The solanaceous alkaloids are generally agreed to be potent parasympatholytics, but they have the undesirable property of producing a wide range of effects through their nonspecific blockade of autonomic functions. Efforts to use the antispasmodic effect of the alkaloids most often result in side effects such as dryness of the mouth and fluctuations in pulse rate. Therefore, synthesis of compounds possessing specific cholinolytic actions has been a very desirable field of study. Few prototypical drugs were as avidly dissected in the minds of researchers as atropine in attempts to modify its structure to separate the numerous useful activities (i.e., antispasmodic, antisecretory, mydriatic, and cyclo-plegic). Most early research was carried out in the pre- and post-World War II era before muscarinic receptor subtypes were known.
Efforts at synthesis started with rather minor deviations from the atropine molecule, but a review of the commonly used drugs today indicates a marked departure from the rigid tropane aminoalcohols and tropic acid residues. Examination of the structures of antispasmodics shows that the acid portion has been designed to provide a large hy-drophobic moiety rather than the stereospecific requirement of (S)-tropic acid in ( — )-hyoscyamine that was once considered important. One of the major developments in the field of aminoalcohol esters was the successful introduction of the quaternary ammonium derivatives as contrasted with the tertiary amine-type esters synthesized originally. Although some effective tertiary amine esters are in use today, the quaternaries, as a group, represent the more popular type and appear to be slightly more potent than their tertiary amine counterparts.
The accompanying formula shows the portion of the atropine molecule (enclosed in the curved dotted line) believed to be responsible for its major activity. This is sometimes called the spasmophoric group and compares with the anesthesiophoric group obtained by similar dissection of the cocaine molecule. The validity of this conclusion has been amply borne out by the many active compounds having only a simple diethylaminoethyl residue replacing the tropine portion.
The aminoalcohol portion of eucatropine may be considered a simplification of the atropine molecule. In eucatropine, the bicyclic tropine has been replaced by a monocyclic aminoalcohol and mandelic acid replaces tropic acid (see under "Products").
Although simplification of the aminoalcohol portion of the atropine prototype has been a guiding principle in most research, many of the anticholinergics now used still include a cyclic aminoalcohol moiety. The aminoalcohol ester anticholinergics are used primarily as antispasmodics or mydriatics, and cholinolytic compounds classed as aminoalcohol or aminoalcohol ether analogs of atropine are, with few exceptions, used as antiparkinsonian drugs.
Another important feature in many of the synthetic anti-cholinergics used as antispasmodics is that they contain a quaternary nitrogen, presumably to enhance activity. The initial synthetic quaternary compound methantheline bromide has served as a forerunner for many others. These compounds combine anticholinergic activity of the antimuscarinic type with some ganglionic blockade to reinforce the parasympathetic blockade. Formation of a quaternary ammonium moiety, however, introduces the possibility of blockade of voluntary synapses (curariform activity); this can become evident with sufficiently high doses.
The antimuscarinic compounds now in use are described in the following monographs.
Clidinium Bromide, USP. Clidinium bromide, 3-hy-droxy-1-methylquinuclidinium bromide benzilate (Quarzan), is a white or nearly white, almost odorless, crystalline powder that is optically inactive. It is soluble in water and alcohol but only very slightly soluble in ether and benzene.
This anticholinergic agent is marketed alone and in combination with the minor tranquilizer chlordiazepoxide (Librium) in a product known as Librax. The rationale of the combination for the treatment of GI complaints is the use of an anxiety-reducing agent together with an anticholinergic agent, based on the recognized contribution of anxiety to the development of the diseased condition. It is suggested for peptic ulcer, hyperchlorhydria, ulcerative or spastic colon, anxiety states with GI manifestations, nervous stomach, irritable or spastic colon, and others. Clidinium bromide is contraindi-cated in glaucoma and other conditions that may be aggravated by the parasympatholytic action, such as prostatic hypertrophy in elderly men, which could lead to urinary retention.
Cyclopentolate Hydrochloride, USP. Cyclopentolate hydrochloride, 2-dimethylaminoethyl 1-hydroxy-a-phenyl-cyclopentaneacetate hydrochloride (Cyclogyl), is a crystalline, white, odorless solid that is very soluble in water, easily soluble in alcohol, and only slightly soluble in ether. A 1% solution has a pH of 5.0 to 5.4.
It is used only for its effects on the eye, where it acts as a parasympatholytic. When placed in the eye, it quickly produces cycloplegia and mydriasis. Its primary field of usefulness is in refraction studies. Cyclopentolate hydrochloride can be used, however, as a mydriatic in the management of iritis, iridocyclitis, keratitis, and choroiditis. Although it does not seem to affect intraocular tension significantly, it is best to be very cautious with patients with high intraocular pressure and with elderly patients with possible unrecognized glaucomatous changes.
Cyclopentolate hydrochloride has one half of the antispasmodic activity of atropine and is nonirritating when instilled repeatedly into the eye. If not neutralized after the refraction studies, its effect dissipates within 24 hours. Neutralization with a few drops of pilocarpine nitrate solution, 1% to 2%, often results in complete recovery in 6 hours. It is supplied as a ready-made ophthalmic solution in concentrations of either 0.5% or 2%.
Dicyclomine Hydrochloride, USP. Dicyclomine hydrochloride, 2-(diethylamino)ethyl bicyclohexyl-1-carboxyl-
ate hydrochloride (Bentyl), has some muscarinic receptor subtype selectivity. It binds more firmly to M1 and M3 than to M2 and M4 receptors.76
Dicyclomine hydrochloride has one eighth of the neu-rotropic activity of atropine and approximately twice the musculotropic activity of papaverine. This preparation, first introduced in 1950, has minimized the adverse effects associated with the atropine-type compounds. It is used for its spasmolytic effect on various smooth muscle spasms, particularly those associated with the GI tract. It is also useful in dysmenorrhea, pylorospasm, and biliary dysfunction.
Eucatropine Hydrochloride, USP. Eucatropine hydrochloride, euphthalmine hydrochloride or 1,2,2,6-tetram-ethyl-4-piperidyl mandelate hydrochloride, possesses the aminoalcohol moiety characteristic of one of the early local anesthetics (e.g., j-eucaine) but differs in the acidic portion of the ester by being a mandelate instead of a benzoate. The salt is an odorless, white, granular powder, providing solutions that are neutral to litmus. It is very soluble in water, freely soluble in alcohol and chloroform, but almost insoluble in ether.
The action of eucatropine hydrochloride closely parallels that of atropine, although it is much less potent than the latter. It is used topically in a 0.1 mL dose as a mydriatic in 2% solution or in the form of small tablets. Use of concentrations from 5% to 10% is, however, not uncommon. Dilation, with little impairment of accommodation, takes place in about 30 minutes, and the eye returns to normal in 2 to 3 hours.
Glycopyrrolate, USP. Glycopyrrolate, 3-hydroxy-1, 1-dimethylpyrrolidinium bromide a-cyclopentylmandelate (Robinul), occurs as a white, crystalline powder that is soluble in water or alcohol but practically insoluble in chloroform or ether.
Glycopyrrolate is a typical anticholinergic and possesses, at adequate dosage levels, the atropine-like effects characteristic of this class of drugs. It has a spasmolytic effect on the musculature of the GI tract as well as the genitourinary tract. It diminishes gastric and pancreatic secretions and the quantity of perspiration and saliva. Its side effects are also typically atropine-like (i.e., dryness of the mouth, urinary retention, blurred vision, constipation). Glycopyrrolate is a more potent antagonist on M1 than on M2 and M3 receptors. The low affinity of M2 receptors may, in part, explain the low incidence of tachycardia during use of this drug as an antispasmodic.77 Because of its quaternary ammonium character, glycopyrrolate rarely causes CNS disturbances, although in sufficiently high dosage, it can bring about ganglionic and myoneural junction block.
The drug is used as an adjunct in the management of peptic ulcer and other GI ailments associated with hyperacidity, hypermotility, and spasm. In common with other anticholinergics, its use does not preclude dietary restrictions or use of antacids and sedatives if these are indicated.
Mepenzolate Bromide. Mepenzolate bromide, 3-hy-droxy-1,1-dimethylpiperidinium bromide benzilate (Cantil), has an activity about one half that of atropine in reducing ACh-induced spasms of the guinea pig ileum. The selective action on colonic hypermotility is said to relieve pain, cramps, and bloating and to help curb diarrhea.
Methantheline Bromide, USP. Methantheline bromide, diethyl(2-hydroxyethyl)methylammonium bromide xanthene-9-carboxylate (Banthine Bromide), is a white, slightly hygroscopic, crystalline salt that is soluble in water to produce solutions with a pH of about 5. Aqueous solutions are not stable and hydrolyze in a few days. The bromide form is preferable to the very hygroscopic chloride.
This drug, introduced in 1950, is a potent anticholinergic agent and acts at the nicotinic cholinergic receptors of the sympathetic and parasympathetic systems, as well as at the myoneural junction of the postganglionic cholinergic fibers. Like other quaternary ammonium drugs, methantheline bromide is absorbed incompletely from the GI tract.
Among the conditions for which methantheline bromide is indicated are gastritis, intestinal hypermotility, bladder irritability, cholinergic spasm, pancreatitis, hyperhidrosis, and peptic ulcer, all of which are manifestations of parasympathotonia.
Side reactions are atropine-like (mydriasis, cycloplegia, dryness of mouth). The drug is contraindicated in glaucoma. Toxic doses may bring about a curare-like action, a not too surprising fact when it is considered that ACh is the mediating factor for neural transmission at the somatic myoneural junction. This side effect can be counteracted with neostig-mine methylsulfate.
Oxyphencyclimine Hydrochloride. Oxyphencyclimine hydrochloride, 1,4,5,6-tetrahydro-1 -methyl-2-pyrimidinyl) methyl a-phenylcyclohexaneglycolate monohydrochloride (Daricon, Vistrax), was introduced in 1958 and promoted as a peripheral anticholinergic-antisecretory agent, with little or no curare-like activity and little or no ganglionic blocking activity. These activities are probably absent because of the tertiary character of the molecule. This activity is in contrast with that of compounds that couple antimuscarinic action with ganglionic blocking action. The tertiary character of the nitrogen promotes intestinal absorption of the molecule. Perhaps the most significant activity of this compound is its marked ability to reduce both the volume and the acid content of the gastric juices, a desirable action in view of the more recent hypotheses pertaining to peptic ulcer therapy. Another important feature of this compound is its low toxicity in comparison with many of the other available anticholinergics. Oxyphencyclimine hydrochloride is hydrolyzed in the presence of excessive moisture and heat. It is absorbed from the GI tract and has a duration of action of up to 12 hours.
Oxyphencyclimine hydrochloride is suggested for use in peptic ulcer, pylorospasm, and functional bowel syndrome. It is contraindicated, as are other anticholinergics, in patients with prostatic hypertrophy and glaucoma.
Propantheline Bromide, USP. Propantheline bromide, 2-hydroxy-ethyl)diisopropylmethylammonium bromide xanthene-9-carboxylate (Pro-Banthine), is prepared in a manner exactly analogous to that used for methantheline bromide. It is a white, water-soluble, crystalline substance, with properties quite similar to those of methantheline bromide. Its chief difference from methantheline bromide is in its potency, which has been estimated variously to be 2 to 5 times as great.
metabolic profile, largely a result of its highly water-soluble characteristics.79
Oxybutynin. Oxybutynin, 4-Diethylaminobut- 2-ynyl2-cyclohexyl-2- hydroxy-2-phenyl-ethanoate, (Oxytrol) was one of the first agents specifically developed to exploit the effects that cholinergic blocking agents have on the bladder. By competitively blocking the muscarinic receptors, it has direct spasmolytic effects on bladder smooth muscle. This reduction in smooth muscle tone allows for greater volumes of urine to be stored in the bladder, which results in less urinary incontinence, urgency, and frequency. Oxybutynin acts as a competitive antagonist on Mi, M2, and M3 receptor subtypes.78
Trospium Chloride. Trosoium chloride, 3a-benziloy-loxynortropane-8-spiro-1'-pyrrolidinium chloride, (Sanctura) was available in Europe for almost 20 years before gaining approval in the United States in May 2004. Much like oxybutynin, it too is a competitive antagonist for muscarinic receptors and is used to manage overactive bladder. The quaternary amine reduces the likelihood that this agent will cross the blood-brain barrier. In addition, it has a limited
Solifenacin Succinate. Solifenacin succinate (Vesicare), ( + )-(1S, 3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahy-droisoquinoline-2-carboxylate, is a competative antagonist for M1, M2, and M3 receptor subtypes. One of the issues surrounding the use of such antagonists is the selectivity for the bladder over other tissue such as the salivary glands. It is reported that the selectivity of solifenacin for bladder muscarinic receptors over salivary receptors is superior to the effects observed with oxybutynin.80
The aminoalcohol ethers thus far introduced have been used as antiparkinsonian drugs rather than as conventional anticholinergics (i.e., as spasmolytics or mydriatics). In general, they may be considered closely related to the anti-histaminics and, indeed, do possess substantial antihistamine properties. In turn, the antihistamines possess anticholinergic activity and have been used as antiparkinsonian agents. Comparison of chlorphenoxamine and or-phenadrine with the antihistaminic diphenhydramine illustrates the close similarity of structure. The use of diphenhydramine in parkinsonism has been cited previously. Benztropine may also be considered a structural relative of diphenhydramine, although the aminoalcohol portion is tropine and, therefore, more distantly related than chlorphenoxamine and orphenadrine. In the structure of benztropine, a three-carbon chain intervenes between the nitrogen and oxygen functions, whereas the others evince a two-carbon chain. However, the rigid ring structure possibly orients the nitrogen and oxygen functions into more nearly the two-carbon chain interprosthetic distance than is apparent at first glance. This, combined with the flexibility of the alicyclic chain, would help to minimize the distance discrepancy.
Benztropine Mesylate, USP. Benztropine mesylate, 3a-(diphenylmethoxy)-1ah,5ah-tropane methanesulfonate (Cogentin), has anticholinergic, antihistaminic, and local anesthetic properties. Its anticholinergic effect makes it applicable as an antiparkinsonian agent. It is about as potent an anticholinergic as atropine and shares some of the side effects of this drug, such as mydriasis and dryness of mouth. Importantly, however, it does not produce central stimulation but instead exerts the characteristic sedative effect of the antihistamines.
The tremor and rigidity characteristic of parkinsonism are relieved by benztropine mesylate, and it is particularly valuable for those patients who cannot tolerate central excitation (e.g., aged patients). It may also have a useful effect in minimizing drooling, sialorrhea, masklike facies, oculo-gyric crises, and muscular cramps.
The usual caution exercised with any anticholinergic in glaucoma and prostatic hypertrophy is observed with this drug.
Orphenadrine Citrate. Orphenadrine citrate, n,n-dimethyl-2-(o-methyl-a-phenylbenzyloxy)ethylamine citrate (1:1) (Norflex), introduced in 1957, is closely related to diphenhydramine structurally but has much lower antihistaminic activity and much higher anticholinergic action. Likewise, it lacks the sedative effects characteristic of diphenhydramine. Pharmacological testing indicates that it is not primarily a peripherally acting anticholinergic because it has only weak effects on smooth muscle, on the eye, and on secretory glands. It does reduce voluntary muscle spasm, however, by a central inhibitory action on cerebral motor areas, a central effect similar to that of atropine.
drug combats mental sluggishness, akinesia, adynamia, and lack of mobility, but this effect seems to diminish rather rapidly with prolonged use. It is best used as an adjunct to the other agents, such as benztropine, procyclidine, cycrimine, and trihexyphenidyl, in the treatment of paralysis agitans. Orphenadrine citrate is also used as an adjunct to rest, physiotherapy, and other measures to relieve pain of local muscle spasm (e.g., nocturnal leg cramps).
The drug has a low incidence of the usual side effects for this group, namely, dryness of mouth, nausea, and mild excitation.
The development of aminoalcohols as parasympatholytics took place in the 1940s. It was soon established, however, that these antispasmodics were equally efficacious in parkinsonism.
Several of the drugs in this class of antimuscarinic agents possess bulky groups in the vicinity of hydroxyl and cyclic amino functional groups. These compounds are similar to the classic aminoester anticholinergic compounds derived from atropine. The presence of the alcohol group seems to substitute adequately as a prosthetic group for the carboxyl function in creating an effective parasympathetic blocking agent. The aminoester group, per se, is not a necessary adjunct to choli-nolytic activity, provided that other polar groupings, such as the hydroxyl, can substitute as a prosthetic group for the carboxyl function. Another structural feature common to all aminoalcohol anticholinergics is the y-aminopropanol arrangement, with three carbons intervening between the hy-droxyl and amino functions. All of the aminoalcohols used for paralysis agitans are tertiary amines. Because the desired locus of action is central, formation of a quaternary ammonium moiety destroys the antiparkinsonian properties. These aminoalcohols have been quaternized, however, to enhance the anticholinergic activity to produce an antispasmodic and antisecretory compound, such as tridihexethyl chloride.
Biperiden, USP. Biperiden, a-5-norbornen-2-yl-a-phenyl-1-piperidinepropanol (Akineton), introduced in 1959, has a relatively weak visceral anticholinergic, but a strong nicotinolytic, action in terms of its ability to block nicotine-induced convulsions. Therefore, its neurotropic action is rather low on intestinal musculature and blood vessels. It has a relatively strong musculotropic action, which is about equal to that of papaverine, in comparison with most synthetic anticholinergic drugs. Its action on the eye, although mydriatic, is much lower than that of atropine. These weak anticholinergic effects add to its usefulness in Parkinson syndrome by minimizing side effects.
This drug is used for the symptomatic treatment of Parkinson disease. It relieves rigidity better than it does tremor, and in certain cases, it may accentuate the latter. The
The drug is used in all types of Parkinson disease (pos-tencephalitic, idiopathic, arteriosclerotic) and helps to eliminate akinesia, rigidity, and tremor. It is also used in drug-induced extrapyramidal disorders to eliminate symptoms and permit continued use of tranquilizers. Biperiden is also of value in spastic disorders not related to parkinsonism, such as multiple sclerosis, spinal cord injury, and cerebral palsy. It is contraindicated in all forms of epilepsy.
Biperiden Hydrochloride, USP. Biperiden hydrochloride, a-5-norbornen-2-yl-a-phenyl-1-piperidinepropanol hydrochloride (Akineton hydrochloride), is a white, optically inactive, crystalline, odorless powder that is slightly soluble in water, ether, alcohol, and chloroform and sparingly soluble in methanol.
Biperiden hydrochloride has all of the actions described for biperiden. The hydrochloride is used for tablets because it is better suited to this dosage form than is the lactate salt. As with the free base and the lactate salt, xerostomia (dry-ness of the mouth) and blurred vision may occur.
Procyclidine Hydrochloride, USP. Procyclidine hydrochloride, a-cyclohexyl-a-phenyl-1-pyrrolidinepropanol hydrochloride (Kemadrin), was introduced in 1956. Although it is an effective peripheral anticholinergic and, indeed, has been used for peripheral effects similar to its methochloride (i.e., tricyclamol chloride), its clinical usefulness lies in its ability to relieve voluntary muscle spasticity by its central action. Therefore, it has been used with success in the treatment of Parkinson syndrome. It is said to be as effective as trihexyphenidyl and is used to reduce muscle rigidity in postencephalitic, arteriosclerotic, and idiopathic types of the disease. Its effect on tremor is not predictable and probably should be supplemented by combination with other similar drugs.
Although this drug, introduced in 1958, has ganglion-blocking activity, its peripheral atropine-like activity predominates; therefore, its therapeutic application has been based on the latter activity. It possesses the antispasmodic and the antisecretory activities characteristic of this group, but because of its quaternary character, it is valueless in relieving Parkinson syndrome.
The drug is useful for adjunctive therapy in a wide variety of GI diseases, such as peptic ulcer, gastric hyperacidity, and hypermotility and spastic conditions, such as spastic colon, functional diarrhea, pylorospasm, and other related conditions. Because its action is predominantly antisecretory, it is more effective in gastric hypersecretion than in hy-permotility and spasm. It is best administered intravenously for the latter conditions.
The side effects usually found with effective anticholiner-gic therapy occur with the use of this drug. These are dryness of mouth, mydriasis, and such. As with other anticholinergics, care should be exercised when administering the drug to patients with glaucomatous conditions, cardiac decompensation, and coronary insufficiency. It is contraindicated in patients with obstruction at the bladder neck, prostatic hypertrophy, stenosing gastric and duodenal ulcers, or pyloric or duodenal obstruction.
Trihexyphenidyl Hydrochloride, USP. Trihexyphenidyl hydrochloride, a-cyclohexyl-a-phenyl-1-piperidinepro-panol hydrochloride (Artane, Tremin, Pipanol), introduced in 1949, is approximately half as active as atropine as an anti-spasmodic but is claimed to have milder side effects, such as mydriasis, drying of secretions, and cardioacceleration. It has a good margin of safety, although it is about as toxic as atropine. It has found a place in the treatment of parkinsonism and is claimed to provide some measure of relief from the mental depression often associated with this condition. It
The toxicity of the drug is low, but when the dosage of the drug is high, side effects are noticeable. At therapeutic dosage levels, dry mouth is the most common side effect. The same care should be exercised with this drug as with all other anticholinergics when it is administered to patients with glaucoma, tachycardia, or prosta-tic hypertrophy.
Tridihexethyl Chloride, USP. Tridihexethyl chloride, 3-cyclohexyl-3-hydroxy-3-phenylpropyl)triethylammonium chloride (Pathilon), is a white, bitter, crystalline powder with a characteristic odor. The compound is freely soluble in water and alcohol, with aqueous solutions being nearly neutral in reaction.
does, however, exhibit some of the side effects typical of the parasympatholytic-type preparation, although adjusting the dose carefully may often eliminate these.
Tolterodine. Tolterodine (Detrol), 2-[3-[bis(1-methyl-ethyl)amino]-1-phenyl-propyl]-4-methyl-phenol, is an an-timuscarinic agent that acts on M2 and M3 muscarinic subtype receptors. By competitively blocking of the muscarinic receptors results in a reduction of the smooth muscle tone, allowing for greater volume of urine to be stored in the bladder. This results in less urinary incontinence, urgency, and frequency.81
From a structural standpoint, the aminoamide type of anti-cholinergic represents the same type of molecule as the aminoalcohol group, with the important exception that the polar amide group replaces the corresponding polar hy-droxyl group. Aminoamides retain the same bulky structural features found at one end of the molecule or the other in all of the active anticholinergics. Isopropamide iodide is the only drug of this class currently in use.
Another amide-type structure is that of tropicamide, formerly known as bis-tropamide, a compound with some of the atropine features.
Isopropamide Iodide, USP. Isopropamide iodide, 3-car-bamoyl-3,3-diphenylpropyl)diisopropylmethylammonium iodide (Darbid), occurs as a bitter, white to pale yellow, crystalline powder that is only sparingly soluble in water but freely soluble in chloroform and alcohol.
quaternary nature, it does not cause sympathetic blockade at the ganglionic level except at high dosages. Its principal distinguishing feature is its long duration of action. A single dose can provide antispasmodic and antisecretory effects for as long as 12 hours.
It is used as adjunctive therapy in the treatment of peptic ulcer and other conditions of the GI tract associated with hypermotility and hyperacidity. It has the usual side effects of anticholinergics (dryness of mouth, mydriasis, difficult urination) and is contraindicated in glaucoma, prostatic hypertrophy, etc.
Tropicamide, USP. Tropicamide, n-ethyl-2-phenyl-N-(4-pyridylmethyl)hydracrylamide (Mydriacyl), is an effective anticholinergic for ophthalmic use when mydri-asis is produced by relaxation of the sphincter muscle of the iris, allowing adrenergic innervation of the radial muscle to dilate the pupil. Its maximum effect is achieved in about 20 to 25 minutes and lasts for about 20 minutes, with complete recovery in about 6 hours. Its action is more rapid in onset and wears off more rapidly than that of most other mydriatics. To achieve mydriasis, either 0.5% or 1.0% concentration may be used, although cycloplegia is achieved only with the stronger solution. Its uses are much the same as those described above for mydriatics in general, but opinions differ on whether the drug is as effective as homatropine, for example, in achieving cycloplegia. For mydriatic use, however, in examination of the fundus and treatment of acute iritis, iridocyclitis, and keratitis, it is quite adequate; and because of its shorter duration of action, it is less prone to initiate a rise in intraocular pressure than the more potent, longer-lasting drugs. As with other mydriatics, however, pupil dilation can lead to increased intraocular pressure. In common with other mydriatics, it is contraindicated in patients with glaucoma, either known or suspected, and should not be used in the presence of a shallow anterior chamber. Thus far, no allergic reactions or ocular damage has been observed with this drug. The ability to clone the various muscarinic receptor subtypes has allowed the observation that tropicamide has modest selectivity for the M4 receptor.82
n = 5 or 6, active as ganglionic blockers (feeble curariform activity)
n = 9 to 12, weak ganglionic blockers (strong curariform activity)
This drug, introduced in 1957, is a potent anticholinergic, producing atropine-like effects peripherally. Even with its
Darifenacin Hydrobromide. Darfenacin (Enablex), (s)-2-(1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphen-ylacetamide, is an antimus-carinic agent that has selectivity for the M3 muscarinic subtype receptor. By competitively blocking of the muscarinic receptors results in a reduction of the smooth muscle tone, allowing for greater volume of urine to be stored in the bladder. This results in less urinary incontinence, urgency, and frequency. It is a white to almost white, crystalline powder, with a molecular weight of 507.5. Darifenacin is metabolized by the isozymes CYP2D6 and CYP3A4 with the primary metabolic routes being monohydroxylation of the dihydrobenzofuran ring, opening of the dihydrobenzofuran ring, and N-dealkylation of the pyrrolidine nitrogen.83
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