3. Anti-muscrinic Drugs (Cholinergic Blockers)

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Anticholinergic Drugs OR Cholinoceptor blockers OR Cholinoceptor Antagonists

CHOLINERGIC BLOCKERS: 

CHOLINERGIC BLOCKERS divided into three categories in accordance with their specific targets in the central and/or peripheral nervous system a- Antimuscarinic drugs b- Antinicotinic drugs - Ganglion blockers - NM junction blockers

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Antimuscarinic Drugs or Muscarinic Antagonist Anticholinergic Drugs / Parasympatholytics Definition An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system Anticholinergics are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition

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CLASSIFICATION ANTIMUSCARINIC DRUGS 1- Chemical 2- Therapeutic

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CHEMICAL CLASSIFICATION

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I: Natural Belladona Alkaloids Atropine ( dl -hyoscyamine) Hyoscine (Scopolamine)

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II. Semi Synthetic & Synthetic Substitutes Tertiary Amines Benztropine , Dicyclomine , Homatropine, Oxyphencylimine , Prienzepine, Tropicamide , Propiverine , Oxybutynin , Darifenacin , Solifenacin , Tolterodine Quaternary Amines Anistropine , Clidinium, Glycopyrrolate , Ipratropium Isopropamide, Methscopolamine , Mepenzolate, Propantheline , Trospium, Tridihexethyl.

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THERAPEUTIC CLASSIFICATION

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I. Mydriatrics & Cycloplegics Atropine, Homatropine , Scopolamine Cyclopentolate , Tropicamide Eucatropine , Lachesine II. Anti-spasmodic / Anti-diarrhoeal Atropine Sulphate / Atropine Methobromide Hyoscine Butyl bromide / Hyoscine Hydrobromide Clidinium , Mepenzolate Specially effective for urinary bladder Oxybutynin , Trospium (Unselective antagonists) Darifenacin , Solifenacin , Tolterodine (Selective M 3 antagonists) Propiverine

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III. Drugs used for parkinsonism Beztropine Biperidine Benzhexol Procyclidine IV. Drugs used for peptic ulcer Pirenzepine Telenzepine V. Drugs Used For Motion Sickness Hyoscine Atropine

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VI. Drug Used For Bronchial Asthma Beztropine Ipratropium Tiotropium VII. Antidote to cholinegric poisoning Atropine VIII. Drugs used in Pre-Anesthetic Medication Atropine Hyoscine IX. Drugs used in cardiovascular disorders Atropine

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Prototype Drug: Atropine Source: Atropa Belladonna & Datura stramonium Chemistry: Alkaloid, recemic mixture dl -hyoscyamine. Tertiary amine ( L isomers are 100 times more potent than d isomers) Structure: Organic ester of Tropic acid ( Aromatic acid) & Tropine (organic base).

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ATROPINE

Structure: 

Structure

Pharmacokinetics: 

Pharmacokinetics Absorption Distribution Plasma Half Life Metabolism & Excretion

Pharmacokinetics… : 

Pharmacokinetics… ABSORPTION Well absorbed from Gut & Conjunctival membrane, Bioavailability 25% 10-30% absorption of quaternary antimuscarinic drug after oral adm. DISTRIBUTION Wide distribution Significant levels achieved in CNS within 30 minutes to 1 hour. Scopolamine fully distributed into CNS

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METABOLISM Rapidly disappears from blood after administration Elimination in two phases: Initial rapid phase Half life 2 hours, slow phase of 13 hrs aproximately Metabolism 50%: hydrolysed to atropine and tropic acid Topically in eye action may last for days EXCRETION 60% of dose excreted unchanged in urine Rest appears as hydrolysis and conjugation products Dose: 0.4 mg tid - qid ROA: Oral, IM, IV, Eye Drops, Eye Ointment

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PHARMACODYNAMICS MOA Competitive reversible (surmountable) antagonist of cholinomimetic actions at muscarinic receptors - blockade by a small dose of atropine can be overcome by a larger conc. of Ach / muscarinic agonists Atropine blocks all subtypes of M receptors i.e. M 1 – M 5 Cause little blockade at nicotinic receptor sites – much lower potency Atropine binding to M receptor Prevents stimulation of PLC IP 3 & DAG at M 1 , M 3 & M 5 . Also prevents inhibition of AC & ↓ cAMP at M 2 & M 4

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PHARMACODYNAMICS…. MOA Recent evidence of being acting as inverse agonist Receptors are constitutively active, shift the equilibrium to the inactive state of receptor

PHARMACODYNAMICS….: 

PHARMACODYNAMICS…. Effectiveness of tissues to Atropine varies Tissues most sensitive - salivary, bronchial & sweat glands. least sensitive - secretion of the gastric parietal cell & accommodation Source of agonist Exogenously administered agonist are more effectively blocked than endogenously released ACh

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Pharmacological Actions CNS Eye CVS GIT Genitourinary Tract Respiratory System Sweat Glands

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Pharmacological Actions… CNS 1. Minimal stimulant effects in usual doses, slower & longer lasting Sedative effects 2. Anti-tremor activity in parkinsonism (tremor & rigidity seem to result from a relative excess of cholinergic activity because of deficiency of dopaminergic activity in the basal ganglia-striatum system Anti-motion sickness activity - interruption of vestibular pathway -- motion sickness involve muscarinic cholinergic transmission (scopolamine is most effective)

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Pharmacological Actions… Eye Mydriasis (unopposed sympathetic dilator activity) Paralysis of accommodation (cycloplegia) photophabia and blurred vision (weaken contraction of ciliary muscle) 3. Rise in intraocular pressure --- CI in Glaucoma (Due to 2 & 3 effects) 4. Decrease in Lacrimal secretions (dry sandy eyes) 5. Sluggish or absent light reflex.

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Drugs Duration of Effect in eye (Days) Usual Concentration (%) Atropine 7-10 0.5-1 Hyoscine 3-7 0.25 Homatropine 1-3 2-5 Cyclopentolate 1 0.5-2 Tropicamide 0.25 0.5-1 Pharmacological Actions…

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Pharmacological Actions… On CVS Heart SA Node, AV Node & Atria are mostly affected Less effect on ventricles. Tachycardia ---- blockade of M 2 in SA Node Preceded by Initial bradycardia with lower doses -- -- block of prejunctional M 1 receptors. Blood vessels Block Muscarinic vasodilatation due to block of M 3 endothelial receptors. Not manifest unless a muscarinic agonist is present

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Pharmacological Actions… GIT Blockade of M 3, M 2 & M 1 Relaxation, slowed peristalsis, sphincters are contracted. ↓ secretions (acid, pepsin, mucin) Basal secretions blocked more effectively

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Pharmacological Actions… Genitourinary Tract Blockade of M 3 & possibly M 1 Relaxation of bladder wall, urinary retention Contraction of sphincter & trigone No significant effect on uterus

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Pharmacological Actions… Respiratory System Blockade of M 3 Bronchodilation , specially if constricted ↓ bronchial secretions

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Pharmacological Actions… Sweat Glands ↓ thermoregulatory sweating mediated by M 3 through sympathetic cholinergic fibers ↑ body temperature Children are very sensitive to this effect-----Atropine fever

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OTHER ANTIMUSCARINIC DRUGS Hyoscine (Scopolamine) Source: Hyoscyamus niger and Scopolia Cariolica Chemistry: Ester of Tropic Acid and Scopine DOA in eye: Shorter than atropine , 3-7 days Actions: More prominent actions on eyes, salivary & bronchial secretions and sweat glands

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Action on CNS Depression from the beginning Amnesia to recent events More useful in Motion Sickness & Parkinsonism Dose: 0.4mg tid ROA: Oral, IM, IV Eye Drops, Transdermal patches

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Semi-synthetic and Synthetic Substitutes of Belladonna Alkaloids 1. Tertiary Amines Benztropine , Dicyclomine , Homatropine, Oxyphencylimine , Prienzepine, Tropicamide , Propiverine Oxybutynin , Darifenacin , Solifenacin , Tolterodine Quaternary Amines Anistropine , Clidinium, Glycopyrrolate , Ipratropium Isopropamide, Methscopolamine , Mepenzolate, Propantheline , Trospium, Tridihexethyl.

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Tertiary Amines More lipid soluble Cross BBB Better penetration into the eye

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Therapeutic Uses - Tertiary Amines CNS Motion sickness Scopolamine --- transdermal patch, 48-72 hrs Parkinsonism Procyclidine, Beztropine , trihexphenidyl, Biperidine For amnesia in surgery / obstetrics Scopolamine

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Therapeutic Uses - Tertiary Amines Ophthalmic uses Mydriatic Cycloplegia To prevent adhesions in Uveitis & Iritis Atropine, Homatropine, Cyclopentolate, Tropicamide

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Drugs Duration of Effect in eye (Days) Usual Concentration (%) Atropine 7-10 0.5-1 Hyoscine 3-7 0.25 Homatropine 1-3 2-5 Cyclopentolate 1 0.5-2 Tropicamide 0.25 0.5-1

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Therapeutic Uses - Tertiary Amines… GIT Antispasmodic --- To reduce cramps. Antidiarrheal a) In common traveler's diarrhea b) Mild or self limiting transient hypermotility conditions c) To discourage abuse , Atropine combined with Antidiarrheal opioids (diphenoxylate) in low doses. d) To reduce gastric secretion - only M 1 selective blockers Pirenzepine , Telenzepine

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Therapeutic Uses - Tertiary Amines… Organophosphorous compounds poisoning It is used for management of cholinergic effects: Atropine sulphate 1-2 mg I/V, every 5-15 minutes until signs of reversal i.e dry mouth ,reversal of miosis, increase in heart rate Atropine may have to be repeated ---- for 24-48 hrs / longer. 1gm / d, for 1 month may be required

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Therapeutic Uses - Tertiary Amines… Mushroom poisoning By mushroom of genus Inocybe (Amanita Muscaria) Symptoms appear within 15-30 minutes Not useful in delayed type of poisoning by other Mushrooms

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Therapeutic Uses - Tertiary Amines… CVS Atropine 1. In certain types of Bradycardia. Myocardial infarction. Hyperactive carotid sinus reflux. 2. Idiopathic dilated myopathy

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Therapeutic Uses - Tertiary Amines… Respiratory System Ipratropium & Tiotropium To produce bronchodilatation in COPD & Asthma Less efficacious than β 2 agonists Have synergistic effect with β 2 agonists Useful in patients intolerant to β 2 agonists

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Therapeutic Uses - Tertiary Amines… Preanaesthetic Medication Atropine & Hyoscine I/V prior to inhalational GA To prevent reflex laryngospasm (which may occur due to increased secretions) To prevent bradycardia which may occur due to stimulation of vagus nerve by handling of viscera

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Therapeutic Uses - Tertiary Amines… Genitourinary tract Oxybutynin, Trospium (Unselective antagonists) Darifenacin, Solifenacin, Tolterodine & Fesoterodine (Selective M 3 antagonists), Propiverine To reduce Urinary urgency Spasm of urinary bladder Painful urethral spasm in urolithiasis (debatable) Incontinence of urine Hyperhidrosis Excessive sweating may be controlled with Atropine

Adverse Effects: 

Adverse Effects Rx directed to one organ system – associated with undesirable effects in other organ systems Dry mouth Blurred vision Precipitation of Glaucoma Hot & flushed skin Palpitations, tachycardia Delirium & agitation Constipation Urinary hesitancy Inhibition of sweating (anhidrosis) Most of these side effects are only manifested with excessive dosing or with repeated dosing

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Acute Atropine poisoning Peripheral symptoms due to muscarinic blockade CNS symptoms due to muscarinic blockade CVS symptoms unrelated to muscarinic blockade

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Treatment of Acute Atropine / Datura poisoning Symptomatic Temperature control with cooling blankets Diazepam I/V for convulsions Antidote use previously --- Physostigmine Not use now in routine , only in severe cases Sometimes small doses slowly I/V 1-4mg in adults / 0.5-1 mg in children may be used

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Acute poisoning with quaternary amines No CNS symptoms Peripheral symptoms like atropine Marked orthostatic hypotension due to ganglionic blockade

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Treatment of Acute poisoning with quaternary amines Symptomatic Antidote --- Neostigmine Phenylephrine

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ATROPINE POISONING Signs & Symptoms Dry mouth Dysarthria Dysphagia Blurring of vision Photophobia Hot dry flushed skin Hyperpyrexia Palpitation/tachycardia Urinary retention

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CNS Restlessness Excitement Hallucinations Delirium Followed by: Depression Coma Death due to respiratory failure Convulsions

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MANAGEMENT 1- Gastric lavage 2- Diazepam – Sedation Controls convulsions 3- Physostigmine: Antidote Abolishes delirium & coma Dose: I/V – Adults: 1-4 mg Children: 0.5-1 mg

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4- Alcohol sponging – reduce fever 5- Mechanical ventilation

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CONTRAINDICATIONS Glaucoma Urinary retention BPH Paralytic ileus Ulcerative colitis GERD Tachycardia Cardiac insufficiency