Distribution Scop

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Blood brain barrier

� The CNS blood brain barrier is created by tight

junctions between endothelial cells and a

basement membrane supported by astrocytic

foot processes; this presents a formidable

barrier to drug penetration. Lipid soluble

agents or drugs with specific transport

mechanisms can penetrate rapidly.







Approaches to BBB

� Use of permeation enhancers such as

dimethyl sulphoxide (DMSO)

� Osmotic disruption of the BBB by infusinginternal carotid artery with mannitol.

� Use of dihydropyridine redox system as drug

carriers to the brain.(Prodrug for polar drugs)



Brain Cerebrospinal fluid barrier

� CSF is formed mainly by the choroid plexus of

the lateral, third and fourth ventricles

� It is similar in composition to the ECF of the

brain.

� Characteristics' similar to that of BBB



� The capillary endothelium that lines the

choroid plexus have open junctions or gapsand drugs can flow freely into the extracellular

space between the capillary walls and the

choroidal cells.

� Choroidal cells are joined to each other bytight junctions forming blood-CSF barrier

which has permeability similar to BBB





� For Any given drug conc. In brain higher than

in CSF, because bulk flow of CSF continuously

removes drug.



Blood placental barrier

� Number of tissue layers

� Mean thickness of the barrier 25 microns in

early pregnancy, 2 microns in full term� < 1000 Daltons MW & moderately high lipid

soluble drugs cross the barrier by simple

diffusion quite rapidly.

� Not as effective a barrier as BBB

� Nutrients carrier mediated process



Drugs in the mother's blood can cross the placental

membrane into blood vessels in the villi and pass

through the umbilical cord to the fetus



PERFUSION OR PERMEATION RATE

LIMITED



� Perfusion rate: defined as the vol. of

blood that flows per unit time per unitvol. of tissue, ml/min/ml

� Highly perfused :lungs,kidneys,liver,heart

,brain

� Moderately perfused: muscles, skin

� Poorly perfused: bones,fat(adipose

tissue)



� Kt=perfusion rate/Kt/b

� Kt/b=tissue/blood partition coefficent of drug

� Kt=Distribution rate constant� Tissue Distribution half life=0.693/Kt=

0.693/Kt/b

� Eg thiopental: lipophilic, high Kt/b towards brain still higher for

adipose tissue. Brain highly perfused organ, iv inj. Rapid onset of

action, adipose tissue poorly perfused, vol 5 times that of brain.

Rapid termination of action due to tissue redistribution.









ORGAN TISSUE AND PERFUSION

RA

TE





Miscellaneous factors

� Age

� Total body water: much greater in infants

� Fat contents: higher in infants& elderly� Skeletal muscles: lesser in infants & elderly

� Organ composition: BBB poorly developed in

infants , mylein content high,>penetration of drugs in brain

� Plasma protein content : low albumin in

infants and elderly



� Pregnancy : Vol. available fordistribution of drugs is high.

� Plasma and ECF vol. also increase but

there is fall in albumin content.



Miscellaneous factors

� Obesity: high adipose tissue

� Diet� Disease States: altered albumin and other

drug-binding protein conc.

� Altered organ/tissue perfusion.� Altered pH



Drugs appear to distribute in the body as if it werea single compartment. The magnitude of the drug¶s

distribution is given by the apparent volume of distribution (Vd). Vd bears no direct relation shipwith real vol of distribution.

Amount of drug in bodyConcentration in Plasma

Vd =

VOLUME OF DISTRIBUTIONVOLUME OF DISTRIBUTION



Volume of Distribution

Volume into which a drug appears todistribute with a concentration equal to its

plasma concentration







Determination of Physio. Vol.

� Plasma vol:Tracers or markers ; subs of high mol

wt totally bound to plasma ALBUMIN Evans

blue, Indocyanine green, I-131

� ECF: easily penetrate capillary membrane &

rapidly distribute through ECF but donot cross

cell memb.:mannitol,inulin,ions(Na+,Cl-

,sulphate)

� TBW: subs that distribute equally in all water

compts. Heavy water, tritiated water,antipyrine







Vd is useful in determining an appropriate dose toobtain a particular plasma level, therapeuticlevels are measured and referenced to plasmalevels.

A large Vd has an important influence on the half-life of a drug because elimination usuallydepends on the amount of free drug deliveredto the liver or kidney, with a large volume of distribution much/most of a drug will beextravascular or protein bound and not readilyavailable to excretory organs.



CONCLUSION:

FACTORS THAT PRODUCE ALTERATION IN

BINDING OF DRUG TO BLOOD COMPONENTS:

INCREASES Vd

FACTORS THAT INFLUENCE DRUG BINDING TO

EXTRAVASCULAR COMPONENTS: DECREASES

Vd

OTHER FACTORS:TISSUEPERFUSION,PERMEATION,IONISATION,

DISEASE STATE ETC.



PROTEIN BINDING



� Intracellular binding: when drug is bound to a

cell protein which may be the drug receptor, if

so, binding elicits a pharmacological

response.receptors:primary receptors

� Extracellular binding: when drug is bound to a

extracellular protein but the binding doesnot

elicits a pharmacologicalresponse.receptors:secondary,silent receptors

� Binding reversible, suggests weak

bonds(hydrogen, vanderwalls)



PROTEIN ± DRUG BINDING



Plasma protein binding

� Entry into systemic circulation, first thing

which can interact with drug: blood

components, like plasma proteins, blood cells,

Hb

� Binding to plasma protein reversible

� Mostly bound to albumin

� HAS: MW 65000, abundant(59% of total

plasma)





Binding of drugs to HSA

� Warfarin site: NSAIDs,bilirubin,phenytoin,

sodium valproate

� Diazepam binding site: benzodiazepines,ketoprofen, ibuprofen, trytophan

� Site III and IV : very few drugs bind.





� Primary site

� Secondary site:

� eg. Dicoumarol primary site1, secondary site 2� Drugs compete for site



Tissue binding of drugs

� 40% of body wt is tissue. 100 times that of HSA.

� it increases Vd

� Results in localisation of drug at specific site in

body, some drugs bind irreversibly to tissues

eg. oxidation pdts of PCM,

phenacetin,chloroform etc. bind covalently to

hepatic tissues.

� Extensive tissue binding suggest tissue can act

as a storage site for drugs.

� liver>kidney>lung>muscles





DETERMINATION OF PROTEIN BINDING

� Indirect techniques: based on separation of

bound form from the free micromolecule.

:equilibrium dialysis, dynamic dialysis, ultra

filtration, gel filtration, ultracentrifugation

� Direct techniques: Do not require separationof bound form of drug from the free

micromolecule: spectroscopy, fluorimetry, ion

selective electrodes



FACTORS AFFECTING PROTEIN BINDING

� Drug related factors

� Protein-tissue related factors

� Drug interactions

� Patient related factors



Drug related factors

� Conc. of drug in the body: HSA

no saturation, lidocaine can saturate AAG

� Drug-protein tissue affinity� Lidocaine greater affinity for AAG than has ,

digoxin greater affinity for protein of cardiacmuscles than skeletal muscles



Physicochemical characteristics of the drug

� Lipophilicity and larger binding, eg.slowabsorption of cloxacillin in comparison to

ampicillin after im inj.

� Anionic or acidic drugs bind more to HAS

� Cationic or basic drugs bind more to AAG

� Neutral unionized drugs bind more tolipoproteins

� Stereo selective binding eg.

Chloroquin,propranolol,ibuprofen



Protein-tissue related factors

� Physicochemical properties of

protein/Binding component

� Lipoproteins & adipose tissue bind lipophilic drugs

by dissolving them in the lipid core.

� Conc. of protein/Binding component

� Number of binding sites on proteins� AAG limited binding sites, albumin large no.



DRUG INTERACTIONS

� Competition between Drugs for binding sites� Drug -drug interaction for the common

binding site is called displacement reaction.

� Displaced drug---displacer� Eg. Warfarin displace by phenylbutazone

phenylbutazone---HAS

� Free warfain may cause hemorrhagicreactionwhich may be lethal.

� Unexpected rise in free drug conc. ---toxicity

or enhanced clinical response



� Clinically significant interaction occurs when:

� Displaced drug:

� is more than 95% bound� Has a small Vd (less than 0.15L/kg)

� Shows rapid onset of therapeutic or adverse

effects� Has a narrow therapeutic index



� Displacer drug:

� has higher degree of affinity for protein

competes for same binding site

� Drug/ protein conc. ratio is high(above 0.10)

� Showa a rapid and large increase in plasma

drug conc.



� 95% bound drug, displacement of 5% bound

drug results in 100% increse in free drug conc.

� Small Vd: remains in blood ---toxicity

� Large Vd; redistributes into large vol of body

fluids----insignificant clinical effects

� increase in free drug conc.---more available for

elimination

� If drug easily metabolisable or excretable

displacement results in in elimination half

life





� Competition between drugs and normal body

constituents

� Free fatty acids are known to interact with a no. of

drugs that bind primarily to HSA.

� Free fatty acid in fasting, pathological conditions,

pcologically induced conditions(after caffeine,heparin admin.)

� Influence binding of several benzodiazepines,

prpranolol, warfarin� Bilirubin binding to HSA-acidic drugs--free bilirubin

not conjugatedneonates---kernicterus.



Patient related factors

� Age

� Inter subject variation� Disease state





Conclusion

� All factors that affect protein bindinginfluence:

� 1. Pharmacokinetics---in plasma-protein

drug binding--- in unbound drug---tissue

redistribution/clearanceenhnace

biotransformation, excretion

� 2. Pharmacodynamics---- in conc. of free or

unbound drug results in intensity of action

(therapeutic/toxic)



Significance of protein tissue binding of drugs

�A

bsorption� Displacement interactions & toxicity

� Systemic solubility of drug

� Distribution

� Tissue binding

� Elimination

� Diagnosis(thyroid gland iodine compds)

� Therapy and drug targeting

















KINETICS OF PROTEIN BINDING













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