4 ANS Intro + Cholinergics -41 ff(1).ppt
- 2. Nervous System Divided into: • Central Nervous System: brain and the spinal cord • Peripheral Nervous System 1. Somatic Nervous System 2. Autonomic Nervous System
- 3. Comparison of somatic and autonomic systems
- 4. Comparison of Autonomic and Somatic Motor Systems Somatic motor system Autonomic nervous system Effectors skeletal muscles cardiac muscle, smooth muscle, and glands Efferent pathways • Heavily myelinated axons of the somatic motor neurons extend from the CNS to the effect “skeletal muscle”. • Axons conduct impulses rapidly • no ganglia Axons are a two-neuron chain •The preganglionic (first) neuron has a lightly myelinated axon •The postganglionic (second) neuron extends to an effector organ •Conduction is slower due to thinly or unmyelinated axons Target organ responses All somatic motor neurons release Acetylcholine (ACh), which has an excitatory effect • Preganglionic fibers release ACh • Postganglionic fibers release norepinephrine or ACh and the effect is either stimulatory or inhibitory
- 5. Autonomic and Somatic Motor Systems
- 6. Divisions of the Autonomic Nervous System • Sympathetic and parasympathetic divisions • Innervate mostly the same structures • Cause opposite effects • Sympathetic – “fight, or flight” • Activated during exercise, excitement, and emergencies • Parasympathetic – “rest and digest” • Concerned with conserving energy
- 7. Anatomical Differences in Sympathetic and Parasympathetic Divisions • Issue from different regions of the CNS • Sympathetic – also called the thoracolumbar division • Parasympathetic – also called the craniosacral division
- 8. Anatomical Differences in Sympathetic and Parasympathetic Divisions Sympathetic Parasympathetic Thoracolumbar outflow Craniosacral outflow Length of preganglionic fibers Short “sympathatic ganglia are located billaterally to spinal cord” long “parasympathatic ganglia are located near effector organs” Length of postganglionic fibers long postganglionic fibers short postganglionic fibers Branching of axons highly branched few branches Neurotransmitter released by preganglionic axons Acetylcholine for both branches (cholinergic) Acetylcholine Neurotransmitter released by postganglionic axons release norepinephrine Except sweat glands, postganglionic sympathetic neuron release ACh release acetylcholine
- 9. Anatomical Differences in Sympathetic and Parasympathetic Divisions
- 10. Anatomical Differences in Sympathetic and Parasympathetic Divisions
- 11. Clinical relevance of ANS pharmacology • Autonomic Drugs are very much Clinically Relevant in: • Treatment of Angina (BBs) • The treatment of Heart Failure (BBs) • TTT of hypertension (alpha and BBs). • TTT of arrhythmias (BBs) • Anaphylactic shock (EP) • Cardiogenic shock (dopamine) • Benign prostatic hypertrophy • Alzheimer’s disease (Physostigmine) • Asthma (adrenergic agonists) • Preanesthetic medication (Atropine) • Parkinsonism (Benzotropine; central anticholinergics)
- 12. NEUROTRANSMISSION • Definition of Neurotransmitters: • Chemical substances that transmit impulses across junctions (synapses): • neuron-neuron synapse= ganglion. • neuron- effector synapse = synaptic cleft. • Role of transmitters: • Communication between nerve cells and between nerve cells and effector organs. • Steps in Neurohumoral Transmission 1. Synthesis 4. Receptor binding 2. Storage 5. Termination 3. Release
- 13. Ca++ Neurohumoral transmission Nerve ending 1. Arrival of action potential 3. Release of neurotransmitter 4. Neurotransmitter binds to its receptor 5. Biological changes 6. Removal of the Neurotransmitter
- 15. Adrenergic neurotransmission • Noradrenaline (nor-epinephrine): • post-ganglionic sympathetic nerve fibers. • Adrenaline (Epinephrine): released from adrenal medulla.
- 16. Noradrenaline (NA) Synthesis: Tyrosine DOPA Dopamine Tyrosine hydroxylase Dopa Decarboxylase Tyrosine Dopamine β-hydroxylase NA Dopamine Active transport NA NA NA NA Do D β-H ATP Storage: Presynaptic neurons ATP
- 17. Termination of NE Action 1) Uptake mechanism: major mechanism. • Neuronal uptake (uptake 1): • NE is uptaken into the adrenergic neurons to be metabolized by MAO enzyme. • Cocaine, TCA inhibit uptake 1. • Relatively selective for NE. • Vesicular uptake: • NE escapes MAO enzyme is transferred from neuronal cytoplasm to storage vesicles. • Extraneuronal uptake (uptake 2): • Non-selective and terminates all catecholamines (NE, EP, dopamine & isoprenaline). • Catecholamines are taken up by the surrounding tissues to be metabolized by COMT in the liver.
- 18. Fate: NA NA NA NA Do D β-H ATP NA β NA a. Re-uptake (80%) b. Enzymatic metabolism 15% Urine C.Excretion: (5%) MAO MAO COMT MAO COMT Neuronal Uptake I Tissue Uptake II Granular Uptake NA NA NA NA NA
- 19. Cont. Termination of adrenergic transmission 2) Enzymatic degradation: Minor pathway. • MAO: in adrenergic nerve endings, brain, intestine & kidneys. • COMT: in liver mainly • Enzymatic degradation inactivates catecholamines to inactive metabolites. • Neuronal NE is metabolized by MAO • Circulating catecholamines are metabolized by COMT.
- 20. Physiology of adrenergic Receptors Pre-synaptic a2 a2 NE a2 a1 b1 b2 b3 a1 Post Synaptic Effector Cell
- 21. Location & functions of Autonomic receptors i. a1 –receptors • Located post-synaptically in smooth muscles. • Excitatory in function except GIT wall. • Mediate the following effects: • All B.V. V.C. BP & coronary blood flow. • Radial muscle of the iris Contraction active mydriasis. • GIT & urinary sphincters Contraction. • Liver: glycogenolysis & gluconeogenesis. • GIT wall (stomach & intestine) Relaxation
- 22. ii- a2- receptors • both pre- & post-synaptics. • Presynaptic a2- receptors are inhibitory & mediate negative feed back inhibition of NE release from adrenergic neurons. • Postsynaptic a2- receptors are also inhibitory except in platelet & BV. • Stimulation of a2- receptors: • insulin secretion • central sympathetic outflow. • GIT relaxation. • platelet aggregation. • vascular smooth muscle contraction.
- 23. iii- b1-receptors • are excitatory in function. • in heart & juxta-glomerular cells . • mediate the following effects: • cardiac stimulation • renin release.
- 24. iv- b2 & b3 –receptors • b2-receptors: • Inhibitory to smooth muscles and excitatory to cardiac muscles. • Smooth muscles of bronchi, uterus, GIT, GUT and BV relaxant effects • Heart excitatory effects. • Skeletal muscles glycogenolysis, tremors & K+ uptake. • Liver: glycogenolysis & gluconeogenesis. • Pancreasse insulin secretion N.B. b1-receptors b2-receptors in the heart. • b3-receptors: • In adipose tissues. • Mediates lipolysis.
- 25. Molecular mechanisms of Adrenergic receptors i) a1-adrenergic receptors: - Activation of a1- receptors phospholipase C ” Gs protein“ formation of two second messengers: 1. IP3 intracellular Ca++ 2. DAG activates PKC. ii) a2-adrenergic receptors: -Activation of a2-adrenergic receptors activate Gi : a) inhibit adenyl cyclase cAMP cAMP-dependent protein kinases. b) K+ conductance & inhibit voltage-dependent Ca++ channels. iii) b-adrenergic receptors: Stimulation of b1 & b2 stimulates Gs protein activates adenylyl cyclase cAMP activity of cAMP-dependent protein kinase which phosphorylates different cellular proteins b receptor effects.
- 26. Signal Transduction by a1 - Adrenergic Receptors Gq q q
- 27. Signal Transduction by a2 - and b - Adrenergic Receptors
- 28. Effects of drugs on adrenergic transmission • Inhibition of vesicular storage of NE by reserpine. • Inhibition of NE release by guanethidine. • Increasing release of NE by indirectly acting sympathomimetics e.g., tyramine, amphetamine and ephedrine. • Inhibition of reuptake 1 of NE by tricyclic antidepressants & cocaine • Blocking reuptake 2 by glucocorticoids. • Inhibition of MAO or COMT by MAO inhibitors or COMT inhibitors. • Interaction with pre-or post-synaptic adrenergic receptors e.g., a or b blockers .
- 31. Cholinergic Receptors • The two types of receptors that bind ACh are nicotinic and muscarinic • These are named after drugs that bind to them and mimic ACh effects • Muscarinic receptors: M1, M2, M3, M4, M5 • Nicotinic receptors: Nn & Nm
- 32. Nicotinic Receptors (cholinergic) • Nicotinic receptors are found on: • Motor end plates (skeletal muscles)…NM • All preganglionic neurons of both sympathetic and parasympathetic divisions….NN • The hormone-producing cells of the adrenal medulla ….NN • The effect of ACh binding to nicotinic receptors is always stimulatory
- 33. Muscarinic Receptors (cholinergic) • Muscarinic receptors occur on all effector cells stimulated by postganglionic cholinergic fibers • The effect of ACh binding: • Can be either inhibitory or excitatory • Depends on the receptor type of the target organ
- 34. Acetylcholine Synthesis of Ach: Acetyl-CoA+choline Choline acetyl transferase (CAT) ACh stored in granules inside nerve terminals nerve impulse release of ACh. Removal of Ach: • ACh is hydrolysed by acetylcholine esterase to choline and acetic acid, and choline is reuptaked by neurons • Acetylcholine esterase has two types: • true (in neurons and different tissues) • pseudo (in plasma and liver) • Hemicholinum inhibits ACh synthesis. • Excess Magnesium or lack of Calcium or botulinum toxin inhibit ACh release.
- 36. ACh Primary transmitter in 1. All autonomic ganglia 2. Parasympathetic postganglionic neurons 3. Post-ganglionic sympathetic to thermoregulatory sweat gland. 4. Neuro-muscular junction (Skeletal muscles)
- 37. Parasympathetic receptors Receptor Action(s) Mechanism Nicotinic (N1 or NN) 1- stimulate all autonomic ganglia 2- secretion of NE and Epi from suprarenal gland opening of Na+/K+ channels depolarization Nicotinic (N2 or NM) 1- Skeletal muscle contraction As N1 Muscarinic (M1) 1- increase HCl secretion from stomach Act on Gs stimulates phospholipase C increase inositol triphosphate (IP3) and Diacylglycerol (DAG) increase intracellular calcium Muscarinic (M2) 1- decrease heart rate, heart conductivity and atrial contraction 2- presynaptic feed-back regulation (decrease ACh release). Act on Gi inhibit adynylyl cyclase Decrease cAMP Muscarinic (M3) 1- contraction of smooth muscles (miosis, bronchoconstriction, contraction of urinary bladder and GIT) 2- relaxation of ureter and sphincters of GIT and UT 3- increase secretion of glands (salivation, sweat, …) 4- Vasodilation due to release of nitric oxide (NO) As M1
- 39. Actions of ACh in the parasympathetic NS: 1. On CVS: • bradycardia, decreases atrial contractility and heart conductivity 2. On the eye: •Miosis by contraction of constrictor (circular) muscle (M3) •Contraction of ciliary muscle (accommodation to near vision) (M3) •Decrease intraocular pressure (IOP) by opening of canal of Schlemm, therefore increases aqueous humour drainage. 3. On UT: • Facilitates urination by contraction of the walls and relaxation of the sphincter of the urinary bladder.
- 40. Actions of ACh in the parasympathetic NS: 4- On GIT: • Increases secretions (HCl, saliva, pancreatic, gastric,…) • Increases motility and relax sphincters thus facilitates defecation. 5- On Respiratory tract: • Bronchoconstriction • Increases bronchial secretions
- 43. Cholinergic Agonists Direct acting: • Choline Esters: Acetylcholine, Bethanechol, Carbachol. • Cholinomimetic Alkaloids: Pilocarpine. Indirect acting (Anticholinesterases): • Reversible : Physostigmine, Neostigmine, Pyridostigmine & Edrophonium. • Irreversible: Isoflurophate & Echothiophate.
- 44. Direct acting parasympathomimetics Mimic the effects of acetylcholine by binding directly to Cholinoceptors 1. Choline esters: ACh, Carbachol, Bethanecol 2. Natural alkaloids: Pilocarpine All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine. Pilocarpine and Bethanechol preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents
- 45. Direct Acting Cholinergic Agonists Choline Esters - Acetylcholine - Methacholine - Bethanechol - Carbachol
- 46. Acetylcholine A quaternary ammonium compound that cannot penetrate membranes • Act on M + N receptors. • Therapeutically ----- No importance. Multiple actions rapid inactivation by Cholinesterases
- 47. What are the actions of ACh?
- 48. Effects of direct-acting cholinoceptors stimulants organ effects Heart : SA-node Atria AV-node ventricles --------------ve chronotropy (↓ H.R.) ----------ve inotropic effect (↓ force of contraction) -----ve dromotropy (↓ conduction) -Small ↓ in contractility. Blood vessels Non-innervated M3- receptors in the vessels VD via endothelial derived relaxing factor (EDRF) Skeletal muscles Contractions due to +++Of motor end plate. Smooth muscles GIT --↑↑ motility ↑↑ salivary & intestinal secretions Bronchi ----- spasm & ↑↑ secretions. Urinary bladder -- contract detrusor musc. & relax sphincter. Eye ------ miosis & contract ciliary muscle “accommodation to near vision” ↓↓ IOP
- 49. ACh vasodilatation • ACh activates M3 receptors found on endothelial cells of blood vessels. • This results in the production of nitric oxide from arginine. • Nitric oxide then diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation.
- 52. Adverse Effects of Cholinergic Agonists
- 53. Bethanechol • Not hydrolyzed by acetyl cholinesterase but hydrolysed slowly by other esterases ---- long acting ( 1 h) • Act on M- receptors • No nicotinic action • Major actions: smooth muscle of GIT, urinary bladder Bethanechol Actions 1) GIT: ↑↑ intestinal motility & tone 2) Urinary bladder -- contract detrusor musc. & relax sphincter ---- urinary urgency Bethanechol Uses • to activate atonic bladder : • postpartum & postoperative non-obstructive urinary retention
- 54. Carbachol • Not hydrolyzed by acetyl cholinesterase but hydrolyzed slowly by other esterases ---- long acting ( 1 h) • Act on M + N receptors. Carbachol Actions • Nicotinic Stimulation ---- ganglion-stimulating activity CVS & GIT ↑---↓ ----- ↑ Adrenal medulla (↑ adrenaline release) • Muscarinic Stimulation ----- locally in Eye miosis & C.M spasm Carbachol Uses Treatment of glaucoma: ↓↓ IOP locally in the eye as a miotic. high potency & long duration Locally ---- The adverse effects is v. little.
- 55. Bethanechol Carbachol ACh synthetic synthetic natural Nature No No True, pseudo Metabolism longer longer Very short Duration +++ +++ +++ Muscarinic NO +++ +++ Nicotinic GIT, UB Eye, GIT, UB NO Selectively
- 56. Direct Acting Cholinergic Agonists Cholinomimetic Alkaloids Pilocarpine • Tertiary amine --- pass to CNS. • ↑↑↑ M- receptors. • Used mainly in ophthalmology Pilocarpine Actions 1. Eye: topically it produces miosis & ciliary muscle contraction. 2. ↑↑ Secretions -----↑↑ sweat , tears & saliva
- 57. Pilocarpine Pilocarpine Uses the drug of choice in the emergency lowering of IOP in --------- narrow- angle and wide-angle glaucoma. Open the trabecular meshwork around Schlemm canal ---- ↑↑drainage of aqueous humor ----- immediate ↓↓ IOP Pilocarpine Adverse effects Enter the brain ------ CNS disturbances. It ↑↑profuse sweating and salivation.
- 60. Indirect acting (Anticholinesterases): 1. Reversible: Produce reversible inhibition of cholinesterase 1) Physostigmine 2) Neostigmine 3) Pyridostigmine 4) Edrophonium 2. Irreversible Irreversible inhibition, bind covalently to the enzyme 1) lsoflurophate 2) Echothiophate
- 61. Indirect-acting parasympathomimetics • Act by inhibiting the enzymes, cholinesterases, thus preventing the hydrolysis of Ach and producing its accumulation at various cholinergic sites • Ach stimulate both M+N receptors
- 62. 1. Physostigmine • 3ry amine ---- CNS • More specific on eye: miosis, ↓ IOP, twitches • Oral, passes BBB • CNS stimulation Therapeutic uses: 1. + pilocarpine in acute Glaucoma 2. Atony of intestine,bladder 3. IV--- atropine, TCA toxicity
- 63. 2. Neostigmine • a synthetic quaternary amine (does not enter the CNS). • Direct skeletal muscle stimulant effect (on nicotinic receptors). It reverses the neuromuscular blockade produced by curare. (cholinesterase inhibition, a direct action on skeletal muscle cholinergic receptors and the increased amounts of Ach released from nerve endings) ACTIONS • EYE: miosis, spasm of ciliary muscles (accomodation), ↓ IOP • GIT: ↑ tone, motility of the GIT • Skeletal muscles: ↑power of skeletal muscles in myasthenia gravis- ---due to accumulation of Ach and direct action (+ Atropine) (autoimmune disease caused by antibodies to the nicotinic receptor at N - M junctions-fewer receptors available for interaction with the neurotransmitter).
- 64. Neostigmine Therapeutic uses: 1 - Symptomatic treatment of myasthenia gravis 2 - Antidote to competitive neuromuscular blockers (tubocurarine) 3 - Stimulate the bladder and GI tract: Contraindicated in mechanical obstruction of the intestine
- 65. Myasthenia gravis Chemical warfare Long action Resemble neostigmine Pyridostigmine Diagnosis of MG, curare poisoning supra-ventricuar tachycardia. It is preferred because of its rapid onset and short duration of action. Rapid onset Like neostig but Short action Edrophonium Alzheimer’s disease oral Cross BBB Tacrine Donzepil Rivastigmine
- 66. • generalized cholinergic (muscarinic) stimulation: salivation, sweating, lacrimation hypotension, bradycardia, bronchospasm nausea, abdominal pain, diarrhea, Miosis Physostigmine overdose----convulsions (not in Neostig…) • Cholinergic crises: weakness of the muscles due to excessive depolarization at the motor end plate • Ttt: stop the drug, large doses of atropine, artificial respiration
- 68. 1. Insecticides: parathion, malathion 2. Nerve gases: soman, sarin 3. Isoflurophate: used in glaucoma 4. Echothiophate: used in glaucoma
- 69. ANTICHOLINESTERASES (IRREVERSIBLE) • Synthetic organophosphate compounds bind covalently to acetylcholinesterase -----long-lasting increase in acetylcholine. • Echothiophate used clinically • Highly lipid soluble-except echothiophate • Well absorbed by all routes including GIT, skin, mucus membranes, lungs except echothiophate • Cross BBB except echothiophate • Long duration of action especially echothiophate
- 70. Therapeutic uses • Echothiophate eye drops in glaucoma resistant to other drugs • Long acting • Used once daily to once weekly
- 71. Organophosphorus poisoning • Accidental/ homicidal/ suicidal • Signs and symptoms: muscarininc and nicotinic actions nausea, vomiting, diarrhea, sweating, ↑salivary and bronchial secretions, bronchospasm muscular weakness and fasciculations (fine tremors) Cause of death: respiratory failure
- 72. Treatment of Organophosphorus poisoning 1. Atropine in large doses: 2-4mg IV / IM, followed by 2mg every 5-10 minutes until the muscarinic symptoms disappear--- pupillary dilatation • Antagonizes muscarinic receptors, ganglionic and central actions • Doesn’t affect neuromuscular paralysis which can be reversed by cholinesterase reactivators 2. Cholinesterase reactivators • Oximes are drugs that can reactivate the enzyme • Pralidoxime (PAM) Oximes should be given early before aging of the enzyme
- 73. Paralidoxime • Aging is a chemical change that makes the enzyme recovery impossible You should give paralidoxime before aging of the enzyme
- 76. Definition 1. Antimuscarinic drugs Atropine 2. Ganglionic blockers Nicotine large dose, trimethaphan, hexamethonium 3. Neuromuscular blockers NB. The nicotinic receptors in skeletal muscle are blocked by d-Tubocurarine while hexamethonium blocks ganglionic nicotinic receptors, i.e. they are different.
- 78. 1. Antimuscarinic agents Atropine Atropine substitutes Scopolamine Block muscarinic receptors causing inhibition of all muscarinic functions, very useful clinically + Sympathetic cholinergic to the sweat glands.
- 79. Atropine • In Italian: Belladonna=beautiful lady. • Italian renaissance: dilated pupils (considered beautiful) achieved through administration of eye drops from plant extract 1. Antimuscarinic agents
- 80. Atropine A competitive antagonist to Ach Block all muscarinic receptors Acts both central and peripheral Actions last for 4 h except in the eye (last for days) 1. Antimuscarinic agents
- 81. Atropine Actions Eye: 1.Persistent mydriasis with absence of light reflex (passive mydriasis) 2. Cycloplegia: paralysis of ciliary muscle (loss of accommodation) 3. Dangerous in narrow angle glaucoma 1. Antimuscarinic agents
- 82. Atropine Actions: cont. GIT: 1. ↓motility, can be used as an antispasmodic 2. HCl secretion is not affected 3. M1 muscarinic antagonist (pirenzepine)↓Hcl secretion 4. It also relaxes the smooth muscle of the biliary tract. Urinary system: ↓hypermotility of the urinary bladder while promoting contractions of the sphincter; thus, favoring urinary retention. Cardiovascular system: 1. Heart rate: block M2 receptors producing tachycardia 2. BP: unaffected, cautaneous vasodilatation at toxic doses 1. Antimuscarinic agents
- 83. Atropine Actions: cont. Secretions: 1. ↓ salivation producing dryness of mucus membranes (Xerostomia) 2. ↓ sweat secretions (hyperthermia in high doses) 3. ↓ lacrimal secretions (Sandy eyes) Effects on the bronchi: Atropine produces a slight bronchodilation. Effects on the CNS: Therapeutic doses exert a little effect on the CNS; however, large doses can produce hallucinations and coma. 1. Antimuscarinic agents
- 84. Atropine Uses Ophthalmic: 1.Mydriatic before fundus examination 2.Measurement of refractive error Contraindicated in patients with narrow angle Glaucoma Antispasmodic agents: To relax GIT and bladder. ☼ Antisecretory: Used to decrease secretions in respiratory tracts prior to surgery ☼ Antidote for cholinergic agonists: 1.Treatment of insecticides and some types of mushrooms poisoning 2. Blocks effects of excess Ach resulting from acetylcholineterase inhibitors eg. physostigmine 1. Antimuscarinic agents
- 85. Atropine Adverse effects Depends on the dose Dilated pupils, resulting in photophobia Dry mouth, blurred vision, sandy eyes, tachycardia, constipation, Flushed skin A rise in body temperature, especially in children. CNS: restlessness, confusion, hallucinations and delerium, depression Collapse of the circulatory and respiratory system and death N.B:. Physostigmine is the antidote in case of atropine poisoning. 1. Antimuscarinic agents
- 86. Dose-dependent effects of atropine >10 mg 5 mg 2 mg 0.5 mg Hallucinations, delirium, coma ↑HR, dryness of the mouth, mydriasis, blurring of vision Bradycardia, some dryness of the mouth, inhibition of sweating 1. Antimuscarinic agents
- 87. Atropine substitutes • Mydriatics, cycloplegic: Cyclopentolate (return to normal in less than 24 hr.) Tropicamide (is effective in less than 30 minutes and lasts less than 4-6 h.) Homatropine and Eucatropine (Mydriasis may persist for 4 days) • For treatment of parkinsonism: Benztropine • Quaternary amine anticholinergic drugs Do not readily cross the BBB. They are effective as antispasmodics. Examples are Hyoscine-butylbromide (Buscopan) 1. Antimuscarinic agents
- 88. Scopolamine Peripheral effects: similar to atropine Central effects: greater and longer than atropine The most useful drug in motion sickness Uses Prevention of motion sickness before anesthetics 1. Antimuscarinic agents Ipratropium quaternary derivative of atropine Uses used as inhalation in: 1. asthmatic patients who are unable to take adrenergic agonists 2. chronic obstructive pulmonary disease (COPD)
- 89. Uses of atropine substitute: 1- Treatment of peptic ulcer (EX. Pirenzipine). 2- Antispasmodic (atropine, propantheline). 3- Antiparkinsonian (benztropine). 4- Treatment of bronchial asthma (ipratropium). 5- Mydriatics/Cycloplegics (cyclopentolate). 6- Treatment of nocturnal enuresis (Oxybutynin). 7- Pre-anaesthetic medication (atropine) to prevent vagal attack (block M2), prevent asphyxia through decreasing bronchial secretions and saliva in addition to central stimulation of respiratory center. 8- Antiemetic and for treatment of motion sickness (hyoscine & scopolamine). 1. Antimuscarinic agents
- 90. 2. Ganglion blockers Act on the nicotinic receptors of both parasympathetic and sympathetic ganglia 1. Depolarizing blockers: • In small dose, they stimulate the ganglia (initial depolarization), but in large dose they cause maintained depolarization (block) leading to blocking or inactivating of the N1 in ganglia. • Ex. Nicotine and lobeline (large dose) • Not used clinically 2. Competitive (non depolarizing) ganglionic blockers: • They competitively block N1. Ex. Hexamethonium, trimethaphan, mecamylamine.
- 91. Ganglionic Blockers Actions: They suppress both sympathetic and parathympathetic NS and the net effect depends on the predominant tone (which of the 2 systems is more active). 1- Heart: Tachycardia (by blocking parasympathetic NS) Decreased contractility and orthoststic hypotension (by blocking the sympathetic NS) 2- Eye: Mydriasis & cycloplegia (by blocking parasympathetic NS) 3- GIT & UT: Decreased motility leading to constipation and urine retention (by blocking parasympathetic NS) - Little used now, only trimethaphan (short duration) is used as IV infusion to control hypertension. They were used as antihypertensive.
- 92. Ganglion Stimulants 2. Ganglion Stimulants • Nicotine small dose • Lobeline small dose • Ach • Carbachol
- 94. Neuromuscular blockers (NMBs) They block neuromuscular junction (motor-end plate) leading to relaxation of skeletal muscles. Uses of NMBs: 1- Surgical operations (pre-anaesthetic medications). 2- Electroshock theapy and certain types of convulsions. 3- Endoscopy and endotrachial intubation. Classification: A- Competitive NMBs: They block N2 receptors at motor-end plate decrease opening of sodium Channels……… no depolarization ………relaxation. Ex. 1- Long acting : Pancuronium, 2- Intermediate : Vecuronium, Atracurium 3- Short acting : Mivacurium. NB. D-tubocurarine, gallamine not used now.
- 95. B- Depolarizing (non-competitive) NMBs: They initially produce stimulation of N2 receptors persistent opening of sodium channels sodium channels stay in the open state which cannot respond to any stimuli (inactivated) muscle paralysis. Ex. Suxamethonium (succinylcholine) and decamethonium. Actions of NMBs: 1- Relaxation of skeletal muscles (eye muscles, face, neck, hands, feet, limbs, and finally respiratory muscles). Recovery is in the opposite direction. 2- Other effects: atropine like-effects and hypotension due to release of histamine. Neuromuscular blockers (NMBs)
- 96. Adverse effects: 1- Histamine release leading to hypotension and allergic reactions. 2- Atropine-like effects. 3- Prolonged apnea if pseudocholinesterase is genetically deficient no hydrolysis of succinylcholine paralysis of respiratory muscles and Apnea 4- Malignant hyperthermia (succinylcholine): usually when given with halothane in this case patient treated by cooling and by administration of dantrolene 5- Increased toxicity if used with aminoglycosides antibiotics because aminoglycosides have neuromuscular blocking effect. 6- Hyperkalemia: Succinylcholine increases potassium release from intracellular stores- dangerous in burn patients or patients with massive tissue damage in which potassium has been rapidly lost from within cells Neuromuscular blockers (NMBs)
- 97. • Cholinesterase inhibitors: neostigmine, physostigmine, pyridostigmine, and edrophonium -can overcome the action of nondepolarizing neuromuscular blockers • Halogenated hydrocarbon anesthetics: halothane- enhance neuromuscular blockade by exerting a stabilizing action at the neuromuscular junction. • Aminoglycoside antibiotics: gentamicin or tobramycin- inhibit acetylcholine release from cholinergic nerves by competing with calcium ions, hence enhance actions of these agents. • Calcium-channel blockers: These agents may increase the neuromuscular block of competitive blockers as well as depolarizing blockers. Neuromuscular blockers and Drug interactions:
- 98. Types of skeletal muscle relaxants: A- Central: acting on cerebral cortex and/or spinal cord: Barbiturates, Benzodiazepines & Baclofen B- Peripheral: 1- NMBs: Competitive NMBs Depolarizing NMBs 2- Direct skeletal muscle relaxant: Dantrolene: decreases Ca2+ release from endoplasmic reticulum. 3- Other Motor-end-plate blockers: Botulinum toxin: decrease ACh release. β-bungarotoxin, Mg2+ and aminoglycosides: decrease ACh release and block N2 Local anaesthetics: block nerve action potential propagation
- 99. Thank You