Page 195 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 181

the circulation. Because of its relatively short half-life and the ADRENERGIC NEURON-BLOCKING
fact that its antihypertensive effect is directly related to blood AGENTS
concentration, oral clonidine must be given twice a day (or as a
patch, below) to maintain smooth blood pressure control. How- These drugs lower blood pressure by preventing normal physi-
ever, as is not the case with methyldopa, the dose-response curve ologic release of norepinephrine from postganglionic sympathetic
of clonidine is such that increasing doses are more effective (but neurons.
also more toxic).
A transdermal preparation of clonidine that reduces blood
pressure for 7 days after a single application is also available. This Guanethidine
preparation appears to produce less sedation than clonidine tablets Guanethidine is no longer available in the USA but may be
but may be associated with local skin reactions. used elsewhere. In high enough doses, guanethidine can produce
profound sympathoplegia. Guanethidine can thus produce all of
Toxicity the toxicities expected from “pharmacologic sympathectomy,”
including marked postural hypotension, diarrhea, and impaired
Dry mouth and sedation are common. Both effects are centrally ejaculation. Because of these adverse effects, guanethidine is now
mediated and dose-dependent and coincide temporally with the rarely used.
drug’s antihypertensive effect. Guanethidine is too polar to enter the central nervous system.
Clonidine should not be given to patients who are at risk for As a result, this drug has none of the central effects seen with many
mental depression and should be withdrawn if depression occurs of the other antihypertensive agents described in this chapter.
during therapy. Concomitant treatment with tricyclic antidepres- Guanadrel is a guanethidine-like drug that is no longer used in
sants may block the antihypertensive effect of clonidine. The the USA. Bethanidine and debrisoquin, antihypertensive agents
interaction is believed to be due to α-adrenoceptor-blocking not available for clinical use in the USA, are similar.
actions of the tricyclics.
Withdrawal of clonidine after protracted use, particularly with
high dosages (more than 1 mg/d), can result in life-threatening A. Mechanism and Sites of Action
hypertensive crisis mediated by increased sympathetic nervous Guanethidine inhibits the release of norepinephrine from
activity. Patients exhibit nervousness, tachycardia, headache, and sympathetic nerve endings (see Figure 6–4). This effect is prob-
sweating after omitting one or two doses of the drug. Because of ably responsible for most of the sympathoplegia that occurs in
the risk of severe hypertensive crisis when clonidine is suddenly patients. Guanethidine is transported across the sympathetic nerve
withdrawn, all patients who take clonidine should be warned of membrane by the same mechanism that transports norepinephrine
this possibility. If the drug must be stopped, it should be done itself (NET, uptake 1), and uptake is essential for the drug’s action.
gradually while other antihypertensive agents are being substi- Once guanethidine has entered the nerve, it is concentrated in
tuted. Treatment of the hypertensive crisis consists of reinstitution transmitter vesicles, where it replaces norepinephrine and causes
of clonidine therapy or administration of α- and β-adrenoceptor- a gradual depletion of norepinephrine stores in the nerve ending.
blocking agents. Because neuronal uptake is necessary for the hypotensive activity
of guanethidine, drugs that block the catecholamine uptake process
or displace amines from the nerve terminal (cocaine, amphetamine,
GANGLION-BLOCKING AGENTS tricyclic antidepressants, phenothiazines, and phenoxybenzamine)
block its effects.
Historically, drugs that block activation of postganglionic auto-
nomic neurons by acetylcholine were among the first agents used B. Pharmacokinetics and Dosage
in the treatment of hypertension. Most such drugs are no longer Because of guanethidine’s long half-life (5 days), the onset of
available clinically because of intolerable toxicities related to their sympathoplegia is gradual (maximal effect in 1–2 weeks), and
primary action (see below). sympathoplegia persists for a comparable period after cessation of
Ganglion blockers competitively block nicotinic cholinocep- therapy. The dose should not ordinarily be increased at intervals
tors on postganglionic neurons in both sympathetic and parasym- shorter than 2 weeks.
pathetic ganglia. In addition, these drugs may directly block the
nicotinic acetylcholine channel, in the same fashion as neuromus- C. Toxicity
cular nicotinic blockers. Therapeutic use of guanethidine is often associated with symp-
The adverse effects of ganglion blockers are direct extensions tomatic postural hypotension and hypotension following exercise,
of their pharmacologic effects. These effects include both sympa- particularly when the drug is given in high doses. Guanethidine-
thoplegia (excessive orthostatic hypotension and sexual dysfunc- induced sympathoplegia in men may be associated with delayed
tion) and parasympathoplegia (constipation, urinary retention, or retrograde ejaculation (into the bladder). Guanethidine com-
precipitation of glaucoma, blurred vision, dry mouth, etc). These monly causes diarrhea, which results from increased gastrointesti-
severe toxicities are the major reason for the abandonment of nal motility due to parasympathetic predominance in controlling
ganglion blockers for the therapy of hypertension. the activity of intestinal smooth muscle.