The root of R serpentina (snakeroot), the natural source of the alkaloid reserpine, has been a Hindu Ayurvedic remedy since ancient times. In 1931, Indian literature first described the use of R serpentina root for the treatment of hypertension and psychoses; however, the use of Rauwolfia alkaloids in Western medicine did not begin until the mid1940s. Both standardized whole root preparations of R serpentina and its reserpine alkaloid are officially monographed in the United States Pharmacopeia. A powdered whole root of 200 to 300 mg orally is equivalent to 0.5 mg of reserpine.
Reserpine was one of the first drugs used on a large scale to treat systemic hypertension. It acts by irreversibly blocking the uptake of biogenic amines (norepinephrine, dopamine, and serotonin) in the storage vesicles of central and peripheral adrenergic neurons, thus leaving the catecholamines to be destroyed by the intraneuronal monoamine oxidase in the cytoplasm. The depletion of catecholamines accounts for reserpine's sympatholytic and antihypertensive actions. Reserpine's effects are long lasting, since recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks. Reserpine lowers blood pressure by decreasing cardiac output, peripheral vascular resistance, heart rate, and renin secretion. With the introduction of other antihypertensive drugs with fewer central nervous system adverse effects, the use of reserpine has diminished. The daily oral dose of reserpine should be 0.25 mg or less, and as little as 0.05 mg if given with a diuretic. Using the whole root, the usual adult dose is 50 to 200 mg/d administered once daily or in 2 divided doses.
Rauwolfia alkaloids are contraindicated for use in patients with previously demonstrated hypersensitivity to these substances, in patients with a history of mental depression (especially with suicidal tendencies), in patients with active peptic ulcer disease or ulcerative colitis, and in patients receiving electroconvulsive therapy. The most common adverse effects are sedation and inability to concentrate and perform complex tasks. Reserpine may cause mental depression, sometimes resulting in suicide, and its use must be discontinued at the first sign of depression. Reserpine's sympatholytic effect and its enhancement of parasympathetic actions account for its well-described adverse effects: nasal congestion, increased gastric secretion, and mild diarrhea.
Stephania tetrandra is an herb sometimes used in traditional Chinese medicine to treat hypertension. Tetrandrine, an alkaloid extract of S tetrandra, has been shown to be a calcium ion channel antagonist, paralleling the effects of verapamil. Tetrandrine blocks T and L calcium channels, interferes with the binding of diltiazem and methoxyverapamil at calcium-channel binding sites, and suppresses aldosterone production. A parenteral dose (15 mg/kg) of tetrandrine in conscious rats decreases mean, systolic, and diastolic blood pressures for more than 30 minutes; however, an intravenous 40-mg/kg dose killed the rats by myocardial depression. In stroke-prone hypertensive rats, an oral dose of 25 or 50 mg/kg produced a gradual and sustained hypotensive effect after 48 hours without affecting plasma renin activity. In addition to its cardiovascular actions, tetrandrine has reported antineoplastic, immunosuppressive, and mutagenic effects.
Tetrandrine is 90% protein-bound with an elimination half-life of 88 minutes, according to dog studies; however, rat studies have shown a sustained hypotensive effect for more than 48 hours after a 25- or 50-mg oral dose. Tetrandrine causes liver necrosis in dogs orally administered 40 mg/kg of tetrandrine 3 times weekly for 2 months, reversible swelling of liver cells with a 20-mg/kg dose, and no observable changes with a 10-mg/kg dose. Given the evidence of hepatotoxicity, many more studies are necessary to establish a safe dosage of tetrandrine in humans.
More recently, tetrandrine has been implicated in an outbreak of rapidly progressive renal failure, termed Chinese herb nephropathy. Numerous individuals developed the condition after using a combination of several Chinese herbs as part of a dieting regimen. It has been hypothesized that the cause may be attributed to misidentification of S tetrandra; nonetheless, questions still remain as to the role of tetrandra in the development of this serious toxic effect.
The root of Lingusticum wallichii is used in traditional Chinese medicine as a circulatory stimulant, hypotensive drug, and sedative. Tetramethylpyrazine, the active constituent extracted from L wallichii, inhibits platelet aggregation in vitro and lowers blood pressure by vasodilation in dogs. With its actions independent of the endothelium, tetramethylpyrazine's vasodilatory effect is mediated by calcium channel antagonism and nonselective antagonism of -adrenergic receptors. Some evidence suggests that tetramethylpyrazine acts on the pulmonary vasculature. Currently, there is insufficient information to evaluate the safety and efficacy of this herbal medicinal.
Uncaria rhynchophylla is sometimes used in traditional Chinese medicine to treat hypertension. Its indole alkaloids, rhynchophylline and hirsutine, are thought to be the active principles of U rhynchophylla's vasodilatory effect. The mechanism of U rhynchophylla's actions is unclear. Some studies point to an alteration in calcium ion flux in response to activation, whereas others point to hirsutine's inhibition of nicotine-induced dopamine release. One in vitro study has shown U rhynchophylla extract relaxes norepinephrine-precontracted rat aorta through endothelium-dependent and -independent mechanisms. For the endothelium-dependent component, U rhynchophylla extract appears to stimulate endothelium-derived relaxing factor and/or nitric oxide release without involving muscarinic receptors. Also, in vitro and in vivo studies have shown that rhynchophylline can inhibit platelet aggregation and reduce platelet thromboses induced with collagen or adenosine diphosphate plus epinephrine. Safety and efficacy cannot be evaluated at this time because of a lack of clinical data.
Veratrum (hellebore) is a perennial herb grown in many parts of the world. Varieties include Veratrum viride from Canada and the eastern United States, Veratrum californicum from the western United States, Veratrum album from Alaska and Europe, and Veratrum japonicum from Asia. All Veratrum plants contain poisonous alkaloids known to cause vomiting, bradycardia, and hypotension. Most cases of Veratrum poisonings are due to misidentification with other plants. Although once a treatment for hypertension, the use of Veratrum alkaloids has lost favor owing to a low therapeutic index and unacceptable toxicity, as well as the introduction of safer antihypertensive drug alternatives.
Veratrum alkaloids enhance nerve and muscle excitability by increasing sodium ion conductivity. They act on the posterior wall of the left ventricle and the coronary sinus baroreceptors, causing reflex hypotension and bradycardia via the vagus nerve (Bezold-Jarisch reflex). Nausea and vomiting are secondary to the alkaloids' actions on the nodose ganglion.
The diagnosis of Veratrum toxicity is established by history, identification of the plant, and strong clinical suspicion. Clinical symptoms usually occur quickly, often within 30 minutes. Treatment is mainly supportive and directed at controlling bradycardia and hypotension. Veratrum-induced bradycardia usually responds to treatment with atropine; however, the blood pressure response to atropine is more variable and requires the addition of pressors. Other electrocardiographic changes, such as atrioventricular dissociation, may also be reversible with atropine. Seizures are a rare complication and may be treated with conventional anticonvulsants. For patients with preexisting cardiac disease, the use of -agonists or pacing may be necessary. Nausea may be controlled with phenothiazine antiemetics. Recovery usually occurs within 24 to 48 hours.
Evodia rutaecarpa (wu-chu-yu) is a Chinese herbal drug that has been used as a treatment for hypertension. It contains an active vasorelaxant component called rutaecarpine that can cause endothelium-dependent vasodilation in experimental models.
Reserpine was one of the first drugs used on a large scale to treat systemic hypertension. It acts by irreversibly blocking the uptake of biogenic amines (norepinephrine, dopamine, and serotonin) in the storage vesicles of central and peripheral adrenergic neurons, thus leaving the catecholamines to be destroyed by the intraneuronal monoamine oxidase in the cytoplasm. The depletion of catecholamines accounts for reserpine's sympatholytic and antihypertensive actions. Reserpine's effects are long lasting, since recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks. Reserpine lowers blood pressure by decreasing cardiac output, peripheral vascular resistance, heart rate, and renin secretion. With the introduction of other antihypertensive drugs with fewer central nervous system adverse effects, the use of reserpine has diminished. The daily oral dose of reserpine should be 0.25 mg or less, and as little as 0.05 mg if given with a diuretic. Using the whole root, the usual adult dose is 50 to 200 mg/d administered once daily or in 2 divided doses.
Rauwolfia alkaloids are contraindicated for use in patients with previously demonstrated hypersensitivity to these substances, in patients with a history of mental depression (especially with suicidal tendencies), in patients with active peptic ulcer disease or ulcerative colitis, and in patients receiving electroconvulsive therapy. The most common adverse effects are sedation and inability to concentrate and perform complex tasks. Reserpine may cause mental depression, sometimes resulting in suicide, and its use must be discontinued at the first sign of depression. Reserpine's sympatholytic effect and its enhancement of parasympathetic actions account for its well-described adverse effects: nasal congestion, increased gastric secretion, and mild diarrhea.
Stephania tetrandra is an herb sometimes used in traditional Chinese medicine to treat hypertension. Tetrandrine, an alkaloid extract of S tetrandra, has been shown to be a calcium ion channel antagonist, paralleling the effects of verapamil. Tetrandrine blocks T and L calcium channels, interferes with the binding of diltiazem and methoxyverapamil at calcium-channel binding sites, and suppresses aldosterone production. A parenteral dose (15 mg/kg) of tetrandrine in conscious rats decreases mean, systolic, and diastolic blood pressures for more than 30 minutes; however, an intravenous 40-mg/kg dose killed the rats by myocardial depression. In stroke-prone hypertensive rats, an oral dose of 25 or 50 mg/kg produced a gradual and sustained hypotensive effect after 48 hours without affecting plasma renin activity. In addition to its cardiovascular actions, tetrandrine has reported antineoplastic, immunosuppressive, and mutagenic effects.
Tetrandrine is 90% protein-bound with an elimination half-life of 88 minutes, according to dog studies; however, rat studies have shown a sustained hypotensive effect for more than 48 hours after a 25- or 50-mg oral dose. Tetrandrine causes liver necrosis in dogs orally administered 40 mg/kg of tetrandrine 3 times weekly for 2 months, reversible swelling of liver cells with a 20-mg/kg dose, and no observable changes with a 10-mg/kg dose. Given the evidence of hepatotoxicity, many more studies are necessary to establish a safe dosage of tetrandrine in humans.
More recently, tetrandrine has been implicated in an outbreak of rapidly progressive renal failure, termed Chinese herb nephropathy. Numerous individuals developed the condition after using a combination of several Chinese herbs as part of a dieting regimen. It has been hypothesized that the cause may be attributed to misidentification of S tetrandra; nonetheless, questions still remain as to the role of tetrandra in the development of this serious toxic effect.
The root of Lingusticum wallichii is used in traditional Chinese medicine as a circulatory stimulant, hypotensive drug, and sedative. Tetramethylpyrazine, the active constituent extracted from L wallichii, inhibits platelet aggregation in vitro and lowers blood pressure by vasodilation in dogs. With its actions independent of the endothelium, tetramethylpyrazine's vasodilatory effect is mediated by calcium channel antagonism and nonselective antagonism of -adrenergic receptors. Some evidence suggests that tetramethylpyrazine acts on the pulmonary vasculature. Currently, there is insufficient information to evaluate the safety and efficacy of this herbal medicinal.
Uncaria rhynchophylla is sometimes used in traditional Chinese medicine to treat hypertension. Its indole alkaloids, rhynchophylline and hirsutine, are thought to be the active principles of U rhynchophylla's vasodilatory effect. The mechanism of U rhynchophylla's actions is unclear. Some studies point to an alteration in calcium ion flux in response to activation, whereas others point to hirsutine's inhibition of nicotine-induced dopamine release. One in vitro study has shown U rhynchophylla extract relaxes norepinephrine-precontracted rat aorta through endothelium-dependent and -independent mechanisms. For the endothelium-dependent component, U rhynchophylla extract appears to stimulate endothelium-derived relaxing factor and/or nitric oxide release without involving muscarinic receptors. Also, in vitro and in vivo studies have shown that rhynchophylline can inhibit platelet aggregation and reduce platelet thromboses induced with collagen or adenosine diphosphate plus epinephrine. Safety and efficacy cannot be evaluated at this time because of a lack of clinical data.
Veratrum (hellebore) is a perennial herb grown in many parts of the world. Varieties include Veratrum viride from Canada and the eastern United States, Veratrum californicum from the western United States, Veratrum album from Alaska and Europe, and Veratrum japonicum from Asia. All Veratrum plants contain poisonous alkaloids known to cause vomiting, bradycardia, and hypotension. Most cases of Veratrum poisonings are due to misidentification with other plants. Although once a treatment for hypertension, the use of Veratrum alkaloids has lost favor owing to a low therapeutic index and unacceptable toxicity, as well as the introduction of safer antihypertensive drug alternatives.
Veratrum alkaloids enhance nerve and muscle excitability by increasing sodium ion conductivity. They act on the posterior wall of the left ventricle and the coronary sinus baroreceptors, causing reflex hypotension and bradycardia via the vagus nerve (Bezold-Jarisch reflex). Nausea and vomiting are secondary to the alkaloids' actions on the nodose ganglion.
The diagnosis of Veratrum toxicity is established by history, identification of the plant, and strong clinical suspicion. Clinical symptoms usually occur quickly, often within 30 minutes. Treatment is mainly supportive and directed at controlling bradycardia and hypotension. Veratrum-induced bradycardia usually responds to treatment with atropine; however, the blood pressure response to atropine is more variable and requires the addition of pressors. Other electrocardiographic changes, such as atrioventricular dissociation, may also be reversible with atropine. Seizures are a rare complication and may be treated with conventional anticonvulsants. For patients with preexisting cardiac disease, the use of -agonists or pacing may be necessary. Nausea may be controlled with phenothiazine antiemetics. Recovery usually occurs within 24 to 48 hours.
Evodia rutaecarpa (wu-chu-yu) is a Chinese herbal drug that has been used as a treatment for hypertension. It contains an active vasorelaxant component called rutaecarpine that can cause endothelium-dependent vasodilation in experimental models.
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