Cholinergic drugsCholinergic drugs

Are drugs act on receptors that are activated by Are drugs act on receptors that are activated by acetylcholine(ACH) which is the neurotransmitter of the acetylcholine(ACH) which is the neurotransmitter of the parasympathetic nervous system.ACH is synthesized in the parasympathetic nervous system.ACH is synthesized in the cholinergic neurons from choline and acetyl CoA then cholinergic neurons from choline and acetyl CoA then stored in synaptic vesicles then it will be release into stored in synaptic vesicles then it will be release into synaptic gap to bind post synaptic receptors and lead to synaptic gap to bind post synaptic receptors and lead to biological response.biological response.ACH is metabolized by acetylcholine esterase enzyme that ACH is metabolized by acetylcholine esterase enzyme that cleaves it to choline and acetate.cleaves it to choline and acetate.Choline will be recaptured by uptake system back into the Choline will be recaptured by uptake system back into the

neuron and recycling will occurneuron and recycling will occur..

Cholinergic receptors( cholinoceptors ) are two families Cholinergic receptors( cholinoceptors ) are two families muscarinic and nicotinic depending on their affinities to muscarinic and nicotinic depending on their affinities to cholinomimetic agents(agents that mimic ACH actions).cholinomimetic agents(agents that mimic ACH actions).Muscarinic receptors bind ACH and also recognize Muscarinic receptors bind ACH and also recognize muscarine, they are located in autonomic effector organs muscarine, they are located in autonomic effector organs such as heart, smooth muscle, brain, and exocrine glands.such as heart, smooth muscle, brain, and exocrine glands.Nicotinic receptors bind ACH and also recognize nicotine. Nicotinic receptors bind ACH and also recognize nicotine. They are located in the CNS, adrenal medulla, autonomic They are located in the CNS, adrenal medulla, autonomic

ganglia, and neuromuscular junctionganglia, and neuromuscular junction..

Direct acting cholinergic agonists:Direct acting cholinergic agonists:Are agents mimic the effect of ACH by Are agents mimic the effect of ACH by binding directly to cholinoceptors. They are binding directly to cholinoceptors. They are synthetic esters of choline such as carbachol synthetic esters of choline such as carbachol and bethanechol or naturally occurring and bethanechol or naturally occurring alkaloids such as pilocarpine. All of these alkaloids such as pilocarpine. All of these drugs have longer duration of action than drugs have longer duration of action than

ACHACH..

ACH:ACH: Is the neurotransmitter of the Is the neurotransmitter of the parasympathetic N.S and cholinergic nerves, parasympathetic N.S and cholinergic nerves, it is therapeutically of no importance due to:it is therapeutically of no importance due to:1. Multiplicity of actions.1. Multiplicity of actions.2. Rapid inactivation by acetyl-cholinesterase.2. Rapid inactivation by acetyl-cholinesterase.3. Has both muscarinic and nicotinic activity3. Has both muscarinic and nicotinic activity..

Actions:Actions:Decrease in heart rate and cardiac output: Due to SA node Decrease in heart rate and cardiac output: Due to SA node depression.depression.Decrease in blood pressure: It causes vasodilatation due to Decrease in blood pressure: It causes vasodilatation due to its effect on cholinergic receptors in blood vessels, it will its effect on cholinergic receptors in blood vessels, it will lead to increase in intracellular nitric oxide (NO) which is lead to increase in intracellular nitric oxide (NO) which is called endothelium derived relaxing factor (EDRF).called endothelium derived relaxing factor (EDRF).Other actions: Other actions: GIT: Increase salivary secretion and increase intestinal GIT: Increase salivary secretion and increase intestinal motility and secretion.motility and secretion. Respiratory: stimulate bronchiolar secretions. Respiratory: stimulate bronchiolar secretions. Genitourinary tract: Increase detrusor muscle tone. Genitourinary tract: Increase detrusor muscle tone. Eye: Miosis (marked constriction of the pupil Eye: Miosis (marked constriction of the pupil

Bethanechol:Bethanechol:

Structurally related to ACH, has strong Structurally related to ACH, has strong

muscarinic activity but no nicotinic actions.muscarinic activity but no nicotinic actions.

It directly stimulates muscarinic receptors It directly stimulates muscarinic receptors

of the GIT causing increase intestinal of the GIT causing increase intestinal

motility and tone, it also stimulates motility and tone, it also stimulates

detrusor muscle of the bladder causing detrusor muscle of the bladder causing

urine expulsionurine expulsion..

Clinical usesClinical uses: 1.Atonic bladder stimulation : 1.Atonic bladder stimulation such as in postpartum and post operative non such as in postpartum and post operative non obstructive urine retention.obstructive urine retention.Side effectsSide effects: Sweating, salivation, flushing, : Sweating, salivation, flushing, hypotension, nausea, abdominal pain, hypotension, nausea, abdominal pain,

diarrhea, and bronchospasmdiarrhea, and bronchospasm..

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

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

Pilocarpine:Pilocarpine:Mainly used in ophthalmology, it exhibit Mainly used in ophthalmology, it exhibit muscarinic activity, it produces rapid muscarinic activity, it produces rapid miosis and contraction of the ciliary miosis and contraction of the ciliary muscle.muscle.Clinical uses; It is the drug of choice in Clinical uses; It is the drug of choice in the emergency lowering of inrtra-ocular the emergency lowering of inrtra-ocular pressure in case of glaucomapressure in case of glaucoma..

Side effects:Side effects:It can enter the brain and It can enter the brain and cause CNS disturbances, cause CNS disturbances, it stimulate profuse it stimulate profuse sweating and salivationsweating and salivation..

Indirect acting cholinergic agonists:Indirect acting cholinergic agonists:Are drugs that exert cholinergic actions by Are drugs that exert cholinergic actions by prolonging the life time of ACH via inhibition of prolonging the life time of ACH via inhibition of acetyl-cholinesterase enzyme, this results in acetyl-cholinesterase enzyme, this results in accumulation of ACH in synaptic space and accumulation of ACH in synaptic space and provoke response at all cholinoceptors in the body provoke response at all cholinoceptors in the body including both muscarinic and nicotinic receptors including both muscarinic and nicotinic receptors as well as neuromuscular junction and the brain, as well as neuromuscular junction and the brain, these drugs are termed (anti-cholinesterases) which these drugs are termed (anti-cholinesterases) which

are reversible and irreversibleare reversible and irreversible..

Reversible Reversible anticholinesteraseanticholinesterase

This group include: physostigmine, This group include: physostigmine, neostigmine, pyridostigmine, and neostigmine, pyridostigmine, and edrophonium, ambenonium, and edrophonium, ambenonium, and demecarium.demecarium.The major therapeutic uses of the The major therapeutic uses of the cholinomimetics are for diseases of the eye cholinomimetics are for diseases of the eye (glaucoma, accommodative esotropia), the (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), (postoperative atony, neurogenic bladder), the neuromuscular junction (myasthenia the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular gravis, curare-induced neuromuscular paralysis), and very rarely, the heart paralysis), and very rarely, the heart (certain atrial arrhythmias)(certain atrial arrhythmias)..

Cholinesterase inhibitors are Cholinesterase inhibitors are occasionally used in the occasionally used in the treatment of atropine treatment of atropine overdosage. Several newer overdosage. Several newer cholinesterase inhibitors are cholinesterase inhibitors are being used to treat patients with being used to treat patients with Alzheimer's diseaseAlzheimer's disease..

Physostgmine:Physostgmine: It is an alkaloid which is nitrogenous It is an alkaloid which is nitrogenous compound found in plants, it is a reversible compound found in plants, it is a reversible inhibitor of acetylcholinesterase and inhibitor of acetylcholinesterase and potentiate cholinergic activity through out potentiate cholinergic activity through out the body.the body.Physostigmine stimulates muscarinic and Physostigmine stimulates muscarinic and nicotinic receptors of ANS and nicotinic nicotinic receptors of ANS and nicotinic receptors of neuromuscular junction, its receptors of neuromuscular junction, its duration of action is 2-4 hours, it can enter duration of action is 2-4 hours, it can enter and stimulate CNSand stimulate CNS..

Clinical uses:Clinical uses:1. Bladder and intestinal atony 1. Bladder and intestinal atony (increase their motility). (increase their motility). 2.Glaucoma ( decrease intraocular 2.Glaucoma ( decrease intraocular pressue).pressue).3.Overdose of anticholinergic 3.Overdose of anticholinergic drugs like atropine, drugs like atropine, phenothiazines, and tricyclic phenothiazines, and tricyclic antidepressantsantidepressants..

Clinical uses:Clinical uses:1. Bladder and intestinal atony 1. Bladder and intestinal atony (increase their motility). (increase their motility). 2.Glaucoma ( decrease intraocular 2.Glaucoma ( decrease intraocular pressue).pressue).3.Overdose of anticholinergic 3.Overdose of anticholinergic drugs like atropine, drugs like atropine, phenothiazines, and tricyclic phenothiazines, and tricyclic antidepressantsantidepressants..

Side effects:Side effects:1.Convulsion at high doses.1.Convulsion at high doses.2. Bradycardia.2. Bradycardia.3. Skeletal muscle paralysis due to 3. Skeletal muscle paralysis due to inhibition of acetylcholinesterase inhibition of acetylcholinesterase at neuromuscular junction and ACH at neuromuscular junction and ACH accumulationaccumulation

•Neostigmine:Neostigmine:Synthetic compound reversibly inhibits Synthetic compound reversibly inhibits acetylcholinesterase, it does not enter CNS, acetylcholinesterase, it does not enter CNS, it has greater effect on skeletal muscle that it has greater effect on skeletal muscle that can increase contractility then paralysis.can increase contractility then paralysis.Uses:Uses:1.stimulate atonic bladder and intestine.1.stimulate atonic bladder and intestine.2.Antidote for neuromuscular blocking 2.Antidote for neuromuscular blocking agents like tubocurarine.agents like tubocurarine.3.Symptomatic treatment in myasthenia 3.Symptomatic treatment in myasthenia gravis. gravis. Side effects:Side effects:Salivation, flushing, hypotension, nausea, Salivation, flushing, hypotension, nausea, abdominal pain, diarrhea, and abdominal pain, diarrhea, and bronchospasmbronchospasm..

Pyridostigmine:Pyridostigmine:Used in chronic treatment of Used in chronic treatment of myasthenia gravis, its myasthenia gravis, its duration of action 3-6 hoursduration of action 3-6 hours..

Edrophonium:Edrophonium:Has short duration of action (10-Has short duration of action (10-20 minutes) used in diagnosis of 20 minutes) used in diagnosis of myasthenia gravis (i.v injection of myasthenia gravis (i.v injection of edrophonium lead to rapid edrophonium lead to rapid increase in muscle strength).increase in muscle strength).AmbenoniumAmbenonium: Has duration of : Has duration of action 4-8 hours used in action 4-8 hours used in myasthenia gravis.myasthenia gravis. Demecarium: Demecarium: Has duration of Has duration of action 4-6 hours used in action 4-6 hours used in glaucomaglaucoma..

Myasthenia gravis:Myasthenia gravis: is an autoimmune disease affecting skeletal is an autoimmune disease affecting skeletal muscle neuromuscular junctions. In this disease, muscle neuromuscular junctions. In this disease, antibodies are produced against nicotinic antibodies are produced against nicotinic receptor. Antibodies are detected in 85% of receptor. Antibodies are detected in 85% of myasthenic patients. The antibodies reduce myasthenic patients. The antibodies reduce nicotinic receptor function by (1) cross-linking nicotinic receptor function by (1) cross-linking receptors, a process that stimulates their receptors, a process that stimulates their internalization and degradation; (2) causing lysis internalization and degradation; (2) causing lysis of the postsynaptic membrane; and (3) binding to of the postsynaptic membrane; and (3) binding to the nicotinic receptor and inhibiting function. the nicotinic receptor and inhibiting function. Frequent findings are ptosis, diplopia, difficulty in Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity speaking and swallowing, and extremity weakness. Severe disease may affect all the weakness. Severe disease may affect all the muscles, including those necessary for muscles, including those necessary for respiration. The disease resembles the respiration. The disease resembles the neuromuscular paralysis produced by neuromuscular paralysis produced by dd--tubocurarine and similar nondepolarizing tubocurarine and similar nondepolarizing neuromuscular blockingneuromuscular blocking

Patients with myasthenia are sensitive to Patients with myasthenia are sensitive to the action of curariform drugs and other the action of curariform drugs and other drugs that interfere with neuromuscular drugs that interfere with neuromuscular transmission, eg, aminoglycoside transmission, eg, aminoglycoside antibiotics.antibiotics.Cholinesterase inhibitors—but not direct-Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are acting acetylcholine receptor agonists—are extremely valuable as therapy for extremely valuable as therapy for myasthenia. Patients with ocular myasthenia. Patients with ocular myasthenia may be treated with myasthenia may be treated with cholinesterase inhibitors alonecholinesterase inhibitors alone . .

Patients having more widespread Patients having more widespread muscle weakness are also treated with muscle weakness are also treated with immunosuppressant drugs (steroids, immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In cyclosporine, and azathioprine). In some patients, the thymus gland is some patients, the thymus gland is removed; very severely affected removed; very severely affected patients may benefit from patients may benefit from administration of immunoglobulins administration of immunoglobulins and from plasmapheresisand from plasmapheresis..

Edrophonium is sometimes used as a Edrophonium is sometimes used as a diagnostic test for myasthenia. A 2 mg diagnostic test for myasthenia. A 2 mg dose is injected intravenously after dose is injected intravenously after baseline muscle strength has been baseline muscle strength has been measured. If no reaction occurs after measured. If no reaction occurs after 45 seconds, an additional 8 mg may 45 seconds, an additional 8 mg may be injected. If the patient has be injected. If the patient has myasthenia gravis, an improvement in myasthenia gravis, an improvement in muscle strength that lasts about 5 muscle strength that lasts about 5

minutes can usually be observedminutes can usually be observed..

Edrophonium is also used to assess Edrophonium is also used to assess the adequacy of treatment with the the adequacy of treatment with the longer-acting cholinesterase inhibitors longer-acting cholinesterase inhibitors in patients with myasthenia gravis. If in patients with myasthenia gravis. If excessive amounts of cholinesterase excessive amounts of cholinesterase inhibitor have been used, patients inhibitor have been used, patients may become paradoxically weak may become paradoxically weak because of nicotinic depolarizing because of nicotinic depolarizing

blockade of the motor end plateblockade of the motor end plate..

Clinical situations in which severe Clinical situations in which severe myasthenia (myasthenic crisis) must myasthenia (myasthenic crisis) must be distinguished from excessive drug be distinguished from excessive drug therapy (cholinergic crisis) usually therapy (cholinergic crisis) usually occur in very ill myasthenic patients occur in very ill myasthenic patients and must be managed in hospital with and must be managed in hospital with adequate emergency support systems adequate emergency support systems such as mechanical ventilatorssuch as mechanical ventilators..

Long-term therapy for myasthenia gravis is Long-term therapy for myasthenia gravis is usually accomplished with pyridostigmine; usually accomplished with pyridostigmine; neostigmine or ambenonium are neostigmine or ambenonium are alternatives. The doses are titrated to alternatives. The doses are titrated to optimum levels based on changes in optimum levels based on changes in muscle strength. These drugs are relatively muscle strength. These drugs are relatively short-acting and therefore require frequent short-acting and therefore require frequent dosing (every 6 hours for pyridostigmine dosing (every 6 hours for pyridostigmine and ambenonium and every 4 hours for and ambenonium and every 4 hours for

neostigmineneostigmine..

Sustained-release preparations Sustained-release preparations are available but should be used are available but should be used only at night and if needed. only at night and if needed. Longer-acting cholinesterase Longer-acting cholinesterase inhibitors such as the inhibitors such as the organophosphate agents are organophosphate agents are not used, because the dose not used, because the dose requirement in this disease requirement in this disease changes too rapidly to permit changes too rapidly to permit smooth control of symptoms smooth control of symptoms with long-acting drugswith long-acting drugs..

If muscarinic effects of such therapy If muscarinic effects of such therapy are prominent, they can be controlled are prominent, they can be controlled by the administration of by the administration of antimuscarinic drugs such as atropine. antimuscarinic drugs such as atropine. Frequently, tolerance to the Frequently, tolerance to the muscarinic effects of the muscarinic effects of the cholinesterase inhibitors develops, so cholinesterase inhibitors develops, so

atropine treatment is not requiredatropine treatment is not required..

Irreversible Irreversible anticholinesteraseanticholinesterase

Are synthetic Are synthetic organophosphorus compounds organophosphorus compounds bind acetylcholinesterase bind acetylcholinesterase covalently and inhibit it covalently and inhibit it irreversibly, so there will be irreversibly, so there will be increase in ACH at all the sites increase in ACH at all the sites of its releaseof its release..

These drugs are extremely toxic and used These drugs are extremely toxic and used in military as nerve agents (soman, sarin, in military as nerve agents (soman, sarin, VX), some agents like parathion and VX), some agents like parathion and malathion used as insecticides. The malathion used as insecticides. The covalent phosphorus-enzyme bond is covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours). at a very slow rate (hundreds of hours). After the initial binding-hydrolysis step, the After the initial binding-hydrolysis step, the phosphorylated enzyme complex may phosphorylated enzyme complex may

undergo a process called undergo a process called agingaging..

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

as "cholinesterase regeneratoras "cholinesterase regenerator ." ."

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

oxime regenerator compoundsoxime regenerator compounds..

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

effectseffects..

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

OrganophosphorusOrganophosphoruspoisoningpoisoning

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

nicotinic effectsnicotinic effects..

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

seizuresseizures..

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

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

Atropine:Atropine:A belladonna alkaloid has a A belladonna alkaloid has a high affinity for muscarinic high affinity for muscarinic receptors, it is a competitive receptors, it is a competitive inhibitor of muscarinic inhibitor of muscarinic receptors preventing ACH receptors preventing ACH

from binding to that sitefrom binding to that site..

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

its action lasts for daysits action lasts for days..

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

dangerous elevation in IOPdangerous elevation in IOP..

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

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

producing urine retentionproducing urine retention . .

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

vesselsvessels..

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

increase body temperatureincrease body temperature..

Clinicaluses:Clinicaluses:Antispasmodic agent: Relax GIT and Antispasmodic agent: Relax GIT and

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

to surgeryto surgery..

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

history is requiredhistory is required..

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

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

Ganglionic blockersGanglionic 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.

-

NicotineNicotine

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.

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

TrimethaphanTrimethaphan::

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.

 

MecamylamineMecamylamine::

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

 

Neuromuscular blocking Neuromuscular blocking drugsdrugs::

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

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

Non depolarizing Non depolarizing ( competitive) ( competitive)

blockersblockers : :

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

Pharmacological actionsPharmacological 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 usesTherapeutic uses::

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

Side effectsSide effects::

Histamine release, ganglionic blockade and hypotension.

Postoperative muscle pain and hyperkaleamia .

Increase IOP and intra-gastric pressure.

Malignant hyperthermia.

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