Cholinergic Receptors and Agonists

• The autonomic nervous system (ANS) regulates involuntary, unconscious, and automatic bodily functions.
• Acetylcholine is the primary neurotransmitter in the parasympathetic nervous system.

Cholinergic Receptors

• Cholinergic receptors include nicotinic and muscarinic receptors.
• Nicotinic receptors are of type N1 or Nm, located at the neuromuscular junction
• Nicotinic receptors are of type N2 or Nn, located at autonomic ganglia, in the central nervous system and the adrenal medulla
• Muscarinic receptors are of type M1, primarily found in nerves
• Muscarinic receptors are of type M2, primarily found in the heart and smooth muscle
• Muscarinic receptors are of type M3, primarily found in exocrine glands, smooth muscles, and vascular endothelium
• Muscarinic receptors are of type M4, primarily found in the striatum and cortex
• Muscarinic receptors are of type M5, primarily found in the CNS ganglia and brain vasculature

Cholinergic Agonists

• Cholinergic agonists stimulate cholinergic receptors, mimicking the effects of acetylcholine
• Direct cholinergic agonists bind directly to receptors
• Indirect cholinergic agonists inhibit cholinesterase, preventing the breakdown of acetylcholine

Direct Cholinergic Agonists

• Acetylcholine is the endogenous neurotransmitter but is not used as a drug
• Pilocarpine is a direct cholinergic agonist
• Muscarinic actions cause a negative chronotropic effect. It slows the SA node, resulting in bradycardia
• Muscarinic actions cause a negative inotropic effect, affecting atria only
• Muscarinic actions cause a negative dromotropic action, affecting the atrioventricular (AV) node
• Muscarinic actions stimulate the gastrointestinal tract, increasing tone, motility, and secretion, while relaxing sphincters
• Muscarinic actions stimulate the detrusor muscle of the urinary tract, relax the trigone and sphincter muscles of the bladder
• Muscarinic actions cause bronchoconstriction and increased bronchial secretion in the bronchioles
• Muscarinic actions cause miosis due to stimulation of the constrictor pupillae muscle in the eye
• Muscarinic actions stimulate salivary, gastric, and bronchial exocrine glands
• Nicotinic actions stimulate NN receptors in both sympathetic and parasympathetic autonomic ganglia, as well as the adrenal medulla, releasing adrenaline and noradrenaline
• Nicotinic actions stimulate NM receptors at the neuromuscular junction (NMJ), enabling skeletal muscle actions
• Nicotinic actions of ACh at the NMJ are blocked by neuromuscular blockers like pancuronium

Indirect Cholinergic Agonists (Anticholinesterases)

• This drug inhibits true and pseudocholinesterases to prolong and potentiate ACh action
• Reversible anticholinesterases like neostigmine form temporary bonds with the enzyme through competitive inhibition
• Irreversible anticholinesterases (OPCs) initially bind loosely and reversibly, but then bind firmly, leading to permanent inactivation through irreversible non-competitive inhibition. These are used as insecticides and in chemical warfare

Therapeutic Uses of Cholinergic Agonists

• Cholinergic agonists treat postoperative ileus (atony/paralysis of the bowel) and urinary retention
• Neostigmine is used to reverse paralysis induced by competitive neuromuscular blocking agents during surgical anesthesia
• Donepezil is a selective acetylcholinesterase inhibitor used to treat cognitive dysfunction in Alzheimer's patients, delaying but not stopping disease progression

Myasthenia Gravis

• Myasthenia Gravis is an autoimmune disease of the skeletal muscle NMJ where antibodies are produced against the nicotinic receptor-channel complex
• Symptoms include ptosis, diplopia, difficulty speaking/swallowing, and extremity weakness
• Cholinesterase inhibitors are valuable in managing myasthenia Gravis, used alone or with immunosuppressants

Toxicity of Cholinergic Agonists

• Direct cholinergic agonists cause vomiting, diarrhea, urinary urgency, salivation, sweating, miosis, and bronchial constriction, blocked by atropine.
• Cholinesterase inhibitors cause muscarinic excess and CNS involvement such as confusion, convulsions, and coma

Treatment of Irreversible Anticholinesterases (OPCs) Toxicity

• Administer atropine 2 mg I.V. or I.M. every 5–10 minutes until the pupil dilates, dry mouth occurs, and tachycardia is present, to antagonize muscarinic effects
• Administer cholinesterase reactivators such as IV oximes in order to reactivate cholinesterase. They bind with OPCs, freeing up cholinesterase, and can inactivate residual inhibitor before it reaches the enzyme
• Oximes should be used with atropine, as they are insufficient alone
• Oximes are effective only in early cases of poisoning. They are ineffective in late cases due to aging or complete inactivation of the enzyme
• Administer anticonvulsants, e.g., diazepam, and care of respiration. Gastric lavage is essential in oral poisoning. Contaminated skin should be washed with NaHCO3

Cholinergic Antagonists

• Cholinergic antagonists bind to cholinoceptors (muscarinic or nicotinic) and prevent the actions of ACh and other cholinergic agonists
• Cholinergic antagonists include muscarinic antagonists (antimuscarinic drugs) and neuromuscular blockers

Antimuscarinic Drugs

• Natural alkaloids include atropine and scopolamine (hyoscine)
• These drugs act by non-selectively blocking muscarinic receptors

Pharmacological Actions of Antimuscarinics

• Atropine has minimal stimulant effects on the CNS, particularly on parasympathetic medullary centers in therapeutic doses
• Scopolamine has a marked central depressant effect, producing drowsiness and amnesia in therapeutic doses
• Antimuscarinics may cause tachycardia due to blockade of the vagal slowing effect on the SA and AV nodes.
• Antimuscarinics generally have no action on blood vessels or blood pressure due to a lack of parasympathetic innervation. Toxic doses in adults and therapeutic doses in children produce cutaneous vasodilation and flushing (atropine flush) due to inhibition of sweating, leading to atropine fever.
• Reductions in gastrointestinal smooth muscle motility from the stomach to the colon and reductions in both tone and propulsive movements. Reduction of some secretory functions like gastric secretions
• Smooth muscle relaxation of the ureters and bladder wall and slowed voiding, which may lead to urinary retention
• Reduces most exocrine secretions, including salivary, lachrymal, and sweat secretions
• Causes bronchodilation and reduction of bronchial secretion in the respiratory system
• Causes passive mydriasis (pupil dilation) and loss of the light reflex, paralysis of the ciliary muscle (cycloplegia) leading to loss of accommodation to near objects. It also increases intraocular pressure and inhibits lachrymation (dry eye)

Therapeutic Uses of Muscarinic Antagonists

• They are used in several system disorders and organophosphorus poisoning
• Scopolamine is effective in prophylaxis of motion sickness, available as a transdermal patch providing protection for up to 3 days
• Atropine or its substitutes produce mydriasis with cycloplegia and are used topically as eye drops for accurate measurement of refractive error, ophthalmoscopic examination, and prevention of adhesion formation in uveitis and iritis
• Atropine is injected half an hour before general anesthesia to decrease airway secretions and protect the heart from excessive vagal tone
• In COPD, chronic smokers benefit from bronchodilators, especially antimuscarinic agents like ipratropium and tiotropium
• Parenteral atropine treats vasovagal attacks
• Hyoscine butylbromide is used as antispasmodics in intestinal colics
• Treats bladder spasm and involuntary voiding
• Atropine is used as an antidote in toxicity of organophosphorus compounds

Adverse Reactions of Antimuscarinics

• Mydriasis and cycloplegia with blurred vision may precipitate acute glaucoma
• Can cause dry mouth, hot and flushed skin, and tachycardia
• Scopolamine, and to a lesser extent atropine, can cause agitation, hallucinations, and coma in toxic doses

Contraindications for Antimuscarinics

• Glaucoma
• Elderly men with benign prostatic hyperplasia due to the risk of urine retention

Dental Implications of Parasympathomimetics

• Sialogogues such as pilocarpine and bethanechol activate muscarinic cholinergic receptors to increase salivary flow in patients with xerostomia

Xerostomia (Dry Mouth)

• Xerostomia may result from Sjogren's syndrome, rheumatoid arthritis, diabetes insipidus, pernicious anemia, radiation, side effects of drugs, and aging
• Patients suffering from xerostomia may have difficulty using dentures and are at increased risk of intraoral candidal infection
• Other measures to relieve dry mouth include sugar-free gum/candies, lozenges containing citric acid/sorbitol/mannitol, and drinking at least eight glasses of water