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Clonidine Metabolites

a2-receptors located in regions of the brain such as the nucleus tractus solitarius. Stimulation of these a2-receptors brings about a decrease in sympathetic outflow from the CNS, which in turn leads to decreases in peripheral vascular resistance and blood pressure.20,38 Bradycardia is also produced by clonidine as a result of a centrally induced facilitation of the vagus nerve and stimulation of cardiac prejunctional a2-receptors.39 These pharmacological actions have made clonidine quite useful in the treatment of hypertension.

The ability of clonidine and its analogs to exert an anti-hypertensive effect depends on the ability of these compounds not only to interact with the a2-receptor in the brain but also to gain entry into the CNS. For example, in the case of clonidine, the basicity of the guanidine group (typically pKa = 13.6) is decreased to 8.0 (the pKa of clonidine) because of the inductive and resonance effects of the dichlorophenyl ring. Thus, at physiological pH, clonidine will exist to a significant extent in the nonionized form required for passage into the CNS. It has an oral bioavailability of more than 90%.

Although various halogen and alkyl substitutions can be placed at the two ortho positions of the (phenylimino)imida-zolidine nucleus without affecting the affinity of the derivatives for a2-receptors, methyl analogs are much more readily metabolized to the corresponding acids (inactive) and thus have short DOA. Halogen substituents such as chlorine seem to provide the optimal characteristics in this regard.40 One of the metabolites of clonidine, 4-hydroxyclonidine, has good affinity for a2-receptors, but because it is too polar to get into the CNS, it is not an effective antihypertensive agent.

In addition to binding to the a2-adrenergic receptor, cloni-dine, as well as some other imidazolines, shows high affinity for what has been termed the imidazoline receptor.4142 Through the use of imidazoline and a2-antagonists, specific nonadrenergic imidazoline binding sites (I1-IBS) have recently been characterized in CNS control of blood pressure, which are GPCR, with agmatine (decarboxylated arginine) being the endogenous ligand for IBS.43,44 However, other studies involving both site-directed mutagenesis of the a2A-receptor subtype and genetically engineered knockout mice deficient in either the a2A- or a2B-receptor subtypes provide evidence that the hypotensive response of the a2-receptor agonists such as clonidine primarily involves the a2A-receptor subtype.45,46 Thus, the central hypotensive activity for clonidine and other 2-aminoimidazolines need both a2-receptors and I1-IBS to produce their central sympatholytic response. Clonidine appears to be more selective for a2-receptors than for I1-IBS.

Apraclonidine (Iopidine) and Brimonidine (Alphagan). In addition to its therapeutic use as an antihyperten-sive agent, clonidine has been found to provide beneficial effects in several other situations,47 including glaucoma, spasticity, migraine prophylaxis, opiate withdrawal syndrome, and anesthesia. This has prompted the development of analogs of clonidine for specific use in some of the mentioned areas. Two of such examples are apraclonidine and brimonidine. Apraclonidine does not cross the BBB. However, brimonidine can cross the BBB and hence can produce hypotension and sedation, although these CNS effects are slight compared with those of clonidine. CNS effects of these drugs are correlated well to their log P, pKa, and thus log D value. Both apraclonidine and brimonidine are selective a2-agonists with a1:a2 ratios of 30:1 and 1,000:1, respectively. Brimonidine is a much more selective a2-agonist than clonidine or apraclonidine and is a firstline agent for treating glaucoma. Apraclonidines's primary mechanism of action may be related to a reduction of aqueous formation, whereas brimonidine lowers intraocular pressure by reducing aqueous humor production and increasing uveoscleral outflow. Apraclonidine is used specifically to control elevations in intraocular pressure that can occur during laser surgery on the eye. Another example is tizanidine (Zanaflex), which finds use in treating spasticity associated with multiple sclerosis or spinal cord injury. By stimulating a2-adrenergic receptors, it is believed to decrease the release of excitatory amino acid NTs from spinal cord interneurons.48

Guanabenz (Wytensin) and Guanfacine (Tenex) (Open-Ring Imidazolidines). Studies on SAR of central a2-agonists showed that the imidazoline ring was not necessary for a2-activity. Two clonidine analogs, guanabenz (pKa = 8.1) and guanfacine (pKa = 7), which are closely related chemically and pharmacologically, are also used as antihypertensive drugs. In these compounds, the 2,6-dichlorophenyl moiety found in clonidine is connected to a guanidino group by a two-atom bridge. In the case of

Clonidine Pka

guanabenz, this bridge is a —CH=N— group, whereas for guanfacine, it is a —CH2CO— moiety. For both compounds, conjugation of the guanidino moiety with the bridging moiety helps to decrease the pKa of the basic group, so that at physiological pH a significant portion of each drug exists in its nonionized form. This accounts for their CNS penetration and high oral bioavailability (70%-80% for guanabenz and >80% for guanfacine).

Guanfacine is more selective for a2-receptors than is clonidine. Their mechanism of action is the same as that of clonidine. Differences between clonidine and its two analogs are seen in their elimination half-life values and in their metabolism and urinary excretion patterns. The elimination half-life of clonidine ranges from 20 to 25 hours, whereas that for guanfacine is about 17 hours. Guanabenz has the shortest DOA of these three agents, with a half-life of about 6 hours. Clonidine and guanfacine are excreted unchanged in the urine to the extent of 60% and 50%, respectively. Very little of guanabenz is excreted unchanged in the urine.

Methyldopa (L-a-methyldopa, Aldomet) differs structurally from l-DOPA only in the presence of a amethyl group. Originally synthesized as an AADC inhibitor, methyldopa ultimately decreases the concentration of DA, NE, E, and serotonin in the CNS and periphery. However, its mechanism of action is not caused by its inhibition of AADC but, rather, by its metabolism in the CNS to its active metabolite (a-methylnorepinephrine). Methyldopa is transported actively into CNS via an aromatic amino acid transporter, where it is decarboxylated by AADC in the brain to (1^,2^)-a-methyldopamine. This intermediate, in turn, is stereospecifically j-hydroxylated by DBH to give the (1^,2^)-a-methylnorepinephrine. This active metabolite is a selective a2-agonist because it has correct (1^,23) configuration (Fig. 16.13). It is currently postulated

Tizanidine Mechnaism

Figure 16.13 • Metabolic conversion of methyldopate and methyldopa to a-methyl-norepinephrine.

L-Dopa (a precursor of NE and a substrate of AADC)

Figure 16.13 • Metabolic conversion of methyldopate and methyldopa to a-methyl-norepinephrine.

that a-methylnorepinephrine acts on a2-receptors in the CNS in the same manner as clonidine, to decrease sympathetic outflow and lower blood pressure.

Absorption can range from 8% to 62% and appears to involve an amino acid transporter. Absorption is thus affected by food, and about 40% of that absorbed is converted to methyldopa-O-sulfate by the intestinal mucosal cells. Methyldopa is used only by oral administration because its zwitterionic character limits its solubility. The ester hy-drochloride salt of methyldopa, methyldopate (Aldomet ester), was developed as a highly water-soluble derivative that could be used to make parenteral preparations. It is converted to methyldopa in the body through the action of esterases (Fig. 16.13).


Dobutamine (Dobutrex) is a positive inotropic agent administered intravenously for congestive heart failure. It resembles DA structurally but possesses a bulky 1-(methyl)-3-(4-hydroxyphenyl)propyl group on the amino group. It possesses a center of asymmetry, and both enantiomeric forms are present in the racemic mixture used clinically. The ( —) isomer of dobutamine is a potent a1-agonist, which is capable of causing marked pressor responses. In contrast, ( + )-dobutamine is a potent a1-antagonist, which can block the effects of (—)-dobutamine. Importantly, the effects of these two isomers are mediated via j1-receptors. Both isomers appear to be full agonists, but the (+) isomer is a more potent j1-agonist than the ( —) isomer (approximately tenfold).4950

Dobutamine oxidazed slightly by air COMT metabolism and conjugation orally inactive and short DOA

Dobutamine contains a catechol group and is orally inactive and thus is given by intravenous infusion. Solutions of the drug can exhibit a slight pink color because of oxidation of the catechol function. It has a plasma half-life of about 2 minutes because it is metabolized by COMT and by conjugation, although not by MAO.

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