cholinergic agoinsts and Antagonists.pptx

Autonomic nervous system Sympathetic thoracolumber Parasympathetic. crainosacral Neurotransmitter :  Acetylcholine : its neurotransmitter of parasympathetic.  Two receptor of acetycoline 1 - nicotinic 2-muscarinic Site of function Preganglionic of sympathic. (by ni...

Autonomic nervous system Sympathetic thoracolumber Parasympathetic. crainosacral Neurotransmitter :  Acetylcholine : its neurotransmitter of parasympathetic.  Two receptor of acetycoline 1 - nicotinic 2-muscarinic Site of function Preganglionic of sympathic. (by nicotinic receptors in ganglia ) Some of postganglionic of sympathetic (by muscarinic receptors ) Preganglionic of parasympathetic ( by nicotinic receptors in gangila) Postganglionic of parasympathetic ( by muscarinic receptor s) Some postganglionic of sympathetic 1 - sweat gland 2 - arterioles of skeletal muscle. 3-piloecector muscle). Also act in neuromusclar junction of somatic (by nicotinic receptor) Neurotransmitter Norepinephrine and epinphrine :  Has to receptors 1-alpha receptor 2- beta receptor Relase from postganglionic sympathetic except Some postganglionic of sympathetic 1- sweat gland. 2-arterioles of skeletal muscule. 3-piloecetor muscle. And also release adrenal medulla. Adrenal medulla : it modified sympathetic ganglia has Preganglionic neuron but lost postganglionic. It stimulated by acetylcholine at nicotinic receptors and it release norepinephrine, epinphrine (mainly). Cholinergic agonist Neurotransmission at cholinergic neurons: 1-synthesis of acetylcholine 2-storage of acetylcholine 3 - release of acetylcholine 4-Binding acetylcholine to receptor (N, M) 5- degradation of acetylcholine in synaptic cleft 6-recycling of choline and acetate. 1- synthesis of ACh : Choline transport to cholinergic neuron with Na as cotransport ( inhibited by hemicholinium). Choline + acetylco enzyme A in present of choline acetyltransferase lead to formation of acetylcholine. 2 - storage of ACh : Ach storaged in pre vesicle with co tranmitter (adenosine triphosphate and proteoglycan). 3 - Release of ACh : Action potential in cholinergic neuron propagated Na channels lead open Ca channel, elevated Ca level promote release of vesicle into synaptic cleft (blocked by botulinum and stimulated by black widow spider venom). 4 - Binding of ACh to receptors: Binding to muscarinic and nicotinic receptors. 5-Degradation : After postjunctional effecter site ACh degraded by acetylcholine esterase to choline and acetate. 6- Recycle of choline : Choline enter presynaptic neuron with Na to use in synthesis of acetylcholine. Direct cholinergic agoinsts: act like acetylcholine by binding directly to nicotinic or muscarinic receptors. Divided two groups : 1- choline ester ( carbachol, bethanechol) 2 - alkaloids ( nicotine, pilocarpine). Cholinergic agoinst has long action than ACh. A-Acetylcholine : Lack of therapeutic importance due multiplicity of action (diffuse) and rapid inactivation. Action : 1-heart A- decrease HR, SV. decrease BP ( stimulated M3 lead to release nitric oxide which lead to vasodilation ) Antidote of acetycoline is atropine. 2- GIT Increase saliva secretion and intestinal motility and secretion. 3- pulmonary Increase secretion and bronchoconstriction. 4- UT Contraction of detrusor muscle lead urination. 5-eye : Pupillea muscle constriction (miosis). B - Bethanechol: It is carbamoyl ester Not hydrolysis by ACh estease. It is strong muscarinic receptors agoinst and lack of nicotinic actions. Act on smooth muscle of bladder, GIT. * therapeutic uses: 1-urologic treatment A- Atonic bladder (postoperative and postpartum). B- Non obstructive urine retention. 2- GIT Megacolon and neurogenic atony * Adverse effects :  Sweating Flushing Decrease BP Nausea, Abdo pain , Diarrhea Bronchospasm  * Antidote by atropine. C- Carbachol (carbamoylcholine) Act in both muscarinic and nicotinic receptors.  Poor substrate for ACh esterase Act in eye cause miosis, spasm, accomodition. * therapeutic use: Eye(miotic agent to treated glaucoma by pupillary contraction, decrease ocular pressure. #Adverse effect : No systemic side effect by topical use in eye. D - Pilocarpine : It alkaloid. Hydrolysis by ACh esterase. Has muscarinic activity. Use in ophthalmology. Action : Miosis, contraction of ciliary muscle, spam of accommodation. Antidote :atropine. It is stimulator of sweat, saliva, tear so can use to treat xerostomia (sjogren syndrome) and after head radiation. *therapeutic uses : Frist choice for emergency lowering ocular pressure (glaucoma). Act as Antidote of atropine. #Adverse effect : 1-blurred vision 2-night blindness 3-Browache 4-poisioning (cholinergic stimulation sweating, salivation..... Indirect acting cholinergic agoinsts ' Anticholinesterase' reversible : AchE is enzyme degreded Ach to acetate and choline and terminates it action. Anticholinesterase agents or cholinestrase inhibitors indirectly provide cholinergic action by prevent Ach degradation lead to accumulation of Ach in synaptic stimulated both muscarinic and nicotine receptors as well as NMJ and brain. A-Edrophonium : Short acting (10_20) minute. Reversibly acting to AchE. Rapid absorbed. It action limited periphery. It uses to diagnosis myasthenia gravis (autoimmone diease, antibodes agonist NMJ). IV injections of edrophonium lead to increase muscle strenght. Antidotes by atropine. Ituse to reversing the effect of depolarizing neuromuscular blocker after sugery. Edrophonium has limited use due to availability of other agent. B- physostigmine : Itis nitrogenous carbamic acis ester Intermediate acting agent Reversibly inactivated of AChE. Has wide range effect in nicotinic, muscarinic receptors and nicotinic of NMJ. Duration of action : 30 minutes to 2 hour. Can acting central and peripheral. *therapeutic uses : 1-increases intestinal and bladder motility (use in atony) 2-to Antidote of atropine overdose. *Adverse effects : 1- CNS... Convulsions 2-cardio....decrease HR and decrease COP. 3-accumulation of ACh lead paralysis of skeletal muscle. C- Neostigmine : Also it Reversibly acting. Intermediate acting (30 minutes to 2 hour). More polar is absorbed poorly on Gi and CNS. *therapeutic use : 1-stimulate bladder and GIT. 2-also Antidote to competitive neuromusclar blocker. Manage sypmtom of myasthenia gravis. *Adverse effects :generalized cholinergic stimulation : 1-salivation 2-flushing. 3-decrease HR, COP, BP. 4- nausa, Abdpain, Diarrhea. 5-bronchospasm.  * dose not cause convulsions... Why??? Due it act peripherally. Can not use to Antidote of Atropine. Contraindicated when intestinal or urinary bladder obstruction is present. D- Pyriodostigamine and ambenonium :  Uses in chronic management of myasthenia gravis. Intermediate acting (longer than Neostigmine). Pyrido (3 th 6 hour) and ambe(4to 8 hour). Same adverse effects of Neostigmine. E-Tacrine, donepezil, rivastigmine, galantamine : Use to treated Alzheimer disease (deficiency of chlingeric neuron in CNS). Tarcine is hepatotoxic Used to delayed Alzheimer disease progression. GI distress is primary adverse effect. Indirect acting cholinergic agoinst s, Anticholinesterase (irreversible) Number of synthetic organophophate. Long lasting increases ACh at all site where released. Toxic agent Parathion and malathion are used as insecticides. A-Echothiophate : Organophophate that binds its phophate group at active site of AChE. It is inactivated the enzyme permanently and to restore must be synthesis new enzyme molecule. When it is inactivated of AchE cannot reactivated by pralidomixe due to aging (loss of ALkyl group). Actions : 1-generlized cholinergic stimulation. 2-paralysis of motor function (breathing difficulties). 3- convulsions. 4- Intense miosis (therapeutic use) 5- decrease intraocular pressure. *Atropine (high dose) can reverse many of pheripherl and some central muscarinic receptor. *therapeutic use : topical ophthalmic solution to treated open angle glaucoma rarely use do to side effect (risk of cataract). Toxicology of Anticholinesterase agents : Irreversible AchE inhibitor (most organophophate) used commonly in agricultural insecticides which has lead to numerous poisioning. Also can used for suicidal and homicidal agents. Organophophate nreve gas such as sarin used as agent of warfare and chemical terrorism. Toxicity of these agents manifested as cholinergic crisis. *Reactivation of acetylcholine esterase : Pralidomixe can reactivated inhibited AChE. Has charged group displaces phosphate group of organophophate. It act peripheral and can not penetrate CNS therefor it not useful to treated CNS effect of organophophate. It is weak AChE inhibitor and at high dose may cause side effects similar to Ach. It can reverse both muscarinic and nicotinic peripheral effect. Itcan reverse irreversible AchE inhibitor only and can not over toxicity of reversible. Other treatment : Atropine administered to prevent muscarinic (bronchial and saliva secretion, bronchoconstriction and bradycardia). Dizepam can used to reduce persisent convulsions. General supportivs measurement (maintance of airway , oxygen supply , artifical respiration. Cholinergic Antagonist Agents that bind to cholinoreceptor (M, N) and prevent of Ach and other Ach agoinst. Divided to 3 group : 1 - Anti muscarinic Antagonist Most clinicaly useful agent 2-ganglionic Antagonist Show it effect nicotinic receptors of parasympathetic and sympathetic ganglia. Least clinical useful. 3-Neuromuscular Blocking agent (mostly nicotinic Antagonist) : Interfere transmission of effect if efferent impulses to sketeal muscle. It is used skeletal muscle relaxant in anesthesia during surgery, intubation, orthopedics procedure. Anti muscarinic agents : Commonly known as anticholinergic drugs. These agent (Atropine, scopolamine). Block M receptors with few synaptic neuron (sweat , saliva) Has not effect NMJ and Automatic gangila due it not act in nicotinic receptor. Anticholinergic has beneficial in varity of clinical situations ( Antihistamines, Antidepressan). A-Atropine : Teritary amine belladonna alkaloid with high affinity for muscarinic receptors. It bind competitively and prevent Ach to form binding of muscarinic receptors. Atropine acts centrally and peripherally. It action about 4 hour except in eye topical it effects last for days. The greatest inhibitory effect are on bronchial tissue and secretion of sweat and saliva. *Action : 1-Eye : BlockM receptor lead to mydriasis (diluation of pupil), unresponsiveness to light,, cycloplegia (inability to focus for near vision). Risk to patient with glaucoma. 2- GIT : Anti spasmodic to reduce activity of GIT. It effect of GI motility only but not effect in hydrochloric acid production there for atropine not effective for treatment of peptic ucler. (note : pirenzepine an M1 muscarinic Antagonist decrease gastric acid secretion). Dose of Atropine that reduce GI spasms can reduce saliva secretion, ocular accommodation, urination these effects decrease compliance with atropine. 3- cardiovascular : It has divergent effect on CVS depending on the dose. A-at low dose : Block M1 receptor on inhibitory prejunctional (presynaptic) neurons lead to increasine Ach release. B-at high dose : Block M2 receptor on sinatrial node lead to increasine HR. 4-secretion : decrease saliva secretion (xerostomia). decrease sweat and lacrimal glands. *note :decrease sweating cause increase of body temperature which can be dangerous in children and elderly. * Therapeutic uses: A- Opthalmic : topical atropine 1-mydriatic 2- cycloplegia. Short acting (cyclopentolate and tropicamide use due to short acting (6_24)hour but atropine long acting for (7_14)days. B-Antispasmodic C-Antisecretory : to block upper and lower respiratory before surgery. D-Antidotes for cholinergic agoinsts : organphophate (insecticides, nerve gas) poisoning. **Pharmacokinetic : Partially metabolized by liver, eliminated primarily in urine. **Adverse effects :depending on dose 1-Dry mouth. 2-blurred of vision (sandy eye). 3-tachycardia. 4- urine retention. 5- constipation. 6-CNS : A- restlessness B-confusion C-hallucinations D-delirium E-depression F-collapse of circulatory and respiatory system. * Antidote of atropine : physostigmine. "atropine dangerous to child due to they are sensitive to rapid elevation of body temperature. B- scopolamine : Teritery amine plant alkaloid. Produce effects peripherally similar to atropine but has great effect can observed in therapeutic dose. Has long duration of action as compared to atropine. Actions: One of the most effective antimotion sickness drug available. In contract of atropine in low dose produce sedation but at high it can excitement. Can produce euphoria (susceptible to abuse). **Therapeutic uses: Limited to prevention (prophylactic) of motiom sickness and postoperative nausa and vomiting. Pharmakintic and adverse effects : Similar to atropine. C- Ipratropium and tiotropium : Quaternary derivates of atropine. They act bronchodilutor for maintance treatment of bronchospasm with chronic obstructive pulmonary disease (COPD). Ipratropium is used in acute management of bronchospasm in asthma. Both agents deliverd by inhalation. Tiotropium is administratered once daily, major advantage over Ipratropium which requires dose up to 4 time daily. D-Tropicamide and cyclopentolate : They used as ophthalmic solution for mydriasis and cycloplegia due short duration of action as compared with atropine. E- Benztropine, Trihexphenidyl: They are used to treated Parkinson diseases. F- Darifenacin, Fesoterodine : They are used to treat over active bladder. Block M receptor bladder, intravesical pressure is lowered bladder capacity is increased and frequency of bladder contraction is reduced. **Side effect : 1-Dry mouth. 2- constipation. 2-blurred vision. Ganglionic blockers : Act in nicotinic receptor of both parasympathetic and sympathetic ganglia. No selective toward para or sympathetic. Used in experimental pharmacology. Nicotine : Depending on dose nicotine depolarize autonomic gangila resulting first in stimulation and then paralysis of all ganglia. *stimulation phase : Increases released of dopamine and norepinephrine be associated with pleasure as well as appetite suppression. Also increase HR. At high dose : Blood pressure falls due of ganglionic blockade. Neuromuscular blocking agents : They blocks cholinergic transmission between motor nerve ending and nicotinic receptor on the sketeal muscle. Types : 1-Antagoinst (Nondepolarizing). 2-Agoinst (depolarizing). * clinically useful during surgery to faciliate treacheal intubation and provide complete muscule relaxation at lower anesthestic dose. 1- Nondepolarizing (competitive) blockers : Firstdrug known to block sketeal NMJ is curare. Cisatracurium, pancuronium , Rocuronium , vecuronium. NMB agent have significanttly increased saftey of anesthesia due to less anesthesia is required to produce muscle relaxation, allowing patients to recovery quickly and completely after surgery. *machanism of action s: 1-at low dose : They competitively block Ach at N receptor without stimulating it lead to prevent depolarization of muscle cell membrane and inhibit muscle contraction. Their competitively action can overcome by administration of Ach E inhibitor (Neostigmine and edrophonium) that increase concentration of Ach.  At low dose : The muscle will respond to electrical stimulation from peripherl nerve stimulator allowing for monitoring of extent of NMB. At high dose : They can block the ion channels of motor endplate. This lead to weaking of neuromusclar transmission there by reducing ability of AchE inhibitor to reverse the action of Nondepolarizing. **the muscle does not respond to direct electrical stimulation. Actions : Not all muscle are qually sensitive to blocke by competitive firstly paralyzed face and eye than finger, limb, neck, trunk muscle lastly intercostal and diaphragm. Pharmacokinetics : All neuromusclar blocking are injected IV and IM due to their bulky ring structure that prevent absorption from gut. Many of drugs not metabolized and their action terminated by redistribution. Pancuronium is excreted unchanged in urine. Cisatracurium is degraded in plasma (by ester Hydrolysis) Vancuronium and Rocuronium are deacetylated in liver. **Drug interaction : A - cholinestrase inhibitors : Can overcome Nondepolarizing NMB at low dose but at high dose Nondepolarizing depolarizing block(ion channle) the Ach E inhibitor are not effective. B-halogented hydrocarbon anesthesia : Desflurane enhance NMB by stabilizing action at NMJ. C-Aminoglucoside antibotic : As gentamicin anf tobramycin inhibit of Ach release by competitive with Ca. D-Calcium channel blocker : increase NMB. 2- depolarizing agents : These works by depolarizing of plasma membrane of muscle fiber similar to Ach. However these agent more resistance to degradation by AchE. Succinylcholine only depolarizing muscle relaxant in use today. Duration of action of Succinylcholine dependent on diffusion from motor endplate and Hydrolysis by pseudocholinesterase. Genetic variation in pseudocholinesterase level affect on duration of action of Succinylcholine when level is low or absent lead tp prolonged NMparalysis. Machanism of action : 1-phase (1): Opening Na channel resulting depolarization (twitching muscle fasciculation). 2-phase (2) Resistance to depolarizing by proloned depolarized lead to close or blocked Na channel. ***action s: Like Nondepolarizing agent it paralysis respiratory muscle lastly. Succinylcholine intially produce muscle fasciculation that cause muscle soreness (pain) this can be prevented by adimistered of Nondepolarizing agent before Succinylcholine. Succinylcholine has short duration of action due to Hydrolysis by pseudocholinesterase and not metabolized by Ach E. **Therapeutic uses: Due to it rapid action it use in rapid endotreacheal intubation during induction of anesthesia. It also used during electroconvulsive shoch treatment. **Pharmacokinetic : Succinylcholine is injected IV. It short duration of action result of redistribution and rapid Hydrolysis by plasma pseudocholinesterase so to maintance longer duration of action giving by continous infusion. **Adverse effects: 1-malignant hyperthermia. 2-Apnea : Can occur in patients A- has low or absent pseudocholinesterase lead prolonged durations of action. B-Rapid release of K with electrolytes imbalance. C-pateint receiving digoxin or diuretic. 3- hyper kalemia : Succinylcholine increases release of K particularly in burn patient and patient with massive tissue damage.