Cholinergic

• Cholinergic agonists promote activation of cholinergic transmission either by:

  • Direct activation of cholinergic receptors (Direct-acting Drugs)

  • Prevention of acetylcholine degradation (Indirect-acting Drugs)
• • Agents for direct-acting drugs: Choline esters, cholinomimetic alkaloids
• Agents indirect-acting drugs: Edrophonium, Carbamates, Organophosphates
• Cholinergic receptors include:

  • Muscarinic (M1-M5)

  • Nicotinic (Nn or Nm)
• Muscarinic (M1-M5)

  • These are receptors found in visceral organs.
• Nicotinic (Nn or Nm)

  • Nicotinic neural (Nn) is found in the post-synaptic neuron of both

  sympathetic and parasympathetic ANS.

  • Nicotinic muscular (Nm) is found in the skeletal muscle.
• Direct-Acting Agents

  • Muscarinic receptors are G-protein coupled receptors.
• Direct-Acting Agents

  • Agonist agents will activate it and the effect is mediated by intracellular secondary messengers, leading to altered organ function.
• intracellular secondary messengers:

  • Inositol triphosphate (IP3)

  • Diacyl glycerol (DAG)

  • Cyclic guanosine monophosphate (cGMP)
• Direct-Acting Agents

  • Nicotinic receptors are ligand-gated ion channels. These channels have 2 agonist binding sites and are permeable to Na+, K+, and Ca+ ions.
• Direct-Acting Agents:

  Agonist binds to receptors allowing Na+ influx (depol) producing an

  excitatory postsynaptic potential (EPSP).
• EPSP creates the action potential triggering contraction.
• indirect-Acting Agents

  Activity of AChE has 2 steps:

  • Bind acetylcholine and hydrolyze it to acetyl-enzyme complex and free choline.

  • Acetyl-enzyme complex is hydrolyzed to free the enzyme.
• Indirect-Acting Agents

  Drugs will bind the metabolizing enzyme Acetylcholinesterase (AChE) and prevents degradation of neurotransmitter, indirectly increasing the levels of acetylcholine available to bind to the receptor.
• Other name of M2 is cardiac M2
• Location of M1 is nerves
• Location of M2 are heart, nerves, and smooth muscle
• Location of M3 is glands, smooth muscle, endothelium
• Location of M4 and M5 is CNS
• Other name of Nm are muscle type and end plate receptor
• Other name of Nn are neuronal type and ganglion receptor
• Location of Nm: Skeletal muscle neuromuscular junction
• Location of Nn: CNS, postganglionic cell body, dendrites
• Structural features of M1, M3, M5: Seven transmembrane segments, Gq/11 protein-linked
• Structural features of M2 andM4: Seven transmembrane segments, Gi/o protein-linked
• Structural features of Nm: Pentamer1 [(alpha1)2 Beta 1 Deltay)]
• Structural features of Nn: Pentamer1 with alpha and beta subunits only, eg, (alpha4)2 (beta2)3 (CNS) or

  alpha3alpha5(beta2)3 (ganglia)
• Postreceptor Mechanism of M1, M2, and M3: IP3, DAG cascade
• Postreceptor Mechanism of M2: Inhibition of cAMP pro-duction, activation of K+ channels
• Postreceptor Mechanism of M4: Inhibition of CAMP protein-linked production
• Postreceptor Mechanism of Nm and Nn: Na+, K+ depolarizing ion channel
• Choline Esters (direct-acting)

  Drugs included in this group:

  • Acetylcholine (M, N)

  • Carbachol (M, N)

  • Metacholine (M, less N)

  • Bethanecol (M)
• Choline Esters

  • A quaternary ammonium group is important for its activity.
• A quaternary ammonium group is important for its activity.

  • It render agents to be relatively lipid insoluble (hydrophilic).

  • These drugs are poorly absorbed and poorly distributed in the CNS.
• Choline Esters

  • Acetylcholine is hydrolyzed easily by acetylcholinesterase (very short T1/2).
• Metacholine, Betanechol, and Carbachol are all resistant to acetylcholinesterase
• Cholinomimetic Alkaloids (direct-acting)

  • Drug included in this group:

  • Nicotine (N)

  • Lobeline (N) - trying hard to be nicotine; hard to find

  • Muscarine (M) - found first; mostly from mushrooms

  • Pilocarpine (M) - clinically used among these 4
• Cholinomimetic Alkaloids

  • These drugs do not share a structural similarity as that of acetylcholine but they are capable activating the same cholinergic receptors
• Cholinomimetic Alkaloids

  • Cholinomimetic alkaloids are well-absorbed from the site of administration.

  • Nicotine, Lobeline, and Pilocarpine only contains a tertiary amine group.

  • Muscarine is less absorbed in the GIT can be toxic upon ingestion.
• Cholinomimetic Alkaloids

  • Nicotine has more effect in the CNS than in the skeletal muscles.