Page 194 - Basic _ Clinical Pharmacology ( PDFDrive )

180 SECTION III Cardiovascular-Renal Drugs

nasal decongestant. After intravenous injection, clonidine produces Pharmacokinetics & Dosage
a brief rise in blood pressure followed by more prolonged hypoten-
sion. The pressor response is due to direct stimulation of α adreno- Pharmacokinetic characteristics of methyldopa are listed in
ceptors in arterioles. The drug is classified as a partial agonist at α Table 11–2. Methyldopa enters the brain via an aromatic amino
receptors because it also inhibits pressor effects of other α agonists. acid transporter. The usual oral dose of methyldopa produces its
Considerable evidence indicates that the hypotensive effect maximal antihypertensive effect in 4–6 hours, and the effect can
of clonidine is exerted at α adrenoceptors in the medulla of the persist for up to 24 hours. Because the effect depends on accu-
brain. In animals, the hypotensive effect of clonidine is prevented mulation and storage of a metabolite (α-methylnorepinephrine)
by central administration of α antagonists. Clonidine reduces in the vesicles of nerve endings, the action persists after the
sympathetic and increases parasympathetic tone, resulting in parent drug has disappeared from the circulation.
blood pressure lowering and bradycardia. The reduction in pres-
sure is accompanied by a decrease in circulating catecholamine Toxicity
levels. These observations suggest that clonidine sensitizes brain The most common undesirable effect of methyldopa is sedation,
stem vasomotor centers to inhibition by baroreflexes. particularly at the onset of treatment. With long-term therapy,
Thus, studies of clonidine and methyldopa suggest that patients may complain of persistent mental lassitude and impaired
normal regulation of blood pressure involves central adrenergic mental concentration. Nightmares, mental depression, vertigo,
neurons that modulate baroreceptor reflexes. Clonidine and and extrapyramidal signs may occur but are relatively infrequent.
α-methylnorepinephrine bind more tightly to α than to α adre- Lactation, associated with increased prolactin secretion, can occur
2
1
noceptors. As noted in Chapter 6, α receptors are located on pre- both in men and in women treated with methyldopa. This toxicity
2
synaptic adrenergic neurons as well as some postsynaptic sites. It is probably mediated by inhibition of dopaminergic mechanisms
is possible that clonidine and α-methylnorepinephrine act in the in the hypothalamus.
brain to reduce norepinephrine release onto relevant receptor sites. Other important adverse effects of methyldopa are develop-
Alternatively, these drugs may act on postsynaptic α adrenocep- ment of a positive Coombs test (occurring in 10–20% of patients
2
tors to inhibit activity of appropriate neurons. Finally, clonidine undergoing therapy for longer than 12 months), which sometimes
also binds to a nonadrenoceptor site, the imidazoline receptor, makes cross-matching blood for transfusion difficult and rarely is
which may also mediate antihypertensive effects. associated with hemolytic anemia, as well as hepatitis and drug
Methyldopa and clonidine produce slightly different hemody- fever. Discontinuation of the drug usually results in prompt rever-
namic effects: clonidine lowers heart rate and cardiac output more sal of these abnormalities.
than does methyldopa. This difference suggests that these two
drugs do not have identical sites of action. They may act primar-
ily on different populations of neurons in the vasomotor centers CLONIDINE
of the brain stem.
Guanabenz and guanfacine are centrally active antihyper- Blood pressure lowering by clonidine results from reduction
tensive drugs that share the central α-adrenoceptor-stimulating of cardiac output due to decreased heart rate and relaxation of
effects of clonidine. They do not appear to offer any advantages capacitance vessels, as well as a reduction in peripheral vascular
over clonidine and are rarely used. resistance.

METHYLDOPA CI
N
Methyldopa was widely used in the past but is now used primar- NH
ily for hypertension during pregnancy. It lowers blood pressure N
chiefly by reducing peripheral vascular resistance, with a variable CI
reduction in heart rate and cardiac output.
Most cardiovascular reflexes remain intact after administration of Clonidine
methyldopa, and blood pressure reduction is not markedly dependent Reduction in arterial blood pressure by clonidine is accompa-
on posture. Postural (orthostatic) hypotension sometimes occurs, nied by decreased renal vascular resistance and maintenance of
particularly in volume-depleted patients. One potential advantage renal blood flow. As with methyldopa, clonidine reduces blood
of methyldopa is that it causes reduction in renal vascular resistance. pressure in the supine position and only rarely causes postural
hypotension. Pressor effects of clonidine are not observed after
OH ingestion of therapeutic doses of clonidine, but severe hyperten-
HO
C O sion can complicate a massive overdose.
HO CH 2 C NH 2
Pharmacokinetics & Dosage
CH 3
Typical pharmacokinetic characteristics are listed in Table 11–2.
α-Methyldopa
(α-methyl group in color) Clonidine is lipid-soluble and rapidly enters the brain from