Clonidine metabolism

Metabolic pathways due to its lipophilicity, epidural clonidine is quickly absorbed into systemic circulation, with peak arterial concentrations after 10 minutes, peak venous concentrations after 30-45 minutes, and peak CSF concentrations after 30-60 minutes. The liver is responsible for metabolism of 50% of clonidine into inactive metabolites. Approximately two-thirds of clonidine, metabolized and unmetabolized, are excreted renally. While the effects of epidural clonidine may last only 3-5 hours, elimination takes longer. The plasma elimination half-life of clonidine is 22 15 hours and can be prolonged in renal failure [1,2]. 

Clonidine is well absorbed after oral administration. Peak plasma levels occur between 2 and 4 hours after drug administration and correlate well with pharmacological activity. The plasma half-life in patients with normal renal function is 12 hours. Urinary excretion of clonidine and its metabolites accounts for almost 90% of the administered dose, and fecal excretion accounts for the rest. Approximately 50% of an administered dose is excreted unchanged the remainder is oxidatively metabolized in the liver. 

Our cerebrospinal fluid (CSF) observations and. . . studies of the locus ceruleus (LC) and clonidine call for the assessment of noradrenergic metabolism and clonidine in Tourette s syndrome. 

Elimination of clonidine is 65% by renal excretion and 35% by liver metabolism, while guanfacine and its metabolites are excreted primarily in the urine, with approximately 50% as unchanged drug. These differences in elimination may account for differences in the pharmacodynamic properties of the two drugs. The behavioral effects of clonidine last only 3 to 6... 

From the observation that tics were exacerbated by stress, and because cerebrospinal fluid flndings suggested possible alterations in central nervous system catecholamine metabolism, Cohen and colleagues (1979) used clonidine in the treatment of TS in what was among the first theory-based treatments for the disorder. 

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. 

Clonidine is useful in diabetic patients because there is no effect on lipids or on glucose metabolism. 

Postoperative shivering following mild hypothermia has been associated with increased myocardial oxygen demand, which may lead to myocardial ischemia (48). It can also cause increased intracranial pressure (49). In addition, shivering may result in metabolic acidosis secondary to increased carbon dioxide production. Shivering can be minimized by careful rewarming of the patient before extubation and by using low-dose meperidine or clonidine. 

Fluoxetine, paroxetine, bupropion, duloxetine, and other CYP450 2D6 inhibitors may increase TCA concentrations Cimetidine may increase plasma concentrations of TCAs and cause anticholinergic symptoms Phenothiazines or haloperidol may raise TCA blood concentrations May alter effects of antihypertensive drugs may inhibit hypotensive effects of clonidine Use of TCAs with sympathomimetic agents may increase sympathetic activity Methylphenidate may inhibit metabolism of TCAs... 

Transdermal administration can avoid first-pass metabolism as well as provide a large surface area for continuous-controlled administration of drugs with short biological half-lives and narrow therapeutical indices. The route has been used for nitroglycerin ointments, and transdermal therapeutical systems (patches) have been developed for scopolamine, nitroglycerin, clonidine, estradiol, and nicotine. 

Clonidine inhibits the hepatic metabolism of bupivacaine in mice (27). 

Affrime MB, Lowenthal DT, Rufo M. Failure of rifampin to induce the metabolism of clonidine in normal volunteers. Drug Intell Clin Pharm 1981 15(12) 964-6. 

Metabolism of Representative lmida> zolines and Guanidines. In humans, clonidine (35) is excreted about 50% unchanged in the... 

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