Cholinergic & Its Antagonist Agents PDF

Cholinergic & its antagonist agents Objectives By end of this lecturewe must know following 1-types of receptor on which cholinergic agents act. 2-Whats are cholinergic &its mimic drugs , their clinical effects ,uses. 3-anticholinesterase agents both reversible & irreversible. 4-cholinergic antagoni...

Cholinergic & its antagonist agents Objectives By end of this lecturewe must know following 1-types of receptor on which cholinergic agents act. 2-Whats are cholinergic &its mimic drugs , their clinical effects ,uses. 3-anticholinesterase agents both reversible & irreversible. 4-cholinergic antagonist agents like a- anti-mucarinic agents b-ganglionic blocker agents c-neuro-muscular blocker agents Cholinergic drugs two type of receptor on which acetylcholine or its mimic agents acts , muscarinic & nicotinic receptors. A-Muscarinic receptor : of high affinity for acetylecholine & muscarine(poisnous in mushroom) & low affinity for nicotine. 5 sub- types of muscarinic receptor found on both autonomic effector organ like heart ,smooth muscle , exocrine gland brain or ganglia of peripheral nervous system M1 M2 M3 M4 M5. all found on neorons , but M1 in addition on parietal cells of stomach , M2 on the heart & smooth muscle , M3 on exocrine gland and smooth muscle. Drug on high conc. its effects extent to involve nicotic receptor. when the MI or M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, which in turn activates phospholipase C.,TI- is leads to the hydrolysis of phoshatidylinositol-(4,5)-bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol (I,4 ,5)-trisphosphate (IPS), which cause an increase in intracellular Ca++. This cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion or contraction , In contrast, activation of the M2 subtype on cardiac muscle stimulates a G protein that inhibits adenylyl cyclase increase K+ conduction that decrease heart rate & contraction force. Pirenzepine (tricyclic anticholinergic drug), selectively inhibits MI in the gastric mucosa , useful in the treatment of gastric and duodenalulcers (there are no clinically important agents that interact with the M4 and M5 receptors). B-Nicotinic receptors: bind acetylcholine & nicotine but show only a weak affinity for muscarine , located in the CNS ,adrenal medulla, autonomic ganglia (block by hexamethonium), and the neuromuscular junction(block by tubocurarine). Direct Acting Cholinergic Agonist Cholinergic agonists mimic the effects of acetylcholine by binding directly to cholinoceptors. These agents are synthetic esters of choline, such as carbachol and bethanechol, or naturally occurring alkaloids such as pilocarpine. All of the direct-acting cholinergic drugs have longer durations of action acetylcholine. A-Acetylcholine : It is a quarternary ammonium compound that cannot penetrate membranes , of no importance because of its multiplicity of actions and its rapid inactivation by acetylcholinesterase. Acetylcholine has both muscarinic and nicotinic activity. Its actions include: 1-decrease in heart rate & cardiac output (like vagal stimulation that regulate heart by releasing of acetylcholine at SN node). 2-decrease in blood pressure (via vasodilation effects insite of no parasympathetic innervation but cholinergic receptors found) , by increase intracellular Ca++(atropine block this receptors). 3-other effects like GIT(↑salivery secretion , intestinal secretion & motility ) , on Rsstimulate bronchial secretion , GUT (↑tone of detrusor urinae muscle) , on eye ↑ciliary muscle contraction for near vision & constriction of pupillae sphincter muscle →miosis. B-Bethanechol :Its srtucturally related to Acetylcholine , but acetate replace by carbamate & choline is methylated , not hydrolyzed by acetylcholinestrase but by other esterases. of strong muscarnic effect & little or no nicotinic action , duration of action 1 hour , act on smooth muscle of GIT & bladder. Their action increase GIT motility & tone , & stimulate the detrusor muscle of bladder while triggone & sphincter relax →urine expulsion. So use to treat atonic bladder(postpartum & postoperative non-obstructive retension).Side effects :sweating , salivation, flushing , decrease blood pressure , nausea , abdominal pain , diarrhea , bronchospasm. C-Carbachol (carbamylcholine) :Its of both muscarinic & nicotinic action , its ester of carbamic acid & a poor substrate fo acetylcholinesterase , of 1 hour action. Its effects on both CIT& CVS because its of ganglion-stimulating activity (1st stimulat then depress these system ), on local eye application cause miosis like acetylcholine , its release epinephrine from adrenal nedulla by its nicotinic action.Its use rarely(long duration&high potency) so used in eye only cause constriction of pupil& ↓intraocullar pressure(IOP). D-Pilocarpine :- Its a tertiary amine & stable to hydrolyze by acetylecholinesterase , less potent than acetylcholine , used for eye application only(muscarinic action) cause rapid miosis & not able to focus(spasm of accommodation).its potent stimulant of sexcretion of sweat, tears, saliva but not use for this purpose(nonselective agents ). uses 1-Drug of choice for emergency lowering IOP in both open & close angel glaucoma its effect last for 1 day, 2-to promot salivation in xerostomia(result from head-neck irradiation) & sjogren,s syndrome(lack of tear& dry mouth) treated by oral tablet of pilocarpine.its side effect it enter CNS cause disturbance , its cause sever sweating & salivation. E-Cevimeline other non-specific cholinergic agent like pilocarpine Anticholinesterase(reversible) :Acetylcholinesterase enzyme that cleaves acteylcholine to acetate & choline , locat in pre& post synaptic in terminal nerve. by ithibition of acteylcholinesterase →prolong lifetime of acetylcholine & accumulate in synaptic space troduce a respone at muscarinic & nicotinic receptors(NMJ& Autonomic NS). Alzheimer is treated by acetylcholinesterase inhibitors. A-Physostigmine :- Is an alkaloid (a nitrogenous compound found in plants) and a tertiary amine. It is a substrate for acetylcholinesterase, and forms a relatively stable enzymesubstrate intermediate that reversibly inactivates acetylcholinesterase , result in potentiation of cholinergic activity through-out the body.its duration of action 2-4 hours , enter & stimulate CNS , its of wide range of action ( stimulate muscarinic & nicotinic receptors(NMJ& Autonomic NS ). Uses: 1-its increases intestinal and bladder motility, which serve as its therapeutic action in atony of either organ. 2-Placed topically in the eye, it produces miosis and spasmof accommodation and a lowering IOP. It is used to treat glaucoma, but pilocarpine is more effective.3-also used in the treatment of overdoses of drugs with anticholinergic action like atropine, phenothiazine & tricyclic antidepressant. side effects ;-1- convulsion in eye using on high dose ,2-bradycardia ,3- paralysis of skeletal muscle (all rare at therapeutic dose ). B- Neostigmine its a synthetic compound that reversibly inhibits acetylcholinesterasea as does physostigmine, not enter CNS sice it more polar , their effect on skeletal muscle more than of physostigmine(stimulate contraction before paralysis) ,2-4 hours their duration of action , 1-used to stimulate the bladder& GIT plus as antidote for tubocurarine & other NM blocking agents(competitive) , 2- treatment of myasthenia gravis (autoimmune disease caused by antibodt to nicotinic receptor that bind to the acetylcholine receptors of neuromuscular junctions. This causes their degradation, and thus makes fewer receptors available for interaction with the neurotransmitter. Adverse effects (salivation,flushing,↓BP,abdominal pain,nausea,diarrhea bronchos-pasm). C. Pyridostigmine & ambenomium : used as chronic management of myasthenia gravis. Its duration of action (3-6 hours) & (4-8 hours) respectively. D-Edrophonium Its action like neostigmine , but of rapid absorbed& short duration of action (10-20 minutes). Edrophonium is a quarternary amine and is used in the diagnosis of myasthenia gravis. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. Care must be taken since excess drug may provoke a cholinergic crisis. Atropine is the antidote, E-Demecarium ;Its a quaternary amine structuraly related to neostigmine like its action& side effects , used for 1-trea open angle gluacoma(referactory to other drugs) , 2-in closed angel glaucoma after irredectomy , 3- diagnosis & treatment of accommodative esotropia. F-(Tacrine , Donepezil , Rivastigmine , Galantamine) :In alzeheimers disaese ( deficiency of cholinergic neorons in CNS) , tacrine is the 1st one available but replace by other due to its hepatotoxicity , all able to delay the progression of disease but not stop it. GIT distress its side effects. Anticholinesterase (irreversible) A number of synthetic organophosphate compounds have the capacity to bind covalently to acetylcholinesterase(→ long lasting increase in acetylcholine at all sites ). Many of these drugs are extremely toxic and were developed by the military as nerve agents. Related compounds(parathion)are employed as insecticides. Echothiophate 1. Mechanism of action: is an organophosphate covalently binds by its phosphate group to a serine -OH at the active site of acetylcholinesterase.Once this occurs, the enzyme is permanentlv inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules., their action include generalize cholinergic stimulation , paralysis of motor function(→breathing difficulties), convulsion , intense miosis , high atropine dose reverse most of its effects. their uses 1- chronic treatment of open angle glaucoma as solution(effects last for 1 week after single use) its side effects& causing catracts limit its uses. Reactivation of acetylcholinesterase(pralidoxime) :- Its able to reactivate the enzyme if used at time before aging of acetylcholinesterase(before loss its alkyl group) , not cross intoCNS , act by displace phosphate group from organophosphate & regenerate the enzyme. side effects like acetylcholinesterase inhibitors as high dose. Cholinergic antagonist agents :- Also called parasympatholytic or anticholinergic or cholinergic blockers or cholinergic antagonist.Anti-muscarinis agents :- selectively bind muscarinic receptor&block it. Ganglionic blockers show prefernce for nicotinic receptors in both sympathatic & parasympathatic ganglia (least important of anticholinergic agents). Neuromuscular blocker agents interfere with impulse transmission to skeletal muscle ,used in anesthesia during surgery. l-Anti-muscarinic agents :Like atropine & scopolamine block muscarinic receptors causing inhibition of all muscarinic function plus block few of sympathatic neuron that innervate salivary & sweat glands with little or no action on Nmjunction or ganglia. A-Atropine :- Its tertiary amine belladonna alkaloid , compete with acetylcholine for muscarinic receptors acts centrally & peripherally , its duration of action 4 hours on local eye application may last for 1 day. Orally absorbed , t1/2 4 hours , eliminate via urine. Action :-1- on eye :-persistance mydriasis(dilate pupil), unresponsiveness to light & cycloplegia(inable to focus for near vision ) , dangerous elevation of IOP , so short acting agent like tropicamide or alpha adrenergic like phenylphrine used for ophthalmic examination. 2-GIT:-as antispasmolytic to reduce GIT activity , not affecting HcL production.3-GUT :-reduce hypermotility of urinary bladder (rare use in enuresis instate). 4-CVS:-at low dose cause bradycardia(central activation of vagal efferent outflow block M1), atr high dose cause tachycardia(block M2 in SA node ).5-Secretion:-decrease salivation sweat & lacrima glands. Uses :- for eye to measure refractive errors(induce mydriasis& cycloplegia). relax both GIT & bladder , antidote for cholinergic agonist poisening , as antisecretary to reduce block secretion fromupper & lower RS prior surgery. Side effects (dry mouth ,blurred vision ,tachycardia ,constipation , on CNS delirium, hallucination that end with depression , collapse respiratory system & death , increase body temperature especially in childern) , its over dose treated by physostigmine. B-Scopolamine Its a tertiary amine belladonna derived , of peripheral effects like atropine , of high action on CNS than atropine. Action :-most effective antimotion sickness agent sedation but at high dose excitment , induce euphoria(subject for abuse). Uses : motion sickness ,& amnesic action so use in anesthesia. C-Ipratropium :Inhaled ipratropium its a quaternary derivative of atropine use to treat asthma & chronic obstructive pulmonary disease , its +ve charge prevent its entery to circulation & CNS. D-Tropicamide & Cyclopentolate :Use as eye solution to induce mydriasis & cyclopegia as atropine , its duration 6 & 24 hours respectively while atropine 7-14 days. ll-Ganglionic blocker :A-Nicotine : its a compenent of cigarette , of no therapeutic benefit , it deleteriuos for health, available as patches, lozenges, gums & other form , patches absorbed via skin & reduce the craving for nicotine (for person wish stop cigarette).Its cause depolarize autonomic ganglia (1st stimulate then paralyse all ganglia) stimulation by effect on both para & sympathatic causing increase blood pressure , heart rate , secretion & persistalsis , on high dose BP fall(ganglionic blockade) & activity on GIT & bladder cease. B-Mecaylamine :-its a competitive nicotine recepto blockade , its duration of action 10 hours after single dose , good orally absorbed , used in treatment of emergency hypertension. lll-Neuro-Muscular Blocker agents: its block trasmission of cholinergic between motor nerve ending & the nicotinic receptor on the neuromuscular end plate of skeletal muscle ,they are structurally analogs of acetylcholine , its divided into depolarizing(acetylcholine agonist )& non-depolarizing (acetylcholine antagonists) agents , its useful 1- during surgery to produce complete muscle relaxation ,2- facilitating intubation. Other central muscle relaxant like diazepam(bindGABA receptor) , baclofen act at GABA receptor in CNS , dantrolene(interferwith calicium release from sacroplasmic reticulum). Depolarizing agent like succinylcholine Use as IV but of short duration of action so used as continuous infusion , unlike to acetylcholine its persist for long time in the synaptic cleft(time depend on diffusion from motor end plate & hydrolysis by plasma cholinesterase) within synaptic cleft not metbolise by cholinesterase till diffuse to circulation. Mode of action :-attach to nicotinic receptor & depolarize the junction , 1st open Na channel →depolarize of the receptor (phase l) →transient musle fasciculation ,then within few minutes , on contiue attachment to receptor make receptor incapable to transmit further impulses , continous depolarizing give way to gradual repolarization as Na channel closed or block this cause resistance to depolarization(phase ll) & flaccid paralysis. Uses:1-endotracheal intubation(anesthesia induction),2- electoconvulsive shock treatment. Side effects: 1- apnea , 2-hyperthermia , 3-hyperkalemia. Non-depolarizing (competive) blockers :1st agent is curare , while tubocurarine consider as prototype of this group , replace by other due to their side effects(lowering BP & cause histamine release promote ganglionic blockade ) , its ↑ safety of anesthetic agent since it ↓amount of anesthesia to induce muscle relaxant & recover patient quickly after surgery (high anesthesia dose cause respiratory paralysis , cardiac depression & prolong recover time ). Mode of action :-at low dose ; its interact with nicotinic receptor so prevent acetylcholine bind , so prevent muscle depoloarization& inhibit muscle contraction (so called competitive blockers ). Its effects over come by either ↑conc. of acetylcholine in the synaptic cleft or by adminstration of chloinesterase inhibitors like()neostigmine , pyridostigmine or edrophonium)→short the duration of NM blocker. But at high conc. it can block ion channel of the end plate→ further weakening of NM trasmission &↓ ability of acetylcholinesterase inhibitors to reverse the action of nondepolarizing muscle relaxant. =1st muscle paralyzed is muscle of[ eye & face → fingers→limbs→neck→trunk→intercostal →diaphram]. Some agents release histaminelike()tubocurarine, mivacurium , atracurium)→ BP↓, flushing & bronchconstriction. Uses :-in anesthesia during surgery to relax skeletal muscle , facilitate intubation & in othropedic surgery. Kinetics :-used as IV , not used orally due to(1- their absorption minimal , 2- they possess 23 quaternary amine in their srtucture make them orally ineffective). Most of them excrete unchange in urine like(tubocurarine ,metocurine, mivacurium, pancuronium , doxacurium) ,while atracurium degreded spontaneously in plasm then ester hydrolysis , its release histamine & metabolite into laudanosine →provoke seizures so it replace by its isomer cisatracurium less likely cause these , (rocuronium& vecuronium) both are aminosteroid drug that deacetylated in liver (liver disease may prolong their clearance). Drugs interaction:-1-aminoglycoside antibiotics like getamycin & tobramycin (↓acetylcholine release) so ↑ blockade.2-Ca++ channel blocker ↑ blockade NM blockers.3halogenated hydrocarbon anesthetics like halothane sensitize NM junction for action of NM blocker(enhance blockade). 4- cholinesterase inhibitors , overcome the action of nondepolarizing NM blockers.