CLORTALIDONA EN VADEMECUM

CLORTALIDONA

Nota importante

DESCRIPCION

La clortalidona es un diúretico de la familia de las tiazidas, utilizado en el tratamiento de la hipertensión y el edema. En comparación con otras tiazidas, la clortalidona es la que tiene la mayor duración de su acción, aunque su efecto diurético global es similar al de otras. A diferencia de los diuréticos de asa, la clortalidona muestra una eficacia reducida en los pacientes con insuficiencia renal.

Mecanismo de acción: la clortalidona aumenta la eliminación de sodio, cloruros y agua al inhibir el transporte de sodio a través del epitelio del túbulo renal. Su lugar de acción es el segmento cortical de la parte ascendente del asa de Henle. Las tiazinas, incluyendo la clortalidona, también reducen la velocidad de filtración glomerular lo que reduce la eficacia de estos fármacos en los pacientes con insuficiencia renal. Al aumenta la entrada de sodio en el túbulo renal distal la clortalidona incrementa la eliminación de potasio a través de un mecanismo de intercambio sodio-potasio. La hipokaliemia e hipocloremia subsiguientes pueden originar una alcalosis metabólica, aunque la eficacia diurética de la clortalidona no es afecta por el estado ácido-base del paciente. La clortalidona no es un antagonista de la aldosterona y sus efectos son independientes de una inhibición de la anhidrasa carbónica.

En general, los diuréticos reducen la presión arterial, reduciendo el gasto cardíaco y el volumen de plasma y de líquido intracelular. Eventualmente, el gasto cardíaco retorna a la normalidad y el volumen del plasma y del fluido extracelular se mantienen a un nivel ligeramente por debajo de los normal, pero se mantiene la reducción de la resistancia vascular y, por tanto de la presión arterial. La reducción del volumen plasmático induce un aumento de actividad de la renina y de la secreción de aldosterona, lo que contribuye a la pérdida de potasio, característica del tratamiento con tiazidas

En general, las tiazidas incluyendo la clortalidona empeoran la insuficiencia cardíaca congestiva y la tolerancia a la glucosa y muestran efectos negativos sobre el perfil lipídico.

Farmacocinética: después de una dosis oral, la clortalidona se absorbe en el tracto digestivo, siendo su biodisponibildad del 65%. El fármaco se une en un 75% a las proteínas del plasma y también a las membranas de los hematíes. La clortalidona atraviesa la barrera pacentaris y se excreta en la leche materna. El inicio de los efectos diuréticos se observa a las 2 horas, alcanzando estos un máximo a las 2-6 horas y manteniéndose durante 48 a 72 horas. La semi-vida plasmática de la clortalidona es del 40 a 60 horas

La mayor parte de la clortalidona es eliminada en la orina sin alterar (50-70%) y una pequeña parte es excretada en la bilis.

INDICACIONES Y POSOLOGIA

Tratamiento del edema periférico:

Administración oral:

  • Adultos: inicialmente 50-100 mg una vez al día o 100 mg en días alternos. Las dosis se deben ajustar de acuerdo con la respuesta clínica. Algunos pacientes pueden necesitar entre 150 y 200 mg/día. Las dosis superiores a los 200 mg/día no mejoran usualmente la respuesta clínica
  • Ancianos: mismas dosis que los adultos aunque estos pacientes pueden ser más sensibles al fármaco.
  • Niños: la dosis recomendada es de 2 mg/kg (equivalentes a 60 mg/m2/día)

Tratamiento de la hipertensión (sola o asociada a otros antihipertensivos)

Administración oral

  • Adultos: el tratamiento se suele iniciar con una dosis única de 15 mg/día. Si esta dosis es insuficiente después de unos días, se deben incrementar a 30 mg/día y, si esto es todavía insuficientre a 45-50 mg. Si con estas dosis no se consigue un controle adecuado de la presión arterial se debe añadir un fármaco antihipertensivo, como por ejemplo un inhibidor de la ECA o un antagonista del calcio. En el rango de dosis de 15 a 50 mg se observa un aumento del ácido úrico y una disminución del potasio plasmáticos

CONTRAINDICACIONES y PRECAUCIONES

La clortalidona está contraindicada en pacientes con una hipersensibilidad al fármaco y a otros fármacos de la familia de las sulfonamidas.

La clortalidona puede producir rápidamente fluctuaciones de los electrolitos séricos y precipitar un coma en pacientes susceptibles

 

Contraindications Chlorthalidone-induced fluctuations in serum electrolyte concentration can occur rapidly and precipitate hepatic coma in susceptible patients. Therefore, the drug should be used with caution in patients with hepatic disease. Chlorthalidone should not be used if there is an electrolyte imbalance. Hyponatremia, hypochloremia, or hypokalemia should be corrected before chlorthalidone is initiated. Initiation of thiazide diuretics under these circumstances can produce life-threatening situations such as cardiac arrhythmias, hypotension, or seizures. Chlorthalidone can cause increase in serum calcium concentrations and should be used with caution in patients with hypercalcemia. Chlorthalidone should be used cautiously in patients with renal disease such as severe renal impairment or renal failure. Drug-induced hypovolemia can precipitate azotemia in these patients. Therapy should be interrupted or discontinued if renal impairment worsens, as evidenced by an increase in concentrations of BUN, serum creatinine, or nonprotein nitrogen. With the exception of metolazone, thiazide diuretics are considered ineffective when the creatinine clearance is less than 30 ml/minute. Chlorthalidone is contraindicated in patients with anuria. Thiazide diuretics have been associated with a slight increase in serum cholesterol and triglyceride concentrations. Data from long-term studies, however, suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.

 

 

 
Clasificación de la FDA de riesgo en el embarazo [658] The safety of chlorthalidone administration during pregnancy has not been established, and the drug should be administered to pregnant women only when absolutely necessary. Chlorthalidone is structurally related to the thiazides. Thiazides cross the placenta, and jaundice can occur in the fetus or neonate. Chlorthalidone is classified as pregnancy category D. Thiazide diuretics distribute into breast milk, and it has been recommended by some manufacturers that women should not nurse while receiving thiazide diuretics. The American Academy of Pediatrics recommends breast-feeding be avoided during the first month of lactation in patients receiving thiazide diuretics, because suppression of lactation has been reported. Thiazide diuretics should be avoided in neonates with jaundice. Thiazide-induced hyperbilirubinemia is greater in this patient population.  
 

Hyperglycemia, reduced glucose tolerance, and glycosuria can occur during chlorthalidone therapy. Blood and/or urine glucose levels should be more carefully assessed in patients with diabetes mellitus who are receiving chlorthalidone. Although hyperglycemia did occur, chlorthalidone has been shown to reduce cardiovascular disease events in elderly diabetic patients with isolated systolic hypertension.[1353] Greater sensitivity to the hypotensive and diuretic effects of bumetanide is possible in elderly patients. Thiazide diuretics, including chlorthalidone, should be used with caution in patients with sulfonamide hypersensitivity or carbonic anhydrase inhibitor hypersensitivity because of the risk of cross-sensitivity. Although furosemide and, to a lesser extent, bumetanide are chemically related to the sulfonamides and theoretically should also be used cautiously, in fact, cross-sensitivity with furosemide is an extremely rare occurrence.[178] Caution should be used when chlorthalidone is administered to patients with gout or hyperuricemia since thiazide diuretics have been reported to reduce the clearance of uric acid. Thiazide diuretics have been reported to cause pancreatitis. They should be used with caution in patients with a history of pancreatitis. Caution should be used when administering thiazides to patients with a history of systemic lupus erythematosus (SLE) because thiazides have been reported to reactivate or exacerbate this disease. Antihypertensive effects of thiazide diuretics may be enhanced in patients with a sympathectomy.

 

 
 

INTERACCIONES

Chlorthalidone can have additive effects when administered with other antihypertensive agents or diuretics. In some patients, this may be desirable, but orthostatic hypotension is possible. Dosages should be adjusted accordingly. In addition, amiloride hydrochloride, spironolactone, and triamterene can reduce the risk of hypokalemia associated with chlorthalidone because of their potassium-sparing effects; these agents have been used as therapeutic alternatives to potassium supplements. Chlorthalidone-induced electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) can predispose patients to digoxin toxicity, resulting in possibly fatal arrhythmias. Electrolyte balance should be corrected prior to initiating digoxin therapy. Hypokalemia also potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers. The risk of severe hypokalemia may be increased when other hypokalemia-causing agents (e.g., corticosteroids, corticotropin, ACTH, amphotericin B, other diuretics) are coadministered with chlorthalidone. Monitoring serum potassium concentrations and cardiac function is advised, and potassium supplementation may be required. Concomitant administration of chlorthalidone to patients receiving nondepolarizing neuromuscular blockers can cause prolonged neuromuscular blockade due to chlorthalidone-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy. Thiazide diuretics reduce lithium renal clearance and can increase lithium serum concentrations. Conversely, thiazide diuretics can be used to counteract lithium-induced polyuria. Lithium dosage should be reevaluated and serum lithium concentrations monitored if a thiazide is added. Thiazide diuretics can decrease insulin sensitivity thereby leading glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely. Enhanced hyperglycemia is also possible during concurrent use of diazoxide and thiazide diuretics. NSAIDs can decrease the diuretic, natriuretic, and antihypertensive actions of diuretics through inhibition of renal prostaglandin synthesis. Concomitant administration of NSAIDs with diuretics also can increase the risk for renal failure secondary to decreased renal blood flow. Patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment. Cholestyramine, an anion-exchange resin, can bind to acidic drugs, such as the thiazide diuretics in the GI tract, and decrease their absorption and therapeutic effectiveness. It is recommended that thiazide doses be administered at least 4 hours before cholestyramine. Although to a lesser extent than cholestyramine, colestipol has been shown to inhibit the GI absorption and therapeutic response of thiazide diuretics. Administering the diuretic at least 2 hours before colestipol has been suggested. Thiazide diuretics may increase the photosensitization effects griseofulvin, phenothiazines, sulfonamides, sulfonylureas, tetracyclines, vitamin A analogs, and photosensitizing agents used in photodynamic therapy. . Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed. Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean dofetilide clearance of dofetilide was 16% lower in patients on thiazide diuretics.

 

El espino blanco, (Crataegus laevigata) puede reducir las resistencias vasculares periféricas. Si se consume en combinación con fármacos que reducen la presión arterial, puede sumar sus efectos a los de estos. Si se utiliza el espino blanco, se recomienda una frecuente monitorización de la presión arterial

 
La escina, un saponina activa de las semillas del castaño de las Indias (Aesculus hippocastanum) tiene una actividad diurética moderada, si bien se desconoce el mecanismo exacto de active saponin in the horse chestnut seed, appears to have weak diuretic activity, but the exact mechanism is not clear. The effect appears to be dose-dependent and may be additive with traditional diuretics.  
 

REACCIONES ADVERSAS

Los pacientes tratados con clortalidona deben ser vigilados cuidadosamente ya que se puede producir un desequilibrio de los electrolitos caracterizado por hiponatremia, hipotasemia y/o hipomagnesemia. Los pacientes deben ser advertidos sobre los signos de este desequilibrio que se caracteriza por lasitud, confusión mental, fatiga, mareos, calambres musculares, taquicardia, jaquecas, parestesias, sed, anorexia, náuseas y vomitos, comunicando al médico la aparición de cualquiera de ellos. En estos casos, las dosis deben ser reducidas o discontinuadas hasta que se recupere la homeostasia. La corrección del desequilibrio electrolítico requiere unas medidas apropiadas.

Chlorthalidone Adverse Reactions Patients receiving chlorthalidone should be monitored closely for signs of electrolyte imbalance including hyponatremia, hypokalemia, hypochloremia, and/or hypomagnesemia. Patients should be aware of the symptoms of these disturbances (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, muscle cramps, tachycardia, headache, paresthesia, thirst, anorexia, or nausea/vomiting), and report these signs immediately. Dosages should be reduced or withdrawn until homeostasis is achieved; electrolyte imbalances require correction by appropriate measures. Hypercalcemia can occur, mainly in patients taking calcium supplements. Hypokalemia is one of the most common adverse effects associated with thiazide diuretic therapy and can lead to cardiac arrhythmias. This effect is especially important to consider in patients receiving cardiac glycoside therapy because hypokalemia increases the risk of digitalis toxicity. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose a patient to developing hypokalemia during chlorthalidone therapy. Low dietary-potassium intake, potassium-wasting diseases, or administration of potassium-wasting drugs also can predispose a patient to chlorthalidone-induced hypokalemia. Patients receiving chlorthalidone therapy may require supplemental potassium to prevent hypokalemia or metabolic alkalosis. Hypochloremic metabolic alkalosis can occur with hypokalemia during chlorthalidone therapy, and it is particularly likely to occur in patients with other sources of potassium and/or chloride loss including severe vomiting, diarrhea, excessive sweating, GI drainage, paracentesis, or potassium-losing renal diseases. Patients receiving chlorthalidone therapy can develop a dilutional hyponatremia, but it usually is asymptomatic and moderate. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal. Severe hyponatremia occurs rarely. Geriatric patients are especially susceptible to developing hyponatremia, so care should be taken when chlorthalidone is administered to these patients. Thiazides have reportedly caused azotemia and interstitial nephritis, resulting in reversible renal failure. These effects have occurred mainly in patients with preexisting renal disease. Chlorthalidone can produce impaired glucose tolerance, glycosuria, and hyperglycemia in diabetic patients. Increased monitoring and, possibly, dosage adjustments may be necessary in these patients. Since thiazides reduce the clearance of uric acid, patients with gout or hyperuricemia can have exacerbations of their disease. Hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy. Although elevations in total cholesterol concentrations of 8% can negate the protection against coronary heart disease provided by a 5 mmHg reduction in blood pressure,[659] data from long-term studies suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk. After approximately one year of treatment, total serum cholesterol concentrations will subside to baseline or lower, suggesting diuretic-induced cholesterol changes are not a significant coronary heart disease risk factor.[658] Orthostatic hypotension can occur during chlorthalidone therapy and can be exacerbated by alcohol, narcotics, or antihypertensive drugs. Thiazide diuretics have been associated with cholestatic jaundice, and caution should be used when chlorthalidone is administered to jaundiced infants due to the risk of hyperbilirubinemia. Adverse GI effects associated with chlorthalidone therapy include anorexia, gastric irritation, nausea/vomiting, cramps, diarrhea, constipation, and pancreatitis. Adverse CNS effects associated with chlorthalidone therapy include dizziness, headache, paresthesias, vertigo, and xanthopsia. Due to the diuretic action of chlorthalidone, polyuria can be troublesome for some patients during therapy. While their incidence is rare, agranulocytosis, aplastic anemia, pancytopenia, leukopenia, hemolytic anemia, and thrombocytopenia have been reported with thiazide diuretic therapy. Other adverse effects reported with chlorthalidone include restlessness, muscle spasm, impotence, libido decrease, and weakness. Adverse dermatologic reactions to chlorthalidone and other thiazide diuretics are uncommon but may occur. These reactions include purpura, photosensitivity, rash, alopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis (TEN), and polyarteritis nodosa.

 
  Chlorthalidone Hygroton®, Chlorthalidone by Mylan | Thalitone®  
 

REFERENCIAS

  • The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000;283:1967—75.
  • Freis ED. Critique of the clinical importance of diurectic-induced hypokalemia and elevated cholesterol level. Arch Intern Med 1989;149:2640—8.
  • Curb JD, Pressel SL, Cutler JA et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886—92.
  • Schneiweiss F. Cross-sensitivity between sulfonamides and furosemide. Clin Pharm 1983;2:510.
  • Houston MC. New insights and new approaches for the treatment of essential hypertension: selection of therapy based on coronary heart disease risk factor analysis, hemodynamics profiles, quality of life, and subsets of hypertension. Am Heart J 1989;117:911—51.
 
  Monografía revisada el 30 de mayo de 2011. Equipo de Redacción de IQB