Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.
These agents have broad effects due to their actions in nerves located vastly over the body. These nerves include motor nerves in somatic nervous system which innervate skeletal muscles as well as nerves in the sympathetic and parasympathetic nervous systems. Organs that receive innervations from these systems include exocrine glands, heart, eyes, gastrointestinal tract etc. Antimuscarinic and antinicotinic agents can increase heart rate, inhibit secretions, and gastrointestinal motility.
Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison and pupil-dilating cosmetics. While curare, the naturally occurring antinicotinics derived from Chondrodendron and Strychnos, was a poison used by South American Indians for hunting.
According to their site of actions, cholinergic blocking drugs can be classified into two general types — antimuscarinic and antinicotinic agents. Antimuscarinic agents (also known as muscarinic antagonists), including atropine and hyoscine, block acetylcholine at the muscarinic acetylcholine receptors. Antinicotinic agents (also known as ganglionic blockers, neuromuscular blockers), including tubocurarine and hexamethonium, block acetylcholine action at nicotinic acetylcholine receptors. Their effects are based on the expression of corresponding receptors in different parts of the body.
There are many adverse effects, interactions and contraindications for antinicotinic and antimuscarinic agents. Adverse effects include hypotension, dry mouth, dry eyes etc. They interact with grapefruit juice and various medications, e.g. warfarin, metoclopramide. Therefore, cautions should be exercised and advice from medical professionals should be sought before using medications.
History
Discovery of cholinergic nervous system In 1900, Reid Hunt, a pharmacologist (1870-1948), realised a fall in blood pressure in rabbits after removing adrenaline (epinephrine) from adrenal glands extract. While he initially attributed this effect to choline, he later discovered acetylcholine was 100 000 times more potent in lowering blood pressure.
British physiologist Sir Henry Hallett Dale (1875-1968) observed acetylcholine for causing blood vessel dilation and slowing down heart rate. In 1914, Dale noted that the physiological effect of acetylcholine resembled the stimulation of parasympathetic nervous system and hypothesized acetylcholine as the neurotransmitter. Later, Dale named substances that mimic acetylcholine action as "cholinergics".
In 1914, Dale also distinguished two types of activities of acetylcholine, namely muscarinic and nicotinic, as they mimic the effects of injecting muscarine, extracted from poisonous mushroom Amanita muscaria, and nicotine.
Antimuscarinic agents Naturally occurring antimuscarinics were found in alkaloids from Belladonna (Solanaceae) plants. They were used as deadly poison in Roman Empire and Middle Ages. The name Belladonna, meaning beautiful ladies, was derived from women using berry juice from the plant cosmetically to dilate their pupils.
The mydriatic effect was studied by the German chemist Friedlieb Ferdinand Runge (1795-1867), in which the active ingredient, atropine, was first discovered by Vaquelin in 1809 and was first isolated by Heinrich F. G. Mein in 1813.
In the 1850s, atropine was used as antispasmodic in asthma treatment and as morphine antidote for its mydriatic effect. Bezold and Bloebaum showed that atropine blocked the effects of vagal stimulation on the heart in 1867. Subsequently in 1872, Heidenhain found its ability to prevent salivary secretion.
Antinicotinic agents Curare, derived from Chondrodendron and Strychnos, was used as poison by South American Indians to coat arrow tips or blow-pipe darts for hunting animals. It is first identified when Spanish soldiers were attacked by these indigenous tribes in the 16th century.
In 1906, Langley studied the actions of nicotine and curare on chicken and frog muscles. Curare was found to block the stimulant action of nicotine in both innervated and chronically denervated muscles. In 1940, Jenkinson identified tubocurarine as a competitive antagonist of acetylcholine.
Curare and tubocurarine had important roles in establishing the concept of specific cholinoceptors in the motor end plate. At right dose, they are used as general anesthetic for relaxing abdominal muscles in operations.
General effects on body
Antimuscarinic agents Muscarinic receptors are G-protein coupled receptors that present mainly in the parasympathetic system and sweat gland. Antimuscarinc agents, therefore, generally produce effects that are opposite to the stimulation of the parasympathetic system, which is responsible for "rest and digest". Location EffectsExocrine glands Inhibition of secretions in salivary, lacrimal, bronchial and sweat glands Dry mouth, dry skin Gastric secretion is only slightly reduced Bronchial mucociliary clearance inhibition leading to accumulation of residual secretion in lungsCardiovascular system Increased heart rate (tachycardia) Unaffected arterial blood pressure and response to exercise Eye Pupil dilation (mydriasis) and unresponsive to light Relaxation of ciliary muscle causes paralysis of accommodation (cycloplegia) and impaired near vision Raised intraocular pressureGastrointestinal tract Inhibition of motilityOther smooth muscle Relaxation of bronchial smooth muscle Biliary and urinary tract smooth muscle only slightly affected, might precipitate urinary retentionCentral Nervous System (CNS) Restlessness, agitation, disorientation
Antinicotinic agent Nicotinic receptors are ligand-gated ion channels that present in both parasympathetic and sympathetic ganglions, while the antagonistic effect of antinicotinic agents depend on which system predominates in a particular site. Nicotinic receptors are also present in neuromuscular junctions and the brain. Location Predominant system EffectsExocrine glandsParasympathetic except sweat glands Inhibition of secretions in salivary, lacrimal, bronchial and sweat glandsHeartParasympathetic Increased heart rate (tachycardia)Blood vesselsSympathetic Vasodilation Decreased blood pressure Loss of cardiovascular reflex causing postural hypotensionEyeParasympathetic Pupil dilation (mydriasis) and unresponsive to light Relaxation of ciliary muscle causes paralysis of accommodation (cycloplegia) and impaired near visionGastrointestinal tract Parasympathetic Decreased peristalsis Decreased secretionOther smooth muscleParasympathetic Relaxation of bronchial, urinary bladder smooth muscleNeuromuscular junctionN/A Muscle relaxation Neuromuscular block or paralysis
Clinical uses Listed below are some examples of antimuscarinic and antinicotinic agents according to the British National Formulary, including non-clinically one for better illustration of their site of actions.
Antimuscarinic agents Antimuscarinic agents are muscarinic antagonists and they bind to muscarinic cholinergic receptors postsynaptically without activating them. They occupy and prevent acetylcholine from binding to the active sites of receptors to elicit their effect. Examples Properties Clinical use NotesAtropine Non-selective antagonist Good oral absorption CNS stimulant (cross blood-brain barrier)Ophthalmologic examination
Cause cycloplegic effect, i.e. paralysis of ciliary muscle and loss of accommodation Topical application
Surgery Premedication
Inhibit saliva secretion Maintain normal heartbeat
Myopia
Slow down Myopia progression in children. New off-label treatment Animal studies showed dopamine and DOPAC increase in the chick retina, important in ocular growth and myopia development.
Acute symptomatic bradycardia
Increase heart rate, improve signs and symptoms First-line treatment Intravenous administration Belladonna alkaloid Side effects include urinary retention, dry mouth, blurred visionGlycopyrrolate Quaternary ammonium compound Does not cross blood-brain barrier Hyperhidrosis Reduce rate of sweating by blocking parasympathetic receptors in the central nervous system, smooth muscle, and sweat glands First drug approved by FDA in 2018 for hyperhidrosis Dicycloverine (Dicyclomine) Similar to atropineBowel Colic
Relax intestinal smooth muscles and cramps by inhibiting parasympathetic system and intrinsic primary afferent nerves (IPAN) Taken orally or intramuscularly Hyoscine (Scopolamine) Similar to atropine CNS depressantMotion sickness
Prevent vomiting by inhibiting cerebellum and solitary nucleus from activating vomiting centre Taken before travelling as antiemetics
Bowel Colic
Similar to Dicycloverine Belladonna alkaloid Causes sedation Side effects similar to atropine Prevention drug for motion sickness instead of treatment medicationTiotropium Similar to atropine Does not inhibit bronchial mucociliary clearance Poor absorption Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Dilate airway by relaxing bronchial smooth muscles Quaternary ammonium compoundIpratropiumTropicamide Similar to atropine May increase intraocular pressureOphthalmologic examination
Similar to atropine Similar to atropine but shorter actingCyclopentolateDarifenacin M3 receptor selectiveUrinary incontinence Inhibit micturition by relaxing bladder smooth muscles Used in urinary incontinence Few side effects
Antinicotinic agents Antinicotinic agents are classified into ganglionic blockers and neuromuscular blockers.
Ganglionic blockers are of little clinical use as they act at all autonomic ganglions. They act by:
Interfering acetylcholine release Prolonged depolarization (depolarisation block), i.e. stimulation then block stimulation Competitive inhibition of nicotinic receptor
Examples Mechanism of action Properties Clinical useNicotineProlonged depolarization Non-competitive blockSmoking Cessation
Eliminate symptoms of nicotine withdrawing Given in low dose Acetylcholine (in presence of cholinesterase inhibitors)No clinical use as ganglionic blockerHexamethoniumCompetitive inhibition of nicotinic receptor Selective First effective hypertension drug treatmentNo longer clinically use due to side effectTrimethaphan Selective Short duration of actionBlood pressure lowering in surgery (rarely use)Tubocurarine Non-selective Cause histamine release, so greater side effects comparing with AtracuriumRarely usedAtracurium Safer alternative to tubocurarine with less side effectsSurgical anaesthetic & intubation
facilitate endotracheal intubation and provide skeletal muscle relaxation to reduce the risk of laryngeal injury. Neuromuscular blockers act at neuromuscular junction by:
Inhibiting acetylcholine synthesis Inhibiting acetylcholine release Blocking acetylcholine receptors postsynaptically Prolonged depolarization of motor end plate
Examples Mechanism of action Onset Duration of action Properties Clinical useHemicholiniumInhibiting acetylcholine synthesis// Block choline transport into nerve terminal Use experimentally onlyNo clinical useVesamicol Block acetylcholine transport into synaptic vesicle Use experimentally to investigate potential treatment in situ pulmonary adenocarcinomaNo clinical useBotulinum toxinInhibiting acetylcholine release3–5 days3–4 months Very potent Botulinum poisoning cause parasympathetic and motor paralysisMuscle relaxants
Treat cervical dystonia, spasticity, blepharospasm and overactive bladder Injected to paralyse muscles around face, hence reducing wrinkles (clinical or cosmetic uses)
Reduce secretion
Used in patients with hyperhidrosis and sialorrhoea
Headache prophylaxis