Antimuscarinics

Hydroxybenzoate preservatives inactivate atropine sulfate in physical mixtures. Atropine can be used for treating acetylcholine poisoning. Organophosphorous pesticides are treated by use of diazepam, phenothiazines, and physostigmine.149 

Atropine interacts with antipsychotics, antihistamines, phenothiazines, and antidepressant drugs. Benzhexol, orphenadrine, and oxybutynin hydrochloride are drugs of potential abuse poisoning and withdrawal symptoms are reported.150 

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Quinidine, the classical class IA drug, binds to the open state oftheNa+ channel, and prolongs the action potential by block of the delayed rectifier-. In higher concentrations, L-type Ca2+ channels are inhibited. Quinidine exerts antimuscarinic effects, thereby accelerating AV-nodal... 

Further class IA drugs include the open state blockers procainamide and disopyramide with electrophysiolog-ical effects similar to those of quinidine procainamide lacks the antimuscarinic and antiadrenergic effects. Characteristic side effects of procainamide are hypotension and immunological disorders. 

The antimuscarinic drug atropine, and its derivative ipratropiumbromide, can also be used for antiarrhyth-mic treatment. Muscarinic receptors (M2 subtype) are mainly present in supraventricular tissue and in the AV node. They inhibit adenylylcyclase via G proteins and thereby reduce intracellular cAMP. On the other hand, activation of the M2 receptor leads to opening of hyperpolarizing Ik.acii and inhibits the pacemaker current If probably via the (3y-subunit of the Gi protein associated with this receptor. The results are hyperpolarization and slower spontaneous depolarization. Muscarinic receptor antagonists like atropine lead to increased heart rate and accelerated atrioventricular conduction. There are no or only slight effects on the ventricular electrophysiology. 

Antimuscarinic drugs such as atropine have been used to modest effect in the treatment of PD for more than a century attenuating tremor and rigidity but with little effect on akinesia. Currently benzhexol and benztropine are sometimes added to levodopa therapy but peripheral effects such as dry mouth, blurred vision and constipation are unpleasant. They are also often used to counteract neuroleptic-induced extrapyramidal effects. 

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

Figure 17.7 Possible mechanism by which atypical neuroleptics with antimuscarinic activity produce few EPSs. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. 15.2). An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced...

It has been known for many years that antimuscarinic drugs like hyoscine, which enter the brain, cause amnesia when used clinically, e.g. pre-operatively, to reduce bronchial secretions. In experimental studies in both humans and animals they disrupt both the acquisition and the performance of learned behaviour. Anti-cholinestrase drugs have the opposite effect. It is by no means certain, however, that the memory defects induced by antimuscarinics are identical to those seen in AzD. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

A smooth muscle relaxant apparently of the antimuscarinic type whose actions, therefore, are somewhat reminiscent of atropine, is isomylamine (43). Its synthesis begins with the sodamide catalyzed alkylation of cyclohexyl nitrile (40) with l-bromo-3-methylbutane and the resulting nitrile (41) is hydrolyzed to the acid (42) with HBr in acetic acid. Alkylation of the sodium salt of this acid using p-chloroethyldiethylamine leads to the desired 43. 

Which of the following antimuscarinic drugs is used by inhalation in the treatment of bronchial asthma ... 

The answer is c. (Hardman, pp 156-158.) A wide variety of clinical conditions are treated with antimuscarinic drugs. Dicyclomine hydrochloride and methscopolamine bromide are used to reduce Gl motility, although side effects—dryness of the mouth, loss of visual accommodation, and difficulty in urination—may limit their acceptance by patients. Cyclopentolate hydrochloride is used in ophthalmology for its mydriatic and cycloplegic properties during refraction of the eye. Trihexyphenidyl hydrochloride is one of the important antimuscarinic compounds used in the treatment of parkinsonism. For bronchodilation in patients with bronchial asthma and other bronchospastic diseases, ipratropium bromide is used by inhalation. Systemic adverse reactions are low because the actions are largely confined to the mouth and airways. 

Acetylcholine is the neurotransmitter that mediates both volitional and involuntary contractions of the bladder. Bladder smooth muscle cholinergic receptors are mainly of the M2 variety however, M3 receptors are responsible for both emptying contraction of normal micturition and involuntary bladder contractions, which can result in UI. Therefore, most pharmacologic antimuscarinic therapy is anti-M3 based. 

Many patients discontinue oxybutynin IR because of adverse effects due to antimuscarinic effects (e.g., dry mouth, constipation, vision impairment, confusion, cognitive dysfunction, and tachycardia), a-adrenergic inhibition (e.g., orthostatic hypotension), and histamine 111 inhibition (e.g., sedation, and weight gain). 

Brading The only drugs at the moment that are of any use in treating one of the biggest bladder problems are antimuscarinics. And no one has a clue as to why they are working. People have been trying for years to develop other drugs. 

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