Can CBD help with autoimmune diseases, and if so, how?

Autoimmunity is an “attack on the self.”(1) When the body’s natural defense system is unable to tell the difference between its innate cells and foreign cells, autoimmune disease happens (2). 

When the immune system gets triggered, it thinks that the body’s healthy tissues are invaders, causing the body to attack normal cells mistakenly.

Adaptive immune cells T cells (thymus cells) and B cells (bone marrow-derived cells) are the primary cellular components of the adaptive immune response of the body’s immune system.

In an autoimmune response, T cells take action, as if the body’s cells were foreign, to bring the body back into homeostasis. This self-attack is the root of autoimmune diseases (3).

Traditional medications that are used to treat autoimmune conditions are immunosuppressive and synthetically produced. 

Unfortunately, as these medicines shut down the overactive immune system, they also leave individuals more susceptible to infection and illness.

CBD and Autoimmune Diseases: What the Research Says

Data from a review published in Cannabis and Cannabinoid Research in 2020 overwhelmingly support the concept that CBD is immunosuppressive (suppresses immune response) (4). 

Cannabis is known to be immune-modulating, meaning they can bring an over- or under-reacting immune system back into balance (5).

Research has shown that cannabis therapies may provide benefits for autoimmune diseases in three ways: modulating the immune system, reducing general inflammation, and helping with the digestive system (6).

Cannabis medicine has been shown to potentially help treat symptoms of specific autoimmune diseases (also called autoimmune disorders), such as amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, multiple sclerosis, Crohn’s disease, fibromyalgia, and Huntington disease. 

CBD may also help reduce chronic pain, inflammation, and spasms associated with some of these conditions (7).

CBD’s potent anti-inflammatory properties were demonstrated in a 2018 study published in the Journal of Pharmacology and Experimental Therapeutics (8). 

Many studies have also reported the potential anti-inflammatory benefits of CBD for specific autoimmune disorders, like multiple sclerosis and rheumatoid arthritis (9).

How CBD Works to Control Immune Response

The therapeutic effects of cannabinoids, such as CBD (cannabidiol) and THC (tetrahydrocannabinol), are realized by their interaction with the body’s endocannabinoid system (ECS) and its cannabinoid receptors. 

Integral to the body’s physiologies, the ECS is responsible for regulating various body functions, such as immune response, pain sensation, metabolism, anxiety, sleep, mood, appetite, and memory.

For instance, it is through the interaction with cannabinoid receptors that anandamide, an intestinal cannabinoid, functions. Anandamide regulates appetite and stress response (10).

CB1 and CB2 receptors are found in specific parts of the human body, and each type of receptors have particular roles in the ECS. 

CB1 receptors are mostly located in the central nervous system and the brain (11). Meanwhile, CB2 receptors are mostly found on cells in the immune system and its associated structures. 

Once the CB2 receptor is triggered, it stimulates a response that combats inflammation, reducing pain and minimizing tissue damage.

This anti-inflammatory response is useful for treating inflammation-related conditions, such as Crohn’s disease, arthritis, and inflammatory bowel syndrome (12). 

CBD indirectly acts against cannabinoid agonists, which are substances that attach to a cannabinoid receptor and induce the same action as the substances that typically bind to the receptor.

CBD also interacts with other receptors in the body, such as the 5-HT1A receptor, which is linked to serotonin, a neurotransmitter believed to contribute to feelings of well-being. Through this interaction, these cannabinoids promote healing and balance (13). 

Conclusion

Autoimmune conditions are an area of medicine that remain widely misunderstood. While more than 80 registered autoimmune disorders are affecting various parts of the body, more conditions may prove to be also autoimmune-related (14).

Many causes of autoimmune diseases are shared or linked to other causes. Thus, people living with an autoimmune disease are more likely to suffer from more than one of these conditions (15).

Cannabinoid therapies may help decrease inflammation, modulate the immune system, and help bring the system back into balance (16). 

Studies have shown that CBD’s anti-inflammatory benefits might help treat symptoms of specific autoimmune disorders. 

However, more research is absolutely necessary to understand CBD’s impact on autoimmunity and determine CBD’s long-term side effects. 

Before using CBD or any CBD products, such as CBD tincture (CBD oil), gummies, salves, lotions, and patches, consult with a doctor experienced in cannabis use for advice.

Medically reviewed DR. WIEGMANN on 06-22-2020


  1. Fundacion Canna. Molecular Mimicry: The Role of Cannabis in Healing Autoimmune Disease. Retrieved from https://www.fundacion-canna.es/en/molecular-mimicry-role-cannabis-healing-autoimmune-disease.
  2. Johns Hopkins Medicine. What Are Common Symptoms of Autoimmune Disease? Retrieved from https://www.hopkinsmedicine.org/health/wellness-and-prevention/what-are-common-symptoms-of-autoimmune-disease
  3. Fundacion Canna. op. cit.
  4. Nichols J and Kaplan B. Immune Responses Regulated by Cannabidiol. Cannabis and Cannabinoid ResearchVol. 5, No. 1. 27 Feb 2020. https://doi.org/10.1089/can.2018.0073
  5. Russo S. Molecular Mimicry: The Role of Cannabis in Healing Autoimmune Disease. Retrieved from https://www.fundacion-canna.es/en/molecular-mimicry-role-cannabis-healing-autoimmune-disease
  6. Fundacion Canna. op. cit.
  7. Grinspoon, P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476; NINDS. (2018, Aug). Peripheral Neuropathy Fact Sheet. Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet.
  8. Petrosino S et al. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis. Journal of Pharmacology and Experimental Therapeutics June 2018, 365 (3) 652-663; DOI: https://doi.org/10.1124/jpet.117.244368
  9. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333–1349. DOI:10.4155/fmc.09.93; Elliott DM, Singh N, Nagarkatti M, Nagarkatti PS. Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells. Front Immunol. 2018;9:1782. Published 2018 Aug 3. DOI:10.3389/fimmu.2018.01782. 
  10. Hao S et al. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol. 2000 Mar 31;392(3):147-56. DOI: 10.1016/s0014-2999(00)00059-5.
  11. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17(14):1468–1486. DOI:10.2174/092986710790980005.
  12. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73(23):4449–4470. DOI:10.1007/s00018-016-2300-4.
  13. ECHO. (2017, March 29). Retrieved from https://echoconnection.org/differences-cbd-thc/.
  14. Fundacion Canna. op. cit. 
  15. BRI. Progress Against One Autoimmune Disease Is Progress Against Them All. Retrieved from https://www.benaroyaresearch.org/what-is-bri/about-the-institute.
  16. Russo S. Molecular Mimicry: The Role of Cannabis in Healing Autoimmune Disease. Retrieved from https://www.fundacion-canna.es/en/molecular-mimicry-role-cannabis-healing-autoimmune-disease.

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Azathioprine

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS number

      1.4.2 Other numbers

   1.5 Main brand names/main trade names

   1.6 Main manufacturers/main importers

   1.7 Presentation/formulation

  1. SUMMARY

   2.1 Main risks and target organs

   2.2 Summary of clinical effects

   2.3 Diagnosis

   2.4 First-aid measures and management principles

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Properties of the substance

         3.3.1.1 Colour

         3.3.1.2 State/form

         3.3.1.3 Description

      3.3.2 Properties of the locally available formulation

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Shelf-life of the locally available formulation

      3.4.3 Storage conditions

      3.4.4 Bioavailability

  1. USES

   4.1 Indications

      4.1.1 Uses

      4.1.2 Description

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Others

  1. KINETICS

   6.1 Absorption by route of exposure

   6.2 Distribution by route of exposure

   6.3 Biological half-life by route of exposure

   6.4 Metabolism

   6.5 Elimination by route of exposure

  1. PHARMACOLOGY AND TOXICOLOGY

   7.1 Mode of action

      7.1.1 Toxicodynamics

      7.1.2 Pharmacodynamics

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Relevant animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

   7.7 Main adverse effects

  1. CLINICAL EFFECTS

   9.1 Acute poisoning

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 CNS

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

  1. MANAGEMENT

   10.1 General principles

   10.2 Relevant laboratory analyses

      10.2.1 Sample collection

      10.2.2 Biomedical analysis

      10.2.3 Toxicological analysis

      10.2.4 Other investigations

   10.3 Life supportive procedures and symptomatic/specific treatment

   10.4 Decontamination

   10.5 Elimination

   10.6 Antidote treatment

      10.6.1 Adults

      10.6.2 Children

   10.7 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. Additional information

   12.1 Availability of antidotes

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES
  2. AUTHOR(S):
  3. NAME

        1.1  Substance

             Azathioprine

        1.2  Group

             ATC Code: L04AX Other Immunosuppressive agents

        1.3  Synonyms

             BW 57322

             azothioprine

             NCI-C03474

             NSC-39084

             methylnitroimidazolylmercaptopurine

        1.4  Identification numbers

             1.4.1  CAS number

             Azathioprine 446-86-6

             1.4.2  Other numbers

             RTECS:     UO8925000

        1.5  Main brand names/main trade names

             Azamune, Azanin, Azapress, Berkaprine, Immunoprin, 

             Imuran, Imurek, Imurel, Rorasul, Thioprine.

        1.6  Main manufacturers/main importers

             To be added by the centre using the monograph.

        1.7  Presentation/formulation

             To be added by the centre using the monograph.

  1. SUMMARY

        2.1  Main risks and target organs

             Azathioprine is a myelotoxic and hepatotoxic 

             immunosuppressive agent. Bone marrow and liver are the main 

             targets but gastrointestinal tract, kidney, lungs, CNS and 

             skin may also be affected. Transient gastroenteritis may be 

             observed with massive overdose. Leukopenia is the main toxic 

             effect which may occur during azathioprine therapy and in the 

             overdose patients. Liver and kidney function tests may be 

             altered but usually returned to normal after discontinuation 

             of the drug.

        2.2  Summary of clinical effects

             Oral ulceration occurs rarely with therapeutic doses but 

             may be seen with large doses. Gastrointestinal disturbances 

             such as nausea, vomiting, abdominal pain and diarrhoea can 

             appear mainly at higher doses. Acute pancreatitis was also 

             reported following long term azathioprine treatment. 

             Suppression of the bone marrow mainly leukopenia and 

             occasionally pancytopenia may be seen after therapeutic doses 

             and overdoses of azathioprine. Septic shock due to this 

             immunosuppression may occur. Hepatic dysfunction 

             (hepatocellular and cholestatic), venocclusive disease and 

             haemangioma of the liver following azathioprine therapy were 

             documented. Acute restrictive lung disease, interstitial 

             nephritis and a case of progressive leukoencephalopathy after 

             4 years azathioprine therapy were reported. Skin rash, 

             alopecia and urticaria and a case of palmar-plantar erythema 

             with desquamation and pain were also documented.

        2.3  Diagnosis

             Diagnosis of azathioprine overdose is based on history 

             of the drug taken and clinical findings mainly 

             gastrointestinal dysfunction, leukopenia and liver 

             dysfunction. Peripheral cell blood counts and liver function 

             tests are required. Estimation of 6-thioguanine nucleotide, a 

             cytotoxic metabolite of azathioprine in red blood cell may 

             confirm the diagnosis and could also be used to predict bone 

             marrow toxicity of azathioprine.

        2.4  First-aid measures and management principles

             Emesis may be indicated in substantial recent ingestion 

             of azathioprine. It is most effective if initiated within 30 

             minutes of ingestion. In massive overdose patients, gastric 

             aspiration and lavage should be performed as soon as possible 

             and within 3 to 4 hours of ingestion. Activated charcoal (1 

             to 2 g/kg every 3 to 4 hours) as slurry in water or mixture 

             with sorbitol should be given orally or through the gastric 

             tube. Haemodialysis should be used in severe azathioprine 

             overdose patients.

  1. PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Azathioprine is a chemical analogue of the physiologic 

             purines and is of synthetic origin.

        3.2  Chemical structure

             6-(1-Methyl-4-nitroimidazol-5-ylthio)purine

             Relative molecular mass: 277.3  

             Molecular formula: C9H7N7O2

        3.3  Physical properties

             3.3.1  Properties of the substance

                    3.3.1.1  Colour

                             Pale yellow. 

                    3.3.1.2  State/form

                             Powder. 

                    3.3.1.3  Description

                             Odourless.    

                             Insoluble in water and very slightly soluble 

                             in ethanol.   

                             Solutions of azathioprine sodium for 

                             injection have a pH of 9.8 to 11.0.

             3.3.2  Properties of the locally available formulation

                    To be filled in by centre using the 

                    monograph.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    Azathioprine tablets have a shelf-life of five 

                    years and the azathioprine injection has a shelf-life 

                    of three years (Dollery, 1991).

             3.4.2  Shelf-life of the locally available formulation

                    To be added by the centre using the 

                    monograph.

             3.4.3  Storage conditions

                    Azathioprine tablets should be protected from 

                    light and stored at a temperature that does not exceed 

                    35 °C. The azathioprine injection should be stored in 

                    a dry place at a temperature that does not exceed 25 

                    °C(Dollery, 1991).

             3.4.4  Bioavailability

                    To be added by the Center using the 

                    monograph.

  1. USES

        4.1  Indications

             4.1.1  Uses

             4.1.2  Description

 

                    Azathioprine is used as an adjunct for the 

                    prevention of the rejection of kidney allografts. The 

                    drug is used in conjunction with other 

                    immunosuppressive therapy including local radiation 

                    therapy, corticosteroids, and other cytotoxic 

                    agents.

                    Azathioprine may be used for the treatment of 

                    conditions which involve derangement of the immune 

                    system including chronic active hepatitis, severe 

                    rheumatoid arthritis, systemic lupus erythematosus, 

                    dermatomyositis, pemphigus vulgaris, polyarteritis 

                    nodosa, acquired haemolytic anaemia, Crohn’s disease 

                    and idiopathic thrombocytopenia. (Dollery, 1991; 

                    McEvoy, 1993).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Prophylatic therapy is usually initiated in a 

                    dose of 3 to 10 mg/kg one or two days prior to renal 

                    transplantation, or on the day of the operation 

                    (Calabresi and Chabner, 1990). Maintenance doses are 

                    lower.

                    For the treatment of conditions which involve 

                    derangement of the immune system the dose of the drug 

                    is usually decided by titration against the clinical 

                    activity of the disease, in the range of 1 to 3 mg/kg 

                    daily (Dollery, 1991).

             4.2.2  Children

                    The dose in children is the same (per kilogram 

                    body weight) as in adults.

        4.3  Contraindications

             Azathioprine is contraindicated in patients who are 

             hypersensitive to the drug. If severe, continuous rejection 

             occurs, it is probably preferable to use another agent, 

             rather than to increase the dosage of azathioprine to very 

             toxic levels (McEvoy, 1993).

             Azathioprine is also contraindicated in those patients with 

             renal failure, impaired hepatic function and in pregnant 

             women (Dollery, 1991).

  1. ROUTES OF ENTRY

        5.1  Oral

             Azathioprine is usually administered orally.

        5.2  Inhalation

             Not known

        5.3  Dermal

             Not known

        5.4  Eye

             Not known

        5.5  Parenteral

             Following renal transplantation, azathioprine may 

             initially be given intravenously to patients unable to 

             tolerate oral medication. Oral therapy should replace 

             parenteral therapy as soon as possible.

        5.6  Others

             Not known

  1. KINETICS

        6.1  Absorption by route of exposure

             Azathioprine is readily absorbed from the 

             gastrointestinal tract with only 12.6% of the dose being 

             detected in the stool over a 48 hour period. After oral 

             administration of 100 mg of azathioprine the peak levels of 

             azathioprine and its metabolites are equivalent to 2 mg.L-1 

             (Dollery, 1991)

        6.2  Distribution by route of exposure

             Azathioprine is rapidly distributed throughout the body 

             with peak plasma concentrations being reached at 1 to 2 hours 

             after dosing. Small amounts of azathioprine bind to plasma 

             proteins (to a maximum of 30%) and only very small amounts 

             enter the brain(Dollery, 1991).

             Azathioprine crosses the placenta and trace amounts of the 6- 

             mercaptopurine metabolite have been detected in foetal blood 

             (Briggs et al., 1990).

        6.3  Biological half-life by route of exposure

             The plasma half-life of azathioprine is 3 to 5 hours 

             (Dollery, 1991).

        6.4  Metabolism

             Azathioprine is metabolized  in vivo to mercaptopurine, 

             apparently by sulphydryl compounds such as glutathione. 

             Mercaptopurine is oxidised and methylated to several 

             derivatives among which 6-thiouric acid predominates; the 

             proportion of metabolites varies amongst individuals. The 

             fate of the nitromethylimidazole portion of azathioprine has 

             not been completely elucidated. Small amounts of azathioprine 

             are also split to give 1-methyl-4-nitro-5-thioimidazole 

             (McEvoy, 1993). The active metabolites, 6-thioguanine 

             nucleotides, responsible for the therapeutic action, are 

             formed intracellularly and appear to have very long half- 

             lives (Maddocks et al., 1986).

        6.5  Elimination by route of exposure

             The metabolites of azathioprine are excreted by the 

             kidneys; only small amounts of azathioprine and 

             mercaptopurine are excreted intact (McEvoy, 1993). In the 24 

             hour period after administration up to 50% of the dose is 

             excreted in the urine with 10% as the parent drug. There is 

             no data concerning azathioprine excretion in breast milk 

             (Briggs et al., 1990)

  1. PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    The principal toxic effect of azathioprine is 

                    bone marrow depression manifested by leukopenia, 

                    macrocytic anaemia, pancytopenia, and 

                    thrombocytopenia, which may result in prolongation of 

                    clotting time and eventual haemorrhage (McEvoy, 1993). 

                    In a concentration of 50 œg. mL-1, azathioprine 

                    produced cytogenetic damage to human lymphocytes  in 

                     vitro (Dollery, 1991).

             7.1.2  Pharmacodynamics

                    The exact mechanism of immunosuppressive 

                    activity of azathioprine has not been determined. 

                    Azathioprine which is an antagonist to purine 

                    metabolism, may inhibit RNA and DNA synthesis. The 

                    drug may also be incorporated into nucleic acids 

                    resulting in chromosome breaks, malfunctioning of the 

                    nucleic acids, or synthesis of fraudulent proteins. 

                    The drug may also inhibit coenzyme formation and 

                    functioning, thereby interfering with cellular 

                    metabolism. Mitosis may be inhibited by the drug.

                    In patients who undergo renal transplantation, 

                    azathioprine suppresses hypersensitivities of the 

                    cell-mediated type and causes variable alterations in 

                    antibody production (McEvoy, 1993).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Severe pancytopenia has been 

                             observed in about 1% of patients who receive 

                             more than 2.5 mg.kg-1. A renal patient who 

                             took 7500 mg of azathioprine with 1000 mg of 

                             prednisone developed leucopenia and the drug 

                             was discontinued for 11 days (Carney et al., 

                             1974).

                    7.2.1.2  Children

                             Lymphopenia, decreased IgG and IgM 

                             concentrations, cytomegalovirus infection, 

                             and a decreased thymic shadow were observed 

                             in one infant whose mother had received 150 

                             mg of azathioprine and 30 mg of prednisone 

                             daily throughout pregnancy; most of these 

                             findings had apparently normalised by 10 

                             weeks of age. Pancytopenia and severe 

                             immunodeficiency were reported in a premature 

                             infant whose mother received 125 mg of 

                             azathioprine and 12.5 mg of prednisone 

                             throughout pregnancy (McEvoy, 

                             1993).

             7.2.2  Relevant animal data

                    Studies with animals have shown that the 

                    haemopoietic system is affected by azathioprine with 

                    depression of granulopoiesis, megakaryocytes and, 

                    hence, platelet formation. Reversible hepatoxicity has 

                    been observed in dogs at doses of 5 mg.kg-1 

                    (Dollery, 1991).

                    Various teratogenic effects have been observed in 

                    rabbits, showing skeletal abnormalities at doses of 5 

                    to 15 mg.kg-1 given daily on days 6 to 14 of 

                    pregnancy, and in mice where azathioprine was lethal 

                    to the embryos at doses of 1 to 2 mg.kg-1 on days 3 

                    to 12 of pregnancy (Dollery, 1991).

             7.2.3  Relevant  in vitro data

                    Cytogenetic damage was observed in human 

                    lymphocytes  in vitro at a dose of 50 µg.mL-1 

                    (Dollery, 1991).

        7.3  Carcinogenicity

             Azathioprine is carcinogenic in animals and may increase 

             the risk of neoplasia in humans. The exact risk of neoplasia 

             asscoiated with azathioprine use has not been defined; 

             however, evidence suggests that the risk may be elevated both 

             in patients with rheumatoid arthritis and in renal allograft 

             recipients receiving the drug. Acute myelogenous leukemia and 

             solid tumours have occurred in patients with rheumatoid 

             arthritis who received the drug (McEvoy, 1993).

        7.4  Teratogenicity

             Azathioprine is teratogenic in rabbits and mice when 

             given in dosages equivalent to the human dosage (5 mg/kg 

             daily). Abnormalities included skeletal malformations and 

             visceral anomalies.

             Immunologic and other abnormalities have been reported in 

             newborn infants who were exposed to azathioprine during 

             pregnancy. However, the association that may exist between 

             these abnormalities and azathioprine has not been determined 

             (Briggs et al., 1990).

        7.5  Mutagenicity

             Azathioprine is mutagenic in animals and humans. 

             Chromosomal abnormalities have been documented in humans 

             receiving azathioprine, but the abnormalities were reversed 

             following discontinuance of the drug (McEvoy, 1993). 

             Azathioprine is mutagenic in the Ames test (Dollery, 

             1991).

        7.6  Interactions

             Azathioprine dose should be reduced 75% when 

             administered with allopurinol, as allopurinol affects the 

             metabolism of mercaptopurine, a metabolite of azathioprine 

             (Dollery, 1991).

             Azathioprine may reduce the effect of certain neuromuscular 

             blocking agents including curare and related non-depolarizing 

             drugs (Dollery, 1991).

             Certain cytotoxic agents may be additive or synergistic in 

             producing toxicity when used in conjunction with azathioprine 

             (Dollery, 1991).

             The Committee on Safety of Medicines have advised that 

             azathioprine and penicillamine should not be used 

             concurrently (Dollery, 1991).

             The effects of azathioprine and corticosteroids could be 

             synergistic (Dollery, 1991).

             Azathioprine may reduce the anticoagulant effect of warfarin 

             (Reynolds, 1993).

        7.7  Main adverse effects

             The principal toxic effect of azathioprine is bone 

             marrow depression.

             Adverse GI effects (nausea, vomiting, anorexia and diarrhoea) 

             caused by azathioprine may be minimized by giving the drug in 

             divided doses and/or after meals.

             Hepatoxicity may occur in patients receiving azathioprine 

             principally in allograft patients. Rare, but life-threatening 

             hepatic veno-occlusive disease has occurred during chronic 

             azathioprine therapy.

             Azathioprine may also cause rash, infection, drug fever, 

             serum sickness, alopecia, arthralgia, retinopathy, Raynaud’s 

             disease, and pulmonary edema. Some of these adverse effects 

             can occur as manifestations of rare hypersensitivity 

             reactions. (McEvoy, 1993).

  1. CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Oral ingestion of azathioprine tablets is the 

                    primary route of its administration. It may affect 

                    taste and smell (Ellenhorn & Barcelux,1988). It is 

                    well absorbed from the GI tract (Dorr & Fritz,1980). 

                    The oral bioavailability of therapeutic doses is 

                    approximately 60%. Acute overdosage with 850 mg of 

                    azathioprine has been tolerated by an adult without 

                    producing symptoms. An overdose of 7500 mg 

                    azathioprine produced mild transient alteration of 

                    liver enzymes and leukopenia which was delayed. The 

                    usual therapeutic dose of azathioprine is about 1 to 5 

                    mg/kg/day (Calabresi and Chabner, 1991).

             9.1.2  Inhalation

                    No data available.

             9.1.3  Skin exposure

                    No data available.

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    Acute poisoning due to parenteral exposure of 

                    azathioprine has not been reported. However, transient 

                    side effects following therapeutic intravenous 

                    administration of 100 mg azathioprine may occur. There 

                    has been no specific toxic effects following 

                    parenteral exposure of azathioprine. Idiosyncratic 

                    reactions such as dizziness, nausea, vomiting and 

                    reversible shock may appear during and or right after 

                    I.V. injection of azathioprine (Reynolds, 

                    1989).

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Chronic poisoning due to oral ingestion of 

                    azathioprine has not been reported. However, long term 

                    oral therapeutic administration to 64 patients 

                    revealed reversible leukopenia in 22%, macrocytosis in 

                    20%, systemic illness (vomiting, abdominal pain, 

                    anorexia, rash or urticaria) in 12% and hepatotoxicity 

                    in 9% (Kissel et al, 1986).

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    Parenteral administration of azathioprine may 

                    induce toxic effects such as dizziness, nausea, 

                    vomiting, allergic reactions, hypotension and delayed 

                    leukopenia (Reynolds,1989). Parenteral overdose cases 

                    of azathioprine has not been reported.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Based on very limited reports and experience on 

             azathioprine overdose, it seems that single overdose up to 

             850 mg is asymptomatic. In a case of massive overdose with 

             7500 mg of azathioprine, immediate toxic reactions were 

             nausea, vomiting and diarrhoea followed by mild leukopenia, 

             mild abnormalities in liver and kidney function on the third 

             day after the overdose. On the 6th day of admission white 

             blood cell (WBC) count, liver and kidney function tests 

             returned to normal. The oral azathioprine of 50 mg daily was 

             resumed on this kidney transplant patient, WBC had dropped to 

             2,800/mm3 on the third day after administration. 

             Azathioprine therapy was again discontinued, and WBC 

             increased to 11,000/mm3 after 11 days. Azathioprine therapy 

             was resumed at 50 mg/day without further suppression of 

             peripheral WBC and the patient survived (Carney et al, 

             1974).

             There has been no report of mortality due to azathioprine 

             poisoning. However, several cases of azathioprine induce 

             hepatic venocclusive disease in renal transplant patients 

             with high mortality (6 out of 7 patients) was reported by 

             Katzka et al (1986). Severe bone marrow depression and its 

             complication such as septic shock may also be a cause of 

             death.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Arterial hypertension after renal 

                    transplantation in patients treated with azathioprine 

                    in 72% of the cases compared with cyclosporin (64%) 

                    was investigated (Gordjani et al, 1990). Cases of 

                    portal hypertension in renal transplant patients after 

                    long term azathioprine therapy were reported 

                    (Yanagisawa et al, 1990 and Lorenz et al, 

                    1992).

             9.4.2  Respiratory

                    A single case of acute restrictive lung disease 

                    following long term azathioprine at a dose of 100 

                    mg/day which resolved after the drug was discontinued 

                    has been reported (Dorr & Fritz, 1980). A case of 

                    pulmonary manifestation (pulmonary infiltrations with 

                    haemoptysis) of Goodpasture’s syndrome following 

                    azathioprine therapy in a renal patients has also been 

                    reported (Stetter et al, 1994).

             9.4.3  Neurological

                    9.4.3.1  CNS

                             A case of progressive 

                             leukencephalopathy (PML) after a four year 

                             azathioprine therapy with difficulty in 

                             urinating, articulation, spastic hemiplegia 

                             and eye movement malfunction was reported 

                             (Schnider,1991).

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             There is only a report of artralgia 

                             among many othertoxic effects (Osol, 

                             1980).

             9.4.4  Gastrointestinal

                    Oral ulceration occur rarely with therapeutic 

                    doses but may be seen with large doses (Dorr & Fritz, 

                    1980). Metallic or bitter taste following azathioprine 

                    ingestion has been reported (Ellenhorn & Barcelux, 

                    1988). Gastrointestinal disturbances such as nausea, 

                    vomiting, abdominal pain and diarrhoea have been 

                    reported and appear to occur mainly at higher doses 

                    (Assini et al, 1986). The authors classified this as a 

                    definite adverse reaction based on a positive 

                    rechallenge. Acute pancreatitis with severe vomiting 

                    following long term therapeutic administration of 

                    azathioprine was also reported (Roblin et al, 

                    1990).

             9.4.5  Hepatic

                    Hepatic dysfunction (hepatocellular and 

                    cholestatic), manifested by elevation of liver 

                    function tests and onset of jaundice and also hepatic 

                    venocclusive disease in renal transplant patients 

                    given azathioprine therapy have been reported (Read et 

                    al,1986; Barrowman et al,1986; Katzka et al,1986; 

                    Jeurissen et al,1990; Sternek et al,1991). Hepatic 

                    hemangiomas in a patient with rheumatoid arthritis 

                    treated with azathioprine was reported by Linana-  

                    Santafe et al (1992). Reversible cholestasis with bile 

                    duct injury following azathioprine therapy was also 

                    described (Horsmans et al,1991). A patient with 

                    dermatomyositis developed peliosis hepatis after 

                    treatment by azathioprine and corticosteroids. Liver 

                    enlargement with signs of portal hypertension 

                    disappeared progressively following discontinuation of 

                    azathioprine (Lorcerie et al, 1990).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             There has been no report of the 

                             direct toxic effects of azathioprine on the 

                             kidneys. However, fever, hepatitis and acute 

                             interstitial nephritis in a rheumatic patient 

                             as concurrent manifestations of azathioprine 

                             hypersensitivity was reported (Meys et 

                             al,1992).

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    A severe palmar-plantar erythema with 

                    desquamation and pain was reported in a case receiving 

                    allupurinol as well. This was successfully treated by 

                    discontinuation of the drugs and initiation of topical 

                    steroid therapy. Skin rash, alopecia and urticaria 

                    after azathioprine therapy were also reported (Dorr 

                    and Fritz,1980; Kissel et al,1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    There has been no report on the local effects 

                    of azathioprine on the above organs. However, 

                    retinophathy among the other toxic effects of 

                    azathioprine was reported (Osol, 1980).

             9.4.10 Haematological

                    Myelosuppression is an important and 

                    potentially lethal complication of azathioprine 

                    treatment (Connell et al, 1993). Leukopenia is the 

                    primary haematologic finding following azathioprine 

                    therapy. A mild leukopenia (4,100/mm3) was found on 

                    the third day after a massive azathioprine overdose. 

                    It was increased to 7300/mm3 on the 6th day (Carney 

                    et al,1974). However, severe bone marrow depression 

                    was reported in a 55 year old woman with severe oral 

                    lichen planus treated with azathioprine 100 mg/day 

                    orally for 28 days. Her white blood count (WBC) 

                    continued to fall down to 200/mm3 one week after 

                    azathioprinediscontinuation. Her Hb reduced to 8.4 

                    g/dL over this period. Bone marrow aspirated 12 days 

                    after the drug withdrawal showed reduced cellularity 

                    mainly of WBC precursors. Erythropoiesis was 

                    normocellular with megaloblastic change and 

                    megacaryocytes werenormal (Maddocks et al, 1986). In a 

                    study of 739 patients who were treated with 2 

                    mg/kg/day azathioprine for a median of 12.5 months, 37 

                    patients (5%) developed bone marrow toxicity. 

                    Leukopenia (WBC< 3000 /mm3) occurred in 28 (3.8%) 

                    patients and 3 of them were pancytopenic of which 2 

                    died from sepsis (Connell et al,1993). Pure red blood 

                    cell aplasia was found in a renal transplant patient 

                    who was treated by azathioprine. Discontinuation of 

                    azathioprine was associated with complete recovery 

                    from anaemia as well (Agarwal et al,1993).

             9.4.11 Immunological

                    Azathioprine is an immunosuppressive agent 

                    which induce myelosuppression. However, 

                    hypersensitivity reactions and shock have been 

                    observed during azathioprine treatment (Wilson et 

                    al,1993; Jones and Ashworth,1993). Gastrointestinal 

                    type I hypersensitivity to azathioprine with a massive 

                    duodenal eosinophilia without peripheral blood 

                    eosinophilia was reported (Riedel et al, 

                    1990).

             9.4.12 Metabolic

                    No data available.

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Dermatologic and gastrointestinal allergic 

                    reaction such as rash, urticaria and gastroentritis 

                    during azathioprine therapy were reported (Jeurissen 

                    et al,1990; Riedel et al, 1990).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy & Lactation:

                    There has been no report of bona fide cases of human 

                    malformations attributed to maternal treatment with 

                    azathioprine. There are 77 cases of normal infants 

                    born under azathioprine treatment (Schardein,1985). 

                    Despite the lack of foetal damage associated with 

                    azathioprine, it seems prudent to avoid its use in 

                    pregnancy if possible. There has been no report of 

                    azathioprine excretion in breast milk (Briggs et al., 

                    1990).

        9.5  Other

             No data available.

  1. MANAGEMENT

        10.1 General principles

             Special attention should be given to the haemopoietic 

             system and liver function. In severe intoxication with 

             azathioprine, respiratory and cardiovascular functions 

             shouldbe monitored and supported.

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Blood and urine samples should be collected 

                    for analyses. Gastric contents may also be used for 

                    toxicological analysis (presence of azathioprine) in 

                    azathioprine overdose patient who was admitted early 

                    after ingestion. Blood samples should be collected in 

                    different tubes with and without anticoagulant (EDTA) 

                    for haematological, biochemical and toxicological 

                    tests. Red blood cells have been used in one case for 

                    the estimation of a cytotoxic metabolite of 

                    azathioprine (6-thioguanine nucleotide) (Maddocks et 

                    al., 1986).

             10.2.2 Biomedical analysis

                    Regular white blood cell count monitoring is 

                    required during and 1 to 2 weeks after taking 

                    azathioprine therapy and after overdose as leukopenia 

                    is the most common toxic effect of azathioprine in 

                    humans. Liver and kidney function tests should also be 

                    performed to detect the azathioprine toxicity on these 

                    organ.

             10.2.3 Toxicological analysis

                    Estimation of azathioprine and its metabolites 

                    concentrations in blood and urine may be required. 

                    Concentration of 6-thioguanine nucleotide (TGN) a 

                    cytotoxic metabolite of azathioprine was assayed in 

                    red blood cells 12, 44 and 55 days after intoxication 

                    which were much higher than the control group. The 

                    authors concluded that this active metabolite which is 

                    also produced with 6-mercaptopurine and 6- thioguanine 

                    therapy is related to neutropenia and can be used to 

                    predict bone marrow toxicity of these drugs (Maddocks 

                    et al., 1986).

             10.2.4 Other investigations

                    In severe azathioprine intoxicated patient, 

                    other paramedical investigations such ECG and chest X- 

                    ray may be required and should be performed whenever 

                    indicated.

        10.3 Life supportive procedures and symptomatic/specific treatment

             Treatment should be supportive and symptomatic. Make a 

             proper assessment of airway, breathing, circulation and 

             neurological status of the patient. Open and maintain at 

             least one intravenous route. Administer intravenous fluid. 

             Monitor vital signs in severe intoxicated patients. Monitor 

             fluid and electrolytes and acid-base balance. Haemodialysis 

             has been reported to remove azathioprine and its metabolites. 

             It can therefore be used in severe overdose patients (Bennett 

             et al,1980).

        10.4 Decontamination

             Emesis may be indicated in substantial recent ingestion 

             of azathioprine. It is most effective if initiated within 30 

             minutes of ingestion. If emesis is unsuccessful following 2 

             doses of ipecac, the decision to gastric lavage should be 

             made on an individual basis. In massive overdose patients, 

             gastric aspiration and lavage may be performed as soon as 

             possible. Activated charcoal (1-2 g/kg every 3-4 h) as slurry 

             in water or mixed with sorbitol should be given orally or 

             through the gastric tube. Cathartics should not be used in 

             patients with an ileus or impaired renal function. In case of 

             skin and eye exposure, irrigate with copious amounts of water 

             and saline.

        10.5 Elimination

             Azathioprine and its metabolites are haemodialysable. 

             About 44% of the total amount of Azathioprine in 3 men and 3 

             women on chronic haemodialysis(95.4ñ31.0 ml/min) was removed 

             during 8 hours. Haemodialysis should be used in severe 

             azathioprine intoxicated patients (Schusziarra et al, 

             1976).

        10.6 Antidote treatment

             There is no antidote for azathioprine toxicity.

             10.6.1 Adults

             10.6.2 Children

        10.7 Management discussion

             There have been reports only on two azathioprine 

             overdose cases. One had taken 850 mg and was asymptomatic and 

             other who had taken 7500 mg, revealed mild transient 

             gastroenteritis, leukopenia and hepatic function and 

             survived. However, azathioprine toxicity has mainly been 

             reported in patients already taking this immunosuppressive 

             agent. Regular monitoring of peripheral blood count and liver 

             function is required to detect the toxicity in advance. In 

             severe azathioprine intoxicated patients, Supportive and 

             critical care management including barrier nursing, 

             particularly in those with severe leukopenia <1000/Cub.mm or 

             septic shock, is required (Carney et al, 1974; Connel et al, 

             1993). Administration of granulocyte colony stimulating 

             factor (GCS-F) may reduce morbidity in patients with severe 

             neutropenia after cytotoxic chemotherapy, and would be 

             expected to reduce the severity and duration of neutropenia 

             after azathioprine poisoning.

  1. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             There is two case reports from the medical literature. 

             First was asymptomatic who had taken 850 mg azathioprine. The 

             second is as follows:

             A 44 year old disable heavy equipment operator who had 

             suffered from chronic renal failure. He received a cadaver 

             kidney transplantation on September 18, 1970 and went under 

             azathioprine and corticosteroid treatment. On February 8, 

             1972 at 18h ingested 200 x 5mg prednisolone tablets as 

             instructed and 150 x 50 (7500)mg tablets of azathioprine by 

             mistake. He vomited 6 and again 8 hours later and noticed 

             diarrhoea. He was then hospitalised on the following morning 

             for observation. The patient was asymptomatic thereafter for 

             6 days. His white blood cell counts (WBC) decreased from 

             7500/Cub.mm on the first day to 4100/Cub.mm on the third day 

             after overdose and returned to 7300/Cub.mm on the 6th day. 

             There was also a mild transient liver enzymes transaminase 

             alteration. He received no treatment for his overdosage. 

             Azathioprine oral administration, 50 mg/day was resumed. 3 

             days later, the total WBC decreased to 2800/Cub.mm. 

             Azathioprine therapy was again discontinued for 11 days when 

             his WBC increased to 11,000/Cub.mm. Azathioprine was resumed 

             again at 50 mg daily and subsequently to 100 mg daily without 

             further suppression of WBC and the patient survived (Carney 

             et al, 1974).

         11.2 Internally extracted data on cases

             To be added by the Center using the monograph.

        11.3 Internal cases

             To be added by the Center using the monograph.

  1. Additional information

        12.1 Availability of antidotes

             No antidote is available.

        12.2 Specific preventive measures

             Azathioprine is a myelotoxic and hepatotoxic agent. It 

             is therefore advisable to monitor the peripheral blood counts 

             and liver function regularly to detect the early toxic 

             effects. Estimation of 6-thioguanine nucleotide, a cytotoxic 

             metabolite of azathioprine was assayed in red blood cell of a 

             patient 12, 14 and 55 days after stopped taking azathioprine. 

             It was found much higher than the controls. The authors 

             believed that this metabolite is responsible for neutropenia 

             and could be used to predict bone marrow toxicity of 

             azathioprine (Maddocks et al, 1986).

        12.3 Other

             No data available.

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        long-term azathioprine therapy. Clin Investig 70(2): 152-155.

        Maddocks JL, Lennard L, Amess J, Amos R & Meyrick-Thomas R (1986) 

        Azathioprine and severe bone marrow depression. Lancet 1:156.

        McEvoy GK (1993) Drug Information The American Hospital Formulary 

        Service, American Society of Health-System Pharmacists, Inc., 

        MD.

        Meys E, Devogelaer JP, Geubel A, Rahier J & Nagant-de-Deuxchaisnes 

        C (1992) Fever, hepatitis and acute interstitial nephritis in a 

        patient with rheumatoid arthritis, concurrent manifestations of 

        azathioprine. J Rheumatol 19(5): 807-809.

        Osol A (1980) Azathioprine in: Remington’s pharmaceutical 

        sciences, 16th edition, Mack Publishing Co, Easton, Pennsylvania, 

        1085-1086.

        Read AE, Wienser RH, LaBrecque DR, Tifft JG, Mullen KD, Sheer RL & 

        Petrelli M (1986) Hepatic veno-occlusive disease associated with 

        renal transplantation and azathioprine therapy. Ann Intern Med 

        104: 651-655.

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        Pharmacopoeia, 29th edition, The Pharmaceutical Press, London, 

        599-601.

        Riedel RR, Schmitt A, de Jonge JP & Hartmann A (1990) 

        Gastrointestinal type 1 hypersensitivity to azathioprine. Klin. 

        Wochenschr. 68(1): 50-2

        Roblin X, Berot F, Jacquot JM, Nairi A, Abinader J, Monnet D 

        (1990) Azathioprine-induced acute pancreatitis (in French) Ann. 

        Gastroenterol. Hepatol. 26(5):233

        Schardein JL (1985) Chemically induced birth defects. Marcel 

        Dekker Inc, New York.

        Schneider F (1991) Progressive multifocal leukoencephalopathy as a 

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        222-224 (in German).

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        Lake J (1991) Azathioprine hepatotoxicity after liver 

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        Stetter M, Schmidl M & Krapf R (1994) Azathioprine 

        hypersensitivity mimicking Goodpasture’s syndrome. Am J Kidney Dis 

        23(6): 874-877.

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        mimicking sepsis in a patient with Crohn’s disease. Clin. Infect. 

        Dis. 17(5): 940-1

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  1. AUTHOR(S):
  2. Balali-Mood, M.D., Ph.D.,

        Professor of Medicine and Clinical Toxicology,

        Director, Poisons Control Centre,

        Imam Reza Hospital,

        Mashhad University of Medical Sciences,

        Mashhad 91735, I.R.Iran.

        Peer reviewed: Berlin, October 1995

        Finalised: IPCS, September 1996

See Also:

        Azathioprine (IARC Summary & Evaluation, Supplement 7, 1987)

        Azathioprine (IARC Summary & Evaluation, Volume 26, 1981)

    ANAPHYLAXIS

    DEFINITION

    Anaphylaxis is an immunological description of a type I

    hypersensitivity reaction mediated by IgE or IgG.

    Clinically, the term is used to describe a group of symptoms (see

    “clinical diagnosis” for complete description) irrespective of the

    mechanism.  Where an immunological basis for the syndrome is unproven,

    the term “anaphylactoid” is used.

    Clinical expression of anaphylaxis is variable in severity but

    cardiovascular collapse is the most common life-threatening feature

    and bronchospasm occurs frequently.

    TOXIC CAUSES

    Innumerable substances may cause anaphylaxis.  Common causative agents

    include:

         Antivenoms

         Blood products

         Chemicals

         Drugs:    Antibiotics

                   Antiinflammatory agents

                   Analgesics

                   Chemotherapeutic agents

                   Local anaesthetic agents

                   Neuromuscular blocking drugs

                   Radiocontrast agents

         Foods:    Nuts

                   Shellfish

         Insect stings

         Latex

         Plants

    CLINICAL FEATURES

    History of exposure to a substance capable of producing anaphylaxis

    and appropriate clinical manifestations. These may include:

    hypotension, bronchospasm, upper airways obstruction, pulmonary

    oedema, angioedema, generalized oedema, pruritus, rash, vomiting,

    diarrhoea and abdominal pain.  In some cases, there may not be a clear

    history of exposure.

    DIFFERENTIAL DIAGNOSIS

    Anxiety

    Asthma 

    Bronchospasm or laryngeal oedema due to inhalation of irritant gases.

    Cardiogenic shock

    Foreign body in upper airway

    Hypovolaemia

    Pulmonary embolism

    Vasovagal episode

    RELEVANT INVESTIGATIONS

    In such an emergency situation, no biomedical investigations are

    required to commence treatment.

    TREATMENT

     Epinephrine (Adrenaline)

     Epinephrine is the preferred treatment for anaphylaxis and should be

    administered as soon as practicable while assessing and supporting

    vital functions.  It is usually given intramuscularly but may be given

    subcutaneously in mild cases.  Intravenous administration is only

    indicated in severe cases because of the risk of ventricular

    dysrhythmias.  In the intubated patient, endotracheal installation is

    possible if intravenous access is unavailable.

    Doses of  epinephrine:

         1) Intramuscular/subcutaneous:     Adult:         0.5  to 1.0 mg

                                            Paediatric:    0.01 mg/kg

    or                                                          

              Age                 Epinephrine 1:1000 solution                                                   

              < 1  year                0.05      mL

              1    year                0.1       mL

              2    years               0.2       mL

              3-4  years               0.3       mL

              5    years               0.4       mL

              6-12 years               0.5       mL

              > 12 years               0.5 to 1  mL                                                             

    The appropriate dose should be repeated every 3 to 10 minutes until an

    adequate response in pulse and blood pressure is observed. 

         2) Intravenous:     Adult:  0.1 mg (1 mL of 1:10000 solution made

                             by diluting 1 mg of  epinephrine in 10 mL of

                             normal saline) over 2 to 3 minutes. 

                             Paediatric:  0.01 mg/kg over 2 to 3 minutes.

    The appropriate dose should be repeated until an adequate response in

    pulse and blood pressure is observed. 

    Notes on  epinephrine therapy:

         The dosage of  epinephrine is NOT one ampoule.

         For the intubated patient, if intravenous injection is not

         possible, intratracheal instillation (1 to 3 mg) is an

         alternative.

         Patients on beta-blockers may require larger doses of

          epinephrine.

     Oxygen

    Supplemental  oxygen should be administered to all patients.  In

    severe cases, especially those with airways obstruction, establishment

    of an adequate airway (endotracheal intubation or tracheotomy) and/or

    assisted ventilation may be necessary.

     Fluids

    In patients presenting with hypotension, one to two litres of

     intravenous fluids should be given as soon as intravenous access is

    established.  Colloid is preferable to crystalloid but either is

    acceptable.  Persistent hypotension should be treated with further

    doses of  epinephrine.

    Further administration of intravenous fluids should be cautious and

    ideally titrated against central venous pressure.

     Corticosteroids are not life-saving and are never the primary

    therapy of acute anaphylaxis.  They may be useful in the treatment of

    bronchospasm and in the prevention of relapses.  An intravenous dose

    of 200 to 300 mg of  hydrocortisone (or equivalent dose of another

     corticosteroid) may be given.

    Nebulized  salbutamol (albuterol) may be useful for refractory

    bronchospasm, particularly in children.

    CLINICAL COURSE AND MONITORING

    There is usually a rapid response to therapy and recovery is complete. 

    Pulse, blood pressure, respiration and oxygen saturation must be

    monitored until full recovery.

    LONG TERM COMPLICATIONS

    Recurrent episodes of anaphylaxis. 

    The agent that caused the anaphylaxis should be identified where

    possible and the patient adequately advised regarding the avoidance of

    further reactions.  A warning device or letter should be issued. 

    Patients who suffered life-threatening anaphylaxis should be

    instructed in the self-use of  epinephrine. The need for

    desensitization to the allergen should be considered. 

    AUTHOR(S)/REVIEWERS

    Author:        Dr R. Fernando, National Poison Information Centre,

                   Colombo, Sri Lanka.

    Reviewers:     Cardiff 3/95, Berlin 10/95: A. Jaeger, R. Dowsett, J.

                   Szajewski, V. Danel, A. Wong. 

                   Cardiff 9/96: V Afanasiev, T Della Puppa, J Huang, G

                   Muller, L Murray, J Szajewski, C Warden.

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