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  • 1. DR BADAR UDDIN UMAR MBBS, MPhil Senior Lecturer, Pharmacology 1
  • 2.  Classify parasympathetic blockers with suitable examples  Classify antimuscarinic drugs based on their uses with suitable examples  List and describe the pharmacological actions of atropine  Discuss the rationale for using drugs blocking the muscarinic actions of ACh  Discuss the clinical features and drug treatment of atropine poisoning 2
  • 3.  Cholinergic receptors can be divided into two types – • muscarinic and • nicotinic  Muscarinic receptors originally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively
  • 4.  In tissues innervated by postganglionic parasympathetic neurons  In presynaptic noradrenergic and cholinergic nerve terminals  In non-innervated sites in vascular endothelium  In the central nervous system
  • 5.  There are 5 subtypes of muscarinic receptors M1, M2, M3, M4, and M5  They mediate their effects through -  G proteins coupled to -  Phospholipase C (M1,3,5), Potassium channels (M2,4)
  • 6. Muscarinic Acetylcholine ReceptorsMuscarinic Acetylcholine Receptors MM11 MM22 MM33 MM44 MM55 DistributionDistribution Cortex,Cortex, hippocampushippocampus HeartHeart ExocrineExocrine glands, GIglands, GI tracttract NeostriatumNeostriatum SubstantiaSubstantia nigranigra AntagonistsAntagonists AtropineAtropine DicycloverineDicycloverine TolterodineTolterodine OxybutyninOxybutynin IpratropiumIpratropium PirenzepinePirenzepine Mamba toxinMamba toxin MT7MT7 AtropineAtropine DicycloverineDicycloverine TolterodineTolterodine OxybutyninOxybutynin IpratropiumIpratropium GallamineGallamine AtropineAtropine DicycloverineDicycloverine TolterodineTolterodine OxybutyninOxybutynin IpratropiumIpratropium DarifenacinDarifenacin AtropineAtropine DicycloverineDicycloverine TolterodineTolterodine OxybutyninOxybutynin IpratropiumIpratropium Mamba toxinMamba toxin MT3MT3 AtropineAtropine DicycloverineDicycloverine TolterodineTolterodine OxybutyninOxybutynin AgonistsAgonists AcetylcholineAcetylcholine Xanomeline,Xanomeline, CDD-0097CDD-0097 AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine G proteinG protein GGααq/11q/11 GGααi/oi/o GGααq/11q/11 GGααi/oi/o GGααq/11q/11 IntracellularIntracellular responseresponse PhospholipasePhospholipase CCββ AdenylylAdenylyl cyclasecyclase inhibitioninhibition PhospholipasePhospholipase CCββ AdenylylAdenylyl cyclasecyclase inhibitioninhibition PhospholipasePhospholipase CCββ
  • 7.  In sympathetic and parasympathetic ganglia  In the adrenal medulla  In the neuromuscular junction of the skeletal muscle  In the central nervous system
  • 8.  There are two subtypes of nicotinic receptors NM and NN  The NM nicotinic receptor mediates skeletal muscle stimulation  The NN nicotinic receptor mediates stimulation of the autonomic ganglia [agonists and antagonists at this site are sometimes called ganglionic agonists and ganglionic blockers]
  • 9.  Nicotinic receptors are ligand - gated ion channels  Their activation results in a rapid increase in cellular permeability to sodium and calcium  nAChRs are directly coupled to cation channels  They mediate fast excitatory synaptic transmission at the neuromuscular junction, autonomic ganglia, and various sites in the central nervous system (CNS)
  • 10.  Muscle and neuronal nAChRs differ in their molecular structure and pharmacology  They are pentameric arrays of one to four distinct but homologous subunits, surrounding an internal channel  The α subunit has binding sites for ACh.  Agonist binding induce a conformational change that opens the channel  Antagonist may bind to these sites but do not elicit the conformational change
  • 11. 13
  • 12. Parasympatholytics Natural Belladonna Alkaloids Semisynthetic and Synthetic Products of Belladonna alkaloids Atropine Hyoscine l-hyoscyamine Tertiary amines Quaternary amines •Dicyclomine hydrochloride •Oxyphencyclimine hydrochloride •Homatropine hydrobromide •Cyclopentolate hydrochloride •Tropicamide •Atropine methobromide •Atropine methonitrate •Hyoscine butyl bromide •Methantheline bromide •Porpantheline bromide •Mepenzolate bromide •Ipratropium bromide •Oxyphenonium bromide 14
  • 13. Therapeutic uses Name of drugs Clinical Applications Motion sickness drugs Scopolamine • Prevention of motion sickness Postoperative nausea and vomiting Gastrointestinal disorders Dicyclomine Glycopyrrolate Methantheline Propantheline Clidinium Oxyphenonium • Irritable bowel syndrome • Minor diarrhea Mydriatic and cycloplegic Atropine Scopolamine Homatropine Cyclopentolate Tropicamide • Retinal examination • Prevention of synechiae after surgery Respiratory (asthma, COPD) Ipratropium Tiotropium • Prevention and relief of acute episodes of bronchospasm 15
  • 14. Therapeutic uses Name of drugs Clinical Applications Urinary Oxybutynin Darifenacin Solifenacin and Tolterodine (Tertiary amines with somewhat greater selectivity for M3 receptors ) Trospium (Quaternary amine with less CNS effect) • Urge incontinence • Postoperative spasms Cholinergic poisoning Atropine • Mandatory antidote for severe cholinesterase inhibitor poisoning Pralidoxime • Usual antidote for early-stage (48 h) cholinesterase inhibitor poisoning 16
  • 15.  Muscarinic antagonists (parasympatholytic drugs) are competitive antagonists of ACh at muscarinic receptors  Their chemical structures usually contain ester and basic groups in the same relationship as ACh, but  They have a bulky aromatic group in place of the acetyl group Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge 17
  • 16. 18
  • 17. Atropine:  Atropine is the prototype drug of this group  It is an alkaloid, found in the deadly nightshade (Atropa belladonna)  Tertiary amine  Ester of tropic acid 19
  • 18.  The deadly nightshade (Atropa belladonna) contains mainly atropine  The thorn apple (Datura stramonium) contains mainly scopolamine  The Hyoscyamus niger contains Scopolamine (Hyoscine)  These are tertiary ammonium compounds that are sufficiently lipid-soluble to be readily absorbed from the gut or conjunctival sac 20
  • 19.  They also penetrate the blood-brain barrier  The quaternary derivative of atropine, atropine methonitrate, has peripheral actions like atropine but, lacks central actions [can not cross BBB]  Ipratropium [a quaternary ammonium compound] is used by inhalation as a bronchodilator 21
  • 20.  Cyclopentolate and tropicamide are tertiary amines developed for ophthalmic use and administered as eye drops  Pirenzepine is a relatively selective M1 receptor antagonist  Oxybutynin, tolterodine and darifenacin (M3- selective) are new drugs that act on the bladder to inhibit micturition, and are used for treating urinary incontinence  They produce unwanted effects typical of muscarinic antagonists, such as dry mouth, constipation and blurred vision 22
  • 21. ATROPINE 23
  • 22. 24
  • 23.  Used as a homicidal poison  Atropa:  Atropos: Goddess in Greek Mythology  Atropos, Clothos & Lachesis….. 3 sisters  Atropos cuts with shears the web of the life span and woven by her sisters Clothos & Lachesis 25
  • 24.  Bella donna:  Italian meaning: Beautiful Lady  Once fashionable female practice of using the extract of the plant to dilate the pupils…. Process of making herself attractive 26
  • 25. 27
  • 26. Atropine is an antagonist drug-  It blocks all the muscarinic receptors of Ach in the body & antagonizes the effects of Ach  Antagonism is reversible  So, the effects are opposite to Muscarinic effects of Ach 28
  • 27. 29
  • 28. Inhibition of secretions:  Very low doses of atropine inhibits salivary, lacrimal, bronchial and sweat gland secretions producing dry mouth and skin  Gastric secretion is only slightly reduced  Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend to accumulate in the lungs  Ipratropium lacks this effect 30
  • 29. DOSE (mg) EFFECTS 0.5 Slight cardiac slowing; some dryness of mouth; inhibition of sweating 1 Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils 2 Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision 5 Above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis 10 Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma 31
  • 30. Effects on heart:  Biphasic action  Atropine causes transient initial bradycardia due to stimulation of dorsal nucleus of vagus ( with very low doses; due to a central action)  Larger doses cause progressively increasing tachycardia by blocking cardiac mAChRs (up to 80-90 beats/min) in humans 32
  • 31.  This is because there is no effect on the sympathetic system, but only inhibition of the existing parasympathetic tone  This is most pronounced in young people (often absent in the elderly)  The response of the heart to exercise is unaffected 33
  • 32.  Arterial blood pressure is unaffected, because most resistance vessels have no cholinergic innervation  Large doses cause vasodilatation of the skin blood vessels specially in the blush area -‘atropine blush’ 34
  • 33. Effects on the eye:  It dilates the pupil (mydriasis)  Light reflex is lost  Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia), so that near vision is impaired  Intraocular pressure may rise (unimportant in normal individuals but can be dangerous in patients suffering from narrow-angle glaucoma) 35
  • 34. Pupil Normal Dilated
  • 35. Effects on the gastrointestinal tract:  Gastrointestinal motility is inhibited by atropine  Atropine is used in pathological conditions in which there is increased gastrointestinal motility (M3 selective agents may be preferable)  Pirenzepine, owing to its selectivity for M1 receptors, inhibits gastric acid secretion 37
  • 36.  Bronchial, biliary and urinary tract smooth muscle are all relaxed by atropine  Reflex bronchoconstriction (during anaesthesia) is prevented, whereas bronchoconstriction caused by histamine and leukotrienes is unaffected  Biliary and urinary tract smooth muscle are only slightly affected  Precipitate urinary retention in elderly men with prostatic enlargement 38
  • 37.  Atropine stimulates CNS followed by depression  Medulla and higher cerebral centers are stimulated  With therapeutic doses there is mild vagal excitation  Large doses produce marked central stimulation leading to: • Restlessness • Irritability • Disorientation • Hallucinations • Delirium 39
  • 38.  Later; depression occurs leading to coma and death due to medullary paralysis  Atropine has anti tremor activity in Parkinson’s disease  It prevents motion sickness either by acting centrally or peripherally  It counteracts central excitatory actions of physostigmine and OPCs and  Reduces electrical activity of brain 40
  • 39.  Adjunct for anaesthesia (reduced secretions, bronchodilatation)  Anticholinesterase (OPC) poisoning  Bradycardia  As antispasmodic in Gastrointestinal hypermotility  In ophthalmology used topically • as a mydriatic (to examine the retina, optic disk) • Treatment of acute iritis, iridocyclitis, keratitis etc. • Used alternately with a miotic to break or prevent adhesions between iris and lens 41
  • 40.  Nocturnal enuresis  Hyperactive bladder  Motion sickness  Parkinson’s disease  Hyperhidrosis  Mushroom poisoning  Antidiarrheal  Pulmonary obstructive disease 42
  • 41.  Ipratropium and Tiotropium are used in the treatment of chronic obstructive pulmonary disease  They are less effective in most asthmatic patients  These are often used with inhaled long-acting β2 agonists • Ipratropium is administered four times daily via a metered- dose inhaler or nebulizer • Tiotropium is administered once daily via a dry powder inhaler  Ipratropium is used in nasal inhalers in rhinorrhea associated with the common cold or with allergic or non-allergic perennial rhinitis 43
  • 42.  Once widely used for the management of peptic ulcer  Can reduce gastric motility and the secretion of gastric acid  But antisecretory doses produce pronounced side effects like- • such as xerostomia, loss of visual accommodation, photophobia, and difficulty in urination  Patient compliance in the long-term is poor  Pirenzepine, Telenzepine 44
  • 43.  Diarrhea associated with irritation of the lower bowel [mild dysenteries and diverticulitis]  Dicyclomine hydrochloride [weak muscarinic receptor antagonist] also has nonspecific direct spasmolytic effects on smooth muscle of the GI tract  It is occasionally used in the treatment of diarrhea-predominant irritable bowel syndrome 45
  • 44.  Effects on the eye are obtained by topical administration  They cause mydriasis and cycloplegia  Mydriasis is necessary for thorough examination of the retina and optic disc and in the therapy of iridocyclitis and keratitis  The mydriatics may be alternated with miotics for breaking or preventing the development of adhesions between the iris and the lens 46
  • 45.  Complete cycloplegia may be necessary in the treatment of iridocyclitis and choroiditis and for accurate measurement of refractive errors  Homatropine hydrobromide a semisynthetic derivative of atropine, Cyclopentolate hydrochloride and Tropicamide are used in ophthalmological practice 47
  • 46.  Overactive urinary bladder  Lower intravesicular pressure  Increase capacity, and  Reduce the frequency of contractions by antagonizing parasympathetic control of the bladder  They also may alter bladder sensation during filling 48
  • 47.  Enuresis in children, particularly when a progressive increase in bladder capacity is the objective  To reduce urinary frequency and increase bladder capacity in spastic paraplegia 49
  • 48.  Oxybutynin (DITROPAN)  Tolterodine (DETROL)  Trospium chloride (SANCTURA)  Darifenacin (ENABLEX)  Solifenacin (VESICARE) and  Fesoterodine (TOVIAZ); 50
  • 49.  Limited clinical utility  Used only in coronary care units for short-term interventions or in surgical settings  Initial treatment of patients with acute myocardial infarction in whom excessive vagal tone causes sinus bradycardia or AV nodal block 51
  • 50.  Sinus bradycardia is the most common arrhythmia seen during acute myocardial infarction  Atropine may prevent further clinical deterioration in cases of high vagal tone or AV block by restoring heart rate to a level sufficient to maintain adequate hemodynamic status and to eliminate AV nodal block 52
  • 51.  Dry mouth  Blurred vision  Tachycardia  Constipation  Urinary hesitancy and retention  Atropine poisoning 53
  • 52.  Occur through accidental or deliberate ingestion of berries or seeds of belladonna or from over treatment with high doses  Characterized by: • Dryness of mouth, dysarthria, dysphagia • Blurred vision and photophobia • Hot, dry and flushed skin • Hyperpyrexia • Tachycardia (weak and rapid pulse) • Palpitation • Urinary difficulty • Restlessness, excitement, hallucinations, delirium followed by • Depression and death from respiratory failure • Convulsions may occur 54
  • 53.  Gastric lavage  Physostigmine as antidote – slow i.v. injection 1- 4 mg (0.5 mg in children)  Diazepam for sedation and control convulsions  Artificial respiration  Ice bags and alcohol sponge to reduce fever 55
  • 54.  Glaucoma  Elderly males with enlarged prostate  Paralytic ileus  Ulcerative colitis  Gastroesophageal reflux  Tachycardia  Cardiac insufficiency 56
  • 55. 57
  • 56. Property Subgroup M1 M2 M3 Primary locations Nerves Heart, nerves, sm. muscle Glands, sm. muscle, endothelium Antagonists Atropine Pirenzapine Telenzepine Dicyclomine Trihexyphenidyl Atropine Gallamine Methoctramine Atropine 4-DAMP Darifenacin Solifenacin Oxybutynin Tolterodine Atropine does not distinguish among the 3 subtypes of Muscarinic receptors Other antagonists are moderately selective for one or another subtypes of receptors 58
  • 57.  Classify main classes of parasympathetic blockers  Classify antimuscarinic drugs based on their clinical uses with suitable examples  Describe the pharmacological actions of atropine based on the distribution of muscarinic receptors  Discuss the contextual rationale for using drugs blocking ACh  Discuss the clinical features and drug treatment of belladonna (atropine) poisoning 59
  • 58. 60