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Azathioprine, Uses, Dosage, Side Effects, Interactions, Pregnancy

Azathioprine is a purine analog with cytotoxic and immunosuppressive activity. Azathioprine is a prodrug that is converted by hepatic xanthine oxidase to its active metabolite 6-mercaptopurine (6-MP). 6-MP is further metabolized by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanosine-5′-phosphate (6-thio-GMP) and 6-thioinosine monophosphate (6-thio-IMP), both inhibit nucleotide conversions and de novo purine synthesis. This leads to inhibition of DNA, RNA, and protein synthesis. As a result, cell proliferation may be inhibited, particularly in lymphocytes and leukocytes.

Azathioprine(AZA) is an immunosuppressive medication used in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and in kidney transplants to prevent rejection. It is taken by mouth or injected into a vein. An immunosuppressive antimetabolite pro-drug. It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is converted into 6-mercaptopurine in the body where it blocks purine metabolism and DNA synthesis.

Mechanism of Action of Azathioprine

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to the incorporation of thiopurine analogs into the DNA structure, causing chain termination and cytotoxicity. Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation and autoimmune diseases such as rheumatoid arthritis or inflammatory bowel disease or Crohn’s disease. It is a pro-drug, converted in the body to the active metabolite 6-mercaptopurine. Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is a safe and effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given in conjunction with purine analogs such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus the assay of serum TPMT may be useful to prevent this complication.

Azathioprine (AZA), one of the antimetabolite drugs, is a purine analog that is more potent than the prototype 6-mercaptopurine, as an inhibitor of cell replication. Immunosuppression likely occurs because of the ability of the drug to inhibit purine biosynthesis. Although T-cell functions are the primary targets for this drug, inhibition of /(natural killer cells)/ NK function and macrophage activities have also been reported.

Azathioprine inhibits DNA synthesis and, as a purine antimetabolite, exerts its effect on activated lymphocytes, which requires purines during their proliferative phase. It inhibits both cellular and humoral responses but does not interfere with phagocytosis or interferon production. It is a nonspecific cytotoxic agent. Its immunosuppressive effect is believed to be due to mercaptopurine, to which it is metabolized.

The exact mechanism of immunosuppressive action is unknown since the exact mechanism of the immune response itself is complex and not completely understood. The immunosuppressive effects of azathioprine involve a greater suppression of delayed hypersensitivity and cellular cytotoxicity tests than of antibody responses. Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; it may also interfere with cellular metabolism and inhibit mitosis.

The thiopurines, azathioprine and 6 MP are potent inhibitors of both experimental and clinical immune responses. The primary pharmacological activities are mediated by competitive inhibition of enzymes concerned with de novo purine base synthesis; Immunosuppressive activities appear to result from cytotoxic activities directed against antigen-responsive lymphocytes; this inhibition is maximal when the treatment course coincides with the proliferative expansion phase of the response. By contrast, thiopurines are comparatively ineffective if used during an effector phase of an immune response. Furthermore, administration prior to antigenic challenge does not lead to immune inhibition; in fact, it may lead to augmentation of selected immune responses. Treatment with thiopurines does not result in acute lymphopenia; prolonged courses will cause a moderate decrease in circulating lymphocytes. The drug does not selectively deplete peripheral T or B cells but can acutely reduce K (killer) cells, which are effectors in ADCC responses. In addition, short-lived thymocytes and marrow lymphocytes are rapidly depleted by these anti-metabolites. Many in vitro functions of lymphocytes, from treated animals remain normal. Recent studies indicate that, in vitro, azathioprine is specifically able to bind murine T lymphocytes; this can be shown by their ability to inhibit their capacity to rosette with sheep erythrocytes. Azathioprine is also a potent inhibitor of mixed lymphocyte culture responses and can readily suppress the in vitro generation of cytotoxic T cells. These observations suggest that drugs exert preferential toxicities for murine T cells. B lymphocytes for mice appear to vary in their susceptibility for thiopurines. By contrast, the activity of human B cells can be readily suppressed with this drug whereas T helper function is comparatively resistant. In addition to immunosuppressive properties, thiopurines are capable of exerting anti-inflammatory activities, primarily by inhibiting the replication of hematopoietic precursors.

Indications of Azathioprine

Azathioprine is an immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis.
Rheumatoid Arthritis
Psoriatic Arthritis
Renal Transplant
Autoimmune Hepatitis
Crohn’s Disease
Atopic Dermatitis
Behcet’s Disease
Biliary Cirrhosis
Bullous Pemphigoid
Chronic Active Hepatitis
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Cogan’s Syndrome
Crohn’s Disease, Acute
Crohn’s Disease, Maintenance
Dermatomyositis
Eczema
Glomerulonephritis
Idiopathic Thrombocytopenic Purpura
Inflammatory Bowel Disease
Multiple Sclerosis
Myasthenia Gravis
Myopathy
Nephrotic Syndrome
Neurosarcoidosis
Organ Transplant, Rejection Prophylaxis
Systemic Lupus Erythematosus
Takayasu’s Arteritis
Ulcerative Colitis
Uveitis
Wegener’s Granulomatosis
Disseminated Sclerosis
Immune Thrombocytopenia
Kidney Transplant Rejection
Pericarditis

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Contra Indication of Azathioprine

Severe infection
Severe anemia
Decreased Blood Platelets
Severe Decrease in White Blood Cells
A Blood Clot in a Vein of the Liver
Acute Inflammation of the Pancreas
Pregnancy
Malignant Lymphoma
Moderate to Severe Kidney Impairment
Thiopurine S-Methyltransferase Deficiency
Hepatosplenic T-cell Lymphoma
Allergies to Mercaptopurine Analogues

Dosage of Azathioprine

Strengths : 50 mg

Rheumatoid Arthritis

Initial dose: 1 mg/kg (50 to 100 mg) orally or IV per day given in 1 to 2 divided doses
Maintenance dose: Lowest effective dose
Maximum dose: 2.5 mg/kg orally or IV per day
Duration: At least 12 weeks

Crohn’s Disease

1.5 to 4 mg/kg per day for 10 days up to 52 weeks
1.5 to 4 mg/kg per day for 10 days up to 52 weeks in maintenance dose

Atopic Dermatitis

2.5 mg/kg orally once a day, in the morning, for 3 months

Sarcoidosis

Initial dose: 2 mg/kg per day in combination with prednisolone 0.6 to 0.8 mg/kg per day, with prednisolone reduced to 0.1 mg/kg within 2 to 3 months
Maintenance dose: 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months.

Chronic Active Hepatitis

Autoimmune hepatitis: 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)

Uveitis

Treatment of choroidal neovascularization: 1 to 1.5 mg/kg orally per day, in combination with prednisolone and cyclosporine

Ulcerative Colitis

IV: 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
Oral: 2 mg/kg orally per day beginning the day after completion of the IV loading dose

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Renal Transplant

Initial dose: 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
Maintenance dose: 1 to 3 mg/kg orally or IV once a day

Pediatric Dose

Atopic Dermatitis

Greater than 17 years: 2.5 mg/kg orally once a day, in the morning, for 3 months

Eczema

Greater than 6 years: 2.5 to 3.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase

Side Effects of Azathioprine

The most common

stomach pain, especially if it comes along with fever and diarrhea or constipation
yellowing of the skin or eyes
loss of appetite
Constipation
sleepiness or unusual drowsiness
clumsiness or unsteadiness
dizziness
drowsiness
dry mouth
false sense of well-being
increased watering of mouth
lightheadedness
constipation;
vision changes;
breast swelling (in men or women); or
decreased sex drive, impotence, or difficulty having an orgasm.
blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
restless muscle movements in your eyes, tongue, jaw, or neck;

Common

Drowsiness and lightheadedness the day after taking the medicine.
Confusion.
Numbed emotions.
Visual disturbances such as blurred vision or double vision.
Shaky movements and unsteady walk (ataxia).
Loss of memory (amnesia).
Muscle weakness.
Dizziness.
Headache.
Skin rashes.
Disturbances of the gut such as diarrhoea, c onstipation, nausea, vomiting or abdominal pain.
Difficulty in passing urine (urinary retention).
Changes in sex drive.
Low blood pressure (hypotension).
Blood disorders.
Jaundice.
Unexpected aggression, restlessness or irritability (tell your doctor if you experience this).
Nightmares or hallucinations (tell your doctor if you experience this).

Rare

agitation
anxiety
behavioural changes, including aggressiveness, angry outbursts, bizarre behaviour, or decreased inhibitions
confusion
increased trouble sleeping
memory problems
muscle spasms
shortness of breath

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Drug Interactions of Azathioprine

Azathioprine may interact with following drugs, supplyments, & may change the efficacy of drugs

abatacept
anakinra
anti-tumor necrosis factor agents (e.g., adalimumab, etanercept, infliximab, )
azathioprine
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
beta-blockers (e.g., carvedilol, metoprolol, propranolol)
carbamazepine
clonidine
clozapine
corticosteroids (e.g.dexamethasone, hydrocortisone, prednisone)
cyclosporine
diltiazem
imatinib
macrolide antibiotics (e.g., clarithromycin, erythromycin)
methotrexate
methyldopa
mycophenolate
phenobarbital
phenytoin
rituximab
tacrolimus
verapamil

Pregnancy & Lactation of Azathioprine

FDA Pregnancy Category D

Pregnancy

Animal studies have revealed evidence of teratogenicity. There are no controlled data in human pregnancy. Congenital anomalies, including polydactyly, plagiocephaly, congenital heart disease, hypospadias, and bilateral talipes equinovarus have occurred. Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies

Lactation

Studies in women taking azathioprine at doses up to 200 mg per day for immunosuppression in inflammatory bowel disease, systemic lupus erythematosus, or transplantation have found either low or undetectable levels of its active metabolites in milk and infant serum.