Lecture
Medical toxicology as a comprehensive fundamental discipline. Stages in the development of drug toxicology. Basic concepts of toxicology: toxicant, toxicity, xenobiotic, toxic action. Types of classifications of toxic processes. Classification of drugs according to their toxic action. Main toxicometric parameters and calculation formulas. Characteristics of drugs that affect their toxicokinetic properties. Main mechanisms of penetration of chemical substances across the biological barriers of the body. Stages of absorption, distribution and biotransformation of xenobiotics in the body. Main mechanisms of the toxic action of drugs.
Pharmacotoxicology involves the study of the consequences of the toxic effects of pharmaceutical drugs and agents in healthcare. Pharmacotoxicology also includes the treatment and prevention of side effects caused by pharmaceutical drugs. Pharmacotoxicology can be divided into two categories: pharmacodynamics (the effect of a drug on the body) and pharmacokinetics (the effect of the body on a drug).
There are many mechanisms by which pharmaceutical drugs can exert a toxic effect on the body. A common mechanism is the covalent binding of a drug or its metabolites to specific enzymes or receptors in tissue-specific pathways, which then give rise to toxic reactions. Covalent binding can occur in both target and off-target situations, as well as after biotransformation.
Target toxicity is also called mechanism-based toxicity. This type of adverse effect resulting from exposure to pharmaceutical drugs is usually caused by the interaction of the drug with its target. In this case, the therapeutic and toxic targets coincide. To avoid toxicity during treatment, in many cases it is necessary to modify the drug so that it acts on a different aspect of the disease or its symptoms. Statins are an example of a class of drugs that can exert a toxic effect on their therapeutic target (HMG CoA reductase).
Some drugs can cause allergic reactions, as in the case of penicillins. In some people, the administration of penicillin can trigger the production of specific antibodies and initiate an immune response. Activation of such a response in unwarranted cases can cause serious health problems and interfere with the normal functioning of the immune system . Immune reactions to exposure to pharmaceutical drugs can be very common in cases of accidental contamination. Tamoxifen, a selective estrogen receptor modulator, has been found to alter the humoral adaptive immune response in Steller sea lions . In this case, pharmaceutical drugs can cause adverse effects not only in humans, but also in organisms subjected to unintentional exposure.
When non-specific drugs are used, adverse effects often occur on targets other than those intended for the pharmaceutical treatment. If a drug unexpectedly binds to other proteins, receptors, or enzymes, which can alter pathways, making them different from those required for treatment, serious side effects can develop. An example is the drug eplerenone (an aldosterone receptor antagonist), which is supposed to raise aldosterone levels but, as practice has shown, causes prostatic atrophy .
Bioactivation is a critical step in the action of certain pharmaceutical drugs. Often the parent form of a drug is not the active form, and it must undergo metabolism to produce a therapeutic effect. In other cases, bioactivation is not necessarily required for the drug to be active; instead, reactive intermediates may form that cause more severe side effects than the original form of the drug. Bioactivation can occur under the action of phase I metabolism enzymes, such as cytochrome P450 or peroxidase. Reactive intermediates can cause loss of function in certain enzymatic pathways or promote the production of reactive oxygen species, which can lead to increased stress levels and altered homeostasis.
Drug interactions can occur when certain drugs are taken simultaneously. The effect of this can be additive (the result is better than that of a single drug alone), less than additive (the therapeutic effect is smaller than that of a single drug alone), or functional (one drug alters the absorption, distribution, and metabolism of another) . Co-administration of chloroquine, an antimalarial drug, and statins for the treatment of cardiovascular disease can cause inhibition of organic anion-transporting polypeptides (OATPs), and lead to systemic exposure to statins .
There are many pharmaceutical drugs that can cause adverse effects after biotransformation, interaction with alternative targets, or as a result of drug interactions. All pharmaceutical drugs can be toxic depending on the dose .
Acetaminophen (APAP) — is a very common drug used to treat pain. High doses of acetaminophen have been found to cause severe hepatotoxicity following biotransformation with the formation of reactive intermediates. Acetaminophen is metabolized by CYP2E1 to form NAPQI, which then causes significant oxidative stress due to an increase in reactive oxygen species (ROS) . ROS can cause cell damage in a number of ways: some of these include damage to DNA and mitochondria, and depletion of antioxidant enzymes such as glutathione. In terms of «drug — drug» interactions, acetaminophen activates CAR, a nuclear receptor involved in the production of metabolic enzymes, which enhances the metabolism of other drugs. This can lead either to reactive intermediates/drug activity persisting longer than necessary, or to the drug being eliminated from the body faster than usual, preventing any therapeutic effect from occurring. Ethanol induces CYP2E1 enzymes in the liver, which can lead to increased formation of NAPQI in addition to that formed from acetaminophen .
Aspirin — is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammation and pain. Overdose or treatment in combination with other NSAIDs can cause an additive effect, which can lead to increased oxidative stress and ROS activity. Chronic exposure to aspirin can lead to CNS toxicity and ultimately affect respiratory function .
Antidepressants have been prescribed to patients since the 1950s, and their prevalence has increased significantly since then. There are many classes of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants. Many of these drugs, especially SSRIs, block the metabolism or reuptake of neurotransmitters to treat depression and anxiety. Chronic exposure to or overdose of these pharmaceutical drugs can lead to increased serotonin levels and CNS excitation, changes in weight, and in severe cases, suicide .
Doxorubicin — is a highly effective anticancer drug that causes congestive heart failure when used to treat tumors . Doxorubicin is an uncoupling agent, as it inhibits the proper functioning of complex I of the mitochondrial electron transport chain. This leads to the formation of ROS and inhibition of ATP production. Doxorubicin has been found to be selectively toxic to cardiac tissue, although some toxicity has also been observed in other tissues . Other anticancer drugs, such as fluoropyrimidines and taxanes, are extremely effective in treating and reducing tumor proliferation but can cause cardiac arrhythmias and myocardial infarction .
Comments