Cholinergic Agonists and Neurotransmission

Cholinergic Agonists

• Cholinergic neurons are primarily found in the parasympathetic system, but they also participate in sympathetic innervation of sweat glands and blood vessels in skeletal muscle.

Cholinergic Neurotransmission

• Cholinergic neurotransmission involves six major steps:
  • Choline is transported into the neuron by an energy- and sodium-dependent transport system.
  • Choline reacts with acetyl CoA to form acetylcholine, catalyzed by choline acetyltransferase.
  • Acetylcholine is transported into the pre-synaptic vesicle, where it is protected from degradation.
  • The action potential causes voltage-sensitive calcium channels to open, leading to the fusion of the vesicle with the membrane and the release of acetylcholine from the terminal.
  • Acetylcholine binds to post-synaptic receptors, leading to a cholinergic response, and also binds to presynaptic receptors, inhibiting the release of more acetylcholine (negative feedback loop).
  • Acetylcholinesterase terminates acetylcholine function at the synaptic cleft by breaking it down to acetate and choline.

Cholinergic Receptors

• There are two types of cholinergic receptors:
  • Muscarinic receptors (high affinity for muscarine):
    • M1 receptors: found on neurons, gastric glands, and other locations
    • M2 receptors: found on cardiac cells
    • M3 receptors: found on smooth muscle, eye, lungs, digestive tract, and exocrine glands
  • Nicotinic receptors (high affinity for nicotine):
    • Nm receptors: found at neuromuscular junctions, responsible for muscle contraction
    • Nn receptors: found in the central nervous system and autonomic ganglia, involved in transmission of cholinergic signals

Direct Acting Cholinergic Agonists

• These agents mimic the effects of acetylcholine by binding to muscarinic or nicotinic receptors:
  • Acetylcholine: decreases cardiac output, heart rate, and blood pressure; increases GI activity
  • Carbachol: structurally similar to acetylcholine, has a long duration of action
  • Pilocarpine: used ophthalmically to constrict the pupil and decrease intraocular pressure
  • Bethanechol: selectively stimulates urinary and gastrointestinal tract

Indirect Acting Cholinergic Agonists

• These agents bind to acetylcholinesterase, resulting in a buildup of acetylcholine in the synaptic cleft:
  • Edrophonium: reversibly binds to acetylcholinesterase, short duration of action, used for diagnosis of myasthenia gravis
  • Physostigmine: stimulates both nicotinic and muscarinic receptors, intermediate-acting agent
  • Neostigmine: intermediate-acting agent, used for symptoms of myasthenia gravis, stimulating bladder and GI tract, and reversing the effects of anesthesia
  • Pyridostigmine: similar to Neostigmine, used for Alzheimer's disease
  • Donepezil, Rivastigmine, and Galantamine: used to enhance cholinergic effects and improve cognitive function in Alzheimer's disease

Irreversible Cholinesterase Inhibitors

• These agents form covalent bonds with acetylcholinesterase, leading to strong cholinergic stimulation:
  • Echothiophate: used to treat open-angle glaucoma, rarely used due to side effects

Side Effects of Cholinergic Agonists

• DUMBBELLS mnemonic: diarrhea, urination, miosis, bronchorrhea, emesis, lacrimation, and salivation.

Cholinergic Agonists

• Cholinergic neurons are primarily found in the parasympathetic system, but also participate in sympathetic innervation of sweat glands and blood vessels in skeletal muscle.

Cholinergic Neurotransmission

• Cholinergic neurotransmission involves six major steps:
  • Choline is transported into the neuron by an energy- and sodium-dependent transport system.
  • Choline reacts with acetyl CoA to form acetylcholine, catalyzed by choline acetyltransferase.
  • Acetylcholine is transported into the pre-synaptic vesicle, where it is protected from degradation.
  • The action potential causes voltage-sensitive calcium channels to open, leading to the fusion of the vesicle with the membrane and the release of acetylcholine from the terminal.
  • Acetylcholine binds to post-synaptic receptors, leading to a cholinergic response, and also binds to presynaptic receptors, inhibiting the release of more acetylcholine (negative feedback loop).
  • Acetylcholinesterase terminates acetylcholine function at the synaptic cleft by breaking it down to acetate and choline.

Cholinergic Receptors

• There are two types of cholinergic receptors:
  • Muscarinic receptors (high affinity for muscarine):
    • M1 receptors: found on neurons, gastric glands, and other locations.
    • M2 receptors: found on cardiac cells.
    • M3 receptors: found on smooth muscle, eye, lungs, digestive tract, and exocrine glands.
  • Nicotinic receptors (high affinity for nicotine):
    • Nm receptors: found at neuromuscular junctions, responsible for muscle contraction.
    • Nn receptors: found in the central nervous system and autonomic ganglia, involved in transmission of cholinergic signals.

Direct Acting Cholinergic Agonists

• These agents mimic the effects of acetylcholine by binding to muscarinic or nicotinic receptors:
  • Acetylcholine: decreases cardiac output, heart rate, and blood pressure; increases GI activity.
  • Carbachol: structurally similar to acetylcholine, has a long duration of action.
  • Pilocarpine: used ophthalmically to constrict the pupil and decrease intraocular pressure.
  • Bethanechol: selectively stimulates urinary and gastrointestinal tract.

Indirect Acting Cholinergic Agonists

• These agents bind to acetylcholinesterase, resulting in a buildup of acetylcholine in the synaptic cleft:
  • Edrophonium: reversibly binds to acetylcholinesterase, short duration of action, used for diagnosis of myasthenia gravis.
  • Physostigmine: stimulates both nicotinic and muscarinic receptors, intermediate-acting agent.
  • Neostigmine: intermediate-acting agent, used for symptoms of myasthenia gravis, stimulating bladder and GI tract, and reversing the effects of anesthesia.
  • Pyridostigmine: similar to Neostigmine, used for Alzheimer's disease.
  • Donepezil, Rivastigmine, and Galantamine: used to enhance cholinergic effects and improve cognitive function in Alzheimer's disease.

Irreversible Cholinesterase Inhibitors

• These agents form covalent bonds with acetylcholinesterase, leading to strong cholinergic stimulation:
  • Echothiophate: used to treat open-angle glaucoma, rarely used due to side effects.

Side Effects of Cholinergic Agonists

• DUMBBELLS mnemonic: diarrhea, urination, miosis, bronchorrhea, emesis, lacrimation, and salivation.