Drugs Acting on the Autonomic Nervous System

Introduction
• The autonomic nervous system, along with the endocrine system, regulates body functions. • The endocrine system sends signals to target tissues by varying the levels of blood-borne hormones. • The nervous system exerts its influence by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells. • Autonomic drugs act either by stimulating portions of the autonomic nervous system or by blocking the action of the autonomic nerves.

Introduction
• The nervous system is divided into two anatomical divisions: the CNS and the peripheral nervous system. • The peripheral nervous system is subdivided into the efferent division, the neurons of which carry signals from the brain and spinal cord to the peripheral tissues, and the afferent division, the neurons of which bring information from the periphery to the CNS.

Role of the CNS in autonomic control functions (afferent neurons)
• Reflex arcs: a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers (CVC) in the brain. This prompts a reflex response of increased sympathetic output to the heart and vasculature and decreased parasympathetic output to the heart. This results in a compensatory rise in blood pressure and tachycardia.

Introduction
• The efferent portion is further divided into two major functional subdivisions, the somatic and the autonomic systems. • The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles. • The autonomic system (ANS) regulates the everyday requirements of vital body functions without the conscious participation of the mind. • The ANS is composed of efferent neurons that innervate smooth muscle of the viscera, cardiac muscle, vasculature, and the exocrine glands, thereby controlling digestion, cardiac output, blood flow, and glandular secretions.

• The postganglionic neuron has a cell body originating in the ganglion and terminates on effector organs. Preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic connection in ganglia. . • These ganglia function as relay stations between a preganglionic neuron and a second nerve cell. • The first nerve cell is called a preganglionic neuron.Introduction (efferent neurons) • Efferent neurons of the ANS carries nerve impulses from the CNS to the effector organs by way of two types of efferent neurons. and its cell body is located within the CNS. the postganglionic neuron.

• In most instances there is a one-to-one connection between the preganglionic and postganglionic neurons.Parasympathetic neurons • The parasympathetic preganglionic fibers arise from the cranium (from cranial nerves III. with the ganglia close to or within the organ innervated. • In contrast to the sympathetic system. and the postganglionic ones are short. the preganglionic fibers are long. . enabling the discrete response of this division. and X) and from the sacral region of the spinal cord and synapse in ganglia near or on the effector organs. IX. VII.

The preganglionic neurons of the sympathetic system come from thoracic and lumbar regions of the spinal cord. and lesser amounts of norepinephrine into the blood. and they synapse in two cordlike chains of ganglia that run in parallel on each side of the spinal cord. also known as adrenaline. secretes epinephrine. receives preganglionic fibers from the sympathetic system. • Axons of the postganglionic neuron extend from these ganglia to the tissues that they innervate and regulate. . • The adrenal medulla (large sympathetic ganglion).Sympathetic neurons • The preganglionic neurons are short in comparison to the postganglionic ones. The adrenal medulla. in response to stimulation.

• It is a collection of nerve fibers that innervate the gastrointestinal tract. • It is modulated by both the parasympathetic nervous systems. sympathetic and . • This system functions independently of the CNS and controls the motility.Enteric neurons • The enteric nervous system is the third division of the autonomic nervous system. exocrine and endocrine secretions. and gallbladder. pancreas. and microcirculation of the gastrointestinal tract.

For example. and sweat glands. with essentially no participation by the parasympathetic system. pilomotor muscles. one system usually predominates in controlling the activity of a given organ. the vagus nerve is the predominant factor for controlling rate. • Despite this dual innervation. • The control of blood pressure is also mainly a sympathetic activity. in the heart. Organs receiving only sympathetic innervation • The adrenal medulla. .Innervation by the autonomic nervous system Dual innervation • Most organs in the body are innervated by both divisions of the autonomic nervous system.

Patterns of sympathetic and parasympathetic innervation .

adrenal medulla. sweat glands.Parasympathetic Neurons Origin Ganglia Pre-ganglionic Post-ganglionic Innervation Sympathetic Neurons Thoraco-lumbar Paravertebral (sympathetic chain) Cranio-sacral Terminal or embedded Long Short Short Long Dual innervation with few exceptions Constrictor pupilae muscle Dilator pupilae muscle. most blood vessels (contain noninnervated muscarinic receptors) . ventricles of the heart.

Effects of stimulation of the parasympathetic division (rest and digest) • Eye: miosis (contraction of circular muscles) • Heart: decrease in heart rate and contractility • Lung: constriction of bronchioles • GIT: increase in tone and motility • Salivary gland: copious and watery secretion • Bladder: contraction of detrusor and relaxation of trigone and sphincter .

Effects of stimulation of the sympathetic division (fight or flight) • • • • • • • • Eye: mydriasis (contraction of radial muscles) Heart: increase in heart rate and contractility Blood vessels to skin & mucous membranes: constriction Blood vessels to skeletal muscles: dilatation Lung: dilatation of bronchioles GIT: decrease in tone and motility Salivary gland: thick viscous secretion Bladder: relaxation of detrusor and contraction of trigone and sphincter • Uterus (females): relaxation .

ParaSympathetic Actions Type Aim Pupil Salivation Bronchi Heart Sympathetic Usually antagonistic but both enhance salivation & conductivity Localized. discrete Conserve energy & discharge excreta Miosis +++ watery Constriction All cardiac properties ( atrial conductivity) Usually generalized Stress “Fight & Fright” Mydriasis + viscid Relaxation All cardiac properties .

mus. Adrenal medulla Blood pressure GIT Urinary Bladder Para-Sympathetic -----Hypotension Increase in muscle motility & tone Contraction of detrusor muscles & Relaxation of sphincter ----------Variable Erection Sympathetic E & NE release Hypertension Decrease in muscle motility & tone Relaxation of detrusor muscles & Contraction of sphincter Constriction Relaxation Relaxation Ejaculation BV to skin & mm BV to sk.Cont. Females (Uterus) Male genitalia .

Neurotransmitters in the peripheral nervous system .

Second Messenger Systems in Intracellular Response • Receptor coupled to ion channels • Receptors coupled to G protein: G5: adenylyl cyclase Gq: phospholipase C .

Cholinergic Agonists II. Adrenergic Agonists IV. Adrenergic Antagonists .Drugs Acting on the Autonomic Nervous System I. Cholinergic Antagonists III.

Cholinergic Agonists (Parasympathomimetics) .

Cholinergic Transmittion Acetylcholine is the chemical transmitter at: • • • • • • All post-ganglionic parasympathetic neurons Post-ganglionic sympathetic neurons to sweat glands All autonomic ganglia (sympathetic & parasympathetic) Adrenal medulla Neuromuscular junction CNS .

Degradation of ACh 6. Release of ACh 4.Neurotransmission at cholinergic neurons 1. Storage of ACh in vesicles 3. Synthesis of ACh 2. Binding to the receptor 5. Recycling of choline .

Muscarinic receptors 2.Cholinergic receptors 1. Nicotinic receptors .

Exocrine glands. M4.Cardiac cells.non-specific Location Mechanism of signal transduction Agonists and Antagonists .intacellular Ca++ M2 ----. M1 ---------. M3 ----. M3 and M5 are excitatory M2 & M4 are inhibitory Only M1.K+ conductance Pirenzepine ---.PIP2 ---.selective M1 blocker (peptic ulcer) Darifenacin ----. M2. M3 are pharmacologically important.Gi ------inhibit AC ---.IP3 + DAG ----.cAMP ----.Bladder.Gastric parietal cells M2 ---------. M3.Muscarinic receptors Subtypes M1. CNS M1.Gq ---. smooth muscles M3 ---------. M2. M5 M1.Stimulate PLC ---. smooth muscle.selective M3 blocker (overactive bladder) Atropine ----.

resulting in the depolarization of the effector cell.CNS.Nicotinic Receptors Subtypes Location NN NM NN ---------.----.Neuromuscular junction Mechanism of signal transduction Agonists and Antagonists Binding of ACh elicits a conformational change that allows the entry of Na+ ions. adrenal medulla.selective NM blocker (Neuromuscular blocker) . ---. autonomic ganglia NM ---------.selective NN blocker (Ganglion blocker) Tubocurarine. Hexamethonium.

Donepezil Rivastigmine. Demecarium Tacrine. Neostigmine Pyridostigmine. Ambenomium Edrophonium. Galantamine INDIRECT ACTING REVERSIBLE IRREVERSIBLE Echothiophate Isoflurophate Sarin Tabun Malathion Parathion .Classification of cholinergic agonists CHOLINERGIC AGONISTS DIRECT ACTING Acetylcholine Bethanechol Carbachol Pilocarpine Physostigmine.

motility and secretions Salivary glands: Increase secretions Lung: Bronchoconstriction and increased bronchiolar secretions Bladder: Increase in the tone of detrusor muscle & relaxation of sphincter causing expulsion of urine Eye: Enhancement of lacrimation. open canal of Schlem. CNS: ACh modulates sleep. decreased IOP. wakefulness. Blood Pressure: Decrease in blood pressure due to NO-mediated vasodilatation Gastrointestinal tract: Increase tone. stimulation of the constrictor pupillae muscle causing miosis and constriction of the ciliary muscle (accommodation for near vision).Direct-Acting Cholinergic Agonists A. Acetylcholine (M&N) Actions Heart: Decrease in heart rate and cardiac output (the vagaus regulates the heart by the release of ACh at the SA node). and memory . learning.

Endothelial regulation of nitric oxide-mediated vascular smooth muscle relaxation .

born Dept. Robert F born 1936 born 1941 Furchgott. Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system". of and Physiology Medical Pharmacology. has awarded the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott. of Dept. Ferid Murad. University of Pharmacology SUNY Health Texas Medical Science Center UCLA School of School. Sweden. Louis J Ignarro. of 1916 Pharmacology Molecular and Dept.The Nobel Prize in Medicine 1998 The Nobel Assembly at the Karolinska Institute in Stockholm. Houston Medicine New York Los Angeles .

Acetylcholine (Cont.) Nicotinic actions of Ach • Ach (LD) + atropine ---------.skeletal muscles twitches Therapeutic uses • No clinical use • Cannot be given orally • Short duration • Non specific .Hypertension (Stimulation of sympathetic ganglia + adrenal medulla) • Stimulation of motor end plate ---.

2. .B. • Adverse effects: Sweating. salivation. although it is inactivated through hydrolysis by other esterases. decreased blood pressure. causing expulsion of urine. Bethanechol increases intestinal motility and tone. and bronchospasm. can be taken orally. nausea. flushing. • It has a longer duration of action (1 h) as it is not hydrolyzed by acetylcholinesterase. • Actions: (Its major actions are on the bladder and GIT) 1. particularly in postpartum or postoperative. Bethanechol (M only) • Bethanechol is structurally related to acetylcholine. abdominal pain. diarrhea. • It lacks nicotinic actions but has strong muscarinic activity. nonobstructive urinary retention. It also stimulates the detrusor muscles of the bladder whereas the trigone and sphincter are relaxed. • Therapeutic applications Atonic bladder.

• Actions: CVS: Initial stimulation (It can cause release of epinephrine from the adrenal medulla by its nicotinic action) followed by inhibition Eye: Miosis and spasm of the ciliary muscles • Therapeutic uses: Because of its receptor non-selectivity.C. but at a much slower rate (duration is 1 h). carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma to decrease the intraocular pressure. and relatively long duration of action. • Carbachol is an ester of carbamic acid and a poor substrate for acetylcholinesterase. • Adverse effects: At doses used ophthalmologically. It is biotransformed by other esterases. Carbachol (M&N) • Carbachol has both muscarinic & nicotinic actions. little or no side effects occur due to lack of systemic penetration (quaternary amine). .

salivation and CNS disturbances • . saliva): increase Therapeutic use: Glaucoma (both narrow-angle and wide-angle) as pilocarpine causes opening of the trabecular meshwork around Schlemm's canal. It can penetrate the CNS at therapeutic doses. Pilocarpine is a tertiary amine (can pass BBB) and is stable to hydrolysis by acetylcholinesterase. Also.D. Pilocarpine (M only) • • • • • Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology. tears. it may be used in hair lotion to promote growth of hair. Adverse effects: sweating. increasing drainage of aqueous humor causing an immediate drop in intraocular pressure It may be used to counteract the action of mydriatics (after fundus examination). Actions: Eye (locally): Miosis and contraction of the ciliary muscle Secretions (sweat.

TCAs) • Adverse effects: CNS: convulsions Heart: badycardia and a fall in cardiac output . The drug increases intestinal and bladder motility. which serve as its therapeutic action in atony of either organ. phenothiazines. it is used to treat glaucoma. It can be absorbed orally and can pass BBB. It is also used in the treatment of overdoses of drugs with anticholinergic actions (atropine. The result is potentiation of cholinergic activity. Placed topically in the eye. • Therapeutic uses: 1. Physostigmine • It is a substrate for and reversibly inhibits acetylcholinesterase. • Its duration of action is about 2 to 4 hours. • Physostigmine s a tertiary amine. 3. • Actions: It has a wide range of effects as a result of its action on the M and N sites of the ANS and the N receptors of the neuromuscular junction.Indirect-Acting Cholinergic Agonsists Reversible Anticholinesterases A. 2.

• Adverse effects: (no CNS effects) Salivation. It is used to stimulate the bladder and GI tract 2. decreased blood pressure. • Neostigmine has a moderate duration of action (30 min to 2 h). flushing. and bronchospasm. • Its effect on skeletal muscle is greater than that of physostigmine. diarrhea. Myasthenia gravis 3. . • Uses: 1. An antidote for tubocurarine and other competitive neuromuscular blocking agents. Neostigmine • Neostigmine is a synthetic compound that reversibly inhibits acetylcholinesterase in a manner similar to that of physostigmine.B. abdominal pain. nausea. hence. it is more polar and does not enter the CNS. • Neostigmine has a quaternary nitrogen.

C. respectively). . but longer than that of neostigmine. Pyridostigmine and ambenomium • Pyridostigmine and ambenomium are other cholinesterase inhibitors that are used in the chronic management of myasthenia gravis. • Their durations of action are intermediate (3 to 6 hours and 4 to 8 hours. • Adverse effects: similar to those of neostigmine.

E. Mechanisms of actions and side effects are similar to those of neostigmine. Demecarium • Demecarium is a quaternary amine that is structurally related to neostigmine.D. Edrophonium • The actions of edrophonium are similar to those of neostigmine. • Used to treat glaucoma. • Edrophonium is a quaternary amine and is used in the diagnosis of myasthenia gravis. except that it is more rapidly absorbed and has a short duration of action of 10 to 20 minutes (prototype shortacting agent). . Intravenous injection of edrophonium leads to a rapid increase in muscle strength.

Tacrine. and galantamine • Used to treat Alzheimer's disease • Tacrine was the first to become available. but it has been replaced by the others because of its hepatotoxicity. but cannot stop it. donepezil. • Donepezil.F. and galantamine can only delay the progression of the disease. rivastigmine. rivastigmine. • Side effects: GI distress .

This process is called aging and makes it impossible for chemical reactivators. bronchospasm. Organophosphate insecticides (malathion. Following covalent modification of acetylcholinesterase. such as pralidoxime.Irreversible Anticholinesterases Echothiophate. tabun). the phosphorylated enzyme slowly releases one of its ethyl groups. diarrhea. lacrimation. bradycardia Nicotinic: skeletal muscle twitches CNS: Excitation. Isoflurophate. salivation. vomiting. to break the bond between the remaining drug and the enzyme. convulsions . War gases (sarin. • Actions: Muscarinic: miosis. parathion) • Mechanism of action: organophosphates covalently bind via their phosphate group to the serine-OH group at the active site of acetylcholinesterase.

it can reverse the effects of echothiophate.Reactivation of acetylcholinesterase Pralidoxime • Therapeutic uses: Echothiophate & Isoflurophate are used as eye drops for the chronic treatment of openangle glaucoma. The presence of a charged group allows it to approach an anionic site on the enzyme. where it essentially displaces the phosphate group of the organophosphate and regenerates the enzyme. • . Management of toxicity: Artificial respiration Decontamination Atropine (for muscarinic symptoms) Acetylcholinesterase reactivator (Pralidoxime) If given before aging of the alkylated enzyme occurs. except for those in the CNS.

Competitive Nicotine A. Competitive Tubocurarine. Depolarizing Trimetaphan Mecamylamine B. Rocuronium Vecuronium B. Mivacurium Pancuronium. Depolarizing Succinylcholine Decamethonium . Tolterodine Darifenacin Benzotropine Trihexphenidyl GANGLIONIC BLOCKERS NEUROMUSCULAR BLOCKERS A.Cholinergic Antagonists (Parasympatholytics) CHOLINERGIC ANTAGONISTS MUSCARINIC ANTAGONISTS Atropine Scopolamine Ipratropium Tropicamide Cyclopentolate Emepronium Trospium. Atracurium Cisatracurium. Doxacurium Metocurine.

Thus. Atropine (3ry amine & blocks M receptors) Eye Mydriasis (due to paralysis of CPM) and cycloplegia (inability to focus for near vision. but at toxic doses. Higher doses (> 1mg) ----. Arterial BP is unaffected.constipation At low doses ---.Tachycardia (bockade of the M2 receptors on the SA node). due to paralysis of ciliary muscles. Although gastric motility is reduced. causing closure of canal of Schlem). IOP may rise dangerously. Antimuscarinic Agents A.I. HCl production is not significantly affected at therapeutic doses. Increase A-V conduction Decrease atrial conductivity Reverses hypotension of Ach & carbachol (M & NN) Abolishes hypotension of bethanechol and pilocarpine (M only) GIT CVS . Relaxation of walls and spasm of sphincters --------.Bradycardia (due to blockade of the presynaptic M1 receptors ) thus permitting increased Ach release. atropine will dilate the cutaneous vasculature. Reduction of activity of the GI tract (antispasmodic).

) Urinary system Relaxation of detrusor muscle and constriction of sphincter (urine retention).e dryness of airways. . It is contraindicated in BPH. This is why atropine is not used in bronchial asthma. Atropine is occasionally used in enuresis (involuntary voiding of urine) among children. Secretions Atropine blocks the salivary glands (xerostomia).A. Atropine (Cont. Lung Bronchorelaxation with decreased bronchial secretions i. lacrimal glands and sweat glands (can cause elevated body temperature).

4. Antidote for organophosphates and drugs like physostigmine. Cycloplegic effect b. Long duration (days) c. Antispasmodic: To relax the GI tract and bladder 3. Ophthalmic: Mydriatic But it suffers the following disadvantages: a.Therapeutic uses of atropine (Cont.) 1. . Increases IOP in patients with narrow angle glaucoma 2. Antisecretory: The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery.

tachycardia • Urinary retention.) • Dry mouth. and delirium. which may progress to depression. confusion. constipation • Increase in body temperature (in children) • On the eye: cycloplegia and mydriasis which is considered to be too risky. and death. because it may exacerbate an attack of glaucoma in someone with a latent condition. hallucinations. • Its antidote is: physostigmine . collapse of the circulatory and respiratory systems. • Effects on the CNS: restlessness.Adverse effects of atropine (Cont.

Scopolamine (Hyoscine) • • Scopolamine is a tertiary amine (can pass BBB) belladonna alkaloid. used prophylactically) Pre-anesthetic medication (to produce sedation & amnesia) . Actions • Parasympatholytic actions: Stronger on secretions & eye Weaker on heart & GIT • CNS: Sedation (contrary to atropine) but at toxic doses may cause excitement Inhibits the vomiting center -------.B. Scopolamine has greater action on the CNS and a longer duration of action in comparison to those of atropine.e.anti-motion sickness Blocks short-term memory (causing amnesia) • Therapeutic uses Prevention of motion sickness (i.

Trihexphenidyl • For Parkinson’s disease . Cyclopentolate • These agents are used as ophthalmic solutions for similar conditions as atropine (mydriasis). Beztropine. Tropicamide.C. Darifenacin • For urinary incontinence F. • Their duration of action is shorter than that of atropine E. • It is used as inhalation and useful in treating asthma and COPD in patients who are unable to take adrenergic agonists. Emepronium. Trospium. D. Ipratropium • Ipratropium is a quaternary derivative of atropine. Tolterodine. • It does not have CNS effects.

• Therefore. making it impossible to achieve selective actions. • The responses observed are complex and unpredictable. . ganglionic blockade is rarely used therapeutically. Ganglionic Blockers • Ganglionic blockers act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.II. • These drugs block the entire output of the autonomic nervous system at the nicotinic receptor.

Effects of Autonomic Ganglionic Blockade Site Arterioles Veins Heart Predominant tone Effects of ganglion blockade Sympathetic Sympathetic Arteriodilation. ↓ venous return. ↓ PR. ↓ cardiac output. hypotension Tachycardia Mydriasis Cycloplegia ↓ Tone and motility. hypotension Venodilation. constipation Parasympathetic Iris Parasympathetic Ciliary Muscle Parasympathetic Parasympathetic Bladder Parasympathetic Salivary gland Parasympathetic Sweat gland Sympathetic GIT Urine retention Xerostomia (dry mouth) Anhidrosis (absence of sweating) .

B. nicotine stimulates (low doses) then inhibits (high doses) autonomic ganglia. Nicotine (high dose) • Nicotine is a poison with many undesirable actions.) A. Trimetaphan &Mecamylamine • Trimetaphan: IV only and short acting • Mecamylamine: can be given orally & has a long duration • They are be used in emergency hypertension. • The stimulatory effects: increased BP and HR (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions.Ganglion Blocks (Cont. • Depending on the dose. It is without therapeutic benefit and is deleterious to health. • At higher doses: fall in BP. . decreased activity of the GI tract and bladder.

• Neuromuscular blockers are structural analogs of acetylcholine. the central muscle relaxants. and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the end plate of the neuromuscular junction. Dantrolene acts directly on muscles by interfering with the release of calcium from the sarcoplasmic reticulum. .III. • Neuromuscular blockers are clinically useful during surgery and tracheal intubation as well. Neuromuscular Blocking Drugs • These drugs block cholinergic transmission between somatic nerve endings and the nicotinic receptors on the motor end plate of skeletal muscles. • A second group of muscle relaxants. are used to control spastic muscle tone. These include diazepam and baclofen.

A. . Competitive Neuromuscular blockers • The first drug that was found to be capable of blocking the skeletal neuromuscular junction was curare. • Curare was used by native hunters of the Amazon in South America to paralyze animals. • The drug was ultimately purified and introduced into clinical practice in the early 1940s. it has been largely replaced by other agents. • Although tubocurarine is considered to be the prototype agent in this class.

• They are antagonized by neostigmine. they produce no initial stimulation. all neuromuscular blocking agents are administered IV.e. • They are pure antagonists i. • These agents possess two or more quaternary amines in their bulky ring structure.Competitive Neuromuscular blockers (Cont. Therefore. Tubocurarine Atracurium Cisatracurium Doxacurium Metocurine Mivacurium Pancuronium Rocuronium Vecuronium . making them orally ineffective.) • Mechanism of action: They interact with the nicotinic receptors to competitively prevent the binding of acetylcholine.

Cholinesterase inhibitors: Drugs such as neostigmine. physostigmine.Halogenated hydrocarbon anesthetics (e.g.) Side Effects: • Tubocurarine may release histamine and lower BP. • Atracurium may release histamine and may provoke seizures.Calcium-channel blockers: These agents may enhance the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers.Competitive Neuromuscular blockers (Cont. . pyridostigmine. halothane): Potentiation c. and edrophonium: Antagonism b. Aminoglycoside antibiotics: Synergism (Drugs such as gentamicin or tobramycin inhibit acetylcholine release from cholinergic nerves by competing with calcium ions) d. Drug interactions: a.

Decamethonium) Mechanism of action • Succinylcholine (as an example) binds to the nicotinic receptor and acts like ACh to depolarize the junction. continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked. succinylcholine persists at high concentrations in the synaptic cleft for a relatively longer time and providing a prolonged stimulation. • The drug first causes the opening of the sodium channel associated with the nicotinic receptors. This causes a resistance to depolarization (Phase II) and a flaccid paralysis. . This leads to a transient twitching of the muscle (fasciculations). However.B. Depolarizing Neuromuscular Blockers (Succinylcholine. which results in depolarization of the receptor (Phase I). • With time.

Genetic variants in which plasma cholinesterase levels are low or absent may suffer prolonged neuromuscular paralysis.) • They are potentiated by neostigmine. the duration of action of succinylcholine is short.Succinylcholine (Cont. because it is rapidly broken down by plasma cholinesterase (pseudo-cholinennsterase). • Therapeutic uses: Because of its rapid onset and short duration of action. • Normally. succinylcholine is useful for endotracheal intubation and during electroconvulsive shock treatment. .

This is treated by rapidly cooling the patient and by administration of dantrolene. . • Hyperkalemia: Succinylcholine increases potassium release from intracellular stores. • Malignant hyperthermia: When halothane is used as an anesthetic. thus reducing heat production and relaxing muscle tone. administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity and hyperpyrexia) in genetically susceptible people.) Adverse effects • Apnea: Administration of succinylcholine to a patient who is genetically deficient in plasma cholinesterase or has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm. This may be particularly dangerous and cause cardiac arrest.Succinylcholine (Cont. which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells.

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