Anticholinergic drugs

General adverse effects and adverse reactions

An indication of what may be expected in the way of adverse reactions can be obtained by fitting a drug into its structural class (see Table 1 ), since the pattern of effects of drugs in each class is generally very similar. The drugs closely related to atropine have the full range of antinicotinic and antimuscarinic activity of atropine itself. Of the synthetic compounds used in visceral disorders, the quaternary compounds are fully ionized in the pH range found in body fluids and are therefore less lipid-soluble than the corresponding tertiary amines. This means that they penetrate physiological barriers less readily; less drug is absorbed in the intestine, less enters the cerebrospinal fluid and aqueous humor, and less enters cells. Consequently, these drugs tend to be relatively less active by mouth and to have fewer effects on the brain and the eye than the tertiary amines. Of the latter, some have little antimuscarinic activity and indeed probably very little useful activity at all; they may have some specific relaxant effect on smooth muscle, but it seems to be of little clinical significance.

Of the drugs in this class used largely in parkinsonism, the tertiary amines related to diphenhydramine have some antihistaminic activity, as one would expect; some of these drugs are also related to atropine. The derivatives of trihexyphenidyl (benzhexol) are also pharmacologically closely similar: for example, they have some excitatory effects if given in sufficient doses.

The unwanted peripheral effects of all atropine-like drugs include flushing of the skin, dryness of the mucous membranes with fever, tachycardia, reduced salivary secretion and dryness of the mouth, drying up of the gastrointestinal secretions and decreased gastric acidity, and reduced muscle tone in the gut and constipation. Bladder tone and frequency of micturition are reduced and acute urinary retention is a risk, especially in older men with prostatic hyperplasia. Nasal, bronchial, and lacrimal secretions are reduced.

In 532 patients mean age 74 years, of whom 27% used at least one anticholinergic drug, only two symptoms were statistically more prevalent in those who used anticholinergic drugs: dry mouth (58% versus 46%) and constipation (42% versus 29%) [ ].

An anticholinergic drug scale has been developed to rank anticholinergic properties [ ]:

• level 0: no known anticholinergic properties;

• level 1: potentially anticholinergic as evidenced by receptor binding studies;

• level 2: anticholinergic adverse events sometimes noted, usually at excessive doses;

• level 3: markedly anticholinergic.

All conventional anticholinergic drugs ( Table 1 ) are classed as being at level 3 ( Table 2 ), and the usefulness of this scale therefore lies in comparing the anticholinergic effects of drugs that are not called anticholinergic drugs. It would be helpful if level 3 drugs could be further subdivided according to their affinities for muscarinic receptors ( Table 3 ).

Anticholinergic adverse effects of newer anticholinergic drugs

Various new anticholinergic drugs have been developed in the hope of treating the symptoms of an over-active bladder and other bladder conditions. The hallmark of some of these newer compounds, such as darifenacin, solifenacin, and tolterodine, is that they are supposed to have greater specificity for muscarinic (M ₃ ) receptors than more traditional antagonists. They might therefore be expected to reduce the risks of the traditional adverse effects of these drugs, such as dry mouth, constipation, and blurred vision. Contraction of the detrusor muscle is mediated mainly by M ₃ receptors, even though M ₂ receptors are more highly represented in the bladder. M ₃ receptors are also found in salivary glands and are important in salivary secretion. However, the relative affinities of the different drugs for M ₃ receptors in the bladder and salivary glands may be different. For example, oxybutynin has a higher affinity for mouse salivary M ₃ receptors than solifenacin [ ]. The affinities of some antimuscarinic drugs for human muscarinic receptor subtypes are shown in Table 3 .

Herbal sources of anticholinergic drugs

Tropane alkaloids, such as hyoscyamine and/or scopolamine, occur in the solanaceous plants Atropa belladonna , Datura stramonium , Hyoscyamus niger , and Mandragora officinarum . These alkaloids are powerful anticholinergic agents and can elicit peripheral symptoms (for example blurred vision, dry mouth) as well as central effects (for example drowsiness, delirium). They can potentiate the effects of anticholinergic medicaments.

Observational studies

In two large 12-week studies, from the USA and Germany, the adverse effects of extended-release formulations of oxybutynin and tolterodine in patients with overactive bladder and urinary incontinence were as expected from the pharmacological actions of these drugs. The first study involved 576 patients (94% women) and a parallel group of 399 patients taking extended-release tolterodine 4 mg/day [ ]. The second study involved nearly 1700 patients (44% men) taking tolterodine 4 mg/day or placebo [ ]. Dry mouth was by far the most common adverse effect, although the prevalences were different in the two series. In the German series it was 23% and in the US study 11%, about three times the rate in those taking placebo. The reason for this discrepancy was unclear. In both cases constipation was the next most commonly reported adverse event. No novel or unexpected problems emerged in either study.

Urinary urgency and incontinence are a frequent problem not only in older adults but also transiently in primary school-aged children. There have been relatively few studies on the use of anticholinergic medications in this group, although there is general agreement that they are efficacious. In a multinational, 12-month, open study of extended-release tolterodine 2 mg/day in 318 children aged 5–11 years (54% boys), only four reported dry mouth and the most common adverse events were urinary tract infection (7%), nasopharyngitis (5%), and headache (5%) [ ]. Whether the first two of these really were related to the treatment must be questionable. No fewer than 35% of the subjects withdrew from the study, mostly because of either symptomatic improvement or conversely failure to respond; only 3% of the withdrawals were due to adverse drug effects.

Systematic reviews

In a systematic review of 61 trials, 42 with parallel-group designs and 19 crossover trials in 11 956 adults, in which nine drugs were studied (darifenacin, emepronium bromide or carrageenate, oxybutynin, propiverine, propantheline, tolterodine, trospium chloride, and solifenacin) the rate of dry mouth was increased three-fold in the medication group (RR = 3.00; 95% CI = 2.70, 3.34), but there was no statistically significant difference in the rate of withdrawals (RR = 1.11; 95% CI = 0.91, 1.36) [ ].