Pindolol and Hydrochlorothiazide

(PIN doe lole & hye droe klor oh THYE a zide)

Pindolol: Blocks both beta1- and beta2-receptors and has mild intrinsic sympathomimetic activity; has negative inotropic and chronotropic effects and can significantly slow AV nodal conduction. Augmentive action of antidepressants thought to be mediated via a serotonin 1A autoreceptor antagonism.

Hydrochlorothiazide: Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions

Note: Not approved in the US

Hypertension: Treatment of hypertension; not for initial therapy

Hypersensitivity to pindolol, hydrochlorothiazide, any other component of the formulation, or sulfonamide-derived drugs; or cross-sensitivity to other beta blockers; decompensated heart failure, right ventricular failure secondary to pulmonary hypertension, significant cardiomegaly, sinus bradycardia (≤50 bpm), second/third degree atrioventricular (AV) block; sick sinus syndrome; cardiogenic shock; prinzmetal angina (variant angina); severe peripheral arterial circulatory disorders; bronchospasm (including bronchial asthma) or severe chronic obstructive pulmonary disease (COPD); anesthetic agents producing myocardial depression; anuria; pheochromocytoma (untreated)

Additionally, the manufacturer of hydrochlorothiazide contraindicates use for increasing azotemia and oliguria during treatment of severe progressive renal disease; breast-feeding

Note: Although the product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.

Mild to moderate impairment: No dosage adjustment necessary. Use with caution.

Severe impairment: No dosage adjustment provided in manufacturer’s labeling. However, dosage reduction may be necessary; use with caution.

Concerns related to adverse effects:

• Acute renal failure: Patients with severe heart failure or volume depletion may be at increased risk for developing acute renal failure with hydrochlorothiazide.

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects. Hypersensitivity to thiazides may occur in individuals without prior history of bronchial asthma or allergy.

• Bradycardia: Pindolol may cause bradycardia; dose reduction may be necessary if excessive bradycardia occurs.

• Electrolyte disturbances: Hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia can occur with hydrochlorothiazide. Development of electrolyte disturbances can be minimized when used in combination with other electrolyte sparing antihypertensives (eg, ACE inhibitors or angiotensin receptor blockers) (Sica 2011). Hypercalcemia and hypophosphatemia have been observed with prolonged thiazide therapy; discontinue use prior to parathyroid testing.

• Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by hydrochlorothiazide. This risk may be increased with doses ≥25 mg (Gurwitz 1997).

• Hypersensitivity reactions: Hypersensitivity reactions may occur with hydrochlorothiazide. Risk is increased in patients with a history of allergy or bronchial asthma.

• Ocular: Conjunctival xerosis (dryness of eye surface) has been reported with use of beta blockers; therapy discontinuation may be indicated if severe. Hydrochlorothiazide may cause acute transient myopia and acute angle-closure glaucoma, typically occurring within hours to weeks following initiation; discontinue therapy immediately in patients with acute decreases in visual acuity or ocular pain. Additional treatments may be needed if uncontrolled intraocular pressure persists. Risk factors may include a history of sulfonamide or penicillin allergy.

• Photosensitivity: Photosensitization may occur.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Conduction abnormality: Consider preexisting conditions before initiating. Use of this combination product is contraindicated in patients with sick sinus syndrome, second/third degree atrioventricular (AV) block.

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms, also may see a change in glucose control

• Heart failure (HF): Use with caution in patients with compensated HF and monitor for a worsening of the condition. If condition worsens, consider temporary discontinuation or dosage reduction of pindolol. Patients should be stabilized on heart failure regimen prior to initiation of beta-blocker. Beta-blocker therapy should be initiated at very low doses with gradual and very careful titration. Adjustment of other medications (ACE inhibitors and/or diuretics) may be required. Beta-blockers with intrinsic sympathomimetic activity (eg, pindolol) have not been demonstrated to be of value in HF.

• Hepatic impairment: Use with caution in patients with hepatic impairment; pindolol levels may increase significantly with hepatic impairment. In progressive or severe liver disease, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy/coma

• Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations.

• Myasthenia gravis: Use beta blockers with caution in patients with myasthenia gravis.

• Parathyroid disease: Thiazide diuretics reduce calcium excretion; pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged use; should be discontinued prior to testing for parathyroid function.

• Peripheral vascular disease (PVD) and Raynaud's disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's disease. Use with caution and monitor for progression of arterial obstruction Contraindicated for use in severe peripheral arterial circulatory disorders.

• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

• Psychiatric disease: Use with caution in patients with a history of psychiatric illness; beta-blockers may cause or exacerbate CNS depression.

• Renal impairment: Use with caution in patients with renal impairment; thiazides may precipitate azotemia. Discontinue use with worsening of renal function. Hydrochlorothiazide is ineffective in severe renal disease. Use is contraindicated with anuria.

• Respiratory disease: Use with caution in patients prone to nonallergic bronchospasm (eg, emphysema, chronic bronchitis). Use in patients with bronchospasm (including bronchial asthma) or severe chronic obstructive pulmonary disease (COPD) is contraindicated.

• Systemic lupus erythematosus (SLE): Thiazides can cause SLE exacerbation or activation.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Other warnings/precautions:

• Abrupt withdrawal: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered over 1-2 weeks to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery (Fleischmann 2009).