DRUG INTERACTIONS ( CASE STUDIES RELATED TO ALTERED DRUG ABSORPTION - 2 )

CONTINUATION OF MY PREVIOUS BLOG...........

ii) COMPLEXATION AND ADSORPTION :

a) TETRACYCLINE-METALS :

The interaction between tetracycline derivatives and certain metal ions is well known. Tetracyclines can combine with metal ions such as calcium, magnesium, aluminium and iron in the gastrointestinal tract to form complexes that are poorly absorbed. Thus, administration of certain dietary items (example, milk, containing calcium) or drugs (example, antacids, iron preparations, products containing calcium salts) to patients on tetracycline therapy could cause a significant decrease in the amount of tetracycline absorbed. Some early tetracycline capsule formulations contained dicalcium phosphate as a filler and it was observed that tetracycline was not being effectively absorbed so various adjuvants were added to the formulations in an effort to improve absorption and produce higher blood levels. Such approaches, included the addition of citric acid, glucosamine and potassium metaphosphate in formulations of tetracycline. When excipient calcium phosphate was replaced with lactose, the availability of tetracycline enhanced. Since the new formulations did not contain calcium, higher blood levels were achieved.

NOTE : Absorption of DOXYCYCLINE and MINOCYCLINE is not markedly influenced by simultaneous ingestion of food or milk and one of these agents is preferred to tetracycline when gastric irritation occurs. However, concurrent administration of aluminium hydroxide gel decreases absorption of these analogues also. When two drugs are recognized as being capable of interacting, it is believed that one of them should be discontinued. In the case of antacid tetracycline interaction, problems can be avoided by allowing an appropriate interval of time to separate administration of the two agents. A minimum period of one to two hours should elapse between administration of the drugs; i.e. administer tetracycline one hour before or after food and milk intake.

b) CHOLESTYRAMINE and COLESTIPOL :

Complexation might occur when the drugs like cholestyramine and colestipol are used. These materials which are not absorbed from the gastrointestinal tract, bind with bile acids and prevent their reabsorption. In addition to binding with bile they also bind with drugs that are present in gastrointestinal tract. Cholestyramine can interfere with absorption of thyroid hormone and the interference can be minimized by allowing the interval of at least four hours between the administration of two agents. It is also indicated that cholestyramine can significantly decrease MEAN PLASMA WARFARIN LEVELS and the HYPOTHROMBINEMIC EFFECT of this anticoagulant is not observed even after a three-hour interval between ingestion of the two drugs. Prolonged administration of cholestyramine can decrease absorption of fat soluble vitamins such as VITAMIN K. This could lead to increased bleeding tendencies in some patients if the vitamin K intake is not increased.

c) ANTIDIARRHOEAL MIXTURES and ANTACIDS :

Since antidiarrhoeal mixtures can adsorb toxic substances responsible for causing diarrhoea, they might also adsorb certain medications that are administered concurrently, resulting in a decrease in their absorption. Administration of antidiarrhoeal preparations can decrease the bioavailability of PROMAZINE, TETRACYCLINE, DIGOXIN and LINCOMYCIN. Diarrhoea has been associated with the use of lincomycin. Since kaolin-pectin mixtures (example, PECTOCAB) are often used in treating diarrhoea, studies were conducted to determine the effect of this mixture when given at the same time as lincomycin. Serum levels of the antibiotic were reduced in some patients to about one-tenth the levels achieved when the patients were fasting. Absorption of digoxin is significantly reduced by simultaneous use of kaolin-pectin mixtures or antacids. In one study, coadministration of a kaolin pectin suspension and digoxin, delayed absorption of the latter and decreased by 62% the amount absorbed. When the antidiarrhoeal preparation was given two hours before the digoxin, the absorption rate was not affected although the extent of absorption was reduced by about 20%. When the antidiarrhoeal was given two hours after the digoxin, neither the rate nor the extent of absorption was altered. It has been reported that concomitant use of a magnesium trisilicate-aluminium hydroxide type of antacid resulted in significant lowering of CHLORPROMAZINE, attributed to decreased absorption resulting from adsorption of the PHENOTHIAZINE. Administration of the antacid at least one hour before or two hours after the phenothiazine is a solution to the problem.

d) ANTACIDS :

In addition to those already discussed, there have been a number of other reports of interactions attributed to antacid-induced alteration of absorption. For example, administration of ALUMINIUM HYDROXIDE GEL has been reported to decrease absorption of ISONIAZID. Studies suggest that aluminium hydroxide gel will delay gastric emptying time, although the mechanisms of adsorption/complexation and elevation of gastric pH cannot be excluded as contributing factors. In what manner and to what extent magnesium and calcium salts which are commonly used in antacids influence gastric emptying has not been adequately studied and different antacid preparations exhibit varying effects relative to the absorption of another drug administered simultaneously. Unless there is a specific reason for administering the two agents simultaneously, a general guideline for concurrent use would be to give the antacid separately from other agents in the patient's therapeutic regimen, allowing as long an interval as possible - but at least one hour - to elapse between the administration of the two agents.

e) FOOD :

It is well known that food can influence absorption of a number of drugs. In some cases absorption may be delayed and not reduce, while in others, the total amount of drug absorbed may be reduced. The effect of food in influencing drug absorption is often due to its action in slowing gastric emptying rate. Food may, also effect absorption by binding with drugs, by decreasing access of drugs to sites of absorption, or by decreasing the dissolution rate of solid dosage forms.

The presence of food in the gastrointestinal tract will adversely affect absorption of many ANTI-INFECTIVE AGENTS. Although there are some exceptions, it is recommended that PENCILLIN DERIVATIVES, TETRACYCLINES, ISONIAZID, RIFAMPIN and LINCOMYCIN be given at least one hour before or two hours after meals to achieve maximal absorption. In many hospitals drug administration time schedules may closely correspond to times at which meals are served. It is important that a proper dosage schedule for these antibiotics and other drugs that should be administered apart from meals, be established. Food may enhance absorption of selected drugs. Absorption of NITROFURANTOIN and HYDROCHLOROTHIAZIDE has been reported to be enhanced in the presence of food, probably as a result of the delay in gastric emptying.

The bioavailability of PROPRANOLOL and METAPROLOL is observed to be enhanced in presence of food. Both of these drugs are subject to extensive first pass metabolism in the liver after oral administration. It is suggested that transient increase in hepatic blood flow associated with ingestion of food may reduce the first pass metabolism resulting in increased bioavailability.

Food has also been reported to enhance bioavailability of the active metabolite of SPIRONOLACTONE. The absorption of spironolactone is incomplete because of its low water solubility and it is suggested that food induced delay in gastric emptying may promote disintegration of tablets and dissolution of the drug. Another possibility is due to enhanced solubility of spironolactone by cholic acids secreted in response to food.

Ingestion of a fatty meal can increase absorption of GRISEOFULVIN and this approach is used to advantage with this incompletely absorbed agent. It has been reported that food is likely to alter the extent of absorption of DIGOXIN when given with high fibre meal. (Example, bran flakes). Therefore it has become mandatory to study food effects while investigating new drug formulations.