Cholinergic Agonists & Neurotransmission

Cholinergic Agonists Overview

• Cholinergic neurons are primarily found in the parasympathetic nervous system.
• They are also involved in sympathetic innervation of sweat glands and blood vessels in skeletal muscles.

Steps in Cholinergic Neurotransmission

• Choline is transported into the neuron via a sodium-dependent transport system during step one.
• Once inside the neuron, choline reacts with acetyl coenzyme A to form acetylcholine; choline acetyltransferase is the responsible enzyme.
• Acetylcholine is transported into presynaptic vesicles during step two, protecting it from degradation.
• An action potential causes voltage-sensitive calcium channels to open, allowing calcium to enter the axon during step three.
• Vesicles fuse with the membrane, releasing acetylcholine into the synapse.
• Acetylcholine binds to postsynaptic receptors during step four, resulting in a cholinergic response.
• Acetylcholine also binds to presynaptic receptors, inhibiting further acetylcholine release, acting as a negative feedback loop.
• Acetylcholinesterase terminates acetylcholine's function in the synaptic cleft during step five by breaking it down into acetate and choline.
• Free choline gets taken back up by the presynaptic neuron during step six, and the cycle repeats.

Cholinergic Receptors

• Two main types of cholinergic receptors: muscarinic and nicotinic.
• Muscarinic receptors have a high affinity for muscarine; nicotinic receptors have a high affinity for nicotine.

Muscarinic Receptors

• There are five subtypes: M1, M2, M3, M4, and M5; M1, M2, and M3 are the most functionally defined.
• M1 receptors are located in gastric glands.
• M2 receptors are located on cardiac cells.
• M3 receptors are located on smooth muscle in the eye, lungs, GI tract, and exocrine glands (e.g., sweat and salivary glands).
• Muscarinic receptors are G protein-coupled receptors (GPCRs).
• M1 and M3 receptors are coupled to Gq proteins.
• Gq stimulation leads to an increase in intracellular calcium levels, which can result in processes like secretion, contraction, and neurotransmission.
• M2 receptors are coupled to Gi proteins.
• Gi stimulation can lead to the opening of potassium channels, causing hyperpolarization and a reduced heart rate.

Nicotinic Receptors

• Nicotinic receptors are ligand-gated ion channels.
• When acetylcholine binds, these receptors undergo a conformational change that allows sodium ions to flow into the cell.
• Two types exist:
  • Neuromuscular junction (Nm): Responsible for muscle contraction.
  • Central nervous system and autonomic ganglia (Nn): Primarily involved in cholinergic signal transmission.

Cholinergic Drugs

• Drugs are divided into three groups:
  • Direct-acting
  • Indirect-acting reversible
  • Indirect-acting irreversible

Direct-Acting Cholinergic Agonists

• These mimic the effects of acetylcholine by binding to muscarinic or nicotinic receptors.
• Acetylcholine:
  • Produces non-specific cholinergic effects and is rapidly inactivated by cholinesterases.
  • It has limited clinical use.
  • When injected, it decreases cardiac output and heart rate, reduces blood pressure, and increases GI activity.
  • It is available in an ophthalmic solution to produce miosis during eye surgery.
• Carbachol:
  • Structurally similar to acetylcholine and mimics its effects.
  • It has limited therapeutic use.
  • Not readily hydrolyzed by acetylcholinesterase, giving it a relatively long duration of action.
  • It is used topically to constrict pupils during eye surgery and to decrease eye pressure.
• Pilocarpine:
  • Works on smooth muscle of the eye to reduce pupil size.
  • Increases aqueous outflow, leading to a rapid decrease in eye pressure.
  • Useful in treating acute glaucoma.
• Bethanechol:
  • Selectively stimulates the bladder and GI tract.
  • Administered orally or subcutaneously to treat urinary retention or GI atony.

Indirect-Acting Cholinergic Agonists (Cholinesterase Inhibitors)

• Bind to acetylcholinesterase, preventing the breakdown of acetylcholine, and leading to its accumulation in the synaptic cleft.
• Divided into reversible and irreversible agents

Reversible Indirect-Acting Agonists

• Edrophonium:
  • Reversibly binds to acetylcholinesterase.
  • It has a very short duration of action (10-20 minutes).
  • It is used to diagnose myasthenia gravis.
  • In myasthenia gravis, antibodies block acetylcholine receptors, causing muscle weakness; administration of edrophonium leads to a rapid increase in muscle strength.
• Physostigmine:
  • Stimulates both nicotinic and muscarinic receptors.
  • It has an intermediate duration of action (30 minutes to 2 hours).
  • It is used to treat overdoses of anticholinergic drugs, such as atropine.
• Neostigmine:
  • Another intermediate-acting agent.
  • Has a more polar structure, so it is poorly absorbed from the GI tract and does not enter the CNS.
  • It is used to treat myasthenia gravis, stimulate the bladder and GI tract, and reverse the effects of neuromuscular blocking agents.
• Pyridostigmine:
  • Is similar to neostigmine, producing very similar effects.
• Drugs for Alzheimer's Disease (Donepezil, Rivastigmine, Galantamine):
  • Cholinergic neuron activity is reduced in Alzheimer's disease.
  • These agents enhance cholinergic effects and may lead to improved cognitive function.
  • Unfortunately, none of these agents can stop the progression of Alzheimer's disease.

Irreversible Indirect-Acting Agonists

• Highly toxic and developed by the military as nerve agents.
• Sarin gas is a prime example.
• Echothiophate:
  • Forms a covalent bond with acetylcholinesterase, leading to a very strong cholinergic stimulation.
  • Therapeutic use is limited to treating open-angle glaucoma.
  • Rarely used due to its side effect profile.

Side Effects of Cholinergic Agonists

• It is due to excessive stimulation of cholinergic receptors.
• DUMBBELLS is a mnemonic to remember the side effects:
  • Diarrhea
  • Urination
  • Miosis (pupil constriction)
  • Bronchospasm
  • Bradycardia (decreased heart rate)
  • Emesis (vomiting)
  • Lacrimation (tearing)
  • Lethargy
  • Salivation