Anticholinergic / Parasympatholytic / Cholinergic Blocking Agent

Anticholinergic drugs are those which block actions of acetylcholine on autonomic effectors & in the CNS exerted through muscarinic receptors. Though nicotinic antagonistic also block certain action of acetylcholine. They are also called antimuscarinic agents.

Classification:

  1. Natural Alkaloids: Atropine, hyoscine.
  2. Semisynthetic Derivatives: Atropine methonitrate, hyoscine methyl bromide, hyoscine butylbromide, homatropine methyl bromide, tiotropium bromide, ipratropium bromide.
  3. Synthetic Compound:
    • Mydriatics:Cyclopentolate, tropicamide.
    • Antisecretory – Antispasmodics: Propantheline, oxyphenonium, clidinium, pipenzolate methyl bromide, mepenzolate methylbromide, isopropamide, glycopyrrolate, dicyclomine, pirenzepine, telenzepine.
    • Antiparkinsonian: Benzhexol, procyclidine, biperiden, benztropine, cycrimine, ethopropazine.

Belladona Alkaloid

The two important alkaloids of belladonna are atropine & hyoscine (scopolamine). Atropine is an ester of an aromatic organic acid (tropic acid) with a complex of organic base tropine.

Hyoscine is an ester of tropic acid with another base ‘Scopine’.

Mechanism of Action:

The belladonna alkaloids block the muscarinic effects of endogenous as well as externally administered acetylcholine by competing with acetylcholine for muscarinic receptors. They donot interfere with the release of acetylcholine at the cholinergic nerve endings.

The antagonism between atropine and acetylcholine is a competitive type. Atropineis more effective in blocking the effects of externally administered acetylcholine than the effects of cholinergic nerve stimulation. Atropine can completely abolish the effects of choline esters on the gastrointestinal tract but it does not completely abolish the effect of vagal stimulation. Atropine is a specific inhibitor of the muscarinic effects but in very large doses it can block the nicotinic action of acetylcholine at autonomic ganglia and the neuromuscular junction. It can also block the actions of histamine, 5-hydroxy-tryptamine and adrenaline.

Pharmacological Actions:

The action of atropine on various organs are-

  1. CNS: Atropine has an overall CNS stimulant action. Due to their restricted entry into the brain. The actions of its are not appreciable at low doses. Atropine stimulates many medullary centres, vagal, respiratory and vasomotor. It depress vestibular excitation and has anti-motion sickness properly. It suppresses tremor and rigidity of Parkinsonism, high doses causes cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression and coma.
  2. Cardiovascular System: Atropine in therapeutic doses may initially decrease the heart rate. Owing to its action as a partial agonist of acetylcholine. This effect is usually followed by tachycardia, particularly in young individuals whom the heart rate may increase 30 to 40 beats per minute. In therapeutic doses, atropine completely counters the peripheralvasodilation and hypotension produced by parasympathomimetic agents. Toxic doses of atropine produce hypotension as a result of either depression of the vasomotor centre or peripheral vasomotor paralysis.
  3. Eye: On local instillation, atropine produces mydriasis by blocking the cholinergic nerve supplying the smooth muscles of the sphincter of the iris. The ciliary smooth muscles also paralysed by atropine. If produce paralysis of accommodation or cycloplegia. Atropine is thus both a mydriatic and cycloplegic drug. Local instillation of 1% atropine drops produces maximum mydriatic response within 30 – 40mins and recovery occurs within 7 to 10 days.
  4. Smooth Muscles: All visceral smooth muscles that receive parasympathetic motor innervations are relaxed by atropine. Tone and amplitude of contractions of stomach and intestine are reduced, the passage of rhyme is slowed constipation may occur, spasm may be relieved.

Atropine causesbronchodilationand reduces airway resistance, especially in COPD (Chronic obstructive pulmonary disease) and asthma patients. Inflammatory mediators like histamine, PGS and kinins increase vagal activity in addition totheir direct action on bronchial smooth muscles and glands. Atropine partially blocks their action by antagonizing the reflex vagal component.

It has a relaxant action on ureter and urinary bladder, urinary retention may occur in older males with prostatic hypertrophy.

  1. Glands: Atropine markedly decreases sweat, salivary tracheobronchial and lachrymal secretion. Skin and eyes becomes dry, talking and swallowing may be difficult. Atropine decreases the secretion of acid, pepsin and mucous in the stomach, but the primary action is on volume of secretion. Intestinal and pancreatic secretions are not significantly reduced. Bile production is not affected.
  2. Body: Temperature: Rise in body temperature occurs at higher doses. It is due to both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus.

Local Anesthetics: Atropine has a mild anaesthetic action on the cornea.

Absorption & Excretion:

The belladonna alkaloids are satisfactory absorbed from GIT, from parenteral sites of administration and from mucous membranes. Also absorb from eye and intact unbroken skin. It is excreted unchanged from by kidneys. Atropine crosses the placenta barrier and is secreted in milk and saliva.

Adverse Reactions:

Belladonna poisoning may occur due to drug over dose or consumption of seeds and berries of belladonna plant children are highly susceptible. The common side effects are dry mouth, difficulty in swallowing and talking, fever, difficulty in micturition, dilated pupil, photophobia, blurring of near vision, palpitation, excitement delirium, ataxia, hallucinations, hypotension, weak and rapid pulse, cardiovascular collapse with respiratory depression.

Treatment of Belladonna Poisoning:

If poison has been ingested, gastric lavage should be done with tannic acid. The patient should be kept in a dark quiet room. Cold sponging ice bags are applied for reducing body temperature. Physostigmine 1-3 mg S.C. or I.V. antagonizes both central and peripheral effects. It may be repeated4-6 hourly.

Contra Indications:

Hypersensitivity, glaucoma, elderly males with prostatic hypertrophy, congestive cardiac failure with tachycardia.

Preparation & Dose:

Atropine sulphate may be administered orally as 0.5 mg tablets or in powder form.

Atropine eye ointment contains 1% of atropine sulphate hyoscine (scopolamine) injection contains 0.4mg of hyoscine hydrobromide tablets 0.3 – 0.6 mg.

  1. Hyoscine Butyl Bromide (BUSCOPAN): 20 – 40 mg oral, I.M, I.V, S.C, less potent and longer acting than atropine used for esophageal and gastrointestinal spastic conditions.
  2. Atropine Methonitrate (MYDRINDON): 5 – 10 mg oral, I.M. for abdominal colics and hyper acidity. As an aerosol it is used in bronchial asthma and asthmatic bronchitis.
  3. Homatropine Methylbromide: 5 – 10 mg oral,I.M. has about four time’s greater ganglion blocking property than atropine, used mainly as antispasmodic.
  4. Propantheline (PROBANTHINE): 15 – 30 mg oral has been the most popular anticholinergic used for peptic ulcer and gastritis. It also delayed gastric emptying time.
  5. Clidinium (SPASRIL): 5 – 5 mg oral used in combinationwith benzodiazepine, for nervous dyspepsia, gastritis, irritable colon, peptic ulcer etc.
  6. Isopropamide (STELABID): 5 mg oral indicated in hyperacidity, nervous dyspepsia, irritablebowel and other gastrointestinal problems, especially when associated with emotional mental disorders.
  7. Dicyclomine (SPASMEX): 20 mg oral has direct smooth muscle relaxant action in addition to weak anticholinergic, exerts antispasmodic at doseswhich produce few atropinic side effects. It also has antiemetic property that is used in morning sickness and motion sickness. Dysmenorrhoea and irritable bowel are other indications.
  8. Tropicamide (TROPICAMIDE): It has the quickest (20 – 40 minutes) and briefest (3 – 6 hrs) action, but it relatively unreliable cycloplegic. However, it is satisfactory for refraction testing in adults and as a short acting mydriatic for fundoscopy.

Uses of Anticholinergic Drugs:

  • As Antisecretory:
    1. Preanaesthetic Medication: It reduce salivary and tracheobronchial secretions. Atropine drugs also prevent laryngospasm, not by an action on laryngeal muscles, which are skeletal muscles but by reducing respiratory secretions that reflexly predispose to laryngospasm, vasovagal attack during anaesthesia may also be prevented.
    2. Peptic Ulcer: Atropinic drugs decrease gastric secretion and afford symptomatic relief in peptic ulcer. Due to their side effects now days they are not used.
    3. Pulmonary Embolism (obstruction of pulmonary artery): These drugs are benefit by reducing reflex secretions.
    4. These drugs are also used to check excessive sweating or salivation.
  • As Antispasmodic:
    1. Intestinal and renal colic, abdominal cramps: Symptomatic relief is afforded if there is no mechanical destruction. Atropine is less effective in biliary colic and is not able to completely counteract biliary spasm due to opiates.
    2. Nervous and drug induced diarrhoea, functional diarrhoea but not effective in infective diarrhoea.
    3. For the treatment of spastic constipation and irritable colon.
    4. Pylorospasm, gastric hyper motility, gastritis, nervous dyspepsia.
    5. To relieve urinary frequency and urgency, enuresis in children.
  • Bronchial Asthma, Asthmatic Bronchitis:

Reflex vagal activity is an important factor is causing bronchoconstriction and increased secretion in chronic bronchitis and COPD, but to a lesser extent in bronchial asthma. Inhaled atropine methonitrate or ipratropium bromide has been found to be especially effective in asthmatic bronchitis and COPD.

  • Eye:

Atropine is used to produced mydriasis and cycloplegia. Mydriasis is necessary for a through fundoscopicexamination & in the treatment of acute iritis, iridocyclitis (inflammation of iris & ciliary body) & keratitis (Inflammation of the cornea). Atropine reduces pain in these conditions. Atropine may be instilled into the eye alternately with miotics to break the adhesions between the iris & the lens or the cornea. When maximum cycloplegia is desired e.g. in correction of accommodative esotropia, atropine is preferred. Atropine is also used to treat corneal ulcer & correcting accommodation spasm.

  • Atropine is used for the treatment for organophosphorus poisoning.
  • Atropine is useful in counteracting bradycardia & partial heart block in selective patients where increased vagal tone is responsible.
  • Atropine is the specific antidote for anticholine and mushroom poisoning. It is also given to block muscarinic actions of neostigmine, decurarization or cobra envenomation.
  • For central action:
    1. Parkinsonism – Belladonna alkaloids are used for the treatment of Parkinsonism.
    2. Motion Sickness – Hyoscine is the most effective drugs for motion sickness. It is particularly valuable in highly susceptible individuals and for vigorous motions. The drug should be given prophylactically. A transdermal preparation applied behind the pinna, 4 hours before journey, it has been shown to protect for 3 days.
    3. Lie Detector – Hyoscine has been used to produce sedation and amnesia during labour (twilight sleep) and to control maniacal states. It had earned a reputation as a ‘lie detector’ during world war- 2, its amnesic and depressant action was believed to put the subject ‘off guard’ in the face of sustained interrogation and sleep deprivation, so that he come out with the truth.

 

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