Pharmacokinetics-1( Absorbtion of drug) & prolongation of drug action

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Pharmacokinetics: (Greek : Kinesis – movement) Pharmacokinetics is‘ What the body does to the drugs.’ It is the branch of pharmacology which deals with the quantitative study of absorption, distribution, binding / localization / storage, biotransformation & excretion of drugs. Together with dose of drugs these parameters determine the onset, intensity & duration of action. : 

Pharmacokinetics : (Greek : Kinesis – movement) Pharmacokinetics is‘ What the body does to the drugs.’ It is the branch of pharmacology which deals with the quantitative study of absorption, distribution, binding / localization / storage, biotransformation & excretion of drugs. Together with dose of drugs these parameters determine the onset, intensity & duration of action.

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Absorption of Drugs Absorption can be defined as process by which drug passes from its site of administration into the systemic circulation.

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Factors that Affect Drug Absorption General factors: Physiochemical factors affecting drug permeation. Drug solubility. Dosage forms. Concentration of drug at site of absorption. Circulation at site of absorption The area of absorbing surface. Related to routes of administration

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Absorption from G.I. T Mechanisms: Mainly---- Lipid diffusion Some role of Active transport & facilitated diffusion Minor role of Endocytosis

Factors Affecting Drug Absorption from G.I.T A: Factors related to drug B: Factors related to body / Biological Factors A. Factors related to drug 1. Physiochemical Factors Affecting the transport i. Concentration ii. Molecular size iii. Lipid Solubility depends upon . Lipid- Aqueous partition co-efficient . Degree of ionization a.   pKa of drug b.   pH of Medium   : 

Factors Affecting Drug Absorption from G.I.T A: Factors related to drug B: Factors related to body / Biological Factors A. Factors related to drug 1. Physiochemical Factors Affecting the transport i . Concentration ii. Molecular size iii. Lipid Solubility depends upon . Lipid- Aqueous partition co-efficient . Degree of ionization a. pKa of drug b.   pH of Medium

2. Factors related to Form of the Drug i.       Drug solubility ii.       Dosage forms iii. Pharmaceutical factors iv. Chemical nature of the drug: 

2. Factors related to Form of the Drug i . Drug solubility ii.       Dosage forms iii. Pharmaceutical factors iv. Chemical nature of the drug

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i. Drug solubility It effects the extent of absorption: Extremely lipid soluble / Lipophilic, drug is not soluble enough to cross the water layer adjacent to the cell , less abs. e.g. Acyclovir -- only 23% . Highly lipid soluble drugs with some water solubility are absorbed to a better extent. e.g. Diazepam ---- 90% Less lipid soluble / hydrophilic drugs are absorbed to lesser extent. e.g. Atenolol ---- 56%

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ii. Dosage forms : Liquid preparation better absorbed than solids. Amongst liquids crystalloids are better absorbed than colloidal. Slow release preparations--- to delay absorption.

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iii. Pharmaceutical factors affect Quality control . Disintegration of solid dosage forms & Dissolution time of the drug depends on: a. Compression pressure. b. Moisture content. c. Nature of additives / diluents or vehicles d. Particle size of the active drug. e. Polymorphism. Faulty manufacturing and formulation leads to decreased absorption.

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iii. Chemical nature of the drug Drugs are divided into 4 groups. Variably ionized drugs --- Weak acids and bases… Most of these bases are amine-containing molecules. Primary ,secondary & tertiary amines have a pair of unshared electrons . So each of these can reversibly combine with a proton &can vary lipid solubility with pH Quaternary amines are always in poorly lipid soluble form. Ipratropium bromide ----

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2. Permanently ionized/ charged drugs --- Heparin (- vely charged )not absorbed from GIT given I/V or S/C 3. Drugs incapable of becoming ionized --- Digoxin , Chloramphenicol --- 100% abs. Not charged but lipid insoluble due to their structure --- Aminoglycosides --- water soluble not absorbed from intact GIT.

Biological Factors: 1. Site 2. pH of G.I.T contents 3. Area of absorbing surface 4. Functional Integrity 5. Structural Integrity 6. Blood flow /circulation 7. Presence of food 8. Presence of other Drugs/ Agents. 9. Destruction of Drug by Acid /Digestive Enzymes 10. Bacterial metabolism 11. Reverse transporter : 

Biological Factors : 1. Site 2. pH of G.I.T contents 3. Area of absorbing surface 4. Functional Integrity 5. Structural Integrity 6. Blood flow /circulation 7. Presence of food 8. Presence of other Drugs/ Agents. 9. Destruction of Drug by Acid /Digestive Enzymes 10. Bacterial metabolism 11. Reverse transporter

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Site: Mainly small intestine Not stomach , because: Thin epithelium Large surface area ,villi, microvilli. Main function is absorptive Stomach : Thick mucosa Small surface area High electrical resistance Main function is digestive

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2. pH of G.I.T contents: The absorption of weak electrolytes is pH dependent. Weak acids are better absorbed at low pH and weak basis are better absorbed at high pH. They can under go variable degree of ionization & hence degree of lipid solubility depending on the pH.

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3. Area of absorbing surface: As drugs are mainly absorbed by lipid diffusion so larger the area greater the absorption. So the main site of drug absorption is small intestine.

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4. Functional Integrity: Gastric emptying time ↑ --- delayed abs. By drugs like Atropine, in migraine and Diabetes mellitus. Gastric emptying time ↓ : quick abs. By drugs like Metoclopramide. Intestinal peristalsis ↑ in diarrhea– ↓ absorption. In chronic heart failure ↓ absorption due to mucosal edema.

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5. Structural Integrity: Intestinal resection due to injury or gangrene– ↓ absorption. 6. Blood flow /circulation: Good blood flow maintains the concentrration gradient for lipid diffusion--- better abs, In shock -- ↓ circulation --- ↓ absorption 7. Presence of food: Food generally delays & ↓ absorption

7. Presence of other Drugs/Agents. Absorption of Iron is ↑ by Vit C, ↓ by Phytates    “ “ Vit.K is ↓ by liquid paraffin    “ “ Tetracyclines is ↓ by Calcium   “ “ Thyroxin & Warfarin ↓ by Cholestyramine 8. Destruction of Drug by Acid (Benzyl penicillin) / Digestive Enzymes (Hormones like Insulin) 9. Bacterial metabolism : Digoxin--- 30 % metabolized by intestinal bacteria so absorption is 70 % . : 

7. Presence of other Drugs/Agents. Absorption of Iron is ↑ by Vit C, ↓ by Phytates “ “ Vit.K is ↓ by liquid paraffin “ “ Tetracyclines is ↓ by Calcium “ “ Thyroxin & Warfarin ↓ by Cholestyramine 8. Destruction of Drug by Acid (Benzyl penicillin) / Digestive Enzymes (Hormones like Insulin) 9. Bacterial metabolism : Digoxin --- 30 % metabolized by intestinal bacteria so absorption is 70 % .

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Reverse transporters: They pump the drugs out from gut wall cells into the lumen. P-glycoprotein or multidrug resistance type 1 (MDR1) transporter. Multidrug resistance –associated protein (MRP1 ) Inhibition of P-glycoprotein by grapefruit juice may be associated with ↑ absorption .

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Absorption from sublingual/ buccal mucosa: Rapid & instantaneous into the sub lingual veins. Avoids hepatic first pass effect. Rectal Absorption Often irregular & incomplete. 50% bypasses liver.

Absorption from parenteral site of Administration: General Factors 1. Physiochemical factors that affect transport of drug across cell membrane. 2. Drug’s solubility 3. Dosage form of drug 4. Concentration of drug at site of absorption 5. Circulation at site of absorption 6. The area of absorbing surface. : 

Absorption from parenteral site of Administration: General Factors 1. Physiochemical factors that affect transport of drug across cell membrane. 2. Drug’s solubility 3. Dosage form of drug 4. Concentration of drug at site of absorption 5. Circulation at site of absorption 6. The area of absorbing surface.

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Absorption from parenteral site of Administration : I.V Route: No absorption required. Absorption from Subcutaneous site of injection Mainly by lipid diffusion along a conc. gradient. Some by aqueous diffusion through endothelial lining. Very large molecules (Proteins), slowly enter the circulation through lymphatics.

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It is slow & constant to produce sustained effect. Application of heat/ massage ↑ absorption. ↑ absorption by hyaluronidase. ↓ absorption in circulatory failure / shock. So never use this route in shock. Absorption can be intentionally slowed by: e.g. Addition of vasoconstrictor (Epinephrine) to LA. Modification of preparation ---- repository preparation

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Absorption from Intramuscular site of injection : By lipid diffusion. Quite rapid, depends upon rate of blood flow. Absorption better than S/C injection. Rapid from aqueous, slow & sustained from colloidal solution. Application of heat/ massage or exercise ↑ absorption. Cooling the site, ↓ the absorption. Absorption differs according to body fat. Absorption is slow from repository preparation.

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Special preparations to delay absorption from S/C or I/M Inj. 1. Insoluble Solution (procaine penicillin, lente insulin) 2. Oily solution (depot progestins) 3. Pellet implantation (Testosterone) 4. Sialistic and biodegradable implants. (Norplant) 5. Inclusion of vasoconstrictor (Epinephrine with local anaesthetics).

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Pulmonary Absorption: By lipid diffusion. Rapid due to large absorbing surface. Gaseous & volatile GA. Environmental allergens.

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Absorption from Topical Application Absorption from Skin Intact skin. Abraded skin. Transdermal Patches for systemic effects:

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Transdermal Patches for systemic effects: The drug in solution or bound to polymer, is delivered at the skin surface by the micropore membrane. The rate of drug delivery is less than the slowest rate of absorption from skin . The absorption is at constant & predictable rate irrespective of site of application.

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Absorption from mucous membrane Absorption from eye Through cornea for local effects. e.g. Pilocarpine eye drops for glaucoma. Drainage of drops through nasolacrimal canal & systemic absorption ---- Adverse effects e.g. Atropine/ Homeatropin , Timolol

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Absorption from Nasal mucosa Occurs through MM over lying lymphiod tissue to provide systemic effects. e.g. Antidiuretic hormone, calcitonin

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Prolongation Of Drug Action Some times deliberately action of drugs may be prolonged. The action is prolonged by 4 to 6 hrs. Drugs with plasma half life < 4 hrs are suitable for controlled release formulations. No need of such formulation for drugs with plasma half life > 12 hrs.

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Methods of prolonging drug action By slowing absorption from site of administration. By increasing plasma protein binding. By retarding rate of metabolism. By retarding renal excretion.

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1. By prolonging absorption from site of administration. Oral: Sustained release tablets, spansule capsules. Controlled release preparation:

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Parenteral: Absorption from S/C & I/M. Injection site can be delayed by: 1. Insoluble Solution (procaine penicillin, lente insulin) 2. Oily solution (depot progestins) 3. Pellet implantation (Testosterone) 4. Sialistic and biodegradable implants. (Norplant) 5. Inclusion of vasoconstrictor (Epinephrine with local anaesthetics).

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Topical 1. Transdermal drug delivery systems e.g. nitroglycerine. 2. Corneal inserts e.g. pilocarpine for glaucoma

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2. By increasing plasma protein binding. Highly PPB Congeners Drug is slowly released in the free active form e.g. sulfadoxine.

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By retarding rate of metabolism. Small chemical modification may markedly affect the rate of metabolism without affecting the biological action.

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Examples: 1. Addition of ethinyl group to estradiol makes it longer acting and suitable for use as oral contraceptive. 2. Inhibition of specific enzyme by one drug can prolong the action of another drug. e.g. Cilastatin protects imipenem from degradation in kidney by dehydropeptidase enzyme .

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By retarding renal excretion. The active tubular secretion of drug , can be suppressed by a competing substance. e.g. probenecid prolongs duration of action of penicillin and ampicillin.

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Advantages: Frequency of administration is ↓ ---- convenient. Improved patient compliance Large fluctuations in plasma conc. are avoided. Drug effect can be maintained overnight without disturbing sleep.