Clonidine toxicity

Since the mid-1990 s, there have been no further reports of seriouse methylphenidate-clonidine toxicity, possibly owing to less frequent use of this medication combination. However, more recent studies have ques-... 

Ingestion is the most common route of both accidental and intentional exposures to clonidine. Toxicity may also occur via dermal exposure from transdermal patches. 

Chemo-therapeut rug Toxic Clonidine Megestrol (Megace) 0.1 mg patch weekly 20-40 mg PO BID-QID... 

Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic). 

Clonidine, methyldopa Activate K-2 adrenoceptors Reduce central sympathetic outflow reduce norepinephrine release from noradrenergic nerve endings Hypertension clonidine also used in withdrawal from abused drugs Oral t clonidine also patch Toxicity sedation t methyldopa hemolytic anemia... 

Some toxicants that affect body temperature are shown in Figure 6.11. Among those that increase body temperature are benzadrine, cocaine, sodium fluoroacetate, tricyclic antidepressants, hexachlorobenzene, and salicylates (aspirin). In addition to phenobarbital and ethanol, toxicants that decrease body temperature include phenothiazine, clonidine, glutethimide, and haloperidol. 

Toxicants may have three effects on pulse rate bradycardia (decreased rate), tachycardia (increased rate), and arrhythmia (irregular pulse). Alcohols may cause either bradycardia or tachycardia. Amphetamines, belladonna alkaloids, cocaine, and tricyclic antidepressants (see imi-primine hydrochloride in Figure 6.12) may cause either tachycardia or arrhythmia. Toxic doses of digitalis may result in bradycardia or arrhythmia. The pulse rate is decreased by toxic exposure to carbamates, organophosphates, local anesthetics, barbiturates, clonidine, muscaric mushroom toxins, and opiates. In addition to the substances mentioned above, those that cause arrhythmia are arsenic, caffeine, belladonna alkaloids, phenothizine, theophylline, and some kinds of solvents. 

The gastrointestinal tract responds to a number of toxic substances, usually by pain, vomiting, or paralytic ileus (see Intestines, Section 6.4.5). Severe gastrointestinal pain is symptomatic of poisoning by arsenic or iron. Both of these substances can cause vomiting, as can acids, bases, fluorides, salicylates, and theophyllin. Paralytic ileus can result from ingestion of narcotic analgesics, tricyclic antidepressants, and clonidine. 

V-Na+ CH ligand (22) (odA-R, 2A-R, 5HT-R) [blocks vas deferens contraction [0.2] Clonidine antagonism antidepressant, aphrodisiac, mydriatic, toxic]... 

Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med 2002 156(4) 392-6. 

Medications play an important part in the treatment of ADD. Stimulants are the mainstay of the treatment of ADD methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and pemoline (Cylert). These differ in their half-lives, with Ritalin having the shortest and Cylert the longest. A warning has recently been issued about Cylert because of reports of sometimes fatal liver toxicity. Thus, it is recommended that it be used only if methylphenidate and dextroamphetamine are ineffective. There is individual variability in resporise, so that a person who does not respond to one may respond well to another. Other medications can also be effective in the treatment of ADD and may be useful, especially in residual ADD, where substance abuse may be an issue. These include tricyclic antidepressants (especially desipramine and imi-pramine) SSRIs, bupropion, venlafaxine, and clonidine. There are reports of antipsy-chotics and lithium being helpful in selected cases, as well. 

As little as 0.1 mg of clonidine has produced toxicity in children determination of adult toxicity is based on observation as there is no milligram per kilogram toxic dose established. Clonidine levels are not clinically useful. Toxicity can result from ingestion of used clonidine transdermal patches as residual clonidine remains after full therapeutic use. Symptoms generally begin within 30-90 min and include hypotension, central nervous system depression, bradycardia, and... 

The most common side effect of clonidine is dose-dependent sedation that usually subsides after 2 to 3 weeks of therapy. Of concern are reports of bradycardia, rebound hypertension, heart block, and sudden death. Four children have died on the combination of methylphenidate and clonidine however, complicating factors make it impossible to link the drug combination directly with the cause of death. Of 10,060 children exposed to clonidine and assessed by a poison control center over a 7-year period, moderate (19%) to major (2%) toxic effects (bradycardia, hypotension, and respiratory depression) including one death were reported. Overdoses, concurrent clonidine and stimulant administration, as well as missed doses of clonidine aU add to the risk of adverse cardiovascular events. Similar adverse-effect concerns apply to treatment with guanfacine, although its U2a selectivity may result in less sedation and hypotension than clonidine. ... 

The glucuronide metabolite of AZT was isolated from rat and human liver microsomal incubations (177), and the formation of a toxic metabolite of AZT was demonstrated in rat hepatocytes and liver microsomes (177). The metabolism of tamoxifen was examined in human liver homogenate and human Hep G2 cell line preparations by LC/API/MS (178). Several metabolites were detected in the human liver homogenate extracts, namely, N-didesmethyltamoxifen, a-hydroxy-tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, and tamoxifen N-oxide. All of these metabolites, except the N-didesmethyltamoxifen, were observed in the samples after incubating tamoxifen with the human Hep G2 cell line. In-vitro studies have also used MS to examine potential drug-drug interactions. For example, (179) demonstrated that the a2-agonist, dexmedetomidine, inhibited metabolism of the anesthetic alfentanil, whereas clonidine had no effect. 

Guanfacine is an a2 agonist drug that is similar to clonidine in mechanism of action, toxicity and side effects. It is administered orally. The duration of action is longer than that of clonidine (16-20 hours) and so is normally administered once per day. 

Clonidine (Catapres) Acts in brain as postsynaptic a2-adrenergic agonist causing a reduction in sympathetic nervous system activity (decreased heart rate, cardiac ouput and blood pressure). Exact mechanism unknown. Mild to moderate hypertension. Rash, drowsiness, dry mouth, constipation, headache, impaired ejaculation. Rebound hypertension if withdrawn abruptly. To limit toxicity, start with low dose and increase slowly. 

Aronstam, R. S., M. D. Smith, and J. J. Bucca-fusco. 1986. Clonidine protection from soman and echothiophate toxicity in mice. Life Sci. 39(22) 2097-2102. 

Buccafusco, J. J., and R. S. Aronstam. 1986. Clonidine protection from the toxicity of soman, an organophosphate acetylcholinesterase inhibitor in themonse. J. Pharmacol. Exp. Ther. 239(1) 43-47. 

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