Drug related hypersensitivity to Paracetamol

Paracetamol was discovered by McNeil Laboratories in 1955 as an analgesic and antipyretic for children and is further said to be a non-opiod analgesic and is often known as acetaminophen. It is considered as a first line analgesic and is considered safe and effective in pain relieve against muscoskeletal pain caused due to rheumatoid arthritis and fever. Furthermore, it should be noted that it is primarily metabolized by the liver and converted into inactive compounds and then consequently it is excreted by the kidneys. There are several symptoms of Paracetamol allergy that includes:

  • rashes on the skin like Steve-Johnson Syndrome (SJS),
  • toxic epidermal necrosis (TEN),
  • acute generalized exanthematous pustulosis (AGEP),
  • shortness of breath,
  • rhino conjunctivitis,
  • eczema anaphylaxis and
  • urticarial (Jha, 2016).

The toxicity of the Paracetamol is due to metabolite from the drug known as N-Acetyl-p-bezoquinoneimine (Jha, 2016).

 Structure of Paracetamol

Structure of Paracetamol

Mechanism of action of Paracetamol

First of all, as a mechanism of action, the main function of Paracetamol is to inhibit the prostaglandins when the level of the archidonic substrates becomes low. In order to do so, it penetrates the blood brain barrier and blocks the cyclooxygenase (COX3) in brain. Furthermore, it leads to inhibition of formation and release of prostaglandin (PGE) in the central nervous system. Consequently, it inhibits the action of endogenous pyrogens on the heart regulating the centers in the brain. In terms of pain management, it acts by inhibiting Nitric oxide (NO)  pathway through a variety of neurotransmitter receptors like N-Methyl-D-Aspartate  (NMDA) further which have been found to relieve symptoms within in few minutes (Pub Med, 1983).

Furthermore, the mechanism by which it induces the hypersensitivity reaction is when it attacks the cyclo-oxygenase, COX3 and COX1 which results in inhibition of its formation and reduces the formation of Prostaglandin 2. Therefore, it decreases the inhibition of the 5-lipoxygenase enzyme and leads to increase in the production of the cysteinyl leukotrienes from arachidonic acid which in turn induces the IgE mediated immune system leading to hypersensitivity (Mohamed, 2013).

Prevalence of Paracetamol allergy

In terms of prevalence, it should be noted that Nonsteroidal Antiinflammatory Drugs (NSAID) are second most common cause of drug hypersensitivity. In all they are responsible for 21-25% of adverse drug reactions due to both immunological and non-immunological reactions. Among the world population most of all Paracetamol affects 0.5% to 1.9% (Settipane, Constantine and Settipane, 1980). In comparison to world population, the prevalence in Indian population is noted to be 12.96% (Patel, Patel, Barvaliya, & Tripathi, 2014). Furthermore, nearly 5% of population of India also suffers from Paracetamol induced angioedema (“Paracetamol Induced Angioedema,” 2008). It should also be noted that prevalence of drug hypersensitivity of NSAID affects patients suffering from asthma or chronic urticaria.

Diagnostic Considerations

Consequently, it should be noted that an increase in the IgE mediated immune response with the release of histamine shows the presence of hypersensitivity reactions. In order to diagnose allergy to NSAID, it is important to trace information related to symptoms and expose the drug. For effective diagnosis, it is important to determine the patient history in terms of symptoms and also repetitive episodes of urticarial, angioedema or asthma.  Other than the patient management, the most common tests used for the diagnostic purpose of allergy are the skin prick test and blood test (Marek L Kowalski & Makowska, 2015). Furthermore, oral provocation test or accidental re-challenge with the molecules are the methods to diagnose the allergy.

Other than the common tests there are tests which are found to reflect higher efficiency and some of these are:

  • inhalation provocation test or
  • a nasal test with lysine.

These tests have been found to have higher efficacy in comparison to oral provocation challenge (Niżankowska-Mogilnicka et al., 2007). Furthermore, lymphocyte activation test is a commonly used test outside India because, but they have limited diagnostic values (Anderson et al., 1992; M. L. Kowalski et al., 2011) in India.

References

  • Anderson, J. A., Anderson  JA, A. N. J., Levenson  DE, Arndt KA, S. R., Classen  DC, Pestotnik SL, Evans RS, B. J., Bigby  M, Jick S, Jick H, A. K., Jr, V. A. P., … NJ, S. (1992). Allergic Reactions to Drugs and Biological Agents. JAMA: The Journal of the American Medical Association, 268(20), 2845. https://doi.org/10.1001/jama.1992.03490200097011.
  • Haleem, K. (2015). Mechanism of action of Paracetamol and brands and dosage of Ibuprofen. Health and Medicine. Retrieved from http://www.slideshare.net/komalhaleem/mechanism-of-action-of-paracetamo-and.
  • Jha, N. (2016, January). Random use makes even paracetamol unsafe: IMA. The Times of India, p. 1. Ne Delhi.
  • Kowalski, M. L., & Makowska, J. S. (2015). Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? Allergy, Asthma & Immunology Research, 7(4), 312–20. https://doi.org/10.4168/aair.2015.7.4.312.
  • Kowalski, M. L., Makowska, J. S., Blanca, M., Bavbek, S., Bochenek, G., Bousquet, J., … Brockow, K. (2011). Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) – classification, diagnosis and management: review of the EAACI/ENDA# and GA2LEN/HANNA*. Allergy, 66(7), 818–829. https://doi.org/10.1111/j.1398-9995.2011.02557.x.
  • Mohamed, N. P. (2013). FDA’s advice on_acetaminophen_(paracetamol)_associated serious skin r…. Retrieved December 23, 2016, from http://www.slideshare.net/pnmcologist/fdas-advice-onacetaminophenparacetamolasso-ciated-serious-skin-reactions.
  • Nanoparticle injections may be future of osteoarthritis treatment. (2016, September). PhYy Org, p. 1. Washington.
  • Niżankowska-Mogilnicka, E., Bochenek, G., Mastalerz, L., Świerczyńska, M., Picado, C., Scadding, G., … Szczeklik, A. (2007). EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy, 62(10), 1111–1118. https://doi.org/10.1111/j.1398-9995.2007.01409.x.
  • Paracetamol Induced Angioedema. (2008). Indian Journal of Medical Sciences, 62(10), 1–3. Retrieved from www.bioline.org.br/pdf?ms08075
  • Patel, T. K., Patel, P. B., Barvaliya, M. J., & Tripathi, C. B. (201.4). Drug-induced anaphylactic reactions in Indian population: A systematic review. Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine, 18(12), 796–806. https://doi.org/10.4103/0972-5229.146313.
  • Patel, T. K., Patel, P. B., Barvaliya, M. J., & Tripathi, C. B. (2014). Drug-induced anaphylactic reactions in Indian population: A systematic review. Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine, 18(12), 796–806. https://doi.org/10.4103/0972-5229.146313.
  • Shahani S, N. S. (2009). Adverse drug Reactions in Dermatology and a growing need for Pharmacovigilance. J Pharmacovig Drug Saf., 6(35), 7.
  • Sharma, V. K., Sethuraman, G., & Kumar, B. (2001). Cutaneous adverse drug reactions: clinical pattern and causative agents–a 6 year series from Chandigarh, India. Journal of Postgraduate Medicine, 47(2), 95–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11832597.
  • Sriram, S., Ghasemi, A., Ramasamy, R., Devi, M., Balasubramanian, R., Ravi, T. K., & Sabzghabaee, A. M. (2011). Prevalence of adverse drug reactions at a private tertiary care hospital in south India. Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, 16(1), 16–25. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21448378.
Shruti Datt

Shruti Datt

Project Handler at Project Guru
Shruti is B-Tech & M-Tech in Biotechnology. Some of her strengths include, Good interpersonal skills, eye for detail, well devised analytical and decision making skills and a positive attitude towards life. Her aim in life is to obtain a responsible and challenging position where her education and work experience will have valuable application.
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