Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
NMDA receptor wikipedia , lookup
5-HT2C receptor agonist wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
Toxicodynamics wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
Cholinoceptor activating drugs M.R. Zarrindast Cholinergic Receptors: Where are they? 1. Postganglionic parasympathetic neuroeffector junctions 2. All autonomic ganglia 3. At the neuromuscular endplate Cholinergic Receptors: Types 1. Muscarinic receptors 2. Nicotinic receptors Based on selective activation and antagonism. Subtypes and characteristic of cholinoceptors Receptor Other Type Names M 1a M1 M2 Location Nerves Structual Features Postreceptor Mechanism Seven IP3,DAG transmembrane cascade segments, G proteinlinked M 2a, Heart,nerves, Seven Inhibition of Cardiac transmembrane cAMP smooth M2 segments,G production, muscle protein-linked activation of K+ channels Receptor Type M3 m41 Other Names Location Structual Features Postreceptor Mechanism M2b, Glands, Seven IP3 , DAG transmemb cascade glandular M2 smooth rane muscle, segments, endotheli G proteinum linked ?CNS Seven Inhibition transmemb of cAMP rane production segments, G proteinlinked Receptor Type m51 NM Other Names Location ?CNS Structual Features Postreceptor Mechanism Seven IP3 , DAG transmem cascade brane segments, G proteinlinked Muscle Skeletal Pentamer NA+, K+ type, end muscle ( α2βδγ)2 depolarizing plate neuromuscular ion channel receptor junction Recep tor Type NN Other Names Location Neuronal Postganglionic type, cell body, ganglion dendrite receptor Structual Features Postreceptor Mechanism α and β subunits only as α2β2 or α3β3 NA+, K+ depolarizing ion channel Muscarinic receptors (Stimulated by muscarine) • on cells innervated by PNS – smooth muscle – heart – exocrine glands • endothelial cells of the vascular beds (even though these are not innervated) • brain Nicotinic receptors (Stimulated by nicotine) • autonomic ganglia - CNS & PNS • neuromuscular junction (somatic nerves) • brain – esp. the spinal cord The major groups of cholinoceptoractivating drugs Cholinoceptor stimulants Direct-acting (receptor agonists) Muscarinic Indirect-acting (cholinesterase inhibitors) Nicotinic Choline esters Ganglionic Alkaloids Neuromuscular Cholinergic agonists • Two (2) types – Direct – • occupy and activate receptors – Indirect • inhibit acetylcholinesterase • levels of Ach increase • Ach stimulates receptors Esters of Choline O CH H C - C - O - CH - CH - N CH Ac e t y l c ho l i ne CH O CH H C - C - O - CH - CH - N CH Me t h a c h o l i n e CH CH CH H N - C - O - CH - CH - N CH CH CH Be t h a n e c h o l Esters of Choline • hydrophilic • differ in breakdown by Ach’esterase – acetylcholine - very susceptable – methacholine - 3X less susceptible – bethanechol - not susceptible • methacholine & bethanechol – longer duration of action than Ach – mostly activate muscarinic receptors Direct • Esters of choline – mostly activate muscarinic receptors – methacholine – bethanechol • Alkaloids – activate both muscarinic and nicotinic receptors – pilocarpine – nicotine Properties of choline esters Choline Ester Acetylcholine chloride Methacholine chloride Carbachol chloride Bethanechol chloride Susceptibility to Muscarinic Cholinesterase Action Nicotinic Action ++++ +++ +++ + ++++ None Negligible ++ +++ Negligible ++ None Alkaloids (pilocarpine and nicotine) • Highly lipid soluble – well absorbed from GI tract – get into brain • Capable of both muscarinic and nicotinic receptor activation Nicotinic to depolarizing blockade receptors are susceptible • depolarizes ganglion cell or neuromuscular endplate • if present in high concentration, they produce a “depolarizing block” – neuron or endplate stays depolarized – skeletal muscle relaxation – ganglia of both PNS & SNS systems may be paralyzed Effects of Muscarinic Agonists • Eye • Cardiovascular system – Heart – Blood vessels • Respiratory tract • Gastrointestinal tract Effect of direct-acting cholinoceptor stimulants Organ •Eye Sphincter muscle of iris Ciliary muscle •Lung Bronchial muscle Bronchial glands Response Contraction (miosis) Contraction for near vision Contraction (bronchoconstriction) Stimulation Organ •Heart Sinoatrial node Atria Atrioventricular node Ventricles Response Decrease in rate (negative chronotropy) Decrease in contractile strength (negative ionotropy),Decrease in refractory period Decrease in conduction velocity, Increase in refractory period Small decrease in contractile strength Organ •Blood vessels Arteries Veins •Urinary bladder Detrusor Trigone and sphincter Response Dilation (via EDRF), Constriction (high-dose effect) Dilation (via EDRF), Constriction (high-dose effect) Contraction Relaxation Organ •Gastrointestinal tract Motility Sphincters Secretion •Glands Sweat, salivary, lacrimal, nasopharyngeal Response Increase Relaxation Stimulation Secretion Eye • pupillary sphincter muscle contraction (miosis) • ciliary muscle contraction – opens drainage canals in anterior chamber – lowers intraocular pressure – lens thickens for near vision CV Effects • Direct effects on heart – decreased SA and AV conduction velocity – decreased force of atrial contraction • Reduced vascular resistance – – activation of receptors on endothelium – generation of nitric oxide (NO) – NO causes vascular muscle relaxation • Effects on BP modified by reflexes Cardiac Conduction - Ach • Increased K+ conduction – slows conduction – SA node – AV node • Decreased inward Ca++ current – reduces force of contraction • Slowed pacemaker rate opposed by reflexes • Ventricles are less directly affected (parasympathetic innervation of ventricles much less than atria) Respiratory Effects • bronchial smooth muscle contraction • respiratory gland secretion • asthmatics highly sensitive GI Effects • Increased secretion – gastric glands – salivary glands • Increased motility - diarrhea Cholinergic receptors in the brain • Brain has muscarinic receptors – Esters don’t penetrate – Alkaloids penetrate well • Brainstem and spinal cord contain nicotinic receptors – Mild alerting from smoking – Seizures in overdose Nicotine • Complex effects on receptors – Agonist effects • brain nicotinic receptors • ganglionic nicotinic receptors – turns on both PNS and SNS • neuromuscular nicotinic receptors – only in overdose – Blockade - may produce a “depolarizing block” of nicotinic receptors in high doses Nicotine • Organ effects – Determined by predominate branch of the autonomic nervous system in that organ – CV effects - largely sympathetic • Increased HR, SV, CO • Vasoconstriction of vascular beds – GI & Urinary - largely parasympathetic • Chronic toxicity is the most serious from a societal point of view Indirect-Acting Agents • inhibit Ach’esterase • buildup of Ach at ganglia, neuroeffector and neuromuscular junctions • amplify effects of endogenous Ach • chief use: insecticides Acetylcholinesterase Inhibitors 1. simple alcohols (edrophonium) 2. carbamic acid esters (neostigmine) 3. organophosphates (isoflurophate) Enzyme Binding • simple alcohols - bind to enzyme reversibly (edrophonium) • carbamates - bond with Ach’ase more long-lasting e.g. 30 mins • organophosphates - bond irreversibly; very long acting Duration of Action of Cholinesterase Inhibitors • Determined mostly by length of binding to enzyme –simple alcohols - short –carbamates - intermediate –organophosphates - very long Therapeutic uses and durations of action of cholinesterase inhibitors Uses •Alcohols Edrophonium •Organophosphates Echothiophate Approximate duration of action Myasthenia gravis, ileus, arrhythmias 5-15 minutes Glaucoma 100 hours Uses •Carbamates and related agents Neostigmine Approximate duration of action Myesthenia gravis, ileus Pyridostigmine Myesthenia gravis 0.5-2 hours Physostigmine Glaucoma 0.5-2 hours Ambenonium Demacarium Myesthenia gravis Glaucoma 3-6 hours 4-8 hours 4-6 hours Edrophonium (Tensilon) • Short acting alcohol type • Uses – Diagnosis of myasthenia gravis* • Muscle strength tested after administration • Marked improvement is a positive test – Adequacy of treatment *Look up the pathogenesis of myasthenia gravis Edrophonium (Tensilon) – Test adequacy of treatment with longer acting agents (e.g. pyridostigmine) • Improvement means dose of long acting agent too low • No improvement or worsening indicates “depolarizing block” by longacting agent. Lower dose indicated. Organophosphates • phosphorylates Ach’esterase enzyme • covalent phosphorus-enzyme bond strong • After time the bond “ages” or gets stronger • enzyme may be rejuvenated with pralidoxime, esp. before “aging” Signs and symptoms of organophosphate poisoning Muscarinic manifestations •Bronchoconstriction •Increased bronchial secretions •Sweating •Salivation, Lacrimation •Bradycardia •Hypotention •Miosis, Blurring of vision •Urinary incontinenc Nicotinic manifestations •Muscular fasciculation •Tachycardia •Hypertension CNS manifestations •Restlessness •Insomnia •Tremors, Ataxia •Confusion •Convulsions •Respiratory depression •Circulatory collapse Some Insecticides • Organophosphates – chlorpyrifos (Dursban) – malathion – diazinon • Carbamate – Carbaryl (Sevin) Cholinesterase Inhibitors • CNS - may cause convulsions • GI, respiratory, urinary – stimulatory, like direct-acting agents Cholinesterase Inhibitors • Cardiovascular – both sympathetic & parasympathetic stimulation – parasympathetic predominate – bradycardia, decreased CO, modest fall in BP Cholinesterase Inhibitors • Skeletal muscle – therapeutic doses • moderately prolong Ach • intensify Ach actions – toxic doses • fibrillation of muscle fibers • depolarizing blockade and muscle paralysis Clinical Uses of Cholinergic Agonists • Glaucoma – physostigmine once used • GI and urinary stimulation bethanechol • myasthenia gravis – edrophonium for diagnosis or testing – pyridostigmine for treatment SLUDGE: Toxicity • • • • • Salivation Lacrimation Urination Defecation Gastric Emptying Cholinesterase Inhibitor Toxicity • approximately 100 organophosphates & 20 carbamate insecticides available • SLUDGE • convulsions in bad toxicities • depolarizating nmj blockade Cholinergic Blockers More selective than agonists; may block muscarinic or nicotinic receptors selectively M.R. Zarrindast Cholinergic Blockers • muscarinic blockers - very useful in medicine • ganglionic blockers - not used much • neuromuscular blockers - used for skeletal muscle relaxation in surgery Antimuscarinic Drugs • alkaloids – naturally occurring – atropine – scopolamine • tertiary amines – dicyclomine – benztropine • quaternary amines - ipratropium Antimuscarinic Drugs • tertiary amines & alkaloids – lipid soluble – good absorption from mucous membranes and skin – penetration into brain – wide distribution e.g. brain & periphery – highly selective for muscarinic receptor • quaternary amines - opposite of above Antimuscarinic drugs used in gastrointestinal and genitourinary conditions Drug •Quaternary amines Anisotropine Clidinium Glycopyrrolate Isopropamide Mepenzolate Mthantheline Methscopolamine Oxyphenonium Propantheline Usual Dosage 50 mg tid 2.5 mg tid-qid 1 mg bid-tid 5 mg bid 25-50 mg qid 50-100 mg qid 2.5 mg qid 5-10 mg qid 15 mg qid Antimuscarinic drugs used in gastrointestinal and genitourinary conditions Drug •Tertiary amines Atropine Dicyclomine Oxybutynin Oxyphencyclimin Propiverine Scopolamine Tolterodine Tridihexethyl Usual Dosage 0.4 mg tid-qid 10-20 mg qid 5 mg tid 10 mg bid 15 mg bid-tid 0.4 mg tid 2 mg bid 25-50 mg tid-qid Antimuscarinic drugs used in ophtalmology Drug Duration of Effects (days) 7-10 Usual Concentration (%) 0.5-1 Scopolamine 3-7 0.25 Homatropine 1-3 2-5 1 0.5-2 0.25 0.5-1 Atropine Cyclopentolate Tropicamide Atropine & Scopolamine • plant origin – atropine - Atropa belladonna – scopolamine - Hyoscyamus niger • well absorbed from mucous membranes or skin • competes with Ach for muscarinic receptors • organs differ in sensitivity to these drugs Atropine • most sensitive – salivary glands – bronchial glands – sweat glands • intermediate sensitivity - heart tissues • least sensitive - parietal cells • highly selective for muscarinic receptors Atropine - CNS • sedation in therapeutic doses • hallucinations in toxic doses • bradycardia when given parenterally • antimotion sickness effects • antiparkinsonism effects Atropine - Eye • relaxes pupillary sphincter muscle – unopposed sympathetic effects – mydriasis or dilation • paralysis of the ciliary muscle cycloplegia • reduction in lacrimal secretion - dry eye Atropine Heart & Cardiovascular System • initial bradycardia - central effect (?) • tachycardia due to blockade of vagal slowing – Opposes ach effects on SA depolarization – Opposes ach effects on AV conduction • ventricles are less affected • overall - little affect on BP Atropine • respiratory tract – some bronchodilation – reduction of respiratory secretions – a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma • genitourinary tract - ureter and bladder relaxation • sweat glands - suppressed by atropine Atropine • dry mouth • slight, if any, decrease in gastric secretion • GI motility decreased – decreased gastric emptying – constipation Anticholinergics: Contraindications • Glaucoma • Urinary retention esp. in patients with Begnin prostatic hypertrophic Atropine Poisoning • • • • dry as a bone blind as a bat red as a beet very dangerous in children hyperpyrexia Therapeutic Uses • antiparkinsonism effects • motion sickness - scopolamine given via transdermal patch • eye examinations - usually something short-acting (e.g. phenylephrine) is used rather than atropine • asthma - ipatropium aerosol • insecticide poisoning Ganglionic Blockers block the action of Ach and similar agonists at nicotinic receptors at both sympathetic and parasympathetic ganglia Ganglionic Blockers • lack of selectivity • almost completely abandoned for clinical use • used for short-term reduction of BP • agents – mecamylamine – only one available in the US – trimethaphan Ganglionic Blockers • trimethaphan is devoid of CNS effects • mecamylamine is not – sedation, tremor, choreiform movements • eye – cycloplegia – pupil variously affected • BP decreased - highly orthostatic Neuromuscular Blockers Neuromuscular Blockers • interfere with transmission at the nmj • used as adjuncts to general anesthesia • 2 types – non-depolarizing - typified by tubocurarine – depolarizing - typified by succinylcholine Neuromuscular transmission ach’esterase axon ach receptors nerve terminal muscle muscle End-plate Curare • • • • • South American Indian arrow poison crude material called curare active principle is tubocurarine polar, water soluble prevents access of ach to its receptor (competitive antagonist) • prevents depolarization of end-plate • relaxes skeletal muscles Tubocurarine • • • • limited distribution in the body acts for > 30 mins jaw & eye paralyzed first larger muscle (trunk & limbs) paralyzed second • diaphragm paralyzed last • releases histamine - lowers BP Other Non-depolarizing Agents • • • • • • • Atracurium doxacurium mivacurium pancuronium vecuronium pipecuronium rocuronium Depolarizing type: Succinylcholine • consists of 2 Ach molecules end-to-end • produces a depolarizing block – phase I - depolarizes the end-plate & adjacent muscle – phase II - with continued presence, it desensitizes the end-plate to Ach • metabolized by plasma pseudocholinesterases Succinylcholine • not metabolized at the nmj • plasma cholinesterase determines – concentration that reaches the nmj – duration of action • some people have atypical cholinesterase and can’t metabolize succinylcholine; they over-react to the drug • block lasts only 10 to 15 minutes in normal patients • blockade NOT overcome by Ach or ach’esterase inhibitors Depolarizating Blockers adverse effects • • • • hyperkalemia - not well understood increased intraocular pressure increased intragastric pressure muscle pain - presumably because of the unsynchronized contractions just before paralysis