OverviewIndirect cholinergic agonistsMechanisms of indirect agonismAchE Inhibitors (quaternary alcohols and carbamates)OrganophosphatesAgingOrgan effects/therapeutic usesTreatment of organophosphate poisoningMuscarinic antagonismMuscarinic AntagonistsSlide 11Mechanism of drug actionHistory/sourcesSlide 14Effect of muscarinic inhibition in the heart and salivary glandsGraphic summary of atropine effectsOrgan effect – drug review AntidotesToxicity of muscarinic antagonistsNicotinic – Acetylcholine ReceptorSignaling through Ach-nicotinic receptor (competitive and depolarizing blockers)Competitive/depolarizingExamples of competitive/depolarizing drugsClinical usesAgents/Features/DurationPrecautions/ToxicitySummaryMovieOverview•- Indirect cholinergic agonism (AchE inhibition)•- Muscarinic antagonism (emphasis on drugs and organ effects)•- Nicotine-Ach receptor (emphasis on drugs and therapeutics)Indirect cholinergic agonistsInhibitors of acetylcholinesterase-Increase acetylcholine concentration and lifetime by inhibiting degradation-Act by binding to AchE active site causing reversible(non covalent) or long lasting (covalent modification)Mechanisms of indirect agonism- Quaternary alcohols (ephodronium) – reversible binding (limit acetylcholine access)Non covalent – enzyme-inhibitor complex lifetime (2 - 10 minutes)-Carbamate esters – neostigmine, physostigmine – reaction with AchE active siteCovalent carbamoylation – enzyme-inhibitor complex lifetime (0.5 - 6h) -Organophosphates – Parathion, Sarin, Soman - phophorylates AchE active siteCovalent phosphorylation – very stable enzyme-inhibitor complex, days (especially after aging)AchE Inhibitors (quaternary alcohols and carbamates)OrganophosphatesAgingOrgan effects/therapeutic uses•- Effects are due to acetylcholine accumulation and are both sympathetic and parasympatheticUSES Approx DurationALCOHOLSEdrophonium Myasthenia gravis 5 – 15 minutesarrythmiasCARBAMATESNeostigmine Myasthenia gravis 0.5 – 2hPyridostigmine Myasthenia gravis 3 – 6hPhysostigmine Glaucoma 0.5 – 2hDemecarium Glaucoma 4 – 6hOrganophosphatesEchotiophate Glaucoma 100 h (> 4 days)Treatment of organophosphate poisoning•1 - maintenance of vital signs (respiration particularly important)•2 - Decontamination (to avoid further absorption)•3 - Atropine parenterally (to minimize muscarinic effects) as required •4 - Rescue of AchE activity with Hydroxylamines (Pralidoxime, Diacetylmonoxime)Muscarinic antagonismAttropa belladonaMuscarinic AntagonistsATROPINESCOPOLAMINEMuscarinic AntagonistsATROPINESCOPOLAMINEAttropa belladona- Atropine and Scopolamine are belladona alkaloids (competitive inhibitors)-Drugs differ in their CNS effects, scopolamine permeates the blood-brain barrier-At therapeutic doses atropine has negligible effects upon the CNS, scopolamine even at low doses has prominent CNS effects.Mechanism of drug action-Competitively block muscarinic receptors- Salivary, bronchial, and sweat glands aremost sensitive to atropine- Smooth muscle and heart are intermediatein responsiveness-In the eye, causes pupil dilation and difficulty for far vision accomodation-Relaxation of the GI, slows peristalsisHistory/sources•Atropa belladona - used in the renaissance•Deadly nightshade - used in the middle ages to produce prolonged poisoningJimson plant leaves burned in India to treat Asthma (1800) purification of atropine (1831)Effect of muscarinic inhibitor in the eyePupil dilation vs accomodationEffect of muscarinic inhibition in the heart and salivary glands- Increases the heart rate after a transient bradychardia at the low dose- Diminishes gland excretory functionGraphic summary of atropine effectsOrgan effect – drug reviewAntidotes•ORGAN DRUG APPLICATIONCNS Benztropine Treat Parkinson’s disease Scopolamine Prevent/Reduce motion sickness Eye Atropine Pupil dilation Bronchi Ipatropium Bronchodilate in Asthma, COPDGI Methscopolamine Reduce motility/crampsGU Oxybutinin Treat transient cystitisPostoperative bladder spasmsToxicity of muscarinic antagonists•“DRY AS BONE, RED AS A BEET, MAD AS HATTER.”•Dry is a consequence of decreased sweating, salivation and lacrimation•Red is a result of reflex peripheral (cutaneous) vasodilation to dissipate heat (hyperthermia) •Mad is a result of the CNS effects of muscarinic inhibition which can lead to sedation, amnesia (hypersensitivity), or hallucinationNicotinic – Acetylcholine Receptor polarizedRelaxation depolarizedcontractionSignaling through Ach-nicotinic receptor(competitive and depolarizing blockers)Competitive/depolarizingCompetitivePhysically blocks Ach bindingINHIBITORDepolarizingBinds and locks the receptoropenExamples of competitive/depolarizing drugsCompetitiveTubocurarineMivacuriumDepolarizingAchEButyrylcholinesteraseSensitive sitesSuccinylcholineClinical uses•Adjuvant use in surgical anesthesia (muscular relaxation)•Advantage – much lighter levels of anesthesia required•Other uses: muscular relaxation for orthopedics (correction of dislocation/alignment of fractures)•(short duration) – facilitate intubation, laryngoscopy, bronchoscopy, esophagoscopy•Control of muscular spasms, strabism, hemifacial spasms, oromandibular and cervical dystonia, spasms of the lower esophageal sphincter•Cosmetic – Bottox (Botulinum toxin A)•Paralytic action on skeletal muscleAgents/Features/Duration•AGENT CLASS PROPERTY ONSET DURATION Succinylcholine Dicholine ester Depolarization 1 min 5 – 8 minTubocurarine Alkaloid Competitive 5 min 80 – 120 minAtracurium Benzylisoquinoline Competitive 3 min 30 – 60 minMivacurium Benzylisoquinoline Competitive 3 min 12 – 18 minPancuronium Ammonio Steroid Competitive 5 min 120 – 180 minVecuronium Ammonio Steroid Competitive 3 min 60 – 90 minHydrolysis by esterasesLiver clearance/renal eliminationBothPrecautions/Toxicity•- Prolonged apnea, cardiovascular collapseSequence of paralysis : Eye muscles, Jaw, Larynx, limbs and trunk, intercostal muscles and the dyaphragm-Generally caused by diminished esterase activity, renal malfunction, liver insufficiency, poor circulatory function.-Special caution in patients with electrolyte imbalance (K+)-Antidote : Neostigmine/Ephodronium to increase Ach, and atropine to block Ach muscarinic stimulation.-Malignant hyperthermia – results from a discharge of
View Full Document
Unlocking...