Introduction:
Pharmacotherapy is considered the first line of treatment for any disease. Drugs target particular biomolecules and are responsible for changes in their form and functions. The action of the drugs is divided into several steps, which are influenced by several factors. Recently researchers have identified the effect of genetic factors on the action of drugs. Chronic gastrointestinal diseases are prevalent worldwide. Most of the time, such conditions are treated with different drugs. But, factors like genetic influence often provide hindrances in the path of the desired results.
What Is Pharmacogenetics?
Pharmacogenetics, or pharmacogenomics, is the branch of medicine that deals with the effects of genes on medications. So, the hereditary effects on drug metabolisms are studied in this field. In general, the choice of drug for a particular disease is determined on the basis of several factors like age, sex, pregnancy status, severity of the condition, and body type. However, researchers have discovered that in some circumstances, the medicine is not performing as it should. The main reason behind such complications is genetic factors. Genetic factors determine drug metabolisms and drug transportation. In 1957, Vogel coined the term pharmacogenetics. Genetic pleomorphism is one of the main reasons behind the altered action of drugs. Genetic pleomorphism is nothing but two or more variations of the specific DNA (deoxyribonucleic acid) sequencing present in an individual. This pleomorphism affects the genes that encode metabolic proteins, transporters, and drug receptors. All these factors cause the following changes:
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Primary changes can be seen in drug metabolism. The change in the drug metabolism can be of two types. In Phase I metabolism, the primary breakdown of the drug components takes place. In phase II, the altered drug compounds are conjugated with different compounds. In certain cases, alteration in both of these pathways takes place.
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Drugs are designed to target specific bio-molecules. Due to genetic factors, in some cases, drugs are unable to target designated biomolecules.
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Altered genetic functioning is associated with T-lymphocyte-mediated adverse drug reactions.
What Are the Application of Pharmacogenetics in Gastroenterology?
The application of pharmacogenetics can be seen in a wide variety of gastrointestinal diseases.
One of the main applications of pharmacogenetics can be seen in functional gastrointestinal disorders and in cancerous conditions. Functional gastrointestinal disorders are a group of chronic conditions that cause various complications like constipation, abdominal pain, abdominal discomfort, diarrhea, and abdominal bloating. Conditions like GERD or gastroesophageal reflux disease, inflammatory bowel disease, and irritable bowel syndrome belong to this category.
What Are the Implications of Pharmacogenetics on GERD?
GERD, or gastroesophageal reflux disease, is a chronic condition characterized by the retrograde flow of the stomach's contents to the esophagus. This causes increased acid exposure to the esophagus and esophageal lumen. As a result, erosion of the esophageal lining causes severe discomfort. One of the most commonly used drugs in this condition is proton pump inhibitors. This drug is also used in cases of peptic ulcers, esophagitis, and in Helicobacter pylori infection. The effects of pharmacogenetics on the functioning of proton pump inhibitors are:
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Cytochrome P450 enzymes play a pivotal role in the metabolisms of different proton pump inhibitors like Rabiprazole. CYP2C19, CYP2D6, CYP2C9, and CYP3A4/5/7 are the different enzymes that belong to this group. Among these, CYP2C19 is the primary enzyme associated with the bio-transformation of proton pump inhibitors. But, in three to five percent Caucasian population genetic pleomorphism is associated with the gene that encodes CYP2C19. These alterations are responsible for decreased activity of hydroxylase. As a result, the drug metabolism that is responsible for the alteration of the pH of the stomach is not formed. This causes increased concentration of the drug. Such patients required higher concentrations of drugs for therapeutic actions.
What Are the Implications of Pharmacogenetics in Inflammatory Bowel Disease?
The presence of different symptoms like altered bowel habits, abdominal pain, and abdominal discomfort characterizes inflammatory bowel syndrome. This condition is mainly seen prevalent in women and commonly seen in persons younger than 50 years of age. Azathioprine (AZA) is the key drug used in this disease. This drug helps to cure the inflammation of the gastrointestinal tract. This is also used as a steroid-sparing agent. As a result, the potentially harmful effect of steroids can be avoided. Thiopurine-S-methyltransferase (TPMT) is the primary liver enzyme that is useful in the digestion process of these drugs. Polymorphism of the gene present in chromosome 6 is associated with altered drug activity. As a result, decreased metabolism of Azathioprine causes the accumulation of metabolites like 6-mercaptopurine (6-MP). This has cytotoxic effects and causes suppression of the bone marrow.
Infliximab is a well-known biological therapeutic drug used for the treatment of inflammatory bowel disease. This drug act against the tumor necrosis factor-alpha and reduce the amount of inflammation. Polymorphism of the gene responsible for encoding tumor necrosis factor responsible for decreased functioning of Infliximab.
Polymorphism of the gene present on chromosome 20 is associated with altered functioning of the enzyme inosine triphosphate pyrophosphatase (ITPA). This enzyme is associated with the metabolism of Azathioprine. Decreased metabolism of Azathioprine leads to the accumulation of a substance known as 6-thioinosine triphosphate (ITP). Patients with such complications show symptoms of rash and flu-like symptoms.
What Are the Effects of Pharmacogenetics on Irritable Bowel Syndrome?
Irritable bowel syndrome is regarded as one of the main causative factors for inflammatory bowel disease. Irritable bowel syndrome causes abdominal pain, uneasiness, bloating, and gas formation. Gut mortality, sensation, and secretions are maintained by the serotonin receptors present in the gut. Alosetron, a drug mainly used for the treatment of diarrhea-predominant irritable bowel syndrome, is affected by genetic polymorphism. Alteration of the SLC6A4 gene causes decreased expression of serotonin rector 5- HT3. As a result, decreased function of the drug can be seen.
What Are the Application of Pharmacogenetics in Hepatology?
Liver failure may be caused by several factors, like cirrhosis of the liver, fatty liver, liver cancer, and liver failure due to heart disease. Such patients are often treated by liver transplantation. But, liver transplantation leads to immune suppression. Cyclosporine and Tacrolimus are often prescribed to such patients to fight against any infections. Cytochrome P450 3A4 enzymes expressed from the liver and intestinal epithelial cells are responsible for the metabolism of these drugs. Gene, known as CYP3A4, located in chromosome seven, is associated with the secretion of this enzyme. But in some cases, two variations can be seen in this gene. This causes lower genetic transcription and lower drug levels. As a result, an increased amount of drugs is needed in such patients.
Conclusion:
The action of the drugs is influenced by several factors. Genetic factors are one of them. The study of the genetic influence on drugs is known as pharmacogenetics. Modification of genetic functions is responsible for altered drug action in conditions like GERD, inflammatory bowel disease, and liver transplant.
