Drug Interactions between hydrochlorothiazide / timolol and sertraline

MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

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MONITOR: Limited clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may potentiate the pharmacologic effects of some beta-blockers. There have been case reports of patients stabilized on beta-blocker therapy who developed bradycardia, hypotension, and complete heart block following the addition of a SSRI, subsequently requiring discontinuation of one or both agents and/or institution of a permanent pacemaker. The interaction is also corroborated by data from in vitro and clinical studies involving paroxetine and metoprolol conducted by one group of investigators. The proposed mechanism is SSRI inhibition (competitive and/or noncompetitive) of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of beta-blockers such as carvedilol, labetalol, metoprolol, nebivolol, propranolol, and timolol. Paroxetine and norfluoxetine (the active metabolite of fluoxetine), in particular, are potent inhibitors of CYP450 2D6 and may be more likely than other SSRIs to cause the interaction. On the other hand, fluvoxamine is a potent inhibitor of CYP450 1A2 and may significantly interact with propranolol, which is a substrate of both CYP450 2D6 and 1A2.

MANAGEMENT: During concomitant therapy with SSRIs, a lower initial dosage and more cautious titration of the beta-blocker may be appropriate. Cardiac function should be closely monitored and the beta-blocker dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of SSRI in patients who are stabilized on their beta-blocker regimen. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine. To avoid the interaction, use of beta-blockers that are primarily eliminated by the kidney such as atenolol, acebutolol, betaxolol, carteolol, and nadolol may be considered.

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MONITOR: Coadministration with diuretics may potentiate the risk of hyponatremia associated with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The mechanism by which SSRIs and SNRIs produce hyponatremia has not been clearly established. In many cases, the hyponatremia appears to be secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. These events are generally reversible following discontinuation of therapy and/or medical intervention. Elderly patients and patients taking diuretics or who are otherwise volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

MONITOR: Antihypertensive agents such as diuretics may potentiate the orthostatic effect that is occasionally observed upon the initiation of SSRI or SNRI therapy. Syncope and orthostatic hypotension tend to occur within the first week of SNRI/SSRI therapy but can occur at any time during treatment, particularly after a dosage increase. The use of SSRIs or SNRIs may also cause sustained increases in blood pressure and heart rate, which may antagonize the therapeutic effects of antihypertensive medications. Cases of elevated blood pressure requiring immediate treatment have been reported in postmarketing experience.

MANAGEMENT: Caution is recommended if SSRIs or SNRIs are prescribed in combination with diuretics, particularly in the elderly. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hyponatremia such as nausea, vomiting, headache, malaise, lethargy, irritability, difficulty concentrating, memory impairment, confusion, weakness, muscle spasm, and unsteadiness (which may lead to falls). More severe and/or acute cases may include hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinuation of SSRI/SNRI therapy should be considered in patients who develop symptomatic hyponatremia, and appropriate medical intervention instituted as necessary. Patients should also have their blood pressure and pulse monitored before and during SSRI/SNRI therapy, especially during the first few weeks and following a dosage increase. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their doctor if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them. Dose reduction or drug discontinuation should be considered in patients who experience a sustained increase in blood pressure or pulse rate during SSRI or SNRI therapy.

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