School of Pharmacy, University of Nizwa Cholinergic Agonist Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-14 October 25, 2011

Cholinergic Neuron Preganglionic fibers terminating in the adrenal medulla, autonomic ganglia (parasympathetic and sympathetic), and postganglionic fibers of parasympathetic division use acetylcholine (ACh) as a neurotransmitter Cholinergic neurons innervate the muscles of the somatic system Important role in the CNS

Peripheral Nervous System

Neurotransmission at Cholinergic Neurons Six steps in the normal cholinergic transmission process: 1. Synthesis of the ACh 2. Storage of the ACh 3. Release of the ACh by a nerve action potential 4. Binding to receptor 5. Degradation of ACh 6. Recycling of choline

Synthesis and Storage of ACh

Neurotransmission at Cholinergic Neurons 1. Synthesis of the ACh Choline is transported from the extra-cellular fluid into the cytoplasm of the cholinergic neuron an energy-dependent carrier system that cotransports sodium can be inhibited by the drug hemicholinium. Uptake of choline is the rate-limiting step in ACh synthesis Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form ACh in cytosol 2. Storage of the ACh Packaged into presynaptic vesicles by an active transport Mature vesicle contains not only ACh but also ATP and proteoglycan

Neurotransmission at Cholinergic Neurons 3. Release of the ACh Propagation of action potential at the nerve ending increases intracellular calcium concentration Elevated calcium levels promote the fusion of vesicles with the cell membrane and release ACh into the synaptic space This release can be blocked by botulinum toxin Black widow spider venom facilitates ACh release 4. Binding to receptor ACh binds postsynaptic receptors on the target cell presynaptic receptors in the neuron that released the ACh Postsynaptic cholinergic receptors on surface of effector organs are divided into 2 classes, muscarinic and nicotinic Binding to a receptor leads to a biologic response

Neurotransmission at Cholinergic Neurons 5. Degradation of ACh Acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the synaptic cleft 6. Recycling of choline Choline is taken up by the neuron, where it is acetylated into ACh that is stored until released by a subsequent action potential

Cholinergic Receptors (Cholinoceptors) Two families of cholinoceptors: 1. Muscarinic receptors Affinity towards ACh High affinity towards muscarine, low affinity towards nicotine Five subclasses: M1, M2, M3, M4 and M5 2. Nicotinic receptors High affinity towards nicotine, low affinity towards muscarine

Muscarinic Receptors 1. Locations Found on ganglia and on the autonomic effector organs, such as heart, smooth muscle, brain, and exocrine glands M1 receptors found on gastric parietal cells M2 receptors on cardiac cells and smooth muscle M3 receptors on bladder, exocrine glands, and smooth muscle 2. Mechanism of ACh signal transduction When activated, receptor undergoes a conformational change and interacts with a G protein, which in turn transmits the signal to initiate different molecular events 3. Muscarinic agonists and antagonists Attempts are currently underway to develop muscarinic agonists and antagonists

Nicotinic Receptors Located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction The nicotinic receptors of autonomic ganglia differ from those of the neuromuscular junction. For example, ganglionic receptors are selectively blocked by hexamethonium, whereas neuromuscular junction receptors are specifically blocked by tubocurarine

Direct-acting Cholinergic Agonists Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptors These agents may be broadly classified into two groups: choline esters, include ACh and synthetic esters of choline, such as carbachol and bethanechol Naturally occurring alkaloids, such as pilocarpine All of the direct-acting cholinergic drugs have longer durations of action than ACh

Acetylcholine (ACh) ACh is a quaternary ammonium compound that cannot penetrate membranes ACh has both muscarinic and nicotinic activity Its actions include: Decrease in heart rate and cardiac output Causes vasodilation and lowering of blood pressure Increases salivary secretion and stimulates intestinal secretions Involved in stimulating ciliary muscle contraction for near vision

Bethanechol Structurally related to ACh, in which the acetate is replaced by carbamate and the choline is methylated. Hence, it is not hydrolyzed by AChE Actions: Directly stimulates muscarinic receptors, causing increased intestinal motility Adverse effects: Causes the effects of generalized cholinergic stimulation. These include sweating, salivation, decreased blood pressure, nausea, abdominal pain, and diarrhea

Carbachol Carbachol has both muscarinic as well as nicotinic actions It has effects on both the cardiovascular system and the GI system

Pilocarpine Pilocarpine is stable to hydrolysis by AChE. It exhibits muscarinic activity Actions: Applied topically to the cornea, pilocarpine produces a rapid miosis and contraction of the ciliary muscle Therapeutic use in glaucoma: Drug of choice in the emergency lowering of glaucoma Adverse effects: Can enter the brain and cause CNS disturbances. It stimulates sweating and salivation

Indirect-Acting Cholinergic Agonists: Anticholinesterases (Reversible) AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its actions Located both pre- and postsynaptically in the nerve terminal Inhibitors of AChE indirectly provide a cholinergic action. This results in the accumulation of ACh in synaptic space

Physostigmine Physostigmine is a substrate for AChE Actions: Acts on both muscarinic and nicotinic receptors. Its duration of action is about 2 to 4 hours. It stimulates the cholinergic sites in the CNS Therapeutic uses: Increases intestinal & bladder motility. Placed topically in the eye, it produces miosis, as well as a lowering of intraocular pressure. It is also used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine Adverse effects: Effects on CNS may lead to convulsions when high doses are used. Bradycardia may also occur

Neostigmine Neostigmine reversibly inhibits AChE. Unlike physostigmine, it has a quaternary nitrogen; hence, it is more polar and does not enter the CNS Neostigmine has a moderate duration of action, usually 30 minutes to 2 hours Actions: Used to stimulate the bladder and GI tract. Also, used in symptomatic treatment of myasthenia gravis, an autoimmune disease at neuromuscular junctions Adverse effects: Generalized cholinergic stimulation, such as salivation, decreased blood pressure, nausea, abdominal pain, and diarrhea

Pyridostigmine Pyridostigmine is a AChE inhibitor that is used in the chronic management of myasthenia gravis Its durations of action is 3 to 6 hrs Adverse effects: Similar to that of neostigmine

Edrophonium The actions of edrophonium are similar to those of neostigmine, except that it is more rapidly absorbed and has a short duration of action of 10 to 20 minutes Edrophonium is a quaternary amine and is used in the diagnosis of myasthenia gravis Intravenous injection of edrophonium leads to a rapid increase in muscle strength Care must be taken, because excess drug may provoke a cholinergic crisis. Atropine is the antidote