Adverse reactions to drugs can be sudden or develop over time and it has been acknowledged that many different patients have a varying response to drugs and toxicity. This can be debilitating and often fatal and can be affected by bother over the counter medication and prescription medication.
In this essay I am going to discuss why drug reactions occur and whether they are avoidable.
All new drug molecules have to go through many phases during discovery and development and can take up to 20 years from discovery to development. These phases are :-
Once a new drug has met all the above targets it is then ready for clinical trials, of which there are three phases. These trials examine the pharmacological actions of the drugs in humans and look extensively into the overall benefit-risk relationship of the drug. Once this has happened the drug is ready to be marketed to the population in which there are further marketing studies carried out, this is where adverse reaction reporting is examined at great length this is very important to the pharmaceutical companies in regards to any legal action and future revenue.
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Adverse drug reactions (ADR's) occur in a variety of the population but are found more commonly in the elderly due to health and the fact that many elderly have a lot of different ailments which requires more than one drug, this is referred to as polypharmacy. There are 2 times of ADRs these are Type A - intrinsic which is usually dose dependent and Type B - idiosyncratic this type is more serious and not dose dependent (1)
There have been a number of studies carried out looking at hospital admissions due to adverse drug reactions. Patel et al (2007) carried out one of these studies to examine trends in hospital admissions due to adverse drug reactions in hospitals in England between 1998 and 2005. They found that over this period of time there were 447, 071 ADRs and in 2005 there were 76,692 drug related adverse reaction admissions. The most implicated class was antineoplastic drugs with 15.7% then analgesics with 11.7% these are followed by cardiovascular drugs with 10.1%. Patients over the age of 60 were in the majority with 59% of cases. (1) There are many drugs that cause ADRs but a list of the most commons can be seen in table 1 (2)
Pirmohamed et al (2005) carried out a study looking at two hospitals in England over a period of 6 months in 2001 to 2002, analysing 18,820 admissions over the two hospitals. Through their observations they concluded that ADRs accounted for approximately 6.5% of admissions, and many deaths of which 72% were classed as avoidable. (2)
A study carried out by Hopf et al (2008) looking at hospital admissions due to ADRs in a Scottish hospital, they looked at a smaller number of patients. Over a two week period 1,101 patients were observed and 30 of these patients were confirmed as being admitted to hospital with ADRs as with Patel et al and Pirmohamed et al they found that the majority of ADRs were within the female population and the elderly see table 2) (3)
The data collected from these studies show that ADRs are a major burden to the public and to an overstretched NHS of which the majority are avoidable. There are a few ways in which ADRs can be avoided including more informative clearer information leaflets and education starting at school especially with over the counter medication. Pharmacogenomics is at the forefront of drug discovery and development and has been gaining momentum for the past few years and will be especially beneficial with prescription medicines and personalised medication.
Through these studies it has also shown that ages, sex, gender and race are factors in ADRs and perhaps through pharmacogenomics personalised medication may be a promising solution in alleviating the burden on the population and the NHS.
Variations in the human genome sequences may be responsible for many ADRs and the efficacy of drugs that each individual takes. The technology of pharmacogenomics can give us information about the genes involved in drug metabolism giving us a greater understanding that will allow us to prevent ADRs, improving overall prescribing safety and efficacy. Although we know the human genome sequence and how certain drugs interact with the body we are still not at the point where we can use personalised medication on the general population this is perhaps due to the cost and ethical issues surrounding this technology.
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Mancinelli et al (2000) carried out a review looking at pharmacogenomic and how this would allow us to move forward from a one drug for all process, towards personalised medicine. There are many enzymes and receptors in the human genome that have variations that affect responses to drugs (see table 3). Cytochrome P450 enzyme is of particular interest to pharmaceutical companies of which there is extensive research carried out. This is due to the important role that these enzymes have on the metabolism of drugs. Variations in these enzymes are the cause of many human diseases they are also responsible for converting procarcinogens to carcinogens. CYP2D6 is an example of this variation it causes poor metabolism of drugs used in psychiatric conditions, such as debrisoquine. Another example is CYP2C19 patients with a variation of this P450 are poor metabolisers of drugs such as diazepam. Patients displaying these variations are more likely to suffer from ADRs. Studies have also shown that the aforementioned CYP2D6 enzyme are more likely to occur in the Caucasian population although it does occur (to a lesser degree) in Asian and African Americans populations. And CYP2C19 affects the Asian population over Caucasian populations. (4)
Kuehl et al (2001) carried out studies using CYP3A promoters and in particular CYP3A5 which is one member of the CYP3A family. CYP3A4 and CYP3A5 are similar and are found to contribute to metabolising the same types of drugs. This study looked at Splice variants of these enzymes in particular CYP3A5*3 and found that a splicing at this allele codes for a STOP codon. CYP3A5*3/*3 variant is found more commonly in Caucasians. CYP3A5*1 is found more commonly in African Americans. Combinations of lower amounts of CYP3A4 and CYP3A5 in the population are seen to predispose populations to ADRs via inhibition of CYP3A. (5)
Jorgensen et al carried out a study looking at the drug warfarin, which is an anticoagulant widely used in preventing thromboembolisms. This is a difficult drug to administer, because it very much a dose dependent drug and varies between patients. Once warfarin has been administered it is metabolised in the liver by cytochrom P450's. Warfarin has S-enatiomers and R-enantiomers, the S-enatiomers is metabolised by CYP2C9 and R-enantiomer is metabolised by CYP1A1, CYP1A2 and CYP3A4. This study shows that it is SNPs in CYP2C9 that affect the metabolism of warfarin. Vitamin K reductase activity (VKORC1) is inhibited by warfarin, this results in a decrease in activated clotting factors, SNPs in either of these genes has a great affect on the metabolism of warfarin which leads to bleeding. This is why with a drug such as this personalised medication is very important. (6)
Palomaki et al carried out a review in order to observe the effects of the drug Irinotecan, which is involved in the treatment of colorectal cancer. This drug acts by initiating the death of cancerous cells by inhibiting topoisomerase I in DNA replication thus causing DNA damage. Irinotecan is a prodrug and once Irinotecan is taken it is converted to SN-38 by carboxylase enzymes (CES1 and CES2), once this happens UGT enzymes (UGT1A1) inactivate SN-38 via glucuronidation converting it into its inactive form SN-38G. This study concluded that any population that has a variant of UGT1A1 enzyme will be unable to metabolise SN-38 which will in turn accumulate in the system resulting in an adverse reaction to Irinotecan. (7)
From these studies we can see the importance of knowing the genotypes of patients with these diseases and how it would be of great benefit in the prescribing of medication.
Due to the populations varying responses to drugs and toxicity, personalised medicine has been researched extensively using pharmacogenomic. Pharmacogenetic technology will help the pharmaceutical companies in discovering potential new therapies and renewing failed drug candidates. This technology has its benefits and drawbacks for the pharmaceutical companies such as reduced clinical trials, decrease in ADRs thus reducing legal action due to ADRs. Decreased number of failed trials and reduced time from discovery to marketing. Since it costs hundreds of millions to bring a drug to market, will these companies be willing to develop alternative drugs that serve only a small portion of the population as the drug companies require a vast population requiring their drug over a period of time in order to create more revenue to invest in new drug discovery.
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There are concerns about this technology in regards to the population; there are many questions, such as how far do we take genome sequencing? Does every baby born automatically receive genome sequencing when they are born? If so who will govern this information? This will not happen in the immediate future but it will become the forefront of medicine as it will be beneficial in the prevention of diseases and in patients who already have these diseases in regards to avoiding ADRs