Adverse drug reactions – The genetic factorFebruary 7, 2020
Adverse drug reactions (ADRs) are a significant cause of hospitalisations and deaths the world over. ADRs to treatments are estimated to affect between 7 percent and 14 percent of patients in US hospitals.
No systemic data pertinent to drug reactions are available with hospitals in India.
Many of the “one size fits all” drugs currently available don’t always benefit everyone the same way. A drug which may work wonders for one could prove dangerous for another and itt may not work at all for some others.
Therefore, it is often difficult to predict the efficacy of drugs.
It is now clear that the sequence of a person’s genome can determine how he or she responds to certain medications.
The rather nascent field of pharmacogenomics combines pharmacology with the knowledge gained from Human Genome Project. Optimising treatments and avoiding adverse reactions are key objectives of healthcare professionals. Pharmacogenomics helps tailor a person’s medications based on their genome.
Many of the common, widely used drugs are associated with serious adverse reactions.
People with clopidogrel resistance who receive the anti-platelet drug are at a risk of serious, sometimes fatal, complications.
CYP2C19 gene polymorphisms account for most of the variations in clopidogrel activation due to genetic factors. Polymorphisms in other genes likely have smaller effects on clopidogrel activation.
The two most common CYP2C19 gene polymorphisms associated with clopidogrel resistance (known as CYP2C19*2 and CYP2C19*3) result in the production of a non-functional CYP2C19 enzyme, which fails to convert clopidogrel to its active form. Without active clopidogrel to interfere, the P2RY12 receptor, which helps platelets to cluster together to form a clot to seal off damaged blood vessels and prevent blood loss, continues to promote platelet aggregation and blood clot formation.
Clopidogrel resistance is inherited in an autosomal codominant pattern, in which two different versions of the gene are expressed, and both versions influence the genetic trait.
About half of individuals with Asian ancestry have clopidogrel resistance, with 10 percent of these individuals classified as poor metabolizers who process little or no clopidogrel.
Warfarin sensitivity is a condition in which individuals have a low tolerance for the anticoagulant.
The polymorphisms associated with warfarin sensitivity often differ by population and ethnic background.
Polymorphisms in the CYP2C9 and VKORC1 genes account for most of the variation in warfarin metabolism.
The CYP2C9 enzyme is responsible for breaking down steroids, fatty acids and certain drugs, including warfarin.
Several CYP2C9 gene polymorphisms decrease the activity of the CYP2C9 enzyme and slow the body’s metabolism of warfarin. As a result, the drug remains active in the body for a longer period of time, leading to warfarin sensitivity.
The average dose (or more) of warfarin can cause abnormal bleeding in the brain and gastrointestinal tract in warfarin-sensitive people.
Another enzyme that plays an active role in blood clotting is VKORC1. Certain VKORC1 gene polymorphisms decrease the amount of functional VKORC1 enzyme available to activate clotting proteins. Individuals with such a condition require a lower warfarin dose to inhibit the VKORC1 enzyme, as there is less functional enzyme that needs to be suppressed.
The polymorphisms associated with this condition are inherited in an autosomal dominant pattern, in which one copy of the altered gene in each cell is sufficient to result in warfarin sensitivity.
Stevens-Johnson syndrome (SJS) is a severe allergic reaction caused by infections as well as by very common medications like NSAIDS, anti-seizure drugs and antibiotics. SJS can progress to toxic epidermal necrolysis (TEN), an even worse condition. TEN is diagnosed when patients have shed at least one-third of the skin off their bodies.
SJS and TEN are no longer considered two different diseases and are now considered part of a continuum in which the former represents the less severe end of the disease spectrum, while the latter represents the more severe end.
Beginning with a fever and flu-like symptoms, SJS/TEN soon progresses to blisters and peels in the skin, forming very painful raw areas called erosions that resemble a severe hot-water burn.
The painful blistering can also affect the urinary tract, genitals, the conjunctiva and the cornea.
Severe damage to the skin and mucous membranes makes SJS/TEN a life-threatening disease.
Changes in several genes that are involved in the normal functioning of the immune system have been found to increase the risk of SJS/TEN.
The genetic variation most strongly associated with SJS/TEN occurs in the HLA-B gene. The HLA complex helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders (such as viruses and bacteria). The HLA-B gene has many different normal variations, allowing each person’s immune system to react to a wide range of foreign proteins. Certain variations in this gene occur much more often in people with SJS/TEN than in people without the condition.
The drugs most frequently associated with SJS/TEN include carbamazepine, lamotrigine, phenytoin, allopurinol, sulfonamide antibiotics, nevirapine and oxicam groups of NSAIDs.
SJS/TEN is not an inherited condition. However, the genetic changes that increase the risk of developing SJS/TEN can be passed from one generation to the next.
Nevertheless, most people with genetic variations that increase the risk of SJS/TEN never develop the disease, even if they are exposed to drugs that can trigger it.
Thiopurine S-methyltransferase (TPMT) deficiency leads one to lose the ability to process thiopurine drugs such as 6-thioguanine, 6-mercaptopurine and azathioprine.
People with TPMT deficiency are at the highest risk of haematopoietic toxicity with thiopurine drugs.
Many clinicians recommend TPMT activity levels be tested before thiopurine drugs are prescribed to avoid bone marrow damage.
Changes to the TPMT gene have been found to result in the deficiency.
TPMT gene mutations reduce the stability and activity of the TPMT enzyme, which is responsible for ’turning off’ these drugs. So, they stay in the body longer and continue to destroy cells unchecked, leading to potentially life-threatening myelosuppression.
Studies suggest that less than 1 percent of individuals in the general population have TPMT deficiency. Another 11 percent have moderately reduced levels of TPMT activity.
TPMT gene activity shows an autosomal codominant inheritance pattern. People with two low-activity copies of the TPMT gene in each cell have TPMT deficiency and are at the greatest risk of developing haematopoietic toxicity when treated with thiopurine drugs unless they are given much less than the usual dose. People with two high-activity copies have normal TPMT activity and do not have an increased risk of haematopoietic toxicity with thiopurine drug treatment.
Malignant hyperthermia (MH) is a condition that triggers a severe reaction to certain drugs used as part of anaesthesia for surgery.
This reaction occurs in response to some anaesthetic gases. If given these drugs, people at risk for MT may experience muscle rigidity, rhabdomyolysis, high fever, acidosis and a rapid heart rate. The complications of malignant hyperthermia can be life-threatening.
Mutations in the RYR1 or CACNA1S gene cause the RYR1 channel to open more easily and close more slowly in response to certain drugs. An increase in calcium ion concentration within muscle cells also activates processes that generate heat and produce excess acid.
The genetic causes of several other types of MH (MHS2, MHS4 and MHS6) are still under study. Susceptibility to MH is probably more frequent, because many people with an increased risk of this condition are never exposed to drugs that trigger a reaction, according to the NIH website.
At least six forms of MH susceptibility are described, which are caused by mutations in different genes. Mutations in the RYR1 gene are responsible for a form of the condition known as MHS1. These mutations account for most cases of MH susceptibility. Another form of the condition, MHS5, results from mutations in the CACNA1S gene. These mutations are less common, causing less than 1 percent of all cases of MH susceptibility.
MH susceptibility is inherited in an autosomal dominant pattern.