logging in or signing up Factors affecting drug absorption AJ07 Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Copy Does not support media & animations WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 6712 Category: Science & Tech.. License: All Rights Reserved Like it (5) Dislike it (1) Added: April 27, 2011 This Presentation is Public Favorites: 13 Presentation Description No description available. Comments Posting comment... By: gpriyan (2 month(s) ago) hi it is nice pls send to my mail id gpriyan@gmail.com Saving..... Post Reply Close Saving..... Edit Comment Close By: basir12 (14 month(s) ago) hello brother; your ppt is really good can u plz.. send it to my email samiulbasir50@@gmail.com ,, its urgent Saving..... 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Guide : Nayana Pathak@ What is drug Absorption ? : @ What is drug Absorption ? “ Drug absorption “ is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.“Systemic events during administration to absorption of drug” : “ Systemic events during administration to absorption of drug ” “Systemic events during administration to absorption of drug” DISINTEGRATION DEAGGREGATION GI lumen Blood DISSOLUTION NON – IONIC NON- IONIC { DRUG AT ABSORPTION SITE IONIC IONIC A)Physicochemical factors:: A)Physicochemical factors : which affects due to the “ Physicochemical properties of drugs.” 1) Drug solubility & dissolution rate 2) Particle size & effective surface area 3) Polymorphism & amorphism 4) Psuedoploymorphism ( hydrates/solvates) 5) Salt form of the drug 6) Lipophillicity of the drug PH-PARTITION HYPOTHESIS 7) pKa of drug & gastrointestinal pH 8) drug stability 9) Steriochemical nature of the drugB)Pharmaceutical factors : : B)Pharmaceutical factors : which affects due to the” Dosage form characteristic & pharmaceutical ingredients “ 1) Disintegration time ( tablets/capsules) 2) Dissolution time 3) Manufacturing variables 4) Pharmaceutical ingredients ( excipients/ adjuvants) 5) Nature & type of dosage form 6) Product age & storage conditionC) Physicality factors : : C) Physicality factors : which affects due to “anatomical , physiological & pathological characteristics of patient.” 1) Age 2) Gastric emptying time 3) Intestinal transit time 4) Gastrointestinal pH 5) Disease states 6) Blood flow through the GIT 7) Gastrointestinal contents: a) Other drugs b) Food c) Fluids d) Other normal GI contents 8) Pre systemic metabolism by: a) Luminal enzymes b) Gut wall enzymes c) Bacterial enzymes d) Hepatic enzymesA] Physicochemical factors: 1) Drug solubility & Dissolution Rate: : A] Physicochemical factors: 1) Drug solubility & Dissolution Rate: DRUG SOLUBILITY : Desired solubility for good oral absorption depends on the permeability of the compound & the required dose. Now a days solubility parameter is very much useful to correlate the drug absorption by the concept of “ MAXIMUM AVAILABLE DOSE “ { MAD } MAD = Ka SGI VGI tr Ka = Intrinsic absorption rate constant SGI = Solubility of drug in GI fluid VGI = volume of GI fluid tr = residence time of drug in GI By this equation we can find the limited parameters of drug absorption like.. Solubility of drug in the GI tract Intrinsic absorption rate constant specific to drug in solution. THE HIGHER THE MAD NO. HIGHER SOLUBILITY. DESIRED SOLUBILITY CORRELATED WITH THERAPEUTIC DOSE: : By this equation we can find the limited parameters of drug absorption like.. Solubility of drug in the GI tract Intrinsic absorption rate constant specific to drug in solution. THE HIGHER THE MAD NO. HIGHER SOLUBILITY. D ESIRED SOLUBILITY CORRELATED WITH THERAPEUTIC DOSE: Dose (mg/kg) Desired solubility values for drugs with… High permeability Medium permeabilty Low permeability 0.1 mg/kg 1 mg/ml 5 mg/ml 21 mg/ml 1 mg/kg 10 mg/ml 52 mg/ml 207 mg/ml 10 mg/kg 100 mg/ml 520 mg/ml 2100mg/ml @ BIOPHARMACEUTICAL CLASSIFICATION SYSTEM: : @ BIOPHARMACEUTICAL CLASSIFICATION SYSTEM : high SOLUBILTY low high PERMEABILITY 1 2 solubility permeability 3 4 low@: @ @Brief idea about BCS:: Brief idea about BCS: CLASS SOLUBILTY PERMEABILITY ABSORPTION Rate Limiting Step EXAMPLES ❶ HIGH HIGH WELL ABSORBED Gastric Emptying Acetaminophen,metoprolol,NsAIDS,verapamil,etc. ❷ LOW HIGH VARIABLE Dissolution Carbamazepine,digoxin, grieseofulvin,spironolactone,etc. ❸ HIGH LOW VARIABLE Permeability Bi sphosphonates,captopril , insulin,furosemide,etc . ❹ LOW LOW POORLY ABSORBED Case by case Neomycin, taxol,etc.A brief idea about ENHANCEMENT OF BIOAVAIBILITY on the bases of BCS. : A brief idea about ENHANCEMENT OF BIOAVAIBILITY on the bases of BCS. CLASS 1 : This drugs do not require such treatment in general. But still several methods can be used depending upon the drug to be formulated. CLASS 2 : This types of drugs are poorly soluble so methods like precipitation , solvent disposition or use of different forms like Amorphs , Anhydrates , Solvates & Metastable polymorphs or by using Salt forms. All these things are useful for this drugs. CLASS 3 : This drugs are poorly permeable so we can use surfactants & techniques like micronisation , nanonisation which reduce particle size or they can be formulated as targeted or PH specified delivery system since these drugs mainly absorbed from several specific sites. CLASS 4 : This drugs are poorly soluble & poorly permeable so they should be formulated in several targeted delivery formulation in which they can skip the absorption profiles like solubility & permeability.: 2) DISSOLUTION RATE & DRUG DISSOLUTION : Dissolution is a process in which a solid substance solubilises in a given solvent ie… mass transfer from the solid surface to the liquid phase. $ How it occurs ? Several different theories are proposed for these as. @ Diffusion layer model / film theory It gives possibilities of formation of a diffusion layer at the solid liquid interface in the solution & after it the solutes comes out or diffuse from the diffusion layer. $ noyes & whitney gave a chemical equation for this dc /dt = k ( Cs - Cb ) dc /dt = dissolution rate of drug k = dissolution rate constant Cs = concentration of drug in the stagnant layer Cb = concentration of drug in the bulk at time t@: @ THE above equation is based on fick’s second law of diffusion. @*Nernest & burner incorporated fick’s law of diffusion& modified the previous equation to dc/ dt = DAK w/o ( Cs - Cb) v h where , D = diffusion coefficient A = surface area K w/o= intrinsic dissolution rate constant v = volume of dissolution media h = thickness ( Cs - Cb )= concentration gradient for diffusion of drug@ SINK CONDITION :: @ SINK CONDITION : *In in-vitro the driving force is concentration gradient & the condition is called ‘ non – sink conditions ‘. *But in in-vivo the dissolution is always rapid than in-vitro. because in body as the drug dissolves it is rapidly taken up in to systemic circulation So, in case of in vivo studies the Cb in the equation will always be ZERO ( Cb = 0 ) Some concentration gradient always maintained & Cs is>> Cb. So sink condition are always be maintained so equation reduce to dc/dt= K here k = all constants in previous eq. So in case of dissolution rate studies to achieve a good correlation b/w in vitro – in vivo the in vitro studies should always be done under “ sink conditions“. In general in the in-vitro studies sink conditions are always maintained that cb is always less than 10 % of Cs.@ : @ fast dissolution after concentration 1 st order ( non sink) slow dissolution I N – VITRO time GI lumen Blood Blood stream concentration 0 order (sink) IN-VIVO Blood stream cb = 0 time2) Particle size & Surface area : : 2) Particle size & Surface area : These both factors are inversely proportional to each other , smaller the particle greater the surface area. A drug dissolves rapidly when it has larger surface area of particles this achieved by reducing particle size. Two types of surface area are important.. 1 ) Absolute surface area which is the total area of solid surface of any particle. 2 ) Effective surface area which is the area of solid surface exposed to the dissolution medium. For use in absorption studies the effective surface area is of much important than absolute.@: @ To increase the effective surface area up to a very powerful extent we have to reduce the size of particles up to 0.1 micron. So these can be achieved by ‘’ micronisation process’’. MICRONISATION DECREASE PARTICLES SIZE UP TO O. 1 MICRON INTRINSIC SOLUBILITY DISSOLUTION INCREASE RATE INCREASED But in these case one most important thing to be keep in mind that which type of drug is micronised if it is : 1) HYDROPHILLIC OR 2) HYDROPHOBIC@: @ 1 ) HYDROPHILLIC DRUGS: in hydrophilic drugs the small particles have higher energy than the bulk of the solid resulting in an increased interaction with the solvent. Griesiofulvin – Dose reduced to half due to micronisation. Spironolactone – the dose was decreased to 20 times. Digoxin – the bioavailability was found to be 100% in micronized tablets. 2) HYDROPHOBIC DRUGS: in this it is seen that this micronisation techniques results in decreased effective surface area & thus fall in dissolution rate. REASON FOR THESE: 1) The hydrophobic surface of the drugs adsorbs air on to their surface which inhibits their wettability. 2) The particles reaggregates to form large particles due to their high surface free energy , which either float on the surface or settle on the bottom of the dissolution medium. 3) Electrically induced agglomeration owing to surface charges prevents intimate contact of the drug with the dissolution medium. For such hydrophobic drugs can be converted to their effective surface area.3) POLYMORPHISM: : 3) POLYMORPHISM: Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs, and the phenomenon as polymorphism. The polymorphs differ from each other with respect to their physical properties such as solubility, melting point, density, hardness and compression characteristics. Thus, these change in physical properties affect the dissolution properties and hence the absorption. Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. They also exhibit different melting points , solubilities (which affect the dissolution rate of drug and consequently its bioavailability in the body is also affected), X-ray crystal and diffraction patterns.@: @ Various conditions in the crystallisation process is the main reason responsible for the development of different polymorphic forms. These conditions include: 1) solvent effects (the packing of crystal may be different in polar and nonpolar solvents) 2) certain impurities inhibiting growth pattern and favour the growth of a metastable polymorphs 3 ) the level of supersaturation from which material is crystallised (in which generally the higher the concentration above the solubility the more likelihood of metastable formation) 4) temperature at which crystallisation is carried out 5) geometry of covalent bonds (differences leading to conformational polymorphism) 6) change in stirring conditions@: @ Plot of Cp Vs Time for three formulations of Chloramphenicol palmitate Chloramphenicol palmitate is one example which exists in at least two polymorphs. The B form is apparently more bioavailable. The recommendation might be that manufacturers should use polymorph B for maximum solubility and absorption.@: @ 4) PSEUDO-POLYMORPHISM When the solvent molecules are entrapped in the crystalline structure of the polymorph, it is known as pseudo-polymorphism. Hydrates/Solvates are pseudo-polymorphs where hydrates are less soluble and solvates are more soluble and thus affect the absorption accordingly. For example: n- pentanol solvates of fudrocortisone and succinyl -sulfathiazole have greater aqueous solubility than the non-solvates.@: @ AMORPHISM: Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drug represents the highest energy state and can be considered as super-cooled liquids. They have greater aqueous solubility than the crystalline forms because a energy required to transfer a molecule from the crystal lattice is greater than that required for non-crystalline (amorphous form). For example: the amorphous form of Novobiocin is 10 times more soluble than the crystalline form. Thus, the order of different solid dosage forms of the drugs is Amorphous > Meta-stable > stable 5) SALT FORM OF THE DRUG:: 5) SALT FORM OF THE DRUG: At given pH, the solubility of drug, whether acidic/basic or its salt form, is a constant. While considering the salt form of drug, pH of the diffusion layer is important not the pH of the bulk of the solution. Example of salt of weak acid. - It increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid. Dissolution and absorption of an acidic drug administered in a salt form.@: @ One more important thing to be note is that the dissolution rate of a particular salt is usually different from that of parent compound. Sodium or potassium salts of weak acids dissolves more rapidly then the free acids , regardless of the ph of dissolution medium. In market also several drugs are formulated according to their dissolution rate profile like… Barbiturates are often available in the form of sodium salt to achieve a rapid onset of sedation. NSAIDS - well marketed as the free acids for the treatment of rheumatoid & osteoarthritis. New indications are in treatment of mild to moderate pain including dysmenorrhoea , prompted development of Naproxen sodium6) & 7) pH-PARTITION HYPOTHESIS: : 6) & 7) pH-PARTITION HYPOTHESIS: The theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the bio-membrane by passive diffusion, the process of absorption is governed by: 1. The dissociation constant pKa of the drug. 2. The lipid solubility of the un-ionized drug. 3. The pH at the absorption site. A) Drug pKa and GI pH Amount of drug that exists in un-ionized form and in ionized form is a function of pKa of drug and pH of the fluid at the absorption site, and it can be determined by Handerson-Hasselbach equation: For weak acids , pH = pKa + log [ionized] [un-ionized] …………………..(1.1) % Drug ionized = 10 pH-pKa x 100 ……………..…… (1.2) 1+10 pH-pKa For weak bases , pH = pKa + log [un-ionized] [ionized] …….(1.3) % Drug ionized = 10 pKa-pH x 100 ……(1.4) 1+10 pKa-pH@: @ If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by the following equations: For weak acids, R a = C GIT = 1+10 pHGIT-pKa C plasma 1+10 pHplasma-pKa ………. (1.5) For weak bases, R b = C GIT = 1+10 pKa-pHGIT C plasma 1+10 pKa-pHplasma ………. (1.6) B) Lipophilicity and Drug absorption : The lipid solubility of the drug is determined form its oil/water partition co-efficient (Ko/w) value, whereby the increase in this value indicates the increase in percentage drug absorbed. Ko/w = Distribution of the drug in the organic phase ( octanol ) Distribution of the drug in the aqueous phase …………. (1.7)C) Limitations pH partition hypothesis: : C) Limitations pH partition hypothesis: a) Presence of Virtual Membrane pH: There is a presence of virtual membrane pH or the micro-climate pH, different from the luminal pH which exists at the membrane surface. b) Absorption of the ionized drug: Despite of the assumption that only un-ionized and lipophilic drugs are absorbed to a greater extent, some drugs e.g. Morphinan derivatives which are much more ionized are absorbed passively owing to their very high lipophilicity. c) Influence of the GI surface area and residence time of the drug: Irrespective of the GI pH and degree of ionization, both acidic and basic drugs are more rapidly absorbed from the intestine, primarily because of its large surface area and secondly, because of the long residence time of the drug in the intestine. d) Presence of Aqueous Unstirred Diffusion Layer: The drugs having a large partition co-efficient can readily penetrate the lipid membrane but the diffusion through the unstirred water layer is the rate limiting step in their absorption. This applies in particular to high molecular weight fatty acids and bile acids.8)drug stability : 8)drug stability A drug for oral use may destabilized either during its shelf life or in the GIT . Two major stability problems resulting in poor bioavailability of an orally administered drug are -degradation of the drug into inactive form, and interaction with one or more different component(s) either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is unabsorbable.B] PHARMACEUTICAL FACTORS : B] PHARMACEUTICAL FACTORS 1) DISINTEGRATION TIME Rapid disintegration is important to have a rapid absorption so lower disintegration time is required. Disintegration time of tablet is directly proportional to –amount of binder and compression force. It is important to note that in vitro disintegration test gives no means of a guarantee of drugs B.A. because if the disintegrated drug particles do not dissolve then absorption is not possible. 2) Dissolution time:: 2) Dissolution time: Dissolution is a process in which a solid substance solubilises in a given solvent ie … mass transfer from the solid surface to the liquid phase. Dissolution time is also an important factor which affect the drug absorption .3) MANUFACTURING VARIABLES:: 3) MANUFACTURING VARIABLES: Several manufacturing processes influence drug dissolution from solid dosage forms. For example: For tablet it is Method of granulation Compression force Method of granulation: Different methods like wet granulation , dry granulation and direct comprssion etc. yields product with different dissolution,@: @ B ) Compression force Fig Influence of compression force on the dissolution rate of tablets The compression force employed in tableting process influence density, porosity, hardness, disintegration time and dissolution rate of tablets.4) PHARMACEUTICAL INGREDIENTS/EXCIPIENTS:: 4) PHARMACEUTICAL INGREDIENTS/EXCIPIENTS: More the number of Excipients in the dosage form, more complex it is & greater the potential for absorption and Bioavailability problems. A) Vehicle Rate of absorption – depends on its miscibility with biological fluid. Miscible vehicles (aqueous or water miscible vehicle) causes rapid absorption e.g. propylene glycol. Immiscible vehicles – Absorption depends on its partitioning from oil phase to aqueous body fluid. B) Diluents Hydrophilic diluents – Imparts Absorption Hydrophobic diluents – Retards Absorption Also, there is a drug- diluent interaction, forming insoluble complex and retards the absorption. E.g. Tetracycline-DCP@: @ C) Binders & granulating agent - Hydrophilic binders – Imparts hydrophilic properties to the granule surface – gives better dissolution properties of the poorly wettable drugs. E.g. Starch, Gelatin. PVP. But more amount of binder increases the hardness of the tablet and retards the absorption rate. D) Disintegrants Mostly hydrophilic in nature. Decrease in amount of disintegrants – significantly lowers B.A. E) Suspending agents/viscosity agent Stabilized the solid drug particles and thus affect drug absorption. Macromolecular gum forms un-absorbable complex with drug e.g. Na CMC. Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage form and retard GI transit of drug.@: @ G) Surfactants May enhance or retards drug absorption by interacting with drug or membrane or both. Physiologic surfactants – bile salts – promotes absorption – e.g. Griseofulvin , steroids It may decrease absorption when it forms the un-absorbable complex with drug above CMC. H) Coating In general, deleterious effects of various coatings on the drug dissolution from a tablet dosage form are in the following order. Enteric coat > sugar coat > non-enteric coat. The dissolution profile of certain coating materials change on aging; e.g. shellac coated tablets, on prolonged storage, dissolve more slowly in the intestine. This can be however, be prevented by incorporating little PVP in the coating formulation.@@: @@ F) Lubricants Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus dissolution and disintegration. I) Buffers Buffers are sometimes useful in creating the right atmosphere for drug dissolution as was observed for buffered aspirin tablets. However, certain buffer systems containing potassium cations inhibit the drug absorption as seen with Vitamin B 2 and sulfanilamide. J) Colourants Even a low concentration of water soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs. The dye molecules get absorbed onto the crystal faces and inhibit the drug dissolution. For example: Brilliant blue retards dissolution of sulfathiazole.5) NATURE AND TYPE OF DOSAGE FORM : 5) NATURE AND TYPE OF DOSAGE FORM Apart from the proper selection of the drug, clinical success often depends to a great extent on the proper selection of the dosage form of that drug. For a given drug, a 2 to 5 fold or perhaps more difference could be observed in the oral bio-availability of a drug depending upon the nature and type of dosage form. As a general rule, the bio-availability of a drug form various dosage forms decrease in the following order: Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric Coated Tablets > Sustained Release Products.Fig : Bio-availability risk and absorption of various dosage forms. : Fig : Bio-availability risk and absorption of various dosage forms. @6) PRODUCT AGE AND STORAGE CONDITIONS: : 6) PRODUCT AGE AND STORAGE CONDITIONS: Product aging and storage conditions can adversely affect the bio-availability by change in especially the physico -chemical properties of the dosage forms. For example: Precipitation of the drug in solution Hardening of tablet Change in particle size of suspension.C] PHISICALITY FACTORS: : C] PHISICALITY FACTORS: 1) AGE In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults. In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial over growth in small intestine. 2) Gastric emptying and motility: : 2) Gastric emptying and motility: Several parameters are used to quantify gastric emptying such as: Gastric emptying rate: which is the speed at which the stomach contents empty into the intestine. Gastric emptying time: which is the the time required for the gastric contents to the SMALL INTESTINE. Gastric emptying half-life: which is the time taken for half the stomach contents to empty.@: @ Fig Dependence of peak Acetaminophen plasma concentration as a function of stomach emptying half-life.3) Intestinal transit:: 3) Intestinal transit: Since, intestinal transit time is the major site of absorption of most of drugs, long intestinal transit time is desirable for complete absorption of drugs. Transit time for contents from different regions of intestine Intestinal region Transit time Duodenum 5 minutes Jejunum 2 hours Ileum 3 to 6 hours Caecum 0.5 to 1 hour Colon 6 to 12 hours@: @ It is influenced by various factors such as food, diseases and drugs e.g. metoclopramide which promotes intestinal transit, enhance absorption of rapidly soluble drugs while anticholinergic retards intestinal transit and promotes the absorption of poorly soluble drugs.4) Gastrointestinal PH:: 4) Gastrointestinal PH: GI fluid pH affecet in several ways: Disintegration: The Disintegration of some drugs is pH sensitive with enteric coating the coat dissolves in only the intestine at specific PH. Dissolution : A large no of drugs whose solubility is greatly affected by pH are either weak acids or weak bases. Weakly acidic drugs dissolves rapidly in alkaline pH of the intestine whereas basic drugs dissolve in the acidic pH of the stomach.@: @ Stability :GI pH also affect the chemical stability of drugs . EX> the acidic stomach pH gives a degradation of penicillin G and erythromycin.So such drugs to be formulated by preoaring prodrugs Ex. Carindacillin and erythromycin estolate or in any other way . Dependin upon the pKa and wether it is an acidic or basic drug the amount of drug that would exist in the unionized form at site of absorption. This was covered in pH partition hypothesis.5) DISEASES:: 5) DISEASES: A) Gastric diseases: The influence of achlorhydria (decreased gastric acid secretion and increases stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs (decreased absorption e.g. aspirin) has been studied. B) Intestinal diseases: Two of the intestinal disorders related with malabsorption syndrome that influence drug availability are Celiac disease and Chron’s disease . C) Cardio-vascular diseases: Several changes associated with congestive cardiac failure influence bio-availability of a drug viz., edema of the intestine, decreased blood flow to the GIT and gastric emptying rate and altered GI pH, secretions and microbial flora. D) Hepatic diseases: Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that undergo considerable first-pass hepatic metabolism e.g. propranolol6) Blood flow through GIT: : 6) Blood flow through GIT: The GIT is extensively supplied by blood capillary network and blood flow rate to GIT (splanchnic circulation) is 28% of the cardiac output. Therefore, it helps in maintaining sink conditions and concentration gradient for drug absorption by rapidly removing drug from the site of action. Table : Influence of blood flow effect on various types of drugs DRUGS BLOOD FLOW EFFECT A) For highly lipid soluble drugs More B) For many lipophilic drugs such as ethanol, glycerol, etc. Intermediate C) Polar compounds such as ribitol Less@: @ 7) Gastro intestinal contents: 1) food- drug interactions : presence of food will affect absorption in following way a) delay absorption _ ex. Aspirin , paracetamol , diclofenac , nitrofurantoin , digoxin etc. b) decreased absorption : ex. Penicillin, erythromycin, ethanol, tetracycline, levodopa etc. c)increased absorption : grieseofulvin, diazepam, vitamins etc. in some cases it do not affect ex. methyldopa, propylthiouracil etc. 2) fluid volume : administration of a drug with large fluid volume results in better dissolution , rapid gastric emptying and enhanced absorption- for ex.. erythromycin is better absorbed when taken with a glass of water under fasting condition than when taken with meals.@: @ 3) Interaction of drug with normal GI constituents : the GIT contains a number of normal constituents such as mucin –which is a protective mucopolysaccharides that lines the GI mucosa , interact with streptomycin. Bile salts- which affect the absorption of lipid soluble drugs like grieseofulvin and vitamins. 4) drug-drug interactions : they can either be physiological or physiochemical…@: @ 8) Pre-systemic metabolism For a drug administered orally, the 2 main reasons for its decreased bio-availability are: 1. Decreased absorption 2. First-pass/pre-systemic metabolism The four primary systems which affect the pre-systemic metabolism of a drug (Fig ) Lumenal Enzymes Gut wall enzymes/mucosal enzymes Bacterial enzymes Hepatic enzymes.@: @ Fig Different sites of pre-systemic metabolism@: @ Thank you all for your Tolerance You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
Factors affecting drug absorption AJ07 Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Copy Does not support media & animations WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 6712 Category: Science & Tech.. License: All Rights Reserved Like it (5) Dislike it (1) Added: April 27, 2011 This Presentation is Public Favorites: 13 Presentation Description No description available. Comments Posting comment... By: gpriyan (2 month(s) ago) hi it is nice pls send to my mail id gpriyan@gmail.com Saving..... Post Reply Close Saving..... Edit Comment Close By: basir12 (14 month(s) ago) hello brother; your ppt is really good can u plz.. send it to my email samiulbasir50@@gmail.com ,, its urgent Saving..... Post Reply Close Saving..... Edit Comment Close By: dsnbkprasanth (17 month(s) ago) hi it is nice pls send to my mail id - dsnbkprasanth@gmail.com Saving..... Post Reply Close Saving..... Edit Comment Close By: anniedev (18 month(s) ago) hi,it's very informative ,can you plz send me to anniedev.m@gmail.com,thank u Saving..... Post Reply Close Saving..... Edit Comment Close By: sara.azad1986 (18 month(s) ago) hello,can you plz send me email,its really well,thanx sarah_azad@yahoo.com Saving..... Post Reply Close Saving..... Edit Comment Close loading.... See all Premium member Presentation Transcript Factors affecting drug absorption: F actors affecting drug a bsorption Presented by : AJAYRAJSINH N. CHUDASAMA M.Pharm sem-1 C.C.P.R. Guide : Nayana Pathak@ What is drug Absorption ? : @ What is drug Absorption ? “ Drug absorption “ is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.“Systemic events during administration to absorption of drug” : “ Systemic events during administration to absorption of drug ” “Systemic events during administration to absorption of drug” DISINTEGRATION DEAGGREGATION GI lumen Blood DISSOLUTION NON – IONIC NON- IONIC { DRUG AT ABSORPTION SITE IONIC IONIC A)Physicochemical factors:: A)Physicochemical factors : which affects due to the “ Physicochemical properties of drugs.” 1) Drug solubility & dissolution rate 2) Particle size & effective surface area 3) Polymorphism & amorphism 4) Psuedoploymorphism ( hydrates/solvates) 5) Salt form of the drug 6) Lipophillicity of the drug PH-PARTITION HYPOTHESIS 7) pKa of drug & gastrointestinal pH 8) drug stability 9) Steriochemical nature of the drugB)Pharmaceutical factors : : B)Pharmaceutical factors : which affects due to the” Dosage form characteristic & pharmaceutical ingredients “ 1) Disintegration time ( tablets/capsules) 2) Dissolution time 3) Manufacturing variables 4) Pharmaceutical ingredients ( excipients/ adjuvants) 5) Nature & type of dosage form 6) Product age & storage conditionC) Physicality factors : : C) Physicality factors : which affects due to “anatomical , physiological & pathological characteristics of patient.” 1) Age 2) Gastric emptying time 3) Intestinal transit time 4) Gastrointestinal pH 5) Disease states 6) Blood flow through the GIT 7) Gastrointestinal contents: a) Other drugs b) Food c) Fluids d) Other normal GI contents 8) Pre systemic metabolism by: a) Luminal enzymes b) Gut wall enzymes c) Bacterial enzymes d) Hepatic enzymesA] Physicochemical factors: 1) Drug solubility & Dissolution Rate: : A] Physicochemical factors: 1) Drug solubility & Dissolution Rate: DRUG SOLUBILITY : Desired solubility for good oral absorption depends on the permeability of the compound & the required dose. Now a days solubility parameter is very much useful to correlate the drug absorption by the concept of “ MAXIMUM AVAILABLE DOSE “ { MAD } MAD = Ka SGI VGI tr Ka = Intrinsic absorption rate constant SGI = Solubility of drug in GI fluid VGI = volume of GI fluid tr = residence time of drug in GI By this equation we can find the limited parameters of drug absorption like.. Solubility of drug in the GI tract Intrinsic absorption rate constant specific to drug in solution. THE HIGHER THE MAD NO. HIGHER SOLUBILITY. DESIRED SOLUBILITY CORRELATED WITH THERAPEUTIC DOSE: : By this equation we can find the limited parameters of drug absorption like.. Solubility of drug in the GI tract Intrinsic absorption rate constant specific to drug in solution. THE HIGHER THE MAD NO. HIGHER SOLUBILITY. D ESIRED SOLUBILITY CORRELATED WITH THERAPEUTIC DOSE: Dose (mg/kg) Desired solubility values for drugs with… High permeability Medium permeabilty Low permeability 0.1 mg/kg 1 mg/ml 5 mg/ml 21 mg/ml 1 mg/kg 10 mg/ml 52 mg/ml 207 mg/ml 10 mg/kg 100 mg/ml 520 mg/ml 2100mg/ml @ BIOPHARMACEUTICAL CLASSIFICATION SYSTEM: : @ BIOPHARMACEUTICAL CLASSIFICATION SYSTEM : high SOLUBILTY low high PERMEABILITY 1 2 solubility permeability 3 4 low@: @ @Brief idea about BCS:: Brief idea about BCS: CLASS SOLUBILTY PERMEABILITY ABSORPTION Rate Limiting Step EXAMPLES ❶ HIGH HIGH WELL ABSORBED Gastric Emptying Acetaminophen,metoprolol,NsAIDS,verapamil,etc. ❷ LOW HIGH VARIABLE Dissolution Carbamazepine,digoxin, grieseofulvin,spironolactone,etc. ❸ HIGH LOW VARIABLE Permeability Bi sphosphonates,captopril , insulin,furosemide,etc . ❹ LOW LOW POORLY ABSORBED Case by case Neomycin, taxol,etc.A brief idea about ENHANCEMENT OF BIOAVAIBILITY on the bases of BCS. : A brief idea about ENHANCEMENT OF BIOAVAIBILITY on the bases of BCS. CLASS 1 : This drugs do not require such treatment in general. But still several methods can be used depending upon the drug to be formulated. CLASS 2 : This types of drugs are poorly soluble so methods like precipitation , solvent disposition or use of different forms like Amorphs , Anhydrates , Solvates & Metastable polymorphs or by using Salt forms. All these things are useful for this drugs. CLASS 3 : This drugs are poorly permeable so we can use surfactants & techniques like micronisation , nanonisation which reduce particle size or they can be formulated as targeted or PH specified delivery system since these drugs mainly absorbed from several specific sites. CLASS 4 : This drugs are poorly soluble & poorly permeable so they should be formulated in several targeted delivery formulation in which they can skip the absorption profiles like solubility & permeability.: 2) DISSOLUTION RATE & DRUG DISSOLUTION : Dissolution is a process in which a solid substance solubilises in a given solvent ie… mass transfer from the solid surface to the liquid phase. $ How it occurs ? Several different theories are proposed for these as. @ Diffusion layer model / film theory It gives possibilities of formation of a diffusion layer at the solid liquid interface in the solution & after it the solutes comes out or diffuse from the diffusion layer. $ noyes & whitney gave a chemical equation for this dc /dt = k ( Cs - Cb ) dc /dt = dissolution rate of drug k = dissolution rate constant Cs = concentration of drug in the stagnant layer Cb = concentration of drug in the bulk at time t@: @ THE above equation is based on fick’s second law of diffusion. @*Nernest & burner incorporated fick’s law of diffusion& modified the previous equation to dc/ dt = DAK w/o ( Cs - Cb) v h where , D = diffusion coefficient A = surface area K w/o= intrinsic dissolution rate constant v = volume of dissolution media h = thickness ( Cs - Cb )= concentration gradient for diffusion of drug@ SINK CONDITION :: @ SINK CONDITION : *In in-vitro the driving force is concentration gradient & the condition is called ‘ non – sink conditions ‘. *But in in-vivo the dissolution is always rapid than in-vitro. because in body as the drug dissolves it is rapidly taken up in to systemic circulation So, in case of in vivo studies the Cb in the equation will always be ZERO ( Cb = 0 ) Some concentration gradient always maintained & Cs is>> Cb. So sink condition are always be maintained so equation reduce to dc/dt= K here k = all constants in previous eq. So in case of dissolution rate studies to achieve a good correlation b/w in vitro – in vivo the in vitro studies should always be done under “ sink conditions“. In general in the in-vitro studies sink conditions are always maintained that cb is always less than 10 % of Cs.@ : @ fast dissolution after concentration 1 st order ( non sink) slow dissolution I N – VITRO time GI lumen Blood Blood stream concentration 0 order (sink) IN-VIVO Blood stream cb = 0 time2) Particle size & Surface area : : 2) Particle size & Surface area : These both factors are inversely proportional to each other , smaller the particle greater the surface area. A drug dissolves rapidly when it has larger surface area of particles this achieved by reducing particle size. Two types of surface area are important.. 1 ) Absolute surface area which is the total area of solid surface of any particle. 2 ) Effective surface area which is the area of solid surface exposed to the dissolution medium. For use in absorption studies the effective surface area is of much important than absolute.@: @ To increase the effective surface area up to a very powerful extent we have to reduce the size of particles up to 0.1 micron. So these can be achieved by ‘’ micronisation process’’. MICRONISATION DECREASE PARTICLES SIZE UP TO O. 1 MICRON INTRINSIC SOLUBILITY DISSOLUTION INCREASE RATE INCREASED But in these case one most important thing to be keep in mind that which type of drug is micronised if it is : 1) HYDROPHILLIC OR 2) HYDROPHOBIC@: @ 1 ) HYDROPHILLIC DRUGS: in hydrophilic drugs the small particles have higher energy than the bulk of the solid resulting in an increased interaction with the solvent. Griesiofulvin – Dose reduced to half due to micronisation. Spironolactone – the dose was decreased to 20 times. Digoxin – the bioavailability was found to be 100% in micronized tablets. 2) HYDROPHOBIC DRUGS: in this it is seen that this micronisation techniques results in decreased effective surface area & thus fall in dissolution rate. REASON FOR THESE: 1) The hydrophobic surface of the drugs adsorbs air on to their surface which inhibits their wettability. 2) The particles reaggregates to form large particles due to their high surface free energy , which either float on the surface or settle on the bottom of the dissolution medium. 3) Electrically induced agglomeration owing to surface charges prevents intimate contact of the drug with the dissolution medium. For such hydrophobic drugs can be converted to their effective surface area.3) POLYMORPHISM: : 3) POLYMORPHISM: Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs, and the phenomenon as polymorphism. The polymorphs differ from each other with respect to their physical properties such as solubility, melting point, density, hardness and compression characteristics. Thus, these change in physical properties affect the dissolution properties and hence the absorption. Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. They also exhibit different melting points , solubilities (which affect the dissolution rate of drug and consequently its bioavailability in the body is also affected), X-ray crystal and diffraction patterns.@: @ Various conditions in the crystallisation process is the main reason responsible for the development of different polymorphic forms. These conditions include: 1) solvent effects (the packing of crystal may be different in polar and nonpolar solvents) 2) certain impurities inhibiting growth pattern and favour the growth of a metastable polymorphs 3 ) the level of supersaturation from which material is crystallised (in which generally the higher the concentration above the solubility the more likelihood of metastable formation) 4) temperature at which crystallisation is carried out 5) geometry of covalent bonds (differences leading to conformational polymorphism) 6) change in stirring conditions@: @ Plot of Cp Vs Time for three formulations of Chloramphenicol palmitate Chloramphenicol palmitate is one example which exists in at least two polymorphs. The B form is apparently more bioavailable. The recommendation might be that manufacturers should use polymorph B for maximum solubility and absorption.@: @ 4) PSEUDO-POLYMORPHISM When the solvent molecules are entrapped in the crystalline structure of the polymorph, it is known as pseudo-polymorphism. Hydrates/Solvates are pseudo-polymorphs where hydrates are less soluble and solvates are more soluble and thus affect the absorption accordingly. For example: n- pentanol solvates of fudrocortisone and succinyl -sulfathiazole have greater aqueous solubility than the non-solvates.@: @ AMORPHISM: Some drugs can exist in amorphous form (i.e. having no internal crystal structure). Such drug represents the highest energy state and can be considered as super-cooled liquids. They have greater aqueous solubility than the crystalline forms because a energy required to transfer a molecule from the crystal lattice is greater than that required for non-crystalline (amorphous form). For example: the amorphous form of Novobiocin is 10 times more soluble than the crystalline form. Thus, the order of different solid dosage forms of the drugs is Amorphous > Meta-stable > stable 5) SALT FORM OF THE DRUG:: 5) SALT FORM OF THE DRUG: At given pH, the solubility of drug, whether acidic/basic or its salt form, is a constant. While considering the salt form of drug, pH of the diffusion layer is important not the pH of the bulk of the solution. Example of salt of weak acid. - It increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid. Dissolution and absorption of an acidic drug administered in a salt form.@: @ One more important thing to be note is that the dissolution rate of a particular salt is usually different from that of parent compound. Sodium or potassium salts of weak acids dissolves more rapidly then the free acids , regardless of the ph of dissolution medium. In market also several drugs are formulated according to their dissolution rate profile like… Barbiturates are often available in the form of sodium salt to achieve a rapid onset of sedation. NSAIDS - well marketed as the free acids for the treatment of rheumatoid & osteoarthritis. New indications are in treatment of mild to moderate pain including dysmenorrhoea , prompted development of Naproxen sodium6) & 7) pH-PARTITION HYPOTHESIS: : 6) & 7) pH-PARTITION HYPOTHESIS: The theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the bio-membrane by passive diffusion, the process of absorption is governed by: 1. The dissociation constant pKa of the drug. 2. The lipid solubility of the un-ionized drug. 3. The pH at the absorption site. A) Drug pKa and GI pH Amount of drug that exists in un-ionized form and in ionized form is a function of pKa of drug and pH of the fluid at the absorption site, and it can be determined by Handerson-Hasselbach equation: For weak acids , pH = pKa + log [ionized] [un-ionized] …………………..(1.1) % Drug ionized = 10 pH-pKa x 100 ……………..…… (1.2) 1+10 pH-pKa For weak bases , pH = pKa + log [un-ionized] [ionized] …….(1.3) % Drug ionized = 10 pKa-pH x 100 ……(1.4) 1+10 pKa-pH@: @ If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by the following equations: For weak acids, R a = C GIT = 1+10 pHGIT-pKa C plasma 1+10 pHplasma-pKa ………. (1.5) For weak bases, R b = C GIT = 1+10 pKa-pHGIT C plasma 1+10 pKa-pHplasma ………. (1.6) B) Lipophilicity and Drug absorption : The lipid solubility of the drug is determined form its oil/water partition co-efficient (Ko/w) value, whereby the increase in this value indicates the increase in percentage drug absorbed. Ko/w = Distribution of the drug in the organic phase ( octanol ) Distribution of the drug in the aqueous phase …………. (1.7)C) Limitations pH partition hypothesis: : C) Limitations pH partition hypothesis: a) Presence of Virtual Membrane pH: There is a presence of virtual membrane pH or the micro-climate pH, different from the luminal pH which exists at the membrane surface. b) Absorption of the ionized drug: Despite of the assumption that only un-ionized and lipophilic drugs are absorbed to a greater extent, some drugs e.g. Morphinan derivatives which are much more ionized are absorbed passively owing to their very high lipophilicity. c) Influence of the GI surface area and residence time of the drug: Irrespective of the GI pH and degree of ionization, both acidic and basic drugs are more rapidly absorbed from the intestine, primarily because of its large surface area and secondly, because of the long residence time of the drug in the intestine. d) Presence of Aqueous Unstirred Diffusion Layer: The drugs having a large partition co-efficient can readily penetrate the lipid membrane but the diffusion through the unstirred water layer is the rate limiting step in their absorption. This applies in particular to high molecular weight fatty acids and bile acids.8)drug stability : 8)drug stability A drug for oral use may destabilized either during its shelf life or in the GIT . Two major stability problems resulting in poor bioavailability of an orally administered drug are -degradation of the drug into inactive form, and interaction with one or more different component(s) either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is unabsorbable.B] PHARMACEUTICAL FACTORS : B] PHARMACEUTICAL FACTORS 1) DISINTEGRATION TIME Rapid disintegration is important to have a rapid absorption so lower disintegration time is required. Disintegration time of tablet is directly proportional to –amount of binder and compression force. It is important to note that in vitro disintegration test gives no means of a guarantee of drugs B.A. because if the disintegrated drug particles do not dissolve then absorption is not possible. 2) Dissolution time:: 2) Dissolution time: Dissolution is a process in which a solid substance solubilises in a given solvent ie … mass transfer from the solid surface to the liquid phase. Dissolution time is also an important factor which affect the drug absorption .3) MANUFACTURING VARIABLES:: 3) MANUFACTURING VARIABLES: Several manufacturing processes influence drug dissolution from solid dosage forms. For example: For tablet it is Method of granulation Compression force Method of granulation: Different methods like wet granulation , dry granulation and direct comprssion etc. yields product with different dissolution,@: @ B ) Compression force Fig Influence of compression force on the dissolution rate of tablets The compression force employed in tableting process influence density, porosity, hardness, disintegration time and dissolution rate of tablets.4) PHARMACEUTICAL INGREDIENTS/EXCIPIENTS:: 4) PHARMACEUTICAL INGREDIENTS/EXCIPIENTS: More the number of Excipients in the dosage form, more complex it is & greater the potential for absorption and Bioavailability problems. A) Vehicle Rate of absorption – depends on its miscibility with biological fluid. Miscible vehicles (aqueous or water miscible vehicle) causes rapid absorption e.g. propylene glycol. Immiscible vehicles – Absorption depends on its partitioning from oil phase to aqueous body fluid. B) Diluents Hydrophilic diluents – Imparts Absorption Hydrophobic diluents – Retards Absorption Also, there is a drug- diluent interaction, forming insoluble complex and retards the absorption. E.g. Tetracycline-DCP@: @ C) Binders & granulating agent - Hydrophilic binders – Imparts hydrophilic properties to the granule surface – gives better dissolution properties of the poorly wettable drugs. E.g. Starch, Gelatin. PVP. But more amount of binder increases the hardness of the tablet and retards the absorption rate. D) Disintegrants Mostly hydrophilic in nature. Decrease in amount of disintegrants – significantly lowers B.A. E) Suspending agents/viscosity agent Stabilized the solid drug particles and thus affect drug absorption. Macromolecular gum forms un-absorbable complex with drug e.g. Na CMC. Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage form and retard GI transit of drug.@: @ G) Surfactants May enhance or retards drug absorption by interacting with drug or membrane or both. Physiologic surfactants – bile salts – promotes absorption – e.g. Griseofulvin , steroids It may decrease absorption when it forms the un-absorbable complex with drug above CMC. H) Coating In general, deleterious effects of various coatings on the drug dissolution from a tablet dosage form are in the following order. Enteric coat > sugar coat > non-enteric coat. The dissolution profile of certain coating materials change on aging; e.g. shellac coated tablets, on prolonged storage, dissolve more slowly in the intestine. This can be however, be prevented by incorporating little PVP in the coating formulation.@@: @@ F) Lubricants Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus dissolution and disintegration. I) Buffers Buffers are sometimes useful in creating the right atmosphere for drug dissolution as was observed for buffered aspirin tablets. However, certain buffer systems containing potassium cations inhibit the drug absorption as seen with Vitamin B 2 and sulfanilamide. J) Colourants Even a low concentration of water soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs. The dye molecules get absorbed onto the crystal faces and inhibit the drug dissolution. For example: Brilliant blue retards dissolution of sulfathiazole.5) NATURE AND TYPE OF DOSAGE FORM : 5) NATURE AND TYPE OF DOSAGE FORM Apart from the proper selection of the drug, clinical success often depends to a great extent on the proper selection of the dosage form of that drug. For a given drug, a 2 to 5 fold or perhaps more difference could be observed in the oral bio-availability of a drug depending upon the nature and type of dosage form. As a general rule, the bio-availability of a drug form various dosage forms decrease in the following order: Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric Coated Tablets > Sustained Release Products.Fig : Bio-availability risk and absorption of various dosage forms. : Fig : Bio-availability risk and absorption of various dosage forms. @6) PRODUCT AGE AND STORAGE CONDITIONS: : 6) PRODUCT AGE AND STORAGE CONDITIONS: Product aging and storage conditions can adversely affect the bio-availability by change in especially the physico -chemical properties of the dosage forms. For example: Precipitation of the drug in solution Hardening of tablet Change in particle size of suspension.C] PHISICALITY FACTORS: : C] PHISICALITY FACTORS: 1) AGE In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults. In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial over growth in small intestine. 2) Gastric emptying and motility: : 2) Gastric emptying and motility: Several parameters are used to quantify gastric emptying such as: Gastric emptying rate: which is the speed at which the stomach contents empty into the intestine. Gastric emptying time: which is the the time required for the gastric contents to the SMALL INTESTINE. Gastric emptying half-life: which is the time taken for half the stomach contents to empty.@: @ Fig Dependence of peak Acetaminophen plasma concentration as a function of stomach emptying half-life.3) Intestinal transit:: 3) Intestinal transit: Since, intestinal transit time is the major site of absorption of most of drugs, long intestinal transit time is desirable for complete absorption of drugs. Transit time for contents from different regions of intestine Intestinal region Transit time Duodenum 5 minutes Jejunum 2 hours Ileum 3 to 6 hours Caecum 0.5 to 1 hour Colon 6 to 12 hours@: @ It is influenced by various factors such as food, diseases and drugs e.g. metoclopramide which promotes intestinal transit, enhance absorption of rapidly soluble drugs while anticholinergic retards intestinal transit and promotes the absorption of poorly soluble drugs.4) Gastrointestinal PH:: 4) Gastrointestinal PH: GI fluid pH affecet in several ways: Disintegration: The Disintegration of some drugs is pH sensitive with enteric coating the coat dissolves in only the intestine at specific PH. Dissolution : A large no of drugs whose solubility is greatly affected by pH are either weak acids or weak bases. Weakly acidic drugs dissolves rapidly in alkaline pH of the intestine whereas basic drugs dissolve in the acidic pH of the stomach.@: @ Stability :GI pH also affect the chemical stability of drugs . EX> the acidic stomach pH gives a degradation of penicillin G and erythromycin.So such drugs to be formulated by preoaring prodrugs Ex. Carindacillin and erythromycin estolate or in any other way . Dependin upon the pKa and wether it is an acidic or basic drug the amount of drug that would exist in the unionized form at site of absorption. This was covered in pH partition hypothesis.5) DISEASES:: 5) DISEASES: A) Gastric diseases: The influence of achlorhydria (decreased gastric acid secretion and increases stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs (decreased absorption e.g. aspirin) has been studied. B) Intestinal diseases: Two of the intestinal disorders related with malabsorption syndrome that influence drug availability are Celiac disease and Chron’s disease . C) Cardio-vascular diseases: Several changes associated with congestive cardiac failure influence bio-availability of a drug viz., edema of the intestine, decreased blood flow to the GIT and gastric emptying rate and altered GI pH, secretions and microbial flora. D) Hepatic diseases: Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that undergo considerable first-pass hepatic metabolism e.g. propranolol6) Blood flow through GIT: : 6) Blood flow through GIT: The GIT is extensively supplied by blood capillary network and blood flow rate to GIT (splanchnic circulation) is 28% of the cardiac output. Therefore, it helps in maintaining sink conditions and concentration gradient for drug absorption by rapidly removing drug from the site of action. Table : Influence of blood flow effect on various types of drugs DRUGS BLOOD FLOW EFFECT A) For highly lipid soluble drugs More B) For many lipophilic drugs such as ethanol, glycerol, etc. Intermediate C) Polar compounds such as ribitol Less@: @ 7) Gastro intestinal contents: 1) food- drug interactions : presence of food will affect absorption in following way a) delay absorption _ ex. Aspirin , paracetamol , diclofenac , nitrofurantoin , digoxin etc. b) decreased absorption : ex. Penicillin, erythromycin, ethanol, tetracycline, levodopa etc. c)increased absorption : grieseofulvin, diazepam, vitamins etc. in some cases it do not affect ex. methyldopa, propylthiouracil etc. 2) fluid volume : administration of a drug with large fluid volume results in better dissolution , rapid gastric emptying and enhanced absorption- for ex.. erythromycin is better absorbed when taken with a glass of water under fasting condition than when taken with meals.@: @ 3) Interaction of drug with normal GI constituents : the GIT contains a number of normal constituents such as mucin –which is a protective mucopolysaccharides that lines the GI mucosa , interact with streptomycin. Bile salts- which affect the absorption of lipid soluble drugs like grieseofulvin and vitamins. 4) drug-drug interactions : they can either be physiological or physiochemical…@: @ 8) Pre-systemic metabolism For a drug administered orally, the 2 main reasons for its decreased bio-availability are: 1. Decreased absorption 2. First-pass/pre-systemic metabolism The four primary systems which affect the pre-systemic metabolism of a drug (Fig ) Lumenal Enzymes Gut wall enzymes/mucosal enzymes Bacterial enzymes Hepatic enzymes.@: @ Fig Different sites of pre-systemic metabolism@: @ Thank you all for your Tolerance