves the conjugation of the parent compound

 Synthetic reaction often result in inactivation of

 Example of synthetic (conjugation) reactions

2. conjugation of phenol with sulphate

3. conjugation of sulphonamide with acetic acid

4. conjugation of sailcylate with glycine.

 These drugs induce or stimulate the microsomal

 These drugs inhibit the microsomal

1-Delay drug absorption by

2-Delay drug distribution by

4-Delay drug excretion in the kidney

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