Distribution of drugs

distribution of drugs

1. Distribution of drugs Dr Shinde Viraj Ashok Jr1 pharmacology

2. overview

3. Distribution Reversible transfer of drugs between one compartment and another ( between blood & extravascular fluids & tissues)

4. Distribution is predominantly a passive process - T he driving force is the c oncentration g radient between the blood and extravascular tissues P rocess occurs by the diffusion of free d rug until equilibrium is established

5. As the pharmacological action of a drug depends upon its concentration at the site of action distribution plays a significant role in the o nset, intensity, and duration of action. Distribution of a drug is not uniform throughout the body because different tissues receive the drug from plasma at different rates and to different extents.

6. Steps in drug distribution Permeation of free or unbound drug into interstitial / extracellular fluid Permeation of drug present in extracellular fluid into intracellular fluid { rate limiting step}

7. Factors affecting distribution of drugs

8. Tissue permeability Physicochemical properties of drug Molecular size Degree of ionisation Oil/Water partition coefficient

9. Physicochemical properties of the drug Molecular size – < 500-600 d easily cross capillary membrane. Water soluble molecules & ions of size < 50 d pass through aqueous filled channels. 9

10. pKa - pH of blood & ECF (7.4) play a role in degree of ionization, unionized drug diffuse rapidly. eg . Acidosis →↓ ionization of acidic drugs → ↑ concentration and duration of action Alkalosis (sodium bicarbonate)→↑ ionization of acidic drug like barbiturate → prevents further entry into CNS and promote urinary excretion

11. Lipid solubility - L ipoidal drug penetrate the tissue rapidly. Among drugs with same lipid solubility but difference in ionization of blood pH Less ionized drug - Better distribution. E.g. Phenobarbital > salicylic acid 11

12. Physiological barriers Simple capillary endothelial barrier Simple cell membrane barrier Blood brain barrier Blood CSF barrier Blood placental barrier Blood testis barrier

13. Simple capillary endothelial barrier All drugs ionised / unionised with molecular size < 600 daltons diffuse through capillary endothelium into interstitial fluid Simple cell membrane barrier Similar to lipoidal barrier in GIT

14. Blood brain barrier

15. A solute may enter to brain via 1} Passive diffusion through the lipoidal barrier 2} Active transport of essential nutrients like sugars and amino acids As a rule o nly lipid soluble, nonionized form of drug penetrate more easily to brain

16. Blood brain barrier Constraints passage of drug to brain and CSF Numerous efflux transporters at BBB ( Molecular barrier) Clinical importance - Protects brain tissue 1] Toxic substances in blood 2] Peripheral neurotransmitters

17. Inflammatory conditions ( meningitis, viral infection of brain , heat stress) alter permeability of BBB Examples- Penicillins

18. Blood CSF barrier Mainly formed by choroid plexus of lateral, third & fourth ventricle The capillary endothelium that line choroid plexus have open junctions however the choroid cells are joined to each other by tight junctions Only highly lipid soluble, unionized drugs can pass through it

19. Blood cerebrospinal fluid barrier: But CSF-brain barrier is not connected with tight junction  extremely permeable to drug molecule Clinical significance - Penicillin being less lipid soluble has poor penetration through BBB but if given by intrathecal route  cross CSF-brain barrier to treat the condition like brain abscess 20

20. Blood placental barrier M aternal & fetal blood vessels are separated by a number of tissue layers made of fetal trophoblast , basement membrane & endothelium - placental barrier Drugs having molecular size less than 1000 D and moderate lipid solubility cross the placental barrier 21

21. Blood placental barrier Transfer of substances - Passive diffusion – Non polar lipid soluble substances Active transport - Amino acids and glucose Pinocytosis - Maternal immunoglobulins Drugs that can cross Blood-Placental barrier Ethanol, sulfonamides, barbiturates, gaseous anesthetics, steroids, narcotics, anticonvulsants etc. Teratogen - A gent that causes toxic effect on fetus Teratogenicity - F etal abnormality caused by administration of drugs during pregnancy 22

22. Blood placental barrier Drug administered in last trimester affect vital functions of fetus Morphine - Fetal asphyxia Antithyroid drugs - Neonatal goitre Hypoxia increase placental permeability for drugs Fetus to some extend is exposed to all drugs taken by mother hence drug administration should be severly restricted in pregnancy

23. Blood testis barrier Located at the sertoli-sertoli cell junction Tight junction between neighboring sertoli cells that act as barrier Restrict the passage of drugs to spermatocyte and spermatids 24

24. Organ /tissue size & perfusion rate Distribution is permeability related in following cases 1] When the drug is ionic/polar/water soluble 2] Where the highly selective physiology barrier restrict the diffusion of such drugs to the inside of cell. Distribution will be perfusion rate limited 1] When the drug is highly lipophilic 2] When the membrane is highly permeable. 25

25. When highly lipid soluble drug passes through the highly permeable membrane  rate limiting step is rate of blood flow / perfusion Greater  faster Perfusion rate - I t is defined as the volume of the blood that flows per unit time per unit volume of the tissue Unit : ml/min/ml Highly perfused organs are - Lungs > Kidneys > Adrenals > Liver > Heart > Brain 26

26. Special compartments for drug distributions Drugs that have high affinity to tissue proteins Digoxin , emetine – Skeletal muscle , heart , liver , kidney 2. Iodine – Thyroid 3. Chloroquine - Liver , retina 4. Cadmium , lead , mercury - Kidney Cellular reservoir

27. Fat as reservoir Highly lipid soluble drugs { DDT , Organophosphate compounds & thiopentone ( if given repeatedly )} accumulate in adipose tissue Starvation - Drug toxicity

28. Bones and connective tissue Tetracyclines , cisplatin , lead , arsenic , flourides – Form complex with bones Antifungal drugs accumulates in skin and finger nails Phosphonates – Sodium etidronate - Forms complex with hydoxyappetite crystals in bone

29. Plasma protein binding as drug reservoir Drugs bind to plasma proteins or cellular proteins in reversible and dynamic equillibrium Protein bound drug not accessible Capillary diffusion Metabolism Excretion

30. Important proteins - drug binding Plasma albumin (acidic drugs) Warfarin Penicillin Sulfonamides Tolbutamide Salycylic acid

31. Several drugs are capable to binding at more than one binding site e.g.- F lucoxacillin , flurbiprofen , ketoprofen , tamoxifen and dicoumarol bind to both primary and secondary site of albumin Indomethacin binds at three different site 32 S ite 1 Site 2 Site 3 Site 4 Drug binding site on Human Serum Albumin Warfarin binding site Diazapam binding site Digitoxin binding site Tamoxifen binding site

32. Other drugs binding at sites on albumin Site I – on albumin Several NSAIDS ( phenylbutazone , naproxane , indomethacin), Sulphonamides Phenytoin Sodium valproate Bilirubin 33

33. Site II – on albumin Medium chain fatty acids Ibuprofen, ketoprofen Tryptophan Cloxacillin Probenecid Very few drugs bind to site III and site IV 34

34. Drugs that bind more than one site Main binding site – Primary site Other – Secondary site Groups of drugs that bind to same site compete with each other for binding 35

35. Protein binding drug displacement Plasma Tissue Drug A protein bound Drug A free Drug A free Drug B Drugs A and B both bind to the same plasma protein & when drug B has higher affinity to site on plasma protein than drug A

36. Displacement interaction and toxicity 37 Displacement interactions Drug A Drug B % Drug before displacement Bound F ree 99 1 90 10 % Drug after displacement Bound Free 9 8 2 89 11 % Increase in free drug concentration 100 10 Interaction is clinically significant if drug bind more than 95 %

37. More than one drug can bind to same site of albumin give rise to displacement reaction Clinically important displacement reactions

38. Alpha 1 acid glycoprotein {Acute phase reactant} (basic drugs) 1. Quinidine 2. Imipramine 3. Lidocaine 4. Chlorpromazine 5. Propranalol

39. Drugs bound to tissue proteins and nucleoproteins (High aVd ) Example Digoxin Emetine Chloroquine Miscellanous protein binding Corticosteroid - Transcortin globulin Thyroxine -Alpha globulin

40. Clinically important aspects of plasma protein binding High plasma protein bound drug - Vd lower High protein bound- Binding of drugs to plasma proteins is capacity limited and saturable Difficult to remove by dialysis

41. 4.Disease state Disease Influence on plasma protein Influence on protein drug binding Renal failure (uremia) Albumin content Decrease binding of acidic drug , neutral or basic drug are unaffected Hepatic failure Albumin synthesis Decrease binding of acidic drug ,binding of basic drug is normal or reduced depending on AAG level. Inflammatory state (trauma , burn, infection ) AAG levels Increase binding of basic drug , neutral and acidic drug unaffected 42

42. Apparent volume of distribution Total space which should be available in body to contain known amount of drug aVd = Total amount of drug (mg/kg) Concentration of drug in plasma (mg/l)

43. Apparent volume of distribution Drugs doesn’t cross capillary wall High molecular weight – Heparin, insulin ( Vd = plasma water= 3L) Lesser lipid soluble drugs Drugs that bind to proteins Highly bound to plasma proteins – Low aVd ( tolbutamide , furosemide & warfarin ) Lesser bound to plasma proteins – High aVd ( chloroquine , metoprolol )

44. aVd of some drugs is much more than actual body volume Widely distributed in body Digoxin , imipramine , phenobarbitone & analogues of morphine Difficult to remove by dialysis if toxicity occurs Drugs good candidates for dialysis – drugs with low Vd & low plasma protien bound

45. Clinical significance of large volume of distribution May require a loading dose initially for quick onset of action E.g. chloroquine used in malaria Tb Chloroquine 600mg stat as loading dose followed by 300mg after 8hrs & then 300mg daily for next 2days

46. Redistribution Highly lipid soluble drugs when given by I.V. or by inhalation initially get distributed to organs with high blood flow, e.g. brain, heart, kidney etc. Later, less vascular but more bulky tissues (muscles, fat) take up the drug and plasma concentration falls and drug is withdrawn from these sites. 48

47. If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action. Greater the lipid solubility of the drug, faster is its redistribution. E.g T hiopentone sodium

48. Conclusion S tudy of distribution of drug is an important aspect of the pharmacokinetic study P lasma protein binding ,tissue storage & distribution in adipose tissue have important clinical implications. These along with barriers like BBB give us insight into unequal distribution of drugs aVd is an important pharmacokinetic parameter . Knowledge of aVd helps us to understand why some drugs require loading dose

49. Refrences Goodman & gillman’s 12 th edition, the pharmacological basis of therapeutics Principles of pharmacology 2 nd by H. L. Sharma & K .K. Sharma Biopharmaceutics and pharmacokinetics a treatise 2 nd edition by D. M. Brahmankar and Sunil B. Jaiswal

50. Stages of teratogenicity 53 Period Significance Effect 1 st 2 weeks Fertilization and implantation Miscarriage 2-8 weeks Period of organogenesis Cleft palate, optic atrophy, mental retardation, neural tube defect etc. 8 weeks onwards Growth and development Development and functional abnormilities

51. Transcellular reservoir Aqueous humour – Chloramphenicol , prednisolone CSF- Aminosugars and sucrose Joint fluid – Ampicillin Pleural fluid – Imipramine and methadone

52. miscellanous Age − Differences are due to Total body water – More in infants Fat content - More in infants Skeletal muscles – Lesser in infants and elderly Organ composition – BBB is poorly developed in infants Plasma protein content – Low albumin content in infants and elderly 55

53. Pregnancy - ↑ In plasma & ECF volume and ↓ in albumin Obesity - A dipose tissue has high affinity to lipophilic drugs ( hence high concentration ) - High fatty acid levels → Alters binding characteristics of acidic drugs Diet - High fatty diet → H igh free fatty acid levels Disease states - Changes distribution due to Altered albumin and other proteins Altered / reduced perfusion Altered tissue ph 56