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(26/03/2020) PARASYMPATHOLYTIC (Muscarinic Receptor Antagonists

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(26/03/2020) PARASYMPATHOLYTIC (Muscarinic Receptor Antagonists THURSDAY (26/03/2020) PARASYMPATHOLYTIC (Muscarinic receptor antagonists, Anticholinergic Drugs) Conventionally, the term ‘anticholinergic drugs’ is restricted to those which block actions of ACh on autonomic effectors and in the CNS exerted through muscarinic receptors. Though nicotinic receptor antagonists also block certain actions of ACh, they are generally referred to as ‘ganglion blockers’ and ‘neuromuscular blockers.’ Mechanism of Action: Competitive antagonists Compete with acetylcholine Block acetylcholine at the muscarinic receptors in the PSNS Reversible blockade of acetylcholine at muscarinic receptors by competitive binding Reversal by increasing acetylcholine or agonist ----> decreased blockade Once these drugs bind to receptors, they inhibit nerve transmission at these receptors. CLASSIFICATION 1. Natural alkaloids Atropine, Hyoscine (Scopolamine). 2. Semisynthetic derivatives Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide. 3. Synthetic compounds a) Mydriatics: Cyclopentolate, Tropicamide. b) Antisecretory-antispasmodics: i. Quaternary compounds: Propantheline, Oxyphenonium, Clidinium, Pipenzolate methyl bromide, Isopropamide, Glycopyrrolate. ii. Tertiary amines: Dicyclomine, Valethamate, Pirenzepine. c) Vasicoselective: Oxybutynin, Flavoxate, Tolterodine. d) Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden. Atropine: Atropine is a prototype antimuscarinic drug - derived from Atropa belladonna (deadly nightshade) and Datura stramonium (thorn apple) Actions: 1. Cardiovascular effects: • Decreased cardiovascular response to vagal stimulation resulting in tachycardia • Mainly, tachycardia due to antagonism of the vagal affect. • Vascular – no (direct) effect – except, dilate cutaneous vessels (red as a beet) – block hypotensive effect of muscarinic agonists 2. CNS: • At normal doses atropine stimulates medullary centers, However, at higher doses produce excitement, agitation, hallucinations and coma. • Depresses vestibular excitation and has anti motion sickness properties • Supresses tremor and rigidity of parkinsonism by blocking cholinergic overactivity in basal ganglia. 3. Eye: • Dilated pupils (mydriasis) • Blocks muscarenic innervations on the circular muscles (Mydriasis) and relaxes cilairy muscles (Cycloplegia) 4. Gastrointestinal: • Relax smooth muscles of GI tract • Decrease intestinal and gastric secretions • Decrease motility and peristalsis • antispasmodic effect • Sphincter contraction 5. Respiratory system: • Decreases bronchial secretion (used as preanesthetic Medication,COPD) • Dilated bronchial airways (used for treatment of Asthma) 6. Glandular: • Decrease salivary secretion (Dry mouth) • gastric Acid (used for Peptic Ulcer) • Sweating → Dry skin → Fever in infants and children. • Bronchial Secretion (used for COPD) Therapeutic Uses : 1. Central Nervous System Disorders- • Parkinson’s disease – Benztropine, Trihexyphenidyl • Those who cannot take Levodopa • Helpful in decreasing salivation, spasticity and tremors • Motion Sickness (Scopolamine) • Drug-induced extrapyramidal reactions(due to antipsychotics) 2. CVS – • Atropine is used to increase heart rate in symptomatic bradycardias. • Sinus node dysfunction • Symptomatic second-degree heart block • Sinus or nodal bradycardia (due to myocardial infarction) 3. Respiratory system- • Decreased secretions from nose, mouth, pharynx, bronchi • Relaxed smooth muscles in bronchi and bronchioles • Decreased airway resistance • Bronchodilation Respiratory agents are used to treat: Exercise-induced bronchospasms, Chronic bronchitis, Asthma, Chronic obstructive pulmonary disease, Ipratropium as inhalation (or Tiotropium) 4. Gastrointestinal- • Relaxation of smooth muscle • Decreased GI motility and peristalsis • Gastrointestinal agents are used to treat peptic Ulcer (Pirenzepine), as antispasmodic (Butylscopolamine), irritable bowel disease (Propantheline), GI hypersecretory states Side Effects of anticholinergics: Body System Side/Adverse Effects Cardiovascular Increased heart rate, dysrhythmias CNS CNS excitation, restlessness, irritability, disorientation, hallucinations Eye Dilated pupils, decreased visual accommodation, increased intraocular pressure Gastrointestinal Decreased salivation, decreased gastric secretions, decreased motility Genitourinary Urinary retention Glandular Decreased sweating Respiratory Decreased bronchial secretions Toxicity of Anticholinergics: • Anticholinergic overdose syndrome (Belladona poisoning- consumption of seeds or berries of belladona or dhatura plant) is characterized by: Hyperthermia, delirium, dry mouth, tacycardia, ileus, urinary retention. Seizures, coma and respiratory arrest may occur. Contraindications: • Glaucoma • Prostatic hypertrophy • Urinary tract obstruction • Gastrointestinal tract obstruction • Infectious diarrhea • Reflux esophagitis • Tachyarrhythmias • Angina • Hyperthyroidism • Pregnancy Individual Drugs • Atropine - prototype. Antidote in OP Poisoning. • Ipratropium - Useful in rhinorrhea. Also, excellent bronchodilator. • Scopolamine - depresses CNS and causes amnesia, drowsiness, euphoria, relaxation and sleep. Also good for motion sickness. Given parenterally, orally and transdermally. • Benztropine - temporary use in Parkinson’s disease. Useful for dystonic reactions caused by antipsychotics. • Trihexyphenidyl - also used for treating EPS by some antipsychotics. Contraindicated in glaucoma. • Flavoxate - relieves dysuria, urgency, frequency, and pain with GU infections • Oxybutynin - has direct antispasmodic effects on smooth muscle and anticholinergic effects. Decreases frequency of voiding. .
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