Pharmacology Drug Absorption,Distribution & Elimination

1. PharmacologyDrug Absorption,Distribution&Elimination Dr.Eby Isaac

2. Drugs: • Agents that modify biological responses • Transfer across cell membrane produce pharmacological response • Cell Membrane: • 10 nm wide bi molecular layer of phospholipid and protein. Lipid layer is regarded as fluid.

3. Extrinsic Proteins:- • Situated on the internal and external aspects of the membrane can be removed by pH and ionic changes • Intrinsic Proteins:- • Traverse entire width of the plasma membrane • From annulus surrounding small pores 0.5 nm in diameter • Act as enzymes or receptors • Mediate active transport of drugs

4. Glycolipids & Glycoproteins :- • 5-10%, play a part in molecular recognition • Insulation:- • Potential difference across cell membranes facilitate transport through ionic channels

5. Transfer of Drugs across Cell Membrane • Passive Process:- • Diffusion from higher to lower concentration gradient • Depends on • Concentration • Lipid solubility

6. Drugs with high lipid aqueous partition coefficient means fast diffusion • Eg: Fentanyl, Diazepam • Drugs with low lipid aqueous partition coefficient means slow diffusion • Eg: Morphine

7. A typical cell membrane

8. Most drugs are weak acids or weak bases AH ⇌ A- + H+ ( for Acids) BH- ⇌ B + H+ ( for Bases)

9. Non-iomic diffusion of the week acid AH (pKa= 6)

10. In acid solutions AH and BH+ • In alkaline solutions A- and B • Non ionised form lipid soluble AH and B

11. Henderson-Hesselbach’s Equation • pKa – pH = log [ AH ] [ A- ] • pKa value is a pH at which ionised and non-ionised forms of a drug are equal

12. Basic Drug • B + H+⇌ BH+ • pKa – pH = log [ BH+] [ B ]

13. Non-iomic diffusion of the weak base B (pKa=7)

14. IV opioids Fentanyl & phenoperidines (weak bases) • Initial plasma conc. Decline followed by rise 30min. Later • Diffusion into stomach because of conc. Gradient • Subsequent absorption from small intestine

15. Urine pH modification • Weak acids and bases present in ionic forms • Forced alkaline and acid diuresis • Limited applicability unless drugs are • Non protein bound • Confined to ECF • Eliminated unchanged in Urine

16. Alkaline Diuresis:- • Salicylates and barbiturate poisoing • Acid Diuresis:- • Amphetamine, fenfluramine, Phencyclindine poisoing

17. Carrier Transport of Drugs • Facilitated diffusion: • Faster than anticipated than their lipid solubility • Combination with specific sites on protein and conformational changes • Sugars, aminoacids & Pyramidines • L-Dopa absorbed by a carrier that normally transports aminoacids & flourouracil by pyramidine base transporter

18. Active Transport • Cellular or Metabolic energy required • For Transfer across conc.gradient • by active transport of Na+ • Hydrolysis of ATP • Electrochemical gradient by Na+/ K+ ATPase • Drug + Protein transported across cell membrane • Active transport is saturable can be inhibited by other drugs • Active transport concerned with transfer of endogenous substance eg: reuptake of NA at sympathetic nerve endings coupled with Na+ transport

19. Factors determining plasma conc. Of Drug • Absorption • Distribution • Metabolism • excretion

20. Bioavailability: • Extent to which a drug reaches its site of action following administration • Estimated by comparing plasma conc. Of drug given by IV injection with levels obtained after administration of dose from which the drug must be absorbed ( pharmacokinetic analysis)

21. Oral Administration • Most convenient • Non-compliance • Some drugs unstable in gastric fluid • Eg: Benzylpenicillin, erythromicin • Salicylates phenyl butazone irritate gastric mucosa • Circumvented by gastric coating, slow release • Plams conc. Time required 30-120 mts

22. Adequate Plasma conc. Depend on • Dissolution • Absorption • Absence of significant first pass effects in gut wall or liver

23. Drug Dissolution • Occurs usually in stomach • Dependent of gastric acidity • Gastric emptying • Absorbed mainly from upper part of small intestine • Factors effecting drug dissolution • Particle size • Chemical formulation • Inclusion of inert fillers • Outer coating applied

24. Variation in Dissolution • Lactose excipient in diphenylhydantoin tablets cause toxicity • Difference in potency of digoxin tablets were traced to variations in the dissolution of different preparations

25. Programmed or sustained oral Preparations • Erodable polymers • Greater convenience • Improved bioavailability • Less variation in plasma conc. • Decrease side effects • Decreased drug dosage • Decreased frequency of admn.

26. Drug Absorption • Dependent on ability to penetrate • Non-ionised compounds • LMW substances readily absorbed eg; Urea, ethyl alcohol • Weakacids • Eg: Asprin, non-ionised in acidic conditions absorbed from stomach • Basic drugs • Eg: Propranolol, benzodiazepines less ionised in alkaline conditions absorbed from duodenum • Strong bases eg: Quarternary amines are always ionised not readily absorbed from gut

27. Factors affecting Drug absorption • 1.Mucosal surface area. More in small intestine so both acids and bases absorbed from small intestine • 2.Non-ionised compounds and acidic drugs are absorbed from stomach so rapid increase in plasma conc. • 3.Compounds affecting gastric motility modify gastric absorption eg. Atropine and morphine decreased drug absorption

28. Drugs absorption decreased in pathological conditions of GIT • Coeliac disease • Obstructive jaundice • After extensive resection of small intestine

29. First Pass Effect • Metabolism by gutwall or liver • Gutwall-dopamine, Isoprenaline • Liver-lidocaine, Pethidine • When concentration in the hepatic vein<50% of portal vein – called high extraction ratio • Limited by liver blood flow • To avoid first pass effect drugs administered SL or PR • Propranolol reduce liver blood flow, so reduce first pass effect

30. SC & IM Administration • For drugs broken down in the gut. Eg.Benzyl Pencilin, Polypetide hormones • Drugs with significant First Pass effect. Eg.Opioids • Intolerent to oral preparations. Eg. Iron salt • Patient compliance poor. Eg. Schizophrenia

31. Factors Affecting Absorption • Dependant on regional blood flow. So IM route faster than SC route. • Not dependant on PH or dissociation constant • IV admn.- effects dependable & reproducable • Mini infusion pumps for intermittent drug delivery, syringe pumps, gravity methods.

32. Other Routes • Mucous membranes, Eg. Conjunctive, nose, larynx, mucosal part of GIT. • Antibiotics, steroids are used for local effect • Buccal route for GTN, hyoscine, prochlor perazine. • Nasal route – for hypothalamic polypeptides-rapid absorption to CSF, submucous space in direct contact with subarchnoide space of olfactory lobes.

33. Transdermal Absorption • Stratum corneum major barrior • Potent drugs with high lipid solubility absorbed. Eg. GTN, Fentanyl • Lidocaine, Prilocaine mixture EMLA • Tetracaine alone also used

34. Intrathecal Administration • Local anesthetics • Analgesics • Antibiotics

35. Inhalational Administration • Inhalational anesthetics – depends upon transfer from Alveoli to pul.capillaries. Steroids & Bronchodilators • Particles > 10 micro meter deposited URT • 2 to 10 microns deposited in bronchioles • < 2 microns reach alveoli

36. Drug Distribution • Drug initially present in plasma partly bount to plasma proteins subsequently access tissues. • When ECF conc = plasma water conc.- distribution complete. • Distribution variable. Eg. Warfarin, Tolbutamide extremely protein bound. • Ionised compounds lithium cannot rapidly penetrate cell membrane, limited to ECF. Vol. D < 20L

37. Lipid soluble drugs widely distributed us. Vol. D = total body water (30 – 45 L). • Morphine, STP, Digoxin penetrate cells bound to tissue proteins (Vol.D > 30 – 45L) • IV barbiturates rapidly redistributed from brain to muscle then to fat

38. Drugs – Localised in tissues • Guanethidin – post ganglionicsymp: nerve endings • Iodine – thyroid gland • Sulph bromophthalein in liver • Tetracyclines in developing teeth & bone

39. Blood Brain Barrier • Dynamic interface between blood and brain • Cerebral Capillary endothelial overlapping tight junctions restrict passive diffusion • Pinocytic vesicles are usually absent • Cerebral Capillary basement membrane closely applied to peripheral process of astrocytes. • Drugs have to cross 1) Endothelium, 2) Basement membrane 3) Peripheral process of astocytes. This is collectively called B.B.barrior (structural)

40. Enzymatic or Metabolic B.B.Barrier • Associated with peripheral process of astrocytes • Neurotoxic substances. Eg. Ammonia, Freefatty acids are metobolized after crossing endothelium • MAO & Cholinestrases present in capillary endothelium • Drugs Eg. NA, Dopamine, local anestheticesters metabolised as they cross

41. Metabolic substrates & hormones cross B.B.barrior by endocytosis or carrier transport. Eg. Glucose, insulin L-amino acids, L-thyroxine, transferin • LMW lipid soluble drugs local anesthetics, opioids, general anesthetics easily cross B.B. barrior • Highly protein bound drugs warfarin & tolbutamide only unbound fraction enter brain • Highly ionised cannot cross B.B. barrior so muscle relaxants do not enter brain

42. Drugs cannot penetrate B.B. barrier unless there is inflammation, Edema, Hypertension. Eg. Benzyl penicillin in Meningitis • Area posterma, median eminence, pineal gland and choroid plexus are deficient in B.B. Barrier

43. Placental Transfer • At term maternal & fetal blood compartment are separated by syncitiotrophoblast in continues contact with fetal capillaries • Behave like a lipid membrane • LMW lipid soluble drugs readily transferred • All drugs that cross B.B barrier cross placenta

44. Factors affecting rate of transfer • Placental blood flow • Area available for diffusion • Magnitude of diffusion gradient

45. Drugs causing fetal anomalies • Cyto-toxic agents • Folate antagonists • Phenytoin • Aminoglycoside antibiotics • Inhalational anesthetics • Barbiturates • Local anesthetics • Analgesics-morphine & pethidine

46. Protein binding • Method of rapid distribution from site of absorption to site of action. • Lipid soluble drugs highly bound because not soluble in water. • Tissue perfusion causes unbound drug to decrease concentration so maintains a concentration gradient • Conce: in saliva & CSF reflects unbound drug level in plasma

47. Globulins • Mainly bound to basic drugs Eg. Chlorpromazine, bupviccaine, opioid analgesics, vitamins, minerals, hormones. • Hydrocortsone

48. Albumin Binds mainly neutral or acidic compounds • Salicylates, Phenylbutazone, indomethacine, Tolbutamide, anticoagulants, carbenaxolone • Some basic drugs and physiological substrates Bilirubin, fatty acids, tryptophan • dTc & Pancuronium bound to igG & albumine • Binding modified in hypoalbuminemia cirrohosis nephrosis

49. Globulin Binding • Binds to basic drugs. Eg. Bupvicaine, Opioid • Hydrocortisone transported by transcortin • Resistance to muscle relaxants in liver disease due to extensive globulin binding • Alpha 1 acid like protein increased in MI, R.arthritis, renal failure, post surgery • So binding of basic drugs increased Eg. Propranolol

50. Drug Metabolism • Conversion from lipid soluble drug to water soluble drug • Liver plays major part • Others are hydrolysed by plasma estrases • Gut chlorpromazine, isoprenaline • Kidney-midazolam, dopamine • Lung, angiotensin 1, Prilocine