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Beta-adrenergic Blocking Agents and Thiazide Diuretics (Systemic )

This monograph includes information on the following:

1) Atenolol and Chlorthalidone
2) Bisoprolol and Hydrochlorothiazide  
3) Metoprolol and Hydrochlorothiazide 
4) Nadolol and Bendroflumethiazide
5) Pindolol and Hydrochlorothiazide *
6) Propranolol and Hydrochlorothiazide
7) Timolol and Hydrochlorothiazide

VA CLASSIFICATION
Primary: CV408

Commonly used brand name(s): Corzide4; Corzide 40/54; Corzide 80/54; Inderide6; Inderide LA6; Lopressor HCT3; Tenoretic1; Tenoretic 1001; Tenoretic 501; Timolide7; Timolide 10-257; Viskazide5; Ziac2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antihypertensive.—

Indications

Accepted

Hypertension (treatment)—Beta-adrenergic blocking agent (beta-blocker) and thiazide diuretic combinations are indicated in the management of hypertension .
—Fixed-dosage combinations generally are not recommended for initial therapy, but are utilized in maintenance therapy after the required dose is established, in order to increase convenience, economy, and patient compliance.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Atenolol: 266.34
    Bisoprolol fumarate: 766.97 {01}
    Bendroflumethiazide: 421.41
    Chlorthalidone: 338.76
    Hydrochlorothiazide: 297.73
    Metoprolol tartrate: 684.82
    Nadolol: 309.40
    Pindolol: 248.32
    Propranolol hydrochloride: 295.81
    Timolol maleate: 432.49

pKa—
    Bendroflumethiazide: 8.5
    Chlorthalidone: 9.4
    Hydrochlorothiazide: 7.9 and 9.2
    Metoprolol: 9.68
    Nadolol: 9.67
    Timolol: Approximately 9 in water at 25 °C


Lipid solubility
    Atenolol: Very {02} low (log partition coefficient for octanol/water=0.23).
    Bisoprolol: Moderate (equally hydrophilic and lipophilic).
    Metoprolol: Moderate.
    Nadolol: Low.
    Pindolol: Moderate.
    Propranolol: High.
    Timolol: Moderate.

Mechanism of action/Effect:


Beta-blockers:

Beta-adrenergic blocking agents block the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. When they predominantly block the beta-1 receptors in cardiac tissue, they are said to be cardioselective. When they block both beta-1 receptors and beta-2 receptors (primarily located in tissues other than cardiac), they are said to be nonselective; nonselective beta-adrenergic blocking agents include nadolol, pindolol, propranolol, and timolol. In general, so-called cardioselective beta-adrenergic blocking agents are relatively cardioselective—at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases; cardioselective beta-adrenergic blocking agents include atenolol and metoprolol.

Intrinsic sympathomimetic activity (ISA or partial agonist activity) is the ability of a beta-adrenergic blocking agent to cause weak stimulation of beta-adrenergic receptors simultaneously with beta-blockade; however, the significance of this property has not been established. Possession of ISA may theoretically result in fewer adverse effects related to unopposed beta blockade (e.g., bradycardia, heart block, bronchoconstriction, peripheral vascular constriction), but studies have not proven clinical benefit. Pindolol exhibits the most ISA of the beta-adrenergic blocking agents currently available; the other members of the group have little, if any, such activity.

Propranolol possesses moderate membrane-stabilizing (quinidine-like) activity; metoprolol has slight activity. The other beta-adrenergic blocking agents of this group show little, if any, such activity. At one time membrane-stabilizing activity was thought to be related to an antiarrhythmic effect, but it is no longer considered to be significant because it occurs only at very high (much greater than therapeutic) doses.

Antihypertensive: Not known but possibilities include reduced cardiac output, decreased sympathetic outflow to peripheral vasculature, and inhibition of renin release by the kidneys.



Thiazide diuretics:

Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, cardiac output returns to normal. Thiazide diuretics decrease peripheral resistance by a direct peripheral effect on blood vessels. {09} {10} {11}


Absorption:

Atenolol—50%. {02}

Bisoprolol—80%. {03}

Metoprolol—95% (first-pass metabolism results in a significant decrease in bioavailability).

Nadolol—30%. {06}

Pindolol—90 to 100%.

Propranolol—90% (first-pass metabolism results in a significant decrease in bioavailability).

Timolol—90% (first-pass metabolism results in a significant decrease in bioavailability). {08}

Thiazide diuretics—Absorbed relatively rapidly after oral administration.

Protein binding:

Atenolol—Very low to low (6 to 16%). {02}

Bendroflumethiazide—Very high (94%).

Bisoprolol—Low (approximately 30%). {03}

Chlorthalidone—High (75% [58% to albumin]); increased affinity to carbonic anhydrase in red blood cells.

Metoprolol—Low (12%).

Nadolol—Low (30%). {06}

Pindolol—Moderate (40%).

Propranolol—Very high (93%).

Timolol—Very low (less than 10%). {08}

Biotransformation:

Atenolol—Hepatic (minimal). {02}

Metoprolol—Hepatic.

Nadolol—None. {06}

Pindolol—Hepatic.

Propranolol—Hepatic. {07}

Timolol—Hepatic. {08}

Half-life:


Atenolol:

6 to 7 hours; {02} increased to 16 to 27 hours or more in patients with renal function impairment (up to 144 hours when severe).



Bendroflumethiazide:

8.5 hours.



Bisoprolol:

9 to 12 hours. {03}



Chlorthalidone:

35 to 50 hours.



Hydrochlorothiazide:

5.6 to 14.8 hours.



Metoprolol:

3 to 7 hours; no change in renal failure.



Nadolol:

20 to 24 hours; increased in renal failure. {06}



Pindolol:

3 to 4 hours. {12}

Hepatic function impairment: Varies from 2.5 to more than 30 hours.

Renal function impairment: 3 to 11.5 hours.

Elderly: Average, 7 hours (and as high as 15 hours).



Propranolol:

3 to 5 hours. {07}



Timolol:

4 hours. {08}


Time to peak effect:

Atenolol—2 to 4 hours. {02}

Metoprolol—1 to 2 hours.

Nadolol—4 hours.

Pindolol—1 to 2 hours.

Propranolol—1 to 1.5 hours. {07}

Timolol—1 to 2 hours. {08}

Thiazide diuretics—Up to 3 to 4 weeks may be required for optimal effect.

Elimination:


Atenolol—
        Renal, 85 to 100%.
        In dialysis: Removable by hemodialysis. Patients should receive 50 mg atenolol after each dialysis and remain under supervision since marked hypotension may occur.



Bisoprolol—
        Renal (50% as unchanged drug); fecal, less than 2%. {03}



Metoprolol—
        Renal (3 to 10% unchanged).
        In dialysis: Not removable by hemodialysis.



Nadolol—
        Renal (70% unchanged).
        In dialysis: Removable by hemodialysis.



Pindolol—
        Renal (40% unchanged). {12}



Propranolol—
        Renal (less than 1% unchanged).
        In dialysis: Not removable by hemodialysis. {07}



Timolol—
        Renal (20% unchanged); fecal.
        In dialysis: Not removable by hemodialysis. {08}



Thiazide diuretics—
        Unchanged; almost totally via the kidneys, with minute quantities in the bile.



Precautions to Consider

Note: In general, because of the similarity of effect and because the cardioselectivity of beta-1 blockers is relative, the same precautions, especially drug interactions and medical problems, apply to all beta-adrenergic blocking agents.


Cross-sensitivity and/or related problems

Patients sensitive to other sulfonamide-type medications, bumetanide, furosemide, or carbonic anhydrase inhibitors may be sensitive to thiazide diuretics also.

Carcinogenicity/Tumorigenicity

Atenolol—Two 18- to 24-month studies in rats and one study for up to 18 months in mice found no evidence of carcinogenicity at doses up to 150 times the maximum recommended human dose (MRHD). {02}

Bendroflumethiazide—Carcinogenicity studies have not been done. {06}

Hydrochlorothiazide—Carcinogenicity studies have not been done in either animals or humans.

Metoprolol—A 1-year study in dogs at or below oral dosages of 105 mg per kg of body weight (mg/kg) per day, a 2-year study in rats at 3 oral dosage levels up to 800 mg/kg per day, and a 21-month study in mice at 3 oral dosage levels up to 750 mg/kg per day found no evidence of carcinogenicity, although the incidence of small benign adenomas of the lung was higher in the treated female mice. A repeat of the 21-month study in mice found no increased incidence of any type of tumor.

Nadolol—A 2-year study in rats and mice found no evidence of carcinogenicity. {06}

Pindolol—Two-year studies in rats and mice found no evidence of carcinogenicity at doses as high as 50 and 100 times the MRHD, respectively.

Propranolol—Eighteen-month studies in rats and mice found no evidence of carcinogenicity at doses up to 150 mg/kg per day. {07}

Timolol—A 2-year study in rats found an increased incidence of adrenal pheochromocytomas in male rats at doses 300 (but not at 25 or 100) times the MRHD. {08} A lifetime study in mice found an increased incidence of benign and malignant pulmonary tumors and benign uterine polyps in female mice at doses of 500 (but not at 5 or 50) mg/kg per day and an increase in mammary adenocarcinomas associated with elevations in serum prolactin at 500 mg/kg per day. {08}

Mutagenicity

Atenolol—Mutagenicity studies were negative. {02}

Hydrochlorothiazide—Hydrochlorothiazide was not found to be mutagenic in vitro in the Ames microbial mutation test or on examination of urine from patients who received hydrochlorothiazide; however, it did induce nondisjunction in Aspergillus nidulans .

Timolol—Mutagenicity studies in vivo (mouse) and in vitro were negative; in Ames tests, some changes were seen, but not enough to make the test positive. {08}

Pregnancy/Reproduction

Pregnancy—

Beta-adrenergic blocking agents

Beta-adrenergic blocking agents cross the placenta. {13} The safety of these agents in pregnancy is not fully established. {13} {15} Fetal and neonatal bradycardia, hypotension, hypoglycemia, and respiratory depression have been reported with administration of a cardioselective or a noncardioselective beta-adrenergic blocking agent to pregnant women. {16} {17} {18} {19} {20} In addition, intrauterine growth retardation has been reported rarely with atenolol and nadolol. {19} {21} {22} However, other reports seem to indicate successful treatment of maternal hypertension during pregnancy with no apparent effects on the fetus or neonate {14}.



Thiazide diuretics

Thiazide diuretics cross the placenta and appear in cord blood. Studies in humans have not been done. However, possible hazards include fetal or neonatal jaundice, thrombocytopenia, or other adverse reactions seen in adults. {02}

Studies in animals have not shown that thiazide diuretics cause adverse effects on the fetus at several times the human dose.



Atenolol and chlorthalidone combination

Studies in rats and rabbits given doses up to 100 times the maximum recommended human dose (MRHD) did not reveal teratogenic effects; however, embryonic resorptions were observed. {02}

FDA Pregnancy Category D.



Bisoprolol and hydrochlorothiazide combination

Studies in rats and rabbits given doses up to 129/514 times (bisoprolol/hydrochlorothiazide) and 25/100 times the MRHD, respectively, did not reveal teratogenic effects. {03} However, an increase in resorptions was seen in rats and rabbits at doses 43/172 times and 25/100 times the MRHD, respectively. {03}

FDA Pregnancy Category C.



Metoprolol and hydrochlorothiazide combination

Adequate and well-controlled studies have not been done in humans. {05}

FDA Pregnancy Category C.



Nadolol and bendroflumethiazide combination

Studies have not been done with this combination.

FDA Pregnancy Category C.



Pindolol and hydrochlorothiazide combination

Studies have not been done with this combination.



Propranolol and hydrochlorothiazide combination

Studies have not been done with this combination.

FDA Pregnancy Category C.



Timolol and hydrochlorothiazide combination

Studies in mice and rabbits given up to 8/10 mg/kg (timolol/hydrochlorothiazide) per day did not reveal teratogenic, embryotoxic, or fetotoxic effects. {08}

FDA Pregnancy Category C.


Breast-feeding

Beta-adrenergic blocking agents—Atenolol {02} {23} {24} {25} {26}, metoprolol {05} {24} {26} {27} {28}, nadolol {06} {29}, pindolol, propranolol {07} {25} {30}, and timolol {08} are distributed into breast milk. It is not known whether bisoprolol is distributed into breast milk. Cyanosis and bradycardia have been reported in breast-fed infants whose mothers were receiving atenolol. {02} {23} Although the risk appears to be small, breast-fed infants should be monitored for signs of beta-adrenergic blockade, especially bradycardia, hypotension, respiratory distress, and hypoglycemia.

Thiazide diuretics—Thiazide diuretics are distributed into breast milk. The American Academy of Pediatrics recommends that nursing mothers avoid use of thiazide diuretics during the first month of lactation because of reports of suppression of lactation. {32}

Pediatrics

Beta-adrenergic blocking agents—Use of beta-adrenergic blocking agents in a limited number of neonates, infants, and children has not demonstrated pediatrics-specific problems that would limit the usefulness of these medications in children. {33} {34} {35} {36}

Thiazide diuretics—Although appropriate studies on the relationship of age to the effects of thiazide diuretics have not been performed in the pediatric population, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected. However, caution is required in jaundiced infants because of the risk of hyperbilirubinemia.


Geriatrics



Beta-adrenergic blocking agents:

Beta-adrenergic blocking agents have been used safely and efficaciously in elderly patients. {37} {38} {39} However, elderly patients may be more susceptible to some adverse effects of these agents. Beta-adrenergic blocking agents have been reported to cause or exacerbate mental impairment in the elderly. {42} However, other evidence suggests that these agents do not produce significant lethargy or impairment in mental performance. {40} It is possible that the likelihood of central nervous system (CNS) effects may be related to lipophilicity of the beta-adrenergic blocking agent. {41} However, this relationship has not been conclusively established. {40} {42}

Elderly patients are more likely to have age-related peripheral vascular disease, which may require caution in patients receiving beta-adrenergic blocking agents. In addition, the risk of beta-blocker–induced hypothermia may be increased in elderly patients.



Thiazide diuretics:

Although appropriate studies on the relationship of age to the effects of thiazide diuretics have not been performed in the geriatric population, the elderly may be more sensitive to the hypotensive and electrolyte effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving thiazide diuretics.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Allergenic extracts for skin testing or
» Allergen immunotherapy    (use of these agents in patients taking beta-adrenergic blocking agents may increase the potential for serious systemic reaction or anaphylaxis; {43} {44} {45} {46} if possible, another medication should be substituted for the beta-adrenergic blocking agent and thiazide diuretic combination in patients receiving allergen immunotherapy; {44} allergen immunotherapy for conditions that are not life-threatening should be avoided in patients who cannot discontinue beta-adrenergic blocking agent and thiazide diuretic combination therapy {47})


Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone    (thiazide diuretics may raise the concentration of blood uric acid; dosage adjustment of antigout medications may be necessary to control hyperuricemia and gout)

    (caution is advised when allopurinol and thiazide diuretics are used concurrently in patients with known or possible renal function impairment because severe hypersensitivity reactions to allopurinol may occur; although it has been suggested that compromised renal function, rather than the combination of medications, may be responsible for the adverse reactions, it has been proposed that thiazide diuretics may increase serum oxipurinol [active metabolite of allopurinol] concentrations by decreasing its renal excretion)


Amiodarone    (concurrent use of amiodarone with thiazide diuretics may lead to an increased risk of arrhythmias associated with hypokalemia)

    (concurrent administration with beta-adrenergic blocking agents may result in additive depressant effects on conduction and negative inotropic effects, especially in patients with underlying sinus node dysfunction or atrioventricular node dysfunction {48} {49})


Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Cyclopropane
Enflurane
» Halothane
Isoflurane
Methoxyflurane
Trichloroethylene    (concurrent use with beta-adrenergic blocking agents may increase the risk of myocardial depression and hypotension because beta-blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli; if it is necessary to reverse the effects of beta-adrenergic blocking agents during surgery, agonists such as dobutamine, dopamine, isoproterenol, or norepinephrine may be used but should be administered with caution. In patients scheduled for major surgery, most practitioners believe the danger of precipitating myocardial infarction following abrupt cessation of beta-adrenergic blocking agent therapy prior to surgery outweighs the risks of continuing therapy while compensating for medication effects by anesthetic techniques)


Anticoagulants, coumarin- or indandione-derivative    (anticoagulant effects may be decreased when used concurrently with thiazide diuretics as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)


» Antidiabetic agents, oral or
» Insulin    (concurrent use with beta-adrenergic blocking agents may impair glycemic control; {50} {51} {52} there may be an increased risk of hyperglycemia secondary to a slight deterioration in carbohydrate metabolism and peripheral insulin resistance; {51} {52} beta-adrenergic blocking agents may impair recovery from hypoglycemia in diabetics because they block the effects of catecholamines, which promote glycogenolysis and mobilize glucose in response to hypoglycemia; {50} {53} {54} beta-adrenergic blocking agents also may mask certain symptoms of developing hypoglycemia such as increases in pulse rate and blood pressure, {53} {55} thus complicating patient monitoring; cardioselective or relatively cardioselective beta-adrenergic blocking agents, such as atenolol, bisoprolol, or metoprolol, may cause fewer problems with blood glucose levels, especially at lower dosages, although they may still mask the symptoms of hypoglycemia)

    (thiazide diuretics may raise blood glucose concentrations; for adult-onset diabetics, dosage adjustment of hypoglycemic medications may be necessary during and after thiazide diuretic therapy; insulin requirements may be increased or decreased or may remain unchanged)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (NSAIDs may reduce the antihypertensive effects of beta-adrenergic blocking agents, possibly by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention)

    (in addition, concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis)


Beta-adrenergic blocking agents, ophthalmic    (if significant systemic absorption of the ophthalmic beta-adrenergic blocking agent occurs, concurrent use may result in an additive effect either on intraocular pressure or on systemic effects of beta-blockade)


» Calcium channel blocking agents or
» Clonidine or
Diazoxide or
» Guanabenz or
Reserpine or
Hypotension-producing medications, other (See Appendix II ), with the exception of monoamine oxidase (MAO) inhibitors    (blood pressure control may be impaired when clonidine or guanabenz is used concurrently with a beta-adrenergic blocking agent; potentiation of antihypertensive effect should be anticipated when other hypotension-producing medications are used concurrently; although the beta-adrenergic blocking agent and thiazide diuretic combinations may be used with other antihypertensive agents for therapeutic advantage, dosage adjustment may be needed when any hypotension-producing medication is added to or withdrawn from a regimen including a beta-adrenergic blocking agent)

    (symptomatic bradycardia, with or without serious hemodynamic effects, has been reported during concurrent use of diltiazem or verapamil with systemic beta-adrenergic blocking agents; {56} {57} {58} {59} {60} although these effects may occur in the absence of overt pre-existing sinoatrial disease, {56} older patients and patients with left ventricular dysfunction or sinoatrial or atrioventricular conduction abnormalities may be at increased risk; {57} concurrent use of nifedipine with beta-adrenergic blocking agents, although usually well tolerated, may produce excessive hypotension and in rare cases may increase the possibility of congestive heart failure {61} {62} {63})

    (calcium channel blocking agents may decrease the hepatic metabolism of propranolol, metoprolol, and possibly other beta-adrenergic blocking agents with substantial hepatic biotransformation; although the clinical significance of this effect appears to be minimal, caution is warranted given the potential for additive cardiodepressant effects during concurrent use {64} {65} {66} {67})

    (concurrent use of diazoxide with beta-adrenergic blocking agents prevents the tachycardia produced by diazoxide but may also increase the hypotensive effects)

    (concurrent use of reserpine with beta-adrenergic blocking agents may result in additive and possibly excessive beta-adrenergic blockade; close observation is recommended during concurrent use since bradycardia and hypotension may occur)


Calcium-containing medications    (concurrent use of thiazide diuretics with large doses of calcium may result in hypercalcemia because of reduced calcium excretion)


Cholestyramine or
Colestipol    (these medications may inhibit gastrointestinal absorption of the thiazide diuretics; administration of thiazide diuretics 1 hour before or 4 hours after cholestyramine or colestipol is recommended)


Cimetidine    (cimetidine may reduce the clearance of hepatically metabolized beta-adrenergic blocking agents, resulting in elevations of plasma concentrations {68} {69} {70} {71})


» Cocaine    (cocaine may inhibit the therapeutic effects of beta-adrenergic blocking agents)

    (although beta-adrenergic blocking agents are recommended to reduce tachycardia, myocardial ischemia, and/or arrhythmias induced by cocaine, concurrent use of a beta-adrenergic blocking agent with cocaine may increase the risk of hypertension, excessive bradycardia, and possibly heart block, because beta-blockade may leave cocaine's alpha-adrenergic activity unopposed)


Contrast media, iodinated    (concurrent use of beta-adrenergic blocking agents with intravenous contrast media may increase the risk of moderate to severe anaphylaxis; {72} {73} an anaphylactic event may be refractory to treatment {72} {73} {74})


Diflunisal    (concurrent use of diflunisal with hydrochlorothiazide produces significantly increased plasma concentrations of hydrochlorothiazide; in addition, the hyperuricemic effect of hydrochlorothiazide is decreased)


» Digitalis glycosides    (concurrent use with thiazide diuretics may enhance the possibility of digitalis toxicity associated with hypokalemia or hypomagnesemia)


Dopamine    (concurrent use may increase the diuretic effect of either thiazide diuretics or dopamine, as a result of dopamine's direct effect on dopaminergic receptors to produce vasodilation of renal vasculature and increase renal blood flow; dopamine also has a direct natriuretic effect)


Estrogens    (concurrent use may decrease the antihypertensive effect of beta-adrenergic blocking agent and thiazide diuretic combinations because estrogen-induced fluid retention may lead to increased blood pressure)


Fentanyl derivatives    (preoperative chronic use of systemic beta-adrenergic blocking agents may decrease the frequency and/or severity of hypertensive responses to surgery, especially during sternotomy and sternal spread in cardiac or coronary artery surgery; however, chronic preoperative use of systemic beta-adrenergic blocking agents may also increase the risk of initial bradycardia following induction doses of a fentanyl derivative)


Flecainide    (although there have been no reports of adverse effects during concurrent administration of flecainide with the beta-adrenergic blocking agents, caution is recommended because of the potential for additive negative inotropic effects, especially in patients with compromised left ventricular function [ejection fraction < 30%] {75})


Hypokalemia-causing medications, other (See Appendix II )    (concurrent use with thiazide diuretics may increase the risk of severe hypokalemia; monitoring of serum potassium concentrations and cardiac function and potassium supplementation may be necessary)


Lidocaine    (concurrent use with beta-adrenergic blocking agents may reduce lidocaine elimination and increase the risk of lidocaine toxicity because of reduced hepatic blood flow; lidocaine dosage should be adjusted on the basis of serum lidocaine concentrations {76})


» Lithium    (concurrent use with thiazide diuretics is not recommended, as diuretic use may increase the risk of lithium toxicity because of reduced renal clearance; in addition, lithium has nephrotoxic effects)


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (significant hypertension may theoretically occur up to 14 days following discontinuation of the MAO inhibitor; although sufficient clinical reports are lacking, concurrent use with beta-blockers is not recommended)


Neuromuscular blocking agents, nondepolarizing    (thiazide diuretics may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations may be necessary prior to administration of nondepolarizing neuromuscular blocking agents; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade)

    (beta-adrenergic blocking agents may potentiate and prolong the action of nondepolarizing neuromuscular blocking agents when used concurrently; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade)


Nicotine chewing gum or
Smoking deterrents, other or
Smoking, tobacco, cessation of    (smoking cessation may increase therapeutic effects of propranolol by decreasing metabolism, thereby increasing serum concentrations; dosage adjustments may be necessary)


Phenothiazines    (concurrent use with beta-adrenergic blocking agents results in an increased plasma concentration of each medication)


Phenytoin    (concurrent use of propranolol, and probably other beta-adrenergic blocking agents, with intravenous phenytoin may produce additive cardiac depressant effects)


Propafenone    (concurrent use with metoprolol or propranolol may result in significant increases in plasma concentrations and half-life of propranolol and metoprolol, without affecting plasma propafenone concentrations; dosage reduction of the beta-adrenergic blocking agent and thiazide diuretic combination may be necessary {77} {78})


» Sympathomimetics    (concurrent use of beta-adrenergic blocking agents with sympathomimetic amines having beta-adrenergic stimulant activity may result in mutual inhibition of therapeutic effects; sympathomimetics may antagonize the antihypertensive effect of the beta-adrenergic blocking agent and thiazide diuretic combination)

    (for sympathomimetic agents with both alpha- and beta-adrenergic effects [amphetamines, ephedrine, epinephrine, metaraminol, norepinephrine, phenylephrine, pseudoephedrine], beta-blockade may result in unopposed alpha-adrenergic activity with a risk of hypertension and excessive bradycardia and possible heart block; beta-blockade also antagonizes the bronchodilating effect of ephedrine and epinephrine)

    (for sympathomimetic agents with beta-adrenergic effects, beta-blockade may antagonize beta-1-adrenergic cardiac effects [dobutamine, dopamine] or the beta-2-adrenergic bronchodilating effect [albuterol, ethylnorepinephrine, isoetharine, isoproterenol, metaproterenol, terbutaline] or both [isoproterenol]; use of a cardioselective beta-1-adrenergic blocker [atenolol, bisoprolol, or metoprolol] at low doses may prevent antagonism of the bronchodilating effect)


» Xanthines, especially aminophylline or theophylline    (concurrent use with beta-adrenergic blocking agents may result in mutual inhibition of therapeutic effects; in addition, concurrent use of beta-adrenergic blocking agents with the xanthines [except dyphylline] may decrease xanthine clearance, especially in patients with increased theophylline clearance induced by smoking; concurrent use requires careful monitoring)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bentiromide    (administration of thiazide diuretics during a bentiromide test period will invalidate test results since thiazide diuretics are also metabolized to arylamines and will thus increase the percent of para-aminobenzoic acid [PABA] recovered; discontinuation of thiazide diuretics at least 3 days prior to the administration of bentiromide is recommended)


Glaucoma screening test    (may be interfered with by systemic beta-blockade, which reduces intraocular pressure)


Radionuclide ventriculography    (beta-adrenergic blocking agents may blunt the exercise-induced changes in cardiac function in the evaluation of coronary artery disease by decreasing heart rate)

With physiology/laboratory test values
Alkaline phosphatase and
Lactate dehydrogenase (LDH) and
Transaminases    (values may be increased by metoprolol)


Antinuclear antibody (ANA) titers    (may be increased by beta-adrenergic blocking agents; effect may be dose-related)


Bilirubin concentrations, serum    (may be increased by displacement from albumin binding by thiazide diuretics)


Blood urea nitrogen (BUN) (usually in patients with severe heart disease)    (may be increased by beta-adrenergic blocking agents)


Calcium concentrations, serum    (may be increased by thiazide diuretics; beta-adrenergic blocking agent and thiazide diuretic combinations should be discontinued before parathyroid function tests are carried out)


Calcium concentrations, urinary    (may be decreased by thiazide diuretics)


Glucose concentrations, blood    (nonselective beta-adrenergic blocking agents impair glycogenolysis and the hyperglycemic response to endogenous epinephrine, leading to persistence of hypoglycemia and delayed recovery of blood glucose to normal levels, especially in diabetics; studies have shown no such effect in resting nondiabetics with therapeutic doses; beta-adrenergic blocking agents, especially nonselective agents, decrease the release of insulin in response to hyperglycemia; effects on blood glucose may be less likely with cardioselective agents such as atenolol, bisoprolol, and metoprolol, especially at lower doses)

    (may be increased by thiazide diuretics, usually only in patients with a predisposition to glucose intolerance)


Lipoproteins, serum and
Triglycerides, serum    (may be increased by beta-adrenergic blocking agent and thiazide diuretic combinations)


Magnesium concentrations, serum and
Sodium concentrations, serum    (may be decreased by thiazide diuretics; serum magnesium concentrations may increase in uremic patients)


Potassium concentrations, serum    (may be increased by beta-adrenergic blocking agents; may be decreased by thiazide diuretics)


Uric acid concentrations, serum    (may be increased by beta-adrenergic blocking agent and thiazide diuretic combinations)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: In general, because of the similarity of effect and because the cardioselectivity of beta-1 blockers is relative, the same precautions apply to all beta-adrenergic blocking agents.


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiac failure, overt or
» Cardiogenic shock or
» Heart block, 2nd- or 3rd-degree atrioventricular (AV) block or
» Sinus bradycardia (heart rate less than 45 beats per minute)    (risk of further myocardial depression; risk may be less with pindolol; beta-adrenergic blocking agents may be used with extreme caution in some patients with cardiac failure [e.g., high output failure associated with thyrotoxicosis])


Risk benefit should be considered when the following medical problems exist
» Allergy, history of or
» Asthma, bronchial or
» Emphysema or nonallergenic bronchitis    (beta-adrenergic blocking agents may promote bronchospasm and block the bronchodilating effect of epinephrine; cardioselective agents, such as atenolol, bisoprolol, or metoprolol, or agents with ISA, such as pindolol, are theoretically less likely to cause such effects when used at lower doses; however, caution is necessary with all beta-adrenergic blocking agents)

    (severity and duration of anaphylactic reactions to allergens and allergen immunotherapy may be increased in some patients being treated with beta-adrenergic blocking agents; if possible, another medication should be substituted for a beta-adrenergic blocking agent and thiazide diuretic combination in patients receiving allergen immunotherapy, or, for conditions that are not life-threatening, allergen immunotherapy should be avoided in patients who cannot discontinue beta-adrenergic blocking agent and thiazide diuretic combination therapy; caution is also recommended during skin testing in patients using beta-adrenergic blocking agents)


» Anuria or severe renal function impairment    (thiazide diuretics may be ineffective and may precipitate azotemia; may produce cumulative effects)


» Congestive heart failure    (risk of further depression of myocardial contractility; agents with ISA, such as pindolol, may theoretically be associated with less risk and may be used with caution in patients who are well-compensated)


» Diabetes mellitus    (beta-adrenergic blocking agents may mask tachycardia associated with hypoglycemia, but not dizziness and sweating; beta-adrenergic blocking agents may adversely affect recovery from hypoglycemia {50} {53} and impair peripheral circulation; these effects are theoretically more likely with the noncardioselective agents and less likely with the cardioselective agents)

    (hypoglycemic medication requirements may be altered by thiazide diuretics)


Gout, history of or
Hyperuricemia    (serum uric acid concentrations may be elevated by thiazide diuretics)


Hepatic function impairment    (metabolism of beta-adrenergic blocking agents that undergo hepatic metabolism may be decreased; patients with impaired hepatic function may require lower doses of beta-adrenergic blocking agent and thiazide diuretic combinations [exceptions are combinations containing atenolol, metoprolol (except in severe impairment), and nadolol, which require no dosage adjustment]; such reduction in dosage frequently applies to geriatric patients, many of whom have reduced hepatic function)

    (risk of dehydration with thiazide diuretics, which may precipitate hepatic coma and death; plasma half-life is unaltered)


Hypercalcemia or
Hypercholesterolemia or{85}{86}{87}
Hypertriglyceridemia or{85}{86}{87}
Hyponatremia    (conditions may be exacerbated by thiazide diuretics; onset of hyponatremia can be sudden and life-threatening)


» Hyperthyroidism    (beta-adrenergic blocking agents may mask tachycardic symptoms; abrupt withdrawal may intensify symptoms)


Lupus erythematosus, history of    (exacerbation or activation by thiazide diuretics has been reported)


» Mental depression, or history of    (although the association between beta-adrenergic blocking agents and depression is not fully established, {79} {80} {81} {82} beta-adrenergic blocking agent and thiazide diuretic combinations should be used cautiously in these patients {82})


Myasthenia gravis    (beta-adrenergic blocking agents may potentiate a myasthenic condition, including muscle weakness and double vision {83} {84})


Pancreatitis
Pheochromocytoma    (there is a risk of hypertension if effective alpha-adrenergic blockade is not achieved first)


Psoriasis    (may be exacerbated)


Raynaud's syndrome and other peripheral vascular diseases    (beta-adrenergic blocking agents may reduce peripheral circulation; cardioselective agents, such as atenolol, bisoprolol, or metoprolol, or agents with ISA, such as pindolol, are theoretically less likely to produce adverse effects)


Renal function impairment    (may impair beta-adrenergic blocking agent clearance; risk of reduced renal blood flow. Patients with impaired renal function may require reduced doses of beta-adrenergic blocking agent and thiazide diuretic combinations [exceptions are combinations containing metoprolol, pindolol (unless impairment is severe), propranolol, and timolol, which require no dosage adjustment]; such reduction in dosage frequently applies to geriatric patients, many of whom have reduced renal function)


Sensitivity to the beta-adrenergic blocking agent prescribed or to thiazide diuretics or other sulfonamide-derived medications
Sympathectomy    (antihypertensive effects of thiazide diuretics may be enhanced)


» Caution is required also in jaundiced infants because of the risk of hyperbilirubinemia caused by thiazide diuretics.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood cell counts and
Blood glucose concentrations (for diabetic patients) and
» Cardiac function monitoring and
Hepatic function determinations and
» Pulse rate determinations and
Renal function determinations    (may be required at periodic intervals)


» Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)


» Blood urea nitrogen (BUN) and
Creatinine, serum and
Uric acid, serum    (determinations recommended prior to initiation of thiazide diuretic therapy and if clinical signs of a significant increase occur)


Cholesterol, serum and
Triglycerides, serum    (determinations recommended after 6 months of therapy and annually thereafter)


Electrolyte concentrations, serum    (may be required for patients on long-term thiazide diuretic therapy, especially if they are also taking cardiac glycosides or systemic corticosteroids, or when severe cirrhosis is present)




Side/Adverse Effects

Note: Signs and symptoms of overdose may include sudden bradycardia, hypotension, bronchospasm, cardiac failure, peripheral cyanosis, and seizures; hypoglycemia may occur rarely. In contrast, pindolol overdose may result in tachycardia and hypertension because of intrinsic sympathomimetic activity (ISA). Signs of overdose usually occur within 1 to 2 hours of ingestion.
Beta-adrenergic blocking agents, when taken over an extended period of time, have produced cardiac failure in some patients who had no history of cardiac failure.
As shown with propranolol, the abrupt withdrawal of a beta-adrenergic blocking agent that has been given in high dosage to angina patients and patients with atherosclerotic heart disease may result in severe adverse effects including myocardial infarction, angina, and ventricular tachycardia. Intensified symptoms of hyperthyroidism in patients with a pre-existing condition may result from abrupt discontinuation of beta-blockers.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Electrolyte imbalance such as hyponatremia (confusion; convulsions; decreased mentation; fatigue; irritability; muscle cramps), hypochloremic alkalosis and hypokalemia (dryness of mouth; increased thirst; irregular heartbeat; mood or mental changes; muscle cramps or pain; nausea or vomiting; unusual tiredness or weakness; weak pulse)

Note: Hyponatremia as a complication is rare, but constitutes a medical emergency as onset may be rapid. {88}


Incidence less frequent
    
Bradycardia (slow heartbeat—especially less than 50 beats per minute)
    
bronchospasm (breathing difficulty and/or wheezing)
    
congestive heart failure (swelling of ankles, feet, and/or lower legs; shortness of breath)
    
mental depression
    
reduced peripheral circulation (cold hands and feet)

Note: Risk of bronchospasm or reduced peripheral circulation is theoretically reduced with combinations containing atenolol, bisoprolol, metoprolol, or pindolol.
Mental depression is usually reversible and mild, but may progress to catatonia.


Incidence rare
    
Allergic reaction (skin rash or hives)
    
arrhythmias (irregular heartbeat)
    
agranulocytosis (fever or chills; cough or hoarseness)
    
back pain or joint pain
    
chest pain
    
cholecystitis or pancreatitis (severe stomach pain with nausea and vomiting)
    
confusion
    
hallucinations
    
hepatotoxicity (dark urine; yellow eyes or skin)
    
hyperuricemia or gout (joint pain; lower back or side pain)
    
leukopenia (fever and sore throat)
    
psoriasiform eruption (red, scaling, or crusted skin)
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

Note: Hepatotoxicity is usually reversible.
Confusion is more likely to occur in the elderly.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Decreased sexual ability
    
dizziness or lightheadedness
    
drowsiness, mild
    
trouble in sleeping
    
unusual tiredness or weakness

Incidence less frequent
    
Anorexia (loss of appetite)
    
anxiety or nervousness
    
constipation
    
diarrhea
    
nasal congestion (stuffy nose)
    
nausea or vomiting
    
numbness or tingling of fingers and toes
    
photosensitivity (increased sensitivity of skin to sunlight)
    
stomach discomfort or upset

Incidence rare
    
Changes in taste
    
dry, sore eyes
    
itching of skin
    
nightmares and vivid dreams



Those indicating possible withdrawal and the need for medical attention if they occur after the medication is discontinued
    
Arrhythmias (fast or irregular heartbeat)
    
chest pain
    
general feeling of discomfort, illness, or weakness
    
headache
    
shortness of breath, sudden
    
sweating
    
trembling




Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Signs and symptoms of overdose (in order of occurrence)
    
Bradycardia (slow heartbeat)
    
dizziness, severe, or fainting
    
difficulty in breathing
    
bluish-colored fingernails or palms of hands
    
seizures


Treatment of overdose
Immediate evacuation of the stomach.

Supportive symptomatic treatment.

Monitoring of serum electrolyte concentrations and renal function.


For beta-adrenergic blocking agents:
Decontamination—Gastric lavage {89} {90} {91} {92} and administration of activated charcoal. {93} {94} {95} {96}


Specific treatment—
Atropine: May be administered for severe bradycardia in the presence of hypotension. {97} {98} {99} {100} {101} {102} {103} {104}

Diazepam or lorazepam: May be used intravenously to treat associated seizures. {96} {100} {104}

Dobutamine, dopamine, epinephrine, norepinephrine, or isoproterenol {89} {94} {99} {100} {101} {102}: May be administered for chronotropic and inotropic support and treatment of severe hypotension. However, the effects of sympathomimetic agents may be inhibited by the presence of significant beta-blockade. {94} {99} {103} Therefore, hypotension and ensuing pump failure may be refractory to treatment with catecholamines. {89} {92} {100} {101} {102} {103}

Glucagon: Glucagon has been used effectively in the treatment of bradycardia and hypotension in beta-adrenergic blocking agent overdose. {89} {91} {95} {96} {99} {100} {101} {102} Glucagon demonstrates major inotropic and less dramatic chronotropic effects. {99} {105} These effects appear to be independent of the beta-adrenergic receptor. {94} {99} {105} Therefore, glucagon may be an advantageous alternative treatment to the sympathomimetic agents for reversal of the hemodynamic depression of beta-adrenergic blocking agent overdose. {94}

Transvenous pacing: May be necessary for heart block. {100} {106}

Other therapy: May include furosemide or digitalis glycoside for pulmonary edema {100} or cardiac failure; or a beta-2 agonist such as isoproterenol and/or a theophylline derivative for bronchospasm.

There is limited evidence that calcium chloride may be effective in improving myocardial contractility and hemodynamic status. {97} {101} {107} It is speculated that hypocalcemia resulting from beta-adrenergic blocking agent overdose may contribute to a decline in myocardial contractility. {97}




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Beta-adrenergic Blocking Agents and Thiazide Diuretics (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the beta-adrenergic blocking agent prescribed, or to any thiazide diuretic or other sulfonamide-type medications

Pregnancy—Risk of hypoglycemia, respiratory depression, bradycardia, and hypotension with beta-adrenergic blocking agents; thiazide diuretics may cause jaundice, thrombocytopenia, hypokalemia in infant





Breast-feeding—Distributed into breast milk; not known for bisoprolol





Use in the elderly—Increased sensitivity to effects; increased risk of beta-blocker-induced hypothermia
Other medications, especially allergen immunotherapy or skin testing, oral antidiabetic agents, calcium channel blocking agents, clonidine, cocaine, digitalis glycosides, guanabenz, insulin, lithium, MAO inhibitors, sympathomimetics, or xanthines
Other medical problems, especially anuria or severe renal function impairment, bronchial asthma, cardiogenic shock, congestive heart failure, diabetes mellitus, emphysema or nonallergenic bronchitis, history of allergy, hyperthyroidism, hypotension, mental depression, overt cardiac failure, second or third degree AV block, or sinus bradycardia

Proper use of this medication
Possible need for control of weight and diet, especially sodium intake

» Compliance with therapy; patient may not experience symptoms of hypertension; importance of taking medication only as directed and keeping appointments with physician, even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; serious consequences of untreated hypertension

Proper administration of extended-release dosage forms: Swallowing whole without crushing, breaking, or chewing

Getting into habit of taking at same time each day to help increase compliance

Checking pulse as directed (checking with physician if less than 50 beats per minute)

Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

» Importance of not missing doses, especially with schedules of one dose per day

» Proper dosing
Missed dose: Taking as soon as possible; not taking at all if within 4 hours of next scheduled dose (8 hours for atenolol and chlorthalidone, nadolol and bendroflumethiazide, or extended-release propranolol and hydrochlorothiazide); not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

» Checking with physician before discontinuing medication; gradual dosage reduction may be necessary

Having enough medication on hand to get through weekends, holidays, and vacations; possibly carrying second written prescription for emergency use

Carrying medical identification during therapy

» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Diabetics: May mask signs and symptoms of hypoglycemia or cause increased blood glucose concentrations

» Possibility of hypokalemia; possible need for additional potassium in diet; not changing diet without first checking with physician

To prevent dehydration, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

» Caution when driving or doing things requiring alertness, because of possible drowsiness, dizziness, or lightheadedness

Caution during exposure to cold weather because of possible increased sensitivity to cold

Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth

Caution if any laboratory tests required; possible interference with test results

Patients with allergies to foods, medications, or stinging insect venom: Possible increase in severity of allergic reactions; checking with physician immediately if severe allergic reaction occurs


Side/adverse effects
Signs of potential side effects, especially electrolyte imbalance, bradycardia, bronchospasm, congestive heart failure, mental depression, reduced peripheral circulation, allergic reaction, arrhythmias, agranulocytosis, back pain, joint pain, chest pain, cholecystitis, pancreatitis, confusion (especially in elderly), hallucinations, hepatotoxicity, hyperuricemia, gout, leukopenia, psoriasiform eruption, and thrombocytopenia


General Dosing Information
Fixed-dosage combinations generally are not recommended for initial therapy, but are utilized in maintenance therapy, after the required dose is established, in order to increase convenience, economy, and patient compliance.

The lowest effective dosage of thiazide diuretics should be utilized to minimize potential electrolyte imbalance and the reflex increase in renin and aldosterone levels.

Although plasma concentrations of beta-adrenergic blocking agents can be ascertained, there is not always a predictable relationship between plasma concentration and pharmacologic effects. Pharmacologic effects have been observed when plasma concentrations were not discernible. Therefore, titration of dosage with measurement of heart rate and blood pressure is used to guide therapy.

In some patients, once-a-day dosing is effective.

A single daily dose is preferably taken on arising to minimize the effect of increased frequency of urination on sleep.

Concurrent administration of potassium supplements or potassium-sparing diuretics may be indicated in patients considered to be at higher risk for developing hypokalemia. Caution in administering potassium supplements is recommended, however; since loss of potassium caused by thiazide diuretics is not clinically significant in most patients, and supplementation leads to a risk of development of hyperkalemia. Self-initiated potassium supplementation by the patient should be discouraged unless monitored by physician.

Patients receiving beta-adrenergic blocking agent and thiazide diuretic combinations who display symptoms of cardiac failure should be digitalized. If cardiac failure persists after adequate digitalis therapy, the beta-adrenergic blocking agent and thiazide diuretic combination should be discontinued gradually.

It is recommended that beta-adrenergic blocking agent and thiazide diuretic therapy be withdrawn if drug-induced mental depression occurs.

When a beta-adrenergic blocking agent and thiazide diuretic combination must be withdrawn from established therapy (especially in patients with ischemic heart disease), it is recommended that the dosage be reduced gradually to minimize risk of exacerbation of angina or development of myocardial infarction. Dosage reduction should occur over a period of approximately 2 weeks. During this time the patient should avoid vigorous physical activity in order to minimize the danger of infarction or arrhythmias. If symptoms of withdrawal (e.g., angina) occur, beta-adrenergic blocking agent and thiazide diuretic combination therapy should be reinstated temporarily and then carefully withdrawn after the patient has stabilized.

In patients scheduled for major surgery, most practitioners believe the danger of precipitating myocardial infarction following abrupt cessation of beta-adrenergic blocking agent therapy prior to surgery outweighs the risks of continuing therapy and compensating for medication effects by anesthetic techniques. Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery may not be desirable. However, the anesthesiologist must be aware of such therapy.

Diet/Nutrition
Beta-adrenergic blocking agent and thiazide diuretic combinations may be given either with food or on an empty stomach. Studies indicate that bioavailability of propranolol and possibly metoprolol may be enhanced by administration with food, which may slow the hepatic metabolism of the medication. Bioavailability of atenolol, nadolol, or pindolol is not affected by food intake. Timolol is subject to only moderate first-pass metabolism and is not affected by concurrent food intake.

ATENOLOL AND CHLORTHALIDONE

Summary of Differences


Atenolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Relatively cardioselective (beta-1); very low lipid solubility.

Biotransformation: Minimal hepatic metabolism.

Elimination: Removable by hemodialysis.



Precautions—
Medical considerations/contraindications: Dosage reduction necessary in renal function impairment but not necessary in hepatic function impairment.



Side/adverse effects—
Theoretical reduced risk of bronchospasm, hypoglycemia, and peripheral vasoconstriction because of cardioselectivity.




Chlorthalidone:


Pharmacology/pharmacokinetics—
Although not chemically the same, chlorthalidone has the same actions as the thiazide diuretics.




Oral Dosage Forms

ATENOLOL AND CHLORTHALIDONE TABLETS

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets once a day, as determined by individual titration with the component agents. {02}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of atenolol and 25 mg of chlorthalidone (Rx) [Tenoretic 50 (scored)][Generic]


100 mg of atenolol and 25 mg of chlorthalidone (Rx) [Tenoretic 100][Generic]

Canada—


50 mg of atenolol and 25 mg of chlorthalidone (Rx) [Tenoretic (scored)]


100 mg of atenolol and 25 mg of chlorthalidone (Rx) [Tenoretic (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



BISOPROLOL AND HYDROCHLOROTHIAZIDE

Summary of Differences


Bisoprolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Relatively cardioselective (beta-1).

Protein binding: Low.



Precautions—
Breast-feeding: Not known if distributed into breast milk.




Oral Dosage Forms

BISOPROLOL FUMARATE AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets once a day, as determined by individual titration with the component agents. {03}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide (Rx) [Ziac]


5 mg of bisoprolol and 6.25 mg of hydrochlorothiazide (Rx) [Ziac]


10 mg of bisoprolol and 6.25 mg of hydrochlorothiazide (Rx) [Ziac]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Do not take other medicine without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



METOPROLOL AND HYDROCHLOROTHIAZIDE

Summary of Differences


Metoprolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Relatively cardioselective (beta-1); moderate lipid solubility.

Absorption: Bioavailability significantly reduced by first-pass metabolism.

Elimination: Not removable by hemodialysis.



Precautions—
Medical considerations/contraindications: No dosage reduction necessary in hepatic function impairment (unless severe) or renal function impairment.



Side/adverse effects—
Theoretical reduced risk of bronchospasm, hypoglycemia, and peripheral vasoconstriction when daily dosage does not exceed 200 mg, because of cardioselectivity; increased risk of central nervous system (CNS) side effects because of lipid solubility and relative ease of penetration into CNS.




Oral Dosage Forms

METOPROLOL TARTRATE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets a day, as a single dose or in divided doses, as determined by individual titration with the component agents. {05}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide (Rx) [Lopressor HCT (scored) (lactose)]


100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide (Rx) [Lopressor HCT (scored) (lactose)]


100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide (Rx) [Lopressor HCT (scored) (lactose)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



NADOLOL AND BENDROFLUMETHIAZIDE

Summary of Differences


Nadolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Nonselective (blocks both beta-1 and beta-2 adrenergic receptors); low lipid solubility.

Biotransformation: Not hepatically metabolized.

Elimination: Removable by hemodialysis.



Precautions—
Medical considerations/contraindications: Dosage reduction or increased dosing intervals recommended in renal function impairment; dosage reduction not necessary in hepatic function impairment.




Oral Dosage Forms

NADOLOL AND BENDROFLUMETHIAZIDE TABLETS USP

Usual adult dose
Antihypertensive
Oral, 1 tablet once a day, as determined by individual titration with the component agents. {06}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


40 mg of nadolol and 5 mg of bendroflumethiazide (Rx) [Corzide 40/5 (scored) (lactose)]


80 mg of nadolol and 5 mg of bendroflumethiazide (Rx) [Corzide 80/5 (scored) (lactose)]

Canada—


40 mg of nadolol and 5 mg of bendroflumethiazide (Rx) [Corzide (scored)]


80 mg of nadolol and 5 mg of bendroflumethiazide (Rx) [Corzide (scored)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



PINDOLOL AND HYDROCHLOROTHIAZIDE

Summary of Differences


Pindolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Nonselective (blocks both beta-1 and beta-2 adrenergic receptors); exhibits the most intrinsic sympathomimetic activity (ISA) of beta-blockers currently available; moderate lipid solubility.

Biotransformation: Although hepatically metabolized, undergoes no significant first-pass effect.



Precautions—
Medical considerations/contraindications: Dosage reduction necessary in hepatic function impairment and severe renal function impairment.



Side/adverse effects—
Theoretical reduced risk of bronchospasm, heart failure, and peripheral vasoconstriction because of ISA; overdose may produce tachycardia and hypertension.




Oral Dosage Forms

PINDOLOL AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets once a day, as determined by individual titration with the component agents. {12}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10 mg of pindolol and 25 mg of hydrochlorothiazide (Rx) [Viskazide]


10 mg of pindolol and 50 mg of hydrochlorothiazide (Rx) [Viskazide]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



PROPRANOLOL AND HYDROCHLOROTHIAZIDE

Summary of Differences


Propranolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Nonselective (blocks both beta-1 and beta-2 adrenergic receptors); high lipid solubility.

Absorption: Bioavailability significantly reduced by first-pass metabolism.

Elimination: Not removable by hemodialysis.



Precautions—
Medical considerations/contraindications: Dosage reduction necessary in hepatic function impairment but not necessary in renal function impairment.



Side/adverse effects—
Increased risk of CNS side effects because of high lipid solubility and ease of penetration into CNS.




Oral Dosage Forms

PROPRANOLOL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE EXTENDED-RELEASE CAPSULES USP

Usual adult dose
Antihypertensive
Oral, 1 capsule a day, as determined by individual titration with the component agents. {04}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


80 mg of propranolol hydrochloride and 50 mg of hydrochlorothiazide (Rx) [Inderide LA (lactose)]


120 mg of propranolol hydrochloride and 50 mg of hydrochlorothiazide (Rx) [Inderide LA (lactose)]


160 mg of propranolol hydrochloride and 50 mg of hydrochlorothiazide (Rx) [Inderide LA (lactose)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



PROPRANOLOL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets two times a day, as determined by individual titration with the component agents. {07}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


40 mg of propranolol hydrochloride and 25 mg of hydrochlorothiazide (Rx) [Inderide (scored)][Generic] (may be scored)


80 mg of propranolol hydrochloride and 25 mg of hydrochlorothiazide (Rx) [Inderide (scored)][Generic] (may be scored)

Canada—


40 mg of propranolol hydrochloride and 25 mg of hydrochlorothiazide (Rx) [Inderide (scored)]


80 mg of propranolol hydrochloride and 25 mg of hydrochlorothiazide (Rx) [Inderide (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



TIMOLOL AND HYDROCHLOROTHIAZIDE

Summary of Differences


Timolol:


Pharmacology/pharmacokinetics—
Mechanism of action/effect: Nonselective (blocks both beta-1 and beta-2 adrenergic receptors); no significant intrinsic sympathomimetic activity (ISA); moderate lipid solubility.

Absorption: Bioavailability significantly reduced by first-pass metabolism.

Elimination: Not removable by hemodialysis.



Precautions—
Medical considerations/contraindications: Dosage reduction necessary in hepatic function impairment but not necessary in renal function impairment.




Oral Dosage Forms

TIMOLOL MALEATE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Antihypertensive
Oral, 1 tablet two times a day or 2 tablets once a day, as determined by individual titration with the component agents. {08}


Note: Geriatric patients may have increased or decreased sensitivity to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


10 mg of timolol maleate and 25 mg of hydrochlorothiazide (Rx) [Timolide 10-25]

Canada—


10 mg of timolol maleate and 25 mg of hydrochlorothiazide (Rx) [Timolide]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • Do not take other medicine without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.




Revised: 08/12/1998



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