Unit-I Distribution of Drugs BPPK @123.pptx

1. Distribution of drug
2. Factor affecting of drug
3. Protein binding of drug
4. Factors affecting of protein binding of drug
5. Significance of protein drug binding
6. Volume of distribution

1. DRUG DISTRIBUTION Presented by Mr. Kshirsagar D. C. Asst. Professor Department of Pharmaceutics GIPER, Limb, Satara.

2. DRUG DISTRIBUTION Once a drug enter in to the blood stream, the drug is subjected to a number of processes called as Disposition Processes that tend to lower the plasma concentration of drug. Distribution which involves reversible transfer of a drug between compartments. Elimination which involves irreversible loss of drug from the body. It comprises of biotransformation and excretion.

3. D E F INI T IO N Drug Distribution is defined as the Reversible transfer of drug between one compartment (blood) to another (extra vascular tissue) compartment

4. 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

5. STEPS IN DRUG DISTRIBUTION Permeation of Free Drug through capillary wall & entry in to Extracellular fluid ( ECF). Permeation of drugs from ECF to ICF through membrane of tissue cell. Rate Limiting Steps Rate of Perfusion to the Extracellular tissue Membrane Permeability of the drug

6. Schematic of the steps involved in drug distribution

7. FACTORS AFFECTING DISTRIBUTION OF DRUGS Tissue Permeability of Drugs Physicochemical Properties of drug like Mol.size, pK a, o/w Partition Coefficient Physiological barriers to diffusion of drugs Organ/tissue size and perfusion rate Binding of drugs to tissue components. binding of drug to blood components binding of drug to extra cellular components Miscellaneous

8. TISSUE PERMEABILITY OF DRUGS Physicochemical Properties of drug Molecular size, pKa o/w Partition Co Efficient. Physiological barriers to Diffusion of Drugs Simple Capillary Endothelial Barrier Simple Cell Membrane Barrier Blood Brain Barrier Blood – CSF Barrier Blood Placental Barrier Blood Testis Barrier

9. 1) TISSUE PERMEABILITY OF DRUG A) Physicochemical property: Molecular Size; Mol. size less then 500 to 600 Dalton easily pass capillary membrane to extra cellular fluid. Penetration of drug from ECF to cells is function of Mol size, ionization constant & lipophilicity of drug From extra cellular fluid to cross cell membrane through aqueous filled channels need particle size less then 50 Dalton (small) with hydrophilic property . Large mol size restricted or require specialized transport system

10. 1) TISSUE PERMEABILITY OF DRUG A) Physicochemical Property ii) Degree of Ionization ( 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 Blood plasma, extra cellular fluid and CSF is 7.4( constant) Except in acidosis and alkalosis All the drugs ionize at plasma pH (i.e. Polar , Hydrophilic Drugs) Can not penetrate the Lipoidal cell membrane

11. 1) TISSUE PERMEABILITY OF DRUG A) Physicochemical Property iii) o/w permeability 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 = Fraction unionized at pH 7.4 x K O/W of unionized drug 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 ……..that can be calculated by above formula

12. Lipoidal drug penetrate the tissue rapidly. Among Drugs with same Ko/w but diff in ionization of blood pH, one which has less ionization show better distribution. E.g. Phenobarbital > salicylic acid Both are having same Ko/w but phenobarbital have more unionized at blood pH therefore distributes rapidly.

13. DISTRIBUTION PROCESS

14. 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 than 600 dalton diffuse through the capillary endothelium to interstitial fluid. Only drugs that bound to that blood components can’t pass through this barrier Because of larger size of complex.

15. 2. Simple Cell Membrane Barrier Once the drug diffuse through capillary to extracellular fluid ,its further entry in to cells of most tissue is limited . Simple cell Membrane is similar to the lipoidal barrier in the GI absorption of drug. Non polar & hydrophilic drugs will passes through it (passively). Lipophilic drugs with 50-600 dalton mol size & Hydrophilic, Polar drugs with ‹ 50dalton will pass this membrane

16. 3) Blood Brain Barrier

17. 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 Pericytes & Astrocytes :- Present @ the base of endothelial tissue and act as supporting materials & it Form Envelop around the capillary thus intercellular passage get blocked. BBB is lipoidal barrier, thus drugs with high o/w partition coefficient diffuse passively others ( moderately lipid soluble and partially ionised molecules passes slowly. Polar natural substance (sugar & amino acid) transported to brain actively thus structurally similar drug can pass easily to BBB.

18. DIFFERENT APPROACHES TO CROSS BBB Permeation Enhancers ;- Dimethyl Sulfoxide (DMSO) Pro- Drug Approach - Dopamine ---- Levodopa (Parkinsonism) and osmotic disruption of the BBB BY infusing internal carotid artery with mannitol Carrier system ;- Dihydropyridine (Lipid soluble) redox system (highly lipophilic & cross the BBB)Complex formation (DRUG-DHP). After entering in brain DHP gets metabolize by (CNS) enzyme in brain and drug gets trapped inside the brain. Polar pyridinium ion can not diffuse back out of the brain. Ex. Steroidal drug

19. 4) Cerebral Spinal Fluid Barrier

20. 4) Cerebral Spinal Fluid Barrier: Capillary endothelial cells;- have open junction or gaps so…. Drugs can flow freely 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) Highly lipid soluble drugs can easily cross the blood-CSF Barrier but moderately soluble & ionize drugs permeate slowly.

21. 5) Blood Placenta l barrier

22. 5) Blood Placental Barriers It’s the barrier b/w Maternal & Fetal blood vessels Both are separated by fetal trophoblast basement membrane & endothelium . Mol wt <1000 Dalton & moderate to high lipid solubility drugs like….. (Sulfonamides, Barbiturets , Steroids, Narcotic some Antibiotics ) cross the barrier by Simple Diffusion rapidly Essential Nutrients for fetal growth transported by carrier-mediated processes. Immunoglobulines are transported by endocytosis. Drugs dangerous to fetus at Two stages Its advisable to avoid drugs during 1 st trimester (fetal organ development) some drugs produce teratogenic effect ex. Phenytoin, methotrexate later stage pregnancy affect physiological functions like respiratory Depression ex. morphine Better to restrict all drugs during pregnancy.

23. 6) Blood - Testis Barrier :- This barrier not located at capillary endothelium level. But at sertoli - sertoli cell junction . It is the tight junction / barrier b/w neighboring sertoli cells that act as blood-testis barrier . This barrier restrict the passage of drugs to spermatocytes & spermatids.

24. 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………………….. Drug is highly lipophilic . Membrane across which the drug is supposed to diffuse highly permeable through capillaries & muscles. Above both the cases, Greater the blood flow , Faster the distribution.

25. Distribution is permeability rate - limited in following cases When the drug under consideration is ionic/polar/water soluble. Where the highly selective physiology barrier restrict the diffusion of such drugs to the inside of cell. (Distribution Rate Constant) Kt = perfusion rate / K t/b Distribution half life = 0.693/Kt =0.693K t/b /perfusion rate K t/b tissue/blood partition coefficient

26. Highly lipophilic drugs can cross most selective barrier like BBB, ex. thiopental Highly permeable capillary wall permits passage of almost all drugs ( except those bound to plasma protein). Highly perfused tissues Lungs, Kidneys, Liver, Heart, Brain are rapidly equilibrated with lipid soluble drugs Drug is distributed in a particular tissue or organ depends upon the size of tissue (tissue volume) & Tissue/blood partition coefficient. Ex. Thiopental i . v. (lipophilic drug) & 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 perfused adipose tissue.

27. 3) Binding Of Drug To Tissue Components Binding of drug to blood and other tissue components Binding of drug falls into 2 classes: Binding of drugs to blood components like Blood cells Plasma proteins Binding of drugs to extra vascular tissues proteins, fats, bones, etc.

28. II) Blood cells bindings:- RBC : 40% of blood comprise of blood cells, out of that 95% cells are RBC (RBC comprise of hemoglobin) drugs like , Phenytoin, Phenobarbitone binds with Hb , imipramine, chlorpromazine binds with RBC Cell wall.

29. The major component of blood is RBC The RBC comprises of 3 components each of which can bind to drugs: 1. Haemoglobin: It has a molecular weight of 64,500 (almost equal to that of HSA) but is 7 to 8 times the concentration of albumin in blood. Drugs like phenytoin, pentobarbital and phenothiazines bind to haemoglobin. 2. Carbonic Anhydrase: Drugs known to bind to it are acetazolamide and chlorthalidone (i.e. carbonic anhydrase inhibitors). 3.Cell Membrane: Imipramine and chlorpromazine are reported to bind with the RBC membrane.

30. BINDING OF DRUGS TO PLASMA PROTEINS The binding of drug to plasma protein is reversible The extent or order of binding of drugs to various plasma proteins is: Albumin >α 1 -Acid Glycoprotein> Lipoproteins > Globulins Human Serum Albumin Most abundant plasma protein with large drug binding capacity Both endogenous compounds such as fatty acids, bilirubin and tryptophan as well as drugs bind to HSA Four different sites on HSA: Site I: warfarin and azapropazone binding site Site II: diazepam binding site, Site I & II responsible for binding of most drugs Site III: digitoxin binding site. Site IV: is also called as tamoxifen binding site, Site III & IV very few drugs binds.

31. Binding of Drugs to alpha 1 -Acid Glycoprotein ( 1 -AGP or AAG): Also called as orosomucoid , molecular weight of 44,000 and a plasma concentration range of 0.04 to 0.1 g%. binds to basic drugs like imipramine, amitriptyline, nortriptyline, lidocaine, propranolol, quinidine and disopyramide. Binding of Drugs to Lipoproteins: Since only lipophilic drugs can undergo hydrophobic bonding , lipoproteins can bind to such drugs because of their high lipid content. However, the plasma concentration of lipoproteins is much less in comparison to HSA and AAG.

32. Classification of Lipoproteins 1. Chylomicrons (least dense and largest in size). 2. Very low density lipoproteins (VLDL). 3. Low-density lipoproteins (LDL) (predominant in humans). 4. High-density lipoproteins (HDL) (most dense and smallest in size).

33. Binding of Drugs to Globulins plasma globulins: alpha1 -, alpha 2 -, beta1 -, beta 2 - and gamma globulins. 1. Alpha 1 -globulin : also called as transcortin or CBG (corticosteroid binding globulin), it binds a number of steroidal drugs such as cortisone and prednisone. It also binds to thyroxine and cyanocobalamin. 2.Alpha 2 -globulin: also called as ceruloplasmin, it binds vitamins A, D, E and K and cupric ions. 3.Beta1 -globulin: also called as transferrin, it binds to ferrous ions. 4.Beta 2 -globulin: binds to carotenoids. 5. Gamma globulin : binds specifically to antigens.

34. 3) BINDING OF DRUG TO TISSUE COMPONENTS B. 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 (Subsequent increase in bio-logical half life.) Irreversible binding leads to drug toxicity. (carbamazepine-autoinduction) liver > kidney > lungs > muscle > skin > eye > bone > Hair, nail

35. 4) Miscellaneous Factors Age: Total body water Fat content Skeletal muscles Organ composition Plasma protein content Pregnancy Obesity Diet Disease states

36. 4) MISCELLANEOUS FACTORS 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 , hence greater penetration of drug in brain Plasma protein content- low albumin in both infants & elderly PREGNANCY:- During Pregnancy, due to growth of UTERUS,PLECENTA,FETUS… Increases the volume available for distribution of drug. fetus have separate compartment for drug distribution, plasma & ECF Volume also increase but albumin content is low . C) OBESITY :- In obese persons, high adipose (fatty acid) tissue so high distribution of lipophilic drugs

37. 4) MISCELLANEOUS FACTORS DIET:- A diet high in fats will increases free fatty acid levels in circulation thereby affecting binding of acidic drugs (NSAIDs to albumin) DISEASE STATES:- A number of mechanism involved in alteration of drug distribution in disease states. Altered albumin & other drug-binding protein concentration. Alteration or reduced perfusion to organ or tissue Altered tissue pH Alteration of permeability of physiological barrier (BBB) E.g.- BBB (in meningitis & encephalitis ) BBB becomes more permeable polar antibiotics ampicillin, penicillin G. & patient affect CCF , Perfusion rate to entire body decreases it affect distribution. DRUG INTERACTION:- Displacement interaction occurs when two drugs administered which having similar binding site affinity. E.g. A. Warfarin (Displaced Drug) & B. Phenylbutazone (Displacer) HSA

38. FACTORS AFFECTING PROTEIN-DRUG BINDING Factors affecting protein-drug binding can be broadly categorized as— 1. Drug related factors a. Physicochemical characteristics of the drug b. Concentration of drug in the body c. Affinity of a drug for a particular binding component 2. Protein/tissue related factors Physicochemical characteristics of the protein or binding agent Concentration of protein or binding component Number of binding sites on the binding agent

39. 3. Drug interactions a. Competition between drugs for the binding site (displacement interactions) b. Competition between the drug and normal body constituents c. Allosteric changes in protein molecule 4. Patient related factors a. Age b. Intersubject variations c. Disease states

40. 1. Drug related factors a. Physicochemical characteristics of the drug: P rotein binding is directly related to the lipophilicity of drug. An increase in lipophilicity increases the extent of binding. for example, the slow absorption of cloxacillin in comparison to ampicillin.

41. b. Concentration of drug in the body: The extent of protein-drug binding can change with both changes in drug as well as protein concentration. The concentration of drugs that bind to HSA does not have much of an influence, as the therapeutic concentration of any drug is insufficient to saturate it. c. Affinity of a drug for a particular binding component: Lidocaine has greater affinity for AAG than for HSA. Digoxin has more affinity for proteins of cardiac muscles than those of skeletal muscles or plasma.

42. 2. Protein/tissue related factors Physicochemical characteristics of the protein or binding agent: Lipoproteins and adipose tissue tend to bind lipophilic drugs by dissolving them in their lipid core. The physiologic pH determines the presence of active anionic and cationic groups on the albumin molecules to bind a variety of drugs. b. Concentration of protein or binding component: Among the plasma proteins, binding predominantly occurs with albumin . The amount of several proteins and tissue components available for binding, changes during disease states.

43. c. Number of binding sites on the binding agent: Albumin has a large number of binding sites as compared to other proteins and is a high capacity binding component. Several drugs are capable of binding at more than one site on albumin, e.g. flucloxacillin, flurbiprofen, ketoprofen, tamoxifen and dicoumarol bind to both primary and secondary sites on albumin.

44. 3. Drug interactions Competition between drugs for the binding site (displacement interactions): When two or more drugs can bind to the same site, competition between them for interaction with the binding site results. If one of the drugs (drug A) is bound to such a site, then administration of another drug (drug B) having affinity for the same site results in displacement of drug A from its binding site. Such a drug-drug interaction for the common binding site is called as displacement interaction . The drug A here is called as the displaced drug and drug B as the displacer .

45. b. Competition between the drug and normal body constituents: Among the various normal body constituents, the free fatty acids are known to interact with a number of drugs that bind primarily to HSA. The free fatty acid level is increased in several physiologic (fasting), pathologic (diabetes, myocardial infarction, alcohol abstinence) and pharmacologically induced conditions (after heparin and caffeine administration). The fatty acids, which also bind to albumin, influence binding of several benzodiazepines and propranolol (decreased binding) and warfarin (increased binding).

46. c. Allosteric changes in protein molecule: A nother mechanism by which drugs can affect protein-binding interactions. The process involves alteration of the protein structure by the drug or its metabolite thereby modifying its binding capacity. The agent that produces such an effect is called as allosteric effector . E .g. aspirin acetylates the lysine fraction of albumin thereby modifying its capacity to bind NSAIDs like phenylbutazone (increased affinity) and flufenamic acid (decreased affinity).

47. 4. Patient related factors Age: Modification in protein-drug binding as influenced by age of the patient is mainly due to differences in the protein content in various age groups. Neonates: Albumin content is low in newborn; as a result, the unbound concentration of drug that primarily binds to albumin, for example phenytoin and diazepam, is increased. Young infants: An interesting example of differences in protein-drug binding in infants is that of digoxin. Infants suffering from congestive cardiac failure are given a digitalizing dose 4 to 6 times the adult dose on body weight basis. Elderly: In old age, the albumin content is lowered and free concentration of drugs that bind primarily to it is increased.

48. Intersubject variations: Intersubject variability in drug binding as studied with few drugs showed that the difference is small and no more than two fold. These differences have been attributed to genetic and environmental factors. Disease states:

49. DISEASE INFLUENCE ON PLASMA PROTEIN INFLUENCE ON PROTEIN-DRUG BINDING Renal failure (uremia) Decreased albumin content Decreased binding of acidic drugs; neutral and basic drugs unaffected Hepatic failure Decreased albumin synthesis Decreased binding of acidic drugs; binding of basic drugs is normal or reduced depending on AAG levels Inflammatory states (trauma, surgery, burns, infections, etc.) Increased AAG levels Increased binding of basic drugs; neutral and acidic drugs unaffected

50. SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUGS Absorption: The absorption equilibrium is attained by transfer of free drug from the site of administration into the systemic circulation and when the concentration in these two compartments become equal. B inding of the absorbed drug to plasma proteins decreases free drug concentration and disturbs such equilibrium. I n case of ionized drugs which are transported with difficulty.

51. II. Systemic Solubility of Drugs: Water insoluble drugs, neutral endogenous macromolecules such as heparin and several steroids and oil soluble vitamins are circulated and distributed to tissues by binding especially to lipoproteins which act as a vehicle for such hydrophobic compounds. III. Distribution: Plasma protein binding restricts the entry of drugs that have specific affinity for certain tissues. This prevents accumulation of a large fraction of drug in such tissues and thus, subsequent toxic reactions.

52. IV. Elimination: Only the unbound or free drug is capable of being eliminated. This is because the drug- protein complex cannot penetrate into the metabolizing organ (liver). The large molecular size of the complex also prevents it from getting filtered through the glomerulus. Thus, drugs which are more than 95% bound are eliminated slowly. V. Displacement Interactions and Toxicity: D isplacement interactions are significant in case of drugs which are more than 95% bound.

53. Influence of Percent Binding and Displacement on Change in Free Concentration of Drugs: Drug A Drug B % drug before displacement bound 99 90 free 1 10 % drug after displacement bound 98 89 Free 2 11 % increase in free drug 100 10 concentration

54. VI. Therapy and Drug Targeting: The binding of drugs to lipoproteins can be used for site-specific delivery of hydrophilic moieties. This is particularly useful in cancer therapies since certain tumor cells have greater affinity for LDL than normal tissues. VII. Diagnosis: The chlorine atom of chloroquine when replaced with radiolabeled I-131 can be used to visualize melanomas of the eye since chloroquine has a tendency to interact with the melanin of eyes.

55. VOLUME OF DISTRIBUTION A drug in circulation distributes to various organs and tissues. After completion of distribution process , different organs and tissues contain varying concentrations of drug which can be determined by the volume of tissues in which the drug is present. Since different tissues have different concentrations of drug, the volume of distribution cannot have a true physiological meaning. A constant relationship between the conc. of drug in plasma, C & amount of drug in the body, X.

56. Apparent Volume of Distribution It is defined as the hypothetical volume of body fluid into which a drug is dissolved or distributed. 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.

57. The apparent volume of distribution is a proportionality constant relating the total amount of drug in the body to the plasma concentration drug.

58. The volume of each of these real physiological compartments can be determined by use of specific tracers or markers.