Cholinergic Agonists

Muscarinic receptor Structure

• M1-M5, M1-3 in ANS

• 7 transmembrane domains with G-coupled receptors

Nicotinic Receptor Structure

• N_M for Muscle and N_N for ANS

• 5 Subunit arranged into a membrane channel that opens Na/Ca channels upon binding of 2 ACh molecules

  

Explain the VERY complex reason why peripheral vasodilation MOSTLY does not occur naturally (except erection that IS innervated) and only through systemically applied cholinergic agonists

• Also explain what happens if there is NO endothelium

There is no PNS innervation directly to the endothelium of blood vessels, so they do have M3 but acetylcholine does not reach to activate

• Now if you inject a cholinergic agonist here, it will activate M3 receptor to release NO, which travels to M3 receptor on smooth muscle cell and causes vasodilation

• If there is no endothelium, injected cholinergic agonists directly bind to M3 receptors and cause vasoconstriction

  • In diseases where endothelium is damaged, this can be a problem

The CNS has both muscarinic and nicotinic receptors, explain how they act

• Muscarinic receptors are mostly involved in the regulation of voluntary movement in basal ganglia

• Nicotinic receptors activate both sympathetic and parasympathetic

  • Sympathomimetic: hypertension, vasoconstriction, tachycardia

  • Parasympathetic: GI and urinary, followed by inhibition (biphasic

  • In NMJ: initial uncoordinated muscle contraction, but continued exposure leads to depolarizing blockade and eventually flaccid paralysis (nicotine toxicity)

Organ system effects of muscarinic over-activation

• Treatment

• Diarrhea

• Urination

• Miosis

• Bradycardia, Bronchoconstriction

• Emesis (vomiting)

• Lacrimation

• Salivation, Sweating

• Treatment: muscarinic antagonists such as atropine

Organ system effects of nicotinic over-activation (Biphasic)

• Treatment

• Muscle weakness

• Adrenal medulla activation

• Tachycardia

• Cramping

• Hypertension

• Treatment: Maintenance of vitals

Direct Acting Cholinergic Agonists

• Name

• Action of Drug

• Clinical use

All these can be reversed with Atropine!

Esters of Choline

• Methacholine (Provocholine) “PROVes bronchial hypersensitivity”

  • Causes bronchoconstriction, muscarinic selective

  • Used for diagnosis of bronchial airway hypersensitivity + also used as a miotic agent (pupil constriction)

• Carbachol (isopto Carbachol, Miostat)

  • Significant nicotinic activity, only used in the eye

  • Used during surgery to induce miosis and reduce rises in intraocular pressure but can cause cardiovascular and GI complications

• Bethanechol (Urecholine) “pregnant bethany urinates”

  • Selective for muscarinic receptors, increases GI tone and motility, promotes emptying of the bladder

  • Oral or subQ for acute postoperative and post-partum non-obstructive urinary retention

Alkaloids

• Muscarine

  • Activates muscarinic receptors

  • No clinical use

• Pilocarpine (Salagen or Pilocar)

  • Parasympathomimetic with muscarinic effects and crosses BBB

  • Induces miosis through contraction of ciliary muscle (reduces IOP), used as a sialagogue for Xerostomia and other systemic effects

  • Cevimeline (Evoxac) “Evades xerostomia”

    • M3 agonist

    • Used for Xerostomia in Sjogren’s syndrome and secondary radiation therapy)

  • Nicotine (Nicorette, NicoDerm CQ, Commit)

    • Specific for nicotinic receptors at all autonomic ganglia, increases

    • Used for patients to commit to tobacco sessation

  • Varenicline (Chantix) “Psychiatix smokers”

    • Partial agonist to nicotinic receptors, stops full agonist (nicotine) from binding

    • Can block effect of a relapse from smoking but can increase psychiatric side effects

Indirect Acting Cholinergic Agonists/ Cholinesterase Inhibitors

• Name

• Reversible or irreversible

• Action of Drug

• Clinical use

These can be used to increase strength of contraction of skeletal muscle*****

Reversible

• Physostigmine salicylate (Antilirium)

  • Intermediate duration, crosses BBB

  • Used for miosis, ciliary paralysis, decreasing IOP, reverses NMJ block, treatment for anti-cholinergic tox, tx for Myasthenia Gravis

• Neostigmine (Prostigmin)

  • Short duration

  • Used for Myasthenia Gravis, reverse NMJ block, reduce IOP, urinary retention

• Pyridostigmine (Mestinon)

  • neostigmine analog that hs longer duration

  • Used primarily for Myasthenia Gravis

• Donepezil (Aricept):

  • Long duration, helps with dementia/AD

• Rivastigmine (Exelon):

  • Similar to donepezil but also approved for Parkinson’s related dementia

  • Pseudo reversible

Irreversible: mostly pesticides and dangerous

• Malathion and Parathion:

  • Used as insecticide, kils fish too

  • Parathion kills all vertebrates

  • Treatment: maintain vital signs, atropine and benzos

• Sarin, Soman, Vx:

  • Rapid nerve agent that causes all the DUMBELS effects

  • Treat with Atropine, Pralidoxime or benzodiazepine

Pralidoxime (Protopam, 2-pam)

Oxime used to regenerate cholinesterase in cases of poisoning with ireversible dugs

• High doses can inhibit ACh

Nicotine Toxicity

• Symptoms

• Treatment

• Vomiting, convulsions, coma, death, respiratory failure

• Treat with atropine, benzodiazepine and mechanical ventilation