Cholinergic Pharmacology: PMY 302

Cholinergic Pharmacology Overview

• PMY 302 is an introduction to pharmacology
• Cholinergic pharmacology concerns drugs affecting cholinergic receptors

Learning Objectives

• Describe the physiological effects of activating cholinergic receptors
• List prototype cholinergic agonists
• Explain how mechanisms of action and chemical properties relate to clinical uses, effects, and adverse effects for cholinergic agonists

Drug Classes

• Muscarinic cholinergic agonists include choline esters and alkaloids
• Bethanechol is a choline ester muscarinic agonist
• Pilocarpine is an alkaloid muscarinic agonist
• Nicotinic cholinergic agonists can be central or peripheral
• Nicotine and varenicline are central nicotinic cholinergic agonists
• Succinylcholine is a peripheral nicotinic cholinergic agonist drug
• Cholinesterase inhibitors can be reversible or irreversible
• Neostigmine, physostigmine, and donepezil are reversible cholinesterase inhibitors
• Echothiophate, sarin, and organophosphates are irreversible cholinesterase inhibitors

Parasympathetic Nervous System

• Mediates rest and digest responses like tightening airways, constricting pupils, lowering heart rate, and stimulating fluid production and digestion
• Post-ganglionic neurons mainly release ACh onto muscarinic receptors

Physiologic Antagonism

• PSNS activity acts as a physiologic antagonist to the SNS
• Opposing effects on organ function include pupil constriction vs dilation

Acetylcholine

• A neurotransmitter produced from acetyl CoA and choline
• Activates nicotinic or muscarinic receptors on postsynaptic cells
• Enzymatic degradation by acetylcholinesterase enzymes rapidly terminates ACh in synapse
• AChE enzymes are key drug targets

Cholinergic Receptor Locations

• All autonomic ganglia have nicotinic receptors
• Target organs of the parasympathetic nervous system have muscarinic receptors
• Neuromuscular junctions have nicotinic receptors
• The brain has nicotinic and muscarinic receptors

Cholinergic Receptor Types

• Muscarinic receptors are GPCRs - Gq or Gi
• Nicotinic receptors are ligand-gated ion channels

Key Nicotinic Effects

• Nicotinic receptors on autonomic ganglia enable both PSNS and SNS signaling
• Non-ANS functions of nicotinic receptors include:
  • Enabling muscle movement with muscle nicotinic receptors (NM)
  • CNS effects/reward pathway with neuronal nicotinic receptors (NN)

Key Muscarinic Effects

• Most pronounced clinically-relevant effects are muscarinic - other than at NMJ
• Selectivity is limited, produce nearly all of these effects to some extent
• Selectivity depends on administration site and dose, and the blockers oppose

Cholinergic Overdose

• In cholinomimetic overdose, patients will exhibit many or most adverse effects
• Mnemonics are a useful way help remember this constellation of effects

Organizing Drugs

• Cholinomimetic drugs include those that are direct and indirect acting
• Direct-acting drugs are either muscarinic or nicotinic
• Indirect-acting drugs which inhibit cholinesterase
• Irreversible inhibitors Cholinesterase are organophosphates
• Reversible inhibitors cholinesterase are carbamates

Direct Acting Drugs

• Direct acting drugs directly bind to and activate the receptor

Choline Esters

• Synthetic derivatives of acetylcholine, often have "chol" in name
• Some (e.g., ACh) are rapidly and extensively metabolized in blood by AChE enzymes
  • Poor oral bioavailability
  • Brief duration of action
• Permanently-charged quaternary ammonium group results in hydrophilicity, and in low penetration into CNS
• Choline esters can activate N, M or both receptors
• A B-methyl group reduces potency at N receptors

Alkaloids

• Nitrogenous organic compounds of plant origin which have pronounced physiological actions on humans, including effects at ANS receptors
• Tertiary amines are lipophilic
  • Well absorbed, readily enter CNS
• Quaternary amines are charged
  • Less well-absorbed
• Cholinomimetic alkaloids can act at N, M or both receptors

Muscarinic Agonists: Pilocarpine

• Pilocarpine is an alkaloid, tertiary amine and M3 agonist
• Treats glaucoma by increasing fluid outflow such as Isopto Carpine®
• Decreases pressure
• Treats xerostomia in Sjogren’s syndrome through PO and Salagen®
• Adverse effects include nausea, urge to urinate, dizziness, weakness, diarrhea, blurred vision (minimized w local administration)

Muscarinic Agonists: Bethanechol

• Bethanechol is a choline ester, minimally metabolized by AChE
• Activates M1-3 receptors in all peripheral tissues
• Approved for treating ileus and postoperative urine retention such as Urecholine ®; PO
• Listed Adverse effects are many contraindications, including asthma, bradycardia, and peptic ulcer disease
• It does not cross blood-brain barrier because a charged quaternary amine

Nicotinic Agonists: Nicotine & Varenicline

• Nicotine is a tertiary amine alkaloid
• Agonist at N and M receptors
• Activates post-ganglionic neurons, skeletal muscle end plates, and CNS
• Used as a smoking cessation aid in gum, lozenge, nasal spray or transdermal patch e.g., Nicorette®
• Varenicline is a partial agonist at specific N subtype, it blocks nicotine activation of reward paths, and is a smoking cessation aid such as Chantix®

Neuromuscular Blockade

• Neuromuscular blockers stop ACh from acting at the neuromuscular junction by preventing skeletal muscle contraction
• Non-depolarizing blockers are competitive antagonists at the NMJ nicotinic receptor
  • Induces paralysis
• Depolarizing blockers are agonists at the receptor
  • Cause rapid depolarization, brief period of uncontrolled contractions, then flaccid paralysis

Nicotinic Agonists: Succinylcholine

• Succinylcholine is a depolarizing neuromuscular blocker
• Activates N receptors, and voltage-sensitive Na+ channels become inactivated
• Resetting is slower with succinylcholine due to plasma cholinesterase
• Sodium receptors remain blocked for junctional transmission until metabolized by succinylcholine