Clonidine HCl

Clonidine Hydrochloride is a centrally acting alpha-agonist hypotensive agent.

Pharmacology and toxicology of chronically infused epidural clonidine.HCl in dogs.[Pubmed:7835532]

Fundam Appl Toxicol. 1994 Oct;23(3):319-35.

To evaluate the physiological effects and toxicity of epidural clonidine.HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 micrograms/hr (N = 6), 200 micrograms/hr (N = 6), or 320 micrograms/hr (N = 12) clonidine.HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steady-state plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320 micrograms/hr and at infusate concentrations up to 2 mg/ml.

Evaluation of the Percutaneous Absorption of Ketamine HCl, Gabapentin, Clonidine HCl, and Baclofen, in Compounded Transdermal Pain Formulations, Using the Franz Finite Dose Model.[Pubmed:26352507]

Pain Med. 2016 Feb;17(2):230-8.

OBJECTIVE: This study evaluates the ability of four commonly used analgesics (ketamine HCl, gabapentin, Clonidine HCl, and baclofen), when incorporated into two transdermal compounding bases, Lipoderm and Lipoderm ActiveMax, to penetrate human cadaver trunk skin in vitro, using the Franz finite dose model. DESIGN: In vitro experimental study. Methods. Ketamine HCl 5% w/w, gabapentin 10% w/w, Clonidine HCl 0.2% w/w, and baclofen 2% w/w were compounded into two transdermal bases, Lipoderm and Lipoderm ActiveMax. Each compounded drug formulation was tested on skin from three different donors and three replicate skin sections per donor. The Franz finite dose model was used in this study to evaluate the percutaneous absorption and distribution of drugs within each formulation. RESULTS: Rapid penetration to peak flux was detected for gabapentin and baclofen at approximately 1 hour after application. Clonidine HCl also had a rapid penetration to peak flux occurring approximately 1 hour after application and had a secondary peak at approximately 40 hours. Ketamine HCl exhibited higher overall absorption rates than the other drugs, and peaked at 6-10 hours. Similar patterns of drug distribution within the skin were also observed using both transdermal bases. CONCLUSIONS: This study suggests that the combination of these 4 analgesic drugs can be successfully delivered transdermally, using either Lipoderm or Lipoderm ActiveMax. Compounded transdermal drug preparations may then provide physicians with an alternative to traditional oral pain management regimens that can be personalized to the specific patient with the potential for enhanced pain control.

Comparison of moxonidine and clonidine HCl in treating patients with hypertension.[Pubmed:3316304]

J Clin Pharmacol. 1987 Jan;27(1):46-51.

In a six-week multicenter, double-blind comparison study, moxonidine and Clonidine HCl were tested in 122 and 30 outpatients, respectively, with mild to moderate hypertension (World Health Organization stage I and II; highest measured diastolic blood pressure, 90 to 115 mm Hg). Each agent reduced systolic and diastolic blood pressure to a similar significant extent: moxonidine, 25.4 and 12.4 mm Hg, respectively; clonidine, 25.3 and 10.0 mm Hg, respectively (P less than .001 vs baseline). The mean individually titrated dose of moxonidine and Clonidine HCl was found to be 0.36 mg/d. Clonidine slightly reduced heart rate in patients assuming an upright position by 3 beats/min at the end of dose titration (P = .018), while moxonidine did not. Two patients receiving moxonidine and three patients taking Clonidine HCl discontinued therapy because of side effects. However, patients administered clonidine experienced significantly more side effects (53%) compared with a 30% incidence of adverse effects associated with moxonidine (P = .031). The most frequent adverse effect of both agents was dryness of mouth, which was mentioned significantly more often with clonidine (47%) than with moxonidine (20%) (P = .005). Edemas were found in 0.8% and 17% of patients during six-week treatment with moxonidine and clonidine, respectively (P = .001). Accordingly, moxonidine was tolerated significantly better than clonidine (P less than .001) in this parallel comparison study. Moxonidine is as effective as clonidine in monotherapy of mild to moderate essential hypertension and, additionally, neither drug produces clinically important changes in biochemical parameters.

Novel targets for Huntington's disease in an mTOR-independent autophagy pathway.[Pubmed:18391949]

Nat Chem Biol. 2008 May;4(5):295-305.

Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the G(i) signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating G(s)alpha, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.

Mechanism of relaxant effect of clonidine in isolated bovine tracheal smooth muscle.[Pubmed:9694921]

J Pharmacol Exp Ther. 1998 Aug;286(2):681-7.

The relaxant effect of clonidine and the possible involvement of imidazoline I1 receptors in bovine tracheal smooth muscle (BTSM) were examined. Clonidine caused concentration-dependent significant relaxation in BTSM precontracted with 0.1 or 1 microM carbachol (CCh) but not in 72.7 mM KCl-induced contraction. The relaxation in CCh-contracted BTSM was inhibited by yohimbine (1 microM) and idazoxan (10 and 30 microM) but not by tetrodotoxin, indomethacin and other adrenoceptor antagonists. Oxymetazoline (0.1-100 microM) and phentolamine (0.1-100 microM) caused concentration-dependent relaxation, which was attenuated by idazoxan (10 microM). Norepinephrine (0.1-100 microM) produced concentration-dependent relaxation, which was completely abolished by propranolol (10 microM) but not by yohimbine (1 microM). In fura-PE3/AM-loaded BTSM, CCh and 72.7 mM KCl increased intracellular calcium concentration ([Ca++]i) followed by contraction. The high K+-induced increase in [Ca++]i was not affected by clonidine. In CCh-stimulated BTSM, clonidine decreased [Ca++]i and muscle force in parallel, whereas verapamil decreased [Ca++]i more strongly than muscle force. Clonidine (100 microM) inhibited the transient increase in [Ca++]i induced by CCh but not by caffeine (20 mM) in Ca++-free solution. Clonidine did not change the cAMP content in the presence of either 72.7 mM KCl or CCh. These results indicate that clonidine relaxes CCh-stimulated BTSM through the inhibition of CCh-induced increases in Ca++-influx, Ca++-release and intracellular signal transduction probably via imidazoline I1 receptors.

Dual effect of clonidine on mesenteric artery adrenoceptors: agonistic (alpha-2) and antagonistic (alpha-1).[Pubmed:8627569]

J Pharmacol Exp Ther. 1996 May;277(2):872-6.

The effect of clonidine on the mesenteric vascular bed and the isolated mesenteric artery was examined in preparations in which tonus was induced by norepinephrine or endothelin. In preparations precontracted by norepinephrine, clonidine caused a relaxation which was not inhibited by the alpha-2 antagonists yohimbine and idazoxan or by the K+ channel blockers apamine, tetraethylammonium and glibenclamide. In preparations precontracted with endothelin, clonidine increased the depolarization and induced a contraction. Both these effects were inhibited by prazosin. In isolated mesenteric arteries, norepinephrine cause a significant depolarization that was inhibited by clonidine or prazosin. On the other hand, clonidine caused a hyperpolarization which was inhibited by idazoxan or yohimbine, but not by prazosin. This hyperpolarization was also abolished by apamine, tetraethylammonium and glibenclamide. It is concluded that clonidine acts on alpha-1 adrenoceptors as a partial agonist, causing relaxation of the mesenteric artery precontracted with norepinephrine or contraction of preparations precontracted with endothelin. Moreover, clonidine can open K+ channels and hyperpolarize the plasma membrane of mesenteric artery by acting on alpha-2 adrenoceptors.

Isolation of a human cerebral imidazoline-specific binding protein.[Pubmed:7883019]

Eur J Pharmacol. 1994 Nov 14;265(1-2):R1-2.

The first isolation of a human brain specific imidazoline binding protein is described. This protein was obtained using affinity chromatography and was revealed with the aid of an anti-idiotypic antibody specific for imidazoline binding sites. The protein (43 kDa) differs from other imidazoline binding proteins previously isolated from peripheral tissues, in particular by being also sensitive to clonidine.

Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla.[Pubmed:3030779]

Eur J Pharmacol. 1987 Jan 28;134(1):1-13.

Binding sites labeled by [3H]p-aminoclonidine ([3H]PAC) were characterized in bovine brain membranes prepared from the ventrolateral medulla, the probable site of the antihypertensive action of clonidine and analogs. Comparison was made with [3H]PAC binding to membranes prepared from frontal cortex, which has been studied extensively. Saturation binding isotherms for [3H]PAC were similar in the two regions, although Bmax values were approximately two-fold lower in ventrolateral medulla relative to frontal cortex. Norepinephrine and other phenylethylamines displaced [3H]PAC from a maximum of 70% of the total sites in the ventrolateral medulla. The remaining 30% were norepinephrine-insensitive, non-adrenoceptor sites which displayed high affinity for imidazole compounds. Ligand selectivity differed markedly between ventrolateral medulla and frontal cortex, since some imidazole compounds which potently inhibited [3H]PAC binding in the ventrolateral medulla had no effect in frontal cortex. Imidazole binding sites may mediate, in part, the hypotensive action of clonidine and other imidazole compounds in the ventrolateral medulla. These sites may also participate in the functions of a putative endogenous clonidine-like substance.