Drug distibution, significance, steps in Drug distribution, Factors affecting,physiochemical properties of drug, volume of distribution,protein binding, mechanism of protein drug binding

1. PRESENTED BY-
ANJALI JOSHI
M.PHARM
(PHARMACEUTICS)

2.  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.

3.  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.

5. Pharmacological action of drug depends upon
its concentration at the site of action.
Distribution plays a significant role in –
a) Onset of action.
b) Intensity of action.
c) Duration of action.

6.  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.of tissue cells and into intracellular fluid.
 This is RATE LIMITING STEPS and depends upon two
factors:-
a) Rate of Perfusion to the extracellular tissue.
b) Membrane permeability of the drug.

8. 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.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

9. 1-Molecular size
2-pKa
1-Simple capillary
endothelial barrier
A) PHYSICOCHEMICAL
PROPERETIES OF
DRUG
B) PHYSIOLOGICAL
BARRIERS TO DIFFUSION
OF DRUG
2-pKa
3-O/W Partition
Coefficient
endothelial barrier
2- Simple cell membrane
barrier
3- Blood brain barrier
4- Blood CSF barrier
5- Blood placental barrier
6- Blood testis barrier

10.  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 ofMol. 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.

11. 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 &(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.

12.  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.

13.  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 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 Koo/w= ( Fraction unionized at pH 7.4) x/w= ( Fraction unionized at pH 7.4) x
KoKo/w of ionized drug/w of ionized drug

14.  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 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.

15. 1-Simple capillary endothelial barrier
2- Simple cell membrane barrier
3- Blood brain barrier
4- Blood CSF barrier4- Blood CSF barrier
5- Blood placental barrier
6- Blood testis barrier

16.  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.endothelium and into the interstitial fluid.
 Only drugs bound to the blood components are
restricted because of the large molecular size of the
complex.

17.  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 Simple cell membrane is similar to lipoidal barrier
(Absorption)
 Non polar & hydrophilic dugs passes through it
passively.
 Lipophillic drugs with 50-600 dalton mol. Size and
hydrophilic, polar drugs with < 50 dalton mol. Size will
pass this membrane.

18.  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 elementsPERICYTES & 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.

19.  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 sugar2) 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

20.  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 indiffuse back out from brain and drug gets trapped in
side the brain.( used for steroidal drugs)

21.  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 andinto 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.

23.  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.

24.  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.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.

25.  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.

26.  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 is2) 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.

27.  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 perfusedshows rapid onset of action than poorly perfused
adipose tissue.

28. 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, hencemyelin 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.

29. 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.a)Altered albumin & other drug-binding protein concentration.
b)Alteration or reduced perfusion to organ or tissue.
c)Altered tissue pH.
d)Alteration of permeability of physiological barrier (BBB)
Ex- BBB (in meningitis & encephalities) BBB becomes more
permeable thus polar antibiotics ampicilin, penicilin G which
do not normally cross gain access to the brain & patient
suffering from CCF perfusion rate to entire body decreases it
affect distribution.

30. 6) DRUG INTERACTIONS:- DI that affect distribution are mainly due
to differences in plasma protein or tissue binding of drugs.
VOLUME OF DISTRIBUTION
XαC
X=Vd.CX=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.

31.  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.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-drug complex
 Protein binding may be divided into: –
 1. Intracellular binding. – 2. Extracellular binding.

32.  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 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.

33.  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.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

34.  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: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.

35.  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 orsubstance 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.

36.  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 aanionic & 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

37.  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 interactconstituents:- 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.

38.  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.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

39.  IGNIFICANCE 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 metabolismc. 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.

40.  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. Naphthoquinoneup 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