Clostridium botulinum Botulinum toxin Direct Cholinomimetics Muscarine Amanita muscaria To identify the mechanism of action of direct acting acetylcholine receptor stimulants Direct Cholinomimetics ID: 1043573
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1. What is botox?A toxin produced by Clostridium botulinumBotulinum toxinDirect CholinomimeticsMuscarineAmanita muscaria
2. To identify the mechanism of action of direct acting acetylcholine receptor stimulantsDirect CholinomimeticsTo discuss the pharmacokinetic aspects and pharmacodynamic effects of direct cholinomimeticsTo outline the therapeutic uses and toxicity of direct cholinergic agonistsILOS
3. Direct Cholinergic AgonistsClassification of cholinergic agonists
4. acetylcholine , methacholine, carbachol, bethanecholTertiary cholinomimeticsProduce primarily effect by activation of muscarinic or nicotinic receptorsDirect Cholinergic AgonistsQuaternary grouppilocarpine, nicotine , lobelineClassification according to chemical structure
5. PharmacokineticsMethacholine is 3 times more resistant to hydrolysisAch is very sensitive to hydrolysis by cholinesterases Hydrolyzed in the GIT , not active by the oral routePoorly absorbed poorly distributed in the CNSAcetylcholine low lipid- solubilityCarbachol & bethanechol are completely resistant to hydrolysis
6. Excretion by kidney, clearance of tertiary amines can be enhanced by acidification of urineMuscarinic quaternary amines , less completely absorbed from the GIT but still toxic when ingested in mushroom.Nicotine, lipid –soluble, absorbed across the skin.Tertiary cholinomimetics are well absorbed from most sites of administrationPresence of a methyl group on bethanechol reduces its potency at nicotinic junction.Pharmacokinetics
7. Direct Cholinergic AgonistsThe parasympathetic innervates the constrictor pupillae , runs cirumferentially in the iris1-EyePharmacodynamic effectsDirect Cholinergic AgonistsDirect Cholinergic AgonistsConstrictor pupillae is important for adjusting the pupil in response to change in light intensity & regulating the intraocular pressure
8. Contraction of ciliary muscle pulls the ciliary body forward & inward , relaxing the tension on the suspensory ligaments of the lens1-EyePharmacodynamic effectsParasympathetic activation contracts the ciliary muscle
9. When the ciliary muscle contracts, the lens bulge more focal length, this parasympathetic reflex is essential to accommodate for near vision1-EyePharmacodynamic effects
10. In some people drainage of aqueous humour is impeded when the iris is dilated folding of the iris tissue occludes the drainage angle intraocular pressurePharmacodynamic effectsAqueous humour secreted by the cells of the epithelium covering the ciliary body , is removed continuously by drainage into the canal of Schlemm
11. Also tension in the ciliary body allow drainageActivation of constrictor pupillae intraocular pressure in these individualsNormal intraocular pressure is 10-15mmHg above atmospheric pressure . Abnormally raised pressure retinal detachmentPharmacodynamic effects
12. Pharmacodynamic effectsBP: Hypotension is opposed by reflex sympathetic dischargeVasodilation occurs , effect not associted with muscarinic innervationsVentricle has sparse parasympathetic innervationsCardiac slowing , COforce of contraction of the atrium2-Cardiovascular effect
13. Glandular secretion, may cause symptoms in individuals with asthmaMuscarinic stimulants contract smooth muscles of bronchial tree3-Respiratory systemPharmacodynamic effects
14. Sphincters relaxed.Peristaltic movementSecretion of gastric glands4-GIT:-Pharmacodynamic effects
15. Pharmacodynamic effectsStimulate secretion of sweat , lacrimal, nasopharyngeal glands6-Miscellaneous secretory glands:-Human uterus is not sensitive to muscarinic agonistsStimulate muscles of bladder & relax sphincters promoting voiding5-Genitourinary tract:-
16. High level of nicotine convulsions & comaPharmacodynamic effects7-CNS:-Nicotine & lobeline alerting actionBoth muscarinic & nicotinic receptors are found in the CNS
17. Clinical UsesB- Open angleA- Angle closurecaused by trauma, inflammation, surgical procedures2- Secondary1- PrimaryGlaucoma1-The Eye
18. Clinical UsesSurgery for permanent correction [irridectomy] Medical emergency , initially treated by drugsAcute angle closuree.g. Direct stimulants2-rate of its secretionMuscarinic stimulants intraocular pressure by:-Methacholine, carbachol,pilocarpine1-facilitating outflow of aqueous humor
19. Direct Cholinergic AgonistsBethanecholB-Postoperative urinary retentionA-Postoperative ileus “atony or paralysis of the stomach following surgery2-GIT & Urinary tractClinical UsesC-Xerostomia → Pilocarpine
20. Sjogren's SyndromeCevimeline is a direct muscarinic agonist with particular effect on M3 receptors. Sjogren's Syndrome is an autoimmune disease. characterized by the abnormal production of antibodies directed to the lacrimal and salivary glands→ eye and mouth dryness.Rapidly absorbed after oral administration and excreted unchanged in urine By activating the M3 receptors cevimeline stimulates secretion by the salivary & lacrimal glands thereby alleviating dry mouth & dry eye
21. Toxicity2-Skeletal muscle endplate depolarization depolarization block & respiratory paralysis1- CNS stimulant action, convulsions , coma , respiratory arrest I] Acute toxicityB-Directly- acting nicotinic stimulants:-A-Directly- acting muscarinic stimulants:- nausea, vomiting ,diarrhoea, salivation, cutaneous vasodilatation, bronchial constriction3-Hypertension & cardiac arrhythmiasDUMBELS
22. ToxicityNeuromuscular block mechanical respirationCNS stimulation central anticonvulsants e.g. diazepamMuscarinic excess atropineTreatment of symptoms:-
23. Nicotine contributes to risk of vascular diseases, sudden coronary death, ulcer30% of deaths due to cancer & coronary heart disease are due to smokingii-Chronic nicotinic toxicityNo. cigarettes / day
24. Pharmacological actionsLocationsReceptorCNS excitationGastric acid secretionCNS gastric parietal cellsM1 ExcitatoryCardiac inhibition(Bradycardia)Heart M2 Inhibitory Secretion of glands Smooth muscle contraction Vasodilatation (via nitric oxide)Exocrine glandsSmooth muscles (GIT, urinary tract, bronchial muscles) Vascular endotheliumM3Excitatorymemory, arousal, attention and analgesiaCNSM4 & M5Muscarinic receptors
25. Muscarinic receptorsPeripheral cholinoceptorsNicotinic receptorsCentral cholinoceptorsExcitatory or inhibitoryAlmost excitatoryOn all peripheral organs innervated by postganglionic parasympathetic fibersAutonomic ganglia Nn sympathetic & parasympathetic stimulation Heart (bradycardia, M2) exocrine glands (secretion, M3)Adrenal medulla Nn release of catecholamines (adrenaline & noradrenaline)Smooth muscles (contraction, M3)(GIT, urinary tract, bronchial muscles, uterus)Skeletal muscles NmcontractionCholinergic or parasympathetic receptors
26. Muscarinic actions of AchCholinergic actionsOrgansContraction of circular muscle of iris (miosis)(M3)Contraction of ciliary muscles for near vision (M3)Decrease in intraocular pressure (IOP)Eyebradycardia ( decrease in heart rate ) (M2)Release of NO (EDRF) HeartendotheliumConstriction of bronchial smooth musclesIncrease in bronchial secretion M3LungIncrease in motility (peristalsis)Increase in secretionRelaxation of sphincter -defecation M3 GITContraction of muscles Relaxation of sphincter M3 UrinationUrinary bladderIncrease of secretions of exocrine glandssweat, saliva, lacrimal, bronchial, intestinal secretions M3Exocrine glands
27. PilocarpineBethanechol CarbacholACh Tertiarynon polarQuaternary PolarQuaternary Polar Quaternary PolarChemistry Completebetter absorbed than Ach better absorbed than AchNOTAbsorption NOT metabolized by cholinesterasemetabolized by cholinesteraseMetabolismby cholinesteraseLonger (++)Longer (++)Longer (++)Very shortDuration oral, eye drops Oral S.C. Oral, eye dropsS.C.I.V.eye dropsadministration
28. Cevimeline M PilocarpineBethanecholMCarbacholM,NAChM, NMuscarinicMuscarinicMuscarinicMuscarinicNicotinic MuscarinicNicotinicReceptors++++++ +++ ++++++MuscarinicExocrine glandsMore on eye, exocrine glands GIT, Urinary bladderEye, GITUrinary bladderNOTSelectivityNONO NO ++++++NicotinicSjogren's syndromeGlaucomaXerostomiaParalytic ileus Urinary retentionGlaucomaNOUsesdirect Cholinomimetic