what is ABSORPTION / Defination of ABSORPTION / Pharmacology

 ABSORPTION

Absorption is movement of the drug from its site of administration into the circulation. Not only the fraction of the administered dose that gets absorbed, but also the rate of absorption is important. Except when given i.v., the drug has to cross biological membranes; absorption is governed by the above described principles. Other factors affecting absorption are:

Aqueous solubility Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. 

Concentration Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution. 

Area of absorbing surface Larger is the surface area, faster is the absorption. 

Vascularity of the absorbing surface Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes. 

Route of administration This affects drug absorption, because each route has its own peculiarities

Aqueous solubility 

Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. Concentration Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution. Area of absorbing surface Larger is the surface area, faster is the absorption. Vascularity of the absorbing surface Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes. Route of administration This affects drug absorption, because each route has its own peculiarities

of the drug in solid dosage form governs rate of dissolution and in turn rate of absorption. Presence of food dilutes the drug and retards absorption. Further, certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with calcium present in milk; moreover food delays gastric emptying. Thus, most drugs are absorbed better if taken in empty stomach. 

However, there are some exceptions, e.g. fatty food greatly enhances lumefantrine absorption. Highly ionized drugs, e.g. gentamicin, neostigmine are poorly absorbed when given orally. Certain drugs are degraded in the gastrointestinal tract, e.g. penicillin G by acid, insulin by peptidases, and are ineffective orally. Enteric coated tablets (having acid resistant coating) and sustained release preparations (drug particles coated with slowly dissolving material) can be used to overcome acid lability, gastric irritancy and brief duration of action. The oral absorption of certain drugs is low because a fraction of the absorbed drug is extruded back into the intestinal lumen by the efflux transporter P-gp located in the gut epithelium.

The low oral bioavailability of digoxin and cyclosporine is partly accounted by this mechanism. Inhibitors of P-gp like quinidine, verapamil, erythromycin, etc. enhance, while P-gp inducers like rifampin and phenobarbitone reduce the oral bioavailability of these drugs. Absorption of a drug can be affected by other concurrently ingested drugs. This may be a luminal effect: formation of insoluble complexes, e.g. tetracyclines and iron preparations with calcium salts and antacids, phenytoin with sucralfate. Such interaction can be minimized by administering the two drugs at 2–3 hr intervals. Alteration of gut flora by antibiotics may disrupt the enterohepatic cycling of oral contraceptives and digoxin. Drugs can also alter absorption by gut wall effects: altering motility (anticholinergics, tricyclic antidepressants, opioids retard motility while metoclopramide enhances it) or causing mucosal damage (neomycin, methotrexate, vinblastine)

Subcutaneous and Intramuscular

 By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions (Fig. 2.9A). Very large molecules are absorbed through lymphatics. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors, e.g. adrenaline injected with the drug (local anaesthetic) retard absorption. Incorporation of hyaluronidase facilitates drug absorption from s.c. injection by promoting spread. Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins, etc. can be given by these routes

Subcutaneous and Intramuscular

 By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions (Fig. 2.9A). Very large molecules are absorbed through lymphatics. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors, e.g. adrenaline injected with the drug (local anaesthetic) retard absorption. Incorporation of hyaluronidase facilitates drug absorption from s.c. injection by promoting spread. Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins, etc. can be given by these routes

get absorbed through the nasolacrimal duct, e.g. timolol eye drops can produce bradycardia and precipitate asthma. Mucous membranes of mouth, rectum, vagina absorb lipophilic drugs: estrogen cream applied vaginally has produced gynaecomastia in the male partner.

 Bioavailability 

Bioavailability refers to the rate and extent of absorption of a drug from a dosage form administered by any route, as determined by its concentration-time curve in blood or by its excretion in urine (Fig. 2.7). It is a measure of the fraction (F ) of administered dose of a drug that reaches the systemic circulation in the unchanged form. Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion because—

 (a) the drug may be incompletely absorbed.

 (b) the absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile

Incomplete bioavailability after s.c. or i.m. injection is less common, but may occur due to local binding of the drug. 

Bioequivalence

 Oral formulations of a drug from different manufacturers or different batches from the same manufacturer may have the same amount of the drug (chemically equivalent) but may not yield the same blood levels—biologically inequivalent. Two preparations of a drug are considered bioequivalent when the rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions. Before a drug administered orally in solid dosage form can be absorbed, it must break into individual particles of the active drug (disintegration).

 Tablets and capsules contain a number of other materials—diluents, stabilizing agents, binders, lubricants, etc. The nature of these as well as details of the manufacture process, e.g. force used in compressing the tablet, may affect disintegration. The released drug must then dissolve in the aqueous gastrointestinal contents. 

The rate of dissolution is governed by the inherent solubility, particle size, crystal form and other physical properties of the drug. Differences in bioavailability may arise due to variations in disintegration and dissolution rates. Differences in bioavailability are seen mostly with poorly soluble and slowly absorbed drugs. Reduction in particle size increases the rate of absorption of aspirin (microfine tablets). The amount of griseofulvin and spironolactone in the tablet can be reduced to half if the drug particle is microfined.

 There is no need to reduce the particle size of freely water soluble drugs, e.g. paracetamol. Bioavailability variation assumes practical significance for drugs with low safety margin (digoxin) or where dosage needs precise control (oral hypoglycaemics, oral anticoagulants). It may also be responsible for success or failure of an antimicrobial regimen.

 However, in the case of a large number of drugs bioavailability differences are negligible and the risks of changing from branded to generic 

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only the fraction of the administered dose that gets absorbed, but also the rate of absorption is important. Except when given i.v., the drug has to cross biological membranes; absorption is governed by the above described principles. Other factors affecting absorption are:

Aqueous solubility Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. 

Concentration Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution. 

Area of absorbing surface Larger is the surface area, faster is the absorption. 

Vascularity of the absorbing surface Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes. 

Route of administration This affects drug absorption, because each route has its own peculiarities

Aqueous solubility 

Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. Concentration Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution. Area of absorbing surface Larger is the surface area, faster is the absorption. Vascularity of the absorbing surface Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes. Route of administration This affects drug absorption, because each route has its own peculiarities

of the drug in solid dosage form governs rate of dissolution and in turn rate of absorption. Presence of food dilutes the drug and retards absorption. Further, certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with calcium present in milk; moreover food delays gastric emptying. Thus, most drugs are absorbed better if taken in empty stomach. 

However, there are some exceptions, e.g. fatty food greatly enhances lumefantrine absorption. Highly ionized drugs, e.g. gentamicin, neostigmine are poorly absorbed when given orally. Certain drugs are degraded in the gastrointestinal tract, e.g. penicillin G by acid, insulin by peptidases, and are ineffective orally. Enteric coated tablets (having acid resistant coating) and sustained release preparations (drug particles coated with slowly dissolving material) can be used to overcome acid lability, gastric irritancy and brief duration of action. The oral absorption of certain drugs is low because a fraction of the absorbed drug is extruded back into the intestinal lumen by the efflux transporter P-gp located in the gut epithelium.

The low oral bioavailability of digoxin and cyclosporine is partly accounted by this mechanism. Inhibitors of P-gp like quinidine, verapamil, erythromycin, etc. enhance, while P-gp inducers like rifampin and phenobarbitone reduce the oral bioavailability of these drugs. Absorption of a drug can be affected by other concurrently ingested drugs. This may be a luminal effect: formation of insoluble complexes, e.g. tetracyclines and iron preparations with calcium salts and antacids, phenytoin with sucralfate. Such interaction can be minimized by administering the two drugs at 2–3 hr intervals. Alteration of gut flora by antibiotics may disrupt the enterohepatic cycling of oral contraceptives and digoxin. Drugs can also alter absorption by gut wall effects: altering motility (anticholinergics, tricyclic antidepressants, opioids retard motility while metoclopramide enhances it) or causing mucosal damage (neomycin, methotrexate, vinblastine)

Subcutaneous and Intramuscular

 By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions (Fig. 2.9A). Very large molecules are absorbed through lymphatics. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors, e.g. adrenaline injected with the drug (local anaesthetic) retard absorption. Incorporation of hyaluronidase facilitates drug absorption from s.c. injection by promoting spread. Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins, etc. can be given by these routes

Subcutaneous and Intramuscular

 By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions (Fig. 2.9A). Very large molecules are absorbed through lymphatics. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors, e.g. adrenaline injected with the drug (local anaesthetic) retard absorption. Incorporation of hyaluronidase facilitates drug absorption from s.c. injection by promoting spread. Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins, etc. can be given by these routes

get absorbed through the nasolacrimal duct, e.g. timolol eye drops can produce bradycardia and precipitate asthma. Mucous membranes of mouth, rectum, vagina absorb lipophilic drugs: estrogen cream applied vaginally has produced gynaecomastia in the male partner.

 Bioavailability 

Bioavailability refers to the rate and extent of absorption of a drug from a dosage form administered by any route, as determined by its concentration-time curve in blood or by its excretion in urine (Fig. 2.7). It is a measure of the fraction (F ) of administered dose of a drug that reaches the systemic circulation in the unchanged form. Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion because—

 (a) the drug may be incompletely absorbed.

 (b) the absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile

Incomplete bioavailability after s.c. or i.m. injection is less common, but may occur due to local binding of the drug. 

Bioequivalence

 Oral formulations of a drug from different manufacturers or different batches from the same manufacturer may have the same amount of the drug (chemically equivalent) but may not yield the same blood levels—biologically inequivalent. Two preparations of a drug are considered bioequivalent when the rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions. Before a drug administered orally in solid dosage form can be absorbed, it must break into individual particles of the active drug (disintegration).

 Tablets and capsules contain a number of other materials—diluents, stabilizing agents, binders, lubricants, etc. The nature of these as well as details of the manufacture process, e.g. force used in compressing the tablet, may affect disintegration. The released drug must then dissolve in the aqueous gastrointestinal contents. 

The rate of dissolution is governed by the inherent solubility, particle size, crystal form and other physical properties of the drug. Differences in bioavailability may arise due to variations in disintegration and dissolution rates. Differences in bioavailability are seen mostly with poorly soluble and slowly absorbed drugs. Reduction in particle size increases the rate of absorption of aspirin (microfine tablets). The amount of griseofulvin and spironolactone in the tablet can be reduced to half if the drug particle is microfined.

 There is no need to reduce the particle size of freely water soluble drugs, e.g. paracetamol. Bioavailability variation assumes practical significance for drugs with low safety margin (digoxin) or where dosage needs precise control (oral hypoglycaemics, oral anticoagulants). It may also be responsible for success or failure of an antimicrobial regimen.

 However, in the case of a large number of drugs bioavailability differences are negligible and the risks of changing from branded to generic