general pharmacology pharmacokinetics distribution of drug

1. GENERAL PHARMACOLOGY
PHARMACOKINETICS
DISTRIBUTION
PRESENTED BY:
CHAURASIYA RAUNAKKUMAR
1ST M PHARM
DEPARTMEN OF PHARMACOLOGY
MALLIGE COLLEGE OF PHARMACY
SUBMITTED TO:
Mrs N.C NAGALAKSHMI
DEPARTMENT OF
PHARMACOLOGY

2. DEFENETION
 Drug distribution refers to the reversible transfer of a drug between the blood and the
extra vascular fluids and tissues of the body(ex: fat, muscle, brain tissue)
 It is a passive process, for which, the driving force is concentration gradient between
the blood and extravascular tissue.

3. Difference in drug distribution occur due
to:
 Tissue permeability of the drug.
 Organ/tissue size and perfusion rate.
 Binding of drugs to tissue components
 Binding of drugs to blood components
 Binding of drugs to extravascular tissue protein
 Miscellaneous
age, pregnancy, obesity, diet, disease status, drug interaction.

4. Tissue permiability
 Two major rate determining steps in distribution
a) rate of tissue permeability
b) rate of blood perfusion.
 Tissue permeability depends on physiochemical properties of the drugs as well as
physiological barriers

5. 1. Tissue permeability of drugs
 The tissue permeability of drugs depends upon the physicochemical properties
of drug as well as the physiological barriers
a) PHYSIOLOGICAL PROPERTIES OF THE DRUG.
The factors are molecular size, degree of ionization and partition co efficient.
 The drugs having MW less than 500 to 600 Daltons easily cross the membrane.
 However entry of drugs from extracellular fluid to cell is the function of
ionization constant, lipophilicity of drug and molecular size
 Small water soluble molecules and ions of size below 50 d enter the cell through
aqueous filled channel

6. Degree of ionization: it is important to determine the tissue permeability.
Ph of the blood and extracellular fluid also play a role in the ionization and diffusion of
drugs into cells.
Most of the drugs either weak acid or weak base and their degree of ionization at plasma or
ECF pH depends on pKa.
Drugs that ionize at plasma ph cannot permeate lipoidal cell membrane. Only unionized
drugs generally lipophilic can cross cell membrane.
The drug that ionizes to lesser extent has more penetrability than the drug which ionizes to
larger extent.(eg: phenobarbital and salicylic acid is unionized at blood pH and therefore
distributes rapidly)

8.  The influence of drug pKa and Ko/w on distribution is illustrated by the example
thiopentanal, a nonpolar lipophilic unionized diffuses easily into brain , where as
penicillin which is polar and ionized at plasma pH does not cross the BBB.
b) PHYSIOLOGIC BARRIERS TO DISTRIBUTION OF DRUGS
A membrane with special structural feature can be a permeability restriction to distribution
of drugs to some tissues . Some barriers are
I. Simple capillary endothelial barrier
II. Simple cell membrane barrier
III. Blood brain barrier
IV. Cerebrospinal barrier
V. Placental barrier

9. i. Simple capillary endothelial barrier.
 The membrane of capillaries that supply blood to most tissues , practically not a
barrier to drug moieties.
 Thus 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 larger
molecular size.

10. ii. Simple cell membrane barrier
 Once the drugs diffuses into extra cellular fluid, its further entry into cells of
most tissues is limited by its permeability through the membrane the lines such
cells

11. III. BLOOD BRAIN BARRIER
 The capillaries in brain are highly specialized and much less permeable to water soluble drugs.
 BBB is that the brain capillaries consist of endothelial cells which are joined to one another by
continuous tight molecular junction .
 There is presence of special cells called astrocytes, which are the elements of the supporting
tissue found at the base of endothelial membrane. and form a solid envelope around the brain
capillaries and passage is blocked. And for the drug to gain access, it has to pass through the cell.
 There are specific site in the brain where BBB is absent i.e. trigger area and the median
hypothalamic eminence.( drugs administered by intranasally may diffuse directly into the CNS)

12. BBB conti…….
 It is lipoidal barrier, it allows only drugs having high ow partition co efficient to
diffuse passively, whereas moderately lipid soluble and partially ionized
molecules penetrate at slow rate.
 Polar natural substance such as sugars and amino acids are transported to brain
actively. Thus structurally similar foreign molecule can also penetrate by same
mechanism
 Most antibiotics such as penicillin's which are water soluble , polar and ionized at
plasma ph., do not cross under normal circumstances
 Selective permeability of lipid soluble moieties makes appropriate choicea of a
drug to treat CNS disorders( Parkinson treated by levodopa rather than
dopamine)

13.  Three approaches have been utilized successfully to promote crossing BBB.
 use of permeation enhancers like dimethyl sulfoxide.
 osmotic disruption of BBB by infusing internal carotid artery with mannitol.
 use of dihydropyridine redox system as a drug carrier to the brain.

14. Iv Blood cerebrospinal fluid barrier
 The CSF is formed mainly by the choroid plexus of the lateral, 3rd and 4th ventricles and
is similar in composition to the ECF of brain.
 The capillary endothelium that lines the choroid plexus have open junctions or gaps and
drugs can flow freely into the extra cellular space between the capillary wall and
choroidal space.
 As similar to BBB , high lipid soluble drugs can cross the BLOOD CSF barrier with
relative ease where as moderately lipid soluble and partially ionized drugs permeate
slowly.
 As the CSF continuously removes the drug hence high concentration cannot be achieved
 Mechanism for diffusion of drug into the CNS and CSF are similar, uptake may vary.

16. v. Placental barrier.
 The maternal and the foetal blood vessels are separated by a number of tissue
layers made of fetal trophoblast basement membrane and the endothelium which
together constitute the placental barrier .
 Many drugs having molecular weight less than thousand Daltons and moderate
to high lipid solubility eg: ethanol, sulphonamide, barbiturates etc and some
antibiotics cross the barrier by simple diffusion rapidly.
 Nutrients essential fir the fetal growth are transported by carrier mediated
processes

17.  Drugs are particularly dangerous to the fetes during two stages
1. in 1st trimester when the fetal organs develop , most drugs shows teratogenic effects
for example thalidomide, phenytoin.
2. in the later stage of pregnancy when drugs are known to affect physiologic function
Form example respiratory depression by morphine.

18. 2. Organ / tissue size and perfusion rate.
 Distribution is permeability rate limited. In the following cases
 when the drug under consideration is ionic , polar or water soluble
 Where the highly selective physiologic barriers restrict the diffusion of such
drugs to the inside of the cell
 Distribution will be perfusion rate limited When
 The drug is highly lipophilic
 The membrane across which the drug is suppose to diffuse is highly permeable
such as these of the capillaries and muscles

19.  Only highly lipophilic drug such as thiopental can cross the BBB, highly
permeable capillary wall permits the passage of all drugs. Rate limiting step is
rate of blood flow or perfusion to tissue. Greater blood flow, faster the adsorption
PERFUSSION RATE
 Is defined as the volume of blood that flows per unit time , per unit volume of
the tissue
 It is expressed in ml/min/ml of the tissue

20. 3. Miscellaneous factors affecting drug
distribution.
a) AGE: differences in distribution pattern of a drug in different age groups are
mainly due to differences in
 Total body water(% of body water contained in various fluid compartment)
 Fat content: higher in infants and elderly
 Skeletal muscle: less in infants and elderly
 Organ composition: BBB is poorly developed in infants
 Plasma protein content.

21. b) PREGNENCY: during pregnancy the growth of uterus, placenta and fetes
increases the volume available for distribution of drug
 the fetes represents a separate compartment in which a drug cam distribute
c) OBESITY :in obese persons, the high adipose tissue content can take up a large
fraction of lipophilic drugs despite the fact that perfusion through it low.
 The high fatty acid level in the obese person alter the binding characteristics of
acidic drugs

22. d) DIET: a diet high in fats will increase free fatty acid levels in circulation there by
affecting binding of acidic drugs such as NSAIDs to albumin.
e) Disease state: a number of mechanisms may be involved in the alteration of drug
distribution characteristics in disease state.
 Altered albumin and other drug binding protein concentration.
 Altered or reduced perfusion to organs or tissues
 Altered ph
Example of altered permeability of physiologic barriers is that of BBB, in meningitis and
encephalitis, the BBB becomes more permeable and thus polar antibiotics such as penicillin
G which does not cross BBB, gain access to brain

23. Volume of distribution
 Since different tissues have different concentration of the drug, their exists a
constant relation between the concentration of drug in plasma, c, and the amount
of drug X.
X=Vd C
where: Vd is proportionality constant having the unit of volume(apparent volume of
distribution) defined as the hypothetical volume of body fluid into which a drug is
dissolved or distributed
apparent volume of distribution= amount of drug in body or Vd = X
plasma drug concentration C

24. 4. PROTEIN BINDING OF DRUGS
 A drugs in the body can interact with several tissue components of which 2 major
categories are blood and extra vascular tissue.
 The phenomena of complex formation with protein is called as protein binding of drugs.
 These are reversible process which has weak chemical bonds such as hydrogen bonds ,
hydrophobic bonds, ionic bonds etc, irreversible bonding occurs rarely as a result of
covalent bond and is often reason for carcinogenicity and tissue toxicity.
CLSSIFICATION
Binding of drugs to blood components a) plasma proteins b) blood cells
Binding of drugs to extravascular tissue proteins, fats , bones etc.

25. a) Binding of drugs to blood components
1) Plasma protein drug binding:
When drugs enters systemic circulation it can 1st interact with blood components like
plasma , blood etc.
The binding of drugs to plasma is reversible . The extent of binding of drugs to
various plasma protein is albumin>glycoprotein> lipoprotein> globulin.

26.  Binding of drugs to human serum albumin.: human serum albumin is most abundant
plasma protein with a large drug binding capacity.
 Four sites have been identified for drug binding.
 SITE 1: called as warfarin and azapropazone binding site. Large number of drugs are
bound is NSAIDS
 SITE 2: diazepam binding site. Drugs that bind are benzodiazepines, ibuprofen,
cloxacillin.
 SITE 3: also called as digitoxin binding site.
 Site 4: called as tamoxifen binding site.
 Drugs can bind to more than 1 site which is primary site and other is secondary site.

27.  Binding of drugs to alpha1 – acid glycoprotein: also called as orosomucoid.it binds to a
number of basic drugs like imipramine, amitriptyline, propranolol etc
 Binding of drugs to lipoproteins: binding of drugs to HSA and AAG involve in
hydrophobic bond. Since lipophilic drugs can undergo hydrophobic bonding, lipoprotein
can also bind to such drugs because of lipid content.
Classified as
 Chylomicrons
 Very low density lipoprotein
 low density lipoprotein
 High density lipoprotein

28.  BINDING OF DRUGS TO GLOBULINS:
1 GLOBULIN: also called transcortin or corticosteroid binding globulin, it binds
to number of steroidal drugs such as cortisone and prednisone
2 GLOBULIN : known as ceruloplasmin. It binds vit A, D , E, K AND cupric ions.
1 GLOBULIN : transferrin, it binds to ferrous ions.
2 GLOBULIN : binds to carotenoids.
 GLOBULIN : binds specifically to antigens

29. II) BINDING OF DRUGS TO BLOOD CELL
More than 40% of the blood comprises of blood cells of which major cell component
is RBC. Hence RBC drug binding is possible. RBC comprise of 3 components each
of which can bind to drugs.
HEMOGLOBIN: it is 7 8 times the concentration of albumin in blood. Drugs like
phenytoin, phenobarbital and phenothiazines etc
CARBONIC ANHYDRASE: drugs known to bind to it are acetazolamide and
chlorthalidone
The rate and extent of entry into RBC is more for lipophilic drugs eg phenytoin.
hydrophilic drugs like ampicillin do not enter RBC

30. b) Tissue binding of drugs.
 A drug can bind to one or more tissue component,
 Tissue drug binding is important from two view point
 It increases the apparent volume of distribution of drugs in contrast to plasma
protein binding which decreases it.
 Tissue drug binding results in localization of drug at a specific site in body . this
more so because number of drugs bind irreversibly to tissues eg: oxidation
product of paracetamol, chloroform, etc
 Majority of drugs bind to extravascular tissue, liver>kidney>lung>muscle

31. Factors affecting protein drug binding.
1. Factors relating to drug.
 physicochemical characteristic of drug
 Concentration of drug in body
 Affinity of a drug for a particular binding component
2. Factors relating to protein and other binding components
 Physicochemical character of protein
 Concentration of protein binding component
 Number of binding sites on the binding agent

32. Conti…
3. Drug interaction
 Competition between drugs for the binding site
 Competition between drugs and normal body constituents
 Allosteric changes in protein molecule
4. patient related factors
 Age
 Intrasubject variation
 Disease state

33. References
Textbook of biopharmaceutics & pharmacokinetics-D M BRAHMANKAR
https://www.slideshare
www.google.com

34. THANK YOU