Atropine substitutes

18,318 views

Published on

A short review of popular atropine substitutes.

Published in: Health & Medicine

Atropine substitutes

  1. 1. Dr Aaditya Udupa
  2. 2. Atropine  Alkaloid of the belladonna plant.  Belladonna: Beautiful Lady.  Preparations of belladonna were known to the ancient Hindus and have been used by physicians for many centuries.  In India, the root and leaves of the jimson weed plant were burned and the smoke inhaled to treat asthma.03/01/2009 Dr Aaditya Udupa 2
  3. 3. Acetylcholine Neurotransmitter involved in Cholinergic transmission. Synthesized in cytoplasm from acetyl-CoA and choline  choline acetyltransferase (ChAT). Released in “quanta” in nerve endings. After release, acetylcholine molecules bind to and activate an acetylcholine receptor (cholinoceptor). Hydrolysis of Ach in milliseconds by Acetylcholinesterase. 03/01/2009 Dr Aaditya Udupa 3
  4. 4. Muscarinic System Organ Parasympathetic Activity Effect of antimuscarinic Action ReceptorEyes Iris Radial Muscle -- -- Iris Circular Muscle Contracts M3 Relaxes (mydriasis) Ciliary Muscle Contracts M3 Paralysis of accommodationHeart Sinoatrial node Decelerates M2 Increase in Heart Rate Contractility Decreases (atria) M2Blood vessels Skin, splanchnic No Actionvessels, Skeletal muscle vessels Endothelium Releases EDRF M 3, M5Bronchiolar smooth Contracts M3 Dialates muscle
  5. 5. Muscarinic System (cont) Organ Parasympathetic Activity Effect of antimuscarinic Action ReceptorGastrointestinal tractSmooth muscle Walls Contracts M3 Relaxes Sphincters Relaxes M3 Contracts Secretion Increases M3 DecreasesGenitourinary smooth muscle Bladder wall Contracts M3 Relaxes Sphincter Relaxes M3 Contracts Uterus, pregnant Contracts M3 Penis, seminal Erection M3 vesiclesGlands Increase secretion Decreases 03/01/2009 Dr Aaditya Udupa 5
  6. 6. Atropine• Formed by combination ofan aromatic acid, tropicacid, and a complex organicbase, tropine• Naturally occurringatropine is l(-)-hyoscyamine• Commercial preparation isracemic 03/01/2009 Dr Aaditya Udupa 6
  7. 7. Mechanism of Action  Competitive antagonist at muscarinic receptor.  Atropine does not distinguish between the M1, M2, and M3 subgroups of muscarinic receptors.  Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands.03/01/2009 Dr Aaditya Udupa 7
  8. 8. Clinical Effects CNS:  Minimal stimulant effects on the central nervous system.  In toxic doses  cause excitement, agitation, hallucinations, and coma.  The tremor of Parkinsons disease is reduced. Eye:  Paralysis of sphincter pupillae (mydriasis).  Paralysis of accommodation (cycloplegia).  Increase in intraocular pressure in people with shallow anterior chamber. 03/01/2009 Dr Aaditya Udupa 8
  9. 9. Clinical Effects CVS:  Tachycardia.  Heart rate decreases transiently.  Counteracts the peripheral vasodilation and sharp fall in blood pressure caused by choline esters.  No effect on circulation when given alone. GIT:  Inhibitory effects on motor activity of the stomach, duodenum, jejunum, ileum, and colon.  Reduction in tone and in amplitude and frequency of peristaltic contractions.03/01/2009 Dr Aaditya Udupa 9
  10. 10. Clinical Effects  Respiratory System:  Inhibits secretions of the nose, mouth, pharynx, and bronchi.  Inhibits mucociliary clearance.  Dry secretions result in mucus plugs.  Secretions:  Reduces salivary, lacrimal and gastric secretions.  Concentration of acid in stomach remains same.03/01/2009 Dr Aaditya Udupa 10
  11. 11. Effects of Atropine in Relation to Dose DOSE EFFECTS 0.5 mg Slight cardiac slowing; some dryness of mouth; inhibition of sweating 1 mg Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils 2 mg Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision 5 mg All the above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis 10 mg and Above symptoms more marked; pulse rapid and weak; iris practically more obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma03/01/2009 Dr Aaditya Udupa 11
  12. 12. Place in TherapeuticsAs Emergency Medication Organophosphorus insecticide poisoning. Overdose of β- blockers. Bradycardia, asystole and pulseless electrical activity (PEA) in MI and cardiac arrest.In Special Circumstances For refraction checking in children. In Iridocyclitis  to relieve ciliary spasm and break adhesions. 03/01/2009 Dr Aaditya Udupa 12
  13. 13. Need for Substitutes  Nonspecific actions  Mydriasis & cycloplegia lasts for over a week  Photophobia  Blurring of vision  Palpitations  Dryness of mouth & difficulty in swallowing.  Difficulty in micturition.  Constipation03/01/2009 Dr Aaditya Udupa 13
  14. 14. Overview Agent Structure Tertiary Amine Quaternary Ammonium Compound Natural Atropine Hyoscine Semisynthetic Homatropine Atropine methonitrate Hyoscine butyl bromide Respiratory Ipratropium Bromide Tiotropium Bromide Oxitropium Bromide03/01/2009 Dr Aaditya Udupa 14
  15. 15. Overview Agent Structure Tertiary Amine Quaternary Ammonium Compound Synthetic Mydriatic Tropicamide Cyclopentolate Antisecretory/ Antispasmodic Dicyclomine Propanthelene Valethamate Oxyphenonium Pirenzepine Clidinium Pipenzolate Isopropamide Glycopyrrolate03/01/2009 Dr Aaditya Udupa 15
  16. 16. Overview Agent Structure Tertiary Amine Quaternary Ammonium Compound Synthetic Vasicoselective Oxybutynin Trospium Flavoxate Valethamate Tolterodine Tartarate Darifenacin Solifenacin Emperonium Anti Parkinson Benzhexol Procyclidine Biperidine03/01/2009 Dr Aaditya Udupa 16
  17. 17. Quarternary Ammonium Compounds  Incomplete oral absorption  Poor penetration in brain and eye  Elimination is slower – longer acting  Higher Nicotinic blocking activity  Postural hypotension Ganglion  Impotence Block  N.M. Block at high doses03/01/2009 Dr Aaditya Udupa 17
  18. 18.  Higher specificity for M1 receptor  Primary:Scopolamine  Treatment of nausea and motion sickness (MC)  For ophthalmic purposes  Less often:Formula - C17H21NO4  As a preanesthetic agentHalf life - 4.5 hoursBioavailability - 10 - 50%  HyperhydrosisRoutes: Transdermal,  As an adjunct to narcotic Ocular, Oral, analgesia, such as the Subcutaneous, product Twilight Sleep which Intravenous contained morphine andPregnancy cat: C scopolamine  To enhance the pain-killing ability 03/01/2009 Dr Aaditya Udupa of various opioids 18
  19. 19. Scopolamine (contd)  Available as transdermal patch.  Delivers 1 mg in 3 days.  Incidence of other ADR is low when used by this route.  The patch formulation produces significant blood levels over 48-72 hours.  Special ADR  Anisocoria  Strabismus (J. Paediatrics 1996, 97: 126-7)03/01/2009 Dr Aaditya Udupa 19
  20. 20. Respiratory Antimuscarinic Drugs03/01/2009 Dr Aaditya Udupa 20
  21. 21.  Non-selective muscarinic antagonist.Ipratropium  Short-acting bronchodilator.  Uses:  It is administered by inhalation for the treatment of obstructive lung diseases  Rhinorrhoea & RhinitisFormula - C20H30NO3  Combined with salbutamolMetabolism - Hepatic chronic obstructiveHalf life - 2 hours pulmonary disease (COPD)Routes: Inhalation and asthmaPregnancy cat: B  Combined with fenoterol  asthma 03/01/2009 Dr Aaditya Udupa 21
  22. 22. Ipratropium (contd)  Does not inhibit mucociliary clearance.  In COPD single therapeutic doses of formoterol and ipratropium bromide are equally effective in improving lung function and reducing dyspnoea. However, formoterol appears to be a better bronchodilator producing a faster improvement in lung function. [Indian J Chest Dis Allied Sci 2006; 48: 97-102]03/01/2009 Dr Aaditya Udupa 22
  23. 23. Ipratropium (contd)  Clinical trials:  Combined treatment with Ipratropium and β2 agonists results in slightly greater and more prolonged bronchodialation than either agent alone in baseline asthma. (Bryant & Rogers, Chest 1992 102: 742-47)  In acute bronchoconstriction the combination of a β2 agonist and Ipratropium is more effective than simply giving more β2 agonist. (Bryant & Rogers, Chest 1992 102: 742-47)03/01/2009 Dr Aaditya Udupa 23
  24. 24. Tiotropium  Acts mainly on M3 muscarinic receptors located in the airways  Bronchodialation.  Tiotropium is indicated as a daily, 24 hour, maintenance treatmentFormula: C19H22NO4S2+ of COPD.Bioavailability: 19.5%  Patient removes (inhalation)Metabolism: Hepatic capsule & rotates (25%) the cap and inha-Half life: 5–6 days les twice or thrice.Excretion: RenalPregnancy cat: B1Routes: Inhalation(oral) 03/01/2009 Dr Aaditya Udupa 24
  25. 25. Anti Secretory Antimuscarinics03/01/2009 Dr Aaditya Udupa 25
  26. 26.  Selective M1blocker  It has no effects on the brain and Pirenzepine spinal cord  Uses:  Treatment of peptic ulcers, as it reduces gastric acid secretion and reduces muscle spasmFormula: C19H21N5O2  A recent study reports that dailyRoutes: oral treatment of 2% pirenzepineHalf life: 12 Hours ophthalmic gel (PIR) couldProtein binding: 12% reduce the rate of progressive myopia or short-sightedness in children 2008 August - Journal of American Association for Pediatric Ophthalmology and Strabismus 03/01/2009 Dr Aaditya Udupa 26
  27. 27. Pirenzepine Clinical trial:  Pirenzepine produces about the same rate of healing of ulcer as the H2 receptor antagonist. It is also effective in preventing recurrence of ulcer. (Carmine & Brodger Drugs 1985, 54: 581-6 And Trybia & Cook Drugs, 1997, 30: 85-126) Telenzepine Higher potency and similar efficacy as Pirenzepine.03/01/2009 Dr Aaditya Udupa 27
  28. 28.  Uses:Glycopyrrolate  In anaesthesia as preoperative medication   reduce salivary, tracheobronchial, and pharyngeal secretions  decreasing the acidity of gastricFormula: C19H28NO3+ secretion.Half life: 0.6–1.2  Conjunction with Neostigmine hours  prevent muscarinic side effectsExcretion: 85% renal,  Neurological conditions suchunknown amount inthe bile as amyotrophic lateral sclerosis to reduce excessive salivaPregnancy cat: BRoutes: oral, IV 03/01/2009 28
  29. 29.  Glycopyrrolate prevents bradycardia at clinically used doses without causing tacycardia.  Clinical trial:  Atropine and hyoscine produced a tachycardia followed by a fall in pulse rate similar to the control group during anaesthesia. Glycopyrrolate maintained the pulse at the same level throughout. In view of the disadvantages of tachycardia, glycopyrrolate is probably the anticholinergic agent of choice when such a drug is indicated. (Journal of Small Animal Practice Volume 28 Issue 11, Pages 1087 - 1094)03/01/2009 Dr Aaditya Udupa 29
  30. 30. Vasicoselective Antimuscarinic Rationale for use in Overactive bladder (OAB)  Antimuscarinics reduce bladder smooth muscle tone  Bladder retains larger volume  Reduction in no of micturation episodes, urgency and incontinence.  Useful in urinary incontinence, neurogenic bladder, idiopathic detrusor instability.03/01/2009 Dr Aaditya Udupa 30
  31. 31.  Competitively antagonizes M1, M2, and M3 Receptor.  Direct spasmolytic effects on Oxybutynin bladder smooth muscle as a calcium antagonist and local anesthetic  (R)-enantiomer is moreFormula: C22H31NO3 potent than either the racemateProtein binding: 91- 93% or the (S)-enantiomerHalf life: 12.4-13.2 hours  Use: Relieve urinary andPregnancy cat: B bladder difficulties, includingRoutes: oral, frequent urination and urgetransdermal incontinence  May be used for treatment of 03/01/2009 hyperhidrosis 31
  32. 32. Oxybutynin  Clinical Trials:  The OBJECT study (2001) examined the tolerability of oxybutinin-ER 10 mg once daily compared with tolterodine-IR 2 mg bid. The incidence of dry mouth was similar and moderate-to-severe dry mouth was observed in similar numbers of patients. Oxybutynin ER was significantly better in reducing weekly urge incontinence episodes and urinary frequency than tolterodine at 12 weeks.  The Transdermal Oxybutynin Study Group (2003) compared the safety of transdermal oxybutynin to tolterodine-ER and placebo. Dry mouth was reported in only 4.1% of the patients in the transdermal oxybutynin group compared with 7.3% of the patients in the tolterodine-ER group.03/01/2009 Dr Aaditya Udupa 32
  33. 33. Alternative drug delivery systems  Intravesical anticholinergics  Intravesical administration of oxybutynin has a direct anesthetic effect within the bladder wall.  This delivery system decreases first-pass effect.  As effective and better tolerated than oral oxybutynin for treating OAB.  A bladder pump  It releases oxybutynin at a constant rate over 30 days  The device would be placed via catheterization and removal would require cystoscopy.03/01/2009 Dr Aaditya Udupa 33
  34. 34.  Muscle relaxant properties may be due to a direct action on the Flavoxate smooth muscle rather than by antagonizing muscarinic receptors.  Uses:  Urinary bladder spasms  For symptomatic relief:Formula:  Interstitial Cystitis, Dysuria,C24H25NO4 Urgency, Nocturia, Suprapubic Pain,  Frequency and Incontinence as may occur in Cystitis, Prostatitis, Urethritis, Urethrocystitis/ Urethrotrigonitis.03/01/2009 Dr Aaditya Udupa 34
  35. 35. Darifenacin  Specific for M3 receptorFormula: C28H30N2O2Bioavailability: 15 to 19%  Uses: Overactive bladder withProtein binding: 98% symptoms of urge urinaryMetabolism: Hepatic(CYP2D6- and CYP3A4- incontinence, urgency andmediated) frequencyHalf life: 13 to 19 hoursExcretion: Renal (60%)and biliary (40%)Pregnancy cat: B3, CRoutes: Oral 03/01/2009 Dr Aaditya Udupa 35
  36. 36. Solifenacin  Specific for M3 receptor  Once-a-day dose can offer 24 hour control of the urinary bladder smooth muscle toneFormula: C23H26N2O2Bioavailability: 90%  Urinary antispasmodicProtein binding: 98%  Treatment of overactive bladderMetabolism: Hepatic with or without urge incontinence(CYP3A4-mediated)  May also prolong the QT intervalHalf life: 45 to 68 hoursExcretion: Renal (69.2%)and fecal (22.5%)Pregnancy cat: B3, CRoutes: Oral 03/01/2009 Dr Aaditya Udupa 36
  37. 37. Solifenacin- Cost Effectiveness In a study of cost-effectiveness analysis, the average medical cost per overactive bladder patient with successful treatment is reported to be lowest for 5 mg solifenacin ($6863 per annum) among anticholinergic drugs to treat overactive bladder in the united states (Pharmacotherapy 2006, 26 1694-1702).03/01/2009 Dr Aaditya Udupa 37
  38. 38. Other Agents Trospium:  Used for urinary frequency, urgency and incontinence in detrusor hyperreflexia. Tolterodine:  Claimed to have greater selectivity on bladder M3 receptors than salivary M3 receptors.  Dose reduction in Hepatic impairment Propiverine:  Causes drowsiness with CNS depressents.03/01/2009 Dr Aaditya Udupa 38
  39. 39. Ophthalmic Antimuscarinics03/01/2009 Dr Aaditya Udupa 39
  40. 40. Ophthalmic Use Agent Onset Duration Atropine Mydriasis 40 min 7 days Cycloplegia 1-3 hrs 6-12 days Hyoscine 30-60 min 3-6 days Tropicamide 20-40 min 6 hrs Cyclopentolate 30-60 min 24 hrs Homatropine 45-60 min 1-3 days03/01/2009 Dr Aaditya Udupa 40
  41. 41. Ophthalmic Use  Used for:  Mydriasis: To visualise retina and fundus in posterior chamber.  Cycloplegia: For refraction testing – To counteract latent hypermetropia.03/01/2009 Dr Aaditya Udupa 41
  42. 42. Tropicamide  Short duration of effect (4–8 hours)  Occasionally administered in combination with p-Formula: C17H20N2O2 hydroxyamphetamine whichProtein binding: 45% is a sympathomimetic  Allow better examination of theRoute: Topical lens, vitreous humor, and retina 03/01/2009 Dr Aaditya Udupa 42
  43. 43. Cyclopentolate  The drops take around 30 minutes to work and around 24 hours to wear off.  Should not be used in first 3Formula: C17H25NO3 months of life amblyopia (journal of paediatrics 1990, 26: 106-7)Pregnancy cat: C  Can be abused for CNS effects.Routes: Topical (NEJM 1992; 326: 1363-4) 03/01/2009 Dr Aaditya Udupa 43
  44. 44. Homatropine  Available as the hydrobromide or methylbromide salt  Less potent and weak cycloplegic effect.Formula:C16H22BrNO3 03/01/2009 Dr Aaditya Udupa 44
  45. 45. Mydriatics & Cycloplegics Atropine Tropicamide, Cyclopentolate  Mydriasis lasts for a week  Shorter duration of action  Photophobia  Used for refraction testing  Spasm of accommodation and visualisation of the retina causes blurring of vision  Cannot be used in children  Used in children who have but preffered in adults. very strong ciliary muscle  Patient can resume activities tone like driving in a day.  Used to break adhesions in iritis, uveitis.03/01/2009 Dr Aaditya Udupa 45
  46. 46. Antispasmodic Antimuscarinics03/01/2009 Dr Aaditya Udupa 46
  47. 47. Dicycloverine  It is a smooth muscle relaxant.  Uses:  GI Spasm  Intestinal hypermotility  Symptoms of Irritable BowelFormula: C19H35NO2 Syndrome (IBS)Protein binding:  A meta-analysis concluded>99% that in IBD if 6 patients are treated with antispasmodics, 1 patient will benefit. Cochrane Database Syst Rev: CD003460 03/01/2009 Dr Aaditya Udupa 47
  48. 48.  It is the levo-isomer to atropine.  Twice as potent as atropine.Hyoscyamine  Use:  Spasms  Peptic Ulcers Formula: C17H23NO3  Irritable Bowel Syndrome Bioavailability: 50%  Pancreatitis Metabolism: Hepatic Half life: 3-5 hrs.  Colic Excretion: Urine  Cystitis Pregnancy cat: C Routes: Oral,  Mostly employed as sulfate or hypobromide. Injection03/01/2009 Dr Aaditya Udupa 48
  49. 49.  Use: Valethamate  Spasmodic pains in the abdominal region smooth muscle spasms  Cervical dilatation in the first stage of labour. Metabolism:  Both intramuscular drotaverine Hepatic hydrochloride and valethamate Half life: 3-5 hrs. bromide are effective in acceleration of labor; however, Excretion: Urine drotaverine accelerates labor Routes: Oral, more rapidly and is associated Injection with less side effects. (Int J Gynaecol Obstet. 2001 Sep;74(3):255-60)03/01/2009 Dr Aaditya Udupa 49
  50. 50. Other Antispasmodics  Propanteline  Oxyphenonium  Glycopyrronium  Pipenzolate03/01/2009 Dr Aaditya Udupa 50
  51. 51. Antimuscarinics for Parkinson’s Disease  Rationale:  Act by reducing unbalanced cholinergic activity in the striatum  Only agents used in drug induced parkinsonism.  Can treat muscular dystonia03/01/2009 Dr Aaditya Udupa 51
  52. 52.  It binds to the M1 muscarinic Benzhexol receptor  Use:  Symptomatic treatment of Parkinsons disease  Postencephalitic  Arteriosclerotic  Idiopathic Forms  Treat extrapyramidal side effectsFormula: C20H31NO occurring during antipsychoticHalf life: 3.3-4.1 treatment hours  Reduces the frequency andRoutes: Oral, as duration of oculogyric crises tablet or  May improve psychotic elixir depression and mental inertia 03/01/2009 Dr Aaditya Udupa 52
  53. 53. Benzhexol Equivocal preliminary results from small studies exist for:  Other Dyskinesias  Huntingtons Chorea  Spasmodic Torticollis  Dystonia Abuse: It has euphoriant and aphrodisiac properties therefore it is abused.  Smoked, insufflated, swallowed, or dissolved under the tongue03/01/2009 Dr Aaditya Udupa 53
  54. 54. Biperiden  Central blocking effect on M1 receptorsFormula: C21H29NO  Adjunctive treatment ofBioavailability: 33 ± 5% (oral) Parkinsons diseaseProtein binding: 60%  Better effects in theMetabolism: Hepatic hydroxylation postencephalitic andHalf life: 18 to 24 hours idiopathic than in theExcretion: Renal arteriosclerotic typePregnancy cat: B2(AU) C(US)  Geriatric patients may reactRoutes: Oral, IM, IV with confusional states or develop delirium. 03/01/2009 Dr Aaditya Udupa 54
  55. 55. Procyclidine  Used for the treatment of:Formula:  Parkinson diseaseC19H30ClNO  Drug-induced parkinsonismProtein binding: and acute dystonia~100%-albumin  Idiopathic or secondaryHalf life: ~12 h dystoniaRoutes: oral, im, iv 03/01/2009 Dr Aaditya Udupa 55
  56. 56. Common A.D.R of Newer Agents  Respiratory agents:  Dry mouth  Postural Hypotension  Antispasmodics:  Dry mouth  Constipation  Blurred vision03/01/2009 Dr Aaditya Udupa 56
  57. 57. Common A.D.R of Newer Agents  Ocular Agents:  Dry mouth  Temporary irritation  Vasicoselective:  Dry mouth  Constipation  Blurred vision03/01/2009 Dr Aaditya Udupa 57
  58. 58. Common A.D.R of Newer Agents  Anti Parkinson Drugs:  Severe mental disturbances  Excitement, nausea, vomiting  Paradoxical sinus bradycardia in Schizophrenic patients  Impairment of memory03/01/2009 Dr Aaditya Udupa 58
  59. 59. CLINICAL SUMMARY  Till now agents which show high degree of receptor subtype selectivity which will eliminate unwanted side effects has been difficult to achieve  Subtype-selective muscarinic receptor antagonists show promise  New drug delivery systems may help in improving organ selectivity and reduce the adverse effects.03/01/2009 Dr Aaditya Udupa 59
  60. 60. 03/01/2009 Dr Aaditya Udupa 60

×