01.05 Oral Administration, Absorption from Gastrointestinal Tract, and First Pass Liver Metabolism

The oral route of administration is the most convenient: subjects prefer to take an oral preparation rather than have an injection, or rectal administration. Oral administration is also the safest. For instance, we have more time to reverse the effects of a drug administered orally than when it is administered directly into a vein. Oral is the most commonly used route of administration. Oral administration usually gives systemic effects (around the body) rather than local effects of drugs. Thus, after oral administration, a drug ends up in the systemic circulation being widely distributed to tissues and organs, with the possibility of having a widespread effect.

A disadvantage of oral administration can be the slow onset of action, as the drug has to be absorbed and taken to its required site of action before it can start to have an effect. In an emergency, drugs that are active after oral administration, may be given intravenously to speed up their onset of action. If the patient is vomiting, the drug may never reach the intestine to be absorbed. Thus, when the patient is vomiting, oral is not an appropriate route of drug administration.

Oral preparations can take several forms. Tablets are compressed powder, often with starch added to swell when in contact with fluids, to aid dissolution (breakdown of the tablet). Capsules contain a shell of gelatine, which is a tasteless natural substance. Hard gelatine capsules contain the drug as solid, whereas soft gelatine capsules contain drug as an oily liquid. Capsules are often preferred to tablets as they disguise the taste. For instance, the antibiotic amoxycillin is given in capsule form to prevent its bad taste upsetting the subject. Children often have problems swallowing tablets or capsules. If swallowing is a problem, oral liquid preparations can be used.

The gastrointestinal tract is designed to handle food and fluids not drugs. Drugs piggyback on the physiological processes to handle food. Also, the physiological processes that normally impact on food and fluids, can affect drug delivery. For instance, the digestive enzymes that breakdown proteins in the diet, can also breakdown some peptide drugs e.g. insulin. Thus, when insulin is being used to treat diabetes, it is not administered orally. The absorption of some drugs is inhibited by forming complexes with components of the diet e.g. the tetracycline antibiotics form non-absorbable complexes with calcium (dairy products). Some drugs irritate the lining of the gastrointestinal tract to cause emesis (vomiting), and such drugs cannot be used orally e.g. some of the cytotoxic (cell killing) anti-cancer drugs.

The processes that need to happen to get drug delivery from the gut into the circulation are given in Figure 1.3. Firstly, the drug has to be released from the dosage form (tablet or capsule). Secondly, the drug has to separate and/or dissolve; this is called drug dissolution. After dissolution most drugs are absorbed by simple diffusion, although a few drugs are transported by physiological processes.

Figure 1.3 Processes to get drug delivery from gut (Copyright QUT, Sheila Doggrell)

The body has many membrane transporters. These are like being transported by a bus; they pick up drugs and take them to their destination across membranes. For instance, after the proteins have been broken down to amino acids, the amino acids are absorbed by active transport across the gut membrane. Drugs with similar structures to the natural substrates (substances) for these transporters can use these transporters. For instance, thyroxine, which is commonly used in the treatment of hypothyroidism, uses the physiological transporter for amino acid absorption. Another example is the drug L-dopa, which is used in the treatment of Parkinson’s disease. L-dopa is a naturally occurring compound, and has its own transporter.

The most common method for drug absorption is diffusion. As cell membranes are lipid, to diffuse through the lipid cell membranes, drugs must be lipid soluble (lipophilic). ‘Philic’ means likes, whereas ‘phobic’ means does not like. Drugs that are not water soluble (hydrophobic) are often lipophilic, and absorbed by diffusion. In contrast, water soluble drugs (hydrophilic), which are not lipid soluble (lipophobic drugs; e.g. curare), are not well absorbed after oral administration.

The case of curare tells us a lot about routes of drug administration. Curare was used on the tips of the arrows of South Americans to kill animals. Once the curare was injected into the animal, it became paralysed. However, when the South Americans ate the curare-injected animals, they were not paralysed. This is because curare is a strong base and not absorbed from the gastrointestinal tract, so has no effect after oral administration. However, it is absorbed after intramuscular injection to give its muscle relaxant effect. Curare is still used today to cause muscle relaxation during operations. In addition to strong bases, strong acids are poorly absorbed after oral administration, and have to be given by another route.

Strong acids and strong bases (e.g. curare) are not absorbed. Thus, drugs are usually designed to be weak acids (e.g. aspirin) or weak bases (e.g. morphine), as these are more lipid soluble and readily diffuse through the gastrointestinal cells membranes. Weak acids are lipophilic at low pH (which occurs in the stomach) and are capable of being absorbed from the stomach. In contrast, weak bases are lipophilic at high pH (in the intestine), and are absorbed from the intestine.

The stomach is acidic, with a pH of 1-3, compared with the small intestine, which has a pH in the range 5-8. Acidity is increased at night, and this may increase the absorption of some drugs. In contrast, antacids decrease the acid in the stomach, and can inhibit the absorption of some drugs. As the acidity in the stomach leads to the association of weak acids, some of these are absorbed from the stomach. However, the stomach is not designed for absorption, and most absorption occurs in the small intestine, which is designed for absorption with villi (projections) and microvilli giving a large surface area.

Drugs will reach the small intestine more rapidly, if administered with water to a patient, whose stomach is empty of food. If a drug is absorbed lower down the gut, the volume of gastric contents will determine the delay before absorption starts. Gastric contents are not the only determinant of rate of gastric emptying and, hence, drug absorption in the intestine. Gastric emptying rate is slowed by diet, especially a diet containing fatty foods or a high bulk diet. Diseases of gastrointestinal tract, such as gastric ulcers or pyloric stenosis, can slow gastric emptying. Gastric emptying is also slowed during pregnancy. Certain drugs (e.g. anti-muscarinics) and alcohol also slow gastric emptying. Indeed, one of the uses of antimuscarinics is to slow gastric emptying in dysentery. With slow gastric emptying, there is more time for the breakdown of drugs by the enzymes and/or acid in the stomach, and this means the subsequent levels in the blood may be lower.

Gastric emptying rate is promoted by hunger, anxiety and certain drugs (e.g. metoclopramide). Increased gastric emptying may promote the absorption of any drug, and lead to increased blood levels. Metoclopramide is not used to promote gastric emptying but as an anti-emetic (prevention of nausea and vomiting). During this use of metoclopramide, there may be higher blood levels of other drugs being used at the same time.

The small intestine is the primary site of drug absorption. The longer the drug remains in the small intestine (residence time), the greater the absorption of the drug from the intestine. However, some drugs are metabolised and inactivated by the intestinal mucosa e.g. progesterone, which means they are not very effective after oral administration. Thus, orally active progesterone-like drugs, designed to be active after oral administration, are part of the oral contraceptive, rather than progesterone itself. Norethisterone is a progesterone-like drug (progestogen), which is used as an oral contraceptive.

Drugs may have a short action if their dissolution and absorption in the gastrointestinal tract is too quick, or metabolism is too quick. This may mean that a drug has to be taken often, say every 2 or 3 hours. People are not very good at remembering to take drugs every 2 or 3 hours, especially during the night, and with such regimens, people miss doses; their adherence to the dosage regimen is low. For this reason, it is best to formulate drugs so that they only need to be taken once or twice a day. To achieve this controlled/slow (sustained) release preparations have been developed. These have a slowed rate of dissolution in the gastrointestinal tract allowing them to be used less frequently and/or allowing the maintenance of a therapeutic effect overnight. For instance, the use of nifedipine in the treatment of hypertension was initially not very effective as nifedipine is rapidly metabolised, and therefore has to be taken frequently, which patients find difficult to adhere to. With nifedipine SR, there is a slower dissolution of the tablet, and prolonged delivery, which allows nifedipine SR to be used twice a day, so nifedipine SR allows a more effective control of blood pressure.

Some drugs are ineffective when administered by the oral route as they are destroyed by the acid in the stomach e.g. erythromycin. Enteric-coated preparations are designed to prevent destruction by acid in the stomach, and this allows some of the drug, which would otherwise be destroyed by acid, to be effective after oral administration. The antibiotic erythromycin can be used in an enteric-coated preparation.

An important term that is often used in association with the use of medicines is bioavailability. Bioavailability is the fraction of an ingested dose of a drug that gains access to the systemic circulation. To reach the circulation (see Figure 1.3), drugs must penetrate the intestinal mucosa and avoid metabolism by the intestinal and liver enzymes. Drugs that reach the blood vessels of the gastrointestinal tract are carried in the blood supply directly to the liver by the portal vein. The liver is a major source of enzymes, and these enzymes are involved in the biochemical processes in the body. While, none of these enzymes have drugs as their natural substrates, they do metabolise drugs. Indeed, many drugs are inactivated by metabolism. After oral administration, drugs cannot avoid being taken to the liver. Metabolism after absorption from the gut is known as First Pass Metabolism. If drugs undergo extensive first pass metabolism after oral administration, they are often administered by another route to avoid this inactivation e.g. sublingual, rectal.

Figure 1.4 First pass metabolism (Copyright QUT University, Sheila Doggrell)

Whether drugs are administered orally or by other routes, they often end up in blood vessels, and, to reach their target site, have to then be absorbed from blood vessels. This occurs predominantly by diffusion. Cardiovascular disease can lead to low perfusion of tissues (e.g. in heart failure, there is low perfusion of tissues) and this can slow the absorption of drugs. Conversely, exercise increases blood flow, and will increase the absorption of drugs from the blood vessels in skeletal muscle.

In addition to oral administration, routes of drug administration include sublingual, rectal, injection, topical, and pulmonary. Each of these routes has both advantages and disadvantages when compared to oral administration.