Clonidine hypertension with

Centrally acting sympathoplegic drugs were once widely used in the treatment of hypertension. With the exception of clonidine, these drugs are rarely used today. 

Similar conclusions could be derived from an investigation of antihypertensive clonidine analogs, with respect to their peripheral hypertensive side effects. For a series of clonidine-related imidazolines, log Papp values were determined in -octanol/buffer at pH 7.4, central antihypertensive activities C2s (molar doses that cause a 25% blood pressure decrease, intravenous application) in anesthesized rats, peripheral hypertensive activities C o (molar doses that cause a 60-mm Hg blood pressure increase, intravenous application) in pithed rats (i.e., rats without central nervous system control), binding affinities IC50ai to ai receptors (replacement of prazosin), and binding affinities IC50+ 10 a2 receptors (replacement of clonidine) [86,87],... 

Alkylation of clonidine (133) with allyl bromide gave alinidine (138) [167] and with 2-chlorotetrahydropyran piclonidine (139) [168]. Preliminary clinical trials of alinidine demonstrated a bradycardic effect mediated through direct action on the atrial sinus [167], The slow and economic heart rate was thought to be desirable in the management of coronary heart disease [169]. Piclonidine is less potent than clonidine, but it does not evoke hypertensive episodes or cause sedation [168,170,171]. 

The use of clonidine with beta biockers can be therapeutically val-uable, but a sharp and serious rise in biood pressure ( rebound hypertension ) can foiiow the sudden withdrawai of cionidine, which may be worsened by the presence of a beta biocker. Isoiat-ed cases of marked bradycardia and hypotension have been seen in patients given cionidine with esmoioi. There are aiso two reports describing paradoxicai hypertension with the combination of cionidine and beta biockers. 

At present, no diugs exist that can selectively activate a2-receptor subtypes. Clonidine stimulates all three a2-subtypes with similar potency. Clonidine lowers blood pressure in patients with hypertension and it decreases sympathetic overactivity during opioid withdrawal. In intensive and postoperative care, clonidine is a potent sedative and analgesic and can prevent postoperative shivering. Clonidine and its derivative brimonidine lower... 

Arrhythmias and hypertension have been reported when the TCAs are administered with the adrenergic drugp. There is a risk of severe hypertension when die TCAs are administered with clonidine. 

There are two main treatments for the opiate withdrawal syndrome. One is replacement therapy with methadone or other X agonists that have a longer half-life than heroin or morphine, and produce mild stimulation rather than euphoria. They also produce cross-tolerance to heroin, lessening heroin s effect if patients relapse. Withdrawal is also treated with the 0C2 agonist clonidine, which inhibits LC neurons, thus counteracting autonomic effects of opiate withdrawal — such as nausea, vomiting, cramps, sweating, tachycardia and hypertension — that are due in part to loss of opiate inhibition of LC neurons. 

Because of their reflex cardiac effect, vasodilators, if used alone in the treatment of hypertension, have not been a successful therapeutic tool. However, the reflex tachycardia and increase in cardiac output can be effectively blocked by the therapeutic association with a sympathetic blocker guanethidine, reserpine, methyldopa, or clonidine. More specifically, blockade of the cardiac beta-adrenergic receptors will also prevent the cardiac response to hydralazine. Thus, the therapeutic combination of hydralazine and propranolol can be successfully employed for effective blood pressure reduction(11). 

Clinically, clonidine has shown great versatility effective in mild, moderate and severe hypertension. The major side effects are drowsiness and dry mouth. Clonidine can be effectively used in combination with a diuretic(32). In addition, a vasodilator (hydralazine) can be usefully added. The brady-cardiac effect of clonidine prevents the reflex tachycardia induced by the vasodilator. 

Another pharmacological approach is to reduce the intensity of the symptoms with the o2 adrenergic antagonist clonidine, which is normally used to treat hypertension. Overactivity of the locus coeruleus is associated with opioid withdrawal signs such as tachycardia, nausea, vomiting, and sweating. 

Clonidine is a selective Oj-adrenergic agonist that exhibits pronounced hypotensive action that is associated with a reduction of overall peripheral vascular resistance, decline in frequency of cardiac contraction, and reduced cardiac output. Clonidine is the drug of choice for treating various degrees of hypertension when used in combination with oral diuretics. 

The primary indication for clonidine use is in mild and moderate hypertension that has not responded adequately to treatment with a diuretic or a p-blocker. Since clonidine causes sodium and water retention and plasma volume expansion, it generally is administered in combination with a diuretic. A vasodilator can be added to the clonidine-diuretic regimen in the treatment of resistant forms of hypertension. Such drug combinations can be quite effective, since the reflex increases in heart rate and cardiac output that result from vasodilator administration are reduced or negated by clonidine-induced decreases in heart rate and cardiac output. 

For severely hypertensive patients, clonidine has been used in combination with a diuretic, a vasodilator, and a -blocker. Some care must be taken, however, because the coadministration of clonidine and a p-blocker may cause excessive sedation. Clonidine is especially useful in patients with renal failure, since its duration of... 

Clonidine 0.003-0.01 bid or tid Tourette s syndrome ADHD Aggression/self-abuse Severe agitation Withdrawal syndromes Sedation (very frequent) Hypotension (rare) Dry mouth Confusion (with high dose) Depression Rebound hypertension Localized irritation with transdermal preparation... 

Hoder et al. (1984) studied clonidine in seven newborn infants with neonatal narcotic abstinence syndrome and found no significant changes in blood pressure, pulse, or electrocardiograms (EKG) in any of the seven infants. One infant had a transient abnormal eye exam and two infants developed a transient mild metabolic acidosis. On follow up 4-9 months later, four infants were found to be developmentally age appropriate. However, Huisjes et al. (1986) reported that 22 children exposed in utero to clonidine as result of treatment for maternal hypertension had increased sleep disturbances and hyperactivity, compared to a control group at a mean age of 6 years. It is unclear whether these differences were a direct effect of clonidine on prenatal development. More sophisticated preclinical studies need to be done in this area. At best the level of short-term and long-term safety regarding clonidine is level C. 

Rebound hypertension Localized irritation with transdermal preparation Same as clonidine Less sedation, hypotension... 

Clonidine has also been useful in one controlled study and in a few case reports. Although this agent has the advantage of avoiding acute and chronic EPS associated with neuroleptics, its effects on blood pressure have appropriately constrained its use in this age population. There is also the concern regarding rebound hypertension if this agent is abruptly discontinued (e.g., noncompliance). 

Although the primary use of the cx2 agonist clonidine is in the treatment of hypertension (see Chapter 11), the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and... 

Clonidine Inhibits adenylyl cyclase and interacts with other intracellular pathways Vasoconstriction is masked by central sympatholytic effect, which lowers BP Hypertension Oral transdermal peak effect 1-3 h half-life of oral drug 12 h produces dry mouth and sedation... 

Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. As with methyldopa, clonidine reduces blood pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate a massive overdose. 

---