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Pharmacogenetics: Variability in drug responses attributed to individual genes
#1
Pharmacogenetics can be defined as the study of genetic response related to drug response. Pharmacogenetics is a combination of Pharmacogenomics: the study of entire genome related to drug response, Pharmacokinetics: drug metabolism and Pharmacodynamics: interaction between drugs and their molecular targets. This is crucial where genetics come to control medicines. In general people say, a certain medicine would not work for one person, while another person can get healed from that for the same disease. Medical Practitioners ask the patient before prescribing medicine about drugs that may cause adverse reactions in their body which may be an antibiotic or any other kind of drug. These adverse reactions caused by drugs in certain people are most of the time genetically inherited. Therefore it is important to take a look at family history, when taking medicine as some responses may be fatal.

During the study of drug metabolism, it’s important to pay attention on absorption of drugs from gut, distribution, drug cell interactions, breakdown of drugs in liver and excretion.

Isoniazid is a drug used for the treatment of tuberculosis. After this drug is absorbed from gut, the level of the drug in blood is initially high and reduces slowly in healthy people. Due to genetic errors, the inactivation of the drug can be slow or rapid in some people. In rapid inactivators, the level of drug decreases rapidly in the blood. In contrast, the level of the drug remains high for some time in slow inactivators. Slow inactivators of this drug are homogenous for autosomal recessive allele which encodes liver enzyme N-acetyl transferase. High levels of isoniazid in blood can be harmful as it causes some side effects such as liver damage. Slow inactivators have a greater risk for this.

Succinyl Choline is a drug that is used for relaxation of muscles that was introduced in 1950’s. It is used in the induction phase of anesthesia which is metabolized by plasma enzyme cholinesterase. In sensitive patients, destruction is slower and resulted in respiratory arrest with the intake of the drug. Succinyl choline sensitivity is inherited as an autosomal recessive trait which is caused by mutations of CHE 1 gene. Sensitive patients can now be identified by a blood test that monitors cholinesterase activity.

Primaquinone is a drug used in treatment for Malaria. Some people were found to be sensitive to this drug. The sensitive people can take the drug for few days without any side effects, but starts to pass very dark/black urine. Jaundice, reduction in red blood cell count and Hemoglobin are symptoms produced by these sensitive people in response to the drug. This occurs due to a deficiency of the enzyme, Glucose 6-phosphate dehydrogenase which is a X linked recessive trait found commonly among Mediterraneans. Patients with the deficiency of this enzyme are also sensitive to drugs such as Phenacetin, Nitrofurantan, Sulfonamides. These drugs should be carefully used for treatments of these patients.

Coumarin(Warfarin) is an anticoagulant which is used in treatments for many diseases to prevent blood clotting. This drug is metabolized by cytochrome P450 encoded by the gene CYP2C9. Isoenzyme 2C9 is the functional enzyme in metabolizing the drug. VKORC1 is another gene important for degradation of this drug. This gene is involved in the production of target enzyme for warfarin action and it converts Vitamin K into an active form which activates Vitamin K dependent clotting factors.
Debrisoquine is used in the treatment of hypertension and it’s a derivative of guanidine. Many Europeans are poor metabolizers of this drug. This metabolic defects are due to an allele which is homozygous for autosomal recessive gene; CYP2D6 in P450 gene in chromosome 22. A mutation in this gene results in poor metabolism. This gene is involved in metabolism of many drugs.

Leukemia is also known as blood cancer. Thiopurines are used to suppress immune response in autoimmune conditions in patients with transplanted organs. This drug has serious side effects including severe liver damage. Poor metabolism of this drug is due to variations in thiopurine methyl transferase activity which is involved in methylation of thiopurines. This variability caused by genetic differences between people is one of the best examples for the importance of Pharmacogenetics in medicine.
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#2
Importance of pharmacogenomic testing

Different people react differently to a prescribed drug. The reason is genetic polymorphism resulting in interindividual variability in a drug response. More than half of the drug metabolizing enzymes are polymorphic, and when they fail to “digest” the drug properly – toxic effect is inevitable. Luckily, a lot of examples of genetic polymorphism are already well known and they could be tested using various methods.

Drug application could result in severe adverse effects and those are the leading cause of death in USA hospitals (hundreds of thousands patients annually), plus hundred billion dollars are spent as additional cost. However, testing patients before prescribing drugs is not a common practice as it’s still expensive. Insurance companies are not covering costs for genetic polymorphism testing since clinical trials are lacking evidence that tests would benefit both patient and the health system.

Most common type of genetic polymorphism is single nucleotide polymorphisms (SNPs) resulting in different gene product. Single DNA base substitutes could alter mRNA processing and translation (structural RNA polymorphisms), transcription (regulatory polymorphisms) or protein sequence and function (polymorphisms in coding regions). Genome wide association study or GWAS is project whose purpose is to discover connection between single nucleotide polymorphism (in the large group of people) and their clinical traits. However, just couple proved to be clinically relevant our of the numerous SNPs candidates. Several key factors need to be fulfilled before genetic testing becomes routine procedure. First, genetic variant candidate needs to be identified. It’s important to confirm how often allelic variant is present in the population. If it’s rare, there’s no point wasting time and money on the research that will not be beneficial to a large group of patients. Association between genetic candidate and phenotype needs to be precisely determined. Clinical trials will determine whether genetic testing could improve current health care system. Cost effectiveness will show how profitable genetic testing could be, can it save or improve patient life, how it will affect clinical events….Finally, when all those steps prove that genetic tests are important, they could become a standard in a health care. FDA will recommend genetic testing through product labels or demand testing prior prescribing drugs to a patient at a high genetic risk.

Why all this is so important?

Warfarin is used to prevent thromboembolic events but it has one of the highest rates of the adverse effects compared to other single used drugs. Out of 2 million patients starting Warfarin therapy each year, around 20% are hospitalized due to bleeding in the first 6 mounts of the treatment. Problem lays in the polymorphism of CYP2C9 and VKORC1 genes. First one is metabolizing the drug, and other is drug’s target. Polymorphism in CYP4F2 and GGCX genes could also influence drug metabolism and activity. Tests for CYP2C9 and VKORC1 genetic polymorphisms are available, but due to lack of clinical evidence of their importance they are not used routinely prior prescribing the drug. When SNPs are determined precisely - Warfarin dose can be adjusted and adverse effects could be avoided. Alternatively, several other marketed drug thinners should be prescribed instead of Warfarin.

Clopidogrel protects against atherothrombotic events and could be combined with aspirin to prevent cardiac stent thrombosis. That is a pro-drug undergoing transformation by CYP2C19 when ingested. People having non functional CYP2C19 allele can’t convert prodrug into chemically active form and they are dealing with recurrent cardiovascular disorders. In a one year study, 21% of patients taking Clopidogrel have experienced cardiac ischemia or died during the study due to inability to convert pro-drug into drug. Routine genetic testing or dose adjustment is still not recommended, but FDA stated in the box warning section that CYP2C19 poor metabolizers could lack positive effect of a drug.

Codeine is an opiate showing analgesic, antitussive, anti-hypertensive and sedative effects. It’s converted into more active form by CYP2D6. In 2006, 14 days long Codeine therapy in the breastfeeding mother resulted in a death of her baby. Both mother and baby were rapid CYP2D6 metabolizers which resulted in extensive conversion of the Codeine to a Morphine and death due to overdose. This case is considered to be a rare genetic variation that resulted fatally and genetic testing is not considered important before Codeine is prescribed.

All people are different and unique and will react differently to a prescribed drug. Genetic testing could help determine appropriate dose or type of medication, but due to high price it’s not economical at the moment. Hopefully, greater demand and need for this kind of tests would reduce the price and ensure more efficient and safe future treatments.
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Pharmacogenetics: Variability in drug responses attributed to individual genes00