Absorption

Absorption of drug

1. Absorption of Drug Kailas K. Mali

2. Contents Cell membrane Absorption mechanism, Oral drug absorption, pH partition hypothesis, Factors affecting: Physicochemical, dosage form related, patient related. Drug absorption through other routes: transdermal , nasal, buccal , Ocular sublingual. In-vitro, In-situ and In-vivo models for drug absorption studies. 2 Absorption of Drug 13/04/2018

3. Introduction pH = 1 - 3 pH = 5 - 7 disintegration disintegration disso- lution disso- lution absorption intestinal metabolism absorption hepatic metabolism clearance faeces Pharmacological effect gastric emptying rate intestinal transit rate 3 Absorption of Drug 13/04/2018

4. Introduction Drug absorption 4 Absorption of Drug 13/04/2018

5. Introduction Drug absorption Routes of administration Oral Parenteral Topical 5 Absorption of Drug 13/04/2018

6. Cell Membrane 6 Absorption of Drug 13/04/2018

7. Mechanisms of drug transport Intercellular ( transcellular ) transport Passive transport Passive diffusion Pore transport Ion-pair transport Facilitated diffusion Active transport Primary Secondary Symport Antiport 7 Absorption of Drug 13/04/2018

8. Mechanisms of drug transport Intracellular ( paracellular ) transport Tight junctions of epithelial cells Persorption Endocytosis Pinocytosis Phagocytosis 8 Absorption of Drug 13/04/2018

9. Passive diffusion Non ionic diffusion Driving force- concentration gradient Drug movement- kinetic energy of molecule Energy independent process Expressed by Fick’s first law of diffusion The drug molecules moves from a region of higher concentration to one of lower concentration until equilibrium is attained and the rate of diffusion is directly proportional to the concentration gradient across membrane. 9 Absorption of Drug 13/04/2018

10. Passive diffusion Fick’s first law of diffusion Characteristics of passive diffusion Downhill transport Process- energy independent & non saturable Drug transfer directly proportional to conc gradient Greater the area & lesser thickness of membrane, faster diffusion Process is rapid over short distance and slower over long distance 10 Absorption of Drug 13/04/2018

11. Passive diffusion Fick’s first law of diffusion Characteristics of passive diffusion Equilibrium is attained when the concentration on either side of membrane becomes equal. Rate of transfer of unionised drug is more than ionised. Greater partition coefficient of drug, faster the absorption. Drug diffusion is rapid- volume of GI fluid is low. Process id dependent on molecular size of the drug. 11 Absorption of Drug 13/04/2018

12. Passive diffusion Fick’s first law – non sink condition Sink condition Equation follows first order kinetics hence passive diffusion process is first order process. Hydrophobic molecules > Small uncharged polar molecules> Large uncharged polar molecules Ions – not absorbed by passive diffusion. 12 Absorption of Drug 13/04/2018

13. Pore transport Connective transport/ bulk flow/ filtration Transport of molecules into the cell through the protein channels present in the cell membrane. Characteristics Driving force- hydrostatic pressure/ osmotic difference across the cell membrane. Water flux promotes transport- solvent drag. Absorption- low molecular size, less than 100. Water soluble drugs- urea, water, sugars Chain like or linear compounds absorbed by filtration. 13 Absorption of Drug 13/04/2018

14. Ion pair transport Formation of reversible neutral complex with endogenous ions ( mucin ). Complex- liphophilic and water soluble Absorbed by passive diffusion. Example- Propranolol - oleic acid, quaternary ammonium compounds. 14 Absorption of Drug 13/04/2018

15. Carrier-Mediated transport Faster than passive diffusion Carriers- component of membrane Reversible/ covalent bonding Carrier-solute complex- transverse across membrane dissociation of solute carrier –returns to original site Carriers – proteins/ enzymes A- Passive diffusion B- Carrier mediated transport 15 Absorption of Drug 13/04/2018

16. Carrier-Mediated transport Characteristics Carrier protein has uncharged outer surface. Carrier protein soluble in lipid. Carrier- any direction - work efficiently. Transport process is structure specific. System is structure specific. Limited carrier- competition – similar agents. System is capacity limited. 16 Absorption of Drug 13/04/2018

17. Carrier-Mediated transport Characteristics Mixed order kinetics Bioavailability decreases with increasing dose Example – Vit B1, B2, B12 Absorption window Two types Facilitated diffusion Active transport 17 Absorption of Drug 13/04/2018

18. Carrier-Mediated transport Intestine Transporters and Examples of Drugs Transported Transporter Examples Amino acid transporter   Gabapentin D- Cycloserine Methyldopa Baclofen L-dopa   Oligopeptide transporter   Cefadroxil Cephradine Cefixime Ceftibuten Cephalexin Captopril Lisinopril Thrombin inhibitor Phosphate transporter Fostomycin Foscarnet Bile acid transporter S3744   Glucose transporter p- Nitrophenyl beta D- glucopyranoside     P-glycoprotein efflux Etoposide Vinblastine   Cyclosporin A   Monocarboxylic acid transporter Salicylic acid Benzoic acid Pravastatin   18 Absorption of Drug 13/04/2018

19. Facilitated diffusion Characteristics Downhill transport Faster than passive diffusion Driving force- concentration gradient Passive process Energy independent Vitamin B1, B2 & B12 Intrinsic factor-B12 19 Absorption of Drug 13/04/2018

20. Active transport diffusion Two Types Primary active transport Secondary active transport Primary active transport Direct ATP requirement Process transfers only ion/ molecule in one direction Hence called uniporter Absorption of glucose Two types Ion transporters ABC transporters 20 Absorption of Drug 13/04/2018

21. Active transport diffusion Primary active transport Ion transporters ATP driven ion pump- proton pump Two types Organic anion transporter atrovastatin Organic cationic transporter diphenhydramine 21 Absorption of Drug 13/04/2018

22. Active transport diffusion Primary active transport ABC ( ATP binding cassette ) transporters Transport small molecules (drug and toxins) out of cell. Exsorption Efflux pumps ABC transporter example- p-glycoprotein (P- gp ) P- gp called multidrug resistant protein Drug- anticancer drugs 22 Absorption of Drug 13/04/2018

23. Active transport diffusion Secondary active transport No direct requirement of ATP Concentration gradient Two types Symport (co transport) Antiport (counter transport) 23 Absorption of Drug 13/04/2018

24. Active transport diffusion Secondary active transport Symport Both molecules moves in same direction Na+ - glucose symporter : uses potential energy of sodium concentration gradient to move glucose against concentration gradient. H+ - coupled peptide transporter – absorption of peptide like drugs- beta lactam antibiotics. Antiport Molecules moves in opposite direction 24 Absorption of Drug 13/04/2018

25. Active transport diffusion Characteristics Uphill transport Faster than passive diffusion Energy required Inhibited by metabolic poison Fluorides, cyanide, Endogenous material absorbed. Drugs- 5 flurouracil , 5-flurobromacil via pyrimidine transport. Methyl dopa , levodopa via L-amino acid transport system. Enalapril via peptide carrier system. 25 Absorption of Drug 13/04/2018

26. Active transport diffusion 26 Absorption of Drug 13/04/2018

27. Endocytosis Engulfing extracellular material. Fats, starch, insulin, vitamin A, D, E, K. Drug absorbed in lymphatic system- bypass first pass. Two types Phagocytosis (cell eating) Pinocytosis (cell drinking) 27 Absorption of Drug 13/04/2018

28. Factors affecting drug absorption Pharmaceutical factors Physicochemical properties of drug Dosage form related factors Patient related factors 28 Absorption of Drug 13/04/2018

29. Physicochemical factors Drug solubility & dissolution rate Rate determining steps Dissolution- hydrophobic like griseofulvin , spironolactone Permeation- hydrophilic like neomycin BCS- Amidon et al Class I drug: high solubility/ high permeability Class II drugs: low solubility/ high permeability Class III drugs: high solubility/ low permeability Class IV drugs: low solubility/ low permeability 29 Absorption of Drug 13/04/2018

30. Physicochemical factors Drug solubility & dissolution rate Intrinsic solubility Maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. Static property Dissolution rate Amount of solid substance that goes into solution per unit time under standard conditions of temperature, pH and solvent composition and constant surface area. Dynamic process 30 Absorption of Drug 13/04/2018

31. Physicochemical factors Theories of dissolution Dissolution Solid substance solubilises in a given solvent. Mass transfer from the solid surface to the liquid phase. Theories Diffusion layer model Surface renewal theory Limited solvation theory 31 Absorption of Drug 13/04/2018

32. Physicochemical factors Diffusion layer model Two steps Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is RDS in drug dissolution 32 Absorption of Drug 13/04/2018

33. Physicochemical factors Diffusion layer model Diffusion layer or stagnant film Formation of thin film or layer at solid-liquid interface is diffusion layer Diffusion layer is saturated with drug Rapid step Diffusion of soluble solute From stagnant layer to bulk of the solution Slower step, hence rate determining 33 Absorption of Drug 13/04/2018

34. Physicochemical factors Diffusion layer model In dissolution theory, it is assumed that an Solute molecules exists in the concentrations from Cs to Cb . beyond the static layer at x greater than h, mixing occurs in the solution and the drug is found in uniform concentration, Cb throughout the bulk phase. At x= 0 drug in the solid is in equilibrium with drug in diffusion layer. The gradient in the concentration with the distance is constant as shown in fig. This is the gradient represented by the term, (Cs-C)/h. When Cb is considerably lower than Cs, the system is represented by Sink conditions 34 Absorption of Drug 13/04/2018

35. Physicochemical factors Diffusion layer model The rate of dissolution is given by Noyes & Whitney Where, dc/ dt = dissolution rate of the drug K= dissolution rate constant C s = concentration of drug in stagnant layer C b = concentration of drug in the bulk of the solution at time t 35 Absorption of Drug 13/04/2018

36. Physicochemical factors Diffusion layer model Modified Noyes-Whitney’s Equation Where, D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw /o = water/oil partition coefficient of drug. V= volume of dissolution medium. h= thickness of stagnant layer. (C s – C b )= conc. gradient for diffusion of drug. 36 Absorption of Drug 13/04/2018

37. Physicochemical factors Diffusion layer model Sink conditions In the derivation of equation it is assumed that D and h remains constant the static diffusion layer thickness is altered by the force of agitation at the surface of the dissolving tablet. Surface area A never remains constant as powder, granule or tablet dissolves and it is difficult to obtain an accurate measure of A. 37 Absorption of Drug 13/04/2018

38. Physicochemical factors Diffusion layer model Sink conditions This is first order dissolution rate process, for which the driving force is concentration gradient. This is true for in-vitro dissolution which is characterized by non-sink conditions. The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. C b =0 and rate of dissolution is maximum. Under sink conditions, if the volume and surface area of the solid are kept constant, then 38 Absorption of Drug 13/04/2018

39. Physicochemical factors Diffusion layer model Sink conditions Under sink conditions, if the volume and surface area of the solid are kept constant, then This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. 39 Absorption of Drug 13/04/2018

40. Physicochemical factors Diffusion layer model Dissolution under sink & non sink conditions Conc. of dissolved drug Time first order dissolution under non-sink condition zero order dissolution under sink condition 40 Absorption of Drug 13/04/2018

41. Physicochemical factors Diffusion layer model Sink conditions can be achieved by Bathing solid in fresh solvent from time to time Increasing volume of dissolution fluid Removing dissolved drug by partitioning Adding water miscible solvent Adding adsorbents 41 Absorption of Drug 13/04/2018

42. Physicochemical factors Diffusion layer model Hixon & Crowell’s cubic root law takes into account the particle size decrease and change in surface area, W 1/3 – W 1/3 = K t Where, W =original mass of the drug W=mass of drug remaining to dissolve at time t K t =dissolution rate constant. 42 Absorption of Drug 13/04/2018

43. Physicochemical factors Danckwert’s Model Turbulence in dissolution medium exists at solid/liquid interface Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory. 43 Absorption of Drug 13/04/2018

44. Physicochemical factors Danckwert’s Model The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma ( γ ) = rate of surface renewal 44 Absorption of Drug 13/04/2018

45. Physicochemical factors Interfacial Barrier model An intermediate concentration can exist at the interface as a result of solvation mechanism and is function of solubility Interfacial barrier model is expressed by equation Where, G = dissolution rate per unit area Ki = effective interfacial transport constant 45 Absorption of Drug 13/04/2018

46. Physicochemical factors Factors affecting drug dissolution and dissolution rate Physicochemical properties of drug Dosage form factors 46 Absorption of Drug 13/04/2018

47. Physicochemical factors Particle size and effective surface area Particle size and surface area are inversely related to each other. Two types of surface area Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the dissolution medium. Effective surface area is directly related to the dissolution rate. Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution. 47 Absorption of Drug 13/04/2018

48. Physicochemical factors Polymorphism & amorphism When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism . Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility. Eg . Chloramphenicol palmitate B 48 Absorption of Drug 13/04/2018

49. Physicochemical factors Polymorphism & amorphism Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms. E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form. Thus, the order for dissolution of different solid forms of drug is – amorphous > metastable > stable 49 Absorption of Drug 13/04/2018

50. Physicochemical factors Hydrates/ Solvates The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates . When the solvent in association with the drug is water, the solvate is known as hydrate . The organic solvates have greater aqueous solubility than the nonsolvates . E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms 50 Absorption of Drug 13/04/2018

51. Physicochemical factors Salt form of drug Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form. With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides. With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs. 51 Absorption of Drug 13/04/2018

52. Physicochemical factors pH partition hypothesis Theory states that for drug compounds molecular weight greater than 100 dalton , primarily transported across biomembrane by passive diffusion and process of absorption is governed by: pKa of drug Lipid solubility of unionised drug pH at the absorption site Most drugs are- weak electrolytes Ionisation depends on the pH of the biological fluid. Unionised with sufficient lipid soluble drug cross barrier until equilibrium is attained. 52 Absorption of Drug 13/04/2018

53. Physicochemical factors pH partition hypothesis Theory is based on following assumptions GIT is a simple lipoidal barrier Larger fraction of unionised drug, faster absorption Greater the partition coefficient of unionised drug, better absorption Drug pka and GIT pH Unionised fraction is function of pKa of drug and pH of GIF Low pKa of acidic drug- strong acid- greater ionisation Higher pKa of basic drug- strong base- greater ionisation 53 Absorption of Drug 13/04/2018

54. Physicochemical factors pH partition hypothesis Drug pka and GIT pH Henderson- Hasselbach equations 54 Absorption of Drug 13/04/2018

55. Physicochemical factors pH partition hypothesis Drug pKa and GIT pH Shore et al Therapeutic ratio (R) given by 55 Absorption of Drug 13/04/2018

56. Physicochemical factors pH partition hypothesis Drug pka and GIT pH Generalisations regarding ionisation & absorption of acids Very weak acids (pKa > 8): unionised at all pH values, absorption is rapid and independent of GI pH. Pentobarbital, hexobarbital , phenytoin , ethosuximide Moderately weak acid ( Pka , 2.5 – 7.5): absorption is pH dependent, better absorbed from acidic pH (pH<pKa). Cloxacillin , aspirin, ibuprofen, phenylbutazone Strong acid ( Pka < 2.5): ionised in the entire pH range of GIT, poorly absorbed. Disodium cromoglycate 56 Absorption of Drug 13/04/2018

57. Physicochemical factors pH partition hypothesis Drug pka and GIT pH Generalisations regarding ionisation & absorption of Bases Very weak bases (pKa < 5): unionised at all pH values, absorption is rapid and independent of GI pH. Theophylline , caffeine, oxazepam , diazepam, nitrazepam Moderately weak bases ( Pka , 5 – 11): absorption is pH dependent, better absorbed from alkaline pH. Morphine, chloroquine , imepramine , amitriptyline Strong bases ( Pka > 11): ionised in the entire pH range of GIT, poorly absorbed. Mecamylamine , Guanethidine 57 Absorption of Drug 13/04/2018

58. Physicochemical factors pH partition hypothesis Aqueous Solubility Total aqueous solubility (St): Sum of concentration of ionised and unionised drug in solution. The solubility of unionised form of drug is known as intrinsic solubility of drug. For acidic drugs For basic drugs 58 Absorption of Drug 13/04/2018

59. Physicochemical factors pH partition hypothesis Conclusions and generalisations For weakly acidic drugs When pH > pKa, St >> Sa, ionisation of drug increases When pH = pKa, St = 2Sa, 50 % ionisation When pH< pKa, St = Sa, drug exists as unionised form For basic drugs When pH > pKa, St = Sb , drug exists as unionised form When pH = pKa, St = 2Sb, 50 % ionisation When pH< pKa, St >> Sb , ionisation of drug increases 59 Absorption of Drug 13/04/2018

60. Physicochemical factors pH partition hypothesis 60 Absorption of Drug 13/04/2018

61. Physicochemical factors Liphophilicity and drug absorption Hydrophilic- lipophilic balance- optimum absorption Partition coefficient Rapid rate of absorption ( K o /w , 0.12-100): Thiopental (67%), Phenylbutazone (54%), Benzoic acid (54%), salicylic acid (60%). Moderate rate of absorption ( K o /w , 0.002 – 0.03): Aspirin (21%), Theophylline (30%), Sulphanilamide (24%) Slow rate of absorption (< 0.002): barbituric acid (5%), sulphaguanidine (2%) 61 Absorption of Drug 13/04/2018

62. Physicochemical factors Limitations of pH partition hypothesis Presence of virtual membrane pH Absorption of ionised drugs Influence of surface area and residence time of drug Presence of aqueous unstirred diffusion layer 62 Absorption of Drug 13/04/2018

63. Physicochemical factors Limitations of pH partition hypothesis Presence of virtual membrane pH Virtual membrane pH different than luminal pH pH absorption curve Basic drugs Acidic drugs pH of GI Lumen pH of GI Lumen 63 Absorption of Drug 13/04/2018

64. Physicochemical factors Limitations of pH partition hypothesis Absorption of ionised drugs pH absorption curve Absorption of ionic drugs Large lipophilic group Influence of surface area and residence time of drug Acidic drugs- stomach Basic drugs- intestine Area available Acidic & basic drugs absorbed well in intestine, long residence 64 Absorption of Drug 13/04/2018

65. Physicochemical factors Limitations of pH partition hypothesis Presence of aqueous unstirred diffusion layer Aqueous GIT fluid Aqueous unstirred diffusion layer Lipoidal biomembrane Blood 65 Absorption of Drug 13/04/2018

66. Physicochemical factors Drug permeability & absorption Absorption is expressed by Where M = amount of drug absorbed P eff = effective membrane permeability A = surface area available for absorption C app = apparent luminal drug concentration t res = residence time of drug in GI lumen Three major properties determine permeability Lipophilicity Polarity of drug Molecular size 66 Absorption of Drug 13/04/2018

67. Physicochemical factors Drug permeability & absorption Rule of five by Lipinski et al Molecular weight of drug < 500 Lipophilicity of drug, log P < 5 Number of H bond acceptors < 10 Number of H bond donors < 5 67 Absorption of Drug 13/04/2018

68. Physicochemical factors Drug stability Shelf life of drug during storage Destabilization in GIT Stereochemical nature of drug 68 Absorption of Drug 13/04/2018

69. Dosage form factors Disintegration time Manufacturing variables Excipients Manufacturing processes Method of granulation Compression force Intensity of packing of capsule content Nature and type of dosage form Product age and storage condition 69 Absorption of Drug 13/04/2018

70. Dosage form factors Method of granulation Wet granulation Dry granulation APOC method 70 Absorption of Drug 13/04/2018

71. Dosage form factors Compression force Rate of drug dissolution A B C D Compression force 71 Absorption of Drug 13/04/2018

72. Dosage form factors Intensity of packing of capsule contents Diffusion of GI fluids into the tightly filled capsules creates a high pressure within the capsule resulting in rapid bursting and dissolution of contents. On other hand, it shows that capsule with finer particles and intense packing have poor drug release and dissolution rate due to decrease in pore size of the compact and poor penetrability by the GI fluids. 72 Absorption of Drug 13/04/2018

73. Dosage form factors Excipients Vehicle Diluents Binders and granulating agent Disintegrants Lubricants Coating agents Suspending agents/ Viscosity imparters Surfactants Buffers Complexing agents Colorants Crystal growth inhibitors 73 Absorption of Drug 13/04/2018

74. Dosage form factors Nature and type of dosage form Solutions Emulsions Suspensions Powders Capsules Tablets Coated tablet Enteric coated tablet Sustained release tablet 74 Absorption of Drug 13/04/2018

75. Patient related factors Gastrointestinal tract Function Length 450 cm Stomach Small intestine Large intestine 75 Absorption of Drug 13/04/2018

76. Patient related factors Stomach Structure- bag like Small surface area Acidic pH- favors absorption of acidic drugs Acidic pH – favors dissolution of basic drugs Limited gastric residence 76 Absorption of Drug 13/04/2018

77. Patient related factors Small Intestine Large surface area 77 Absorption of Drug 13/04/2018

78. Patient related factors Small Intestine Large surface area (200 sqm ) Length of small intestine (300-500 cm) Greater blood flow (1 l/min) Favourable pH range (5-7.5) Slow peristaltic movement Prolonged residence time (3-6h) High permeability 78 Absorption of Drug 13/04/2018

79. Patient related factors Large Intestine Small surface area (0.15 sqm ) Length (110 cm) blood flow (0.02 l/min) pH range (6-8) Residence time (6-12 h) Important in absorption of poorly soluble drug and SRDF 79 Absorption of Drug 13/04/2018

80. Patient related factors Age Infants Gastric pH high Less intestinal surface area Low Blood flow Elderly Altered gastric emptying Decreased intestinal surface area Decreased blood flow Higher incidence of achlorhydria and bacterial overgrowth 80 Absorption of Drug 13/04/2018

81. Patient related factors Gastric Emptying Passage of drug from stomach to small intestine Rate limiting step for absorption Rapid gastric emptying increases bioavailability Rapid gastric emptying is advisable where Rapid onset of action is desired Dissolution occurs in intestine Drug unstable in stomach Drug best absorbed in intestine Gastric emptying can be promoted by taking drug on empty stomach 81 Absorption of Drug 13/04/2018

82. Patient related factors Gastric Emptying Delay in gastric emptying is advisable where Food promotes dissolution and absorption Disintegration and dissolution promoted by gastric fluid Drug dissolves slowly Drug irritates gastric mucosa Drug absorbed in proximal part of intestine Gastric emptying rate Gastric emptying time Gastric emptying half life Barium sulphate is used to determine gastric emptying 82 Absorption of Drug 13/04/2018

83. Patient related factors Gastric Emptying Factors influencing gastric emptying Volume of meal Composition of meal Physical state & viscosity of meal Temperature of meal Gastrointestinal pH Electrolytes & osmotic pressure Body posture Emotional state Exercise Disease state Drugs 83 Absorption of Drug 13/04/2018

84. Patient related factors Intestinal transit Peristaltic movement- promotes absorption Delayed intestinal transit is desirable SR products Drugs dissolves in intestine Absorption window Slow absorption 84 Absorption of Drug 13/04/2018

85. Patient related factors Gastrointestinal pH Disintegration- Enteric coated Dissolution Absorption Stability 85 Absorption of Drug 13/04/2018

86. Patient related factors Disease state Gastrointestinal diseases Achlorhydria Celiac disease Crohn’s disease Malabsorption GI infections Colonic diseases GIT surgery Cardiovascular diseases Hepatic diseases 86 Absorption of Drug 13/04/2018

87. Patient related factors Blood flow to GIT 28% of cardiac output Sink condition Food alters blood flow 87 Absorption of Drug 13/04/2018

88. Patient related factors GIT content Food drug interaction Fluid volume Large fluid volume results better dissolution, rapid gastric emptying Delayed Decreased Increased Unaffected Aspirin Penicillins Griseofulvin Methyldopa Paracetamol Erythromycin Diazepam Propylthiouracil Diclofenac Tetracyclines Vitamins Digoxin Iron 88 Absorption of Drug 13/04/2018

89. Patient related factors GIT content Normal GI constituents Mucin decreases absorption of drug Bile salts increases absorption of lipid soluble drugs Drug-drug interactions Physicochemical Adsorption Complexation pH change Physiological Decreased GI transit ( Propantheline ) Increased gastric emptying ( Metoclopramide ) Altered GI metabolism (Antibiotics) 89 Absorption of Drug 13/04/2018

90. Patient related factors First Pass Effect The loss of drug through biotransformation by GIT and Liver during its passage to systemic circulation. Luminal Enzymes Digestive enzymes Enzymes present in gut fluid include intestinal and pancreatic secretions. Hydrolases Hydrolyses esters chloramphenicol palmitate to chloramphenical Inactivates proteins 90 Absorption of Drug 13/04/2018

91. Patient related factors First Pass Effect Bacterial enzymes Gut wall enzymes Alcohol dehydrogenase Phase I and Phase II enzymes Hepatic enzymes 91 Absorption of Drug 13/04/2018

92. Buccal & Sublingual Administration Sublingual Route Under tongue and allowed to dissolve Buccal Route Between cheek & gum Barrier for absorption- oral epithelium Drug absorbed by passive diffusion Advantages Rapid absorption No first pass 92 Absorption of Drug 13/04/2018

93. Buccal & Sublingual Administration Factors Biphasic solubility of drug is required. pH of saliva (6) Binding of drug to oral mucosa Storage compartment Thickness of oral epithelium Surface area Taste of medicament Antianginals , Antihypertensives , Analgesics, Bronchodilators 93 Absorption of Drug 13/04/2018

94. Rectal Administration Unconscious patients and children If patient is nauseous or vomiting E asy to terminate exposure A bsorption may be variable G ood for drugs affecting the bowel such as laxatives I rritating drugs contraindicated Dosage- solutions, suppositories pH (8) Surface area Bypass first pass (lower half) Analgesics, Bronchodilators, 94 Absorption of Drug 13/04/2018

95. Topical Administration Skin Surface area 2 sqm Blood supply 1/3 rd Stratum corneum Mechanisms of absorption Transcellular (passive diffusion) Intercellular ( paracellular ) Transappendageal Through hair follicles, sweat gland, sebaceous gland 95 Absorption of Drug 13/04/2018

96. Topical Administration Factors Skin conditions Composition of topical vehicle Application conditions Environmental factors 96 Absorption of Drug 13/04/2018

97. Topical Administration Skin conditions Thickness of stratus corneum Presence of hair follicles Trauma Hydration of skin Age Skin microflora Skin pH Skin surface lipids Anatomical site 97 Absorption of Drug 13/04/2018

98. Topical Administration Composition of topical vehicle Vehicle/ base Permeation enhancers Application conditions Rubbing Occulsion Loss of vehicle External factors Environmental humidity and temperature Grooming Exposure to chemicals Chronic use of certain drug 98 Absorption of Drug 13/04/2018

99. Topical Administration Drug administered Nitroglycerine, lidocaine , testosterone Iontophoresis Delivery of ionic drug into the body -an electric current Sonophoresis Delivery of drug- under influence of ultrasound 99 Absorption of Drug 13/04/2018

100. Intramuscular Administration Factors Vascularity of the injection site Blood flow to site Lipid solubility and ionisation Molecular size of drug Volume of injection and drug concentration pH, composition and viscosity of injection vehicle 100 Absorption of Drug 13/04/2018

101. Pulmonary Administration Large surface area of alveoli High perfusion High permeability Bronchodilators, steroids, antiallergics Factors pH Lipid soluble- passive diffusion Ionic, polar- pore transport Particle/ globule size 101 Absorption of Drug 13/04/2018

102. Intranasal Administration Less surface area High perfusion High permeability Peptides, proteins, Bronchodilators, steroids, antiallergics Factors pH (5.5-6.5) Lipid soluble- passive diffusion Ionic, polar- pore transport Molecular size Mucociliary clearance 102 Absorption of Drug 13/04/2018

103. Bibliography D. M. Bramhankar and S. B. Jaiswal . Biopharmaceutics and Pharmacokinetics A Treatise. Delhi;Vallabh Prakashan . 2010 Jambhekar SS, Breen PJ. Basic Pharmacokinetics. London; Pharmaceutical Press. 2009. Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and Pharmacokinetics. McGraw Hill. 2007. 13/04/2018 Absorption of Drug 103