Pharmacology of Anticholinergics - drdhriti


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Pharmacology of Anticholinergics - drdhriti

  1. 1. ANTICHOLINERGIC DRUGS Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Introduction • Drugs that block Cholinoreceptors have important clinical effects, some of which are of great clinical value • What are the Cholinoreceptors learned so far? RECALL !
  3. 3. Cholinergic Receptors • Muscarinic and Nicotinic – M1, M2, M3, M4 ad M5 – NN and NM • Muscarinic blockers – Atropine is the prototype – many synthetic and semi synthetics are available now – All are competitive blockers – Conventionally – Anticholinergics (Blocking of ACh action on autonomic effectors) • Antinicotinic – are ganglion blockers and myomeural junction blockers
  4. 4. Classification - Anticholinergics • Natural: Atropine and Hyoscine (scopolamine) • Semisynthetic derivatives: Homatropine, Atropine methonitrate, Hyoscine butylbromide, Ipratropium bromide, Tiotropium bromide • Synthetic Compounds:  Mydriatics: Cyclopentolate and Tropicamide  Antisecretory:  Quartenary ammonium compounds: Propantheline, Oxyphenonium, Clidinium, Glycopyrrolate, Isopropamide  Tertiary amines: Dicyclomine, Valethamate, Pirenzepine  Vasicoselective: Oxybutynin, Flvoxate, Tolterodine  Antiprkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden
  5. 5. Atropine as Prototype • Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade • Also in Datura stramonium, also known as jimsonweed (Jamestown weed) or thorn apple • Scopolamine (hyoscine) occurs in Hyoscyamus niger • Many antihistaminics: Histamine, Serotonin, & Ergots alkaloids, Antipsychotic Agents & Lithium and antidepressant drugs have similar structures and, predictably, significant antimuscarinic effects Datura stramonium Atropa belladona
  6. 6. Atropine - Chemically • Atropine: Ester of tropic acid (aromatic acid) + tropine • Scopolamine: Ester of tropic acid (aromatic acid) + scopine • Chemically tropine and scopine are closely similar • Most of the actions of both are similar
  7. 7. Atropine - Mechanism • Atropine causes reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors – blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist • Atropine is highly selective for muscarinic receptors • Does not distinguish between the M1, M2, and M3 • Some quaternary amine antimuscarinic agents have significant ganglion-blocking actions
  8. 8. Atropine - Pharmacokinetics • Absorption: – The natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes – some even over the skin (scopolamine) – Penetrates cornea freely – Quaternary ones – only upto 30% • Distribution: – Atropine and the other tertiary agents are widely distributed in the body – Scopolamine is rapidly and fully distributed into the central nervous system where it has greater effects than most other antimuscarinic drugs – Quaternary derivatives are poorly taken up by the brain • Metabolism: – Atropine is metabolized in liver by conjugation and 60% excretes unchanged in urine – Effects disappear quickly within 2 Hrs except eye
  9. 9. Pharmacological Effects - Atropine • Central Nervous System: Overall CNS stimulant – Atropine has only peripheral effects and minimal minimal stimulant effect on CNS – low entry – Scopolamine has more marked central effects – amnesia and drowsiness – Atropine stimulates many medullary centres – vagal, respiratory and vasomotor – Depresses vestibular excitation – antimotion sickness property – Block basal ganglia cholinergic over activity – blocks tremor, rigidity
  10. 10. Pharmacological Effects of Atropine – contd. • CVS: – Moderate and high doses: TACHYCARDIA – Blockade of M2 receptor on SA node (vagal tone decreases HR) – Higher the vagal tone – more Bradycardia - in young adults – AVN – Atropine produces PS blockade – higher AV conduction rate (reduced PR interval in ECG) – IM/SC injection initially – transient BRADYCARDIA – may be due to inhibition of prejunctional postsynaptic M1 autoreceptor inhibition (not due to stimulation of vagal centre) • Evidenced by Pirenzepine injection does not cross BBB – BP: Parasympathetic impulses are not involved in maintenance of vascular tone – little increase due to tachycardia and VMC • But, histamine release cause direct vasodilatation – However, No marked effect on BP
  11. 11. Pharmacological Effects of Atropine – contd. • Eye: Mydriasis – Topical atropine and other tertiary antimuscarinic drug - results in unopposed sympathetic dilator activity and mydriasis – Cycloplegia: desirable in Ophthalmology – Photophobia and blurring of near vision – IOP rises: hazardous in narrow angle glaucoma – Dry Eye: Not desirable
  12. 12. Effect of Scopolamine
  13. 13. Atropine on Smooth Muscle • GIT: Relaxation – mediated by M3 blockade • Contraction of Stomach and Intestine reduced – constpation • But, less peristalsis suppression – ENS (with other neurotransmitters involved) • More effective to exogenous Ach administration • Respiratory: Bronchodilatation (COPD) – Also antagonizes Histamine, PG, leucotrienes etc. mediated vagal overactivity • Urinary: Relaxation of ureter and bladder – BHP – Sometemes useful in neurogenic bladder/enuresis
  14. 14. Atropine on Glands • Decreases salivary, sweat, tracheobronchial tree and lacrimal secretions – dryness of mouth, dry skin and conjunctiva and difficulty in swallowing • Decreases acid pepsin and mucus secretion – and overall volume (pH changes little) – H2 blockers are more effective • No effect on intestinal and pancreatic secretion • No effect on bile production
  15. 15. Pharmacological Effects of Atropine – contd. • Temperature: Increases – decrease sweating + stimulation of temperature regulating centre in hypothalumus • Local anaesthetic action: on cornea
  16. 16. Various Effects of Atropine
  17. 17. Therapeutic Uses Anticholinergics • Antisecretory: 1. Preanaesthetic medication: atropine, hyoscine and glycopyrrolate etc. • To reduce secretions and also halothane induced ventricular arrhythmia • To prevent laryngospasm – due to increased secretions 1. Peptic ulcer 2. Pulmonary embolism: reduce pulmonary secretions induced by embolism 3. Hyperhidrosis
  18. 18. • Antispasmodic: 1. Intestinal and renal colic – not in biliary colic 2. Diarrhoea (nervous and drug induced) – Lomotil 3. Pylorospasm, gastric hypermotility, gastritis, nervous dyspepsia etc. 4. Urinary frequency and urgency and enuresis (children) 5. Dysmenorrhoea
  19. 19. Anticholinergics -Mydriatic and Cycloplegic - Ophthalmic uses • Used as eye drop or ointment: – Diagnostic: Atropine 1% ointment is used – Measurement of refractive error – Preferred ones: Homatropine, Tropicamide and cyclopentolate – shorter action – However – no cycloplegia in children by newer ones – Ophthalmic examination of retina – fundoscopy (shorter acting preferred) – Therapeutic Uses: • For resting eye: Iritis, iridocyclitis, keratitis, corneal ulcer etc. • Alternating with miotics (prevention of synechia)
  20. 20. Anticholinergic uses – contd.Anticholinergic uses – contd. • CVS:CVS: – Vagolytic - Marked reflex vagal discharge in myocardial infarction and digitalis toxicity – sinus bradycardia and paretial heart block - Parenteral atropine or a similar antimuscarinic drugs • Respiratory: – Ipratropium Bromide – in COPD and chronic bronchitis • Improves mucociliary clearance and bronchodilatation
  21. 21. Uses Anticholinergics – contd. – Parkinsonism: Mild cases of parkinsonism (early cases), Drug induced Parkinsonism and adjunct to Levodopa – Motion sickness: • Hyoscine (scopolamine) is the drug used – Oral, injection and transdermal patch • 0.2 mg orally given as prophylaxis before journey • Not effective in other type of vomiting – Twilight sleep: sedation and amnesia • To antagonize Muscarinic effects of Drugs and Poisons: Anti-ChE, Mushroom poisoning, and to block Muscarinic effects of Neostigmine, Cobra envenometion
  22. 22. Anticholinergic - ADRs • Commonly occurring but of non serious type • Mydriasis and cycloplegia – using as antisecretory or Preanaesthetic medication • Poisoning: – Causes: • Drug overdose • Consumption of Belladona and Datura seeds – Symptoms: • Dry mouth, difficulty in swallowing and talking • Dry, flushed and hot skin, fever, decreased bowel sound, photophobia • Excitement, psychotic behavior, delirium and hallucinations • Hypotension and cardiovascular collapse
  23. 23. Atropine Poisoning – contd. • Diagnosis: Methacholine 5 mg or Neostigmine 1 mg SC – no muscarinic effects • Treatment: – Gastric lavage in case of ingestion – tannic acid – Dark Room – Cold sponging and ice bags – Physostigmine 1–3 mg SC or IV – Maintenance of blood volume, assisted respiration and Diazepam to control convulsions – Other supportive measures
  24. 24. Anticholinergic - Contraindications • Glaucoma – Narrow angle (Precipitation of angle closure) • BHP – urinary retention • Acid peptic ulcer diseases (Non-selective ones) – precipitation of symptoms
  25. 25. THANK YOU • NEXT CLASS ???? • Atropine Substitutes, ganglion stimulants and blockers
  26. 26. Atropine Substitutes - Quarternary compounds • Incomplete Oral absorption, Poor penetration in Eye and CNS, Longer acting than Atropine, Higher Nicotinic Blocking Property, NM Blockade • Drugs: – Hyoscine Butylbromide: Oesophageal and GIT spastic conditions – Buscopan – Atropine methonitrate: Abdominal colics and hypercidity – Ipratropium Bromide: Selective action on Bronchial SM • Enhanced mucocilliary clearance (contrast to Atropine) • Slowly acting Bronchodilator - 1-2 Hrs (prophylactic use) • Acts mainly on larger Central airways (contrast to sympoathomimetics) • More effective in COPD than Asthma • Other Drugs – Tiotropium bromide, Propantheline, Oxyphenonium, Clidinium and Glycopyrrolate
  27. 27. Tertiary Amines • Dicyclomine and valethamate • Dicyclomine: Direct SM relaxant and weak antispasmodic – Lesser side effects than Atropine – Atropine toxicity in infants (not recommended below 6 months) • Valethmate: Dilatation of Cervix in delayed labour
  28. 28. Individual Drugs – Vasicoselective • Oxybutynin: – Specific selectivity for receptors in Urinary bladder and salivary gland (M1/M3) – Additional smooth muscle relaxation property – Uses: • Bladder surgery after urologic surgery • Spina bifida and nocturnal enuresis • Involuntary voiding in patients with neurologic disease - children with meningomyelocele • Dose: 5 mg BD/tds or local instillation • Tolterodine – M3 selective • Flavoxate – similar to Oxybutynin • Drotaverine: Newer Drug - Non anticholinergic smooth muscle relaxant – elevation of cAMP/cGMP – Renal colic, biliary colic, IBS, uterine spasms etc. – Dose: 40 – 80 mg tds
  29. 29. Mydriatics Homatropine, Cyclopentolate and Tropicamide – various ophthalmological procedures as substitutes of Atropine
  30. 30. Drugs acting in Autonomic ganglia • Ganglion stimulants: – Selective agonists: Nicotine, Lobeline, DMPP and TMA – Non-selective: Acetylcholine, carbachol, Pilocarpine, Anticholinesterases • Ganglion Blockers: – Competitive blockers: • Quaternary compounds: Hexamethonium, Pentolinium • Secondary/tertiary: Mecamylamine, Pempidine – Persistent depolarizers: Nicotine (large dose) and Anticholinesterases
  31. 31. Remember !!! • Atropine and its Pharmacological Effects – Therapeutic uses of Atropine – Mechanism of Mydriasis and Cycloplegia • Names of Atropine Substitutes with their Uses – Details of Atropine Substitutes – Ipratropium bromide • Treatment of Atropine Poisoning • Ganglion Stimulants and Blockers Drugs
  32. 32. THANK YOU