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Anticholinergic drugs

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Anticholinergic drugs

  1. 1. TOPICS History Classification Muscarinic antagonist Pharmacological actions Therapeutic uses Toxicity
  2. 2. INTRODUCTION  These agents block cholinergic receptors thereby inhibit cholinergic transmission hence these agents are also called as parasympatholytics.  Are they specific?  Yes, these drugs are somewhat specific  these drugs can block specifically either muscarinic receptors or nicotinic receptors.
  3. 3. History • Roman empire and middle ages – Deadly nightshade shrub: Linnaeus : Atropa belladonna • Datura stramonium – In India – Use of Jimson weed – roots and leaves – burnt – smoke was inhaled by asthmatics. • Mein – 1831- isolated atropine in pure form • Bezold and Bleobaum – 1867 – showed that atropine blocked the cardiac effects of vagal stimulation. • Heidenhain – 1872 –atropine prevented salivary secretion produced by the stimulation of the chorda tympani.
  4. 4. BELLADONNA EYES MYDRIASIS
  5. 5. Atropa belladonna Hyoscyamus niger Datura stramonium
  6. 6. SOURCES AT R O P I N E Atropa belladona Atropa acuminata Datura stramonium S C O PA L A M I N E Hyoscyamus niger Scopola carniolica
  7. 7. Anti-muscarinic agents Natural Alkaloids • Atropine(d,l-hyoscyamine) • Scopolamine (l-hyoscine) Semisynthetic Derivatives • Homatropine • Atropine methionitrate • Hyoscine methylbromide • Benztropine • Ipratropium bromide • Tiotropium bromide Synthetic Derivatives • Eucatropine • Cyclopentolate • Tropicamide • Dicyclomine • Flavoxate • Oxybutynin • Pirenzepine • Telenzepine • Trihexyphenidyl • Procyclidine • Tolterodine • Glycopyrrolate • Propantheline • Oxyphenonium • Clidinium • Pipenzolate • Drotaverine • Valethamate
  8. 8. Tertiary and Quaternary derivatives Tertiary • Atropine • Scopolamine • Homatropine • Benztropine • Eucatropine • Cyclopentolate • Tropicamide • Dicyclomine • Flavoxate Quaternary • Atropine methionitrate • Hyoscine methylbromide • Ipratropium bromide • Tiotropium bromide • Propantheline • Oxyphenonium • Glycopyrrolate • Clidinium • Pipenzolate • Valethamate • Oxybutynin • Pirenzepine • Telenzepine • Trihexyphenidyl • Procyclidine • Drotaverine • Tolterodine
  9. 9. CLASSIFICATION
  10. 10. MUSCARINIC ANTAGONISTS • Muscarinic receptors are further classified into M1 to M5 • drugs may produce either selective or non- selective block • we can divide this category further into Non-selective muscarinic antagonists Selective muscarinic antagonists
  11. 11. Atropine Scopolamine Dicyclomine Cyclopentolate Tropicamide Ipratropium Tiotropium Solifenacin Oxybutynin Tolterodine Benztropine Trihexyphenidyl NON-SELECTIVE MUSCARINIC ANTAGONISTS
  12. 12. SELECTIVE MUSCARINIC ANTAGONISTS Selective cholinergic antagonists are available on M1, M2 and M3 receptors. • M1 antagonist • Pirenzepine • M2 antagonist • Gallamine • M3 antagonist • Darifenacin
  13. 13. STRUCTURE-ACTIVITY RELATIONSHIP Tropine Tropi c acid Scopine Mandeli c acid
  14. 14. MECHANISM OF ACTION Competitive antagonism Reversible (surmountable) blockade Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor
  15. 15. ABSORPTION T E R T I A R Y A N T I M U S C A R I N I C D R U G S Absorbed rapidly from the GI tract and conjunctival membrane When applied in suitable vehicle, some are even absorbed across the skin  Scopolamine: transdermal patch in the post-auricular region Q U A T E R N A R Y A N T I M U S C A R I N I C D R U G S only 10-30% is absorbed after oral administration  Decreased solubility of the charged molecule  Less readily penetrate the conjunctiva of the eye
  16. 16. DISTRIBUTION T E R T I A R Y A N T I - M U S C A R I N I C D R U G S Atropine and other tertiary agents widely distributed in the body Significant levels are achieved in CNS within 30 min to 1 hr Scopolamine is rapidly and fully distributed into the CNS where it has greater effects than most others Crosses placental barrier and secreted in milk and saliva Q U A T E R N A R Y A N T I - M U S C A R I N I C D R U G S Quaternary derivatives are poorly taken up by the brain and therefore free of CNS effects
  17. 17. METABOLISM & ELIMINATION Atropine has a t1/2 of ≈4 hours  Hepatic metabolism accounts for the elimination of about half of a dose  Remainder is excreted unchanged in the urine. Rabbit – Atropine esterase – tolerate large doses without toxicity
  18. 18. PHARMACOLOGICAL ACTIONS
  19. 19. 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
  20. 20. EYE • Just like muscarinic agonists, these drugs act on two muscles in the eye.  Constrictor muscle  Ciliary muscle • Relaxation of this muscle by muscarinic antagonists produce pupilary dilatation. • ciliary muscle is required for adjustment of the lens with respect to the distance of the object  Ciliary muscle paralysis  Loss of accommodation – cycloplegia Both atropine and scopolamine produced this effect.  Long duration of action  Pupillary and accommodation reflex recover 7-12 days after.
  21. 21. Other short acting drugs are preferred as mydriatic Sympathomimetic drugs also cause pupillary dilation without cycloplegia Alpha adrenoceptors stimulants drugs • Phenylephrine – short lasting mydriasis sufficient for fundus examination Opposing effect: that can partially or fully reverse the effect of atropine • Pilocarpine • Choline esters • Physostigmine • Isoflurophate (DFP) Contraindications:  Narrow angle glaucoma
  22. 22. THERAPEUTIC USES Mydriasis  Examination of retina and optic disc and for refractive errors  Therapy of iridocyclitis and keratitis Cycloplegia  In Rx of iridocyclitis and choroiditis  Measurement of refractive errors  Young – long acting mdriatics + cycloplegia preferred  Adults- short acting drugs preferred
  23. 23. In therapy of iridocyclitis  Adminstered alternately with miotics  Long lasting preparations like Homatropine  To break/prevent adhesions between iris and lens  Complete cycloplegia is necessary in treatment of iridocyclitis & choroiditis  If complete cycloplegia is required atropine or scopolamine preferred >> cyclopentolate or tropicamide
  24. 24. ANTI-MUSCARINIC DRUGS USED IN OPHTHALMOLOGY Drug Duration of Effect (days) Usual Concentration (%) Ocular side effects Atropine 7–10 0.5–1 Scopolamine 3–7 0.25 Homatropine 1–3 2–5 Photosensitivity, blurred vision Cyclopentolate 1 0.5–2 Tropicamide 0.25 0.5–1
  25. 25. GLANDS All the glandular secretions are inhibited. • Salivary secretions • Lacrimal secretions • Sweat secretion • Bronchial secretions • Gastric secretions Reduction of salivary secretion leads to dry mouth and reduction of lacrimal secretions leads to blurred vision therapeutic uses Drug induced salivation  Heavy metal poisoning  Parkinson disease
  26. 26. Clinical Relevance – Sialorrhoea Sialorrhoea is drooling or excess saliva that cannot be controlled. There are two mechanisms by which this can occur: 1. Lack of swallowing – resulting in saliva pooling in the mouth. This is typically due to neuromuscular dysfunction such as cerebral palsy, Parkinson’s disease or Motor Neuron Disease. 1. Increased secretion of saliva – which is typically due to medication. It is often noted within the treatment of Alzheimer’s disease or myasthenia gravis, as treatment of both conditions involves the use of anti-cholinesterases.
  27. 27. MANAGEMENT • depends on the cause • involves treatment of any reversible factors. • For example, drug regimes may need to be changed or even stopped depending on the severity. • Behaviour modification may be necessary in terms of learning methods to help clear the pooled saliva. • In severe cases • anticholinergic medication can be used. • Belladona alkaloids • Synthetic tertiary amine derivatives like DICYCLOMINE are very effective • Side effects • If nothing else is successful radiation • injection of botulinum toxin or • surgery may be considered.
  28. 28. HEART
  29. 29. So they show +ve ionotropic effect +ve chronotropic effect The decrease in the heart rate leads to tachycardia. Since they produce tachycardia, they can be indicated in sinus bradycardia. Atropine is particularly used for this condition.
  30. 30. CARDIOVASCULAR SYSTEM Effects of increasing doses of atropine on heart rate compared with muscarinic receptor occupancy in humans Parasympathomimetic effect of low-dose atropine is attributed to blockade of presynaptic M1 receptors that suppress acetylcholine release normally
  31. 31. Usual clinical dose (0.4 to 0.6 mg) Larger dose Receptor action M1 M2 mechanism Inhibition of pre synaptic M1  inc. Ach release SA and AV node Effect 1. Bradycardia 2. 4-8 beats pre min. 1. Tachycardia 2. 35-40 beats per min.
  32. 32. PHARMACOLOGICAL ACTIONS Effect on young – high  due to high vagal tone Effect in elderly  lower  due to less vagal tone Effect on rhythmicity  Prevents or abolishes bradycardia or asystole caused by choline esters, ache inhibitors Effect on conduction  Facilitate AV node conduction  removal of vagal influence on the heart and increase ventricular rate  E.g in 1. Atrial fibrillation 2. II degree heart block 3. In digitalis toxicity 4. In complete heart block
  33. 33. Antimuscarinic agent Preparations Atropine Oral: 0.4, 0.6 mg tablets Parenteral: 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/mL for injection
  34. 34. PHARMACOLOGICAL ACTIONS Circulation  In clinical doses, when given along with choline esters  When given alone  In toxic and occasionally in therapeutic doses: atropine flush
  35. 35. BRONCHIOLES These drugs block M3 receptors on bronchioles and produce bronchodilatation. Bronchial secretions are also inhibited which is useful in asthma.
  36. 36. Respiratory System Pharmacological Actions • Broncho-dilation and decrease in tracheobronchial secretion • Reduction of mucous secretion and mucociliary clearance • Inhibits broncho-constriction caused by infl. Mediators • Belladona alkaloids  decreases secretions caused by irritant anaesthetics like diethyl ether – Side effects: decrease mucus secretion and clearance  mucus plugs obstruction • Quarternary ammonium derevatives have minimal inhibitory effect on mucociliary clearance
  37. 37. THERAPEUTIC USES A D V A N T A G E S O F I P R A T R O P I U M • No effect on mucociliary clearance • Inhalational – decreased systemic side effects • Longer acting – can be given once daily • Can be used as adjunct to pulm. Rehab. In increasing exercise intolerance T H E R A P E U T I C U S E S COPD & Asthma  Used along with adrenergic receptor agonists Decrease the rhinorrhea associated with the common cold or with allergic and nonallergic rhinitis
  38. 38. Antimuscarinic agent Duration of action Preaparations Ipratropium 4-6hrs Aerosol: 200 dose metered-dose inhaler(18mcg/puff). Solution for nebulizer: 0.02%(500mcg/vial). Nasal spray: 0.03, 0.06%(21, 42mcg/spray). Tiotropium 24hrs Aerosol: 18 mcg tablet for inhaler
  39. 39. SMOOTH MUSCLE ( GIT)
  40. 40. GI TRACT T H E R A P E U T I C U S E S To facilitate endoscopy and gastrointestinal radiology by relaxing gastrointestinal smooth muscle Once used in management of peptic ulcer disease  Pirenzepine and telenzepine were used Antispasmodic Antisecretory  Mild dysenteries and diverticulitis
  41. 41. Once most widely used for management of peptic ulcer disease. Anti secretory doses produced – S/E- dry mouth, loss of visual accomodation, photophobia, and difficulty urination This reduced patient compliance Pirenzepine  Similar in structure to imipramine  It is tricyclic antidepressant  Selective for M1 receptors (also M4)  Inhibition of gastric acid secretion by Neural stimuli > muscarinic agoinsts Telenzepine  Analogue of pirenzepine  Higher potency  Selective for M1 receptors
  42. 42. Antimuscarinic agent Preparations Pirenzepine Oral: 50mg tablets Telenzepine Oral: 3mg tablets Dicyclomine Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup Parenteral: 10 mg/mL for intramuscular injection Glycopyrrolate Oral: 1, 2 mg tablets Parenteral: 0.2 mg/mL for injection
  43. 43. GENITO-URINARY SYSTEM
  44. 44. GENITO-URINARY TRACT • Relaxes smooth muscles of ureter and bladder wall and slows voiding • lower intra-vesicular pressure • increase capacity • reduce the frequency of contractions • alter bladder sensation during filling • This effect is achieved only after the inhibition of salivation, lacrimation & blurring of vision • Mediated by multiple receptor subtypes M2 < M3 P H A R M A C O L O G I C A L A C T I O N S
  45. 45. GENITO-URINARY TRACT T H E R A P E U T I C U S E S 1. Motor Urge (Hypertonic) Incontinence: • This is the most common incontinence in elderly • Etiology. Involuntary rises in bladder pressure occur from idiopathic detrusor contractions that cannot be voluntarily suppressed • Urge incontinence can be linked to • stroke, • Parkinson's disease, • multiple sclerosis and • other health conditions • which interfere with the brain's ability to send messages to the bladder via the spinal cord. • These conditions can affect a person's ability to hold and store urine.
  46. 46. Motor Urge (Hypertonic) Incontinence: Management. 1. Anticholinergic medications i. Oxybutynin [Ditropan] 5mg BD oral ii. Dicyclomine 10-20 mg BD iii. Solifenacin 5-10 mg BD oral iv. Tolterodine 2 mg BD oral v. Fesoterodine vi. Flavoxate 200 mg TDS oral 2. Non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit detrusor contractions; 3. Tricyclic antidepressants; 4. Calcium -channel blockers Newer addition for the t/t of urge incontinence Mnemonic SOFT bladder Therapeutic uses
  47. 47. 2. Stress incontinence • Involuntary loss of urine • With coughing and sneezing • No urine lost at night Treatment: a) Medical therapy - some success with duloxetine (yentreve) (SNRI) b) Surgical therapy Therapeutic uses
  48. 48. DRUGS - INHIBIT/PROMOTE VOIDING
  49. 49. 3.Rx of enuresis in children - by lowering intra-vesicular pressure, increasing capacity and reducing frequency of contractions 4.Used to reduce urinary frequency in spastic paraplegia and to increase capacity of bladder 5. To relieve spasm after urological surgery Prostatectomy
  50. 50. 6. Used to reduce involuntary voiding in patients with neurological disease - Children with menigomyelocele – Oxybutynin orally or can be instilled via catheter 7. Propiverine is a newer anticholinergic drug used for the treatment of  urinary urgency,  frequency and  urge incontinence,  all symptoms of overactive bladder syndrome.  It is a muscarinic antagonist.  A modified release preparation is also available, taken once daily.
  51. 51. NONPROPRIETAR Y NAME t1/2 (HOURS) METABOLISM & ELIMINATION PREPARATIONS DAILY DOSE (ADULT) Oxybutynin 2-5 CYP3A4 Immediate Release 10-20 mg Extended Release 5-30 mg Transdermal patch 3.9 mg Topical gel 100 mg Tolterodine 2-9.6 CYP2D6, CYP3A4 IR 2-4 mg 6.9-18 ER 4 mg Trospium chloride 20 KIDNEYS IR 20-40 mg 35 ER 60 mg Solifenacin 55 CYP3A4 IR 5-10 mg Darifenacin 13-19 CYP2D6, CYP3A4 ER 7.5-15 mg Fesoterodine 7 ER 4-8 mg
  52. 52. OTHER SMOOTH MUSCLE Biliary Tract Mild antispasmodic action Not effective to prevent the spasm induced by opioids Sweat Glands and Temperature Inhibits the activity of sweat glands Skin becomes hot and dry Sweating may be depressed enough to raise body temperature
  53. 53. CENTRAL NERVOUS SYSTEM
  54. 54. CENTRAL NERVOUS SYSTEM
  55. 55. LDT/PPT (Ach) Dorsal raphe/ locus ceruleus Inhibit wakefulness Promotes REM sleep Thalamus Inhibit slow sleep wave spindles Causes cortical arousal In both WAKEFUL and REM sleep Pontine reticular formation Ach released in to the PRF causes Promotes onset of REM pedunculopontine tegmental (PPT) and laterodorsal tegmental nucleus (LDT)
  56. 56. CENTRAL NERVOUS SYSTEM Atropine : action on CNS is dose dependent  Therapeutic doses  Minimal effects, mild stimulation of the parasympathetic medullary centres  With toxic doses  Central excitation  With still larger doses:  Stimulation followed by depression Scopolamine  Crosses BBB, has prominent central effects at low therapeutic doses;  CNS depression, amnesia  also causes euphoria  In severe pain, same doses cause excitement P H A R M A C O L O G I C A L A C T I O N S
  57. 57. Parkinson disease Adjunct to levodopa Motion sickness Given prophylactically Therapeutic uses
  58. 58. Antimuscarinic agent Preparations Usual daily dose Scopolamine Oral: 0.25 mg tablets Parenteral: 0.3, 0.4, 0.6, 1 mg/mL for injection Transdermal patch: delivers ≈0.5mg over 72hrs Benztropine Oral: 0.5, 1, 2 mg tablets Parenteral: 1mg/ml for injection 1–6mg Biperiden Oral: 2mg tablets Parenteral: 5mg/ml for injection 2–12mg Trihexyphenidyl Oral: 2, 5mg tablets Sustained release: 5mg capsules 6–20mg
  59. 59. Other uses • Uses in Anesthesia – Blocks vagal reflexes induced by surgical manipulation of viscera – In anaesthetic premedication, atropine, and hyoscine block the vagus and reduce mucosal secretions; hyoscine also has useful sedative and amnestic effects
  60. 60. ORGANOPHOSPHORUS POISONING The use of atropine in large doses for the treatment of poisoning by anticholinesterase organophosphorus insecticides. 1-2 mg of atropine sulfate I.V every 5-15 min until signs of effect appear Acute effects of op poisioning last for 24-48 hrs
  61. 61.  Cholinesterase regenerator compounds  PAM or pro-2-PAM  Diacetyl monoxime  The oxime group (=NOH) has very high affinity for phosphorous atom  These drugs cannot hydrolyse if the complex has aged  Ageing involves breaking of one of the oxygen- phosphorous bonds of the inhibitor  further strengthens the phosphorus – enzyme bond
  62. 62. In mushroom poisoning :  Rapid onset type:  Characterized by early signs of muscarinic excess – nausea, vomiting, diarrhea, urinary urgency, vasodilation, reflex tachycardia, sweating, salivation and broncho-constriction  Inocybe genus mushrooms causes rapid type poisioning  Parenteral atropine 1-2 mg  Delayed type  Amanita phylloides  A.virosa  Atropine is of no value
  63. 63. CONTRAINDICATIONS Include Urinary tract obstruction GI obstruction Uncontrolled (or susceptibility to attacks of) angle- closure glaucoma. Benign prostatic hyperplasia.
  64. 64. Atropine poisoning • Atropine has wide margin of safety • Lethal dose – Children: 10-20mg – Adults: 80-130mg • Scopolamine is more toxic than atropine • Poisoning may also occur following ingestion of natural sources.
  65. 65. Adverse effects
  66. 66. Signs and symptoms
  67. 67. diagnosis • Intravenous injection of the anticholinesterase agent physostigmine may be used for confirmation. • If physostigmine does not elicit the expected salivation, sweating, bradycardia, and intestinal hyperactivity, intoxication with atropine or a related agent is almost certain.
  68. 68. Contd… • If Poison ingested – Gastric lavage – Universal antidote – Muscarinic effects- counteracted by IV Physostigmine 1- 4mg(adult), 0.5-1mg(children), repeated at intervals till satisfactory control – Restlessness, delirium- Diazepam – Dark room to alleviate photophobia – Catherization for urinary retention – Tepid sponging for pyrexia – Good nursing care, oxygen, artificial ventilation (when necessary)
  69. 69. Toxicology of drugs with antimuscarinic properties • Histamine H1 receptor antagonists (promethazine, diphenhydramine) • Phenothiazines (chlorpromazine and thioridazine) • Tricyclic antidepressants (protriptyline and amitriptyline) – block muscarinic receptors, and in sufficient dosage, produce syndromes that include features of atropine intoxication.
  70. 70. • In addition, overdose with suicidal intent is a danger in the population using antidepressants. • Fortunately, most of the newer antidepressants, selective serotonin reuptake inhibitors and newer antipsychotic drugs have more limited anticholinergic properties.
  71. 71. Summary • Muscarinic receptor antagonists have a wide variety of therapeutic uses: – Treatment of overactive bladder – COPD – Increased GI motility – Ophthalmology – OP poisioning
  72. 72. References • HL Sharma & KK Sharma’s “Principles of Pharmacology” 3nd edition • Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” • Rang & Dale’s “Pharmacology” 8th edition • Katzung’s “Basic and Clinical Pharmacology” 14th edition • R.S. Satoskar’s “Pharmacology and Pharmacotherapeutics” 23rd edition • KD Tripathi’s “Essentials of Medical Pharmacology” 7th edition
  73. 73. THANK YOU

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