Parasympathetic Nervous System & Neurotransmitters

• The parasympathetic nervous system is a part of the Autonomic Nervous System (ANS)

Neurotransmitters and Receptors

• Acetylcholine (ACh) is a key neurotransmitter
• Acetylcholine is metabolized by Cholinesterase enzyme (AChE)
• Nicotinic (N) and Muscarinic (M) are the two main types of receptors

Cholinergic Receptors and Ion Channels

• These are ion channel receptors
• Activation of Nicotinic receptors involves: ACh + N → ↑Na+ → depolarization

Nicotinic Receptor Subtypes, Sites, and Effects

• Nn subtypes are found in all autonomic ganglia and lead to increased neural transmission
• Nn subtypes are found in the adrenal medulla and lead to increased catecholamine release
• Nm subtypes are present at the neuro muscular junction (NMJ) and cause skeletal muscle contraction

Muscarinic Receptors and G Protein

• G protein coupled receptors are activated

Muscarinic Receptor Subtypes, Sites, Effects, and 2nd Messengers

• M1 subtypes are in the CNS and impact motor control, attention, and memory, involving Gq → ↑ IP3 & DAG →↑ Ca
• M1 receptor subtypes are in the stomach and increase HCL secretion, involving DAG →↑ Ca
• M2 subtypes are in the heart and decrease SAN activity and AV conduction via Gi→↓cAMP
• M2 subtypes are in blood vessels (Non-innervated receptors) and cause vasodilation (VD) which results in decreased blood pressure
• M3 subtypes are in the bronchi and cause broncho constriction and increased secretions
• M3 subtypes are in the eye and cause miosis, ciliary muscle contraction for accommodation. and involve Gq →↑ IP3 & DAG →↑ Ca
• M3 subtypes are in the GIT & Urinary bladder and cause Contraction of wall and relaxation of sphincters
• M3 subtypes are in Exocrine glands and increase all body secretions

Parasympathomimetic Drugs (Cholinomimetic)

• Can be classified as direct or indirect (ChE inhibitors)

Direct Acting Drugs

• Choline Esters: Acetylcholine, Bethanechol, Carbachol, Methacholine
• Alkaloids: Pilocarpine, Cevimeline

Indirect Acting Drugs (ChE inhibitors)

• Reversible: Physostigmine, Neostigmine, Pyridostigmine, Donepezil
• Irreversible: Organophosphate compounds

Acetylcholine Pharmacokinetics

• Administered via injection
• Oral absorption is ineffective
• Action is short in duration because it is rapidly hydrolyzed by cholinesterase enzyme

Acetylcholine Pharmacodynamics

• Direct stimulation of M & N receptors

Acetylcholine Effects

• Heart rate decreases (M2 receptor)
• Blood vessels vasodilate (M3 receptor)
• Blood pressure decreases
• Bronchoconstriction happens
• Bronchial secretion increases
• Miosis happens by stimulation of the constrictor pupillae
• Accommodation happens for near objects via stimulation of ciliary muscles
• Increases motility and relaxes the sphincters in the GIT
• Detrusor muscle is stimulated thus increasing motility, and the internal urethral sphincter is relaxed, resulting in bladder evacuation through M3 receptors
• Salivary, gastric, bronchial, lachrymal and sweat gland secretions are stimulated by M3 receptors
• All types of autonomic ganglia (Nn) increase
• Motor end plate (neuromuscular junction) increases and leads to skeletal muscle contractions (Nm).

Carbachol

• It is a choline ester resistant to hydrolysis by AChE
• Effective orally plus has a long duration
• It stimulates both muscarinic and nicotinic receptors
• Treats Open angle glaucoma as local eye drops causing miosis, increasing aqueous humor drainage and decreasing IOP

Bethanechol

• It is a choline ester resistant to hydrolysis by AChE with a long duration
• It stimulates muscarinic receptors but has no activity on nicotinic receptors
• Treats Post-operative urine retention and Paralytic ileus

Pilocarpine

• It is a natural plant alkaloid
• It has muscarinic effects with no nicotinic effects
• Used as local eye drops to decrease IOP in chronic open angle glaucoma

Cevimeline

• It is a synthetic drug
• It has muscarinic effects with no nicotinic effects
• Treats Dry mouth (xerostomia) associated with Sjögren syndrome

Adverse Effects of Muscarinic Agonists

• Hypotension
• Bronchoconstriction
• Nausea, vomiting, and diarrhea
• Sweating and salivation

Contraindications of Muscarinic Agonists

• Bronchial asthma
• Heart block
• Peptic ulcer