Pharmacotoxicology

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Pharmacotoxicology entails the study of the consequences of toxic exposure to pharmaceutical drugs and agents in the health care field. The field of pharmacotoxicology also involves the treatment and prevention of pharmaceutically induced side effects. Pharmacotoxicology can be separated into two different categories: pharmacodynamics (the effects of a drug on an organism), and pharmacokinetics (the effects of the organism on the drug).

Contents

Mechanisms of Pharmaceutical Drug Toxicity

There are many mechanisms by which pharmaceutical drugs can have toxic implications. A very common mechanism is covalent binding of either the drug or its metabolites to specific enzymes or receptor in tissue-specific pathways that then will elicit toxic responses. Covalent binding can occur during both on-target and off-target situations and after biotransformation.

On-target toxicity.

On-target toxicity is also referred to as mechanism-based toxicity. This type of adverse effect that results from pharmaceutical drug exposure is commonly due to interactions of the drug with its intended target. In this case, both the therapeutic and toxic targets are the same. To avoid toxicity during treatment, many times the drug needs to be changed to target a different aspect of the illness or symptoms. Statins are an example of a drug class that can have toxic effects at the therapeutic target (HMG CoA reductase). [1]

Immune Responses

Some pharmaceuticals can initiate allergic reactions, as in the case of penicillins. In some people, administration of penicillin can induce production of specific antibodies and initiate an immune response. Activation of this response when unwarranted can cause severe health concerns and prevent proper immune system functioning. [1] Immune responses to pharmaceutical exposure can be very common in accidental contamination events. Tamoxifen, a selective estrogen receptor modulator, has been shown to alter the humoral adaptive immune response in gilthead seabream. [2] In this case, pharmaceuticals can produce adverse effects not only in humans, but also in organisms that are unintentionally exposed.

Off-target toxicity

Adverse effects at targets other than those desired for pharmaceutical treatments often occur with drugs that are nonspecific. If a drug can bind to unexpected proteins, receptors, or enzymes that can alter different pathways other than those desired for treatment, severe downstream effects can develop. An example of this is the drug eplerenone (aldosterone receptor antagonist), which should increase aldosterone levels, but has shown to produce atrophy of the prostate. [3]

Bioactivation

Bioactivation is a crucial step in the activity of certain pharmaceuticals. Often, the parent form of the drug is not the active form and it needs to be metabolized in order to produce its therapeutic effects. In other cases, bioactivation is not necessarily needed for drugs to be active and can instead produce reactive intermediates that initiate stronger adverse effects than the original form of the drug. Bioactivation can occur through the action Phase I metabolic enzymes, such as cytochrome P450 or peroxidases. Reactive intermediates can cause a loss of function in some enzymatic pathways or can promote the production of reactive oxygen species, both of which can increase stress levels and alter homeostasis.

Drug-drug interactions

Drug-drug interactions can occur when certain drugs are administered at the same time. Effects of this can be additive (outcome is greater than those of one individual drug), less than additive (therapeutic effects are less than those of one individual drug), or functional alterations (one drug changes how another is absorbed, distributed, and metabolized). [4] Drug-drug interactions can be of serious concern for patients who are undergoing multi-drug therapies. [5] Coadministration of chloroquine, an anti-malaria drug, and statins for treatment of cardiovascular diseases has been shown to cause inhibition of organic anion-transporting polypeptides (OATPs) and lead to systemic statin exposure. [5]

Pharmacotoxicity Examples

There are many different pharmaceutical drugs that can produce adverse effects after biotransformation, interaction with alternate targets, or through drug-drug interactions. All pharmaceuticals can be toxic, depending on the dose. [6]

Acetaminophen

Acetaminophen (APAP) is a very common drug used to treat pain. High doses of acetaminophen has been shown to produce severe hepatotoxicity after being biotransformed to produce reactive intermediates. Acetaminophen is metabolized by CYP2E1 to produce NAPQI, which then causes significant oxidative stress due to increased reactive oxygen species (ROS). [7] ROS can cause cellular damage in a multitude of ways, a few of which being DNA and mitochondrial damage 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 increases the metabolism of other drugs. This could either cause reactive intermediates/drug activity to persist for longer than necessary, or the drug will be cleared quicker than normal and prevent any therapeutic actions from occurring. Ethanol induces CYP2E1 enzymes in the liver, which can lead to increased NAPQI formation in addition to that formed by acetaminophen. [7]

Aspirin

Aspirin is an NSAID used to treat inflammation and pain. Overdoses or treatments in conjunction with other NSAIDs can produce additive effects, which can lead to increased oxidative stress and ROS activity. Chronic exposure to aspirin can lead to CNS toxicity and eventually affect respiratory function. [8]

Anti-depressants

Anti-depressants have been prescribed since the 1950s, and their prevalence has significantly increased since then. There are many classes of anti-depressant pharmaceuticals, such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic anti-depressants. Many of these drugs, especially the SSRIs, function by blocking the metabolism or reuptake of neurotransmitters to treat depression and anxiety. Chronic exposure or overdose of these pharmaceuticals can lead to seratonin and CNS hyperexcitation, weight changes, and, in severe cases, suicide. [8]

Anti-cancer drugs

Doxorubicin is a very effective anti-cancer drug that causes congestive heart failure while treating tumors. [7] Doxorubicin is an uncoupling agent in that it inhibits proper functioning of complex I of the electron transport chain in mitochondria. It then leads to the production of ROS and the inhibition of ATP production. Doxorubicin has been shown to be selectively toxic to cardiac tissue, although some toxicity has been seen in other tissues as well. [7] Other anti-cancer drugs, such as fluoropyrimidines and taxanes, are extremely effective at treating and reducing tumor proliferation, but have high incidences of cardiac arrhythmias and myocardial infarctions. [9]

Related Research Articles

Analgesic Any member of the group of drugs used to achieve analgesia, relief from pain

An analgesic or painkiller is any member of the group of drugs used to achieve analgesia, relief from pain.

Pharmacology Branch of biology concerning drugs

Pharmacology is a branch of pharmaceutical sciences which is concerned with the study of drug or medication action, where a drug can be broadly or narrowly defined as any man-made, natural, or endogenous molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.The related terms therapeutic window or safety window refer to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, and exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation.

Pharmacodynamics study of the biochemical and physiologic effects of drugs

Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.

A prodrug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug. Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Instead of administering a drug directly, a corresponding prodrug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME).

An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or procedure, this is called a medical error and not a complication. Adverse effects are sometimes referred to as "iatrogenic" because they are generated by a physician/treatment. Some adverse effects occur only when starting, increasing or discontinuing a treatment.

A biological target is anything within a living organism to which some other entity is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are proteins and nucleic acids. The definition is context-dependent, and can refer to the biological target of a pharmacologically active drug compound, the receptor target of a hormone, or some other target of an external stimulus. Biological targets are most commonly proteins such as enzymes, ion channels, and receptors.

Anthracycline class of antibiotics

Anthracyclines is a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

Erlotinib chemical compound

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

A toxicophore is a chemical structure or a portion of a structure that is related to the toxic properties of a chemical. Toxicophores can act directly or can require metabolic activation.

Mechanism of action Biochemical interaction through which a drug produces its pharmacological effect

In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.

Drug intolerance

Drug intolerance or drug sensitivity refers to an inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses. Conversely, a patient is said to be "tolerating" a drug when they can tolerate its adverse effects. It is not to be confused with a drug allergy, which is a form of drug intolerance, but requires an immune-mediated component. It is also not to be confused with drug tolerance which refers to a lack of adverse effects even at higher than average doses. Some instances of drug intolerance are known to result from genetic variations in drug metabolism.

Pazopanib chemical compound

Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.

Drug eruption adverse drug reaction of the skin

In medicine, a drug eruption is an adverse drug reaction of the skin. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn. These are called "simple" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as "complex". Drugs can also cause hair and nail changes, affect the mucous membranes, or cause itching without outward skin changes.

Reproductive toxicity Reproductive toxicity is a hazard associated with some chemical substances, which interfere in some way with normal reproduction; such substances are called reprotoxic.

Reproductive toxicity is a hazard associated with some chemical substances, which interfere in some way with normal reproduction; such substances are called reprotoxic. They may adversely affect sexual function and fertility in adult males and females, as well as causing developmental toxicity in the offspring. Reproductive toxicity is usually defined practically, to include several different effects which are unrelated to each other except in their outcome of lowered effective fertility. The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) separates reproductive toxicity from germ cell mutagenicity and carcinogenicity, even though both these hazards may also affect fertility.

Arsenic biochemistry refers to biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element in Earth's crust, and although many arsenic compounds are often considered highly toxic to most life, a wide variety of organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers, potentially affecting many millions of people via biochemical processes.

HU-331 chemical compound

HU-331 is a quinone anticarcinogenic drug synthesized from cannabidiol, a cannabinoid in the Cannabis sativa plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU-331 is a very specific inhibitor of topoisomerase II, compared with most known anticancer quinones. One of the main objectives of these studies is the development of a new quinone derived compound that produces anti-neoplastic activity while maintaining low toxicity at therapeutic doses.

Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level.

Gold nanoparticles in chemotherapy

This article is about gold nanoparticles in chemotherapy and radiotherapy. For colloidal gold, see colloidal gold.

References

  1. 1 2 Guengerich, F. Peter (2011). "Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development". Drug Metabolism and Pharmacokinetics. 26 (1): 3–14. doi:10.2133/dmpk.DMPK-10-RV-062. PMC   4707670 . PMID   20978361.
  2. ↑ Rodenas, M.C.; Cabas, I.; Abellán, E.; Meseguer, J.; Mulero, V.; García-Ayala, A. (December 2015). "Tamoxifen persistently disrupts the humoral adaptive immune response of gilthead seabream (Sparus aurata L.)". Developmental & Comparative Immunology. 53 (2): 283–292. doi:10.1016/j.dci.2015.06.014. PMID   26234710.
  3. ↑ Rudmann, Daniel G. (2013). "On-target and off-target-based toxicologic effects". Toxicologic Pathology. 41 (2): 310–314. doi: 10.1177/0192623312464311 . PMID   23085982.
  4. ↑ Hussar, Daniel A. "Drug Interactions". Merck Manuals Consumer Version.
  5. 1 2 Alam, Khondoker; Pahwa, Sonia; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Abuznait, Alaa H.; Li, Lang; Yue, Wei (2016). "Downregulation of organic anion transporting polypeptide (OATP) 1B1 transport function by lysosomotropic drug chloroquine: implication of OATP-mediated drug-drug interactions". Molecular Pharmaceutics. 13 (3): 839–851. doi:10.1021/acs.molpharmaceut.5b00763. PMC   4970216 . PMID   26750564.
  6. ↑ Klaassen, Curtis D., ed. (2013). Casarett and Doull's toxicology : the basic science of poisons (8th ed.). New York: McGraw-Hill Education. ISBN   978-0-07-176923-5.
  7. 1 2 3 4 Boelsterli, Urs A. (2002). Mechanistic Toxicology the Molecular Basis of How Chemicals Disrupt Biological. London: Taylor & Francis. ISBN   0-203-36176-8.
  8. 1 2 Long, Scott. "Toxicity of Selected Drugs". faculty.swosu.edu.
  9. ↑ Rosa, Gian Marco; Gigli, Lorenzo; Tagliasacchi, Maria Isabella; Di Iorio, Cecilia; Carbone, Federico; Nencioni, Alessio; Montecucco, Fabrizio; Brunelli, Claudio (March 2016). "Update on cardiotoxicity of anti-cancer treatments". European Journal of Clinical Investigation. 46 (3): 264–284. doi: 10.1111/eci.12589 . PMID   26728634.
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