B. CENTRALLY-ACTING ANTIHYPERTENSIVE DRUGS +lt;tab5-2+gt; Sympathoplegics that act in the

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B. CENTRALLY-ACTING ANTIHYPERTENSIVE DRUGS Sympathoplegics that act in the central nervous system (methyldopa, clonidine, guanabenz, guanfacine) produce a moderate hypotensive effect that is usually relatively free of postural hypotension. 1. Methyldopa: Methyldopa is a prodrug. It is converted to alpha- methylnorepinephrine in the body, a catecholamine with higher af- finity for the alpha-2 than for the alpha-1 receptor. Indications: * oral use in chronic outpatient management of hypertension * (Rare) parenteral administration in the treatment of hypertensive emergencies. Contraindications and Warnings: * Acute hepatic disease * hypersensitivity * hemolytic anemia. If a positive Coombs test develops during methyldopa therapy, withdraw slowly and replace with another drug. Adverse Reactions and Overdose Toxicity: * CNS: Sedation is common at therapeutic dosage, especially at the start of therapy. Overdose has resulted in coma. Other unusual signs of toxicity include choreoathetosis and other central signs of dopamine ex- cess. * CV: Little toxicity at therapeutic doses but bradyarrhythmias, AV block, and hypotension may occur with overdosage * Hematologic: positive Coombs test, which indicates the presence of red cell antibodies, occurs in 10-20 % of patients on therapy for more than 12 months. Hemolytic anemia follows only rarely. * Liver: Abnormal liver function tests and jaundice occur in some patients at therapeutic doses. Cytotoxic injury occurs in less than 0.1%. * Treatment of acute overdosage: maintenance of blood pressure with IV fluids in addition to standard overdose therapy (Chapter 24). Interactions: Methyldopa may potentiate the actions (including toxic effects) of levodopa. 2. Clonidine: Clonidine is a alpha-2 selective agonist that, when given chronically in therapeutic doses, acts at a site in the CNS to reduce blood pressure. However, because of its alpha-1 agonist actions, it is causes hypertension when given rapidly IV or in excessive dosage. At the present time it is the only antihypertensive agent that can be given on a once-weekly schedule -- by using a transdermal patch formulation of the drug. Indications: * hypertension * reduction of withdrawal symptoms in the management of narcotic addic- tion (unlabeled). Contraindications and Warnings: * Hypersensitivity (especially dermatologic reactions to use of the patch preparation). * (Warning) Rebound hypertension may be severe if clonidine is suddenly discontinued. Patients should be warned never to stop the drug suddenly. Adverse Reactions and Overdose Toxicity: * Autonomic: Dry mouth and sedation are very common (10-40%) during the first weeks of therapy but tend to decrease with continued use. Miosis may occur, especially at high doses. * CNS: Sleep disturbances. In overdosage, marked CNS depression or (very rarely) seizures, hallucinations or dementia may occur. * CV: Bradycardia and hypotension may occur. Hypertension is uncommon, except as noted above under warnings. * Treatment of clonidine rebound hypertension: resume clonidine or give phentolamine. * Treatment of clonidine overdosage: Conventional overdosage treatment (Chapter 24); control initial hypertension with phentolamine, bradycar- dia with atropine, and give fluids and pressor agents as needed to maintain blood pressure later. Interactions: Clonidine may increase the effects of CNS depressants such as the sedative-hypnotic drugs. 3. Guanabenz and guanfacine: These are the newest drugs in this group of centrally acting antihypertensive agents. Like methyldopa and clonidine, these drugs activate 2 receptors in the CNS and reduce sympathetic out- flow. Indications: * Chronic hypertension. Contraindications and Warnings: * Activities requiring full alertness (Warning): sedation is marked in many patients. Adverse Reactions and Overdose Toxicity: * CNS: Sedation is the most common reported adverse reaction. CNS depression may be marked at overdose levels. * CV: Hypotension and bradycardia may occur after an overdose. * Autonomic: Miosis may occur. Interactions: Increased effects of sedatives.


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