Drug Distribution & Volume of Distribution.

Views:
 
Category: Entertainment
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

PowerPoint Presentation:

Drug Distribution & Volume of Distribution Mr. Vinod D Ramani CKPIPSR- Surat

Definitions:

Definitions DISTRIBUTION:- Is reversible transfer of drug b/w blood & extra vascular tissues.

PowerPoint Presentation:

MICHANISOME:- Diffusion of free drug until equilibrium is achieved.

Significance :-:

Significance :- ☺☺☺ Pharmacological action of drug depends upon its concentration at the site of action Thus distribution plays important role in ♫ onset of action ♫ Intensity of action ♫ Duration of action to ☺ o

Distribution of drug is not Uniform thought the body------- why?????:

Distribution of drug is not Uniform thought the body------- wh y????? Because tissue receive the drug from plasma at different rates & to different extents.

Factors which affects the drug distributions:

Factors which affects the drug distributions 1). tissue permeability of drug a . physicochemical property – i) molecular size ii) pKa iii) o/w partion coefficient b . physiological barriers 2). Organ tissue size and perfusion rate 3). Binding of drug to tissue components a . with blood components b .with extravascular tissue proteins 4). Miscellaneous factors a . age b .Pregnancy d .Obesity e .Diet f .Disease states g .Drug interaction

1). Tissue permeability of drug:

1). Tissue permeability of drug a . physicochemical property: I) Molecular Size; Mol wt less then 500 to 600 Dalton easily pass capillary membrane to extra cellular fluid. From extra cellular fluid to cross cell membrane through aqueous filled channels need particle size less then 50 Dalton with hydrophilic property . Larger size were restricted unless specialized transport system is exists

1). Tissue permeability of drug:

1). Tissue permeability of drug a . physicochemical property ii) Degree of ionization (pKa) ♫ The pH at which half of a drug is unionized is called pKa A weak acid becomes unionized in a strong acidic environment. A weak acid becomes ionized in a neutral or basic environment. & A weak base becomes unionized in a strong basic environment. A weak base becomes ionized in a neutral or acidic environment. BUT The PH of BL ☺☺ d plasma, extra cellular fluide and CSF is 7.4(constent) Except in acidosis and alkalosis All drug that ionize at plasma PH (i.e. polar , hydrophilic drugs) Can not penetrate the lipoidal cell membrane

1). Tissue permeability of drug:

1). Tissue permeability of drug a . physicochemical property iii) o/w permiability ♫ Polar and hydrophilic drugs are less likely to cross the cell membrane Where,,,,,,,, ☺ Nonpolar and hydrophobic drugs are more likely to cross the cell membrane EFFECTIVE K O/W = Fection unionized x K O/W of unionized at pH 7.4 drug In case of polar drugs where permiability is the rate- limiting step in the distribution , the driving force is the effective partion coefficient Of drug ……..that can be calculated by above formula

Conclusively……..:

Conclusively……..

b. physiological barriers:

b . physiological barriers 1) The simple capillary endothelial barrier Capillary supply the blood to the most inner tissue All drugs ionized or unionized molecular size less then 600dalton diffuse through the capillary endothelium to interstitial fluid Only drug that bound to that blood components can’t pass through this barrier Bcoz of larger size of complex

b. physiological barriers:

b . physiological barriers Simple cell membrane barrier once the drug diffuse through capillary to intracellular fluid ,its farther entry in to cells of most tissue Membrane is act as lipoidl barrier Non polar & hydro phallic drugs will passes through it (passively). Lipophilic drugs with 50-600dalton mol size & Hydrophilic ,polar drugs with >50dalton will pass this membrane

b. physiological barriers:

b . physiological barriers 3) Blood brain barrier

b. physiological barriers:

b . physiological barriers 3) Blood brain barrier Capillary in brain is highly specialized & much less permeable to water soluble drugs ENDOTHELIAL CELLS ;- Tightly bonded with each other by intracellular junctions ASTROCYTES :- present @ the base of endothelial tissue and act as supporting materials & it form envelop around the capillary thus intra cellular passage get blocked. BBB is lipoidal thus drugs with high O/W partition coefficient diffuse passively others passes slowly. Polar natural substance (sugar & amino acid) transported actively thus structurally similar drug can pass easily to BBB.

Different approaches to cross BBB:

Different approaches to cross BBB A) permeation enhancers ;- dymethyl sulfoxide B) pro- drug approach ;- dopamine ---- livodopa C) carrier system ;- Dihydropyridine moiety (hilylipophilic & cross the BBB) Form the complex of drug-DHP. After entering in brain DHP gets metabolize by enzyme in brain and drug gets trapped in side the brein.... Haaa haaaa haaa.

b. physiological barriers:

b . physiological barriers 4) Cerebral spinal fluid barrier ;-

b. physiological barriers:

b . physiological barriers 4) Cerebral spinal fluid barrier ;- Capillary endothelial cells ;- have open junction or gaps so…. Drugs can flow freely b/w capillary wall & choroidal cells. Choroids plexus ;- major components of CSF barriers is choroidal cells which are joined with each other by tight junctions forming the blood-CSF barrier (similar permeability to BBB) Mechanism of drug transport is similar but bulk flow of CSF continuously remove drug thus concentration of drug always remain high in brain then CSF .

b. physiological barriers:

b . physiological barriers 5) Placenta barriers ;-

b. physiological barriers:

b . physiological barriers 5) Placenta barriers ;- It’s the barrier b/w maternal & fetal blood vessels Both are separated by fetal trofoblast basement membrane & endothelium . Thickness 25 µ @ early pregnancy later reduce up to 2µ (even its effectiveness remain unchanged) Mol wt <1000 Dalton & moderate to high lipid solubility drugs like….. (sulfonamides,barbiturets,steroids,narcotic some antibiotics ) cross the barrier by simple diffusion rapidly Nutrients transported by carrier-mediated processes . Its advisable to avoid drugs during 1 st trimester (fetal organ development )

b. physiological barriers:

b . physiological barriers 6) blood-Testis Barrier :- Not @capillary endothelial level. But at sertoli-sertoli cell junction . Its barrier b/w neighboring sertoli cells that act as blood-testis barrier . This restrict the passage of drug to spermatocyts & spermatids.

2). Organ tissue size and perfusion rate:

2). Organ tissue size and 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-limited when………………….. 1) drug is highly lipophilic 2) the membrane across which the drug is supposed to diffuse Above both the cases Greater the blood flow , faster the distribution

3).Binding of drug to tissue components:

3).Binding of drug to tissue components a) B inding of drug to blood components;- i) Plasma protein bindings Human serum albumin :-all types drug ά 1- acid glycoprotein :-basic drugs(impra) Lipoproteins :-basic,lipophilic drugs (chlorpromazin ) ά 1- Globuline :-steroids like corticosterone ,vit-B12 ά 2- Globuline :-vit-A,D,E,K,cupric ions. Hemoglobin :-Phenytoin, phenothiazines. ii) Blood cells bindings:- RBC : 40% of blood comprise of blood cells out of that 95% cells are RBC this RBC comprise of hemoglobin drugs like , phenytoin,phenobarbiton binds with Hb ,imipramine,chlorpromazine binds with RBC Cell wall

3).Binding of drug to tissue components:

3).Binding of drug to tissue components b.with extra vascular tissue proteins 40% of total body weight comprise of vascular tissues Tissue-drug binding result in localization of drug at specific site in body and serve as reservoir As binding increases it also increase bio-logical half life. Irreversible binding signify drug toxicity. (carbamazepin-outoinduction) liver > kidney > lungs > muscle > skin > eye > bone > Hair, nail

4). Miscellaneous factors:

4). Miscellaneous factors a) AGE:- Difference in distribution pattern is mainly due to Total body waight Fat content Skeletal muscle plasma composition b) PREGNANCY:- During Pregnancy, due to growth of UTERUS,PLECENTA,FETUS… Increases the volume available for distribution. C) OBECITY :- In obese persons, high adipose (fatty acid) tissue so high distribution of lipophilic drugs

4). Miscellaneous factors:

4). Miscellaneous factors d) DIET:- A diet high in fats will increases free fatty acid levels in circulation thereby affecting binding of acidic drugs (NSAIDs to albumin) e) DISEASE STATES:- mechanism involved in alteration of drug distribution in disease states. Lustration in drug-binding protein concentration. Alteration of perfusion to tissue Altered tissue pH. Alteration of permeability of physiological barrier EX- BBB (in meningitis) f) DRUG INTERACTION:- Displacement interaction occurs when two drugs administered which having similar binding site affinity.

How do I quantify drug distribution?:

How do I quantify drug distribution? Volume of Distribution (V d ) [ml or l]:

Volume of Distribution (Vd):

Volume of Distribution (V d ) @ Equilibrium of distribution, diff organ tissue contains varying concentration of drug Which can be determined by the volume of tissue in which the drug is present. Since diff tissue have diff concentration of drug , the volume of distribution can’t have a true physiologic meaning. So apparent volume of distribution( Vd ) need to take in consideration

Volume of Distribution (Vd) [ml or l]::

Volume of Distribution (V d ) [ml or l]: If C pl is low, V d is high; & if C pl is high, V d is low Lipophilic drugs: Vd > total body volume Extracellularly confined drugs: Vd < total body volume Intravascular confined drugs: Vd << total body volume

Markers used to measure the real physiologic compartments :

Markers used to measure the real physiologic compartments Physiologic fluid Comportment Markers used Approximat volume(liters) Plasma Evans blue,indocyanine green 3 Erythrocytes Cr-51 2 Extra cellular fluid Raffinose,inulin,mannitol, Na,Cl,Br 15 Total body water D2O,antipyrine 42

Calculation of Vd:

Calculation of V d Dose: 500 mg Concentration in plasma: 500 µg/L V d : ?

How is Vd used? :

How is Vd used? Example Mr. Cardiomyopathy has been admitted to the ER with acute heart failure. You decide to put him on digoxin . You want to achieve a serum concentration of 1ng/mL . How much do you administer? Dose = ? C = 1 ng/mL Vd = 500 L

authorStream Live Help