PHARMACOKINETICS

LECTURE THREE

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Learning Objectives
Define PK

Importance of PK

The factors that modify the PK of drugs

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PHARMACOKINETIC IMPORTANCE

 To know the dose

 To know the suitable route of administration
 To know the dosage interval
 To know the period of medication

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 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

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 Pharmacokinetics
Fate of drugs in the animal body

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 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

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 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
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 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.
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 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

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 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

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 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

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Absorption…

b)Area and vascularity of the absorbing surface:

 Absorption is directly proportion to both area and
vascularity

c)State of health of the absorbing surface

d) expression of P-glycoprotein

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 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

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Movement of Drugs Across the Cell
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

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Movement of Drugs Across the Cell
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

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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

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 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
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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:
 plasma
 ECF
 ICF

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 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

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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 concentration

D- total amount of drug in the
body

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III. Biotransformation
Lipophilic Xenobiotic

Absorption (Intestine)

Phase I Reaction

Phase II Reaction

Hydrophilic Metabolite

Excretion (Urine and Feces)

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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.

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Biotransformation…
Biotransformation reaction are classified into
A. Phase I
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
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 Biotransformation…
All the above reaction may result in:

1.Activation of pharmacologically inactive

compounds to active ones.

2.Conversion of an active drug to metabolite that is

also active

3.Inactivation

4.Conversion to a toxic compound

 Methanol ----------- Formadhyde (retinotoxic)
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 Biotransformation…
B-Phase II

 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.

 E.g. Glucuronidation, sulfation, methylation etc.

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 Biotransformation…

Site of transformation
The majority of drugs are metabolized by the
hepatic microsomal enzyme located in the
hepatic endoplasmic reticulum.

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 Effect of drugs on hepatic microsomal enzyme

A-Activators or inducers

e.g.phenobarbitone,phenylbutazone,phenytoi
n, Rifampin, androgen etc.

These drugs induce or stimulate the

microsomal enzyme so increase degradation
of other drugs or their own degradation.

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Effect of drugs on hepatic microsomal enzyme…

b-Inhibitors

 e.g.Cimetidine,chloramphenicol,allopurinol,estr
ogen and progesterone.

 These drugs inhibit the microsomal enzymes

 delay the rate of degradation of the drugs and
prolong their effects.

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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).

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IV. Drug Elimination

Irreversible removal of a drug from the body occurs via

number of routes, the most important being through the
kidney into urine.
• Other route include the bile, intestine, lung or milk in
nursing mothers.

Renal excretion
Factors affecting excretion via kidney:
• size
• Ionization (ionized)
• Solubility (water soluble)
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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.
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Biliary excretion can leads to:
1- increasing half-life of drug
2- increasing hepatic
exposure to drug
3- may cause hepatic damage
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 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 penicillin.
b. reduction of vascularity of absorbing area by
administration of vasoconstrictor drug with the
drug e.g. adrenaline with local anesthetic.
c. administration of drug in oily solution

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How to prolong…
d. 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.

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 How to prolong…
3-Delay drug metabolism in the liver
depression of microsomal enzymes by certain
drugs.

4-Delay drug excretion in the kidney

Probenecid delay the excretion of penicillin by
blocking its renal tubular secretion.

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