Acetylcholine metabolism by Dr. Ashok Kumar J

Acetyl Choline Metabolism

1. Acetyl Choline Metabolism Dr. Ashok Kumar J International Medical School Management and Science University Malaysia 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 1

2. Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by ( 1) The terminals of the large pyramidal cells from the motor cortex ( 2) Several different types of neurons in the basal ganglia (3 ) The motor neurons that innervate the skeletal muscles ( 4) The preganglionic neurons of the autonomic nervous system ( 5) The postganglionic neurons of the parasympathetic nervous system ( 6) Some of the postganglionic neurons of the sympathetic nervous system Acetylcholine 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 2

3. Acetylcholine Acetylcholine ( ACh ) is the transmitter of the parasympathetic autonomic nervous system and of the sympathetic ganglia Stimulation of the parasympathetic system produces effects that are broadly opposite to those of the sympathetic system slowing of the heart rate Bronchoconstriction stimulation of intestinal smooth muscle ACh also acts at neuromuscular junctions ACh may be involved in learning and memory, as neurons containing this transmitter also exist in the brain 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 3

4. Acetyl CoA + Choline Acetylcholine Acetate + Choline choline acetyl transferase Co A Acetylcholine esterase synaptic cleft Acetylcholine Metabolism Serine Ethanolamine CO 2 Serine decarboxylase Choline 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 4 Glucose SAM Methionine Homocysteine Vitamin B12

5. ACh receptors Two main classes of ACh receptors Nicotinic Muscarinic Nicotinic receptors are ionotropic Bind nicotine Found on ganglia and at the neuromuscular junction Binding of Ach opens the channel for both Na + and K + to pass through the membrane Action of the ligand on the channel is direct - so action is rapid 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 5

6. Muscarinic receptors, responding to the fungal toxin, muscarine , are metabotropic More widespread in the brain than are nicotinic receptors The major receptors found on smooth muscle and glands innervated by parasympathetic nerves Atropine specifically inhibits these receptors 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 6

7. Diisopropylflurophosphate ( DFP) inactivates acetylcholinesterase Acetyl choline esterase hydrolyses acetylcholine to acetate and choline. Acetylcholine is a neurotransmitter, a chemical mediator of a nerve impulse at a junction between two neurons or between a neuron and a muscle fiber On arrival of a nerve impulse at the ending of the neuron, acetylcholine (which is stored in the vesicles of the presynaptic nerve terminal) is released. The released acetylcholine acts on the postsynaptic membrane to increase the permeability of Na + entry across the membrane Depolarization results in the inside of the membrane becoming more positive than the outside; normally, the inside of the membrane is more negative than the outside 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 7

8. This process may propagate an action potential along a nerve fiber, or it may lead to contraction of a muscle Acetylcholine is quickly destroyed by acetylcholinesterase in the neuromuscular junction If, however, acetylcholine is not destroyed, as in the case of inactivation of acetylcholinesterase , its continued presence causes extended transmission of impulses In muscle fibers, continuous depolarization leads to paralysis 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 8

9. The cause of death in DPF intoxication is respiratory failure due to paralysis of the respiratory muscles (including the diaphragm and abdominal muscles ) Several organophosphorous compounds (malathion) are used as agricultural insecticides, improper exposure to which can result in toxic manifestations and death due to acetyl choline esterase inactivation Pralidoxime has found use in the treatment of organophosphorous poisoning and is most active in relieving the inhibition of skeletal muscle acetylcholinesterase 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 9

10. ACh agonists ( acetylcholinesterase inhibitors) Used to treat glaucoma an eye disease characterized by high intra-ocular pressure by increasing the tone of the muscles of accommodation of the eye Tissues include three muscles (pupillary dilator and constrictor muscles in the iris and the ciliary muscle) and the secretory epithelium of the ciliary body 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 10

11. Contraction of the pupillary constrictor muscle causes miosis , a reduction in pupil size Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics , especially organophosphate cholinesterase inhibitors 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 11

12. Ciliary muscle contraction causes accommodation of focus for near vision. Marked contraction of the ciliary muscle, often occurs with cholinesterase inhibitor intoxication, is called cyclospasm Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores Facilitating outflow of the aqueous humor into the canal of Schlemm Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma All of these effects are prevented or reversed by muscarinic blocking drugs such as atropine 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 12

13. Myasthenia gravis Myasthenia gravis, autoantibodies are formed against the nicotinic receptor for ACh . By blocking the hydrolysis of ACh , (drug edrophonium ) by inhibiting the enzyme , acetylcholinesterase , the concentration of ACh can be effectively increased It compensates for the reduced number of receptors Improvement in nerve-muscle conduction in response to endrophonium can be used as a diagnostic test Long-acting acetylcholinesterase inhibitors such as pyridostigmine can be used to treat the disease but corticosteroids are often effective 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 13

14. During surgery…….. Succinylcholine acts as competitive inhibitor of acetylcholine esterase Acetylcholine level increases Muscle paralysis – Muscle relaxation – required during surgery Acetyl choline stimulate intestinal function after surgery 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 14

15. Thank you 9/16/2014 Dr. Ashok Kumar J; IMS; MSU. 15