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 à2 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.
