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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.
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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)
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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
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� 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
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� For Any given drug conc. In brain higher than
in CSF, because bulk flow of CSF continuously
removes drug.
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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
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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
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PERFUSION OR PERMEATION RATE
LIMITED
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� 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)
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� 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.
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ORGAN TISSUE AND PERFUSION
RA
TE
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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
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� Pregnancy : Vol. available fordistribution of drugs is high.
� Plasma and ECF vol. also increase but
there is fall in albumin content.
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Miscellaneous factors
� Obesity: high adipose tissue
� Diet� Disease States: altered albumin and other
drug-binding protein conc.
� Altered organ/tissue perfusion.� Altered pH
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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
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Volume of Distribution
Volume into which a drug appears todistribute with a concentration equal to its
plasma concentration
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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
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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.
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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.
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� 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)
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PROTEIN ± DRUG BINDING
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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)
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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.
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� Primary site
� Secondary site:
� eg. Dicoumarol primary site1, secondary site 2� Drugs compete for site
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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
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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
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FACTORS AFFECTING PROTEIN BINDING
� Drug related factors
� Protein-tissue related factors
� Drug interactions
� Patient related factors
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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
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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
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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.
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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
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� 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
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� 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.
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� 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
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� 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.
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Patient related factors
� Age
� Inter subject variation� Disease state
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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)
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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
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KINETICS OF PROTEIN BINDING