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Hypertension is one of the most prevalent chronic medical problems and one of the most readily amenable to pharmacotherapy. Antihypertensive pharamacotherapeutics were first used in the 1960s after two studies independently linked asymptomatic hypertension to significant adverse effects such as stroke, myocardial infarction (MI), and sudden death.74,92 The first antihypertensives used included centrally acting sympatholytics, direct vasodilators, sodium nitroprusside, and diuretics. Unfortunately, these often had significant adverse events, leading to the development of β-adrenergic antagonists, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) (Table 61-1). This chapter reviews early antihypertensives, as well ACEIs, ARBs, and DRIs. In general, the majority of antihypertensives manifest clinical signs and symptoms in terms of the degree of hypotension produced. Particular attention will be placed on mechanisms of action and unique toxicologic considerations for each of these xenobiotics.


Clonidine is an imidazoline compound synthesized in the early 1960s. Because of its potent peripheral α2-adrenergic agonist effects, it was initially studied as a topical nasal decongestant.218 However, hypotension was a common adverse event, which redirected its consideration for other therapeutic applications.101 Clonidine is the most commonly used of all the centrally acting antihypertensives, a group that includes methyldopa, guanfacine, and guanabenz. Although these drugs differ chemically and structurally, they all decrease blood pressure in a similar manner. The imidazoline compounds oxymetazoline and tetrahydrozoline, which are used as ophthalmic topical vasoconstrictors and nasal decongestants (Chap. 49), produce similar systemic effects when ingested.101

Although the increased efficacy and improved adverse event profiles of newer antihypertensives diminished the use of the α2-adrenergic agonists in routine hypertension management, use of these xenobiotics is increasing as a result of a wide variety of applications, including attention deficit hyperactivity disorder, peripheral nerve and spinal anesthesia, and compounded skin creams181 and as an adjunct in the management of opioid, ethanol, and nicotine withdrawal.117,122 In addition, abuse of clonidine remains a problem in opioid-dependent patients and is reportedly used in criminal acts of chemical submission.21,137

Ingestion of centrally acting imidazolines can cause significant toxicity, particularly in children. One report from two large pediatric hospitals identified 47 children requiring hospitalization for unintentional clonidine ingestions over a 5-year period.239 Significant clonidine poisoning also results from formulation and dosing errors in children193,221 and after imidazolines used as ocular vasoconstrictors, especially if ingested.129,141,184


Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily by stimulating two sets of receptors: presynaptic α2-adrenergic receptors22,75 and imidazoline receptors.135,187 Central α2-adrenergic receptor agonism enhances the activity of inhibitory neurons in the vasoregulatory regions ...

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