Autonomic Pharmacology III: Cholinergic

Cholinergic Receptors: Muscarinic receptors (M1, M2, M3, M4, M5) are all?

G-Protein coupled receptors

Cholinergic Receptors: Nicotinic receptors (Nm, Nn) are all?

Ligand gated receptors

What does Acetylcholine acts on?

Muscarine and nicotinic receptors

What do low doses of Muscarinic receptors do lead to?

Bradycardia, bronchoconstriction, Increase in GI motility, Bladder constriction, Fall in BP, Salivation, Lacrimation

What do High doses of Nictotine receptors lead to?

CNS stimulation, Ganglionic stimulation, Release of adrenaline, Rise in BP

What does Bethanechol effect?

Parasympathetic Nervous System

• Direct- acting cholinergic agonist

• Treat non-obstructive urinary retention

What does Atropine effect?

Parasympathetic Nervous System

• Cholinergic Antagonist

• Treatment for overactive bladder and bradycardia

What are Muscarinic Receptor Agonist?

Agents that activate the muscarinic acetylcholine receptor. They are Parasympathomimetics, and their mechanism of action is different depending on which receptor is activated

What are M1 Receptors location and function?

Autonomic Ganglia: Depolarization, alters autonomic nerve messaging

Gastric Glands: Histamine release, acid secretion

Brain: Increase memory, attention, emotional response

What are M2 Receptors location and function?

Heart: Reduces heart rate, slows AV node conduction, reduces force of contraction

What are M3 Receptors location and function?

GI Tract & Gallbladder: Smooth muscle contraction

Pupils: Regulates pupil constriction

Glands: Promotes eye, mouth, sinus, lung, and skin lubrication

Blood Vessels: Increases vasodilation

Muscarinic Receptor Agonist: Carbachol

Works as an agonist of both muscarinic and nicotinic receptors. Mimics the effects of acteylcholine. Gives as eye drops to produce desired effect in eye

• Used in the eye to decrease pressure in certain kinds of glaucoma

Muscarinic Receptor Agonist: Pilocarpine

Works by binding to the muscarinic acetylcholine receptor (M3R) in the salivary glands

• Used to treat dryness in the mouth and throat caused by a decrease in the amount of saliva

Nicotinic Receptor Agonist: Nicotine

Main psychoactive component of tobacco

Nicotinic Receptor Agonist: Varenicline

A partial agonist that binds to the nAChrs and is used to treat tobacco dependence

Muscarinic Receptor Antagonists- “Antimuscarinics”: Atropine

Used tor reduce saliva and fluid in the respiratory tract during surgery

Treatment of insecticide or mushroom poisoning

Can be used in an emergency to treat a slow heartburn

Muscarinic Receptor Antagonists- “Antimuscarinics”: Long-acting muscarinic antagonists (LAMAs)

Bronchodilators that are used to treat COPD and asthma

Muscarinic Receptor Antagonists- “Antimuscarinics”: Oxybutynin

Treat symptoms of an overactive bladder, such as incontinence (loss of bladder control) or a frequent need to urinate

Muscarinic Receptor Antagonists- “Antimuscarinics”: Dicyclomine

Treat the symptoms (such as muscle spasms) associated with irritable bowel syndrome

Anticholinesterase Inhibitors/ Cholinesterase Inhibitors: Donepezil

Non-covalent reversible inhibitor

Used to treat dementia associated with Alzheimer’s disease

Anticholinesterase Inhibitors/ Cholinesterase Inhibitors: Physostigmine

Reversible carbamate inhibitor

Used to treat glaucoma, myasthenia gravis

Anticholinesterase Inhibitors/ Cholinesterase Inhibitors: Neostigmine

Reversible carbamate inhibitor

Used as reversal of non-depolarizing muscle relaxants

Anticholinesterase Reactivators: Pralidoxime (2-PAM)

Used as an antidote for organophosphate poisoning

What is Organophsphate Poisoning?

Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme.

• acetylcholinesterase inhibition causes acetylcholine to accumulate in synapses, producing continuous stimulation of cholinergic fibers throughout the nervous system

Organophsphate Poisoning Muscarinic Effects?

DUMBELLS

Defection

Urination

Miosis

Bronchorrhea

Bronchospasm

Bradycardia

Emesis

Lacrimation

Salivation

Organophosphate Poisoning Nicotinic Effects?

Muscle weakness, muscle fasciculation, Muscle paralysis

Muscarinic Receptor Antagoinst: Atropine MOA?

Competitively blocks the binding of ACh to the muscarinic receptors = reduced ACh activity= relives muscarinic symptoms associated with organophosphate poisoning

Muscarinic Receptor Antagoinst: Atropine Clinical Indications?

Organophosphate poisoning, adjuvant used during neuromuscular blockade reversal to manage bradycardia

• Treatment of symptoms from muscarine-containing mushroom poisoning

Muscarinic Receptor Antagoinst: Atropine Adverse Effects?

Blurred or double vision, difficult or rapid breathing, tachycardia

Oxime/ Acetylcholinesterase Activator 2-PAM (pralidoxime) MOA?

If administered 24 hours after organophosphate exposure, 2-PAM reactivates the AChE enzyme by cleaving the phosphate-ester bond formed b/w the organophosphate and AChE = accumulated ACh is destroyed by AChE

Oxime/ Acetylcholinesterase Activator 2-PAM (pralidoxime) Clinical indications?

Organophosphate poisoning (in conjunction with atropine); AchE overdose

• Because 2-PAM is less effective in relieving respiratory depression, atropine is always requried concomitantly to block the effect of accumulated ACh at this site

Oxime/ Acetylcholinesterase Activator 2-PAM (pralidoxime) Adverse Effects?

Blurred or double vision, difficult or rapid breathing, tachycardia

Antidotes for Organophosphate Poisoning: Alleviation of Symptoms

Bradycardia- due to activation of muscarinic receptors

Salivation- due to activation of muscarinic receptors

Dyspnea- due to activation of nicotinic receptors

Muscle weakness- due to activation of nicotinic receptors

Antidotes for Organophosphate Poisoning: Alleviation of Symptoms: Atropine

Muscarinic receptor antagonist (blocks acetylcholine) so will improve muscarinic symptoms

Antidotes for Organophosphate Poisoning: Alleviation of Symptoms: 2-PAM

Enhances regeneration of acetylcholinesterase enzymes, which inactivates acetylcholine, so will improve both muscarinic and nicotinic symptoms

Antidotes for Organophosphate Poisoning: Muscarinic Effects

Reversed by atropine, a competitive inhibitor

Reversed by pralidoxime, regenerates AChE via dephosphorylation

Antidotes for Organophosphate Poisoning: Nicotinic Effects

Reversed by pralidoxime, regenerates AChE via dephosphorylation

If 2-PAM is more effective at alleviating symptoms, why is atropine considered first-line therapy for organophosphate poisoning?

Atropine: bradycardia and airway secretions

Pralidoxime (2-PAM) muscle weakness and paralysis

Some organophosphates causes a permanent bond with acetylcholinesterase over time- a process called “aging”

• Once aging happens, 2-PAM no longer works. Thus, 2- PAM must be administered fairly quickly after exposure to be effective

What are Neuromuscular blocking agents (NMBAs)?

Usually administered during anesthesia to facilitate endotracheal intubation and/or improve surgical conditions

• Hydrophilic drugs and do not cross the blood-brain barrier

Come in 2 forms: Depolarizing neuromuscular blocking agents (succinycholine) and non-depolarizing neuromuscular blocking agents (rocuronium, vecuronium, atracurium, cisatracurium)

Depolarizing NMBAs: Succinycholine MOA?

Acetylcholine receptor agonist (remain bound to receptor (remain bound to receptor) = inhibits repolarization = persistent depolarization of the motor endplate = flaccid paralysis of the skeletal muscles

Depolarizing NMBAs (Succinycholine) Anesthetic Indication:

Neuromuscular blockade for endotracheal intubation, surgery, or mechanical ventilation

• Preferred NMBA for rapid sequence induction and intubation

Depolarizing NMBAs (Succinycholine) Contradictions:

Hyperkalemia, burns, strokes, susceptibility to malignant hyperthermia

Depolarizing NMBAs (Succinycholine) Boxed Warning:

Ventricular dysrhythmias, cardiac arrest, and death from hyperkalemia rhabdomyolysis in pediatric patients

Non-depolarizing NMBAs (rocuronium, vecuronium, atracurium, cisatracurium, mivacurium) MOA?

Competitive acetylcholine receptor antagonist = inhibits depolarization = no muscle contraction = flaccid paralysis of the skeletal muscle

Non-depolarizing NMBAs (rocuronium, vecuronium, atracurium, cisatracurium, mivacurium) Anesthetic Indication:

Neuromuscular blockade for endotracheal intubation, surgery, or mechanical ventilation

Non-depolarizing NMBAs (rocuronium, vecuronium, atracurium, cisatracurium, mivacurium) Adverse Effects:

Residual postoperative paralysis; adverse effects related to increased histamine release

Non-depolarizing NMBAs (rocuronium, vecuronium, atracurium, cisatracurium, mivacurium) Steroidal:

Rocuronium and Vecuronium

Non-depolarizing NMBAs (rocuronium, vecuronium, atracurium, cisatracurium, mivacurium) Nonsteroidal/benzylisoquinolinium

Atracurium, Cisatracurium, Mivacurium)

Reversal of Non-depolarizing NMBAs: Neostigmine

Acetylcholinesterase inhibitor

Reverses all non-depolarizing NMBAs

Reversal of Non-depolarizing NMBAs: Sugammadex

Only reverse sterodial non-depolarizing NMBAs

Neostigmine MOA?

Acetylcholinesterase inhibitor = initial breakdown of acetylcholine within the synaptic cleft = increased acetylcholine = increased activation of acetylcholine = normal neuromuscular transmission

Neostigmine Anesthetic Indications:

Reversal of non-depolarizing muscle relaxants

Neostigmine Adverse Effects:

Cardiac muscarinic effects (heart block), respiratory muscarainic effects (bronchospasm)

• Administer a muscarainic receptor antagonist (glycopyrrolate or atropine) before neostigmine to prevent muscarainic adverse effects (bradycardia)

Sugammadex MOA?

Selectively binds steroidal non-depolarizing NMBAs = reverses any level of neuromuscular block from these agents

Sugammadex Anesthetic Indications:

Reversal of sterodial non-depolarizing muscle relaxants (rocuronium and vecuronium)

Sugammadex Adverse Effects:

Vomiting, dry mouth, tachycardia, dizziness and hypotension