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Methyclothiazide / reserpine Side Effects

Applies to methyclothiazide / reserpine: oral tablet

Respiratory

Respiratory side effects including nasal congestion has been reported in 8% of patients receiving reserpine. Bronchospasm is a rare respiratory system side effect associated with reserpine.[Ref]

Rare reports of reserpine-induced bronchospasm are believed to be due to inactivation of beta-adrenergic receptors, which can result in a marked potentiation of the bronchoconstrictive effect of histamine.[Ref]

Nervous system

Increased parkinsonian movements upon reserpine withdrawal (as with neuroleptics) may be due to supersensitivity to dopamine as a result of increased dopamine receptors that developed during reserpine therapy.[Ref]

Nervous system side effects associated with reserpine include sedation, lethargy (different from the psychiatric syndrome of depression), drowsiness, weakness, vertigo, insomnia, or headache in approximately 1% to 5% of patients. Vertigo, paresthesias, and restlessness have been associated with the use of methyclothiazide. While reserpine has been used to treat tardive dyskinesia, extrapyramidal movements may worsen upon withdrawal of therapy. A case of CNS hypertension, believed to be due to cerebral edema, has been associated with reserpine.[Ref]

Psychiatric

Psychiatric problems related to reserpine therapy can be serious. Depression occurs in 2% to 28% of patients, is more likely when daily doses exceed 0.5 mg, and can present at any time during therapy. Suicidal ideation has been reported. Reserpine-induced depression is quickly reversible if therapy is withdrawn as soon as the syndrome is recognized, but can persist for several months after drug discontinuation if the syndrome fully develops. Reserpine withdrawal psychosis has been reported.[Ref]

The depressive syndrome associated with reserpine usually consists of melancholy, loss of self confidence, early morning awakening, loss of libido, and reduced appetite.

A case of reserpine withdrawal psychosis has been reported. This uncommon condition may be due to dopamine receptor supersensitivity, which develops during reserpine therapy.[Ref]

Metabolic

Metabolic changes associated with methyclothiazide, as with other thiazide diuretics, are relatively common, especially when daily doses greater than 5 mg are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50%, and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypophosphatemia, hypercalcemia, hyperglycemia, hypercholesterolemia, and hyperuricemia are also relatively common. The electrolyte and intravascular fluid shifts that may occur during methyclothiazide diuresis can provoke hepatic encephalopathy in patients with hepatic cirrhosis.[Ref]

Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may occur, but are usually clinically insignificant except in malnourished patients.[Ref]

Cardiovascular

Cardiovascular side effects associated with reserpine include hypotension in 8% and bradycardia (and rare cases of syncope with bradycardia) in 3% of patients. Orthostatic hypotension secondary to intravascular volume depletion may occur during methyclothiazide therapy. This has resulted in syncope and, in some patients with glaucoma, temporary loss of vision. A rare case of paroxysmal atrial tachycardia with block associated with reserpine in a patient who was not raking a digitalis preparation, and rare cases of cerebrovascular accident associated with thiazide-induced diuresis have been reported.[Ref]

Orthostatic hypotension associated with methyclothiazide may be potentiated by concomitant use of alcohol, barbiturates, or narcotics.

A woman with paroxysmal atrial tachycardia developed sinus pauses during reserpine therapy, which were reproducible by carotid massage except when isoproterenol was given. Reserpine is known to increase vagal tone and to deplete cardiac catecholamines.

One patient, in a series of 231, with emergent hypertension, stroke, and thyrotoxic crisis, developed profound hypotension after reserpine 1 mg IM. Her blood pressure dropped from 180/100 to an unmeasurable level. The patient recovered after isoproterenol therapy.[Ref]

Hypersensitivity

Hypersensitivity reactions to thiazides usually involve the skin (cutaneous vasculitis, urticaria, rash, purpura), but may involve the gastrointestinal system (nausea, vomiting, or diarrhea), the genitourinary system (interstitial nephritis), and the respiratory system (acute noncardiogenic pulmonary edema, pneumonitis). Thiazide diuretics may induce phototoxic dermatitis.[Ref]

Thiazides may induce allergic reactions in patients who are allergic to sulfonamides.[Ref]

Dermatologic

Dermatologic reactions may indicate hypersensitivity to methyclothiazide. Erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been associated with this drug or other thiazides in rare cases.[Ref]

Gastrointestinal

A retrospective case-controlled drug surveillance study has revealed the relative risk of acute cholecystitis associated with the use of a thiazide diuretic is 2.0. The suspected explanation for this association is the potentially deleterious effects of thiazides on the serum lipid profile. Methyclothiazide-induced hypercholesterolemia or hypertriglyceridemia may enhance the formation of some types of gallstones.[Ref]

Gastrointestinal side effects due to unopposed parasympathetic activity produced by catecholamine depletion may occur as a result of increased gastrointestinal motility and secretory activity. Because of this, new diarrhea or worsening of existing diarrhea or increased salivation are reported in 2% of patients. Increased appetite, abdominal pain, or vomiting are rarely associated with reserpine. More common gastrointestinal problems associated with methyclothiazide include diarrhea, vomiting, constipation, or abdominal pain in approximately 5% of patients. Thiazide diuretics have been associated with acute cholecystitis and rare cases of pancreatitis, sialadenitis, and anorexia.[Ref]

Renal

Renal side effects including new or worsened renal insufficiency associated with methyclothiazide therapy is a probably sign of intravascular volume depletion, and serves a signal to reduce or withhold therapy. Rare cases of allergic interstitial nephritis have been associated with some thiazide diuretics.[Ref]

Genitourinary

Genitourinary complaints are limited to sexual impotence, reported in up to 5% of male patients who are taking either reserpine or methyclothiazide.[Ref]

Endocrine

Endocrinologic changes associated with methyclothiazide, as with other thiazide diuretic agents, include decreased glucose tolerance and a potentially deleterious effect on the lipid profile. This may be important in some patients with or who are at risk for diabetes or coronary artery disease. Reserpine may induce hyperprolactinemia, which can result in gynecomastia in men, and breast engorgement or pseudolactation in women.[Ref]

Hematologic

Hematologic side effects are rare. Rare cases of immune-complex hemolytic anemia, aplastic anemia, leukopenia, and thrombocytopenia have been associated with methyclothiazide or other thiazide diuretics.[Ref]

Musculoskeletal

Musculoskeletal cramping or spasms are occasionally reported during thiazide diuresis.[Ref]

Immunologic

Immunologic side effects are rare. A single case of angioimmunoblastic lymphadenopathy has been associated with reserpine. In one study of 231 patients who were taking reserpine, only one case of a lupus-like syndrome was observed in a patient who had previously received hydralazine.[Ref]

A 79-year-old woman with hypertension, taking reserpine, potassium, hydrochlorothiazide, and ibuprofen, developed fatigue, anorexia, fever, night sweats, and weight loss. Associated laboratory findings showed anemia, lymphocytosis, thrombocytopenia, IgA kappa paraproteinemia, an elevated ANA titer, and a positive Coombs' test. Bone marrow biopsy, lymphangiography, and lymph node biopsy showed bone marrow lymphocytosis, enlarged foamy abdominal lymph nodes with irregular filling, and angioimmunoblastic lymphadenopathy, respectively. Within four days after discontinuation of reserpine (her other medications were continued), the paraprotein level normalized and the platelet count rose. After an additional nine months of prednisone therapy, all signs and symptoms resolved.[Ref]

Oncologic

Oncologic concerns were raised after a large drug surveillance center in Boston reported an association between reserpine, a stimulator of prolactin, and breast cancer in 1974. This association was partially, but not completely, confirmed in two similar centers in Europe. A critical review of these studies elucidated several design flaws. Subsequent, controlled studies failed to show an association between reserpine and an increased incidence of breast carcinoma.[Ref]

References

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2. Atuk NO, Owen JA, Jr "Bronchospasm after reserpine." N Engl J Med 281 (1969): 908-9

3. Segal MS "Bronchospasm after reserpine." N Engl J Med 281 (1969): 1426-7

4. Freis ED "Reserpine in hypertension: present status." Am Fam Physician 11 (1975): 120-2

5. Kirschenbaum HL, Rosenberg JM "What to look out for with guanethidine and reserpine." RN 47 (1984): 31-3

6. Diamond L "Drug-induced bronchospasm." J Clin Pharmacol J New Drugs 10 (1970): 215-6

7. Applegate WB, Carper ER, Kahn SE, Westbrook L, Linton M, Baker MG, Runyan JW, Jr "Comparison of the use of reserpine versus alpha-methyldopa for second step treatment of hypertension in the elderly." J Am Geriatr Soc 33 (1985): 109-15

8. Gibb WE, Malpas JS, Turner P, White RJ "Comparison of bethanidine, alpha-methyldopa, and reserpine in essential hypertension." Lancet 2 (1970): 275-7

9. Peters HA "Questioning reserpine's adverse effect on tardive dyskinesia." Am J Psychiatry 140 (1983): 1106

10. Pfeifer HJ, Greenblatt DK, Koch-Wester J "Clinical toxicity of reserpine in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program." Am J Med Sci 271 (1976): 269-76

11. Kennedy CC, Spiekerman RE, Elveback L "Antihypertensive properties of cryptenamine used with reserpine and methyclothiazide." J Pharm Sci 60 (1971): 1139-41

12. Murayama M, Yasuda K, Minamori Y, Mercado-Asis LB, Yamakita N, Miura K "Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation." J Clin Endocrinol Metab 75 (1992): 935-42

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18. Reus VI "Behavioral side effects of medical drugs." Prim Care 6 (1979): 283-94

19. Ross RT "Drug-induced parkinsonism and other movement disorders." Can J Neurol Sci 17 (1990): 155-62

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21. Bryant JM, Schwartz N, Fletcher L, et al. "Clinical studies of the antihypertensive effects of a new benzothiadiazine diuretic." Curr Ther Res Clin Exp 3 (1961): 1-4

22. Donatelli A, Geisen L, Feuer E "Case report of adverse effect of reserpine on tardive dyskinesia." Am J Psychiatry 140 (1983): 239-40

23. Black HR, Chrysant SG, Curry CL, Frishman WH, Grimm RH, Lasseter KC, Okun R, Pool JL, Raizada V, Vlachakis ND, et al "Antihypertensive and metabolic effects of concomitant administration of terazosin and methyclothiazide for the treatment of essential hypertension." J Clin Pharmacol 32 (1992): 351-9

24. Dilsaver SC, Greden JF "Possible cholinergic mechanism in reserpine and tardive dyskinesia." Am J Psychiatry 141 (1984): 151-2

25. Fleishman M "Letter: Reserpine, ECT, and depression." Am J Psychiatry 132 (1975): 1088

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27. Lewis WH "Iatrogenic psychotic depressive reaction in hypertensive patients." Am J Psychiatry 127 (1971): 1416-7

28. Ambrosino SV "Depressive reactions associated with reserpine." N Y State J Med 74 (1974): 860-4

29. Widmer RB "Reserpine: the maligned antihypertensive drug." J Fam Pract 20 (1985): 81-3

30. Sharon E, Paolino JS, Kaplan D "Hematemesis after reserpine for Raynaud's phenomenon." Ann Intern Med 77 (1972): 479-80

31. Kent TA, Wilber RD "Reserpine withdrawal psychosis: the possible role of denervation supersensitivity of receptors." J Nerv Ment Dis 170 (1982): 502-4

32. Blumenthal M, Davis R, Doe RP "Carcinoid syndrome following reserpine therapy in thyrotoxicosis." Arch Intern Med 116 (1965): 819-23

33. Labeeuw M, Pozet N, Aissa AH, Zech PY, Sassard J, Laville M "Uric acid renal handling: spontaneous changes and influence of a thiazide alone or associated with triamterene." Int J Clin Pharmacol Ther Toxicol 26 (1988): 79-83

34. Luther RR, Glassman HN, Estep CB, Maurath CJ, Jordan DC "The effects of terazosin and methyclothiazide on blood pressure and serum lipids." Am Heart J 117 (1989): 842-7

35. Combs RM "Unusual response to reserpine in paroxysmal atrial tachycardia with block unassociated with digitalis." South Med J 60 (1967): 839-42

36. Dillon PT, Babe J, Meloni CR, Canary JJ "Reserpine in thyrotoxic crisis." N Engl J Med 283 (1970): 1020-3

37. Entrican JH, Denburg JA, Gauldie J, Kelton JG "Angioimmunoblastic lymphadenopathy associated with reserpine." Lancet 2 (1984): 820-1

38. Curb JD, Hardy RJ, Labarthe DR, Borhani NO, Taylor JO "Reserpine and breast cancer in the Hypertension Detection and Follow- Up Program." Hypertension 4 (1982): 307-11

39. Jick H "Editorial: Reserpine and breast cancer: a perspective." JAMA 233 (1975): 896-7

40. Newball HH, Byar DP "Does reserpine increase prolactin and exacerbate cancer of prostate? Case control study." Urology 2 (1973): 525-9

41. Labarthe DR, O'Fallon WM "Reserpine and breast cancer. A community-based longitudinal study of 2,000 hypertensive women." JAMA 243 (1980): 2304-10

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Not all side effects for methyclothiazide / reserpine may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

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