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 Table of Contents  
MANAGING A SIDE EFFECT
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 46-49

Acute methotrexate toxicity


Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College, AVBR Hospital, Wardha, Maharashtra, India

Date of Web Publication1-Dec-2015

Correspondence Address:
Bhushan Madke
Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Sawangi, Wardha - 442 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/WKMP-0110.170764

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How to cite this article:
Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol 2015;1:46-9

How to cite this URL:
Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol [serial online] 2015 [cited 2019 Sep 22];1:46-9. Available from: http://www.ijdd.in/text.asp?2015/1/1/46/170764




  Etiopathogenesis Top


Methotrexate (MTX) inhibits mitosis of the cells by antagonizing folic acid required for deoxyribonucleic acid (DNA) synthesis of cells. Once in the cell, MTX inhibits dihydrofolate (DHF) reductase, an enzyme responsible for the conversion of DHF to tetrahydrofolate (THF). Consequently, there is a reduction in thymidylate and purine biosynthesis. DNA synthesis eventually halts and cells can no longer divide. Polyglutamination of MTX prolongs its intracellular presence. Hence, cells with the capability of effective polyglutamination such as leukemic myeloblasts, synovial macrophages, lymphoblasts, and epithelia are more susceptible to the action of MTX.[1] Acute MTX toxicity presents as pancytopenia, gastrointestinal (GI) mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure.[2],[3]

The most common cause of acute MTX toxicity is an accidental overdose of MTX tablets by the patient or physician's prescription error. MTX is prescribed by many physicians as three consecutive dosages of 2.5 mg at an interval of 12 h. Folic acid tablets are prescribed on other non-MTX days. In India, many of our patients may make an error to distinguish between MTX and folic acid tablets and thus may land up with acute MTX toxicity. Predisposing factors for developing MTX toxicity include acute renal failure, hypoalbuminemia, and concurrent use of drugs known to interact with MTX. Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) can decrease the renal elimination and the tubular secretion of MTX while trimethoprim/sulfamethoxazole (Septran ®) can enhance the cytotoxic effects of MTX as trimethoprim is an antifolate reductase inhibitor.[4] Concomitant use of MTX and NSAIDs, increase the risk of MTX toxicity as NSAIDs inhibits MTX clearance and displace MTX from protein binding sites.


  Clinical Features Top


MTX toxicity targets vital organs and structures of the body namely skin, GI mucosa, kidney, liver, and bone marrow. Major toxic effects of MTX, such as hepatic, renal, pulmonary, and bone marrow disorders, occur less frequently than the minor effects but may be life-threatening. Signs and symptoms of acute MTX toxicity are based on extent and severity of organ involvement.

Common case scenario of acute MTX toxicity in psoriasis is a patient having long standing history of chronic plaque psoriasis presenting with sudden onset of erosions or ulcers in psoriatic plaques [Figure 1] and sudden onset of severe mucosal ulceration in the oral cavity. A patient may present with fever secondary to infection. Paradoxically, the patient may have hypothermia due to the development of sepsis. Many-a-times, scaly psoriatic plaque may not be visible due to profound effects of MTX toxicity. Careful history from the patient or patient's relative should be obtained with regard to psoriasis and MTX use.
Figure 1: Trunk showing eroded psoriatic plaques (Image contributed by Dr. Yashpal Manchanda, Consultant Dermatologist, Department of Dermatology, Farwaniya Hospital, Kuwait).

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Most of these patients are admitted to critical care setup or hospital; critical care physician needs to make a complete assessment of the patient to assess underlying sepsis or systemic disease. Average and approximate days for the development of various side effects are summarized in the following [Table 1].
Table 1: Chronology of events in MTX toxicity

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Investigations

Laboratory investigations reveal signs of myelosuppression, that is, pancytopenia. Kidney function tests and liver function tests may reveal organ affection.


  Treatment Top


Ideally, the patient presenting with suspected signs and symptoms of MTX toxicity should be admitted in an intensive care setting, and reverse barrier nursing should be observed by treating staff.

Three broad targets are involved in managing acute MTX toxicity: Folinic acid rescue, elimination of MTX from the body, and organ specific care

Folinic acid rescue

Folinic acid is the antidote of choice for treating MTX toxicity. This rescue regimen replenishes intracellular stores of reduced folate and attenuates the MTX toxicity. Ideally, the serum levels of MTX should be estimated in all cases of acute MTX toxicity, however; the facility for serum MTX measurement is not widely available, and most cases are managed on clinical grounds. Serum MTX levels give guiding schedule for folinic acid rescue therapy. The dose of IV folinic acid should be adjusted according to the MTX levels as shown in [Table 2].
Table 2: Dosages of Folinic Acid and MTX Plasma Concentration (µmol/L)

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Serum MTX levels should be measured every 24 h until the levels fall below 0.2 µmol/L. However, there is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity arising from weekly MTX dosing (5–25 mg/week).

Elimination of methotrexate from the body

Hydration

The vast majority of MTX is cleared by the kidneys (more than 90%). A satisfactory diuresis must be established (approximately 600 ml urine over 6 h, or 200 ml urine over 2 h) and fluid input should be approximately 3 L/m 2/day until MTX levels are 0.2 µmol/L or below, to maintain urine output and facilitate MTX excretion. Fluid balance should be monitored carefully to prevent renal toxicity and fluid overload. Aim for a urine output of approximately 2 L/m 2/day until the MTX level has fallen to 0.2 µmol/L.

Alkalinization of urine

MTX and its metabolites (2, 4-diamino-N(10)-methylpteroic acid [DAMPA]) are poorly soluble at acidic pH levels. An increase in urine pH from 6.0 to 7.0 increases the solubility of MTX and its metabolites by 5- to 8-fold and prevents crystal deposition. Urinary alkalinization with 40–50 mEq of sodium bicarbonate per liter of IV fluid reduces the risk of intratubular crystal formation. MTX and its metabolite 7-OH-MTX, which is seen predominantly with high-dose MTX therapy, show, respectively, 20- and 12-fold increased solubility when pH increases from 5.0 to 7.0. Urine pH must be >7 to promote MTX excretion and prevent MTX crystallization. It should be maintained at this throughout the treatment period and until levels are 0.2 µmol/L or below.[5]

Managing delayed methotrexate excretion

Glomerular filtration, tubular secretion, and tubular reabsorption all play a role in the renal clearance of MTX. Paradoxically, toxic levels of MTX pose a grave danger to renal tubules thereby leading to decreased renal clearance. MTX-induced nephrotoxicity mainly arises by two mechanisms: Crystal nephropathy and direct tubular toxicity.[6],[7]

Glucarpidase (carboxypeptidase, CPDG2 enzyme) was approved by the United States Food and Drug Administration in the treatment of plasma MTX concentrations

(>1 μmol/L) in patients with delayed MTX clearance due to impaired kidney function.[8] Glucarpidase is a recombinant form of the CPDG2 enzyme, produced via modified Escherichia coli. It is a homodimeric protein composed of 390 amino acids. The molecular weight is 83 kDa. The enzyme works by rapidly metabolizing circulating (not intracellular) MTX to two inactive metabolites: Glutamate and 2,4-diamino-N-10-methylpteroic acid (DAMPA). Use of CPDG2 enzyme should be considered if serum MTX concentration ≥10 µmol/L and rise in creatinine of 100% or more after the last dose of MTX. Treatment with glucarpidase reduces serum MTX levels by 97% or more within 15 min. However, treatment with glucarpidase does not affect the intracellular MTX concentration and hence high dose folinic acid should be continued.

The drug is sold as a sterile, preservative-free white lyophilized powder with 1000 units per single-use vial. Each vial also contains lactose monohydrate (10 mg), Tris-HCl (0.6 mg), and zinc acetate dihydrate (0.002 mg). Each vial should be reconstituted (immediately prior to use) with 1 ml sodium chloride 0.9% and administered over 5 min by bolus IV injection. A caution should be borne that both folinic acid and its active metabolite, 5-methyl THF (5-mTHF) are substrates for glucarpidase and may reduce folate levels. Therefore, to minimize a clinically significant drug-drug interaction, patients should receive folinic acid 2 h before or after a dose of glucarpidase.[9]

Organ specific care

Methotrexate induced myelosuppression

All cases of MTX toxicity should be presumed to have neutropenia unless proved otherwise and ideally should be managed under Intensive Care Unit. At the cost of repetition, it is emphasized that all patients of MTX toxicity should be isolated, and reverse barrier nursing protocol should be scrupulously followed by health care staff. A patient of MTX toxicity having neutropenia and febrile episodes have a high risk of developing bacterial sepsis and portends a poor prognosis. A broad spectrum parenteral nonnephrotoxic antibiotic preferably a third generation cephalosporin should be instituted for neutropenic fever. Pending the results of leucovorin rescue, patients can be transfused with packed red blood cells and platelets. Alternately, recombinant granulocyte colony-stimulating factors (G-CSFs) therapy reduces the severity and duration of neutropenia and the consequent risk of febrile neutropenia. Recombinant human G-CSF acts on hematopoietic cells to stimulate production, maturation, and activation of neutrophils.[10]

Oral care

Patient education is important and forms a crucial part in the management of mucositis. A customized patient instruction should be followed to reduce the pain and discomfort of mucositis.

  • Patients are encouraged to sit upright at a 90° angle and lean their head slightly forward
  • Eat slowly, food should be cut into small pieces and chewed completely
  • Eat small frequent meals instead of heavy meals
  • Food taken should be warm, or at room temperature. Hot food and drinks should be avoided
  • Soft food is always encouraged. Finely chopped cooked meat, fruits, and vegetables should be taken. Milkshakes that have very high proteins can also be tried
  • Usage of str aw will not only make drinking easy but will also avoid direct contact with the affected portion
  • Do not talk while food is in the mouth
  • Acidic foods such as tomatoes, grapes, apple fruits or juices, alcohol and tobacco, and spicy foods should be avoided
  • To relieve discomfort of dry mouth, patients are asked to rinse mouth with water before and after every meal
  • Symptomatic treatment should be offered for mucositis
  • Chlorhexidine mouthwash rinse10 ml qid (efficacy is not proven)
  • Folinic acid mouthwash 15 mg QDS (15 mg/2 ml injection diluted to10 ml with water)
  • Syrup viscous lignocaine two teaspoon to be swished and spit 10 min before meals
  • Oral saline rinses.


Topical coating agents: Sucralfate suspension to be kept in the mouth for 5–10 min to allow sufficient contact time before each meal.

Pandya's formula: Mix 5 ml each of syrup prednisolone (5 mg/5 ml), syrup Gelusil ® and syrup Benadryl ®. This mixture should be softly rinsed in the mouth for 2 min and then spitted out.

Local care of eroded psoriatic plaques

Treatment of cutaneous erosions is mostly supportive because cutaneous erosions tend to heal quickly within 1–2 weeks.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-41.  Back to cited text no. 1
    
2.
Bhatnagar A, Verma R, Vasudevan B, Saraswat N. Acute methotrexate toxicity presenting as ulcers in plaques of psoriasis vulgaris. Indian Dermatol Online J 2015;6:232-3.  Back to cited text no. 2
[PUBMED]  Medknow Journal  
3.
Fridlington JL, Tripple JW, Reichenberg JS, Hall CS, Diven DG. Acute methotrexate toxicity seen as plaque psoriasis ulceration and necrosis: A diagnostic clue. Dermatol Online J 2011;17:2.  Back to cited text no. 3
    
4.
Bourré-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: A systematic review. J Rheumatol 2010;37:1416-21.  Back to cited text no. 4
    
5.
Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006;11:694-703.  Back to cited text no. 5
    
6.
Ahmed YA, Hasan Y. Prevention and management of high dose methotrexate toxicity. J Cancer Sci Ther 2013;5:106-12.  Back to cited text no. 6
    
7.
Perazella MA, Moeckel GW. Nephrotoxicity from chemotherapeutic agents: Clinical manifestations, pathobiology, and prevention/therapy. Semin Nephrol 2010;30:570-81.  Back to cited text no. 7
    
8.
Rattu MA, Shah N, Lee JM, Pham AQ, Marzella N. Glucarpidase (Voraxaze), a carboxypeptidase enzyme for methotrexate toxicity. Pharm Ther 2013;38:732-44.  Back to cited text no. 8
    
9.
BTG International, Inc. Voraxaze (glucarpidase) intravenous injection, product information. West Conshohocken, PA: BTG International, Inc.; 2013.  Back to cited text no. 9
    
10.
Yoon KH, Ng SC. Early onset methotrexate-induced pancytopenia and response to G-CSF: A report of two cases. J Clin Rheumatol 2001;7:17-20.  Back to cited text no. 10
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

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