PHARMA - ANS 1: Cholinergic Agonists

Autonomic Nervous System

The unconscious control that branches out from the nervous system. It is largely independent; its activities are not under direct conscious control. It is concerned primarily with visceral functions, such as: Cardiac Output, Blood flow to various organs, Digestion

Sympathetic division

Related to the “fight-or-flight” responses of the individual

Parasympathetic division

Normally functions for the “rest and digest” responses of the body.

Cholinergic neurons

Primarily found in the parasympathetic nervous system, but they also participate in the sympathetic innervation of: Sweat glands, Blood vessels, Skeletal muscles

Parasympathetic Nervous System

“Rest and Digest”. Calm, meditating, relaxed, no danger. These situations are when the parasympathetic nervous system predominates. Critical functions are downregulated because the body does not need them

Acetylcholine (ACh)

Main neurotransmitter in cholinergic transmission. Mediates the transmission of nerve impulses across autonomic ganglia in both sympathetic and parasympathetic nervous system

Synthesis of Acetylcholine

Choline enters the neuron through a sodium-coupled choline transporter (i.e., choline transporter). Choline acetyltransferase catalyzes ACh synthesis from choline and acetyl-CoA

Uptake Into Storage Vesicle

ACh is protected from degradation in the vesicle for it to be released later on and bound to a receptor

Release of Acetylcholine

Release is initiated by an action potential via the depolarization of voltage-gated calcium channels. Release is blocked by botulinum toxin. Spider venom causes the release of Ach

Binding to the Receptor

Postsynaptic receptor is activated by binding of the neurotransmitter, generating the cholinergic response. ACh binding to presynaptic receptor inhibiting the release of ACh through negative feedback

Degradation of Acetylcholine

Unbound ACh in the synaptic cleft is rapidly hydrolyzed by acetylcholinesterase enzymes (AChE) in the synaptic cleft

Recycling of Choline

Choline is taken up by the neuron again for recycling. This transport is inhibited by hemicholinium

Cholinergic receptors

Both nicotinic and muscarinic receptors are targets of acetylcholine

Nicotinic cholinergic receptors

Are ligand-gated channels. When ACh binds to them, receptors undergo conformational change, allowing sodium ions to flow into the cells

Nm (Neuromuscular Junction)

Responsible for muscle contraction

Nn (CNS)

Mainly involved in the transmission of cholinergic signals

Muscarinic receptors

Have a high affinity for muscarine. They are G-protein coupled receptors

Parasympathetic Activation

Parasympathetic nerves operate when the body is at rest, allowing energy assimilation and storage; “rest and digest”

Direct-acting cholinergic agonists

Mimic the effects of ACh by binding to either muscarinic or nicotinic receptors. Increasing ACh release with choline esters or alkaloids

Acetylcholine

Produces non-specific cholinergic effects. Very limited clinical use due to it being rapidly deactivated by acetylcholinesterases. Prototypical direct-acting cholinergic agonist drug. Expected to elicit majority of the responses expected of parasympathetic stimulation

Bethanechol

Strongly muscarinic. No nicotinic agonist activity. Selectively stimulates urinary and GIT. Not hydrolyzed by AChE. Commonly for atonia of the bladder. Sometimes given orally or subcutaneously to treat urinary retention or to treat gastrointestinal lack of muscular tone

Carbachol

Both muscarinic and nicotinic agonist activity. Not hydrolyzed by AChE. Not degraded as fast as ACh

Carbachol

Commonly used for glaucoma treatment by local application in the eye. Facilitates draining of aqueous humor into the canal of Schlemm. Realigns the connective tissue trabeculae through which the canal of Schlemm passes → decreasing intraocular pressure. Sometimes used for bladder and bowel atonia when systemically administered. Sometimes used locally to constrict the pupil during eye surgery

Pilocarpine

Tertiary amide. Stable to hydrolysis by AChE. Muscarinic. Occurs within a few minutes. Lasts 4-8 hours. Can be repeated

Pilocarpine

Primarily for ophthalmology. The drug of choice for emergency lowering of intraocular pressure in both open- and closed-angle glaucoma. Extremely effective in opening trabecular meshwork around the canal of Schlemm → an immediate drop in intraocular pressure as a result of increased drainage of aqueous humor. Very useful in treating acute glaucoma attack

Pilocarpine

Treatment of Xerostomia (dry mouth) following head and neck radiation therapy. Adverse effects: Blurred vision, Night blindness, Brow ache

Cevimeline

Preferred drug over pilocarpine in Sjogren’s Syndrome. Selective for M1 & M3 receptors

Pilocarpine Poisoning

Exaggerated parasympathetic effects whose clinical manifestation includes profuse sweating (diaphoresis) and increased salivation

Atropine

Antidote for pilocarpine poisoning

Indirect-Acting Cholinergic Agonists

Inhibits cholinesterase enzymes that would result in increasing the pool of ACh by preventing its degradation by such enzyme. AChE-inhibitors can provoke responses to both nicotinic or muscarinic receptors and can either be reversible or irreversible

Reversible Indirect-Acting Acetylcholinesterase Inhibitors

Effects are all cholinergic or one that mimics parasympathetic stimulation

Edrophonium

Prototypical short acting AChE inhibitor (which reversibly inhibits acetylcholinesterase). Quaternary Amine ‒ actions limited to the periphery. Reversibly binds to the active center of AChE. Inhibits it consequently preventing hydrolysis of AChE. Rapidly absorbed. Short duration of action (10-20 mins). Rapid renal elimination

Edrophonium

Mainly used for diagnosis of Myasthenia Gravis (MG). Improvement of muscle strength by anticholinesterase is characteristic of MG, but does not occur when muscle weakness is due to other causes. Assess cholinesterase inhibitor therapy. Reversing the effects of Non-depolarizing Neuromuscular Blockers after surgery

Myasthenia Gravis

Autoimmune disease caused by antibodies to the nicotinic receptor at the neuromuscular junction causing nicotinic receptor degradation making fewer receptors available for interaction with ACh. Intravenous (IV) injection of Edrophonium leads to rapid increase in muscle strength

Pyridostigmine

The treatment for Myasthenia Gravis is?

Cholinergic Crisis

Causes of Muscle Weakness: Excess ACh at the neuromuscular junction, producing depolarization blockade similar to one produced by succinylcholine.

Effect of Edrophonium: Maintain or worsen muscle weakness

Myasthenic Crisis

Causes of Muscle Weakness: ACh deficiency

Effect of Edrophonium: Increase ACh levels → Increased muscle strength

Tensilon Test

To determine muscle weakness due to Myasthenia Gravis. Procedure: 2 mg of IV Edrophonium is given initially. Dose is repeated every 2 minutes for a total of 8 mg. Wait for improvement in muscle strength over 2 minutes. (+) Result: rapid improvement (30-45 seconds) in facial muscle strength

Physostigmine

Indications: Intestinal / Bladder atony

Neostigmine

Indications: Neuromuscular blockade reversal

Pyridostigmine

Indications: Myasthenia Gravis

Tacrine, Donepezil

Indications: Improve cognitive function in Alzheimer’s Disease

Physostigmine

Stimulates both nicotinic and muscarinic receptors. Intermediate-acting (Duration of action: 30 mins to 2 hrs). Used in treatment of overdoses of anticholinergic drugs such as atropine

Neostigmine

An intermediate-acting agent. Used for myasthenia gravis. Stimulates bladder and gastrointestinal tract

Donepezil, Rivastigmine, and Galantimine

Relieve symptoms of Alzheimer’s disease by enhancing cholinergic effects, leading to somewhat improved cognitive function. NOT used to stop the progression of Alzheimer’s disease

Neostigmine

Neuromuscular blockers or paralytic agents are given to a patient during an operation. After the operation, this can be administered to reverse the paralysis

Neostigmine

A potent cholinergic agonist, so it is administered with an anticholinergic drug to offset the side effects (e.g., salivating)

Cholinergic Crisis

Adverse effect of reversible cholinesterase inhibitors (parasympathomimetics). Neuromuscular junction is overstimulated due to excessive ACh or cholinesterase inhibitors. Muscle stops responding due to ACh bombardment leading to: Flaccid paralysis and respiratory failure with or without myosis, ↑ Sweating and salivation, ↑ Bronchial secretions

Organophosphates

Extremely toxic. Developed by the military as nerve agents

Echothiophate

Forms covalent bonds with AChE leading to a very strong cholinergic stimulation. Use is restricted to open-angle glaucoma only. Rarely used today due to the side effects associated with cholinergic stimulation

Organophosphates

Generally dispersed as aerosols or dust. Highly lipid soluble = HIGHLY TOXIC. Rapidly absorbed in Skin, mucus membranes following contact with moisture, Lungs after inhalation, GI tract after ingestion. Metabolized by both plasma and liver esterases. Excreted in urine as hydrolysis products

Diarrhea, Urination, Miosis & Muscle Weakness, Bronchorrhea, Bradycardia, Emesis, Lacrimation, Salivation

What are the cholinergic adverse effects, use the mnemonic “DUMBBELS”

Severe Acute Intoxication

Often seen in organophosphate poisoning. Includes a mix of muscarinic and nicotinic excess with generalized cholinergic stimulation. Presents with: Extreme salivation and sweating, Involuntary urination, Hypotension, Bradycardia, Paralysis of motor function (will induce difficulty in breathing to respiratory paralysis), Muscle twitching, Convulsions, Intense miosis

Chronic Intoxication

Slowly progressive peripheral nerve demyelination. Presents with: Progressive muscle weakness, Sensory loss

Respiratory failure

A common cause of death in cholinergic intoxication, and is often heralded with: Laryngospasm, Bronchoconstriction, Increased tracheobronchial and salivary secretions (with compromised voluntary control of the diaphragm, intercostal muscles and latter central respiratory paralysis)

Atropine

In high doses, reverses many peripheral muscarinic effects of cholinergic excesses such as: ↑ Tracheobronchial and salivary secretions, Bronchoconstriction, Bradycardia, Some central muscarinic effect of excessive cholinergic stimulation. Has no effect against peripheral neuromuscular compromise. Procedure: Initial 2-4 mg administered IV/IM. 2 mg IV every 5-10 minutes until muscarinic symptoms disappear

Pralidoxime

Reverses both muscarinic and nicotinic effects on neuromuscular junction of skeletal muscles such as: Fatigability, Generalized weakness, Involuntary twitching, Fasciculation, Paralysis of respiratory muscles. Procedure: Administer 1-2 mg IV infusion over 5 minutes. Repeated every 20-60 minutes until desired effect is reached