1. Introduction
1.1. Background
Modern medicine provides more sanative treatment due to the improvement in pharmaceutical equipment. However, this achievement gives rise to some potential danger in drug usage. An UK national analysis indicates that each year adverse drug reactions are responsible for 5% hospital admission which cost approximately 0.5 billion pounds per year. Besides, fatal adverse drug reactions account for approximately 3% of all death in the general population [1]. The research of drug monitoring reveals that adverse drug reactions can turn into social cost.
The market drugs are required to show indications on the package or in the instructions leaflet. If the pharmacists want drugs to be approved for sale, they must report clinical results to the Food and Drug Administration (FDA). The clinical trial should control some of the confounding variable effect, such as, age, gender, or changes in hormone level. Subjects of the clinical trial are randomly assigned into two groups in double blind procedure. Subjects in the experiment group are given the drug, and the others in control group are receiving placebo. The main purpose of the clinical trial is to confirm the principal treatment effect and the secondary purpose is to find possible adverse reactions.
Side effect is a usual term for the negative consequence of adverse drug reaction.
And the medical record about side effect or adverse drug reaction is a report of adverse drug event (ADE). Since 2004, the FDA set up a Pharmacovigilance system to collect the negative consequence of market drug reports from the health professionals and patients.
All the information about adverse drug events is recorded in adverse effect reporting system (AERS).
Besides, FDA is asked to do some analysis related to adverse drug effects and provides these results to the public. If FDA find some adverse drug effects are not listed on the package or in the instructions leaflet, FDA will ask pharmaceutical company to provide inspection reports, and may have three possible procedures:
i.
The pharmaceutical company should list “new” adverse effects on the package or in the instructions leaflet.ii.
The pharmaceutical company should indicate the eligibility of patients on the package or in the instructions leaflet.iii.
In the worst case, the drugs will be removed from the shelves.We notice the importance to investigate adverse drug events. In consequence, we search the literatures about the hidden risk of approval drugs and start the following research in this thesis for the drug safety issue.
“The occurrence of drug side effect” is one of the most popular topics in the field of modern medicine. Nowadays, experts and scholars have proposed the possible causes of adverse drug effects into four categories [2]:
(1) Adverse events related to the therapeutic effects of drugs:
The first category of adverse drug effects occurs when the therapeutic effects have other additional negative consequences. Generally, these drug side effects occur as the concentration of medication is higher than required for beneficial drug effects. The drug metabolism variation is related to several enzyme activities. The required dose of drug might be different among people due to the individual genomic factor.
In general case, drugs are catalyzed by some enzymes in the liver. The drug effects in human system will become vanished as the time passed. After enzymatic reaction, the catalyzed drug waste will be transported to the kidney and then excreted into urine.
However, the enzyme activity is diverse among people. If the enzyme activity is higher;
that is, the rate of metabolism increases, then the time of drugs functioning in vivo is shorter than average. Therefore, it can result in less treatment effect. However, if the enzyme activity is lower; that is, the rate of metabolism decreases, then the time of drugs
functioning in vivo is longer than average. Thus, it results in higher treatment effect and adverse drug effect (Figure 1.1).
For example, anticoagulant (Warfarin) is to inhibit vitamin K epoxide reductase (VKOR). However, if the concentration of medication in vivo is higher than that required for beneficial drug effect, this will result in over-inhibited clotting, which may lead to hemorrhagic stroke.
Figure 1.1: This figure shows that the drug-metabolizing capability. The black curve
denotes the general case, the orange curve denotes the lower enzyme activity, and the green curve denotes the higher enzyme activity.(2) The therapeutic drug targets existing in multiple cell and tissue types:
The second category of adverse drug events occurs when a drug’s target (a specific protein) serves multiple functions in different tissues of the body.
For illustration, given three different tissues, A, B, and C, all of them contain two proteins x and y and their corresponding expression level in normal case. If the expression of protein y in tissue C is higher, tissue C becomes cancerous. And the design a chemical compound, which can hydrolyze protein y or block its bio-activity, aims to
drug inhibits protein y in tissue C, as well as in tissue A and tissue B. Thus, it causes the function of protein y in tissue A and tissue B becomes less than normal, which we consider as a possible scenario of the cause of adverse drug effect (Figure 1.2).
In real case, Morphine is designed to achieve analgesia by binding with µ-opioid receptors in the brain. However, it may affect the same type of opiate receptors in the intestines, which inhibits peristalsis.
Figure 1.2: Initially, we want to regulate tissue C by inputting an anti-cancer drug. The
function of the anti-cancer drug inhibits the protein y in tissue C. It as well as inhibits protein y in tissue A and tissue B at the same time. Thus, ADEs will be resulted.(3) Adverse drug events mediated by off-targets of a drug:
The third category of adverse drug events occurs when one drug interferes with other unexpected proteins or pathways. This category is different from the second category. The former considers that one drug affects single protein among more than one tissue. The protein or pathway that the drug intends to function is called “drug-target”, and the drug affecting unexpected proteins or pathway is called “off-target”. It should be mentioned that the off-target will be another scenario of side effects.
For example, Delavirdine, HIV reverse transcriptase inhibitor, not only inhibits the reverse transcriptase of HIV, but also interacts with histamine H4 receptor, which will result in severe rash.
(4) Mixture of several drug side effects:
The fourth category is a mixture of the adverse drug events in above three categories.
For example, Domperidone is designed to promote gastrointestinal motility, but also inhibits the human Ether-à-go-go-Related Gene K+ channels (HERG K+ channels), which will result in cardiac arrhythmias.