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Anticholinergics - Lecture 1 DR BADAR UDDIN UMAR MBBS, MPhil Senior Lecturer, Pharmacology 1

Wingdings 2:

Learning Objectives: 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


Cholinergic receptors 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

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Muscarinic receptors are located... 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


Muscarinic receptors There are 5 subtypes of muscarinic receptors M 1 , M 2 , M 3 , M 4 , and M 5 They mediate their effects through - G proteins coupled to - Phospholipase C (M 1,3,5 ), Potassium channels (M 2,4 )


Muscarinic Acetylcholine Receptors M 1 M 2 M 3 M 4 M 5 Distribution Cortex, hippocampus Heart Exocrine glands, GI tract Neostriatum Substantia nigra Antagonists Atropine Dicycloverine Tolterodine Oxybutynin Ipratropium Pirenzepine Mamba toxin MT7 Atropine Dicycloverine Tolterodine Oxybutynin Ipratropium Gallamine Atropine Dicycloverine Tolterodine Oxybutynin Ipratropium Darifenacin Atropine Dicycloverine Tolterodine Oxybutynin Ipratropium Mamba toxin MT3 Atropine Dicycloverine Tolterodine Oxybutynin Agonists AcetylcholineXanomeline, CDD-0097 Acetylcholine Acetylcholine Acetylcholine Acetylcholine G protein G α q/11 G α i/o G α q/11 G α i/o G α q/11 Intracellular response Phospholipase C β Adenylyl cyclase inhibition Phospholipase C β Adenylyl cyclase inhibition Phospholipase C β

Anticholinergics - Lecture 1:

Nicotinic receptors are located... In sympathetic and parasympathetic ganglia In the adrenal medulla In the neuromuscular junction of the skeletal muscle In the central nervous system

Learning Objectives::

Nicotinic receptors There are two subtypes of nicotinic receptors N M and N N The N M nicotinic receptor mediates skeletal muscle stimulation The N N nicotinic receptor mediates stimulation of the autonomic ganglia [agonists and antagonists at this site are sometimes called ganglionic agonists and ganglionic blockers]

Cholinergic receptors:

nAChRs…… 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)

Muscarinic receptors are located...:

nAChRs…… 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

Muscarinic receptors:

Nicotinic receptor

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Pharmacological actions of ACh

Nicotinic receptors are located...:


Nicotinic receptors:

Chemical classification of Parasympatholytics 14


Therapeutic Classification of Anticholinergics 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


Therapeutic Classification of Anticholinergics 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

Nicotinic receptor:

Antimuscarinic drugs [Muscarinic antagonists] 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

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Site of Blockade… 18

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Antimuscarinic drugs 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

Chemical classification of Parasympatholytics:

Antimuscarinic drugs [Parasympatholytic drugs] 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

Therapeutic Classification of Anticholinergics:

Antimuscarinic drugs 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

Therapeutic Classification of Anticholinergics:

Parasympatholytic drugs Cyclopentolate and tropicamide are tertiary amines developed for ophthalmic use and administered as eye drops Pirenzepine is a relatively selective M 1 receptor antagonist Oxybutynin , tolterodine and darifenacin ( M 3 -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

Antimuscarinic drugs [Muscarinic antagonists] :


Site of Blockade…:


Antimuscarinic drugs:

Atropa belladonna 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

Antimuscarinic drugs [Parasympatholytic drugs]:

Atropa belladonna 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

Antimuscarinic drugs :

Datura stramonium 27

Parasympatholytic drugs:

M/A of Atropine: 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

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PowerPoint Presentation:

Pharmacological actions of atropine 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

Atropa belladonna:

Effects of Atropine in Relation to Dose 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

Atropa belladonna:

Pharmacological actions of atropine cont… 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

Datura stramonium:

Effects on heart cont…. 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

M/A of Atropine::

Vascular effects… 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

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Pharmacological actions of atropine cont… 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

Pharmacological actions of atropine:

Atropine - Effects on eye Pupil Normal Dilated

Effects of Atropine in Relation to Dose:

Pharmacological actions of atropine cont… Effects on the gastrointestinal tract: Gastrointestinal motility is inhibited by atropine Atropine is used in pathological conditions in which there is increased gastrointestinal motility (M 3 selective agents may be preferable) Pirenzepine , owing to its selectivity for M 1 receptors, inhibits gastric acid secretion 37

Pharmacological actions of atropine cont…:

Effects on other smooth muscles 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

Effects on heart cont….:

Actions on CNS… 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

Vascular effects…:

Actions on CNS cont… 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

Pharmacological actions of atropine cont…:

Clinical uses of atropine 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

Atropine -Effects on eye:

Clinical uses of atropine cont…. Nocturnal enuresis Hyperactive bladder Motion sickness Parkinson’s disease Hyperhidrosis Mushroom poisoning Antidiarrheal Pulmonary obstructive disease 42

Pharmacological actions of atropine cont…:

Use in the respiratory tract 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 β 2 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

Effects on other smooth muscles:

GIT uses-1 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

Actions on CNS…:

GIT uses-2 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

Actions on CNS cont…:

Ophthalmic use 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

Clinical uses of atropine :

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

Clinical uses of atropine cont….:

Use in Genito-urinary tract conditions 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

Use in the respiratory tract:

Use in Genito-urinary tract conditions 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

GIT uses-1:

The muscarinic receptor antagonists indicated for overactive bladder Oxybutynin (DITROPAN) Tolterodine (DETROL) Trospium chloride (SANCTURA) Darifenacin (ENABLEX) Solifenacin (VESICARE) and Fesoterodine (TOVIAZ); 50

GIT uses-2:

CVS use 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

Ophthalmic use:

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

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Adverse effects of atropine Dry mouth Blurred vision Tachycardia Constipation Urinary hesitancy and retention Atropine poisoning 53

Use in Genito-urinary tract conditions:

Acute atropine poisoning 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

Use in Genito-urinary tract conditions:

Treatment of atropine poisoning 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

The muscarinic receptor antagonists indicated for overactive bladder :

Contraindications of atropine…. Glaucoma Elderly males with enlarged prostate Paralytic ileus Ulcerative colitis Gastroesophageal reflux Tachycardia Cardiac insufficiency 56

CVS use:


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Muscarinic receptor subtypes and their antagonists Property Subgroup M 1 M 2 M 3 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

Adverse effects of atropine:

Learning Outcomes Classify main classes of parasympathetic blockers Classify antimuscarinic drugs based on their clinical uses with suitable examples Describe the pharmacological actions of a tropine 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

Acute atropine poisoning:

Thank You 60

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