Cholinergic Agonists Overview PDF

Cholinergic Agonists Overview - Cholinergic agonists mimic the actions of acetylcholine (ACh). - There are two main types: **ACh-R (Acetylcholine Receptor) stimulants** and **Cholinesterase inhibitors**. - ACh-R stimulants are further categorized by the type of receptors they stimul...

Cholinergic Agonists Overview - Cholinergic agonists mimic the actions of acetylcholine (ACh). - There are two main types: **ACh-R (Acetylcholine Receptor) stimulants** and **Cholinesterase inhibitors**. - ACh-R stimulants are further categorized by the type of receptors they stimulate: **Muscarinic cholinomimetics** and **Nicotinic cholinomimetics**. - Another classification considers their mechanism of action: **Direct acting** (binding directly to the ACh-R) and **Indirect acting** (inhibiting the hydrolysis of endogenous ACh). The Cholinergic Neuron - ACh is the neurotransmitter in: - Autonomic ganglia (both parasympathetic and sympathetic) - Preganglionic fibers terminating in the adrenal medulla - Postganglionic fibers of the parasympathetic division - **Somatic muscle innervations** Neurotransmission at the Cholinergic Neuron - The six steps of neurotransmission in cholinergic neurons include: - Synthesis - Storage - Release - Binding of ACh to a receptor - Degradation of the neurotransmitter (NT) in the synaptic gap - Recycling of choline Synthesis of ACh - Choline is transported from plasma into the neuron by a **high-affinity choline transporter (Na+ dependent)**. - **Choline acetyltransferase** catalyzes the formation of ACh from choline and acetyl CoA in the cytosol. - The uptake of choline is the rate-limiting step in ACh synthesis. - This process can be inhibited by **hemicholinium** Storage of ACh - ACh is packaged into **vesicles called vesiculin** by an active transport process. - These vesicles also contain **adenosine triphosphate (ATP), ions (Ca2+ & Mg2+), and proteoglycan**. Release of ACh - Action potentials stimulate **voltage-sensitive Ca2+ channels** in the presynaptic membrane. - Increased Ca2+ levels promote the fusion of synaptic vesicles with the cell membrane and release of ACh into the synaptic cleft. - This release can be blocked by **botulinum toxin**. - **Black widow spider venom** causes the emptying of all ACh stores in synaptic vesicles into the synaptic gap Binding to a Receptor - Released ACh diffuses across the synaptic space and binds to **postsynaptic receptors (M & N)** on the target cell. - **Presynaptic (auto-) receptors** can also bind to ACh in the membrane of the neuron. - Binding to a receptor leads to a biological response within the cell. Degradation - **Acetylcholinesterase (AChE)** rapidly terminates the signal at the postsynaptic effector site by cleaving ACh into choline and acetate in the synaptic cleft. Recycling of Choline - **A Na+-coupled, high-affinity choline uptake system** recaptures choline and transports it back into the neuron for further ACh synthesis. Cholinergic Receptors (Cholinoreceptors) - **Muscarinic cholinergic receptors (M)** are 7 transmembrane proteins coupled to a G-protein (GPCRs). - They bind to both ACh and muscarine but only have a weak affinity for nicotine. - There are five subclasses: M1-5. - **M1, M3, and M5** lead to cellular excitation. - **M2 and M4** inhibit cellular excitability. Location of M-Receptors - All five subtypes have been found on neurons. - **M1 receptors** are also found on gastric parietal cells (controlling gastric acid secretion). - **M2 receptors** are on cardiac cells and smooth muscle (slowing heart rate and force of contraction). - **M3 receptors** are on the bladder, exocrine glands, and smooth muscle. ACh Signal Transduction Mechanisms (M1 & M3) - When M1 or M3 receptors are activated, they interact with a G protein (Gq). - This activates **phospholipase C**, hydrolyzing **phosphatidylinositol-(4,5)-bisphosphate (PIP2)** into **diacylglycerol (DAG)** and **inositol (1,4,5)-trisphosphate (IP3)**. - **IP3** causes an increase in intracellular Ca2+ from intracellular stores (sarcoplasmic reticulum). - Ca2+ stimulates or inhibits enzymes, or causes hyperpolarization, secretion, or contraction. ACh Signal Transduction Mechanisms (M2 & M4) - Activation of M2 subtypes on the myocardium muscle stimulates a G protein (Gi). - This inhibits **adenylyl cyclase (AC)** activity, which normally converts ATP to cAMP (second messenger). - The inhibition leads to an increased K+ conductance, resulting in decreased heart rate and force of contraction. Nicotinic Cholinergic Receptors (N) - These receptors bind to both ACh and nicotine, but only have a weak affinity for muscarine. - N cholinergic receptors consist of **five transmembrane polypeptide subunits and function as ligand-gated ion channels.** - Binding causes conformational changes that allow Na+ entry, depolarizing the effector cell (excitatory post-synaptic potential; EPSP). Carbachol - **Carbachol** has both M and N actions (not selective). - It\'s an ester of carbamic acid and a poor substrate for AChE. - Its long duration of action allows for a single administration to persist for approximately one hour. - It\'s primarily used topically in the eye as a miotic agent to treat glaucoma. Bethanechol - **Bethanechol** is a direct-acting cholinergic agonist with selective M activity. - It\'s used for urinary retention and postoperative ileus. Methacholine - **Methacholine** is a synthetic choline ester that is highly active at all M receptors, but has little effect on N receptors. - It is primarily used to diagnose bronchial hyper-reactivity in asthma. Neostigmine - **Neostigmine** is a reversible AChE inhibitor used to treat myasthenia gravis. Pyridostigmine and Ambenonium - These are also reversible AChE inhibitors used to manage myasthenia gravis. Edrophonium - **Edrophonium** is a short-acting reversible AChE inhibitor used in the diagnosis of myasthenia gravis. Tacrine, Donepezil, Rivastigmine, & Galantamine - These drugs are reversible AChE inhibitors used to treat Alzheimer\'s disease. Anticholinesterases (Irreversible) - **Organophosphates** bind covalently to AChE, increasing ACh levels at all sites. - Many are highly toxic and were developed as nerve agents (e.g., Sarin). - Related compounds like parathion are used as insecticides. Isoflurophate - **Isoflurophate** is an organophosphate that covalently binds to AChE, inactivating it permanently. - It is used topically in the eye for the chronic treatment of open-angle glaucoma. **Cholinesterase Reactivators** **Oximes** (e.g., pralidoxime and obidoxime) can reactivate inhibited AChE. They displace the organophosphate and regenerate the enzyme. Their effectiveness decreases with time as the enzyme undergoes \"aging\", which strengthens the bond between the organophosphate and the enzyme, making it impossible for reactivators to break the bond.