review

• Parasympathetic Nervous System

  • Preganglionic neurons from the cranial and sacral regions of the spinal cord synapse with the postganglionic neurons on an outside ganglia
  • Parasympathetic innervation results in pupil constriction, salivation, airway constriction, bradycardia, stomach digestion, intestinal digestion, bladder constriction, and reproductive system blood flow increase
  • This system typically innervates cardiac smooth muscle, gland cells, and nerve terminals
• Cranial nerves involved in parasympathetic innervation

  • Oculomotor (3)
  • Facial (7)
  • Glossopharyngeal (9)
  • Vagus (10)
• Sacral nerves involved in parasympathetic innervation

  • 2
  • 3
  • 4
• NN receptors

  Located in the CNS, postganglionic cell body, and dendrites. Their structure is a pentamer with only ɑ and β subunits. They work through Na+ and K+ depolarization ion channels
• NM receptors

  Located in the skeletal neuromuscular junction. Their structure is that of a pentamer with ɑ, β, γ, and δ subunits. They work through Na+ and K+ depolarization ion channels
• M1 receptors

  Located in the nerves. Their structure is a Gq/11 protein coupled receptor. They work through the IP3 and DAG cascade. Has a stimulatory effect. Innervation causes the brain to increase cognition and memory while the stomach is told to increase pepsinogen and HCl release
• M2 receptors

  Located in the heart, nerves, and smooth muscle. Their structure is a Gi/o protein coupled receptor. They work through cAMP inhibition and activation of K+ channels. Has an inhibitory effect. Causes the SA node to decrease chronotropy, atria to decrease inotropy, AV node to decrease dromotropy/increase refractory period, and the ventricles to decrease inotropy
• M3 receptors

  Located in the glands, smooth muscles, and endothelial cells. Their structure is a Gq/11 protein coupled receptor. They work through the IP3 and DAG cascade. Has a stimulatory effect. Causes increased tears, saliva, bronchial secretions and constriction, digestive enzymes, GI mucus and peristalsis, iris miosis and lens, and increases detrusor contraction/trigone and sphincter relaxation
• M4 receptors

  Located in the CNS. Their structure is a Gi/o protein coupled receptor. They work through cAMP inhibition and activation of K+ channels
• M5 receptors

  Located in the CNS. Their structure is a Gq/11 protein coupled receptor. They work through the IP3 and DAG cascade
• Cholinomimetics

  • Direct Acting: Muscarinic and nicotinic receptor agonists
  • Indirect Acting: Cholinesterase inhibitors
• Nicotine

  • Works on the ɑ4, ɑ7 and β2 subunits of nicotinic receptors
  • In the brain, it causes dopaminergic receptors to release dopamine causes euphoria, but also dependence
  • Drug is slowly absorbed transdermally and mucosal dosage forms
• Varenicline

  • Partial nicotinic acetylcholine receptor agonist producing a modest dopamine release while blocking real nicotine from binding
  • This drug is well tolerated, but can lead to some nausea, vomiting, abnormal dreams, depression, headache, insomnia, and irritability
  • This drug is mainly excreted in the urine unchanged
• Cholinergic Toxidrome

  • S - Salivation
  • L - Lacrimation
  • U - Urination
  • D - Diaphoresis
  • G - GI Upset
  • E - Emesis
  • M - Miosis
  • B - Bradycardia
• Bethanechol

  • Direct M3 agonist that stimulates bladder contraction
  • This drug is a quaternary amine, meaning it cannot cross the blood brain barrier
  • This drug can also cause abdominal pain, colicky pain, nausea, diarrhea, and borborygmi
• Carbachol

  • Directly stimulates M1 and M2 to decrease intraocular pressure and constrict the iris
  • May cause blurred vision and ocular irritation
• Methacholine

  • Works by directly acting on M2 and M3 receptor to cause smooth muscle contraction in the airways and increased bronchial secretions during stress tests
  • Used to diagnosis respiratory diseases, not used as their treatment
  • May cause bronchoconstriction when given, but has a short duration of action of ~30 minutes
• Cevimeline

  • Direct agonist of M1 and M3 that results in increased saliva, sweat, and smooth muscle contractions in the glands
  • Adverse effects include diarrhea and hyperhidrosis
• Pilocarpine

  • Directly agonizes M1, M2, and M3 receptors leading to ciliary muscle contraction in open-angle glaucoma, opening of the angle in closed-angle glaucoma, and increasing salivary to treat xerostomia
  • Adverse effects are only hyperhidrosis since they're less likely to occur with eye drops
• Myasthenia Gravis

  • Autoimmune disease that attacks nicotinic receptors in the skeletal neuromuscular junction. This can happen by receptor cross-linking, lysis of the postsynaptic membrane, and/or binding directly to the receptors and inhibiting their function
  • Symptoms: Ptosis, diplopia, muscle weakness, and trouble speaking
  • This disease is treated by AChE inhibitors which increase ACh in the synaptic cleft
• Neostigmine

  • Reversible AChE inhibitor
  • This drug does not cross the blood brain barrier
  • Used to treat myasthenia gravis but has SLUDGE MB side effects
• Physostigmine

  • Reversible AChE inhibitor
  • This drug does cross the blood brain barrier
  • Used to treat anticholinergic poisoning
• Pyridostigmine

  • Reversible AChE inhibitor
  • Used to treat myasthenia gravis and neuromuscular blockade with SLUDGE MB side effects
• Alzheimer's Disease

  • Characterized by the impaired release of ACh and deficits in the expression of nicotinic and muscarinic receptors
  • AChE inhibitors are typically used to treat this disease by prolonging the half-life of ACh in the synaptic cleft
• Donepezil

  • Reversible AChE inhibitor
  • This drug does cross the blood brain barrier
  • Used to treat Alzheimer's disease with SLUDGE MB side effects
• Galantamine

  • Reversible AChE inhibitor and also a positive allosteric modulator of neuronal nicotinic ACh receptors
  • This drug does cross the blood brain barrier
  • Used to treat Alzheimer's disease with dermatological and SLUDGE MB side effects
• Rivastigmine

  • Reversible AChE inhibitor
  • Used to treat Alzheimer's disease and Parkinson's disease
  • Adverse drug reactions are SLUDGE MB
• Anticholinergic Toxidrome

  • Flushed skin 'red as a beat'
  • Xerostomia 'dry as a bone'
  • Mydriasis 'blind as a bat'
  • Confusion ' mad as a hatter'
  • Hyperthermia ' hot as a desert'
  • Urinary retention 'full as a flask'
• Anticholinergic drugs have a high risk of cognitive impairment and tend to lead to dementia if used for long-term
• Scopolamine

  • Competitive antagonist at muscarinic receptor
  • This drug does cross the blood brain barrier
  • Used to reduce vertigo and nausea
  • Adverse drug reactions are tachycardia, blurred vision, xerostomia, and delirium
• Dicyclomine

  • Competitive antagonist at the M1 and M4 receptors that reduces smooth muscle and secretory activity of the gut
  • Likely well absorbed into the body unlike other anticholinergic drugs
  • Used for IBS and minor diarrhea
  • Adverse drug reactions are tachycardia, confusion, urinary retention, and increase intraocular pressure
• Atropine

  • Competitive muscarinic receptor antagonist that relaxes the iris sphincter and ciliary body
  • Has a high duration of action , up to 2 weeks
  • Used for secretions that happen towards the end of the life
  • Anti-SLUDGE MB adverse reactions might happen
• Ipratropium

  • Competitive muscarinic receptor antagonist of the M3 receptor to reduce bronchospasm
  • This drug is quaternary amine so it does not cross the blood brain barrier
  • Used for rhinorrhea and asthma and mainly causes xerostomia and cough
• Oxybutynin

  • Muscarinic antagonist that reduces detrusor muscle tone and spasms
  • Used for incontinence and postoperative spasms
  • This medication does cross the blood brain barrier to a high degree
• Atropine

  Eye drops that are a competitive muscarinic receptor antagonist that relaxes the iris sphincter and ciliary body
• Atropine

  • Has a high duration of action, up to 2 weeks
  • Used for secretions that happen towards the end of life
• Atropine adverse reactions may include anti-SLUDGE MB
• Ipratropium (Atrovent)

  Competitive muscarinic receptor antagonist of the M3 receptor to reduce bronchospasm
• Ipratropium is a quaternary amine so it does not cross the blood brain barrier
• Ipratropium

  Used for rhinorrhea and asthma, mainly causes xerostomia and cough