Absorption

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. 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 it is, 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.

Oral

The effective barrier to orally administered drugs is the epithelial lining of the gastrointestinal tract, which is lipoidal. Nonionized lipid soluble drugs, e.g. ethanol are readily absorbed from stomach as well as intestine at rates proportional to their lipid : water partition coefficient. Acidic drugs, e.g. salicylates, barbiturates, etc. are predominantly unionized in the acid gastric juice and are absorbed from stomach, while basic drugs, e.g. morphine, quinine, etc. are largely ionized and are absorbed only on reaching the duodenum. However, even for acidic drugs absorption from stomach is slower, because the mucosa is thick, covered with mucus and the surface area is small. Absorbing surface area is much larger in the small intestine due to villi. Thus, faster gastric emptying accelerates drug absorption in general. Dissolution is a surface phenomenon, therefore, particle size 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. 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 Pgp located in the gut epithelium. The low oral bioavailability of digoxin and cyclosporine is partly accounted by this mechanism. Inhibitors of Pgp like quinidine, verapamil, erythromycin, etc. enhance while Pgp 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 with iron preparations 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, metoclopramide) 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. 2.8A). 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.

Topical sites (skin, cornea, mucous membranes)

Systemic absorption after topical application depends primarily on lipid solubility of drugs. However, only few drugs significantly penetrate intact skin. Hyoscine, fentanyl, GTN, nicotine, testosterone, and estradiol (see p. 9) have been used in this manner. Corticosteroids applied over extensive areas can produce systemic effects and pituitaryadrenal suppression. Absorption can be promoted by rubbing the drug incorporated in an olegenous base or by use of occlusive dressing which increases hydration of the skin. Organophosphate insecticides coming in contact with skin can produce systemic toxicity. Abraded surfaces readily absorb drugs, e.g. tannic acid applied over burnt skin has produced hepatic necrosis.

Cornea is permeable to lipid soluble, unionized physostigmine but not to highly ionized neostigmine. Drugs applied as eye drops may get absorbed through the nasolacrimal duct, e.g. timolol eye drops may 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.