Les Enantiomeres Du Carteolol

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Receptor Selectivity2

Ch2oh Och3

triceuticals" on the market whose active ingredient is the adrenergic agonist ephedrine. Pseudoephedrine, the threo diastereomer, has virtually no direct activity on adrenergic receptors but acts by causing the release of norepinephrine from nerve terminals, which in turn constricts blood vessels. Although it too crosses the blood-brain barrier, pseudoephed-rine's lack of direct activity affords fewer CNS side effects than does ephedrine. Pseudo-ephedrine is widely used as a nasal deconges-tant and is an ingredient in many nonprescrip-tion cold remedies.

Mephentermine (6) is another general ad-renergic agonist with both direct and indirect activity. Mephentermine's therapeutic utility is as a parenteral vasopressor used to treat hypotension induced by spinal anesthesia or other drugs.

2.1.2 Applications of c^-Agonists. All selective a,-agonists are vasoconstrictors, which is the basis of their therapeutic activity. The sole use of levonordefrin (7)is in formulations with parenteral local anesthetics employed in dentistry. Vasoconstriction induced by the a-agonist activity of (7) helps retain the local anesthetic near the site of injection and prolongs the duration of anesthetic activity. Met-araminol (8) and methoxamine (9) are both parenteral vasopressors selective for a-recep-tors and so have few cardiac stimulatory properties. Because they are not substrates for COMT, their duration of action is significantly longer than that of norepinephrine, but their primary use is limited to treating hypotension during surgery or shock. Methoxamine is also used in treating supraventricular tachycardia. Midodrine (10) is an orally active glycine-

Table L6 Miscellrr^^i

Compound (60)

Table L6 Miscellrr^^i

Structure Activity

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Pharmacological Activity Antiadrenergic

Midodrine Prodrug

amide prodrug, hydrolyzed in vivo to (63), an analog of methoxamine, and a vasoconstrictor. Midodrine is used to treat orthostatic hypotension.

Nist 2011 Table
Orthostatic Hypotension Worksheet

Phenylephrine (11), also a selective a-ago-nist, may be administered parenterally for severe hypotension or shock but is much more widely employed as a nonprescription nasal decongestant in both oral and topical preparations.

The imidazolines naphazoline (29), oxy-metazoline (30), tetrahydozoline (31), and xy-lometazoline (32) are all selective a,-agonists, widely employed as vasoconstrictors in topical nonprescription drugs for treating nasal congestion or bloodshot eyes. Naphazoline and oxymetazoline are employed in both nasal decongestants and ophthalmic preparations, whereas tetrahydrozoline is currently marketed only for ophthalmic use and xylometa-zoline only as a nasal decongestant.

2.1.3 Applications of a2-Agonists. Amino-

imidazolines apraclonidine (33) and bri-monidine (34) are selective a,-agonists employed topically in the treatment of glaucoma. Stimulation of a,-receptors in the eye reduces production of aqueous humor and enhances outflow of aqueous humor, thus reducing intraocular pressure. Brimonidine is substantially more selective for a,-receptors over ax-

receptors than is apraclonidine. Although both are applied topically to the eye, measurable quantities of these drugs are detectable in plasma, so caution must be employed when the patient is also taking cardiovascular agents. Structurally related aminoimidazoline Clonidine (35) is a selective a2-agonist taken orally for treatment of hypertension. The anti-hypertensive actions of clonidine are mediated through stimulation of ^-adrenoceptors within the CNS, resulting in an overall decrease in peripheral sympathetic tone. Guanabenz (36) and guanfacine (37) are ring-opened analogs of by the same mechanism and employed as centrally acting antihypertensives.

Methyldopa (12) is another antihypertensive agent acting as an a,-agonist in the CNS through its metabolite, a-methyl-norepineph-rine (65). Methyldopa [the drug is the l-(S)-stereoisomer] is decarboxylated to a-methyl-dopamine (64) followed by stereospecific ß-hydroxylation to the (l.R,2S) stereoisomer of a-methylnorepinephrine (65). This stereoisomer is an a2-agonist that, like Clonidine, guanabenz, and guanfacine, causes a decrease in sympathetic output from the CNS.

Mechanism Agonist

2.1.4 Applications of /3-Agonists. Most of the /3-selective adrenergic agonists, albuterol (13;salbutamol in Europe), bitolterol (14), formoterol (15), isoetharine (16), isoproterenol (17), levalbuterol [#-(-)-(13)], metapro-terenol (18), pirbuterol (19), salmeterol (21), and terbutaline (22) are used primarily as bronchodilators in asthma and other constrictive pulmonary conditions. Isoproterenol (17) is a general j3-agonist, and the cardiac stimulation caused by its /¡^-activity and its lack of oral activity attributed to first-pass metabolism of the catechol ring have led to diminished use in favor of selective )32-agonists. Noncatechol-selective /32-agonists, such as albuterol (13), metaproterenol (18), and terbutaline (22), are available in oral dosage forms as well as in inhalers. All have similar activities and durations of action. Pirbuterol (19) is an analog of albuterol, in which the benzene ring has been replaced by a pyridine ring. Similar to albuterol, (19) is a selective

-agonist, currently available only for administration by inhalation. Bitolterol (14) is a prodrug, in which the catechol hydroxyl groups have been converted to 4-methylbenzoic acid esters, providing increased lipid solubility and prolonged duration of action. Bitolterol is administered by inhalation, and the ester groups are hydrolyzed by esterases to liberate the active catechol drug (66), which is subject to metabolism by COMT, although the duration of action of a single dose of the prodrug is up to 8 h, permitting less frequent administration and greater convenience to the patient. More recently developed selective /32-agonist bronchodilators are formoterol (15) and salmeterol (21), which have durations of action of 12 h or more. Terbutaline (22), in addition to its use as a bronchodilator, has also been used for halting the contractions of premature labor. Ritodrine (20) is a selective 02-agonist that is used exclusively for relaxing uterine muscle and inhibiting the contractions of premature labor.

2.1.5 Applications of Antiadrenergics. Gua-

nadrel (38) and guanethidine (39) are orally active antihypertensives, which are taken up into adrenergic neurons, where they bind to the storage vesicles and prevent release of neurotransmitter in response to a neuronal impulse, which results in generalized decrease in sympathetic tone. These drugs are available but seldom used.

Simple Water Cycle Diagram

Reserpine (60)is an old and historically important drug that affects the storage and release of norepinephrine. Reserpine is one of several indole alkaloids isolated from the roots cf Rauwolfia serpentina, a plant whose roots were used in India for centuries as a remedy for snakebites and as a sedative. Reserpine acts to deplete the adrenergic neurons of their stores of norepinephrine by inhibiting the active transport Mg-ATPase responsible for sequestering norepinephrine and dopamine within the storage vesicles. Monoamine oxidestroys the norepinephrine and dopamine that are not sequestered in vesicles. As a result the storage vesicles contain little neurotransmitter; adrenergic transmission is dramatically inhibited; and sympathetic tone is decreased, thus leading to vasodilation. Agents with fewer side effects have largely replaced reserpine in clinical use.

Metyrosine (23, a-methyl-l-tyrosine), a norepinephrine biosynthesis inhibitor, is in limited clinical use to help control hypertensive episodes and other symptoms of catechol-amine overproduction in patients with the rare adrenal tumor pheochromocytoma (10). Metyrosine, a competitive inhibitor of tyrosine hydroxylase, inhibits the production of catecholamines by the tumor. Although mety-rosine is useful in treating hypertension caused by excess catecholamine biosynthesis in pheochromocytoma tumors, it is not useful for treating essential hypertension.

2.1.6 Applications of Nonselective a-An-tagonists. Because antagonism of a,-adreno-ceptors in the peripheral vascular smooth muscle leads to vasodilation and a decrease in blood pressure attributed to a lowering of peripheral resistance, alpha-blockers have been employed as antihypertensives for decades. However, nonselective a-blockers such as phe-noxybenzamine (62), phentolamine (40), and tolazoline can also increase sympathetic output through blockade of inhibitory presynap-tic a,-adrenoceptors, resulting in an increase in circulating norepinephrine, which causes reflex tachycardia. Thus the use of these agents in treating most forms of hypertension has been discontinued and replaced by use of selective a,-antagonists discussed below. Current clinical use of the nonselective agents (40), (41), and (62) is primarily treatment of hypertension induced by pheochromocytoma, a tumor of the adrenal medulla, which secretes large amounts of epinephrine and nor-epinephrine into the circulation. Dapiprazole (61) is an ophthalmic nonselective a-antago-nist applied topically to reverse mydriasis induced by other drugs and is not used to treat hypertension.

2.1.7 Applications of Selective a,-Antago-nists. Quinazoline-selective a,-blockers doxazosin (42)f prazosin (43), and terazosin (44) have replaced the nonselective a-antagonists in clinical use as antihypertensives. Their ability to dilate peripheral vasculature has also made these drugs useful in treating Raynaud's syndrome. The a,-selective agents have a favorable effect on lipid profiles and decrease low density lipoproteins (LDL) and triglycerides, and increase high density lipoproteins (HDL).

Contraction of the smooth muscle of the prostate gland, prostatic urethra, and bladder neck is also mediated by ^-adrenoceptors, with a,, being predominant, and blockade of these receptors relaxes the tissue. For this reason the quinazoline a,-antagonists doxazosin (42), prazosin (43), and terazosin (44) have also found use in treatment of benign prostatic hyperplasia (BPH). However, prazosin, doxazosin, and terazosin show no significant selectivity for any of the three known a,-adrenoceptor subtypes, a,,, a,,, and a,, (11) The structurally unrelated phenylethylamine a1-antagonist tamsulosin (24) is many fold more selective for a,,-receptors than for the other

Tamsulosin is employed only for treatment of BPH, given that it has little effect on the a1B- and a1D-adrenoceptors, which predominate in the vascular bed (12) and have little effect on blood pressure (13).

2.1.8 Applications of /^-Antagonists. p-An-tagonists are among the most widely employed antihypertensives and are also considered the first-line treatment for glaucoma. There are 16 j3-blockers listed in Table 1.1 and 15 of them are in the chemical class of aryloxypro-panolamines. Only sotalol (25) is a phenylethylamine. Acebutolol (45), atenolol (46), biso-prolol (48), metoprolol (53), nadolol (54), penbutolol (55), pindolol (56), and proprano-are used to treat hypertension but not glaucoma. Betaxolol (47), carteolol (49), and timolol (58) are used both systemically to treat hypertension and topically to treat glaucoma. Levobetaxolol [S-(-)-(47)], levobunolol (51), and metipranolol (52) are employed only in treating glaucoma. Betaxolol (racemic 47) is available in both oral and ophthalmic dosage forms for treating hypertension and glaucoma, respectively, but levobetaxolol, the en-antiomerically pure S-(—)-stereoisomer is currently available only in an ophthalmic dosage form. Esmolol (50) is a very short acting administered intravenously for acute control of hypertension or certain supraventricular arrhythmias during surgery. Sotalol (25) is a nonselective j3-blocker used to treat ventricular and supraventricular arrhythmias not employed as an antihyperten-sive or antiglaucoma agent. j3-Antagonists must be used with caution in patients with asthma and other reactive pulmonary diseases because blockade of j32_a(lrenoceptors may exacerbate the lung condition. Even the agents listed as being /^-selective have some level of j32-blocking activity at higher therapeutic doses. Betaxolol is the most jSj-selective of the currently available agents.

2.1.9 Applications of a/p-Antagonists. Car-

vedilol (59), an aryloxypropanolamine, has both a- and /3-antagonist properties and is used both as an antihypertensive and to treat cardiac failure. Both enantiomers have selective a,-antagonist properties but most of the ^-antagonism is attributable to the S-(~) isomer. Labetalol (26) is also an antihypertensive with both selective a,-antagonist properties and nonselective jS-antagonism. Labetalol is an older drug than carvedilol and is not as potent as carvedilol, particularly as a j3-antag-onist.

21.10 Applications of Agonists/Antagonists. Dobutamine (27) is a positive inotropic agent administered intravenously for congestive heart failure. The (+)-isomer has both a and ]3 agonist effects, whereas the (-)-isomer is an a-antagonist but a j3-agonist like the en-antiomer. The j3-stimulatory effects predominate as the a-effects cancel. As a catechol it has no oral activity and even given intravenously has a half-life of only 2 min. Isoxsu-prine (28) is an agent with a-antagonist and j3-agonist properties, which has been used for peripheral and cerebral vascular insufficiency and for inhibition of premature labor. Isoxsu-prine is seldom used any more.

2.2 Absorption, Distribution, Metabolism, and Elimination

Because of the large numbers of chemicals acting as either adrenergics or adrenergic-block-ing drugs, only representative examples will be given and limited to metabolites identified in humans. Because drugs with similar structures are often metabolized by similar routes, the examples chosen are representative of each structural class. Although it contains no structural details of metabolic pathways, Drug Facts and Comparisons (14) is an outstanding comprehensive compilation of pharmacokinetic parameters such as absorption, duration of action, and routes of elimination for drugs approved by the FDA for use in the United States.

2.2.1 Metabolism of Representative Phenyl-ethylamines. Norepinephrine (1) and epinephrine (2) are both substrates for MAO, which oxidatively deaminates the side chain of either to form the same product DOPGAL (67), and for catechol-O-methyltransferase (COMT), which methylates the 3'-phenolic OH of each to form (68). Metabolite (68) is subsequently oxidized by MAO to form aldehyde (69), and aldehyde (68) may be methylated by COMT to also form (69). This aldehyde may then be either oxidized by aldehyde dehydrogenase (AD) to (70) or reduced by aldehyde reductase to alcohol (71). Alternate routes to (70) and (71) from (67) are also shown. Several of these metabolites are excreted in the urine as sulfate and glucuronide conjugates (15).As previously mentioned, neither (1)nor (2) is orally active because of extensive first-pass metabolism by COMT, and both have short durations of action because of rapid metabolic deactivation by the routes shown. Any catechol-containing drug will also likely be subject to metabolism by COMT.

Ephedrine (5), a close structural analog of (2), having no substituents on the phenyl ring, is well absorbed after an oral dose and over half the dose is eliminated unchanged in the urine. The remainder of the dose is largely desmethylephedrine (72), deamination product (73), and small amounts of benzoic acid and its conjugates (16). No aromatic ring-hy-droxylation products were detected. This is in marked contrast to the case with amphetamine (3), in which ring-hydroxylated products are major metabolites.

Albuterol (13) is not subject to metabolism by COMT and is orally active but does have a 4'- OH group subject to conjugation. The major metabolite of albuterol (13) is the 4'-0-sulfate (74) (17). The sulfation reaction is ste-

Albuterol Sulfate Reaction

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