Mechanism of Action
Central sympatholytics (e.g., methyldopa, guanabenz, guanfacine, clonidine, moxonidine, and rilmenidine) have a variety of antihypertensive actions that result in increased sodium excretion and decreases in the cardiac output, heart rate, total peripheral resistance, and renin release. Central sympatholytics cross the blood-brain barrier and stimulate the imidazoline 1 (I 1 ) receptors and/or central postsynaptic alpha 2 (α 2 ) adrenoceptors in the brainstem’s sympathetic nervous control centers, the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarii (NTS). As shown in Fig. 26.1 , the various central sympatholytics have differing affinities for these two types of receptors. Moxonidine and rilmenidine selectively stimulate the I 1 -imidazoline receptors. Methyldopa, guanabenz, and guanfacine selectively stimulate α 2 -adrenoceptors more than the I 1 -imidazoline receptors, and clonidine nonselectively stimulates both α 2 -adrenoceptors and I 1 -imidazoline receptors.
Treatment with one of the central sympatholytics that stimulate α 2 -adrenoceptors (e.g., methyldopa, clonidine, guanabenz, and guanfacine) is frequently accompanied by adverse effects such as dry mouth, decreased alertness, sedation, and depression. This is because α 2 -adrenoceptors are present not only in the RVLM but also in the NTS, nucleus coeruleus, and salivary grands. Treatment with a central sympatholytic that selectively stimulates only I 1 -imidazoline receptors (e.g., rilmenidine or moxonidine) results in central adverse effects much less frequently, because the I 1 -imidazoline receptors are located almost exclusively in the RVLM.
Perhaps the oldest agent (founded in the 1930s in India) that affects the sympathetic nervous system is reserpine. In contrast, the adrenergic uptake inhibitor reserpine depletes catecholamine storage in both the central and peripheral nervous systems and is associated with many dose-dependent side effects. It is no longer available in the United States.
Hemodynamic Effects
Stimulating the brainstem’s central I 1 -imidazoline receptors or α 2 -adrenoceptors results in several hemodynamic, neurohumoral, and adverse effects, because the stimulation directly inhibits the sympathetic outflow to the heart and blood vessels ( Box 26.1 ). For the main pharmacodynamic effect of compounds in this class to occur, the drugs must pass the blood-brain barrier. As such, there is an implicit time lag between the plasma drug concentration that is achieved and the antihypertensive effect.
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Reduction of sympathetic nervous activity reflected in lower norepinephrine
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Decrease in peripheral resistance and cardiac output at rest and during exercise
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Reduced baroreflex to compensate for a decrease in blood pressure (BP), resulting in relative bradycardia with exaggerated hypotension on standing
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Decreased plasma levels of renin, angiotensin II, and aldosterone
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Preserved renal blood flow and glomerular filtration despite BP reduction
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Increase in fluid retention
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Frequent adverse effects such as sedation, depression, decreased alertness, dry mouth
The blood pressure (BP)-lowering effect of the central sympatholytics is based on the following: a reduction in norepinephrine; decreased peripheral resistance and decreased cardiac output at rest and during exercise; reduced baroreflex to compensate for the decrease in BP, resulting in relative bradycardia with exaggerated hypotension on standing; decreased plasma levels of aldosterone, angiotensin II, and renin; and preserved glomerular filtration and renal blood flow despite the reduction in BP. However, central sympatholytics often cause fluid retention as overcompensation, and this limits their effectiveness.
Clinical Application
The significant overall effectiveness in reducing BP is a major advantage of the central sympatholytics. They are also useful for treating labile hypertensive patients with associated anxiety, especially when the anxiety is manifested by sympathetic hyperactivity. However, central sympatholytics are currently used less frequently because of their adverse effects, which can be significant. The centrally acting effects of the central sympatholytics(such as depression and sedation)are of particular concern.
Central sympatholytics are also not recommended for use as first-line or second-line monotherapy because they are often less effective in this role and have not been shown in clinical trials to reduce mortality. Moreover, most are associated with a dose-dependent rebound hypertension when abruptly stopped. A combination of a central sympatholytic with a thiazide-type diuretic is often used to manage resistant hypertension and occasionally hypertension in pregnant women, if beta-blockers are contraindicated. In resistant hypertension, these agents are added when combinations of three or more other antihypertensive drugs such as a calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or diuretic have failed to control blood pressure.
Central sympatholytics can be used safely in individuals with diabetes, with no significant loss of glycemic control. They can also be used safely for individuals with pulmonary diseases such as asthma. Intravenous preparations are available only in certain countries for clonidine and α-methyldopa, and clonidine is the only compound in this class that can be administered via a transdermal delivery system.
The central sympatholytics’ quick onset and long duration of action distinguish these drugs. The most rapid onset of action is seen in clonidine, at 30 to 60 minutes.
Adverse Effects
The most common adverse effects of the central sympatholytics that stimulate α 2 -adrenoceptors are sedation and dry mouth (40%), and these effects are the main reason that the use of central sympatholytics has declined. In addition, the sedative effects of drugs within this class are enhanced by other central nervous system (CNS) depressants such as antihistamines, benzodiazepines, sedative-hypnotics, and ethanol. The central sympatholytics that stimulate I 1 -imidazoline receptors do not cause as much sedation and dry mouth, and they are better tolerated by most patients. Dry mouth can be annoying, and the decreased level of saliva can increase an individual’s risk of dental caries and periodontal disease ( Table 26.1 ).
| Drug | Preparation | Pharmacodynamics | Daily Dosage | Adverse Effects | Contraindications |
|---|---|---|---|---|---|
| Clonidine: Oral | 0.1 mg 0.2 mg 0.3 mg | Onset: 0.5-1 hour Peak: 3-5 hours Plasma half-life: 12-16 hours Metabolism: liver | Initial: 0.1 mg Range: 0.2-1.2 mg Max.: 1.2 mg usually bid | Sedation, drowsiness, dry mouth, withdrawal syndrome, rebound hypertension (uncommon with doses <1.2 mg qd), headache, bradycardia, orthostatic hypotension, impotence (uncommon; 4%) | Sick sinus syndrome 2nd- and 3rd-degree atrioventricular block |
| Transdermal | 1 (containing 2.5 mg) 2 (containing 5.0 mg) 3 (containing 7.5 mg) | Duration of BP lowering: 1 week | 1, 2, 3 once weekly | ||
| Methyldopa | 125 mg 250 mg 500 mg | Onset: 2-3 hours Peak: 5 hours Plasma half-life: 12 hours Metabolism: renal | Avg.: 250-300 mg bid Max.: 3000 mg | Sedation, drowsiness, depression, dry mouth, positive Coombs test and anemia, lupuslike syndrome, withdrawal syndrome, rebound hypertension | Active hepatic disease |
| Guanabenz | 4 mg 8 mg | Onset: 1 hour Peak: 4 hours Plasma half-life 6 hours Metabolism: 75% Excretion: renal 80% | Average 16 mg Range 8-48 mg Maximum 48 mg | Sedation, drowsiness, dry mouth, withdrawal syndrome, rebound hypertension, impotence | Pregnancy |
| Guanfacine | 1 mg 2 mg | Onset: 1 hour Peak: 4 hours Plasma half-life: 12 hours Excretion: renal | 1 mg at bedtime Maximum 3 mg | Same as clonidine | Allergy to guanfacine |
The Central Sympatholytics
The pharmacodynamics, available preparations, daily dosages, contraindications, and adverse effects of the various central sympatholytics are listed in Table 26.1 .
Clonidine
Clonidine, the most widely used central sympatholytic. The onset of action for oral clonidine is 30 to 60 minutes, which is advantageous for hypertensive urgencies. For primary hypertension, clonidine is recommended for use as the fourth or fifth line of therapy. Menopause-associated vasomotor syndrome symptoms such as hot flushes, and sympathetic hyperactivity-related hypertension with restless legs syndrome have all been treated successfully with clonidine. Clonidine has also been shown to be more effective in whites than in African Americans, and in older than in younger African Americans. However, in a blinded, randomized trial with a 2-by-2 factorial design study, it was shown that low-dose clonidine (0.2 mg per day) did not reduce the rate of the composite outcome (death or nonfatal myocardial infarction) and increase the risk of clinically important hypotension and nonfatal cardiac arrest in patients undergoing noncardiac surgery.
Antihypertensive Effects
Clonidine is easily absorbed. The plasma levels of clonidine peak within 30 to 60 minutes after its oral administration, and its plasma half-life is 6 to 13 hours. The BP reduction peaks at 3 to 5 hours, and the BP-lowering effect lasts 8 to 12 hours. Oral clonidine preparations include 0.1-, 0.2-, and 0.3-mg dosages. Clonidine treatment is often initiated at 0.1 mg 2× per day and then gradually increased to a maximum dose of 2.4 mg per day.
Transdermal (patch) clonidine is particularly effective for treating labile hypertensive patients who need multiple medications, those who cannot take oral medications, and those with prominent early morning BP surges. Transdermal clonidine is available in three preparations: 2.5, 5.0, and 7.5 mg. The best absorption from a clonidine patch is obtained by placing the patch on the chest or upper arm. An optimal transdermal delivery system provides a constant clonidine dose for 7 days, and the peak effect is reached within days 1 to 2 days. The BP-lowering effect of transdermal clonidine lasts 8 to 24 hours after the patch is removed. However, compared with oral clonidine, at equivalent doses transdermal clonidine treatment is more likely to result in a dose-dependent retention of both water and salt.
Adverse Effects
Dry mouth and sedation, the most frequent adverse effects of clonidine treatment, are more common with clonidine than methyldopa, but clonidine does not present a risk of autoimmune hepatic damage as methyldopa does. Other potential adverse effects of clonidine are headache, impotence, and orthostatic hypotension. Known contraindications for clonidine are sick sinus syndrome and second-degree and third-degree atrioventricular (AV) block, because clonidine’s depression of sinus and atrioventricular nodal function may result in bradycardia.
Clonidine treatment is also subject to the risk of the occurrence of rebound syndrome and discontinuation syndrome. When treatment with any antihypertensive drug is abruptly stopped, the discontinuation syndrome may occur at different degrees of severity as follows: a rapid but asymptomatic return of the BP to the patient’s pretreatment level, a rebound of the BP with sympathetic hyperactivity symptoms, and the patient’s BP overshoots the pretreatment level. The central sympatholytic most frequently cited as resulting in discontinuation syndrome is clonidine (especially at ≥ 1.0 mg), caused by the rapid return of the catecholamine level, which is suppressed by clonidine treatment. Discontinuation syndrome is exacerbated in the presence of a β-blockade, but not in the presence of the α/β adrenergic antagonist labetalol or carvedilol. If discontinuation syndrome is detected in a patient who was treated with clonidine, the clonidine should be restarted, and the symptoms can be expected to quickly resolve.
Rebound hypertension may occur with clonidine transdermal treatment, but it is observed much less frequently than after clonidine oral administration. Skin hypersensitivity (e.g., allergic dermatitis) in response to a clonidine patch occurs in up to 20% of patients, most commonly in white and female patients.
Methyldopa
Methyldopa is used mainly to treat hypertension in pregnant women. It is not teratogenic and has been shown to produce no fetal adverse effects in utero. Methyldopa treatment maintains uterine perfusion and does not hinder the maternal cardiac output or renal or uterine blood flow. As the α-methylated derivative of dopa (the natural precursor of dopamine and norepinephrine), methyldopa is a suitable alternative to clonidine for patients for whom rebound hypertension or intolerable adverse effects preclude the use of clonidine.
Methyldopa is often used for hypertensive emergencies. It is available as an intravenous formulation (as the parent drug ester) at the typical intravenous dose range (for α-methyldopa) 20 to 40 mg per kg per day in divided doses every 6 hours.
Antihypertensive Effect
A relatively slow onset of action is a feature of methyldopa treatment, and the BP-lowering effect starts approximately 2 to 3 hours after dosing (cf. clonidine’s onset at 0.5 to 1.0 hour). At approximately 5 hours after an oral dose of methyldopa, the patient’s BP reaches its lowest point, and the effect persists for up to 24 hours. The commonly used initial dose of methyldopa is 250 mg 2× per day, titrated up to 3.0 g at most. In patients with renal insufficiency, this methyldopa dose should be halved.
Methyldopa also effectively reduces supine BP without producing orthostatic hypotension.
Adverse Effects
Methyldopa’s adverse effects include sedation and drowsiness, dry mouth, depression, postural hypotension, fluid retention, rebound hypertension, withdrawal syndrome, and various autoimmune reactions including flulike high fever, hepatitis, Coombs-positive hemolytic anemia, and lupuslike syndrome. Between 10% and 20% of patients who are treated with α-methyldopa (≥1 g/d) over a period of several months develop one or more of these adverse events. Occasionally, methyldopa treatment has resulted in drug-induced hepatitis with fever, eosinophilia, and increased transaminase values, but this is a self-limited process that resolves with discontinuation of the methyldopa. It is not necessary to stop methyldopa treatment in asymptomatic patients who become Coombs-positive but do not develop hemolytic anemia.
Guanabenz
The direct central α 2 -agonist guanabenz acts in the same manner as methyldopa and has similar adverse effects, but it has the advantage of not causing reactive fluid retention. Compared with clonidine, guanabenz treatment is less effective, but it results in rebound hypertension and orthostatic hypotension less frequently. The efficacy of guanabenz in reducing left ventricular hypertrophy in hypertensive patients and in attenuating morning hypertension when administered at nighttime has also been demonstrated.
Antihypertensive Effect
Guanabenz has a 1-hour onset of antihypertensive action. The most commonly used initial dose of guanabenz is 4 mg 2× per day, titrated to a maximum of 64 mg daily. It is eliminated predominantly via hepatic biotransformation. Thus, unlike clonidine, guanabenz dose adjustment is not required in patients with renal failure but is required in those with chronic liver diseases.
Guanabenz has also been shown to reduce total cholesterol levels by 10% to 20%.
Adverse Effects
The potential adverse effects of guanabenz include dry mouth, sedation, drowsiness, and impotence. Guanabenz treatment may also be followed by withdrawal syndrome and rebound hypertension. The adverse effects of guanabenz are essentially the same as those of clonidine.
Guanfacine
Unlike the other members of the class of central sympatholytics, the 17-hour duration of guanfacine’s action typically allows it to be dosed once daily. It is thought that compared with guanabenz, guanfacine enters the brain more slowly; its antihypertensive effect lasts longer than that of guanabenz. Evening dosing is preferable for guanfacine because its peak effect can be aligned with early-morning catecholamine and BP surges, and the potential sedating effect of guanfacine can play out during sleep. As with other central sympatholytics, the optimal effect of guanfacine can be achieved when it is coadministered with a low-dose diuretic, providing a BP-lowering effect with minimum CNS adverse effects. Patients who are intolerant to clonidine because of it strong sedation effect may benefit from treatment with guanfacine as an alternative.
Adverse Effects
Compared with clonidine, guanfacine has fewer CNS adverse effects and is much less likely to have withdrawal symptoms. The risk of adverse effects from guanfacine treatment increase significantly when doses greater than1 mg daily are administered.
Imidazoline Receptor Agonists
The imidazoline receptor agonists rilmenidine and moxonidine act on the RVLM’s imidazoline receptors. The α 2 -adrenergic receptors are less abundant in the RVLM. Moxonidine and rilmenidine effectively suppress sympathetic nervous activity without causing the adverse reactions observed with clonidine or methyldopa treatment such as sedation and dry mouth. In addition, the rebound syndrome caused by clonidine discontinuation has not been observed in cases of moxonidine or rilmenidine treatment.
Moxonidine
Moxonidine therapy effectively reduces BP although it does not reduce the heart rate as clonidine treatment can. Moxonidine’s plasma half-life is only 2 to 3 hours, and its extended duration of action suggests prolonged binding to central I 1 -imidazoline receptors. The dose of moxonidine must be adjusted according to the patient’s glomerular filtration rate (GFR), because moxonidine is extensively cleared by the kidneys.
For example, for patients with moderate renal impairment (i.e., a GFR 30 to 60 mL/min), single-dose moxonidine should not exceed 0.2 mg, and the daily dose should not go beyond 0.4 mg. For patients with severe renal impairment (i.e., a GFR < 30 mL/min), moxonidine should not be used. The same is true of patients with advanced heart failure; in a large cohort of New York Heart Association class II–IV heart failure patients with reduced ejection fraction, a sustained-release form of moxonidine that was force-titrated to 1.5 mg 2× per day was observed to be associated with early increases in morbidity and mortality.
Rilmenidine
For mild-to-moderate hypertension, oral rilmenidine (1 to 2 mg per day) is effective and well-tolerated, alone or in combination with another antihypertensive medication. The most favorable ratio of efficacy to tolerability has been observed with a 1-mg daily dose. Parasympathetic tone is increased by rilmenidine, which may account for its lack of an effect on the heart rate as it works to reduce BP.
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