Basic principles of pharmacology PDF

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Topic Anatomy and Physiology of the Peripheral Nervous System D YFRM202 2 Anatomy and Physiology of the Somatic N...

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Topic Anatomy and Physiology of the Peripheral Nervous System D YFRM202 2 Anatomy and Physiology of the Somatic Nervous System: Neuromuscular junction 3  Learning Outcomes At the end of this lecture, you should be able to:  Describe the Somatic Nervous System.  Explain the physiology of somatic nerve neurotransmission.  Describe the Neuromuscular junction (NMJ) and its nicotinic muscle-type receptors.  Discuss the pathophysiology at the NMJ in the condition known as Myasthenia gravis. 4 Divisions of the Nervous System Image source: Bioninja (n.d.) Autonomic Control. Available at: https://ib.bioninja.com.au/options/option-a-neurobiology-and/a2-the-human- brain/autonomic-control.html (Accessed: 8 September 2024). 5 Somatic Nervous System 6  Somatic Nervous System The somatic nervous system consists of a single motor neuron which runs from the CNS to the NMJ. The cell bodies of somatic motor neurons reside in the ventral (anterior) horn of the spinal cord. The axon divides into many branches, each of which innervates a single muscle fibre. Osmosis. 2023. Neuromuscular junction and motor unit. (35 seconds) Available at: https://www.osmosis.org/learn/Neuromuscular_junction_and_motor_unit (Date accessed: 12 September 2023) 7 Somatic Nervous System Between the axon of the somatic motor neuron and the Nm receptors on the skeletal muscle, there exists a physical gap termed the synapse or synaptic cleft Osmosis. 2023. Neuromuscular junction and motor unit. (52 seconds) Available at: https://www.osmosis.org/learn/Neuromuscular_junction_and_motor_unit (Date accessed: 12 September 2023) 8  Neurotransmission When an action potential reaches the nerve terminal it causes an influx of Ca²⁺ through voltage-gated Ca²⁺, channels causing exocytosis of the vesicles, releasing ACh into the synapse. The ACh diffuses across the synaptic cleft to bind to Nm receptors on skeletal muscle. Osmosis. 2023. Neuromuscular junction and motor unit. (1 minutes 47 seconds) Available at: https://www.osmosis.org/learn/Neuromuscular_junction_and_motor_unit (Date accessed: 12 September 2023) 9  Somatic Neuromuscular Transmission After Ach is released, it activates post-junctional Nm receptors (ligand- gated ion channels that ↑ Na+ influx) Initiate skeletal muscle contraction (the physiologic effect). Osmosis. 2023. Neuromuscular junction and motor unit. (2 minutes 56 seconds) Available at: https://www.osmosis.org/learn/Neuromuscular_junction_and_motor_unit (Date accessed: 12 September 2023) 10  Source: Brenner & Stevens’ Pharmacology – Figure 6.4 Brenner & Stevens’ Pharmacology. 2023. - Page 64 – Figure 6.4 The nicotinic receptor is an acetylcholine-gated sodium channel. The channel is a polypeptide pentamer composed of varying combinations of α, β, δ, and ε subunits. In the muscle type of nicotinic receptor shown here, acetylcholine-binding sites are formed by pockets at the interface of the α and δ subunits and the α and ε subunits. Acetylcholine binding to the receptor causes sodium influx, membrane depolarization, release of calcium from the sarcoplasmic reticulum, and muscle contraction. Nicotinic receptors at autonomic ganglia and in the brain have a different subunit composition. 11  Acetylcholinesterase (AChE) is an enzyme which very rapidly and efficiently hydrolyses acetylcholine (ACh) into choline and acetate. The time required for hydrolysis of ACh at the NMJ is less than a millisecond. Neither acetate nor choline have significant transmitter effects, thus terminating the NT action of Ach. Most cholinergic synapses are richly supplied with AChE. AChE is found in cholinergic neurons and is highly concentrated at the postsynaptic end plate of the NMJ. AChE is also found in other tissues, e.g. in red blood cells. Rang and Dale’s pharmacology. 2024. Chapter 14. Page 182-204. 12  Other cholinesterase enzymes with a lower specificity for ACh exist Butyrylcholinesterase (BChE, also known as pseudocholinesterase) BChE is synthesised primarily in the liver and is mostly found in the liver and plasma Can also be found in glia and many other tissues However, it is virtually absent in neuronal elements of the central and peripheral nervous systems BChE hydrolyses ACh at a much slower rate than AChE Rang and Dale’s pharmacology. 2024. Chapter 14. Page 182-204. 13 Myasthenia Gravis 14  Myasthenia Gravis Myasthenia gravis is an autoimmune disease affecting the Nm receptors at the skeletal muscle NMJ. Antibodies are produced against the main immunogenic region found on α1 subunits of the Nm receptor-channel complex. The antibodies reduce Nm receptor function by: Cross-linking receptors, which stimulates their internalisation and degradation. Results in a 70-90% reduction in the number of Nm receptors at the NMJ. Causing lysis of the postsynaptic membrane. Binding to the receptor and inhibiting its function. Rang and Dale’s pharmacology. 2024.Chapter 14: Page 182-204. 15  Myasthenia Gravis Results in progressive skeletal muscle weakness. Frequent clinical findings are: Ptosis (drooping upper-eyelid), diplopia (double vision), difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration. Managed with AChE inhibitors which increase the effectiveness and duration of ACh binding to the remaining receptors. Rang and Dale’s pharmacology. 2024.Chapter 14: Page 182-204. 16  Checklist Can you...  Describe the Somatic Nervous System?  Explain the physiology of somatic nerve neurotransmission?  Describe the Neuromuscular junction (NMJ) and its nicotinic muscle-type receptors?  Discuss the pathophysiology at the NMJ in the condition known as Myasthenia gravis? 17  References Brenner & Stevens’ Pharmacology. 2023. Chapter 6 Parasympathetic, neuromuscular and cholinergic agonists. Page 59-73. Osmosis. 2023. Neuromuscular junction and motor unit. Available at: https://www.osmosis.org/learn/Neuromuscular_junction_and_motor_unit (Date accessed: 12 September 2023) Rang and Dale’s Pharmacology, 9th Edition. 2020. Chapter 14 Cholinergic transmission. Page 175-196. 18 19 20