Clonidine applications

Besides the tablet form, clonidine is also available in a patch that is worn on the arm and changed once every 5-7 days. Once the appropriate dose has been found using oral clonidine, both children and adults can be switched to the patch. The patch provides more consistent levels of the medication and obviously minimizes the potential for rebound effects due to poor compliance. This patch does sometimes cause local skin irritation. Rotating the application site from arm to arm each week can minimize this. 

Therapeutic plasma levels, achieved 2 to 3 days after initial application, are lower than during oral therapy with equipotent doses. When system is removed, therapeutic plasma clonidine levels persist for approximately 8 hours and then decline slowly over several days blood pressure returns gradually to pretreatment levels. Elimination half-life is approximately 19 hours. 

Perioperative use Continue administration of clonidine to within 4 hours of surgery and resume as soon as possible thereafter. Carefully monitor blood pressure and institute appropriate measures to control it. If transdermal therapy is started during the perioperative period, note that therapeutic plasma levels are not achieved until 2 to 3 days after initial application. 

Redmond DE Jr (1981) Clonidine and the primate locus coeruleus evidence suggesting anxiolytic and anti-withdrawal effects. Prog Clin Biol Res 71 147-163 Reiman EM, Raichle ME, Robins E, Butler FK, Herscovitch P, Fox P, Perlmutter P (1986) The applications of positron emission tomography to the study of panic disorder. Am J Psychiatry 143 469-477... 

A transdermal preparation of clonidine that reduces blood pressure for 7 days after a single application is also available. This preparation appears to produce less sedation than clonidine tablets but is often associated with local skin reactions. 

Figure 8.7 Plasma concentration of clonidine versus time profile during and subsequent to the 7-day application of a 5 cm2 Catapres-TTS patch (Modified from Rnepp, V.M. Hadgraft, J. and Guy, R.H. (1987) CRC Critical Reviews in Therapeutic Drug Carrier Systems. 4, 13-37)...

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

Guanfacine Is a related centrally active alpha 2 agonist hypotensive agent that has been used for similar CNS applications but has not been as widely Investigated or used as clonidine... 

Guanfacine may be tolerated better than clonidine In some patients (e.g., sedation) or It may work better In some patients for CNS applications than clonidine, but no head-to-head trials... 

When treating alcoholic liver diseases, it should be taken into account that one is generally dealing with chronic alcoholics. Therefore, one should be aware of the fact that a withrawal syndrome might occur, possibly requiring the application of clomethiazole, haloperidol or clonidine. In this complicated phase, the administration of zinc is likewise recommended. (138)... 

Hopkins, K. Ararons, L. Rowland, M. Absorption and excretion of clonidine following application of catapres-TTS to different skin sites. In Low Dose Oral and Transdermal Therapy of Hypertension, Weber, M.A., Drayer, J.I.M., Kolloch, R., Eds. Steinkopff Verlag Darmstadt, Germany, 1985 134-137. 

A high percentage of patients who take clonidine (up to 38%) (34) develop contact allergic reactions, usually due to the active ingredient, at the patch application site (35). This has been reported with a frequency of 15% in 357 African-American hypertensive patients. It can lead to drug discontinuation in 4.2% of patients. 

A 47-year-old woman was given transdermal, oral, and intravenous clonidine at different times, separated by several months. The patches were withdrawn after 2 months because of pruritic erythematous vesiculation at the site of application. Oral clonidine (0.3 mg/day) had to be withdrawn when a generalized maculopapular rash appeared on the third day, and was promptly exacerbated by each dose. Intravenous clonidine 0.150 mg was followed within 30 minutes by a severe, generalized, maculopapular reaction requiring systemic steroids and antihistamines. 

The authors interpreted these reactions as being allergic. A patch test was very positive to the commercial formulation. Clonidine is a weak sensitizer, but occlusion and prolonged skin contact during transdermal application can cause delayed hypersensitivity. 

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],... 

Sudden withdrawal of clonidine from patients on antihypertensive therapy produce symptoms clinically similar to opiate withdrawal. These include headache, nervousness, tachycardia, stomach pains, and sweating. It may be this apparent similarity that gave someone the idea to treat heroin withdrawal symptoms with clonidine. It seems to work with some addicts and is now experimental for this application. 

Three subtypes of 02-adrenoceptors, 02A, Q2B, and 02c, are recognized. Each plays a role in the different clinical applications of a2-agonists, which include use as antihypertensives (see Chapter 29), antiglaucoma drugs, and analgesics. The first of these drugs, clonidine, was introduced as an antihypertensive, an effect attributed to central a2A-adrenoceptors in cardiovascular control areas of the brain (18). 

Ebihara A, Fujimura A, Ohashi K-l, et al. Influence of application site of a new transdermal clonidine, M-5041T, on its pharmacokinetics and pharmacodynamics in healthy subjects. J Clin Pharmacol 1993 33 1188-1191. 

For the same class of compounds Timmermans determined log Papp values (n-octanol/buffer, pH = 7.4), binding affinities to oti adrenoceptors, ICsoOti (displacement of the oti antagonist prazosin), binding affinities to a2 adrenoceptors, IC5(,a2 (displacement of the 2 agonist clonidine), antihypertensive activities (mediated by a central mechanism) in anesthetized normotensive rats (ED2s%, i v. application), and hypertensive activities (mediated by peripheral a stimulation which, in the absence of central nervous system regulation, causes blood vessel contraction) in... 

Another example of a proper QSAR application is given in eqs. 183—185 (chapter 7.5), which describe the central antihypertensive and peripheral hypertensive activities of clonidine analogs. While no predictions for more active analogs can be derived, three most important conclusions can be drawn from these equations first, the analogs can be tested in simple in vitro systems instead of whole animal models, second, log P values around 1.5 are optimal for the central nervous system-mediated antihypertensive activity, and third, one cannot expect to separate the antihypertensive activity from the hypertensive side effect. 

The commercially available transdernal systen of clonidine consists of an outer layer of pigmented polyester a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide a microporous polypropylene membrane that controls the rate of diffusion of the drug and a final adhesive layer that provides an initial release of drug and contains those ingredients found in the reservoir. The adhesive layer is covered by a protective strip which is removed prior to application (1). 

Clonidine hydrochloride is readily absorbed by oral route with an absorption time of 2 to 4 hours (9). Drug is well absorbed from the gastro-intestinal tract. It may also be absorbed when applied topically to the eye, clonidine is well absorbed percutaneously following topical application of a transdermal system to the arm or chest. Plasma clonidine concentrations of 2 ng/mL have been detected one hour after administration of a single 0.39 mg oral dose of radiolabeled drug. Peak plasma concentrations following oral administration occur in approximately 3-5 hours (1). 

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