Antimuscarinic activity

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...

Adverse effects of the TCAs on the brain include confusion, impaired memory and cognition and occasionally delirium some of these effects have been reported to occur in up to 30% of patients over the age of 50. These effects may occasionally be confused with a recurrence of the s)nnptoms of depression and are probably due to the central antimuscarinic activity of these drugs. Tremor also occurs frequently, particularly in the elderly, and may be controlled by the concurrent administration of propranolol. Neuroleptics are normally not recommended to be used in combination with TCAs as they are liable to accentuate the side effects of the latter drugs. The risk of seizures, and the switch from depression to mania in bipolar patients, has also been reported following TCA administration. 

Q69 Urinary retention may occur with the use of trimipramine. Trimipramine has antimuscarinic activity. 

Trimipramine is a tricyclic antidepressant with sedative properties that is used in the management of depression. As with other tricyclic antidepressants, trimipramine has antimuscarinic activity and therefore side-effects include dry mouth, blurred vision, constipation and urinary retention. 

After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major active metabolite. The 5-hydroxymethyl metabolite, which exhibits antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. 

The triazolopyridine trazodone does not have an appreciable effect on the re-uptake of the neurotrans-mittors dopamine or noradrenaline. It is a weak inhibitor of serotonin re-uptake but is a potent antagonist of the serotonin 5-HT2 receptor. Clinical experience has shown unpredictable efficacy. Trazodone has little antimuscarinic activity and has little if any action on cardiac conduction. Like mianserin it can therefore safely be used in patients for which anticholinergics are contraindicated and there are no absolute contraindications for patients with concomitant diseases of the cardiovascular system. 

Nonselective antimuscarinic drugs have been employed in the therapy of peptic ulcers (see Chapter 40) because they can reduce gastric acid secretion they also have been used as adjunctive therapy in the treatment of irritable bowel syndrome. Antimuscarinic drugs can decrease the pain associated with postprandial spasm of intestinal smooth muscle by blocking contractile responses to ACh. Some of the agents used for this disorder have only antimuscarinic activity (e.g., propantheline), while other drugs have additional properties that contribute to their antispasmodic action. Dicyclomine (Bentyl) and oxybutynin (Ditropan) at therapeutic concentrations primarily have a direct smooth muscle relaxant effect with little antimuscarinic action. 

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). 

Many of these drugs have effects that are not mediated by Hi-receptors (Table 38.2). The antimuscarinic activity of several first-generation Hj-blockers may account for their effectiveness in combating motion sickness and their limited ability to suppress parkinsonian symptoms. The phenothiazines have some capacity to block a-adrenoceptors, whereas cyproheptadine Periactin) is an antagonist at serotonin receptors. Diphenhydramine Benadryl), pyrilamine (Ryna), and promethazine Phen-ergan) are effective local anesthetics. Many second-generation antihistamines also have been found to inhibit the non-histamine-mediated release of various... 

Mechanism of Action An antispasmodic that exhibits potent antimuscarinic activity by interceding via cholinergic muscarinic receptors, thereby inhibiting urinary bladder contraction. Therapeutic Effect Decreases urinary frequency, urgency. Pharmacohinetics Rapidly and well absorbed after PO administration. Protein binding 96%. Extensively metabolized in the liver to active metabolite. Primarily excreted in urine. Unknown if removed by hemodialysis. Half-life 1.9-3.7 hr. 

Homatropine methylbromide is the quaternary derivative of homatropine. It is less potent than atropine in antimuscarinic activity, but it is four times more potent as a ganglionic blocking agent. It is available in some combination products intended for relief of gastrointestinal spasm. 

Methylscopolamine is a QTA obtained by N-methylation of scopolamine (Fig. 1). It exhibits non-selective antimuscarinic activity and is used as adjunctive therapy for the treatment of peptic ulcer, to treat nausea and vomiting due to motion sickness and for the management of irritable bowel syndrome [75], The tritiated form of methylscopolamine is often used in in vitro MR binding assays to investigate receptor affinity and competition by other agents [76],... 

The antimuscarinic activity of (hydroxymethyl)diorgano(2-piperidinoalkyl)germanes 8 has been studied58-60. 

In humans, a prominent effect of cocaine consists in increased vigilance and elevated mood. While cocaine itself is not used clinically, several catecholamine and serotonin reuptake blockers are used as antidepressants. Imipramine (Figure 10.13) is a classic but not so very specific in addition to inhibiting the reuptake of serotonin and of norepinephrine, it also has antihistaminic and antimuscarinic activity. This will lead to side effects in both the central nervous system and the peripheral autonomic system. A prominent one is the causation or deterioration of cardiac arrhythmias due to its antimuscarinic action. 

Systemic antimuscarinic agents, including atropine and scopolamine, can be administered in doses that could produce mild dilation of the pupil and accommodative paresis.The degree of mydriasis and decreased pupillary reactivity to light provide a clinical measure of antimuscarinic activity. Other commonly used systemic medications with antimuscarinic activity are the Hi receptor antagonists. 

Of the systemic antihistamines, the ethanolamines, including diphenhydramine, have significant antimuscarinic activity. In addition, the antipsychotic agents, particularly the phenothiazines such as thioridazine (Mellaril), have well-dociunented anticholinergic properties. Therapeutic doses of tricyclic antidepressants, like amitriptyline hydrochloride (Elavil) and imipramine (Tofranil), produce significant anticholinergic actions and thus have the potential for ocular side effects. 

Disopyramide was the most commonly used drug in this class but is much less so now. It has significant antimuscarinic activity. The drug was thought to be effective in ventricular arrhythmias, especially after myocardial infarction, and in supraventricular arrhythmias, although there are no clinical trials to support this idea. 

Adverse reactions. The antimuscarinic activity is a significant problem and may lead to dry mouth, blurred vision, glaucoma and micturition hesitancy and retention. Gastrointestinal symptoms, rash and agranulocytosis occur. Effects on the cardiovascular system include hypotension and cardiac failure (negative inotropic effect)... 

Antimuscarinic drugs (including those classed primarily as histamine Hj receptor antagonists) are described in Chapters 21 and 29. Drugs with antimuscarinic activity probably act both centrally... 

Mebeverine is a reserpine derivative which has a direct effect on colonic muscle activity, especially, it appears, on colonic hypermotility. As it does not possess antimuscarinic activity, it does not exhibit the troublesome imwanted effects of that group of drugs. 

Chlorphenamine (chlorpheniramine) is a first-generation antihistamine, an alkylamine derivative, with sedative and antimuscarinic activity. 

This member of the ethanolamine series is characterized by a lung duration of action, with an activity that reaches a maximum in S to 7 hours and persists for 10 to 12 hours. It is well absorbed when administered orally, and it is excreted primarily in the urine. The side effects arc those usually encountered with this series of antihistamines. Clemastine is closely related to chlorphenoxomine, which is used for its central cholinergic-blocking activity. Therefore, it is not surprising that clemastine has significant antimuscarinic activity. 

---