1. ANTICHOLINERGICS DepartmentOfPharmacology

2. ANTICHOLINERGICS Also called as Muscarinic receptor antagonists Parasympatholytics

3. CLASSIFICATION Natural alkaloids : Atropine, Hyoscine (scopolamine) Natural alkaloids : Atropine, Hyoscine (scopolamine) Semisynthetic derivatives: Semisynthetic derivatives: Homatropine, Atropine methionitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide Homatropine, Atropine methionitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide Synthetic compounds : Synthetic compounds : a) Mydriatics: cyclopentolate, tropicamide a) Mydriatics: cyclopentolate, tropicamide b) Antisecretory - antispasmodics: b) Antisecretory - antispasmodics: i) Quaternary compounds: Propantheline, oxyphenonium, Clidium, Pipenzolate methyl bromide, Isopropamide, glycopyrrolate. i) Quaternary compounds: Propantheline, oxyphenonium, Clidium, Pipenzolate methyl bromide, Isopropamide, glycopyrrolate.

4. Classification continued Classification continued ii) Tertiary amines: Dicyclomine, Oxybutynin, Flevoxate, pirenzepine, Telenzepine. c) Antiparkinsonian : Trihexyphenidyl, Procyclidine, Biperiden, Benztropine, Cycrimine, Ethopropazine. Others : Tricyclic antidepressants, phenothiazines, antihistamines, disopyramide possess significant antimuscarinic actions.

5. Muscarinic receptor antagonists include; 1)Naturally occurring alkaloids: atropine and scopolamine 2)Semi synthetic derivatives different in their disposition in the body or their duration of action 3)Synthetic; Homatropine and tropicamide-slow selectivity for subtypes of muscarinic receptors, shorter duration of action than atropine. Methyl atropine, ipratropium and tiotropium are quaternary amines and do not cross the BBB. Ipratropium and tiotropium are given as inhalation for treatment of bronchial asthma and COPD Synthetic derivatives possessing partial receptor selectivity include: pirenzepine(used for treatment of acid peptic disorder) and tolterodine (used for treatment of urinary incontinence)

6. Mechanism of action Mechanism of action Muscarinic receptor antagonists prevent the effects of Ach by blocking its binding to muscarinic cholinergic receptors at neuro effecter sites on smooth muscle, cardiac muscle, gland cells, in peripheral ganglia, and in CNS. Muscarinic receptor antagonists prevent the effects of Ach by blocking its binding to muscarinic cholinergic receptors at neuro effecter sites on smooth muscle, cardiac muscle, gland cells, in peripheral ganglia, and in CNS. They compete with Ach and other muscarinic agonists for a common binding site on the muscarinic receptors. They compete with Ach and other muscarinic agonists for a common binding site on the muscarinic receptors. Antagonism being competitive can be overcome if concentration of Ach is increased sufficiently. Antagonism being competitive can be overcome if concentration of Ach is increased sufficiently.

7. In general they produce very little In general they produce very little blockade of Ach at nicotinic receptor sites. Quaternary ammonium analogs Quaternary ammonium analogs generally exhibit a greater degree of nicotinic blocking activity and interfere with Nm transmission. In CNS: there is both muscarinic and In CNS: there is both muscarinic and nicotinic transmission nicotinic transmission at spinal, sub cortical, levels at spinal, sub cortical, levels Toxic doses: CNS stimulation followed Toxic doses: CNS stimulation followed by depression. by depression. Quaternary compounds: poor Quaternary compounds: poor penetration of BBB. So –no effect on CNS.

8. Atropine the prototype Atropine the prototype Source: Atropine and scopolamine are alkaloids of belladonna plant (solanaceae). Also called as deadly nightshade shrub-used to produce obscure and prolonged poisoning. Named after Atropos, the oldest of the three fates- who cuts the thread of life. Source: Atropine and scopolamine are alkaloids of belladonna plant (solanaceae). Also called as deadly nightshade shrub-used to produce obscure and prolonged poisoning. Named after Atropos, the oldest of the three fates- who cuts the thread of life. Italian woman used to dilate their pupils. modern day photographers use it for visual appeal. Italian woman used to dilate their pupils. modern day photographers use it for visual appeal. Atropine (hyoscyamine) also found in the plant Datura stramonium /James town/Jimson weed. Roots and leaves are burnt to inhale smoke for treatment of bronchial asthma. Atropine (hyoscyamine) also found in the plant Datura stramonium /James town/Jimson weed. Roots and leaves are burnt to inhale smoke for treatment of bronchial asthma. Scopolamine(hyoscine)obtained from hyoscyamus niger. Scopolamine(hyoscine)obtained from hyoscyamus niger.

9. Role of atropine in relation to dose DOSE EFFECTS DOSE EFFECTS 0.5 mg Slight cardiac slowing; some dryness of mouth; 0.5 mg Slight cardiac slowing; some dryness of mouth; inhibition of sweating inhibition of sweating 1 mg Definite dryness of mouth; thirst; acceleration of 1 mg Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild heart, sometimes preceded by slowing; mild dilation of pupils dilation of pupils 2 mg Rapid heart rate; palpitation; marked dryness of 2 mg Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision mouth; dilated pupils; some blurring of near vision 5 mg All the above symptoms marked; difficulty in 5 mg All the above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis reduced intestinal peristalsis 10 mg Above symptoms more marked; pulse rapid and 10 mg Above symptoms more marked; pulse rapid and weak; and iris practically obliterated; vision very weak; and iris practically obliterated; vision very blurred; skin flushed, more hot, dry, and scarlet; blurred; skin flushed, more hot, dry, and scarlet; ataxia, restlessness, excitement; hallucinations ataxia, restlessness, excitement; hallucinations and delirium; coma and delirium; coma

10. Small doses of atropine: Decreased salivary, bronchial secretions and sweating Large doses: Eye: pupils dilate, inhibition of accommodation of lens to near vision Heart: vagal effects on heart are blocked- HR Urinary bladder: decreased parasympathetic control-decreased micturition GIT: decreased tone and motility Still higher doses: Stomach: Decrease gastric secretion and motility, along with decreased salivation, ocular accommodation & micturition

11. Belladonna poisoning Deliberate-suicidal Deliberate-suicidal Accidental. patients on antipsycotic treatment with phenothiazines and atypical drugs like clozapine and olanzapine, antidepressants- protriptyline, amitriptyline. Accidental. patients on antipsycotic treatment with phenothiazines and atypical drugs like clozapine and olanzapine, antidepressants- protriptyline, amitriptyline. Infants and young children are specially susceptible to toxic doses of atropinic drugs like diphenoxylate – atropine (lomotil) used for treatment of diarrhoea. Infants and young children are specially susceptible to toxic doses of atropinic drugs like diphenoxylate – atropine (lomotil) used for treatment of diarrhoea. Scopolamine: used for motion sickness causes toxic psychosis. Scopolamine: used for motion sickness causes toxic psychosis.

12. Belladonna poisoning Belladonna poisoning Diagnosis Diagnosis Injection Physostigmine i/v (anti cholinesterase agent), methacholine 5mg, neostigmine 1mg s/c-used for confirmation of poisoning. If typical salivation, sweating, bradycardia, intestinal hyperactivity do not occur with physostigmine then diagnosis of intoxication with atropinic drugs is confirmed Injection Physostigmine i/v (anti cholinesterase agent), methacholine 5mg, neostigmine 1mg s/c-used for confirmation of poisoning. If typical salivation, sweating, bradycardia, intestinal hyperactivity do not occur with physostigmine then diagnosis of intoxication with atropinic drugs is confirmed

13. Symptoms of poisoning Symptoms last for more than 48hrs. Symptoms last for more than 48hrs. Depression Depression Circulatory collapse-decreased blood pressure Circulatory collapse-decreased blood pressure Convulsions Convulsions Paralysis Paralysis Coma Coma

14. Treatment of poisoning Measures to limit intestinal absorption if poison taken orally-gastric lavage with tannic acid. Measures to limit intestinal absorption if poison taken orally-gastric lavage with tannic acid. Physostigmine: 1-3mg s/c or slow i/v injection rapidly abolishes the delirium and coma. Since physostigmine is metabolised rapidly, patient may again lapse into coma within 1-2hrs. And repeated doses may be required 2- 6hrly. Physostigmine: 1-3mg s/c or slow i/v injection rapidly abolishes the delirium and coma. Since physostigmine is metabolised rapidly, patient may again lapse into coma within 1-2hrs. And repeated doses may be required 2- 6hrly. If marked excitement is present-Diazepam (Benzodiazepine) is the most suitable agent for producing sedation and control of convulsions If marked excitement is present-Diazepam (Benzodiazepine) is the most suitable agent for producing sedation and control of convulsions Respiratory support Respiratory support Control of hyperthermia; Ice bags and alcohol sponges help to reduce fever specially in children. Control of hyperthermia; Ice bags and alcohol sponges help to reduce fever specially in children.

20. Therapeutic uses of muscarinic receptor antagonists Route : Local administration-pulmonary inhalational, local instillation in eye Route : Local administration-pulmonary inhalational, local instillation in eye Oral Oral Parenteral injection Parenteral injection GIT uses : GIT uses : Acid peptic disease:Pirenzepine-100 to 150mg.reduces gastric acid secretion Acid peptic disease:Pirenzepine-100 to 150mg.reduces gastric acid secretion Irritable bowel syndrome Irritable bowel syndrome Diarrhoea: associated with irritable bowel conditions Diarrhoea: associated with irritable bowel conditions Mild dysenteries and diverticulitis Mild dysenteries and diverticulitis Decreasing excessive salivation associated with heavy metal poisoning or parkinsonism drug induced salivation Decreasing excessive salivation associated with heavy metal poisoning or parkinsonism drug induced salivation

21. Uses in ophthalmology: thorough examination of retina and disc Local administration to produce mydriasis and cycloplegia for Treatment of iridocyclitis and keratitis Alternated with miotics for breaking or preventing the development of adhesions between iris and lens Complete cycloplegia may be necessary in the treatment of iridocyclitis and choroiditis and for accurate measurement of refractive errors. Atropine or scopolamine are preferred to other drugs like cyclopentolate and tropicamide

22. Respiratory uses: Acute rhinitis associated with coryza or hay fever: atropine to reduce the secretions Systemic administration of belladonna alkaloids derivatives for treatment of bronchial asthma or obstructive pulmonary disease Ipratropium bromide and tiotropium are given by inhalation do not produce adverse effects. They are used along with beta adrenergic receptor agonists.

23. CVS uses : Atropine in initial treatment of patients with MI in whom excessive vagal tone causes sinus or nodal bradycardia Atropine used in reducing severe bradycardia and syncope associated with a hyperactive carotid sinus reflex Treatment of premature ventricular contractions associated with slow Atrial rate Can reduce degree of AV Block when increased vagal tone causing conduction defects e.g. 2nd degree AV Block produced by the drug digitalis

24. CNS uses: Preventing Dystonia or parkinsonism symptoms in patients on antipsychotic treatment Parkinsonism- benztropine Prevention of motion sickness-scopolamine is most effective prophylactic agent for short exposure to severe motion(4-6hrs to 72 hrs with TDP of 0.5mg applied on the post auricular mastoid region) Side effects are –dry mouth, drowsiness, blurred vision, psychosis.

25. Uses in anesthesia : Atropine is commonly given as pre anesthetic medication to prevent vagal reflexes induced by surgical manipulation of visceral organs. Atropine or glycopyrrolate are used along with neostigmine to counteract its para sympathetic effects when used to reverse muscle relaxation after surgery. Side effects produced are cardiac arrhythmias.

26. Genitourinary tract uses : Atropine and opioid treatment of renal colic Tolterodine can lower intravesicular (inside bladder) pressure, increase capacity and reduce the frequency of urinary bladder contractions by antagonizing the para sympathetic control Enuresis in children-for progressive increase in bladder capacity To decrease urinary frequency in spastic paraplegia and increase capacity of bladder

27. Anticholinesterase and mushroom poisoning: Atropine in large doses is used for treatment of anticholinesterase organophophorus poisoning To antagonize the para sympathetic effects of neostigmine or other anticholinesterase agents administered in treatment of myasthenia gravis. Antidote for symptoms of mushroom poisoning by cholinomimetic alkaloid muscarine found in certain mushroom species

28. Learning Outcomes Classification with examples of anticholinergics Classification with examples of anticholinergics Mechanism of action Mechanism of action Clinical indications / Uses Clinical indications / Uses ADRs ADRs Treatment of Organophosphorous Poisoning Treatment of Organophosphorous Poisoning giving dose, route of administration, mechanism of action of Atropine & Oximes giving dose, route of administration, mechanism of action of Atropine & Oximes Comparison - Atropine & Scopalamine Comparison - Atropine & Scopalamine Comparison of atropine substitutes acting on eye Comparison of atropine substitutes acting on eye Define & explain ‘passive mydriasis’ Define & explain ‘passive mydriasis’