Drugs Affecting the Autonomic Nervous System

Drugs Affecting the Autonomic Nervous System
Cholinergics and Anti-cholinergics Drugs Pharmacology lecture Dr. Nahla Othman

Agenda A Review Overview of CNS and ANS Neurotransmitters
Cholinergic Agonists and Antagonists

Organization of the Nervous System: CNS
Radiation Fibers Thalamus Visual Inputs Reticular Formation Ascending Sensory Tracts

The Peripheral Nervous System
Sensory Motor Sympathetic Parasympathetic

Peripheral Nervous System
Controls Controls smooth & skeletal cardiac muscle muscle & glands Somatic Autonomic Nervous Nervous System System One Two Neuron Neuron Efferent Efferent Limb Limb Preganglionic Postganglionic

Sympathetic Nervous System (Thoracolumbar Outflow)
Radial Muscle of Iris Ciliary Muscle Sympathetic Nervous System (Thoracolumbar Outflow) Sublingual/Submaxillary & Parotid Gland SA & AV Nodes His-Purkinje System Myocardium Pilomotor Muscles Sweat Glands Bronchi/Bronchial Glands Stomach Kidneys Blood Vessels Intestines Paravertebral Ganglia Bladder//Genitalia Prevertebral Ganglia

Parasympathetic Nervous System (Craniosacral Outflow)
SA & AV Node Bronchi/Bronchial Glands Sphincter Muscle of Iris Ciliary Muscle Stomach Small Intestines Lacrimal Gland Bile Ducts Gallbladder Submaxillary & Sublingual Glands Kidney Large Intestines Bladder Parotid Gland Genitalia

The parasympathetic nervous system consists of preganglionic fibers that originate in the CNS and their postganglionic connections. The regions of central origin are the midbrain, the medulla oblongata, and the sacral part of the spinal cord. The midbrain, or tectal, outflow consists of fibers arising from the Edinger-Westphal nucleus of the third cranial nerve and going to the ciliary ganglion in the orbit. The medullary outflow consists of the parasympathetic components of the seventh, ninth, and tenth cranial nerves. The fibers in the seventh (facial) cranial nerve form the chorda tympani, which innervates the ganglia lying on the submaxillary and sublingual glands. They also form the greater superficial petrosal nerve, which innervates the sphenopalatine ganglion. The autonomic components of the ninth (glossopharyngeal) cranial nerve innervate the otic ganglia. Postganglionic parasympathetic fibers from these ganglia supply the sphincter of the iris (pupillary constrictor muscle), the ciliary muscle, the salivary and lacrimal glands, and the mucous glands of the nose, mouth, and pharynx. These fibers also include vasodilator nerves to these same organs. The tenth (vagus) cranial nerve arises in the medulla and contains preganglionic fibers, most of which do not synapse until they reach the many small ganglia lying directly on or in the viscera of the thorax and abdomen. In the intestinal wall, the vagal fibers terminate around ganglion cells in the myenteric and submucosal plexuses. Thus, in the parasympathetic branch of the autonomic nervous system, preganglionic fibers are very long, whereas postganglionic fibers are very short. The vagus nerve also carries a far greater number of afferent fibers (but apparently no pain fibers) from the viscera into the medulla; the cell bodies of these fibers lie mainly in the nodose ganglion. The parasympathetic sacral outflow consists of axons that arise from cells in the second, third, and fourth segments of the sacral cord and proceed as preganglionic fibers to form the pelvic nerves (nervi erigentes). They synapse in terminal ganglia lying near or within the bladder, rectum, and sexual organs

Role of ANS in homeostasis (CV, smooth muscle of GI and glands)
The autonomic nervous system maintains the internal environment of the body (homeostasis) Role of ANS in homeostasis links to target organs (CV, smooth muscle of GI and glands)

Activation of ocular parasympathetic fibers results in nar- rowing of the pupil and increased curva- ture of the lens, enabling near objects to be brought into focus (accommodation).

In resting state (not fight-or-flight situations)
Important organs that receive dual innervation: heart eye bronchial smooth muscle GI tract smooth muscle genitourinary tract smooth muscle In resting state (not fight-or-flight situations) Most dual innervated organs are controlled by the parasympathetic system (Note: absence from the list of the smooth muscles throughout the vascular system (in the arteries)

Sympathetic: Contraction of radial muscle produces dilation (mydriasis)
Parasympathetic: Contraction of circular muscle produces constriction (miosis)

Autonomic Pharmacology
II. Mechanisms of Neurotransmission in the Autonomic Nervous System

General Features of Peripheral Autonomic Neurotransmission
NT = Neurotransmitter

SYNTHESIS, STORAGE, RELEASE & INACTIVATION

Released ACh is rapidly hydrolyzed and inactivated by a specific acetylcholine esterase, present on pre- and postjunctional membranes, or by a less specific serum choline esterase (butyryl choline esterase), a soluble enzyme present in serum and interstitial fluid.

Parasympathetic Nervous System
Muscarinic Nicotinic Autonomic neuroeffector Ganglia & NMJ junctions Acetylcholine GPCR Ion Channels

CHOLINERGIC NERVES M

CHOLINOCEPTORS Muscarinic GPCR Nicotinic Ion channel

Receptor Type Other Names Location Structural Features Postreceptor Mechanism M1 Nerves Seven transmembrane segments, Gq/11 protein-linked IP3, DAG cascade M2 Cardiac M2 Heart, nerves, smooth muscle Seven transmembrane segments, Gi/o protein-linked Inhibition of cAMP production, activation of K+ channels M3 Glands, smooth muscle, endothelium M4 CNS Inhibition of cAMP production M5

NN NM Receptor Type Other Names Location Structural Features
Postreceptor Mechanism NM Muscle type, end plate receptor Skeletal muscle neuromuscular junction Pentamer [(1)21)] Na+, K+ depolarizing ion channel NN Neuronal type, ganglion receptor CNS postganglionic cell body, dendrites Pentamer with and subunits only, eg, (4)2(2)3 (CNS) or 3 5(2)3 (ganglia)

PARASYMPATHOMIMETIC DRUGS or CHOLINERGIC DRUGS or CHOLINOMIMETIC DRUGS

I. DIRECT-ACTING CHOLINERGIC DRUGS
(1) Choline ester (stimulants of M- and N-receptors): Acetylcholine, Carbachol, etc. (2) Alkaloids a) stimulants of M-receptors: Pilocarpine, Cevimeline (dry mouth), Musacarine, Phalloidin b) stimulants of N-receptors: Nicotine, Cytisine (Tabex®), Lobeline

CHOLINE ESTERS - Acetylcholine - Methacholine - Carbachol - Bethanechol

I. DIRECT-ACTING CHOLINERGIC DRUGS (1) Choline ester
Acetylcholine(ACH): Is the neurotransmitter of the parasympathetic N.S and cholinergic nerves. Is therapeutically of no importance due to: 1. Multiplicity of actions. 2. Rapid inactivation by acetyl-cholinesterase. 3. Has both muscarinic and nicotinic activity.

Carbachol: Has both muscarinic and nicotinic actions. Has strong effect on CVS and GIT, it causes release of epinephrine from adrenal medulla by its nicotinic action using it locally on the eye cause Miosis.

Carbachol: Clinical uses: Rarely used because of high potency and long duration of action except in the eye to cause Miosis and to decrease intraocular pressure.

Carbachol: Side effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration (quaternary amine).

Bethanechol: Structurally related to ACH, has strong muscarinic activity but no nicotinic actions. It directly stimulates muscarinic receptors of the GIT causing increase intestinal motility and tone. It also stimulates detrusor muscle of the bladder causing urine expulsion.

Bethanechol: given orally. Not given IM or IV. Clinical uses: Atonic bladder stimulation such as in postpartum and post operative non obstructive urine retention. May also be used to treat neurogenic atony as well as megacolon.

Bethanechol: Side effects: Sweating, salivation, flushing, hypotension, nausea, abdominal pain, diarrhea, and bronchospasm.

I. DIRECT-ACTING CHOLINERGIC DRUGS (2) Alkaloids
a) stimulants of M-receptors: Pilocarpine

Pilocarpus jaborandi Pilocarpine - in glaucoma

a) stimulants of M-receptors: Pilocarpine: Mainly used in ophthalmology, it exhibit muscarinic activity, it produces rapid miosis and contraction of the ciliary muscle.

a) stimulants of M-receptors: Pilocarpine: Clinical uses; 1. It is the drug of choice in the emergency lowering of inrtra-ocular pressure in case of glaucoma. of both narrow-angle and wide-angle glaucoma. The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine.

- in open angle glаucoma Applied to the eye, it penetrates cornea and
Pilocarpine Hydrochloride eye drops (Pilocar®) - sol. 1%, 2%, 4% - in open angle glаucoma Applied to the eye, it penetrates cornea and promptly causes miosis, ciliary muscle contraction, and fall in intraoccular tension (< 22 mm) lasting 4-8 h.

A. Mydriasis occurs in an eye with narrow iridocorneal angle
Development of angle closure glaucoma and its reversal by miotics A. Mydriasis occurs in an eye with narrow iridocorneal angle and the iris makes contact with the lens blocking passage of theaqueous from the posterior to the anterior chamber. B. Possibly builds up behind the iris which bulges forward and closes the iridocorneal angle thus blocking aqueous outflow. C. Miotic makes the iris thin and pushes it away from the lens removing the pupillary block and restoring aqueous drainage.

a) stimulants of M-receptors: Pilocarpine: Clinical uses; 2- Pilocarpine available as tablet used for treatment of xerostomia (dry mouth), like that occur: a- After irradiation of head & neck. b- Sjogren's syndrome.

a) stimulants of M-receptors: Pilocarpine: Side effects: Painful spasm of accommodation for near vision. Systemic effects: It can enter the brain and cause CNS disturbances, It stimulate profuse sweating and salivation. Cardiovascular effects: in small doses – fall in BP, but in high doses elicits rise in BP and tachycardia, probably due to ganglionic stimulation (through muscarinic receptors)

a) stimulants of M-receptors: Cevimeline (dry mouth),

a) stimulants of M-receptors: muscarine : It is of no therapeutic use. It is present in small amount in the fungus Amanita muscaria. Amanita muscaria (muscarine) Amanita phalloides (phalloidine)

a) stimulants of M-receptors: muscarine : MUSHROOM POISONING Signs of muscarinic excess-salivation, sweating, NVD, visual disturbances, headache, abd. Colic,urinary urgency, bradycardia, bronchospasm, hypotension, shock Atropine (1-2mg I/M every 30mins)

b) stimulants of N-receptors: Nicotine, Cytisine (Tabex®), Lobeline Nicotine: It is available as either gum or as patches used as an adjunct (aid) to stop tobacco smoking.

Cytisine (Tabex® p.o.) Nicorette (chewing gum) Nicotinell® TTS

II. INDIRECT-ACTING CHOLINERGIC DRUGS (anticholinesterase drugs: antiChEs)
Are drugs that exert cholinergic actions by prolonging the life time of ACH via inhibition of acetyl-cholinesterase enzyme, this results in accumulation of ACH in synaptic space and provoke response at all cholinoceptors in the body including both muscarinic and nicotinic receptors as well as neuromuscular junction and the brain. These drugs are termed (anti-cholinesterases) which are reversible and irreversible.

(anticholinesterase drugs: antiChEs)
II. INDIRECT-ACTING CHOLINERGIC DRUGS (anticholinesterase drugs: antiChEs) (1) Reversible drugs (most are carbamates) a) With N3+ (cross BBB) Alkaloids: Galantamine, Physostigmine Synthetic drugs: Donepezil, Rivastigmine, Tacrine b) With N4+ (do not cross BBB) Demecarium, Edrophonium (Tensilon®) Neostigmine, Pyridostigmine

II. INDIRECT-ACTING CHOLINERGIC DRUGS (anticholinesterase drugs: antiChEs)
(2) Irreversible anticholinesterase agents (most of them are organophosphates) a) Thiophosphate insecticides Parathion Malathion (Pedilin® – in pediculosis) b) Nerve paralytic gases for chemical warfare Tabun Sarin Soman

Representative "reversible" anticholinesterase agents employed clinically

II. INDIRECT-ACTING CHOLINERGIC DRUGS (anticholinesterase drugs: antiChEs) Reversible drugs
1- Short acting: Edrophonium: Used parentrally ( by injection). - Short duration of action (10-20 minutes). Clinical uses: 1- Drug of choice for diagnosing Myasthenia gravis (MG). 2- Used to differentiate M.G (which is weakness due to severe disease or inadequate anticholinesterase treatment) from cholinergic crisis (which is weakness due to over treatment with anticholinesterase).

2- Intermediate & long acting Physostigmine Actions: It has a wide range of actions because it stimulates not only muscarinic and nicotinic sites of the ANS but also the NR of the neuromuscular junction (skeletal muscle). PK: Its duration of action is about 2-4 hours. Physostigmine can enter and stimulate the CNS.

2- Intermediate & long acting Physostigmine Clinical uses: Used topically in the eye (but pilocarpine is more effective), it produces meiosis and spasm of accommodation and a decrease of IOP in glaucoma. The drug increases intestinal and bladder motility in case of atony of either organ. Used in the treatment of overdoses of drugs with anticholinergic actions such as atropine, phenothiazines and tricyclic antidepressants.

2- Intermediate & long acting Physostigmine Side effects: 1.Convulsion at high doses. 2. Bradycardia. 3. Skeletal muscle paralysis due to inhibition of acetylcholinesterase at neuromuscular junction and ACH accumulation

2- Intermediate & long acting
Neostigmine - Its effect more on skeletal muscle (N-M junction) and GIT than CVS & eye. - It has a moderate, duration of action, usually 2-4 hours. Clinical Uses: 1- Symptomatic chronic treatment of myasthenia gravis. 2- As an antidote for tubocurarine and other competitive neuromuscular blocking agents. 3- It is used to stimulate the bladder & GlT after surgery.

2- Intermediate & long acting
Pyridostigmine - It is another cholinesterase inhibitor similar to neostigmine. - Its duration of action (3-6 hours) is longer than that of neostigmine (2-4 hours). - Used orally & paranterally. Clinical uses: 1- Chronic management of myasthenia gravis. 2- As an antidote to competitive neuromuscular blocking agents.

Note - Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia, using nondepolarizing neuromuscular blocking drugs (muscle relaxants) such as tubocurarine. - Following the surgical procedure, it is usually desirable to reverse this pharmacologic muscle paralysis rapidly. This can be easily accomplished with cholinesterase inhibitors (neostigmine or pyridostigmine) which are the drugs of choice. They are given intravenously or intramuscularly for rapid effect.

(1914–1986) Galantamine is antiChEs with direct N-action used in:
Myastenia gravis Alzheimer’s disease Poliomyelitis Postoperative paresis of GIT and bladder As antagonist of competitive myorelaxants with less side effects than neostigmine Prof. D. Paskov (1914–1986) Galantamine (Nivalin®)

Myasthenia gravis (MG)
is a disease affecting skeletal muscle neuromuscular junctions. An autoimmune process causes production of antibodies that bind to the a subunits of the nicotinic receptor. This effect causes accelerated degradation of the receptor and blockade of ACh binding to receptors on muscle end plates. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration.

Diagnosis of myasthenia gravis
- Edrophonium is used as a diagnostic test for MG. 2 mg dose is injected IV after baseline measurements of muscle strength have been obtained. If no response occurs after 45 seconds, an additional 8 mg may be injected. - If the patient has MG an improvement in the strength of muscles last for 15 minutes ( this differentiate MG from cholinergic crisis due to excessive drug therapy in which there will be worsening of the condition).

Treatment of myasthenia gravis
Chronic long-term therapy of MG is usually accomplished with neostigmine, pyridostigmine. for myasthenia. Almost all patients are also treated with immunosuppressant drugs and some with thymectomy.

Diagrams of (A) normal and (B) myasthenic
neuromuscular junctions. The MG junction has a normal nerve terminal; a reduced number of AChRs and a widened synaptic space.

Alzheimer’s disease In the in the brain tissue there are amyloid plaques and neurofibrillarly tangles as well as loss of cholinergic neurons. Cholinacetyl trasferase activity in the cortex and hippocampus is reduced from 30% to 70%. Loss of cholinergic neurons contribute for to much of the learning and memory deficit. The number of M-cholinoceptors is not affected, but the number of N-receptors is reduced.

Enlargement ventricles
Thin brain cortex Enlargement ventricles Diminished hypothalamus Alzheimer's disease

Indirect Acting Agents used to treat Alzheimer’s disease
Donepezil (Aricept)—said to delay progression of the disease by up to 55 weeks. Does not cause liver toxicity. Galantamine (Reminyl)—newest kid on the block Rivastigmine (Exelon) long acting. Twice a day dosing. Tacrine (Cognex)—hepatoxic. Elevated liver enzymes usu. Within 18 wks. > in women.

Reversible anti-AChEs used in:
Belladonna poisoning: physostigmine, neostigmine, galantamine Cobra bite (cobra venom has a curare-like neurotoxin): galantamine, neostigmine

b- Indirect acting Cholinesterase inhibitor, Irreversible
Isoflurophate & Echothiophate Therapeutic uses of Isoflurophate: - The drug is used topically in the eye for the chronic treatment of open-angle glaucoma. The effects may last for up to one week after a single administration.

b- Indirect acting Cholinesterase inhibitor, Irreversible
Isoflurophate & Echothiophate Echothiophate: is a newer drug. Its use is the same as Isoflurophate.

Irreversible anticholinesterase
Are synthetic organophosphorus compounds bind acetylcholinesterase covalently and inhibit it irreversibly, so there will be increase in ACH at all the sites of its release. These compounds are extremely toxic and used in military as nerve agents (soman, sarin, VX), some agents like parathion and malathion used as insecticides.

The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours). After the initial binding-hydrolysis step, the phosphorylated enzyme complex may undergo a process called aging.

This process apparently involves the breaking of one of the oxygen- phosphorus bonds of the inhibitor and further strengthens the phosphorus-enzyme bond. The rate of aging varies with the particular organophosphate compound. For example, aging occurs within 10minutes with the chemical warfare agent, and in 48 hours with the agentVX. If given before aging has occurred, strong nucleophiles like pralidoxime are able to break the phosphorus-enzyme bond and can be used as "cholinesterase regenerator".

Once aging has occurred, the enzyme-inhibitor complex is even more stable and is more difficult to break, even with oxime regenerator compounds.

Isoflurophate: This drug cause permanent inactivation of acetylcholinesterase , the restoration of enzyme activity requires synthesis of new enzyme molecules. It cause generalized cholinergic stimulation, paralysis of motor function leading to breathing difficulties, convulsion. It cause intense miosis, atropine in high dose can reverse its muscarinic and central effects.

Clinical uses: Available as ointment used topically for the treatment of glaucoma, the effect may last for one week after a single administration. Echothiophate also is an irreversible inhibitor of acetylcholinestrase with the same uses of isoflurophate. The inhibited acetylcholinesterase can be reactivated by pralidoxime which is synthetic compound can regenerate new enzyme.

Organophosphorus poisoning Acute intoxication must be recognized and treated promptly . The dominant initial signs are those of muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system involvement (cognitive disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicotinic effects.

Treatment: 1.maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent further absorption—this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays; and (3) atropine parenterally in large doses, given as often as required to control signs of muscarinic excess. Therapy often also includes treatment with pralidoxime and administration of benzodiazepines for seizures.

Cholinergic antagonists: They are also called anticholinergic drugs or cholinergic blockers, this group include: 1.Antimuscarinic agents ( atropine, ipratropium, scopolamine) 2. Ganglionic blockers (mecamylamine, nicotine, trimethaphan) 3. Neuromuscular blockers (atracutium, metocurine, mivacurium, pancuronium, succinylcholine, tubocurarine, and vecuronium)

Antimuscarinic agents: These agents block muscarinic receptors and inhibit muscarinic functions, they are useful in different clinical situations, they have no actions on skeletal neuromuscular junctions or autonomic ganglia because they do not block nicotinic receptors.

Atropine: A belladonna alkaloid has a high affinity for muscarinic receptors, it is a competitive inhibitor of muscarinic receptors preventing ACH from binding to that site.

Atropine is both central and peripheral muscarinic blocker, its action lasts about 4 hours, when used topically in the eye its action lasts for days.

Actions: Eye: It cause dilation of the pupil (mydriasis), unresponsiveness to light, and cycloplegia (inability to focus for near vision), if used in patients with glaucoma , it will cause dangerous elevation in IOP.

Respiratory system: Bronchodilatation and reduce secretion
Respiratory system: Bronchodilatation and reduce secretion. CNS: Sedation, amnesia, at high doses cause agitation, hallucination, and coma.

GIT: Reduce motility so it is effective as antispasmodic
GIT: Reduce motility so it is effective as antispasmodic. Urinary system: Reduce motility and cause urine retention so used in treatment of nocturnal enuresis in children, it dangerous to be used in patients with benign prostatic hypertrophy due to its effect in producing urine retention.

CVS: Its actions depend on the dose, at low dose lead to bradycardia due to central activation of vagus nerve, but recently this effect is due to blockade of M1 receptors on the inhibitory prejunctional neurons so increase ACH release. At higher doses of atropine there will be blockade of cardiac receptors on SA node and this will increase heart rate (tachycardia), blood pressure is not affected but at toxic doses atropine will cause dilatation of cutaneous blood vessels.

Secretions: It blocks the salivary gland secretion and produce dry mouth (xerostomia), blocks th Lacrimal glands secretion and cause eye dryness (xerophthalmia), blocks the bronchial secretion, and blocks the secretion of sweat gland and increase body temperature.

Clinicaluses: Antispasmodic agent: Relax GIT and bladder
Clinicaluses: Antispasmodic agent: Relax GIT and bladder. Mydriatic and cycloplegic agent in the eye to permit measurement of refractive errors. Antidote for cholinergic agonists: To treat organophsphorus poisoning (present in insecticides), and mushroom poisoning. Antisecretory agent: To block the secretion of upper and lower respiratory tracts prior to surgery.

Dry mouth, blurred vision, tachycardia, and constipation
Dry mouth, blurred vision, tachycardia, and constipation. On CNS restlessness, confusion, hallucination, and delirium, this may progress to circulatory and respiratory collapse and death. It is very risky in individuals with glaucoma and BPH so careful history is required.

Scopalamine (hyoscine): A belladdona alkaloid produce peripheral effects similar to atropine, it has greater actions on CNS and longer duration of action. It is one of the most effective antimotion sickness, it is effective also in blocking short term memory, it produce sedation but at higher doses cause excitement.

Ipratropium: It is inhaled derivative of atropine useful in treating asthma and COPD in patients unable to take adrenergic agonist. Other agents like homatropine, cyclopentolate, and tropicamide used mainly in ophthalmology.

Ganglionic blockers: - They act on nicotinic receptors of the autonomic ganglia. They have no selectivity toward the parasympathetic or sympathetic ganglia . The effect of these drugs is complex and unpredictable so rarely used therapeutically, used mainly in experimental pharmacology.

Nicotine It is Component of cigarette smoke, has many undesirable actions. Depending on the dose, nicotine depolarizes ganglia resulting first in stimulation then followed by paralysis of all ganglia. The stimulatory effects are complex include ( at low dose ): 1- Increase in blood pressure and heart rate (due to release of the transmitter from adrenergic terminals and adrenal medulla).

Increase peristalsis and secretions
Increase peristalsis and secretions. On large dose , nicotine : The blood pressure falls because of ganglionic blockade, activity both in GIT and UB musculature decrease.

Short acting competitive nicotinic ganglionic blocker that must be given by i.v infusion, it is used for the emergency lowering of the blood pressure in hypertension caused by pulmonary edema or dissecting aortic aneurysm when other agents cannot be used. Trimethaphan:

Mecamylamine: Competitive nicotinic blocker of the ganglia, the duration of action 10 hours after single administration.

Neuromuscular blocking drugs:
- Drugs that block cholinergic transmission between motor nerve ending and the nicotinic receptors on the neuromuscular end plate of the skeletal muscle. - They are structural analogs of ACH.

They are useful in surgery to produce complete muscle relaxation to avoid higher anesthetic doses to achieve similar muscular relaxation.

They are of 2 types : 1- Antagonist (nondepolarizing type)
They are of 2 types : 1- Antagonist (nondepolarizing type). (isoquinoline derivative e.g. atracurium , tubocurarine ) or steroid derivative e.g. pancuronium , vecuronium ) Agonist (depolarizing type) at the receptors on the end plate of the NMJ ( e.g. Succinylcholine ).

Non depolarizing ( competitive) blockers:
mechanism of action: At low dose: they combine with nicotinic receptors and prevent binding with ACH so prevent depolarization of muscle cell membrane and inhibit muscular contraction. Their action can be overcome by administration of acetylcholinesterase inhibitors such as neostigmine or edrophonium.

At high doses: Block the ion channel of the end plate so lead to weakening of neuromuscular transmission and reduce the ability of acetylcholinesterase inhibitors to reverse the effect of nondepolarizing muscle relaxants.

Pharmacological actions:
They cause first paralysis of the small contracting muscles of face, followed by fingers, then after limbs, neck and trunk muscles are paralyzed, then the intercostal muscles are affected, and lastly the diaphragm is paralyzed.

Therapeutic uses: Are adjuvant drugs in anesthesia during surgery to relax skeletal muscles.

Side effects: Histamine release, ganglionic blockade and hypotension.
Postoperative muscle pain and hyperkaleamia . Increase IOP and intra-gastric pressure. Malignant hyperthermia.

Drug interactions: Cholinesterase inhibitors: They can overcome the effect of nondepolarizing NM blockers at high doses. Haloginated hydrocarbone anesthetics: Enhance their actions by exerting stabilizing action at the NMJ. Aminoglycoside antibiotics: Inhibit ACH release from cholinergic nerves by competing with calcium ions, they synergize with all competitive blockers and enhance the blockade. Calcium channel blockers: Increase the effect of both depolarizing and nondepolarizing agents.

Depolarizing agents: Mechanism of action:
Succinylcholine attach to nicotinic receptors and acts like acetylcholine to depolarize NMJ. This drug persist at high concentration at synaptic cleft and attach to the receptor for long time, it cause initially opening of the sodium channel associated with the nicotinic receptor which cause receptor depolarization and this lead to transient twitching of the muscle (fasciculation). The continuous binding of the agent to the receptor renders the receptor incapable to transmit further impulses, then there will be gradual repolarization as the Na- channels will be closed and this causes resistance to depolarization and a flaccid paralysis.

Pharmacological action
Initially produce short lasting muscle fasciculation, followed within a few minutes by paralysis. The duration of action of acetylcholine is short since it is broken rapidly by plasma cholinesterase.

Therapeutic uses: 1.Because its rapid onset of action and short duration of action it is useful when rapid endotracheal intubation is required during the induction of anesthesia. 2. Electroconvulsive shock treatment (ECT). Succinylcholine given by continuous i.v infusion because of it is short duration on action ( due to rapid hydrolysis by plasma cholinesterase).

Side effects: 1- Hyperthermia: When halothane used as an anesthetic, succinylcholine may cause malignant hyperthermia with muscle rigidity and hyperpyrexia in genetically susceptible individuals. This treated by rapidly cooling the patient and by administration of dantroline which blocks Ca release and thus reduce heat production and relaxing the muscle tone.

Apnea: A genetically related deficiency of plasma cholinesterase or presence of an atypical form of the enzyme can cause apnea lasting 1-4 hours due to paralysis of the diaphragm. It is managed by mechanical ventilation.

THERAPEUTIC USES IN DENTISTRY
To decrease the flow of saliva during dental procedures. Small doses given orally or parenterally approximately 30 minutes to 2 hours before the procedure are effective, but these drugs may also produce side effects that may be objectionable to some patients. Atropine and glycopyrrolate are frequently used in oral surgery as intraoperative antisialagogues. They are administered intravenously in doses of 0.4 mg to 0.6 mg and 0.1 mg to 0.2 mg. Because it is a quaternary amine, glycopyrrolate has fewer CNS effects than belladonna alkaloids. Compared with atropine, it is a more selective antisialagogue and less likely to promote tachycardia in conventional doses.

Implications for dentistry
The most characteristic effects of these drugs that concern dentists are xerostomia and the discomfort that this brings to the patient and the deterioration in oral health. Small doses of pilocarpine often are effective in stimulating salivary flow; however, this strategy is complicated by the fact that pilocarpine may also counter the therapeutic benefit being achieved by the antimuscarinic drug. In cases in which using a muscarinic receptor agonist may antagonize therapy involving an antimuscarinic drug, patients can be advised to : drink water, suck on noncariogenic lemon drops, irrigate the mouth with saliva substitutes to alleviate xerostomia.

Implications for dentistry
If saliva flow is reduced, patients need to pay scrupulous attention to oral hygiene, and caries control needs to be more aggressive. If there is progressive deterioration in oral health, consultation with the patient’s physician may be helpful in identifying suitable therapeutic alternatives without as much xerostomia. The use of antimuscarinic drugs should be avoided in patients with prostate hypertrophy and patients with atony in the urinary or gastrointestinal tract.

Drugs Affecting the Autonomic Nervous System

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