HAMMAD RAZA MUSTAFAI

HAMMAD RAZA
MUSTAFAI
ADEEL ARSHAD
hammadrazanhr@gmail.com

Assistant Prof.
The University of Lahore
PhD(University of Nottingham, UK)
Submitted To:

Once a drug enter into a blood stream the drug is subjected
to a numbers of processes called as DISPOSITION
PROCESSES that tend to lower the plasma concentration of
drug.
 DISTRIBUTION is a process which involves reversible
transfer of a drug between compartments.
 ELIMINATION is a process which involves irreversible
loss of drug from the body.

 DISTRIBUTION is reversible transfer of a drug between the
ONE COMPARTMENT (Blood) to ANOTHER (Extravascular
fluids and tissues).
 Distribution is a passive process for which the driving force is
CONCENTRATION GRADIENT between the blood and the
extravascular tissues.

 Pharmacological action of drug depends upon its
concentration at the site of action.
 Distribution plays a significant role in –Onset of
action.
 Intensity of action.
 Duration of action.

 Permeation of free drug present in blood through capillary wall
and entry into extracellular fluid (ECF)
 Permeation of drugs present in ECF through the membrane of
tissue cells and into intracellular fluid.
 This is RATE LIMITING STEPS and depends upon two
factors:-
 Rate of Perfusion to the extracellular tissue.
 Membrane permeability of the drug.

Factors affecting of distribution of drug:
1 Tissue permeability of the drug.
a)Physicochemical properties of drug like Mol. Size, pKa and
o/w partition coefficient.
b) Physiological barriers to diffusion of drugs.
2 Organ/Tissue size and Perfusion Rate. 3- Binding
of drugs to tissue components.
a) Binding of drugs to blood components.
b) Binding of drugs to extravascular tissue protein.
› 4-Miscellaneous

1- Molecular size
2- pKa
3- O/W Partition
Coefficient
1- Simple capillary
endothelial barrier
2- Simple cell membrane
barrier
3- Blood brain barrier
4- Blood CSF barrier
5- Blood placental barrier
6- Blood testis barrier
A) PHYSICOCHEMICAL
PROPERETIES OF
DRUG
B) PHYSIOLOGICAL
BARRIERS TO DIFFUSION
OF DRUG

 Drugs having molecular weight less than 500 to 600
dalton easily pass capillary membrane to ECF.
 Penetration of drug from ECF to cells is function of Mol.
Size, Ionization constant & lipophilicity of drug.
 From ECF to cross cell membrane through aqueous filled
channels need particle size less than 50 dalton with
hydrophilic property.
 Larger mol. size restricted or require specialized
transport system.

DEGREE OF IONIZATION:
 The Ph in which half of drug is unionized is called
pKa.
 The PH of blood and ECF play important role in
ionization & diffusion of drugs into cells.
 The ph of blood plasma, ECF & CSF is 7.4
(constant).Except in systemic acidosis &
alkalosis.
 A drug that remains unionised at this Ph values can
permeate the cells relatively more rapidly.
 Most of the drugs are either weak acids or weak bases
and their degree of ionisation at plasma or ECF Ph
depends upon their pKa.

Continue…
› All drugs that ionise at plasma Ph (i.e. hydrophilic ,
Polar drugs) cannot penetrate the lipoidal cell
membrane and tissue permeability is the rate limiting
step) in the distribution of such drugs.

3- O/W Partition Coefficient:
 Polar and hydrophilic drugs are less likely to cross the
cell membrane where Non- polar and hydrophobic drugs
are more likely to cross the cell membrane.
 In case of polar drugs where permeability is the rate
limiting step in the distribution, the driving force is the
effective partition coefficient of drug.
 Effective Ko/w= ( Fraction unionized at pH 7.4) x Ko/w
of ionized drug

Continue…
 Lipoidal drug penetrate the tissue rapidly. Among drugs
with same Ko/w but different in ionization of blood Ph.
 One which has less ionization show better
distribution.
› Ex. Phenobarbitol > Salicylic acid.
 Both drugs having same Ko/w but phenobarbitol is more
unionised at blood Ph therefore distributed rapidly.

PHYSIOLOGICAL BARRIERS:
o 1-Simple capillary endothelial barrier
o 2- Simple cell membrane barrier
o 3- Blood brain barrier
o 4- Blood CSF barrier
o 5- Blood placental barrier
o 6- Blood testis barrier

SIMPLE CAPILLARY ENDOTHELIAL
BARRIER:
 Membrane of capillary supply blood to the most inner
tissues.
 All drugs ionized or unionized, with a molecular size
less than 600 daltons, diffuse through the capillary
endothelium and into the interstitial fluid.
 Only drugs bound to the blood components are
restricted because of the large molecular size of the
complex.

SIMPLE CELL MEMBRANE
BARRIER:
 Once a drug diffuses through capillary to extracellular
fluid its further entry into cells of most tissues is limited
by its permeability through the membrane that lines such
cells.
 Simple cell membrane is similar to lipoidal barrier
(Absorption)
 Non polar & hydrophilic dugs passes through it
passively.
 Lipophilic drugs with 50-600 Dalton mol. Size and
hydrophilic, polar drugs with < 50 Dalton mol. Size will
pass this membrane.

BLOOD BRAIN BARRIER:
 Capillary in brain are highly specialized & much less
permeable to water soluble drugs.
 The brain capillaries consist of:-
›ENDOTHELIAL CELLS:- These are joined to each other
by continuous tight intercellular junction.
›PERICYTES & ASTROCYTES:-These are the elements
supporting tissue found at the base of endothelial
membrane, form a solid envelope around the brain
capillaries.
›Thus the intercellular(paracellular) passage is blocked
and for a drug to gain access from the capillary
circulation into the brain it has to pass through the
cells (transcellular) rather than between them.

CONTINUE…
• A solute may gain access to brain via :-
1)Passive diffusion through the lipoidal barrier:-thus drugs with
high o/w partition coefficient diffuse passively others
(moderately lipid soluble and partially ionised molecules
passes slowly.
2)Active transport of essential nutrients such as sugar and
amino acid thus structurally similar foreign molecules pass
through BBB by same mechanism.
› DIFFERENT APPROACHES TO CROSS BBB:-
 Permeation Enhancers :- Dimethyl Sulfoxide
 Osmotic disruption of the BBB by infusing internal
carotid artery with mannitol

CONTINUE…
Carrier system :-
Dihydropyridine (Lipid soluble) moiety redox system
(highly lipophilic & cross the BBB) linked as a carrier to
polar drug to form a prodrug & cross BBB. After entering in
brain DHP gets oxidize to polar pyridinium ion by (CNS)
enzyme in brain which cannot diffuse back out from brain
and drug gets trapped in side the brain.( used for steroidal
drugs)

BLOOD CEREBROSPINAL FLUID
BARRIER…
 Formed mainly by the choroid plexus of the lateral,
third and fourth ventricles & is similar in composition to
the ECF of brain.
 The capillary endothelium that lines the choroid plexus
have open junctions or gaps & drugs can flow freely into
extracellular space b/w capillary wall and choroidal cells.
 Choroidal cells joined to each other by tight junctions
forming blood-CSF barrier.
 Highly lipid soluble drugs can easily cross the blood-
CSF Barrier but moderatly soluble & ionize drugs
permeate slowly. hammadrazanhr@gmail.com

BLOOD PLACENTAL BARRIER:
 It’s the barrier b/w maternal & foetal blood vessels
both are separated by a no. of tissue layers made of
foetal trophoblast basement membrane & endothelium
together constitute placental barrier.

CONTINUE…
 Mean thickness 25μ at early pregnancy later reduce up
to 2μ (even its effectiveness remain unchanged).
 M,any drugs having Mol wt <1000 Dalton & moderate to
high lipid solubility drugs like (Sulphonamides,
Barbiturates, Steroids, Narcotic some Antibiotics ) cross
the barrier by simple diffusion rapidly.
 It means that placental barrier is not effective barrier
as BBB.
 Essential Nutrients for fetal growth transported by
carrier-mediated processes & Immunoglobulines are
transported by endocytosis.

BLOOD TESTIS BARRIER:
› This barrier not located at capillary endothelium level
but at sertoli - sertoli cell junction. It is the tight
junction b/w neighbouring sertoli cells that act as
blood-testis barrier . This barrier restrict the passage of
drugs to spermatocytes & spermatids.

ORGAN/TISSUE SIZE & PERFUSION RATE:
 Perfusion Rate :- is defined as the volume of blood that
flows per unit time per unit volume of the tissue
(ml/min/ml)
 Perfusion rate is limited when
1) Drug is highly lipophilic
2)Membrane across which the drug is supposed to diffuse is
highly permeable.
 Distribution is permeability rate - limited in following cases-
1) When the drug is ionic/polar/water soluble
2)Where the highly selective physiology barrier restrict the
diffusion of such drugs to the inside of cell.

CONTINUE…
› Drug is distributed in a particular tissue or organ
depends upon the size of tissue (Volume) &
Tissue/blood partition coefficient Ex.Thiopental i.v
(liphopillic drug) has high tissue/blood partition
coefficient towards brain & adipose tissue but brain is
highly perfused organ so drug is distributed fast and
shows rapid onset of action than poorly perfused
adipose tissue.

MISCELLANEOUS FACTORS:
› 1) AGE:- Difference in distribution pattern is mainly due to:-
 Total body water -(both ICF &ECF) greater in infants
 Fat content - higher in infants & elderly
 Skeletal muscle - lesser in infants & elderly
 Organ composition – BBB is poorly developed in infants &
myelin content is low & cerebral blood flow is high, hence
greater penetration of drug in brain plasma
 Protein content- low albumin in both infants & elderly
› 2) PREGNANCY:-During Pregnancy, due to growth of uterus,
placenta & foetus increases the volume available for
distribution of drug. Foetus have separate compartment for
drug distribution. Plasma & ECF volume also increase but
albumin content is low.

CONTINUE…
3)OBESITY:-
In obese persons, high adipose (fatty acid) tissue so high
distribution of lipophilic drugs and perfusion through it is low.
4) DIET:-
A diet high in fats will increases free fatty acid levels in circulation
thereby affecting binding of acidic drugs (NSAIDs to albumin)
5) DISEASE STATES:-
mechanism involved in alteration of drug distribution in disease
states:-
a)Altered albumin & other drug-binding protein concentration. b)Alteration
or reduced perfusion to organ or tissue.
c)Altered tissue pH.
6) DRUG INTERACTIONS:- DI that affect distribution are mainly
due to differences in plasma protein or tissue binding of drugs

CONTINUE…
› VOLUME OF DISTRIBUTION
›XαC
X=Vd.C
›It is defined as hypothetical volume of body fluid into
which a drug is dissolved or distributed.
› Vd=X/C
› Apparent Vd = amount of drug in the body/ plasma drug
conc.
›Apparent volume of distribution is dependent on
concentration of drug in plasma. Drugs with a large
apparent volume are more concentrated in extra vascular
tissues and less concentrated intravascular.
 37.

CONTINUE…
 The interacting molecules are generally the
macromolecules such as protein, DNA or adipose. The
protein are particularly responsible for such an
interaction.
 The phenomenon of complex formation of drug with
protein is called as protein binding of drug.
 As a protein bound drug is neither metabolized nor
excreted hence it is pharmacologically inactive due to its
pharmacokinetic and Pharmacodynamic inertness. –
 Protein + drug ⇌ Protein-drugcomplex
 Protein binding may be divided into: –
 1. Intracellular binding. – 2. Extracellular binding.

CONTINUE…
 INTRACELLULAR BINDING:- where the drug is bound to a cell protein which
may be the drug receptor so binding elicits a pharmacological response.
 EXTRACELLULAR BINDING:- where drugs bound to an extracellular protein
but the binding does not usually elicit a pharmacological response.
 MECHANISMS OF PROTEIN DRUG BINDING:- Binding of drugs to proteins is
generally-
• Reversible generally involves weak chemical bond such as:
› 1. Hydrogen bonds 2. Hydrophobic bonds 3. Ionic bonds 4. Van der waal’s
forces.
• Irreversible drug binding, though rare, arises as a result of covalent binding
and is often a reason for the carcinogenicity or tissue toxicity of the drug.

CONTINUE…
 BINDING OF DRUG TO BLOOD COMPONENTS A. Plasma protein-drug binding:- • The
binding of drugs to plasma proteins is reversible. • The extent or order of binding of
drug to plasma proteins is: Albumin › 1-Acid glycoprotein
› ›Lipoproteins ›Globulins.ὰ
 6. 1. Binding of drug to human serum Albumin. • It is the most abundant plasma
protein (59%), having M.W. of 65,000 with large drug binding capacity.
• Both endogenous compounds such as fatty acid, bilirubin as well as drug binds to
HSA. • Four diff. sites on HSA for drug binding. Site I: warfarin & azapropazone
binding site. Site II: diazepam binding site. Site III: digitoxin binding site. Site IV:
tamoxifen binding site.
 7. 2. Binding of drug to α1-Acid glycoprotein: (orosomucoid) It has a M.W. 44,000 and
plasma conc. range of 0.04 to 0.1 g%. It binds to no. of basic drugs like imipramine,
lidocaine, propranolol, quinidine. 3. Binding of drug to Lipoproteins: Binding by:
Hydrophobic Bonds, Non-competative. Mol wt: 2-34 Lacks dalton. Lipid core composed
of: Inside: triglyceride & cholesteryl esters. Outside: Apoprotein. e.g. Acidic:
Diclofenac. Neutral: Cyclosporin A. Basic: Chlorpromazine. LDL HDL VLDLChylomicrons
Types
 8. 4. Binding of drug to Globulins Globulin Synonym Binds to 1. α1 Globulin Transcortine
/Corticosteroid Binding globulin Steroidal drugs, Thyroxin & Cyanocobalamine. 2. α2
Globulin Ceruloplasmine Vitamin A,D,E,K. 3. β1Globulin Transferin Ferrous ions 4.
β2Globulin --- Carotinoids 5. γ Globulin --
› - Antigens hammadrazanhr@gmail.com

CONTINUE…
 B. BINDING OF DRUG TO BLOOD CELLS • In blood 40% of blood cells of which major component is
RBC (95%). The RBC is 500 times in diameter as the albumin. The rate & extent of entry into RBC
is more for lipophilic drugs. • The RBC comprises of 3 components. a) Haemoglobin: It has a M.W.
of 64,500 Dal. Drugs like phenytoin, pentobarbital bind to haemoglobin. b) Carbonic anhydrase:
Carbonic anhydrase inhibitors drugs are bind to it like acetazolamide & chlorthalidone. c) Cell
membrane: Imipramine & chlorpromazine are reported to bind with the RBC membrane.
› 2. BINDING OF DRUG TO EXTRAVASCULAR TISSUE PROTEIN • Importance: 1. It increases apparent
volume of distribution of drug. 2. localization of a drug at a specific site in body.
• Factor affecting: lipophilicity, structural feature of drug, perfusion rate, pH differences.
• Binding order: Liver ›Kidney › Lung › Muscles Tissue Binding of 1.Liver Irreversible binding of
Epoxides of Halogenated Hydrocarbon & Paracetamol. 2.Lungs Basic drugs: Imipramine,
Chlorpromazine, & AntiHistaminics.
› Cont… Tissue Binding of 3.Kidney Metallothionin protein binds to Heavy metals & results in
Renal accumulation and toxicity. 4.Skin Chloroquine & Phenothiazine binds to Melanin.
› 5.Eye Chloroquine & Phenothiazine also binds to Eye Melanin & results in Retinopathy. 6.Hairs
Arsenicals, Chloroquine, & Phenothiazine. 7.Bones Tetracycline(yellow discoloration of teeth),
Lead(replaces Ca & cause brittleness) 8.Fats Lipophilic drugs (thiopental), Pesticides (DDT)
9.Nucleic Acid Chloroquine & Quinacrine.

FACTORS:
 Drug-related factors a. Physicochemical
characteristics of the drug:- •. Protein binding is
directly related to the lopophilicity of drug. An
increase in lipophilicity increases the extent of
binding. b. Concentration of drug in the body:-
› •. Alteration in the concentration of drug substance as
well as the protein molecules or surfaces subsequently
brings alteration in the protein binding process. c.
Affinity of a drug for a particular binding component:-
•. This factor entirely depends upon the degree of
attraction or affinity the protein molecule or tissues
have towards drug moieties. •. For Digoxin has more
affinity for cardiac muscles proteins as compared to
that of proteins of skeletal muscles or those in the
plasma like HSA.

CONTINUE…
 Protein/ tissue related factors:
a.Physicochemical characteristics of protein or binding agent:
› •. Lipoproteins & adipose tissue tend to bind lipophilic drug by
dissolving them in their lipid core.
› •. The physiological pH determines the presence of active anionic &
cationic groups on the albumin to bind a variety of drug.
b. Concentration of protein or binding component:
› •. Among the plasma protein , binding predominantly occurs with
albumin, as it is present in high concentration in comparision to
other plasma protein.
› •. The amount of several proteins and tissue components available
for binding, changes during disease state

CONTINUE…
 Drug interactions
a.Competition between drugs for the binding sites[ Displacement
interactions]:- D2 D1+P D2+P D1: Displaced drug. D2: Displacer
drug. e.g. Administration of phenylbutazone to a patient on
Warfarin therapy results in Hemorrhagic reaction.
b.Competition between drug & normal body constituents:- The
free fatty acids are known to interact with a no. of drugs that
binds primarily to HSA. the free fatty acid level increase in
physiological, pathological condition.
c.Allosteric changes in protein molecule:- • The process involves
alteration of the protein structure by the drug or it’s
metabolite thereby modifying its binding capacity. •
› e.g. aspirin acetylates lysine fraction of albumin thereby
modifying its capacity to bind NSAIDs like phenylbutazone.

CONTINUE…
 Patient-related factors
a.Age: 1.Neonates: Low albumin content: More free drug. 2.Young
infants: High dose of Digoxin due to large renal clearance.
3.Elderly:Low albumin: So more free drug.
b.Intersubject variability: Due to genetics & environmental
factors.
› c. Disease states:- Disease Influence on plasma protein Influence
on protein drug binding Renal failure ↓ Albumin content ↓ binding of
acidic drugs; neutral and basic drugs are un affected Hepatic failure ↓
Albumin synthesis ↓ binding of acidic drugs; and binding of basic drugs
is normal or ↓ depending on AAG levels Inflamatory states i.e,truama
surgery etc… ↑AAG levels ↑ binding of basic drugs; neutral and acidic
drugs are un affected

CONTINUE…
 SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUG
a. Absorption- • As we know the conventional dosage form follow first order kinetics. So
when there is more protein binding then it disturbs the absorption equilibrium.
b. Distribution- • A protein bound drug in particular does not cross the BBB, the placental
barrier, the glomerulus. • Thus protein binding decreases the distribution of drugs.
c. Metabolism- • Protein binding decreases the metabolism
› of drugs & enhances the biological half life. • Only unbound fraction get metabolized. • e.g.
Phenylbutazone & Sulfonamide.
d. Elimination • Only the unbound drug is capable of being eliminated. • Protein binding
prevent the entry of drug to the metabolizing organ (liver ) & to glomerulus filtration. •
› e.g. Tetracycline is eliminated mainly by glomerular filtration.

CONTINUE…
 E.Systemic solubility of drug • Lipoprotein act as vehicle
for hydrophobic drugs like steroids, heparin, oil soluble
vit.
 f. Drug action- • Protein binding inactivates the drugs
because sufficient concentration of drug can not be build
up in the receptor site for action. • e.g. Naphthoquinone
 g. Sustain release- • The complex of drug protein in the
blood act as a reservoir & continuously supply the free
drug. • e.g. Suramin sodium-protein binding for
antitrypanosomal action.
 h. Diagnosis- • The chlorine atom of chloroquine replaced
with radiolabeled I- 131 can be used to visualize-
melanomas of eye & disorders of thyroid gland.
 SS

HAMMAD RAZA MUSTAFAI

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