anticholinergic pharmacology

ANTI-CHOLINERGIC DRUGS DR T. IBRAHIM

ANTI-MUSCARINIC DRUGS

Anti-muscarinic ( anti-cholinergic drugs) block the effect of parasympathetic autonomic discharge by binding to the muscarinic receptors. They are referred to as parasympatholytics.

Types of muscarinic receptors

Predominant sites

M1 CNS neurons, sympathetic post-ganglionic cell neurons, many pre-synaptic sites.

M2 Myocardium, smooth muscle, some neuronal sitesM3 Effector cell membrane ( glandular, smooth muscle cell)

M4 and M5 Predominant in CNS

Examples of some anti-muscarinic agents:

Naturally occurring Semi-synthetic synthetic

AtropineScopolamine (Hyoscine)

HomatropineAtropine methonitrateHyoscine butyl bromideIpratropium bromideTiotropium bromide

TropicamideTolterodineTrihexphenidyl….

Anti-cholinergic drugs used in:

ophthalmology

Parkinsonism Bladder disorder

GIT disorder Respiratory disorder

Anti-secretory

AtropineHyoscineHomatropineCyclopentolateTropicamide

BenztropineBiperidenTrihexphenidylOrphenadrineProcyclidine

OxybutyninFlavoxateSolifenacinDarifenacinTolterodineFesoterodineTrospium

DicyclomineHyoscine butyl bromideGlycopyrollateMethscopolamineCimetropiumOtilonium bromidePerenzepineTelezepine

Ipratropium bromideTiotropium bromideAclidinium bromide

Glycopyrollatepropantheline

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Anticholinergic drugs can be tertiary or quartenary amines

Tertiary amines Quartenary amineAtropineHyoscineOxybutyninSolifenacinDarifenacin

GlycopyrollatePropanthelineMethanthelineTrospium

Note: Many drugs (anti-histamine, anti-psychotics, anti-depressant eg diphenhydramine, promethazine, tricyclic anti-depressant) have significant anti-cholinergic action.

ATROPINE (Prototype of anti-cholinergic drugs)It is a naturally occurring tertiary amine, obtained from Atropa Belladonna or Datura Stramonium.

PharmacokineticAtropine and other tertiary amines are lipid soluble drugs and are well absorbed from the GIT and conjunctival membrane.

They are widely distributed in the body including the CNS.

Quartenary compounds are less lipid soluble and have decreased absorption from the GIT tract (10-30%).

They do not penetrate eyes, brain and CNS. Ocular effects are not seen after oral and parenteral administration. They have higher nicotinic binding property compared to the tertiary amines.

Atropine is excreted 50% unchanged in urine and rest undergoes hydrolysis and conjugation.Note: The parasympathetic activity decreases rapidly except for action on the eyes.

Mechanism of actionAtropine causes non-selective surmountable blockade of cholinomimetic action at the muscarinic receptors M1, M2 and M3 (action of a small dose of atropine can be overcome by a large dose of acetylcholine, Ach). Previously, atropine was thought to be a competitive antagonist of Ach but now research has proved it to be an inverse agonist of Ach that shifts the equilibrium towards the inactive state of the receptor.Atropine also prevents the release of IP3 and the inhibition of adenylcyclase.

Exampes of other inverse agonist of Ach: Perenzepine, trihexphenidyl, methyl derivative of scopolamine.

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Pharmacological ActionsTissues that are highly sensitive to atropine are: salivary, bronchial and sweat glands. Gastric parietal cells are least sensitive.

CNS1. Atropine has minimal stimulant effect on the CNS( action on the parasympathetic medullary centres). Toxicity of atropine will lead to excitement, agitation, hallucination, delirium followed by respiratory depression and coma. Hyoscine and many other anti-cholinergic agents have CNS depressant action.2. Depression of vestibular excitation and anti-motion sickness property.3. Tremors of parkinson’s disease and drug induced parkinsonism decreases with centrally acting anti-cholinergic drugs. In these conditions, there is a relative increase in the Ach level with reduction of dopamine level.

EyesThe pupillary constrictor and the ciliary muscle of the eyes are affected.1. When the cholinergic transmission to the pupillary constrictor muscle is blocked by atropine, there is unopposed sympathetic dilator action which leads to dilation of the pupil (mydriasis).2. Atropine also blocks weakens the contraction of the ciliary muscle which leads to the inability to accommodate, ie cannot focus on near objects. This is known as cyclopegia.3. Atropine decreases the lacrimal secretion.

CVS and Blood vessels1. Moderate to high dose of atropine causes vagal blockade and results in tachycardia. The SA node is very sensitive to muscarinic receptor blockade, M2).2. Lower doses (0.4-0.6 mg), initially results in transient bradycardia followed by tachycardia. The transient bradycardia is due to blockade of the prejunctional M1 receptors on the post-ganglionic fibres that limit the Ach release in the SA node and other tissues. The tachycardia is direct M2 receptor blockade in the myocardium. This phenomenon is absent on rapid IV injection of atropine.3. Atropine decreases the P-R interval and also decreases the refractory period of the AV node and facilitates AV conduction.4. Most blood vessels have no direct stimulation from the parasympathetic system. Dilation of coronary arteries is under the control of the parasympathetic system. Sympathetic cholinergic nerves cause vasodilation in the skeletal muscle vascular bed.

Note: Anti-cholinergic drugs do not have much effect on the blood pressure.

Respiratory systemSmooth muscle and the secretory glands of the airway contain muscarinic receptors and receive vagal innervation.Atropine causes bronchodilation and decreases the airway secretion. It also decreases the muco-ciliary clearance which can lead to formation of mucus plugs and alveolar collapse.

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Ipratropium bromide and tiotropium have more selective action on the respiratory tract with less CNS penetration and adverse effects. They do not impair the muco-ciliary clearance.Note: Anti-cholinergics are less potent bronchodilators as compared to selective β2-agonist.

GIT1. Decrease in salivation leading to dryness of mouth.2. Gastrin secretion is reduced to a small extent leading to a decrease in the volume of gastric acid,

mucin and pepsin secretion. Basal secretion is affected more than food, alcohol or nicotine induced gastrin secretion. Perenzepine and Telenzepine decrease the gastric secretion with less adverse effects as they are thought to have selective action.

3. Gastro-intestinal smooth muscle motility is reduced leading to a decrease in propulsive movement and hence prolonged the gastric emptying time.

Genito-urinary tractRelaxation of the smooth muscle of the ureters and bladder wall and hence slows down voiding process and ultimately can lead to urinary retention.

Sweat glands1. Inhibition of sweating.2. Stimulation of the temperature regulating centre in the hypothalamus.

When used in high dose, anti-cholinergic agents will increase the body temperature by the two above mechanisms.

Therapeutic uses of atropine and its substitutes.1. Parkinson’s disease: as adjuvant to other therapy.

Useful in drug-induced Parkinsonism.

Benztropine: 1-6 mg/dayBiperiden: 2-12 mg/dayTrihexphenidyl: 6-20 mg/dayOrphenadrine: 150-400 mg/dayProcyclidine: 7.5-30 mg/day

2. Motion sickness Scopolamine: available as tablet (0.2 mg), injection and transdermal patch, TDS.All agents given for combating motion sickness have to be given prophylactically. If given when motion sickness has already started, they are of no use.

The patch has to be applied 4 hours on the post-auricular mastoid region prior to the journey and significant blood level of the drug remains till 48-72 hours.

3. Ophthalmologic disorders Duration of action/day

Atropine (0.5-1%) 7-10Hyoscine(0.25%) 3-7Homatropine(2-5%) 1-3Cyclopentolate(0.5-2%) 1

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Tropicamide(0.5-1%) 0.25 day (6 h)

a. Accurate measurement of errors of refraction requires ciliary muscle paralysis. Tropicamide is preferred for this purpose as it has quickest onset of action, short duration of action and less adverse effects.

b. Used alternately with a miotic to prevent or to break synechia (adhesion) formation in conditions like uveitis and iritis.

c. To decrease painful spasms and to give rest to ocular muscles in conditions like uveitis , iridocyclitis and iritis.Note: For fundoscopy, phenyl ephrine is preferred (short duration of action + cyclopegia is not desired).

4. Respiratory disorders Ipratropium bromide: 20-40mcg 3-4 times daily via MDI or 250-500 mcg 3-4 times daily via nebulisation.Tiotropium bromide: 18 mcg/day.Aclidinium bromide: 400 mcg BiD

When inhaled, the action of these drugs is confined to the mouth and airways with less systemic adverse effects. They provide little protection against brochoconstriction induced by 5HT or leukotrienes.They are less potent bronchodilator compared to selective β2-agonist.

Indication for using Ipratropium bromide (acts on M1, M2, M3)a. Bronchial asthma in combination with other bronchodilators.b. FDA approved for treatment of rhinorrhea associated with common cold, with allergic or

non-allergic perennial rhinitis.

Indication for using Tiotropium bromide(acts on M1, M3).a. COPD whereby reflex vagal activity is an important component in causing broncho-

constriction.b. Useful adjuvant in pulmonary rehabilitation in increasing exercise tolerance.

Indication for using Aclidinium bromide(long acting).a. For maintenance treatment of COPD

Adverse effectsDry mouth, cough, paradoxical bronchospasm, throat irritation, tachycardia, eye pain, blurring of vision, rise in IOP.

5. CVS a. Parenteral IV atropine 0.6-1.2 mg is used to treat bradyarrythmia (induced by digitalis

toxicity, following MI, partial AV block).b. In patient of hyperactive carotid sinus (fainting/ syncope occurs because of increase vagal

discharge to pressure on neck).

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c. In idiopathic dilated cardiomyopathy and Chaga’s disease, there is auto-antibodies against the M2 receptors which exerts parasympathetic effect on the heart. The action of which is controlled by atropine.

6. GIT Atropine: 0.025 mgDicyclomine: 10-20 mg oral/ ImHyoscine butyl bromide: 20-40 mg oral/IMGlycopyrollate: 1-8 mg Methscopolamine: 2.5-5 mgCimetropiumOtilonium bromide

a. Common Traveller’s diarrheab. Nervousness and drug induced diarrhea.c. Often combined with anti-diarrhoeal agent like diphenoxylate (potentiate its action as well

as preventing drug dependence that can occur with diphenoxylate).d. Intestinal and renal colic in the absence of mechanical obstruction.e. Rarely used in dysmenorrheal-not very effective.f. Perenzepine (was thought to be M1 selective) was used in the treatment of peptic ulcer.

7. Urinary disorders Oxybutynin: 5 mg tds (M3 selective); used as patch, oral or instill through the bladder.Flavoxate: 200 mg tds; weak antihistamine, local anaesthetic and analgesic properties in addition to its anti-cholinergic activity.Solifenacin:5 mg once daily; M3 selective.Darifenacin: 7.5 mg once daily; M3 selective.Propiverin: 15 mg tds.Tolterodine 2mg BDFesoterodine

a. To relieve bladder spasm after urological surgery (prostatectomy) and in inflammatory condition like prostatitis.

b. Decrease voiding in patient with neurological disease-meningomyelocoele.c. Urinary incontinence in adult.d. Enuresis in children.

Botulinium toxin A interferes with neuronal acetylcholine release and is used to decrease urinary incontinence. Action lasts for several months after a single intra-bladder injection.

Note: xerostomia is the most common cause of discontinuation of therapy.

8. Pre-anaesthetic medication Glycopyrollate : 4-5 mcg/kg; preferred as it is long acting with less CNS adverse effects.

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It is used for the following reasons:a. To check increased salivation and tracheo-brochial secretion.b. Prevent laryngospasm by decreasing respiratory secretion.c. Prevent vasovagal attack during anaesthesia and intubation.

9. Cholinergic/ Anti-cholinesterase agent poisoning a. Organophosphorus poisoning

IV atropine 4-6 mg (maximum 50 mg) till drying of trachea-bronchial secretion. IV Pralidoxime 30 mg/kg, slowly (maximum 12 g in 24 hours) + IV phentolamine 5 mg.

Supportive measures:Gastric lavage with activated charcoal in water along with sorbitol if the person has ingested the compound and present s within 4 hours post-ingestion.IV diazepam 10 mg.Correction of fluid and electrolyte imbalances.Aspiration of secretion.Correction of acidosis with IV NaHCO3, 1 ml/kg.Removal of contaminated clothings.Antibiotic prophylaxis.

b. Carbamates poisoning: Atropine IV is used. OXIMES ARE CONTRA-INDICATED.c. Mushroom poisoning , eg: Inocybe genus.

10. Treatment of hyperhidrosis.

11. To decrease salivation induced by heavy metal poisoning.

12. Along with anti-cholinesterase agents in myasthenia gravis and in reversal of block, atropine is given to decrease the muscarinic adverse effects.

Adverse effects1. Dry mouth, difficulty in speech and swallowing.2. Dry, flush, hot skin (especially over the face and neck).3. Raised body temperature.4. Difficulty in micturition and urine retention.5. Constipation.7. Mydriasis, photophobia and blurring of vision.8. Palpitation, excitement..

Atropine poisoningIt is mostly suicidal in nature.

Clinical features

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Exaggeration of the above features along with psychotic behavior, delirium, ataxia, hallucination, seizure hypotension, CVS collapse with respiratory depression, coma and finally death can result.

Treatment Generally treated symptomatically.Temperature control (cooling blankets).Seizure control with IV diazepam 5-10 mg. Correction of fluid and electrolyte imbalances.In very severe case, IV physostigmine 1-4 mg.

Note: Poisoning with quartenary anti-cholinergic drugs will cause blockade of nicotinic receptors with marked orthostatic hypotension and other peripheral signs of parasympathetic blockade.

TreatmentNeostigmine . phenyl ephrine for control of hypotention.

Absolute contra-indication of anti-cholinergic drugs1. Glaucoma (narrow angle).2. Patient with shallow anterior chamber of the eyes.3. BPH.

References:1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12thed. US: McGraw Hill.2. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12thed. US: McGraw Hill.3. HARRISON., 2012. Principle of internal medicine. 18thed. US:McGraw Hill.4. ROYAL PHARMACEUTICAL SOCIETY., 2013. BNF. London: BNF publication.5. www.nlm.nih.gov/medlineplus/druginfo/meds/a613001.htm6. reference.medscape.com/drug/tudorza-pressair-aclidinium-9997637. emedicine.medscape.com/article/167726-overview

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http://www.nlm.nih.gov/medlineplus/druginfo/meds/a613001.htm

anticholinergic pharmacology

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