VA Class:CV490
Guanabenz acetate is a centrally active hypotensive agent1, 3, 4, 6, 17, 18, 25, 27, 28, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 67, 68, 69, 71, 100, 103, 104, 105, 106, 115, 125, 127 that is structurally and pharmacologically related to clonidine.4, 8, 17, 61
Guanabenz is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Thiazide diuretics, however, are considered the preferred initial monotherapy for uncomplicated hypertension by the Joint National Committee (JNC 7) on the Prevention, Detection, Evaluation, and Treatment of Hypertension in the US.181 184 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)
The efficacy of guanabenz in hypertensive patients is similar to that of other adrenergic agonists such as clonidine,4, 17, 18, 31, 36, 37, 41, 69 methyldopa,3, 4, 11, 17, 18, 31, 33, 39 or β-adrenergic blocking agents (e.g., pindolol,106 propranolol).17, 34, 106, 114 As with other hypotensive agents, treatment with guanabenz is not curative;6 after withdrawal of the drug, blood pressure returns to pretreatment levels or greater.48, 49, 51, 54, 55, 56, 58, 71
Although many hypertensive patients may be controlled by guanabenz alone,1, 17, 27, 28, 32, 34, 36, 42, 43, 44, 45, 46, 67, 69, 71, 100, 104, 120, 125, 160, 162 the drug may be more effective when used with a diuretic.1, 3, 16, 17, 27, 28, 33, 34, 35, 36, 42, 68, 85, 100, 157, 160, 162, 166, 168, 169 Guanabenz has been used in conjunction with thiazide diuretics, producing a greater reduction in blood pressure than that obtained with either drug alone.1, 16, 17, 27, 28, 35, 36, 42, 68, 162 Concomitant use with a diuretic may permit dosage reduction of either or both drugs and minimize adverse effects while maintaining blood pressure control.16, 17, 27, 28, 33, 63, 130, 162 However, the possibility that geriatric patients may not tolerate the adverse cognitive effects of central α2-adrenergic agonists such as guanabenz should be considered.168
Guanabenz may be particularly useful in hypertensive patients whose baseline catecholamine concentrations are markedly elevated and whose hypertension is characterized by increased sympathetic activity.82, 107 Guanabenz also may be useful in the treatment of hypertension that is predominantly of the systolic form, commonly occurring in patients 60 years of age and older,107, 128 although thiazide diuretics generally are preferred for the treatment of isolated systolic hypertension in geriatric adults because of established cardiovascular benefits (e.g., stroke reduction).168, 170, 171 Because guanabenz does not appear to induce sodium retention,16, 28, 31, 32, 33, 36, 38, 39, 45, 46, 69, 70, 71, 157, 159 the drug is useful in patients who develop secondary renal- or cardiac-induced sodium retention during therapy with clonidine31, 36, 124, 157 or methyldopa.31, 33, 36, 39, 45, 46, 123, 157 Guanabenz has been used in diabetic hypertensive patients with no adverse effect on control or therapy of diabetes;103 the drug also has been effective in hypertensive patients with chronic obstructive pulmonary disease (COPD), including asthma, chronic bronchitis, or emphysema.104
For additional information on overall principles for treatment of hypertension and overall expert recommendations for such disease, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Guanabenz has been used alone65, 70 or in combination with naltrexone66 in the management of opiate withdrawal† in patients physically dependent on opiates and undergoing detoxification.65, 66, 70 Guanabenz has also been used as an analgesic in a limited number of patients with chronic pain†; use of the drug permitted a reduction in opiate dosage or discontinuance of opiate therapy in these patients, but additional study is necessary.64
Guanabenz acetate is administered orally.1 To ensure overnight blood pressure control and minimize daytime drowsiness, the last dose of the day should be administered at bedtime.6, 157 Guanabenz has also been given as a single daily dose administered at bedtime to minimize adverse effects.36, 62
If guanabenz therapy is to be discontinued, dosage of the drug should be slowly reduced over several days to avoid the possibility of precipitating the withdrawal syndrome.34, 51, 54, 157 (See Cautions: Withdrawal Effects.)
Dosage of guanabenz acetate is expressed in terms of guanabenz.1, 2
Dosage of guanabenz must be adjusted according to the patient's blood pressure response and tolerance.1, 3, 166, 168 Additional dosage adjustment may be necessary in hypertensive patients with hepatic impairment.117
The initial adult dosage of guanabenz, when administered alone or in combination with a thiazide diuretic,1, 3, 17 is 2-4 mg twice daily.1, 3, 4, 6, 17, 18, 163, 166, 168 Dosage may be increased by 4- or 8-mg increments daily at 1- to 2-week intervals or longer until the desired blood pressure response is achieved.1, 4, 6, 17, 18, 166, 168 The usual maintenance dosage of guanabenz ranges from 4-16 mg twice daily.157, 160, 166, 168 The maximum dosage studied in patients with hypertension to date and recommended by the manufacturer and most clinicians is 32 mg twice daily,1, 3, 4, 6, 17, 18, 32, 33, 36, 45, 100, 103, 104, 127, 163 but such dosages are rarely necessary.1, 48
In children 12 years of age and older, the maintenance dosage of guanabenz has been 4-24 mg daily (0.08-0.2 mg/kg daily), administered in 2 divided doses.38, 105 Initial dosages of the drug in these children ranged from 0.5-4 mg daily and were increased in increments of 0.5-2 mg daily, depending on patient weight, age, response, and tolerance.38
Blood Pressure Monitoring and Treatment Goals
Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of guanabenz is recommended.168 181 Large or abrupt reductions in blood pressure generally should be avoided. 168
Once antihypertensive drug therapy has been initiated, dosage generally is adjusted at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if blood pressure control is inadequate at a given dosa it may take months to control hypertension adequately while avoiding adverse effects of therapy. 168 181 (For definition of stages of hypertension, see Initial Drug Therapy under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) Once blood pressure has been stabilized, follow-up visits with the clinician generally can be scheduled at 3- to 6-month intervals, depending on patient status. 168 181
Because systolic blood pressure has been shown to be a more precise indicator of cardiovascular risk than diastolic blood pressure (except in patients younger than 50 years of age), the coordinating committee of the National High Blood Pressure Education Program (NHBPEP) recommends using systolic blood pressure as the principal clinical end point for detecting, evaluating, and treating hypertension, especially in middle-aged and geriatric patients.173 174 181 In addition, once the goal systolic blood pressure is attained, most hypertensive patients also will achieve the goal diastolic blood pressure.181
The goal of hypertension management and prevention is to achieve and maintain a lifelong systolic blood pressure less than 140 mm Hg and a diastolic blood pressure less than 90 mm Hg if tolerated.168, 181, 183 Because treatment to lower levels may be particularly useful to prevent stroke, to preserve renal function, and to prevent or slow heart failure progression in hypertensive patients with diabetes mellitus or renal impairment, the goal of hypertension management and prevention in such patients is to achieve and maintain a systolic blood pressure less than 130 mm Hg and a diastolic blood pressure less than 80 mm Hg.168, 175, 181 182, 183 Many experts recommend a goal of achieving and maintaining a systolic blood pressure of 125 mm Hg or less and a diastolic blood pressure of 75 mm Hg or less in hypertension management in patients with proteinuria (urinary protein excretion exceeding 1 g per 24 hours) and renal insufficiency (regardless of etiology).168, 175
For additional information on initiating and adjusting guanabenz dosage in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
A guanabenz dosage of 4 mg twice daily has been used in the management of opiate withdrawal† in patients physically dependent on opiates and undergoing detoxification; if necessary to control signs and symptoms of withdrawal, dosage has been increased to 4 mg 4 times daily.65
Overall, the frequency of adverse effects produced by guanabenz is similar to or greater than that produced by clonidine17, 31, 36 and by methyldopa.16, 17, 31, 39, 45 Adverse effects of guanabenz generally are mild,28, 34, 36, 38, 46, 103, 105 appear to be dose related,1, 37, 106, 113 usually occur within the first 2 weeks of therapy,17, 32, 33, 105 and tend to diminish with continued therapy17, 28, 33, 35, 37, 38, 45, 46, 100, 125, 127 or may be relieved by a reduction in dosage.40 Adverse nervous system effects (e.g., sedation)1, 3, 4, 11, 16, 17, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 47, 100, 103, 105, 106, 125, 127 and dry mouth1, 3, 4, 11, 16, 17, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 44, 45, 47, 100, 103, 105, 106, 125, 127 occur most frequently during guanabenz therapy. Although adverse effects of the drug generally are not severe, discontinuance of guanabenz therapy has been necessary in about 10-15% of patients,1, 17, 26, 32, 45, 46, 100 principally because of intolerable sedation36, 45, 46, 100 or dry mouth.32, 36, 46, 100 The manufacturer states that the incidence of the most frequently reported adverse effects was similar in patients receiving guanabenz or placebo in some studies.1
Sedation (e.g., drowsiness, tiredness)1, 3, 4, 11, 16, 17, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 47, 100, 103, 105, 106, 125, 127 occurs in about 20% of patients at a guanabenz dosage of 8 mg daily and in about 40% at a dosage of 8 mg twice daily.1 Dizziness,1, 4, 11, 16, 17, 25, 27, 28, 32, 33, 36, 38, 39, 41, 44, 103, 106, 125 weakness,1, 3, 16, 17, 27, 28, 32, 35, 36, 41, 44, 103, 106 and headache1, 3, 17, 25, 33, 38, 42, 44, 103, 105, 106 occur in about 12-17, 10, and 5% of patients receiving the drug, respectively.1 Other adverse nervous system effects, including anxiety,1, 3, 42, 45 irritability,37 tremor,37, 43 ataxia,1, 43 mental depression,1, 3, 11, 30, 33, 38 insomnia,1, 3, 33, 42 and numbness,25, 44 occur in up to 3% of patients receiving guanabenz but have not been directly attributed to the drug.1
Dry mouth1, 3, 4, 11, 16, 17, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 42, 43, 44, 45, 47, 100, 103, 105, 106, 125, 127 occurs in 30-40% of patients receiving guanabenz.1 Other GI effects,3, 25, 46, 103 including nausea,1, 11, 17, 27, 33, 37, 38, 43, 44 epigastric pain,1, 42, 44 diarrhea,1, 11, 44 vomiting,1, 11, 33, 47 constipation,1, 17, 27, 42, 44 anorexia,38 abdominal discomfort,1, 44 and dysgeusia,1, 25, 42, 44 occur in up to 3% of patients receiving the drug.
Adverse cardiovascular effects, such as chest pain,1, 25 bradycardia,17, 42 edema,1 arrhythmias,1, 3 and palpitation,1, 3, 25, 42 occur in up to 3% of patients receiving guanabenz.1 Atrioventricular (AV) node dysfunction, including complete AV block, has been reported rarely during guanabenz therapy.1
Orthostatic hypotension has reportedly occurred in less than 1% of patients during guanabenz therapy,3, 29, 40, 46, 157 and does not appear to be a substantial problem17, 30 since there appears to be little difference in mean supine and standing systolic and diastolic blood pressures in most patients receiving the drug.1, 17, 36, 37, 43, 46, 100, 103, 125
Rarely, an occasional, nonprogressive increase in liver function test results has occurred during guanabenz therapy; however, clinical evidence of liver disease has not been observed.1, 8 Elevated alkaline phosphatase concentrations occurred in a 19-year-old patient receiving guanabenz, but was attributed to adolescent growth since the enzyme was increased before initiation of therapy with the drug and following its discontinuance.38
Other adverse effects occur in up to 3% of patients receiving guanabenz.1 Adverse dermatologic effects include rash1, 3, 25 and pruritus,1, 44 and adverse urogenital effects include urinary frequency1, 3, 17, 25, 41, 44 and sexual dysfunction (e.g., decreased libido, impotence).1, 3, 4, 6, 27, 41, 46Nasal congestion,1, 3, 17, 33 tinnitus,42 blurred vision,1, 3, 17, 25, 33, 38, 44 dry eyes,105 pain in the extremities,1, 25 muscle pain,1 backache,42 dyspnea,1 diaphoresis,25, 44 and gynecomastia1 have also occurred. Exacerbation of asthma, secondary to dryness of the throat and bronchi that was possibly drug related, occurred during guanabenz therapy in a hypertensive patient with chronic obstructive pulmonary disease; the drug was discontinued.104 During administration of 20 mg of guanabenz daily for up to 6 months in one study, small increases in fasting blood glucose concentrations occurred in several patients; however, the clinical importance of this effect has not been determined.34 In the same study, serum uric acid concentrations increased slightly during short- and long-term guanabenz therapy but returned to baseline following discontinuance of the drug.34 Erythrocyte mass and hematocrit decreased during long-term therapy with the drug in these patients.34
The manufacturer states that clinically important laboratory test (i.e., complete blood cell count, urinalysis, electrolytes, AST [SGOT], bilirubin, alkaline phosphatase, uric acid, BUN, serum creatinine, glucose, calcium, phosphorus, total protein, antiglobulin [Coombs']test) abnormalities have not occurred in patients receiving acute or long-term therapy with guanabenz.1
Like other centrally active α-adrenergic agonists (e.g., clonidine),1, 52, 55, 56, 57, 61, 134, 135 abrupt withdrawal of guanabenz may result in rebound increases in serum and urine catecholamine concentrations1, 30, 51, 58, 119, 135 and a rapid increase in systolic and diastolic blood pressure.1, 4, 17, 30, 34, 48, 51, 52, 53, 54, 55, 56, 58, 71, 135 Symptoms associated with abrupt withdrawal of guanabenz may result from sympathetic overactivity48, 49, 51, 54, 55, 57, 135 and may include nervousness,16, 17, 34, 48, 51, 52, 55, 119 agitation,17, 34, 51, 52 anxiety,4, 17, 30, 48, 52, 55, 135 insomnia,6, 16, 17, 48, 51, 52, 55, 135 headache,6, 17, 30, 34, 51, 52, 55, 119 dizziness,17, 34 tingling in the hands,17, 34 tremors,6, 51, 52, 55 fatigue,52 malaise,17, 48, 52 flushing,6, 51, 52 sweating,4, 6, 16, 17, 48, 51, 52, 135 chest pain,6, 52 palpitation,4, 6, 16, 17, 30, 34, 48, 51, 52, 55, 135 nausea,17, 30, 34, 51, 52, 55, 135 vomiting,30, 51, 52, 135 and abdominal pain.6, 17, 30, 48, 52 Following abrupt withdrawal of the drug, increased sympathetic activity and associated symptoms may occasionally occur without a substantial increase in blood pressure.1, 48, 50, 61 The exact mechanism(s) of the withdrawal syndrome following discontinuance of α-adrenergic agonists has not been determined51, 52, 54, 55, 56, 57, 134, 135 but may involve increased concentrations of circulating catecholamines, increased sensitivity of adrenergic receptors, enhanced renin-angiotensin system activity, decreased vagal function, failure of autoregulation of cerebral blood flow, and/or failure of central α2-adrenergic receptor mechanisms that regulate sympathetic outflow from the CNS and modulate baroreflex function.52, 54, 55, 56, 57, 134, 135
The withdrawal syndrome may be dose dependent,17, 25, 48, 52, 54 occurring more frequently following discontinuance of guanabenz dosages greater than 32 mg daily.6 In one study, 75% of patients receiving a guanabenz dosage of 48 mg daily for 2 years developed withdrawal following abrupt discontinuance of the drug, while patients receiving dosages up to 32 mg daily generally did not develop withdrawal.48 However, in another study, withdrawal occurred in patients receiving dosages of 8-32 mg daily for 6 months.17, 34 When guanabenz is discontinued abruptly, withdrawal symptoms begin to appear within 8-72 hours17, 48, 51, 52, 55, 135 and may continue for several days.34, 55 In one study, about 33% of patients developed the withdrawal syndrome following abrupt cessation of guanabenz therapy.17, 34 Diastolic blood pressure increased 6-17 and 9-45 mm Hg compared with pretreatment and long-term treatment values, respectively.17, 34 Like withdrawal following abrupt cessation of clonidine,16, 50, 52, 53, 54, 55, 57, 58, 134, 135 increases in blood pressure following abrupt discontinuance of guanabenz may exceed pretreatment values.34
An excessive rise in blood pressure after guanabenz withdrawal can be reversed and symptoms relieved by resumption of guanabenz.34, 48, 49, 51, 52, 54, 55, 56 Withdrawal from centrally active α-adrenergic agonists has also been managed by combined administration of α- and β-adrenergic blocking agents (e.g., phentolamine or prazosin with atenolol, labetalol, or propranolol).52, 61, 134, 135, 136, 137, 138, 139 Mild withdrawal syndrome without elevated blood pressure has also been adequately treated with oral diazepam.48
Precautions and Contraindications
Because of the risk of rebound or “overshoot” hypertension,1 patients receiving guanabenz should be warned of the danger of missing doses or stopping the drug without consulting their physician.1, 6, 54 (See Cautions: Withdrawal Effects.) When guanabenz therapy must be interrupted for surgery, the drug should be discontinued slowly over several days, if possible, to avoid precipitating the withdrawal syndrome.51, 54, 160 If necessary, parenteral hypotensive therapy should be administered throughout the period that oral medication cannot be given; oral guanabenz should be resumed as soon as possible.157, 160
Guanabenz should be used with caution and blood pressure monitored carefully in patients with hepatic and/or renal impairment, since the pharmacokinetics of the drug may be altered in such patients.1, 117 The drug also should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, and/or cerebrovascular disease.1 Guanabenz should also be used with caution in geriatric patients since they may be more sensitive to the hypotensive and sedative effects of the drug.6
Because of the potential sedative effect of guanabenz, patients should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1, 26 Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines, and patients should be warned that their tolerance for CNS depressants may be decreased.1
Guanabenz is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Although guanabenz has been used in the management of hypertension in a limited number of children 12 years of age and older, further study on the use of the drug in these patients is necessary.38, 105, 157 Safety and efficacy of guanabenz in children younger than 12 years of age have not been established; therefore, the manufacturer does not recommend use of the drug in these children.1 For information on overall principles for treatment of hypertension and overall expert recommendations for such disease in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Mutagenicity and Carcinogenicity
It is not known whether guanabenz is mutagenic or carcinogenic in humans.157 In vitro at concentrations of 200-500 mcg per plate or 30-50 mcg/mL in suspension, guanabenz produced concentration-related increases in the number of mutants in the Ames microbial mutagen test with or without metabolic activation.1, 8 However, no evidence of mutagenicity was observed in vitro with guanabenz concentrations of 500 mcg/mL, which inhibit growth in yeast cells, or 32 mcg/mL, which produce cellular death in ovarian cells;1, 8, 157 guanabenz also produced no mutagenic changes in yeast cells in an assay measuring induction of reparable DNA damage.1 No evidence of carcinogenicity was seen in a 2-year study in mice or rats receiving oral guanabenz dosages up to 1 or 2 times, respectively, the maximum recommended human daily dosage of 64 mg for a 50-kg patient (calculated on the basis of body surface area).1
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans,1 guanabenz has been shown to be teratogenic and fetotoxic in animals.1, 8, 22, 23, 24, 126 Because the drug may adversely affect the fetus when administered to pregnant women, guanabenz should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1
A possible increase in costal and vertebral skeletal abnormalities was observed in mice receiving oral guanabenz dosages 3-6 times the maximum human dosages of 1 mg/kg; however, these skeletal abnormalities were absent in rats and rabbits receiving similar dosages of the drug.1, 8 Delayed ossification of the hindlimbs and forelimbs and of the sternebrae were observed in rats receiving oral guanabenz dosages of 15-30 and 30 mg/kg daily, respectively, beginning on day 7 of gestation;22, 126 however, no external, visceral, or skeletal malformations occurred in rabbits receiving oral dosages of 1-10 mg/kg daily on days 6-18 of gestation.23 An increase in fetal loss has been observed in pregnant rats and rabbits receiving oral dosages of 14 and 20 mg/kg, respectively.1, 8 Reproduction studies in rats using oral guanabenz dosages of 6.4 and 9.6 mg/kg have shown slight decreases in the number of live births and decreases in fetal survival rate and pup body weight.1, 8 Decreases in the number of live births and fetal survival rate occurred in the offspring (second generation) of rats receiving oral dosages of 30 mg/kg;22 in one study in rats receiving oral dosages of 8 or 15 mg/kg from day 17 of gestation through day 21 postpartum, 33 or 100% of offspring were dead at birth, respectively.24, 157
Reproduction studies in rats using guanabenz dosages of 9.6 mg/kg (10 times the maximum human dosage) have shown a decreased rate of pregnancy; the manufacturer states that impaired fertility may have occurred in male rats following a dosage of 9.6 mg/kg, resulting in the decreased rate of pregnancy.1, 8 Female rats received guanabenz only during the third trimester of pregnancy.1, 8 Guanabenz dosages of 8-30 mg/kg inhibited weight gain or produced a decrease in weight in pregnant rats and rabbits.22, 24 Dosages of 15-30 mg/kg appeared to affect the number or rate of implantation;126 however, the number of resorptions was unaffected.22, 23, 126
Since it is not known if guanabenz is distributed into milk, the drug should be used with caution in nursing women.1, 4
Although formal drug interaction studies have not been performed to date,157 the manufacturer states that no drug interactions have occurred during clinical studies in patients receiving guanabenz concurrently with cardiac glycosides, analgesics, anxiolytics, or anti-inflammatory or anti-infective agents.1
Additive CNS depression may occur when guanabenz is administered concomitantly with other CNS depressants including alcohol, phenothiazines, barbiturates, or benzodiazepines.1, 26
Guanabenz withdrawal may result in an excess of circulating catecholamines;1, 30, 51, 58 therefore, caution should be exercised in concomitant use of drugs that affect the metabolism or tissue uptake of these amines (monoamine oxidase inhibitors or tricyclic antidepressants, respectively).157
Although inhibition of the hypotensive effect of guanabenz in patients receiving concomitant tricyclic antidepressants has not been reported,59, 60 tricyclic antidepressants (i.e., imipramine, desipramine) have reportedly inhibited the hypotensive effect of clonidine.59, 60, 61 The increase in blood pressure usually occurs during the second week of tricyclic antidepressant therapy, but occasionally may occur during the first several days of concomitant therapy.60 The possibility of this interaction should be considered in patients receiving guanabenz and tricyclic antidepressants concomitantly; blood pressure should be closely monitored during the first several weeks of concurrent therapy, and dosage of guanabenz should be increased to adequately control hypertension if necessary.59, 60 Alternatively, other hypotensive agents that do not interact with tricyclic antidepressants may be substituted, but guanabenz therapy should not be discontinued abruptly.60
When guanabenz is administered with other hypotensive agents, including diuretics,1, 3, 17, 27, 28, 33, 34, 35, 36, 42, 68, 85, 100, 116 the hypotensive effect of guanabenz may be increased.17 This effect is usually used to therapeutic advantage in antihypertensive therapy;6, 17 however, careful adjustment of dosage is necessary when these drugs are used concomitantly.6
Guanabenz, administered concurrently with antidiabetic agents (e.g., insulin, chlorpropramide), does not appear to interfere with the control of blood glucose concentration.103
Limited information is available on the acute toxicity of guanabenz.1, 12
The oral LD50 of guanabenz has been reported to be 150 and 126 mg (of guanabenz) per kg in mice and rats, respectively.11, 157 Overdosage of guanabenz has occurred in several children and adults following ingestion of 28-480 and 160-320 mg, respectively, of the drug.12
Signs and symptoms of guanabenz overdosage are similar to those following clonidine overdosage.12, 157 Overdosage of guanabenz produces signs and symptoms that are mainly extensions of the usual pharmacologic and common adverse effects of the drug,8, 157 including hypotension, respiratory depression, bradycardia, drowsiness, lethargy, irritability, miosis, and coma.1, 12 Other effects occurring following overdosage of centrally active α2-adrenergic agonists include tachycardia, hypertension, hypotonia, hypothermia, pallor, and arrhythmias (e.g., cardiac conduction defects).12, 13
In acute guanabenz overdosage, the stomach should be emptied immediately by inducing emesis or by lavage followed by administration of an activated charcoal slurry and a saline cathartic.12, 13, 157 Gastric lavage, rather than emesis, is preferred in patients who are sedate and drowsy since coma can develop rapidly.13, 157 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.14 Supportive and symptomatic treatment should be initiated and an adequate airway established and maintained, using assisted respiration as necessary.1 Clinical monitoring of vital signs and fluid balance should also be initiated.1 Hypotension can initially be managed with IV fluids.12, 13, 157 IV infusion of dopamine may be useful for severe, persistent hypotension,12, 13, 157 and atropine may be useful for bradycardia.12 Although tolazoline has been used with some success to reverse the effects of clonidine overdosage,12, 13 use of tolazoline in guanabenz overdosage has not been studied157 and additional information on the efficacy of α-adrenergic blockers in the treatment of guanabenz overdosage is necessary.13, 157IV naloxone has been administered in several patients following clonidine or guanabenz overdosage,12, 141, 142, 143, 144, 145 but often has had little, if any, effect in reversing signs and symptoms of intoxication; additional study on the potential benefit of naloxone therapy in the treatment of acute toxicity with these drugs is necessary.12, 141, 142, 143
The manufacturer states that a complete and uneventful recovery occurred within 12 hours after treatment of acute guanabenz overdosage in several children 1-3 years of a treatment included gastric lavage and administration of an activated charcoal slurry, vasopressors, and fluids.1
Information on removal of guanabenz by peritoneal dialysis and/or hemodialysis is currently not available.1, 157
Like clonidine, guanabenz appears to stimulate α2-adrenergic receptors in the CNS,1, 3, 8, 9, 16, 26, 46, 73, 74, 79, 81, 82, 87, 88, 107, 108, 111, 115, 140, 153, 154, 161causing inhibition of basal or resting sympathetic nervous system activity1, 3, 4, 8, 9, 16, 72, 73, 74, 83, 108, 111, 115, 154, 161 and decreased sympathetic outflow from the CNS.1, 6, 8, 17, 72, 73, 74, 83, 108, 111, 115, 154 The affinity of guanabenz for the α2-adrenergic receptor is greater than that for the α1-adrenergic receptor.107, 109, 157 The central effects of the drug in the lower brain stem result in reduced peripheral sympathetic activity1, 8, 89, 111, 115, 140 and a reduction in systolic and diastolic blood pressure.3, 17, 33, 35, 36, 44, 46, 67, 68, 71, 115, 140, 153, 154 Following IV or oral administration of guanabenz in animals, an initial hypertensive response to the drug occurs and is caused by direct peripheral α2-adrenergic stimulated vasoconstriction;8, 17, 73, 74, 83, 140 however, oral guanabenz usually does not produce an initial increase in blood pressure in hypertensive patients.8 Guanabenz-induced bradycardia appears to result principally from central α2-agonist effects,1, 3, 6, 8, 28, 31, 32, 33, 36, 39, 41, 42, 45, 46, 47, 69, 89, 100, 104, 106, 125, 140, 154, 161 although a peripheral α2-agonist effect on the heart may also be involved.154, 161 In animals, guanabenz-induced bradycardia results from inhibition of sympathetic nervous system activity and activation of cholinergic nervous system activity.80 Although guanabenz is not a true adrenergic blocking agent,8, 17 the drug produces some postganglionic α- (similar to guanethidine)36, 72, 75, 76, 83, 109 and β-adrenergic blockade9 and decreases the response to peripheral sympathetic nerve stimulation in animals.17, 76 Cardiac output,1, 8, 16, 17, 39, 67, 114 left ventricular ejection fraction,1, 8, 16, 17, 39, 67 and left ventricular stroke volume8, 16, 17, 39 remain unchanged during long-term therapy with the drug.
Guanabenz generally reduces blood pressure to essentially the same extent in both supine and standing patients;1, 17, 36, 37, 43, 46, 100, 103, 125, 127 however, in some studies, guanabenz was slightly more effective in lowering blood pressure when patients were standing than when they were supine.3, 11, 27, 28, 33, 34, 39, 42, 44, 45, 47, 67 Orthostatic effects are mild and infrequently encountered.3, 17, 29, 30, 40, 46 Other hemodynamic effects of guanabenz may differ with position of the patient.82 Administration of a single dose of guanabenz to supine patients substantially reduced blood pressure (systolic and diastolic), heart rate, and plasma norepinephrine concentrations; in the standing position, blood pressure (systolic and diastolic) decreased substantially but heart rate and plasma norepinephrine concentrations were essentially unchanged compared with baseline.82 Exercise does not appear to affect the blood pressure response to guanabenz in hypertensive patients.107 Total peripheral resistance remains essentially unchanged during short-term guanabenz therapy;1 however, long-term therapy with the drug results in a decrease in total peripheral resistance.1, 8, 17, 89 Effective guanabenz therapy has been associated with decreased left ventricular mass.105, 114 Tolerance to the hypotensive effect of guanabenz has not been reported.1
Fluid volume does not appear to be affected substantially by guanabenz;1, 34, 71 mean plasma and mean whole blood volume are slightly increased during long-term therapy with the drug.8 In patients with hypertension controlled by guanabenz, slight weight loss (0.5-1.8 kg),1, 8, 28, 31, 32, 33, 36, 45, 46, 69, 104 possibly resulting from fluid loss,4occurs; however, the mechanism of this weight loss has not been fully determined.1, 44
Endocrine and Metabolic Effects
Unlike clonidine,121, 122 guanabenz does not appear to affect serum concentrations of growth hormone, prolactin, insulin, or glucagon at usual dosages (i.e., 8-64 mg daily).112
Plasma norepinephrine1, 4, 17, 34, 58, 89 and epinephrine4, 17, 58 and serum dopamine β-monooxygenase (β-hydroxylase) concentrations are reduced during long-term guanabenz therapy; however, decreases in plasma catecholamine concentrations appear to be highest in those patients whose baseline catecholamine concentrations are highest.1, 4 The increase in systolic and diastolic blood pressure and other signs and symptoms associated with abrupt withdrawal of guanabenz1, 4, 17, 30, 34, 48, 51, 52, 53, 54, 55, 56, 58, 71, 135 may result from sympathetic overactivity following discontinuance of the drug.48, 49, 51, 54, 55, 57, 135 (See Cautions: Withdrawal Effects.)
Serum electrolyte,1, 8, 34, 46, 71 creatinine,34, 71, 103 and calcium concentrations1, 46 and BUN1, 34, 46, 71, 103 are unchanged by administration of guanabenz.1 Although the manufacturer and some clinicians state that fasting and random blood glucose1, 103 and serum uric acid1concentrations are unchanged by administration of guanabenz, increases in fasting blood glucose34 and decreases in serum uric acid concentrations34, 127 have occurred during therapy with the drug. (See Cautions: Other Adverse Effects.)
Guanabenz has reportedly produced a 10-20% decrease in total serum cholesterol concentrations in some patients during long-term therapy with the drug;1, 8, 17, 31, 32, 35, 36, 42, 46, 69, 100, 102, 103, 106 decreases in total serum cholesterol concentrations were greatest in those patients with higher baseline values.102, 127 The low-density lipoprotein (LDL) fraction appears to be principally affected by guanabenz therapy;102 the high-density (HDL)1, 8, 102, 106 and very low-density (VLDL)102 lipoprotein fractions appear to be unaffected by the drug. Guanabenz also has reportedly produced a small decrease in total triglycerides in some patients during long-term therapy with the drug.1, 8, 106 The effects of guanabenz on serum lipid concentrations may result from the drug's actions on hepatic cholesterol and triglyceride biosynthesis; in animals, guanabenz appears to inhibit hepatic cholesterol synthesis during the synthesis of mevalonic acid and after incorporation of this acid in the sterol pathway.101Guanabenz also appears to inhibit triglyceride synthesis by increasing the oxidation of palmitate to CO2 and by decreasing the esterification of palmitate to triglycerides.101
Guanabenz-induced diuresis has been reported in animals secondary to inhibition of vasopressin (antidiuretic hormone) via stimulation of α2-adrenergic receptors.8, 78, 79, 87 The initial renal effects of guanabenz8, 17, 92, 111, 158, 159 may differ from those following chronic administration of the drug.1, 8, 16, 17, 34, 46, 71, 88, 90, 91, 92, 108, 111, 114, 158, 159 Single doses of guanabenz cause decreases in effective renal plasma flow,8, 17, 71, 92, 158, 159 glomerular filtration rate,8, 17, 92, 158, 159 urine volume,1, 8, 92 free water clearance,8, 17, 92, 111, 158, 159 and sodium excretion.1, 8, 17, 92, 111, 158, 159 In patients with hypertension controlled by chronic guanabenz therapy, the drug generally does not substantially change renal blood flow,1, 114 effective renal plasma flow,16, 71, 88, 92, 111, 158 creatinine clearance,34, 71 glomerular filtration rate,1, 8, 16, 88, 90, 111, 114 renal vascular resistance,71, 158, 159 urine flow,92 free water clearance,92 or renal concentrating ability;1 however, renal blood flow,71 glomerular filtration,71, 92, 158, 159 and renal vascular resistance114 may decrease and urine flow71, 114, 158, 159 and free water clearance may increase.71, 158 These changes generally return to pretreatment values within 2 weeks after discontinuance of the drug.71, 158, 159 Urine osmolality may be reduced.71, 90, 158 Short-term (4 weeks) guanabenz therapy may produce a slight increase in potassium excretion.8 Sodium1, 4, 8, 16, 17, 46, 71, 90, 91, 92, 108, 158, 159 and potassium excretion1, 26, 71, 90, 159 do not appear to be substantially changed during long-term guanabenz therapy. In animals, the drug has decreased reabsorption of chloride in the papillary collecting duct.110
Plasma renin activity may be unchanged8, 27, 34, 45, 158, 159 or reduced1, 16, 58, 84, 91, 108 during long-term therapy with the drug. Plasma aldosterone may also be reduced during long-term therapy.84, 91, 108 Long-term therapy with guanabenz administered in combination with hydrochlorothiazide enhances renal perfusion, as shown by decreases in mean arterial pressure and renal vascular resistance and increases in renal plasma flow, renal blood flow, plasma renin activity, and urinary kallikrein excretion;85, 86 glomerular filtration rate and blood volume are unchanged.85, 86
The sedative effect of guanabenz is thought to result from central α2-agonist activity.140, 154 As with clonidine, dry mouth induced by guanabenz may result from both central and peripheral mechanisms, probably involving the drug's α2-agonist activity.140, 154, 155, 156 The peripheral mechanism of decreased salivation may involve inhibition of cholinergic transmission via stimulation of α2-adrenergic receptors.155, 156
Guanabenz,93 like clonidine,93, 146, 147, 148 has been shown to decrease GI motility and control diarrhea in animals, probably secondary to the drugs' α2-agonist activity.93, 146, 148α2-adrenergic agonists have also been shown to increase intestinal absorption of sodium and chloride, with a secondary passive increase in water absorption,149, 150 and the drugs (e.g., clonidine) have been used in a limited number of patients for the management of diarrhea† of various etiologies.93, 150, 151, 152
Like clonidine, IM administration of guanabenz in rabbits in doses exceeding those used in humans decreases intraocular pressure and increases glucose concentration in the lens and aqueous and vitreous humors.94 Guanabenz also produces dose-dependent mydriasis in cats.74 However, it is not currently known whether guanabenz has similar pharmacological effects in humans.157
In vitro, guanabenz enhances ADP-induced human platelet aggregation;95, 129 the drug also antagonizes epinephrine-induced inhibition of adenylate cyclase activity in human platelets and inhibits epinephrine-induced platelet aggregation.9, 95, 129
Guanabenz has been shown to reduce the signs and symptoms of opiate withdrawal in individuals physically dependent on opiates.65, 70 Guanabenz, like clonidine, appears to reduce the severity of opiate withdrawal symptoms by stimulating central presynaptic α2-adrenergic receptors; the stimulation results in attenuation of rebound increases in noradrenergic activity in the CNS, which may be responsible for the behavioral symptoms of opiate withdrawal.65, 70, 96, 97, 98, 99 Psychologic and/or physical dependence or addiction potential have not been associated with guanabenz administration.1
In all studies described in the Pharmacokinetics section, guanabenz was administered as the acetate salt; however, dosages and concentrations of the drug are expressed in terms of guanabenz.
Following oral administration, at least 70-80% of a dose of guanabenz acetate is absorbed.1, 15 The absolute bioavailability of guanabenz acetate in humans has not been determined;17 however, pharmacokinetic studies in animals and in humans suggest that the drug undergoes extensive first-pass metabolism.16, 17, 117 The effect of food on the absorption of guanabenz acetate has not been determined.1, 17 Following oral administration of the drug in fasting individuals, peak plasma guanabenz concentrations usually occur within 2-5 hours.1, 8, 15, 116, 117 Following a single 16-mg oral dose, peak plasma guanabenz concentrations average 2.4-2.7 ng/mL (range: 1.2-5.2 ng/mL) in fasting healthy individuals15, 116, 117 and 7.8 ng/mL (range: 3-16 ng/mL) in fasting individuals with hepatic impairment (chronic alcohol-induced liver disease).117 Although the clinical importance of these higher plasma concentrations in patients with hepatic impairment has not been determined,1 such alterations in these patients may result from enhanced oral bioavailability (secondary to portosystemic shunting and/or decreased intrinsic clearance) and decreased hepatic clearance of guanabenz.117
The hypotensive effect of guanabenz acetate begins within 1 hour after oral administration1, 8, 113 and peaks within 2-7 hours.1, 8, 113 The duration of hypotensive effect is variable; the manufacturer states that the hypotensive effect is substantially diminished within 6-8 hours and that blood pressure returns to baseline values within 12 hours;1, 8 however, the hypotensive effect of a single dose can persist for 12 or more hours.113 A direct relationship between plasma guanabenz concentrations and hypotensive effect has not been established;17 however, several studies have suggested a direct dose-response relationship.43, 44, 113 Following IV administration of the drug in rats, concentrations of guanabenz in the brain are correlated with the hypotensive effect, consistent with the drug's central mechanism of action.19
Information on the distribution of guanabenz is limited.17 Following IV administration in rats, guanabenz is rapidly and extensively distributed into the CNS; brain concentrations of the drug are 3-70 times higher than concurrent plasma concentrations.19 In humans, guanabenz appears to be extensively distributed.8, 15, 16 The apparent steady-state volume of distribution of guanabenz averages approximately 93 and 147 L/kg after 16- and 32-mg oral doses, respectively.15 The apparent volume of distribution of guanabenz appears to be substantially decreased in patients with hepatic impairment.117
Guanabenz is approximately 90% bound to plasma proteins.8, 15, 17, 117 Protein binding of the drug is very slightly decreased in patients with hepatic impairment.117
It is not known whether guanabenz is distributed into milk1 or crosses the placenta in humans.157
The elimination half-life of guanabenz following single oral doses of the drug in healthy adults has been variably reported to average 4-14 hours (range: 3.5-21 hours);1, 8, 15, 116, 117 In one well-designed study, the elimination half-life averaged 12-14 hours.115, 157 In patients with hepatic impairment, the half-life of the drug is only slightly prolonged.117 The elimination half-life of guanabenz also may be prolonged in patients with renal impairment.1
Guanabenz is extensively metabolized.1, 15 The site(s) of guanabenz metabolism has not been determined,1 but the drug probably undergoes extensive first-pass metabolism.16, 17, 117 Guanabenz is metabolized principally by hydroxylation to form ( E )- p -hydroxyguanabenz (4-hydroxyguanabenz), which is largely conjugated with glucuronic acid.15, 21 A small fraction of guanabenz is cleaved at the benzal carbon to form 2,6-dichlorobenzyl alcohol, which is apparently completely conjugated.15, 77 A small fraction of guanabenz also apparently undergoes N -glucuronidation.15 Other minor metabolites include ( Z )-guanabenz10, 15, 20 and possibly ( Z )- p -hydroxyguanabenz ( Z -isomer of 4-hydroxyguanabenz);15, 20 these metabolites are apparently almost completely conjugated.15 Numerous other, unidentified metabolites are also formed.15 The ( Z )-isomer of guanabenz appears to have about 25% of the hypotensive activity of the unchanged drug following oral administration.15 Animal studies indicate that ( E )- p -hydroxyguanabenz is inactive following oral administration15, 17 but produces a slight hypotensive effect following intraperitoneal administration of large doses.15 Other metabolites of guanabenz are inactive.77
Guanabenz and its metabolites are excreted principally in urine.15, 16 Approximately 70-80% of an oral dose of guanabenz is excreted in urine within 72 hours, principally within the first 24 hours, and about 10-30% of the dose is excreted in feces within 6 days in healthy individuals.15 About 10% of an oral dose of guanabenz is excreted in urine as ( E )- p -hydroxyguanabenz, 25% as the glucuronide conjugate of ( E )- p -hydroxyguanabenz, 1% as unchanged guanabenz, 5% as guanabenz conjugates, 1% as ( Z )-guanabenz, 1% as ( Z )-guanabenz conjugates, less than 1% possibly as ( Z )- p -hydroxyguanabenz, 2% as ( Z )- p -hydroxyguanabenz conjugates, 2% as 2,6-dichlorobenzyl alcohol conjugates, and the remainder as unidentified metabolites and their conjugates.15
Total plasma clearance reportedly averages 6 and 10.8 L/hour per kg following oral administration of single 16- and 32-mg doses of guanabenz, respectively; renal clearance is about 1% of total plasma clearance.15 Total plasma clearance of guanabenz is substantially decreased in patients with hepatic impairment.117 Total plasma clearance of the drug may be decreased in patients with renal impairment.1 It is not known whether the drug is removed by hemodialysis or peritoneal dialysis.1, 157
Guanabenz acetate is a centrally active hypotensive agent1, 3, 4, 6, 17, 18, 25, 27, 28, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 67, 68, 69, 71, 100, 103, 104, 105, 106, 115, 125, 127 that is structurally and pharmacologically related to clonidine.4, 8, 17, 61 Guanabenz is a dichlorobenzene derivative1, 4, 10 that differs structurally from clonidine by the presence of an aminoguanidine side chain rather than an imidazoline ring linked by an amino group.4, 5
Guanabenz acetate occurs as a white to almost white powder with not more than a slight odor and has solubilities of 11 and 50 mg/mL in water and in alcohol, respectively, at 25°C.1, 8, 157 The drug has a pKa of 8.1.9 Potency of guanabenz acetate powder is expressed in terms of the acetate while potency of the tablets is expressed in terms of guanabenz.2 Solutions of guanabenz acetate have a pH of 5.5-7.2 Commercially available tablets of the drug also contain cellulose, ferric oxide, lactose, and magnesium stearate.1
Guanabenz acetate tablets should be stored in tight, light-resistant containers1, 2, 8 at room temperature (25°C).157
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 4 mg (of guanabenz)* | Guanabenz Acetate Tablets | |
8 mg (of guanabenz)* | Guanabenz Acetate Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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