Malabsorption of Drugs in Gastrointestinal Diseases: a Review

 

Lakshmi Prasanna J.*, Deepthi B.*, Rama Rao N.

Department of pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Lam, Guntur- 522034

 

ABSTRACT:

Most long term treatments follow the oral administration due to its ease and convenience of administration. After oral administration of any drug, the plasma concentration time curve is a function of many simultaneously operating kinetic processes. The steady state plasma concentration is achieved when the amount of drug absorbed equals the amount of drug eliminated. Both amount and rate of drug absorbed may be altered by diseases which in turn alter other kinetic processes. The amount of drug absorbed is simultaneously affected by physicochemical factors of drug and physiological factors that operate in gut which are also altered by the disease state. The present review focuses on the way in which the absorption of drugs is altered in various conditions of gastro intestinal tract.

 

 

 

INTRODUCTION:

Diseases are the processes that alter the normal functions of the body. Therefore the normal functions involved in absorption of an extravascularly administered drug may be altered by disease there by affecting the bioavailability of the drug. So the effect of disease states on the bioavailability of drugs and it must be always taken into consideration when administering a dose to the patient. The largest group is the chronic gastro intestinal diseases which may alter the bioavailability of drug administered per orally by producing variation in both the amount of drug absorbed and the rate of absorption.¹ Alteration in drug absorption due to the changes in the gut pH will most likely influence the dissolution rate. Changes in the gastric emptying rate are expected to influence the rate and possibly the extent of absorption. Diarrhoea conditions may decrease drug absorptions a result of reduced intestinal residence time. As most drugs are best absorbed from the small intestine any surgical procedure that removes a substantial portion of small intestine is likely to influence drug absorption.^2,3

 

Changes in the amount of drug absorbed can alter the steady state (c_ss) plasma concentration of a drug. A reduced rate of drug absorption may lower the peak plasma concentration below the minimum required for its pharmacological effect. Impaired absorption also affects the timing of the peak plasma concentration and this in turn may alter the normal pharmacological response.⁴

 

The timing of the peak is theoretically important when using drug combinations. In these cases the peak plasma concentrations of the constituents of the combination may not occur at the same time as their peak plasma concentrations.⁵ Differences in the absorption rates of the components of the combined preparations alter the synchronization of these peaks.⁶ This review presents the ways in which various gastro intestinal diseases alter the drug absorption after oral administration of drugs.

 

Gastro intestinal diseases^7,8

Gastrointestinal tract starts with the mouth and terminates at the anus. All diseases that pertain to the gastrointestinal tract are labeled as digestive diseases or gastro intestinal diseases. This includes diseases of the esophagus, stomach, small intestine, large intestine and rectum¹. The gastro intestinal diseases that affect the pharmacokinetics of drugs include gastrointestinal motility, diseases of stomach, gastric and intestinal surgery, diseases of small intestine, diseases of large intestine, gastro intestinal infections.

 

Gastritis:

The term gastritis is generally employed for any clinical condition with upper abdominal discomfort like indigestion or dyspepsia. The main acute causes are excessive alcohol consumption or prolonged use of non steroidal anti-inflammatory drugs. Sometimes gastritis develops after major surgery, burns, or severe infections.  Chronic causes are infection with bacteria, primarily Helicobacter pylori, pernicious anemia, stress and certain autoimmune disorders.

 

 

Table 1:  Influence of disease on bioavailability

DISEASE	DRUG	CMax	TMax	RATE	EXTENT
Atrophy of villi	Chloramphenicol Isoniazid	- -	- -	U U	U U
Celiac disease	Cephalexin Methyldopa Propranolol	↑ ↑ ↑	↓ - ↓	↑ ↑ ↑	↑ ↑ ↑
Diverticulosis	Ampicillin Clindamycin	- -	- -	U ↑	U ↑
Crohn’s disease	Metranidazole Rifampin sulphamethazole	↑ - -	- - -	U U ↑	↑ U ↑

↑ - increased, ↓- decreased, U- unchanged, - not reported.

 

Peptic ulcer:

Ulceration involves the full thickness of the gastrointestinal mucosa. It may be viewed as an extension of the gastric erosions found in acute gastritis. It is associated with Helicobacter pylori. Ulcers can also be caused or worsened by drugs such as aspirin and other nonsteroidal anti-inflammatory drugs, local irritants.⁶ The treatment options include the use of antacids like magnesium hydroxide, aluminum hydroxide gel; histamine H₂ receptor antagonists like cimetidine, ranitidine, famotidine; proton pump inhibitors like omeprazole, rabeprazole, esmoprazole.

 

Coeliac disease:

Coeliac disease is also known as gluten enteropathy. This is due to an abnormal, genetically determined immunological reaction to the protein gluten, present in wheat. When it is removed from the diet recovery is complete. There is marked villous atrophy and malabsorption characterized by the passage of loose, pale colored, fatty stools. This results in the reduced overall surface area i.e., available for the absorption.

 

Steatorrhoea:

Steatorrhoea may be due to impaired micelle formation, primary disease or damage to the small intestine or the absence or a reduction in the supply of bile. Bile acids must be present in the small intestine for the formation of micelles and fat absorption. Obstructive jaundice prevents the secretion of bile into the gut and this leads to Steatorrhoea.

 

Small bowel diverticulosis:

Small intestinal diverticulosis is sac like out pouchings of the wall of the colon, occur in places where the muscularis has weakened and become inflamed. This may be due to intake of low fiber containing food.

 

Inflammatory bowel disease:

 Inflammatory bowel disease commonly includes two idiopathic bowel diseases such as crohn’s disease and ulcerative colitis. Crohn's disease is an inflammatory disease of the intestine that may affect any part of the gastrointestinal tract from mouth to anus. The most commonly associated symptoms of crohn's disease include abdominal pain, diarrhoea, vomiting, weight loss, skin rashes, arthritis and inflammation of the eye. Treatment may include the administration of 5-aminosalicylic acid formulations, prednisolone, and immunomodulators such as

 

azathioprine, mercaptopurine, methotrexate, infliximab, adalimumab, certolizumab and natalizumab.

 

Altered absorption in gastro intestinal diseases:

Physiological factors within the gastro intestinal tract that effect the per oral drug absorption include gastric emptying rate, intestinal motility, p^H of the gastro intestinal fluids, activity of gastro intestinal drug metabolizing enzymes and surface area of the gut.¹ All these factors can be affected by pathological states. Altered absorption of drugs with respect to these factors is discussed here. Influence of different gastro intestinal diseases on various parameters of absorption/ bioavailability is given in Table1.

 

Rate of gastric emptying:

The rate of gastric emptying is not a disease but it may be a consequence of several diseases. Any condition/state that would increase or decrease stomach emptying might alter the rate at which a drug is absorbed. Disease states such as atropic gastritis, gastric carcinoma, pyloric stenosis, pancreatitis or gastric ulcer delay the gastric emptying where as other conditions such as celiac disease, cholecystis, duodenal ulcer, stress and gastro enterostomy accelerate gastric emptying.⁹

 

Malabsorption of levodopa occurs in some patients due to delayed gastric emptying which increases the exposure of levodopa to destruction by gastric decarboxylase there by reducing the plasma concentration of levodopa which can lead to therapeutic failure. The advent of combined preparations of levodopa with a decarboxylase inhibitor can reduce this problem. The rate of gastric emptying can also be altered by the use of metaclopromide, atropine, propantheline, strong analgesics and the tricyclic anti depressants.

 

Metaclopromide is used to reduce the risk of vomiting during induction of an emergency anaesthetic and during labor. Metaclopromide increases the availability of levodopa by delivering it more rapidly to the site of absorption. The time to attain peak plasma levels is reduced and multiple peaks in the absorption profile are eliminated. Although metaclopromide may antagonize dopaminargic action of levodopa, it has been widely used to reduce nausea and vomiting that follows large doses of levodopa. Metaclopromide also improves the absorption of effervescent aspirin taken by patients with migrane.⁴ Factors that influence gastric emptying and the effect of

altered gastric emptying on drug absorption were given in tables 2&3 respectively.¹

 

Gastro intestinal motility:

Rapid intestinal transit owing to diarrhoea may alter, reduce or inhibit drug absorption. This would present a problem for lipid soluble drugs, slow release and enteric coated formulations. The reduced urinary excretion of sulphafurazole and delay in the absorption of aspirin, that is a feature of lactose intolerance is probably due to the rapid transit of these drugs past their absorption sites.¹⁰ Children with acute bacillary dysentery do not absorb adequate amounts of ampicillin or nalidixic acid.¹¹

 

Table 2: Factors that influence the rate of gastric emptying

PATHOLOGICAL FACTORS	GASTRIC EMPTYING RATE
Gastric ulcer	Increases
Duodenal ulcer	Decreases
Malnutrition	Decreases
Pyloric stenosis	Decreases
Intestinal obstruction	Decreases

 

Table 3: Effect of altered gastric emptying on drug absorption

DRUG	GASTIC EMPTYING RATE	EFFECT
L-Dopa	Decreased	L-Dopa metabolised in stomach
L-Dopa	Increased by metaclopramide or gastrectomy	Increased rate of absorption
Aspirin	Decreased by migraine	Decreased absorption; therapeutic failure
Digoxin tablets	Increased by metaclopramide	Decreased rate of absorption.
Penicillin	Decreased	Penicillin is inactivated in stomach

 

Influence of pH:

Achlorhydria has been studied for its effects on drug absorption to know the influence of pH. There are contrasting reports on aspirin and phenoxy methyl penicillin in this condition. Absorption of aspirin was reduced in few patients where as rapid absorption was found in some patients. Reduced plasma concentrations were found with phenoxy methyl penicillin in some patients and no differences in plasma concentrations was observed in others.⁴ The differences in these studies were mostly due to the differences in gastric emptying rate in the two groups of patients with achlorhydria.¹²

 

 

Malabsorption of drugs in coeliac disease:

Impaired absorption/ malabsorption of nutrients and water from the intestine is not a disease but it is a result of disease cause. One or more changes such as atropy of villi of the small intestine mucosa, incomplete digestion of food, influence with the transport of absorbed nutrients from the small intestine to the blood. In celiac disease due to the destruction of numerous villi the overall surface area available for absorption is reduced considerably. This is also associated with enzyme deficiencies.¹

 

There are 4 different patterns of antibiotic absorption in this disease condition, namely increased, delayed, reduced, and normal. The absorption of pivampicillin is reduced in this

 

condition. This may be due to the deficiency of small gut esterase necessary for the hydrolysis of the inactive form of drug to the active drug.^1,13,14 Absorption of water soluble drugs such as amoxicillin and practolol is also delayed in celiac disease.^13,15 Plasma levels of propranolol are increased in celiac disease. Propranolol is a basic drug and it binds to α-1 acid glycoprotein. A high correlation was found between the levels of α-1 acid glycoprotein and binding of propranolol. In these diseases, in which α-1 acid glycoprotein levels are elevated, the increased binding of propranolol causes a distribution shift that favors drug concentration in plasma giving rise to increased circulating drug concentrations.

 

There are several pathophysiological abnormalities in celiac diseases, any or all of which may alter the normal pattern of drugs absorption. Gastric emptying is more rapid in celiac disease. This could lead to more rapid delivery of the stomach contents including the drug to the upper jejunum. The intraluminal p^H is sometimes increased in celiac disease. The absorption of practolol, a drug with a p^ka of 9.5 is delayed in celiac disease. This may be due to the reduced solubility of practolol at a high p^H .Increased plasma concentration of cephalexin, sodium fusidate, sulphamethoxazole and trimethoprim occurring in untreated celiac disease may be due to increased mucosal permeability.^1,4 Effects of various altered physiological conditions on drug absorption in celiac disease were given in Table 4.

 

 

 

 

 

Table 4: Abnormalities in gluten enteropathy that may alter drug absorption

ABNORMALITY	POSSIBLE EFFECT
Increased rate of gastric emptying	Drugs delivered more rapidly to their site of absorption
Increased permeability of gut wall	Increased transport of those drugs absorbed by passive non ionic diffusion
Enzyme deficiencies at the  brush borders	Impaired hydrolysis of esterified drugs (pivampicillin) to their constituents
Altered intestinal drug metabolism	Increase absorption of unchanged drug
Steatorrhoea	Malabsorption of lipid soluble drugs(vitamins A,D, ,K)
Reduced entero hepatic recycling of bile acids	Impaired absorption of drugs which require normal micelle formation for optimum absorption

 

 

 

Malabsorption of drugs in crohn’s disease:

In crohn’s disease marked alterations in plasma AUC have been observed after oral administration of lincomycin, trimethoprim and sulphamethoxazole. Normally peak plasma concentrations occur at 2 hours, but in crohn’s disease the peaks occur at 4 hours. There is a disproportionate increase in the absorption of sulphamethoxazole from co- trimoxazole compared with trimethoprim. This alters the optimum synergistic ratio of trimethoprim to sulphamethoxazole so that there is an excess of sulphamethoxazole. Plasma levels of propranolol appear to be increased in treated patients with crohn’s disease. The absorption and activity of some drugs such as sulphasalazine can apparently be affected by the presence of bacteria in the gut wall which metabolize the drug. Under usual circumstances, sulphasalazine is partially absorbed in the small intestine. The remaining portion of the drug is then metabolized by bacteria in the large bowel, the molecule being cleaved at the azo linkage into aminosalicylate and sulpharidine. The lack of effect of the drug is permanent in those with a colonic resection because sulphasalazine requires the presence of colonic bacteria for biotransformation to its active component.

 

Disproportionate absorption rates of the components of fixed drug combinations (Co-trimoxazole) occurs in crohn’s disease. This alters the ratio of trimethoprim to Sulphamethoxazole in the plasma so that in patients with crohn’s disease the ratio of these drugs in the plasma is far from the optimum that is required to produce maximum antibacterial synergy. Important factors with in the gut that effect the drug absorption include metabolism of the drug by gut enzymes or gut bacteria and the presence of food or the other drugs in the gut. Levodopa is in part metabolized by the gut wall bacteria and in patients with an abnormal gut bacterial flora, the amount of Levodopa available for absorption is decreased.^{6, 16-19} Altered drug absorption due to the changes in physiological conditions in this disease is given in Table 5.

Table 5: Abnormalities in Crohn’s disease that may alter drug absorption

ABNORMALITY	POSSIBLE EFFECT
Reduced surface area available for absorption	Malabsorption of drugs whose optimum site of absorption is at the site of disease
Thickening of bowel wall	Impaired drug diffusion, malabsorption
Bowel flora changed to a predominantly anaerobic population	Absorption patterns of drugs which are active against  anaerobes (lincomycin, metronidazole)
Slower intestinal transit	Unpredictable absorption of orally administered drugs.

 

Malabsorption of drugs in other gastro intestinal tract conditions:

Gastrectomy decreased the peak plasma concentration of cephalexin while the absorption of ampicillin was unchanged. Iron and folic acid were poorly absorbed where as p-aminosalycilic acid was well absorbed. While oral administration would not normally be employed in the presence of intestinal obstruction, undetected changes in gastric emptying can alter the absorption of orally administered drugs.

 

Bacterial over growth in the upper small intestine is a pathological condition most prevalent in the elderly people. It can be of clinical significance during chronic digoxin administration. Bacterial over growth has been reported to enhance the gastro intestinal conversion of digoxin to one of its inactive (dihydrodigoxin) with a resultant decrease in the bioavailability of digoxin.²⁰

 

Other gastro intestinal conditions such as intestinal obstruction, pancreatic disorders, and small bowel diverticulosis may alter the drug absorption. Chronic pancreatitis and obstructive jaundice prevents the secretion of bile into the gut and this leads to steatorrhoea which in turn alters the drug absorption.⁴

 

 

 

Fig 1: Effect of crohn’s disease on intestinal wall.

 

CONCLUSION:

The potential for impaired absorption of drugs in gastro intestinal diseases is large and needs further systematic study. The physiological state of the patient including the degree of physical activity may alter the bioavailability of drugs. Thus malabsorption due to patient variability as well as disease state must be considered during prescribing a dose to a patient.

 

ABBREVIATIONS:

C_Max: peak plasma concentration, T_Max: time to reach peak plasma concentration, AUC: area under curve

 

ACKNOWLEDGEMENTS:

The authors are thankful to Chalapathi Institute of Pharmaceutical Sciences for providing facilities for bringing out this review.

 

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Received on 25.10.2012       Modified on 16.11.2012

Accepted on 23.11.2012      © RJPT All right reserved