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Hypertension is one of the commonest chronic medical problems and one of the most readily amenable to pharmacotherapy. Beginning in the 1960s, when asymptomatic hypertension was linked to significant adverse effects such as stroke, myocardial infarction, and sudden death, antihypertensive pharmacotherapeutics began being used. The first generation 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, more recently, direct renin inhibitors (DRIs). This chapter reviews the first-generation 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 that was synthesized in the early 1960s. Because of its potent peripheral α2-adrenergic agonist effects, it was initially studied as a potential topical nasal decongestant. However, hypotension was a common adverse event, which redirected its consideration for other therapeutic applications.105 Clonidine is the best understood and 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, produce similar systemic effects when ingested.105

Since 1985, the increased efficacy and improved adverse event profiles of the newer antihypertensives have diminished the use of the α2-adrenergic agonists in routine hypertension management. However, their use is increasing as a result of a wide variety of applications, including attention-deficit/hyperactivity disorder (ADHD), peripheral nerve and spinal anesthesia, and as an adjunct in the management of opioid, ethanol, and nicotine withdrawal.120,127,130,224 In addition, abuse of clonidine may be a growing problem in opioid dependent patients, and it has been used in criminal acts of chemical submission.20,145

Although centrally acting α2-adrenergic agonist exposure is relatively uncommon, it may 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.266 Significant clonidine poisoning has also resulted from formulation and dosing errors in children.211,241 Imidazolines used as ocular vasoconstrictors have resulted in significant systemic toxicity, especially when ingested.109,150,137,202


Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily via stimulation of presynaptic α2-adrenergic receptors in the brain.78,194,218,257 This central α2-adrenergic receptor agonism enhances the ...

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