Absorption of Drugs

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ABSORPTION OF DRUGS : 

ABSORPTION OF DRUGS BY Gargeyi.P Hareesha.CH

TOPICS : 

TOPICS Definition Structure Of Cell Membrane Gastro Intestinal Absorption. Factors Affecting Drug Absorption Biological Physiological Physico-chemical Pharmaceutical Dosage Form Methods Determining Absorption. Absorption Of Drugs From Non Oral Route.

DEFINITION : 

DEFINITION It is defined as the process of movement of unchanged drug from the site of administration to the systemic circulation.

STRUCTURE OF CELL MEMBRANE : 

STRUCTURE OF CELL MEMBRANE It consists of double layer of amphiphillic phospholipids molecules arranged in such a fashion that their hydro carbon chains are oriented inwards to form the hydrophobic & polar heads oriented outwards to form hydrophilic boundaries

Slide 5: 

Gastro intestinal barrier( lipoidal sieve) that separates lumen of the stomach and intestine is a semi permeable membrane, permitting the rapid and limited passage of some compounds. Gastro intestinal absorption is more for some nutrients glucose, amino acids, fatty acids &vitamins etc. lipid molecules and some hydrophilic molecules are readily absorbed from git in passive manner where as large polar molecules absorbed by active manner.

Mechanism of gastro intestinal absorption. : 

Mechanism of gastro intestinal absorption. Passive diffusion Carrier mediated absorption Active Facilitated Endocytosis

Passive Diffusion : 

Passive Diffusion Membrane transport of drug and other chemicals directly through the lipid or aqueous channel is called passive diffusion Driving force is concentration or electro chemical gradient. It fallows FICKS FIRST LAW of diffusion. It states drug molecule diffuses from a region of higher conc. to the lower conc. until equilibrium is attained. dc/dt = k(C1-C2). Dc/dt : rate of diffusion C1C2 = drug concentrations on each side of the membrane. K= proportionality constant. Most of the drugs follows first order kinetics.

Carrier Mediated Transport : 

Carrier Mediated Transport It is specialized transport mech with out which many essential water soluble nutrients like mono saccharides &vit will be poorly absorbed. The compound involved is called CARRIER. The carrier binds non covalently or reversibly with solute molecule to be transported. The carrier solute molecule complex travel across the membrane to other side where it dissociates and discharges the solute molecule and travels back. It follows mixed order kinetics.

Facilitated diffusion : 

Facilitated diffusion This carrier mediated transport system that operates down the concentration gradient (down hill transport). It is faster than passive diffusion. Driving force is conc. gradient. Ex: vitamins.

Active Absorption : 

Active Absorption It requires energy in the form of A.T.P. Takes place in the intestine This is a UP HILL TRANSPORT. Ex: Na,Ca,Fe, glucose, galactose, AA, Bile salts. Rate of absorption = VmaxC/Km+C. C=solute conc. at the absorption site. Vmax and Km are const.

Slide 11: 

Passive process Carrier mediated transport Rate of absorption Drug conc. At absorption site

BIOLOGICAL FACTORS : 

BIOLOGICAL FACTORS Gastro intestinal physiology. Gastro intestinal blood flow. Gastro intestinal PH. Gastric emptying. Effect of food on drug absorption. Mal absorption.

Gastro Intestinal Physiology : 

Gastro Intestinal Physiology STOMACH It is a pouch like structure lined by smooth epithelial membrane. Absorption of weekly acidic drugs or un ionized drugs and week basic drugs takes place.

Small intestine : 

Small intestine generally carrier mediated transport is seen in most drugs. Proximal part-absorption of dietary constituents includes mono saccharides, AA, vits, minerals etc. Ileum-Vit B12, bile salts.

Micro villi : 

Micro villi The effective surface area can be made 10 times larger to that of stomach because of the presence of micro villi. These are finger like projections arising from and forming folds in intestinal mucosa. ESA was decreasing from proximal part to distill part of small intestine.

Large intestine : 

Large intestine ESA was less. It is not an effective site In complete absorption was occurred when large amount of drug reaches colon Its an area of absorption of escaped drug It was recommended for certain drugs whose metabolism occurred by intestinal bacteria for bio activation.

BLOOD FLOW : 

BLOOD FLOW It plays a major role in absorption by continuously maintaing the concentration gradient across the epithelial membrane. Absorption of polar molecules doesn’t depends on the blood flow. rate of drug absorption is un effected by mesenteric blood flow. Absorption of lipid soluble molecules highly depends on the blood flow. Enter blood liver systemic circulation

Gastro intestinal PH : 

Gastro intestinal PH PH varies according to the site. Many drugs are week organic acids or bases so PH is the imp factor. Gastric fluid retards week basic drugs. and promotes weekly acidic drugs. Gastric secretions having PH less than 1. It varies because of diet and dilution. Some drugs (penicillin) under goes degradation because of PH, this can be rectified by pro drug preparation. ex: penicillin-------------carindacillin erythromycin--------erythromycinesfolate

Gastric emptying : 

Gastric emptying The passage of food from the stomach to the small intestine is called gastric emptying. This process increases the bioavailability of the drug because mostly the absorption occurs in small intestine. Slow gastric emptying can delay the onset of effect of the drug Ex: Analgesics& sedatives

GASTRIC EMPTYING IS RECOMENDED : 

GASTRIC EMPTYING IS RECOMENDED WHEN Rapid onset of action is desirable. ex: sedatives Dissolution of drug occur in the intestine. ex: enteric coated dosage forms. Which are not suits to gastric fluids. ex:pencillin and erythromycin. Drug is best absorbed from the distal part of the small intestine. ex: Vit B12

Delayed gastric emptying is recommended : 

Delayed gastric emptying is recommended WHEN Food promotes drug dissolution and absorption. ex: gresiofulvin Drugs irritate gastric mucosa. ex: aspirin, phenyl butazone. Drugs are absorbed from the proximal part of the SI & prolonged drug absorption site is desired. Ex:VitB12&C

FACTORS EFFECTING GASTRIC EMPTYING : 

FACTORS EFFECTING GASTRIC EMPTYING Volume of meal. Drugs Posture Composition of meal. Physical state. Temperature. PH. Disease state.

Effect of food on drug absorption : 

Effect of food on drug absorption Food has an unpredictable effect which is irreversible. Food stimulate hepatic blood flow, which have implication for the bioavailability of the drug. Food tends to decrease the rate of gastric emptying which effects drugs like penicillin Forms poorly soluble and un absorbable complexes. High protein food causes poor absorption of drugs. ex: levodopa. High fat food causes poor absorption of drugs. ex:isotertinonin. Administration of drug with large fluid volume enhances the dissolution rate and gastric emptying.

Mal absorption : 

Mal absorption It is a disorder with impaired absorption of fat, protein, carbohydrate, vitamin, minerals& water. Drugs which induce mal absorption Neomycin. Phenytoin. Amino salicylate These drugs mainly damages the gastro intestinal epithelium emphasis the function of mucosa to serve as a barrier to large polar molecule.

Physico -chemical factors : 

Physico -chemical factors Absorption of drug from solution Drug pka and gastro intestinal PH Lipid solubility Absorption of drug from solid dosage form and suspension Dissolution and PH Diffusion layer PH. Salts Soluble pro drug Surface area and particle size Crystal form Drug stability and hydrolysis in the gastro intestinal tract Complexation Adsorption

Absorption of drug from solution : 

Absorption of drug from solution Acidic and neutral drugs are easily absorbed from the stomach. The rate of absorption is related to oil in water partition co-efficient. More the lipophilicity faster is the absorption.

Drug pka and gastro intestinal PH : 

Drug pka and gastro intestinal PH Pka is a dissociation constant. In a solution some amount of the drug remains un ionized , it is a function of dissociation const and PH of the soln. The relation ship b/w PH , pka and the extent of ionization is given by HANDERSON-HESSELBACH equation. For weak acids PH =pka+log( ionized drug/un ionized drug) For weak bases PH =pka+log(un ionized drug/ ionized drug) Acidic drugs are un ionized at lower PH ,and absorption occurs from stomach and intestine.

Lipid solubility : 

Lipid solubility Because of low lipid solubility certain drugs may get poorly absorbed. To know about lipophilic nature mainly the partition co-efficient between fat like solvent and aqueous buffer to be considered. Ex: gentamycin , heparin. For more lipid solubility :- change in the structure of existing drug. pro drug formation. The pro drug formation improves permeability and oral absorption.

Absorption of drug from solid dosage form and suspension. : 

Absorption of drug from solid dosage form and suspension. Mainly depends on how fast they dissolve in fluid at absorption site. Solid drug drug in solution at absorption site drug in systemic circulation. Depends on mainly rate of dissolution rate of drug permeation through biomembrane DISSOLUTION ABSORPTION

Slide 31: 

Rate of dissolution can be given by NOYES&WHITNEY equation. dc/dt = ks (Cs-C) dc/dt= dissolution rate. k= constant s= surface area. Cs =solubility of drug in solvent Dissolution & pH: For weak acids dissolution rate increases with increasing pH. For weak bases it decreases with increasing pH.

Diffusion layer and pH : 

Diffusion layer and pH The hydrogen ion concentration of the bulk is [H+] , is not equal to hydrogen concentration of the diffusion layer [H+] d . [H+] d >[H+] for weak acids. [H+] d <[H+] for weak bases. These equations tend to over predict the dissolution rate of weak acids in small intestine & dissolution rate of weak bases in the stomach.

SALTS : 

SALTS The dissolution rate of the particular salt is usually different from that of the parent compound. Na+ ,k+ of weak acids dissolve faster than the free acids. The effect of salt formation on diffusion rate cannot be explained in terms of solubility and bulk pH but requires a consideration of the pH of diffusion layer. Increasing pH of the diffusion layer, the solubility & dissolution rate of weak acid in this layer is increased. The main principal in the salt formation has been utilized to enhance the dissolution & absorption rate of certain drugs. Ex: Aspirin &penicillin.

Soluble pro drug : 

Soluble pro drug Improve lipid solubility. Increases the permeability &absorption after oral administration. Alternative to drugs which shows in complete absorption. Mainly use of pro drug is to improve the gastro intestinal absorption of water insoluble compounds.

Surface area & particle size : 

Surface area & particle size Reduction in the particle size results in rapid& complete absorption. The greater effective surface area of the drug will have the more intimate contact between the solid surface & aqueous solvent. Some times micronisation may leads to aggregation. which decreases the effective surface area can be over come by use of wetting agents.

CRYSTALS : 

CRYSTALS Many drugs exists in more than one crystal form this property is called polymorphism. At certain temp & pressure only one crystal form will be stable. The energy required by crystalline form to transfer the drug to a solvated state is more than the amorphous form.

STABILITY : 

STABILITY The drug given orally may de stabilize during its shelf life or in GIT so that poor bioavailability or degradation of drug into in active form. Ex: hydrolysis of penicillin-G in the stomach. COMPLEXATION It may alters the rate in GI fluids. The complexing agent may be the substance normal to GIT or dietary components or component of dosage form. This binding causes poor absorption. Ex: tetracycline with milk

Adsorption : 

Adsorption Certain in soluble substances adsorb with co administered drugs. Charcoal has been used for various gastro intestinal disorder &effective antidote in drug intoxication.

Role of dosage form in drug absorption : 

Role of dosage form in drug absorption Different dosage forms:- solutions suspensions tablets capsules Coated tab& enteric coated tab Disintegration test Dissolution test Excipients and adjuvant Product age and storage conditions.

Dosage forms : 

Dosage forms Order of bioavailability of drugs. Solutions>suspensions>capsules>tablets>coated tablets SOLUTIONS Drugs absorbed more rapidly in this form. When this formulation is taken after meal gastric emptying is the rate limiting step. Factors influencing are Nature of the solvent viscosity, surfactant, solubilisers, stabilizers. Drugs which are poorly soluble can be converted to water soluble by the addition of co solvents such as alcohol, propylene glycol etc…

Suspensions : 

Suspensions Dissolution is the rate limiting step for the absorption the drug from suspension. Factors to considered are particle size , inclusion of wettings , formation of insoluble complex, crystal form & viscosity.

Capsules : 

Capsules For hard gelatin capsules the shell should disrupt quickly and expose the contents to the GI fluids. Factors influencing are particle size, density, crystal form of the drug, selection of diluents. For hydrophobic drugs with a fine particle size in capsule results in decrease in porosity of the powdered drug and thus decreased penetrability by the solvent which results clumping of particle. soft elastic capsule dissolve faster than hard gelatin capsule & tablets. Which shows better bioavailability from oily solutions, emulsions, or suspensions. The problem with SGC is high water content of shell, moisture migrate in to the shell causes crystallization of the drug results in altered dissolution characteristics .

Tablets : 

Tablets This is the most widely used dosage form. Problem with this arises from reduction in the ESA due to granulation& subsequent compression in to dosage form. Tab disintegration and granule disintegration are the imp steps in absorption process. Compression force also may be an important factor. Disintegration is the rate limiting step for this.

Coated tablets : 

Coated tablets Coat is generally used to mask unpleasant taste & odor & to protect the ingredients from decomposition during storage. This adds an additional barrier between GIT & drug. It should get dissolve before tablet disintegration & dissolution. Sugar & film coatings Sugar coating will take more time than film coating. Care should be taken while selecting the coating material Ex: methyl cellulose which retards the dissolution Now a days film and press coated are mostly used.

Enteric coated tablets : 

Enteric coated tablets It is a special film coated design to restricts the gastric fluids & to dissolve in small intestine. Protect the drug from the degradation in the stomach Ex: erythromycin. Minimize the gastric distress caused by some drugs. Ex: aspirin. These tablets must empty the stomach before the drug absorption can begin. The polymers with pka values ranging from 4-7 have been found to use. Thickness of coating will effects the bioavailability in these formulations.

In vitro correlation of drug absorption : 

In vitro correlation of drug absorption DISINTEGRATION TESTS it is provided to determine the compliance with the limit on disintegration stated in the individual monograph. Exception is soft gelatin capsule. Formulation tested are un coated tab, plain coated, enteric coated, buccal, sub lingual, hard gelatin capsule For un coated tab and capsules the time is 30 mins. where as for coated tab it is 2 hrs.

Slide 47: 

DISSOLUTION TESTS The development of this test predicts the drug absorption. It shows close relation b/w drug absorption and dissolution rather than disintegration. By using USP apparatus type1- basket method type2- paddle method Basket method- the basket containing tab and capsules are immersed in the dissolution fluid and rotated . Paddle method-the dosage form is placed directly in the dissolution medium and paddle is rotated. Fluids may be water , HCL, buffer maintained at 370c. The samples are removed at desired interval and assayed for drug content.

Non oral route of administration : 

Non oral route of administration Intravenous injection Given to the peripheral vein, used to treat the epileptic seizures, low B.P, life threatening Should be given longer period . In soluble drug materials should not be given. Causes embolism. Ppt in the vein is called- thrombophlebitis. This inj can cause local pain, un desirable cardio-vascular & central effects. Ex: lidocaine, theophylline & antibiotics. This method is used for the drugs having short life &narrow therapeutic index.

Intra-arterial administration : 

Intra-arterial administration Its mainly used in the cancer chemo therapy. The drug is given directly to the arteries. The adv of this are achievement of higher drug conc. In the liver with lower systemic levels should increase local anti tumor effect and decrease systemic toxic effects Improves the therapeutic effect of the treatment.

Spinal administration : 

Spinal administration Many drugs does not crosses the BBB. The systemic administration results in low and in effective drug conc. In cerebrospinal fluid. Life threatening drugs :-antibiotics, anti fungal, anti neo plastics. Lumbar puncture or inj to sub arachnoid's space- morphine- intrathecal –spinal anesthesia.

Intra peritoneal administration : 

Intra peritoneal administration The main example for this is anti neo plastic drug therapy. The rate of removal of a drug from the abdominal cavity will greatly influence the difference in exposure between the cavity and systemic circulation. Large water soluble and ionized molecules will exit more slowly than smaller lipid soluble molecules& demonstrate larger differentials in conc. For hydrophilic drugs the drug concentration in the peritoneal cavity falls with time, while the plasma concentration increases transiently, reaches a peak & then begins to fall more or less in parallel with peritoneal conc. Major exit for drugs from peritoneal is by way of portal circulation.

Intra muscular injection : 

Intra muscular injection Arms – deltoid Thigh – vastuslaterals Buttocks – gluteus maxims. degree of absorption will be Arms> Thigh> Buttocks. These r given to the patients those who are unable to take oral medication. These route is used for the drugs that are poorly absorbed from the GIT. Advantages:-less hazardous, & easier to administrate equal bioavailability as that of IV. More pain full. Some drugs after the drug administration IM is probably result in ppt at injection site. Ex:-digoxin

Subcutaneous injection. : 

Subcutaneous injection. Factors influence are blood supply to this region is poorer than to muscle tissue such that drug absorption is slower. Application of heat increase the blood flow. Local co administration of vasodilators. Inclusion of the enzyme hyluranidase in the drug solution. Absorption of the drug can be slowed by adding vasoconstrictor. Ex: epinephrine Insulin, local anesthesia.

Inhalations : 

Inhalations The lungs are remarkably efficient organ for the transport of gases. The larger surface area of alveoli causes the rich blood supply-exchange takes place. Drug do not under go first pass metabolism. Many drugs absorbed by passive diffusion across the lipid pore membrane. Absorption of lipid soluble drugs was more rapid. Devices generally used are nebulizer. Ex: gaseous or volatile anesthesia.

Topical applications to Eye : 

Topical applications to Eye Mainly for the treatment of local effects such as mydriasis, meiosis, anesthesia and glaucoma. The barrier in the occular membrane is called cornea which contains both hydrophilic and lipophilic characters. Thus for optimum intra occular permeation drug should posses biphasic solubility. The main dis adv is immediate loss that occurs by drainage. So large amount of drug should be administered. The addition of viscosity increasing agents in the ophthalmic solution will increases occular bio availability. Ex: pilocarpine, timmolol, atropine.

Intravaginal applications : 

Intravaginal applications Available in various forms tablets, creams, ointments, douches and suppositories. Used for systemic delivery of contraceptive and other steroids. By passes first pass metabolism. Factors effecting are -pH of the lumen fluid 4-5. -vaginal secretions. -microbes at vaginal lumen. Bio availability of vaginal product was about 20% more compared with oral. Ex: disoprostil vaginal suppository .

Intra Nasal application : 

Intra Nasal application Used for the systemic administration of drugs. Mainly contain decongestants, anti histamines, corticosteroids. Nasal mucosa are more permeable than gastric mucosa. Drugs directly traveled through blood stream no first pass metabolism. Peptides are not actively absorbed from nasal mucosa but can be promoted by surface active agents. Ex: desmopressin acetate