**7. Contraindications to the use of anticholinergic agents**

Anticholinergic agents cause pupillary dilation, which is detrimental in patients with narrow angle or primary angle closure glaucoma. When the pupils dilate, this increases pressure within the eye. This increase in pressure prevents drainage of aqueous humor from the eye resulting in marked increases in ocular pressure and acute pain. If left untreated, this can lead to optic nerve damage and vision loss. The use of anticholinergics is contraindicated in patients with this type of glaucoma [41].

In overactive bladder, there are excessive contractions of the detrusor muscle producing incomplete emptying of the bladder. By blocking M3 receptors in the genitourinary tract, this causes smooth muscle relaxation and detrusor underactivity, which can lead to urinary retention. In the presence of benign prostate hyperplasia, there is compression of the urethra, which blocks the flow of urine. Anticholinergic agents are contraindicated in patients with urinary retention and bladder neck obstruction caused by prostatic hypertrophy since the use of these agents can result in an increased risk of developing an obstructive uropathy [42].

Myasthenia gravis is an autoimmune disorder of the postsynaptic neuromuscular junction caused by antibody-mediated blockade of neuromuscular transmission that results in skeletal muscle weakness. Autoimmune antibodies form at the neuromuscular junction against nicotinic acetylcholine postsynaptic receptors. Anticholinergics, especially agents that block nicotinic cholinergic receptors, are contraindicated

because they exacerbate muscle weakness. Further, acetylcholine esterase inhibitors such as pyridostigmine are considered the mainstay of treatment. The use of anticholinergic agents would antagonize the effects of these drugs [42, 43].

Stimulation of M1 and M2 receptors in the GI tract increases GI motility. Anticholinergics block these receptors resulting in slowed GI motility. Ogilive's syndrome or colonic pseudo-obstruction, which is massive dilation of the colon without underlying mechanical obstruction or other organic causes, can be due to the use of anticholinergic agents. These drugs can lead to an adynamic colon. Anticholinergic drugs are contraindicated in patients with achalasia, esophageal stricture or stenosis, pyloroduodenal stenosing peptic ulcer disease, pyloric obstruction and paralytic ileus [42, 44].

Stimulation of M2 receptors in the heart slow pacemaker activity and atrioventricular (AV) conduction, which decreases contractility. Blocking these receptors leads to sinus tachycardia and increased oxygen demand [45]. Analyses of data from the EPIC (European Prospective Investigation into Cancer)-Norfolk Population Study, which was a longitudinal, observation, community cohort study, found that among the 21,000 study participants there was an increase in total anticholinergic burden and subsequent risk of all-cause mortality and incident cardiovascular disease during the follow up period. ACBS scores of ≥3 were associated with a hazard ratio of 2.17 (p < 0.00001) for cardiovascular disease incidence and higher mortality. It was thought that this was a dose-dependent, class effect for the anticholinergic agents. Potential mechanisms of this effect could be a pro-arrhythmic or pro-ischemic effect, increased hemodynamic lability, cardiac ischemia, cardiac dysrhythmias in the presence of ischemia, decrease heart rate variability, or an inflammatory response resulting in an increased risk of mortality [46]. Studies of the effects of inhalation antimuscarinics on cardiovascular status have been mixed [47]. Inhalation anticholinergic agents used in chronic obstructive pulmonary disease have been found to aggravate the balance of the autonomic nervous system leading to significantly reduced heart rate recovery following maximal cardiopulmonary exercise [48]. In a longitudinal study of over 3700 nursing home residents with coronary artery disease, the use of anticholinergics was associated with an increased risk of hospitalization and all-cause mortality (hazard ratio 1.71 if the ACB score ≥ 2) [49]. Further, the use of antimuscarinics for urinary incontinence may also be associated with drug-dependent cardiovascular risk. Among these agents, darifenacin has not been associated with an increase in heart rate or QT prolongation because it is M3 selective and it appears to have the best cardiovascular safety profile. Tropsium, on the other hand, may have the highest risk of adverse cardiovascular events. On the basis of these drugs' physiological effects and clinical trials showing increased cardiovascular risk associated with their use, it is best to avoid anticholinergics during the post-myocardial infarction period [50].
