Sunday, February 21, 2010

Oral Drug Delivery

Most drugs are absorbed from the gastrointestinal tract and because of the convenience, orally administered drugs are widely used over injectable preparations. Some drugs like benzylpenicillin or insulin are destroyed by the acid and enzymes in the gut and therefore have to be administered parenterally.

Drug Absorption At The Small Intestine

Little absorption occurs before the drug reaches the small intestine. This is because when exposed to the gastric pH, basic drugs are ionised and therefore pass into the more alkaline small bowel before being absorbed. More importantly, most absorption occurs here simply because of it’s massive surface area.

Most drugs are absorbed by passive lipid diffusion though there is a degree of carrier-mediated transport. Levodopa, a drug used in Parkinson’s Disease, is transported by the carrier mechanism usually used for phenylalanine. Fluoruracil is a cytotoxic drug that employs the natural pyrimidine transport system. Iron is transported via specific carriers in the jejunal mucosa and calcium by a vitamin D-dependent carrier system. The rate of transfer is determined by the ionisation state and lipid solubility of the drugs. Strong bases with a pKa of 10 or more or acids with a pKa of less than 3 are fully absorbed because they are fully ionised.

Factors Affecting GI Absorption

It usually takes 1-3 hours for 75% of an ingested drug to be absorbed. There are several factors which alter this, both physiological and relating to drug formulation.

GI motility has a large effect on the rate of drug absorption. Gastric stasis, which occurs in migraine and diabetic neuropathy, slows drug absorption. However rapid gut movement can also impair absorption. Some drugs have an effect of absorption, metoclopramide is given in migraine to increase GI motility and increase absorption of analgesics. Muscarinic receptor blockers decrease motility.

After a meal, drugs are more slowly absorbed simply because progress to the small bowel is delayed by the presence of food. Exceptions to this are propanolol which has higher concentrations after a meal because of the fact that food increases splanchnic blood flow. Clearly a decrease in splanchnic blood flow, for example in hypovolaemia, slows absorption. Drug particle size also plays a part. It has been observed in the past that different formulations of digoxin resulted in different plasma concentrations despite the fact that digoxin content in the tablets was the same. This was as a result of varying particle size.

Therapeutic drugs are formulated pharmaceutically to produce desired absorption characteristics. Capsules are designed to remain intact for several hours after ingestion with the aim of delaying absorption. Tablets with a resistant coating work on the same principle. Some drug formulations have a mix of slow and fast release in a capsule to achieve rapid and sustained drug action. By manipulating absorption rates, dose intervals can be increased and adverse side effects, associated with high peak plasma levels, reduced.

The physicochemical properties of drugs also play a part in drug absorption. Tetracycline binds to calcium ions and calcium-rich foods, delaying absorption. Bile acid resins such as colestyramine, bind warfarin and thyroxine.

Absorption is also decreased by both increasing age and disease.

Usually drugs that are administered by mouth, pass through the gut wall to the liver in the portal circulation and then into the systemic circulation where they can go about exerting their effects. However some drugs taken by mouth are designed to remain within the gut lumen until they are excreted. An example of this is the antibiotic vancomycin which acts within the gut lumen to eradicate Clostridium Difficile.


Bioavailability is loosely defined as the proportion of drug that passes into the systemic circulation after oral administration, taking into account both absorption and local metabolic degradation. This is affected not only by the drug characteristics but also variations in enzyme activity in the gut wall and liver, gastric pH and intestinal motility.

First-Pass Metabolism

First-pass or presystemic metabolism is a process occurring in the liver and even in the gut wall which extracts and metabolises some drugs so efficiently that the amount reaching the systemic circulation for the first time is considerably less than the amount absorbed from the gut. This means that a much larger dose is needed when a drug is taken orally than intravenously (when it is 100% bioavailable to the systemic circulation from the moment of injection). There is also an element of variability between individuals in the extent of first-pass metabolism of a given drug which leads to unpredictability when such drugs are taken orally. A drug that shows rapid first-pass hepatic metabolism has poor oral bioavailability.


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