Antimuscarinic alkaloid

For a long time, muscarinic receptor-blocking drugs occupied a major place in the therapy of asthma, but they have been largely displaced by the adrenergic drugs (see Chapter 41). The problems associated with the use of antimuscarinic alkaloids in respiratory disorders are low therapeutic index and impaired expectoration. The... 

E. Antidiarrbeal Agents The most effective antidiarrheal drugs are the opioids and derivatives of opioids that have been selected for maximal antidiarrheal and minimal CNS effect. Of the latter group, the most important are diphenoxylate and loperamide, meperidine analogs with very weak analgesic effects. Difenoxin, the active metabolite of diphenoxylate, is also available as a prescription medication. Diphenoxylate is formulated with antimuscarinic alkaloids to reduce the already minimal likelihood of abuse loperamide is formulated alone and sold over the counter as such. 

Atropine is an antimuscarinic alkaloid which possesses both central and peripheral actions. It exerts first a stimulating and then a depressing action on the central nervous system (CNS) and exhibits antispasmodic actions on the smooth muscle. On account of its broad spectrum of effects in the body the therapeutic applications are numerous, but unfortunately it lacks selectivity of action. 

Antimuscarinic drags are classified in the following manner alkaloids (atropine, hyocyamine, scopolamine) anticholinergic of the quaternary amine series (anisotropin. 

Furthermore, central-acting antimuscarinic drug are effective in the treatment of motion sickness. In this indication the alkaloid scopolamine has been shown to be effective. It can be applied orally, intra venously or via a transdermal therapeutic system. 

The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopolamine (Scopolamine). They are tertiary amines that contain an ester linkage. Atropine is a racemic mixture of DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active. Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural similarity to the belladonna alkaloids are also in use. All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group. 

Antimuscarinic poisoning can result from the intake of excessive doses of belladonna alkaloids, synthetic antimuscarinic drugs, and drugs from other pharmacological groups that have significant antimuscarinic activity (Table 13.2). 

Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared. 

Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route). In contrast, only 10-30% of a dose of a quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule. 

The solanaceae alkaloids and other other sources of antimuscarinics affect the CNS. They can produce hallucinations in addition to their effects on the peripheral nervous system. Witchcraft of the Middle Ages produced mixtures of plants - deadly nightshade, monkshood, and hemlock among them - as "flying ointments". The combined toxins disturbed the rhythm of the heart and led to delirium which could create a sensation of rising and falling, that is, flying. 

Note The best-known antimuscarinic or anticholinergic drugs are the belladonna alkaloids. The major drugs in this class are atropine, hyoscyamine, and scopolamine. A number of plants belonging to the potato family (Solanaceae) contain similar alkaloids. Atropa belladonna (deadly nightshade), Hyoscyamus niger (henbane), Datura stramonium (jimsonweed or thorn apple), and several species of Scopolia also contain belladonna alkaloids. 

The tertiary members of these classes (Figure 8-2) are often used for their effects on the eye or the central nervous system. Many antihistaminic (see Chapter 16 Histamine, Serotonin, the Ergot Alkaloids), antipsychotic (see Chapter 29 Antipsychotic Agents Lithium), and antidepressant (see Chapter 30 Antidepressant Agents) drugs have similar structures and, predictably, significant antimuscarinic effects. 

John H, Binder T, Hochstetter H, Thiermann H (2010) LC-ESI MS/MS quantification of atropine and six other antimuscarinic tropane alkaloids in plasma. Anal Bioanal Chem 396 751-763... 

As a class, anticholinergics include the antihistamines, atropine and homatropine anti-Parkinsonian agents like benzotropine, procyclidine, and trihexyphenidyl the antimuscarinics of which atropine is the prototype and antispasmodics like dicyclomine and oxybutymin. Most antimuscarinics are amino-alcohols or their derivatives (usually esters or ethers), aminoamides, or other amines. Antimuscarinics can be divided into two groups. These are the naturally occurring alkaloids and their semisynthetic derivatives like atropine, homatropine, scopolamine, and hyoscyamine and the synthetic amine compounds such as anisotropine, dicyclomine, and ipratropium. 

Bronchodilation is another property of belladonna alkaloids of potential usefulness. Due to relaxation of the smooth musculature of bronchial passageways, this effect has found applications in asthma and other pulmonary obstructive conditions. At one time the smoking of cigarettes made of stramonium leaves was popular. More recently, atropine, quater-nized with isopropyl bromide (Ipratropium, Fig. 8-13) has been introduced as an aerosol for inhalation. This renewed interest in antimuscarinics resulted in part from clarifications of the role of the parasympathetic system in bronchial obstructions. The availability of a potent agent such as atropine in a poorly absorbed form (i.e., quatemized) would minimize systemic effects following inhalation. Ipratropium bromide does not cross the BBB. It is longer acting and more bronchoselective than atropine methylbromide and exhibits no CNS effects. 

A. Prototypes and Pharmacokinetics Atropine and other naturally occurring belladonna alkaloids were used for many years in the treatment of asthma with only modest benefits. A quaternary antimuscarinic agent designed for aerosol use, ipratropium, has achieved much greater success. This drug is dehvered to the airways by pressurized tierosol. When absorbed, ipratropium is rapidly metabolized and has little systemic action. 

The term antimuscarinic is derived from the action of acetylcholine at the postganglionic synapse which is closely imitated by the alkaloid, muscarine. 

The prototype antimuscarinic agent is atropine, an alkaloid isolated from Atropa belladona (deadly nightshade) and many other plants. Atropine blocks the muscarinic actions of cholinergic agonists (Table 2.5). 

The classic chemical prototype for the antimuscarinics is atropine, an alkaloid from/Afropa belladonna. Buried within its structure is the amino alcohol ester pharmacophore, where Ri is a hydroxymethyl group, R2 is a hydrogen, and the nitrogen is part of a bicyclic ring system called tropine (Fig. 44.17). 

Areca contains arecoline, an alkaloid with cholinergic activity, which could therefore oppose the antimuscarinic (anticholinergic) actions of procyclidine. As the procyclidine was being used to control the extrapyrami-dal adverse effects of the two antipsychotics, opposing its action allowed the adverse effects to re-emerge and worsen. 

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