Lec 14 + 15 + 16 ☑️.pdf

Autonomic nervous system Dr. Hader I. Sakr Associate professor, Medical Physiology Learning objectives: ANS neurotransmitters, fibers and receptors: o Distribution. o Mode of action. o Drugs acting on them Alarm response. ANS neurotransmitters  ANS neurotransmitters, fibers and recept...

Autonomic nervous system Dr. Hader I. Sakr Associate professor, Medical Physiology Learning objectives: ANS neurotransmitters, fibers and receptors: o Distribution. o Mode of action. o Drugs acting on them Alarm response. ANS neurotransmitters  ANS neurotransmitters, fibers and receptors - Synapses are the sites where the axon of one neuron terminates on the dendrites, soma or axon of another neuron. - The impulses (signals or electric activity) are transmitted at these synapses. - There is a space called cleft at the synaptic sites where a chemical transmitter is released. - Transmission at the synaptic junctions between the pre-and postganglionic neurons and between postganglionic neurons and autonomic effectors is chemically mediated i.e. no direct communication.  ANS neurotransmitters, fibers and receptors The chemical transmitters: On the basis of the released chemical transmitter, the autonomic Ach fibers, and in turn the activated receptors are divided into: cholinergic NE and adrenergic fibers. Acetylcholine: It is the chemical transmitter released by cholinergic fibers: 1. All preganglionic autonomic fibers: NN a) preganglionic sympathetic fibers, including those to the adrenal medulla, the modified sympathetic ganglion. b) preganglionic parasympathetic fibers. 2. All postganglionic parasympathetic fibers. M 3. Some postganglionic cholinergic sympathetic fibers: M a) Secretory fibers to sweat glands. b) Vasodilator fibers to blood vessels of skeletal muscles.  ANS neurotransmitters, fibers and receptors Synthesis of acetylcholine: Inn.com inactive - Acetate + reduced coenzyme-A + ATP  acetyl Co-A. QEM.SN Mind and actively taken up - Choline is synthesized in the neurons into the axoplasm of cholinergic neurons through choline transporter (3) (inhibited by hemicholinium (hemi-choline)). - Choline acetyltransferase (1) or choline acetylase is present in high concentration in the cholinergic axonal terminal. cytoplasm Axon - Most of this synthesis occurs in the axoplasm, and most QE of ACh is then transported to be stored in clear vesicles in the cholinergic fibers terminations by vesicular transporter (VAChT).  ANS neurotransmitters, fibers and receptors my nowhotansmitters Release of acetylcholine: ActionMotival - When AP spreads over the cholinergic fibers’ terminals  opening of voltage-gated Ca+2 channels  Ca+2 diffuses into the nerve terminals  binds to Calmodulin  activates CaM kinases (I & II)  vesicles fuse with the membrane and empty their contents to the exterior by exocytosis. QE Removal of acetylcholine: - Most of secreted ACh within a fraction of a second, is split (hydrolyzed) into acetate ion and choline by the enzyme ACh esterase.  ANS neurotransmitters, fibers and receptors - The true or specific cholinesterase: acts rapidly has a great affinity for ACh, and is present in high concentration in the synaptic area bound with the local collagen (basal lamina) and clustered in the postsynaptic membrane. - The pseudo-cholinesterase (= non-specific) is present in plasma and liver. It acts slowly on ACh that diffuses into the surrounding fluids or in the plasma. It’s under endocrine control and is affected by variations in liver function.  ANS neurotransmitters, fibers and receptors The cholinergic receptors: ACh activates two different receptor types, muscarinic and nicotinic receptors. 1- The muscarinic receptors: Five types M1-5 (GPCR). M2  Heart & presynaptic opens K+ channels &↓adenyly cyclase↓cAMP. at M3  Smooth muscle and gastric parietal cells PLCIP3 and DAG  ANS neurotransmitters, fibers and receptors 2- The nicotinic receptors: - Found in the autonomic ganglia, CNS (NN-2) and skeletal muscle at neuromuscular junction (NM-1). - Ligand-gated ion channels. - Made up of 5 subunits (pentameric). - In adults, it’s 2α1- β1-2δ. - In fetal muscles, it’s 2α1- β1- γ-δ. QE - Each α subunit has a binding site for Ach. When bound, conformational changes occur resulting in channel opening changing ionic conductance.  ANS neurotransmitters, fibers and receptors Noradrenalin (Norepinephrine, NE):caticolamens Ami r - It is the chemical transmitter released by postganglionic sympathetic endings EXCEPT: a) Secretory fibers to sweat glands. b) Vasodilator fibers to skeletal muscles BVs. - It’s also co-secreted with its methyl derivative (epinephrine) by the adrenal medulla. Synthesis: 1. In the liver: Hydroxylase - Phenylalanine  tyrosine. minor.it amnioro - Some tyrosine is synthesized from phenylalanine, but most is of dietary origin.  ANS neurotransmitters, fibers and receptors QE of adrenergic nerves: 2. In the axoplasm site28Formationof NE QE - Tyrosine is transported to catecholamine-secreting neurons and adrenal medulla by a concentrating mechanism via Na+- V9 dependent carrier, then: Hydroxylase Decarboxylase Tyrosine DOPA Dopamine. - Dopamine is then transported by 2 vesicular monoamine transporters (VMAT-1 & -2 inhibited by reserpine) to the vesicles.  ANS neurotransmitters, fibers and receptors 3. In the granulated vesicles: β-Hydroxylase QE - Dopamine Noradrenaline (NE)QEisit go ofNE ediwl.no - NE is stored in the granulated dark vesicles bound to ATP and chromogranin “A” protein. wed ftp.dlmj - Phenylethanolamine-N-methyltransferase (PNMT) is cytoplasmic enzyme present in adrenal medulla and some neurons. - nor NE leaves the vesicles to the cytoplasm  adrenaline  transported to other vesicles.  ANS neurotransmitters, fibers and receptors Release of Noradrenalin: by exocytosis (see before). E HowmanysubRealsfromParkves Q - Catecholamines are released together with ATP, chromogranin A and β-hydroxylase enzyme. - β-hydroxylase enzyme half-life is much longer than catecholamines. bbig Removal of Noradrenalin:OK Within few seconds following its secretion, NE is removed from the secretory site, in three different ways: - 1. Re-uptake. - Accounting for removal of 50-80% of the secreted NE. QE - into the adrenergic nerve endings themselves by an active transport process (inhibited by cocaine and tricyclic anti-depressants QE  ANS neurotransmitters, fibers and receptors arise 2. Diffusion away: from the nerve endings into the surrounding body fluids and then into the blood. inactivation Slow 3. Destruction: by enzymes such as: a) M.A.O. (monoamine oxidase) on the outer surface of mitochondria and is widely distributed in adrenergic nerve fibers, brain, liver and kidneys (deamination). b) C.O.M.T. (catechol-o-methyl-transferase) distributed particularly in postsynaptic neurons, glial cells, liver, kidneys and smooth muscles but none in presynaptic (methylation).  ANS neurotransmitters, fibers and receptors Receptors: - 1. Post-synaptic receptors: - offbeat organ α1 ↑PLC↑IP3 and DAG. Gaq α2↓adenylyl cyclase↓cAMP. G i β1, β2, β3 ↑adenylyl cyclase↑cAMP. G α  ANS neurotransmitters, fibers and receptors 2. The presynaptic receptors: - They are present in the membranes of post ganglionic adrenergic nerve endings regulating the chemical transmitters release from the nerve endings. - Stimulation of the α2 presynaptic receptors decrease, while the stimulation of β1 receptors increases the release of NE. DVA stimulate - Clonidine is an α2 agonist that lowers blood pressure by binding to presynaptic receptors (Peripheral effect). It has also central effect.  ANS neurotransmitters, fibers and receptors - Noradrenaline and adrenalin are secreted by the adrenal medulla. - They have almost the similar but more prolonged (5 to 10 times) effects on the different organs as those caused by direct sympathetic stimulation. - These hormones are removed slowly from the blood. Drug NE Adrenaline Isoprenaline (synthetic) -Receptors Mainly Excites NO action QE -Receptors off Slight Excites Excites MAIN EFFECT Elevates the ABP Cardiac activity Metabolic effect animation e v4 Alarm response  Alarm response Sympathetic nervous system discharges as one unit in emergency situations: Dilates the pupils —> letting more light into the eyes. Accelerates the heart beats, respirations and raises the blood pressure Constricts the blood vessels of the skin. Lowers threshold in RF in the brain. Stimulates Lipolysis and glycogenolysis. Drugs that affect the autonomic activity  Drugs that affect the autonomic activity - The junctions in the efferent autonomic pathway are a logical site for pharmacological manipulation because transmission at them is chemical. - The steps of neurotransmitter synthesis, storage, release, breakdown, reuptake or receptor binding can be stimulated or inhibited by drugs. Drugs that affect the Parasympathetic Nervous System a eyedrop aiif.int in Drugs that affect the autonomic activity ↓ Parasympathetic 3 main.co d wÉÉ e  Drugs that affect the autonomic activity Drugs that affect the Sympathetic Nervous System E guy ak Drugs that affect the autonomic activity Drugs that affect the autonomic activity 6199 EBH sina.ws only am