Factor affecting Drug absorption

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Factors Effecting Drug Absorption : 

Factors Effecting Drug Absorption Physiological factors Pharmaceutical and Absorption of drug from Non-per oral route. HARISH I M.PHARM PHARMACEUTICS 28-Jul-10 1

Physiology of GIT : 

Physiology of GIT GIT comprises of no. of components, Stomach Small Intestine Large Intestine The primary functions of GIT are Secretion Digestion Absorption. 28-Jul-10 2

Physiological factors : 

Physiological factors 1.Age 2.Gastric Empting 3.Intestinal Transit 4.GI pH 5.Blood Flow to GIT 6.Diseased State 7.GI Content 8.First pass effect 28-Jul-10 3

1. Age : 

1. Age In infants GI pH is high and intestinal surface and blood flow to GIT is low as compared to adults results in poor drug absorption. In elderly people, alteration in drug absorption becuase of alteration in gastric emptying, and incidents of achlorhydria and bacterial over growth in small intestine. 28-Jul-10 4

2. Gastric emptying : 

2. Gastric emptying Defined, as passage of contents of stomach into the intestine. Rapid gastric emptying is advisable where: Rapid onset action is required, eg; sedatives. Dissolution of drug occurs in intestine. eg; Enteric coated tablets. Drug is unstable in gastric fluids. Drug is best absorbed from distal part of small intestine, eg vitamin B 12 . 28-Jul-10 5

Kinetics of GI emptying : 

Kinetics of GI emptying GI emptying is first-order kinetics many parameters are used to quantify a gastric emptying; 1.Gastric emptying rate: Is the speed at which the stomach contents are emptied into the intestine. 2.Gastric emptying time: Time required for the GI content to empty into small intestine. 3.G.E.t1/2: Is time taken for half the stomach contents to empty. 28-Jul-10 6

Factors affecting GI emptying : 

Factors affecting GI emptying 1.Volume of meals 2.Composition of meal 3.Physical state of meal 4.GI ph 5.Body posture 6.Emotional state 7.Exercise 8.Drugs 28-Jul-10 7

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1.Volume of meal: Larger the bulk of the meal, longer the gastric time and however an initial rapid rate of emptying is observed with large meal volume and initial lag phase in emptying of small volume meals. 2.Composition of meal: The rate of gastric emptying for various food materials in the following order carbohydrates>proteins>fats. 3.Physical state: Liquid meal takes less time as compared to solid meals. 4.GI ph: Gastric emptying is retarded at low stomach pH and promoted at alkaline pH. 28-Jul-10 8

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5.Exercise: Vigorous physical training retards gastric empting. 6.Body posture: Gastric emptying is favored while standing and by lying on right side. 7. Emotional state: Stress and anxiety promotes GI motility, where as depression retards it. 8.Drugs: That retards gastric emptying are antacids, anti cholinergic, narcotic analgesics and tri cyclic antidepressants. And metoclopramide, domperidone and cisapride stimulate gastric emptying. 28-Jul-10 9

3. Intestinal transit : 

3. Intestinal transit Defined as, the residence time of drug in small intestine. Delayed intestinal transit is desirable for: 1.Sustained release dosage forms, 2.Drug that only release in intestine ie ,enteric coated formulations, 3.Drugs absorbed from specific sites in intestine, eg; several B vitamins 28-Jul-10 10

4. GI pH : 

4. GI pH GI pH influence in several ways: 1.Disintegration: Disintegrating of some dosage forms is pH sensitive, enteric coated tabs dissolve only in alkaline pH. 2.Dissolution: A large no. of drugs either weak acids or weak bases, their solubility is greatly affected by GI pH. -weakly acidic drugs dissolve rapidly in alkaline pH. -basic drugs soluble in acidic pH.. 3.Absorption: Depending upon drug pKa whether its an acidic or basic drug the GI pH influences drug absorption. 4.stability of drug: GI pH influence the stability of drug. Eg; erythromicin 28-Jul-10 11

5. Blood flow to git : 

5. Blood flow to git GIT is extensively supplied by blood capillary, about 28% of cardiac output is supplied to GIT portion, most drug reach the systemic circulation via blood only. Any factor which affects blood flow to GIT may also affect absorption. 28-Jul-10 12

6. Disease state : 

6. Disease state Several disease state may influence the rate and extent of drug absorption. Three major classes of disease may influence bioavailability of drug. GI diseases CVS disease HEPATIC disease 28-Jul-10 13

GI diseases : 

GI diseases A. GI infections : 1.Celiac disease: (characterized by destruction of villi and microvilli) abnormalities associated with this disease are increase GI emptying rate and GI permeability, alter intestinal drug metabolism. 2.Crohn’s disease: alter gut transit time and decreased gut surface area. B. GI surgery: Gastrectomy may cause drug dumping in intestine, osmotic diarrhoea and reduce intestinal transit time. 28-Jul-10 14

CVS diseases : 

CVS diseases In CVS diseases blood flow to GIT decrease, causes decreased drug absorption. Disorders like hepatic cirrhosis influences bioavailability of drugs which under goes first pass metabolism. Hepatic diseases 28-Jul-10 15

7. Gastro intestinal contents : 

7. Gastro intestinal contents 1.Food- drug interaction: In general presence of food either delay, reduce, increase or may not affect absorption. Aspirin Delayed Penicillin's Decreased Griseofulvin Increased Methyldopa Unaffected 2.Interaction of drug with normal GI contents: GIT contains no. of normal constituents such as mucin, bile salts and enzymes, which influence the drug absorption. Eg; Inhibitory action of bile on GI motility. 28-Jul-10 16

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3.Drug-Drug interaction in the GIT: Physico chemical drug- drug interaction: Adsorption: Eg; anti diarrhial preparations contains adsorbents like kaolin, prevents a absorption of many drugs co-administered with them. Complexation: Eg; penicillin derivative with ca-gluconate. pH changes: Basic drugs changes gastric pH Eg; tetracycline with antacids 28-Jul-10 17

8. First pass metabolism : 

8. First pass metabolism Four primary systems which affect pre systemic metabolism of a drugs. 1. Luminal enzymes. 2.Gut wall enzymes or mucosal enzymes. 3. Bacterial enzymes. 4. Hepatic enzymes. 28-Jul-10 18

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Lumenal enzymes: These are enzymes present in gut fluids and include enzymes from intestinal and pancreatic secretions. Gut wall enzymes: Also called mucosal enzymes they are present in gut and intestine, colon. Bacterial enzymes: GI microflora scantily present in stomach and small intestine and is rich in colon. Hepatic enzyme: several drug undergo first-pass hepatic metabolism, highly extracted ones being isoprenaline, nitroglycerin, morphine etc. 28-Jul-10 19

Pharmaceutical Factors : 

Different dosage forms:- Solutions Suspensions Tablets Capsules Coated tab Enteric coated tab Disintegration test Dissolution test Excipients and adjuvant Product age and storage conditions. Pharmaceutical Factors 28-Jul-10 20

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… 28-Jul-10 21

Suspensions : 

Suspensions Dissolution is the rate limiting step for the absorption of the drug from suspension. Factors to considered for drug bioavailability are, particle size , wetting agents , viscosity of the medium, suspending agents. 28-Jul-10 22

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 . 28-Jul-10 23

Tablets : 

Tablets This is the most widely used dosage form. Problem with this arises from reduction in the effective surface area due to granulation & subsequent compression in to dosage form. Tab disintegration and granule deaggreation are the imp steps in absorption process. Compression force also may be an important factor. Disintegration is the rate limiting step for this. 28-Jul-10 24

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 28-Jul-10 25 Coated tablets

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. 28-Jul-10 26

Pharmaceutical Excipients : 

Pharmaceutical Excipients Excipients are add to ensure the acceptability, physiochemical stability, bioavailability and functionability of the drug product. More the number of excipients in a dosage form, the more complex and greater the absorption and bioavailability problems. 28-Jul-10 27

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Commonly used excipients: Diluents Binders Disintegrants Lubricants Coatings Suspending agents Surfactants Buffers Complexing agents Colorants Sweeteners. 28-Jul-10 28

Product Age and Storage Condition : 

Product Age and Storage Condition A number of changes, especially in the physiochemical properties of a drug in a dosage from, can result due to aging and alteration in storage conditions which can adversely affect bioavailability. Solution dosage form. Solid dosage form. 28-Jul-10 29

Slide 30: 

It is provided to determine the compliance with the limit on disintegration stated in the individual monograph. 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. Disintegration can be aided by incorporating disintegrants in suitable amount during formulation . 28-Jul-10 30 DISINTEGRATION

Slide 31: 

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. 28-Jul-10 31 DISSOLUTION

Absorption of drug from Non-per oral route : 

Absorption of drug from Non-per oral route Buccal/Sublingual Administration Rectal Administration Topical Administration Inhalation Administration Intramuscular Administration Subcutaneous Administration Intranasal Administration Intraocular Administration Vaginal Administration 28-Jul-10 32

Buccal/Sublingual Administration : 

Buccal/Sublingual Administration In buccal route the medicament is placed between the cheek and the gum. In sublingual the drug is placed under the tongue. Barrier to drug absorption from these route is epithelium of oral mucosa. Absorption of drug is by passive diffusion. Eg; lozenges nitrates and nitrites, 28-Jul-10 33

Rectal Administration : 

An important route for children and old patients. The drug may be administered as solution or suppositories. Irritating suppositories bases such as PEG promotes defecation and drug loss, and presence of fecal matter retards drug absorption. By passes the presystemic hepatic metabolism. Drug administered by this route includes Aspirin, paracetamol, few barbiturates. Rectal Administration 28-Jul-10 34

Topical Administration : 

Skin is the largest organ in the body weighing around 2kg and 2mtsq in area and receives about 1/3rd of total blood circulating through the body. Topical mode of administration is called as percutaneous or transdermal delivery. The drug act either locally or systemically. Drug that administered precutaneously include lidocaine, testosterone , estradiol, etc. Topical Administration 28-Jul-10 35

Inhalations Administration : 

Inhalations Administration All drugs intended for systemic effect can be administered by inhalation since the larger surface area of alveoli, higher permeability to the alveolar epithelium & rapid absorption just exchange of gases in blood. Route has been limited for drugs such as bronchodilators, anti-inflammatory steroids and antiallergics. Drug do not under go first pass metabolism. lipid soluble drugs absorption rapid by passive diffusion and polar drug by pore transport. Generally administered by inhalation either as gases or aerosols 28-Jul-10 36

Intra muscular injection : 

Intra muscular injection Arms – deltoid Thigh – vastuslaterals Buttocks – gluteus maxims. degree of absorption will be Arms> Thigh> Buttocks. These are 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. Lipophilic drugs absorbed rapidly by passive diffusion whereas hydrophilic drugs are slowly absorbed through capillary pores Advantages:-less hazardous, & easier to administrate equal bioavailability as that of IV. Some drugs when administration IM is probably result in ppt at injection site. Ex:-digoxin 28-Jul-10 37

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 hyaluranidase in the drug solution. Absorption of the drug can be slowed by co-injection of a vasoconstrictor. Ex: epinephrine Insulin, local anesthesia. 28-Jul-10 38

Intraocular Administration : 

Intraocular Administration 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. pH of formulation influences lacrimal output. Rate of blinking. Volume of fluid. The addition of viscosity increasing agents in the ophthalmic solution will increases occular bio availability. Ex: pilocarpine, timmolol, atropine. 28-Jul-10 39

Vaginal Administration : 

Vaginal Administration 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 drug absorption 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: steroidal drugs and contraceptives. 28-Jul-10 40

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 28-Jul-10 41

REFERNCE… : 

REFERNCE… D.M.BRAHMANKAR, SUNIL B. JASWAL “BIOPHARMACEUTICS AND PHARMAKOKINETICS”. Ist Ed., VALLABH PRAKASHAN-DELHI; 1995. P.39-71. 28-Jul-10 42

Slide 43: 

THANK U 28-Jul-10 43

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