Anticholinergics - drdhriti

Anticholinergic DrugsAnticholinergic DrugsDr. D. K. Brahma

Associate ProfessorDepartment of Pharmacology

NEIGRIHMS, Shillong

IntroductionIntroduction

Parasympathetic Nervous System plays an important Role in physiologic and pathophysiologic responses - “Rest and Digest”

Drugs that block Cholinoreceptors have important clinical effects, some of which are of great clinical value

Cholinoceptor antagonists are, like agonists - Muscarinic and Nicotinic

Antinicotinic – ganglion blockers and MN junction blockers◦ Discussed elsewhere (SMR Chapter)

Muscarinic blockers◦ Atropine is the prototype – many synthetic and semi

synthetics are available now◦ All are competitive blockers

Recall - Muscarinic (M) and Nicotinic (N) Receptors:

Muscarinic (M) - GPCR

Nicotinic (N) – ligand gated

M1 M2 M3

Location Autonomic ganglia, Gastric glands and CNS

Heart and CNS SMs of Viscera, Eye, exocrine glands and endothelium

Functions EPSP & Histamine release & acid secretion with CNS learning and motor functions

Less impulse generation, less velocity of conduction, decreased contractility, less Ach release

Visceral SM contraction, Constriction of pupil, contraction of Cilliary muscle and vasodilatation

Agonists Oxotremorine and MCN and MCN-343A

Methacholine Bethanechol

Antagonists

Pirenzepine Methoctramine & Triptramine

Darifenacin

Muscarinic Receptor Subtypes: M1, M2, M3, M4 and M5

Nicotinic (N) ReceptorsNicotinic (N) Receptors

Nicotinic receptors: nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine (Nicotiana tabacum)

Can be blocked by tubocurarine and hexamethonium

ligand-gated ion channels◦ activation results in a rapid increase in

cellular permeability to Na+ and Ca++ resulting - depolarization and initiation of action potential

Sites of Cholinergic transmission Sites of Cholinergic transmission and types of Receptors and types of Receptors

Site Types Selective agonist

Selective antagonist

All Postganglionic Parasympathetic

Postganglionic sympathetic to sweat gland & BV

Muscarinic Muscarine Atropine

Ganglia (Both Para and sympathetic and also Adrenal Medulla

NN DMPP Hexamethonium

Skeletal Muscle NM PTMA Curare

CNS Muscarinic MuscarineOxotremorine

Atropine

Classification - AnticholinergicsClassification - Anticholinergics

Natural: Atropine and Hyoscine (scopolamine) Semisynthetic derivtives: Homatropine,

Atropine methonitrate, Hyoscine butylbromide, Ipratropium bromide, Tiotropium bromide

Synthetic Compounds: Mydriatics: Cyclopentolate and Tropicamide Vasicoselective: Oxybutynin, Flvoxate, Tolterodine Antiprkinsonian: Trihexyphenidyl, Procyclidine, Biperiden Antisecretory:

Quartenary ammonium compounds: Propantheline, Oxyphenonium, Clidinium, Glycopyrrolate, Isopropamide

Tertiary amines: Dicyclomine, Valethamate, Pirenzepine

Atropine as PrototypeAtropine as Prototype

Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade

Also in Datura stramonium, also known as jimsonweed (Jamestown weed) or thorn apple

Scopolamine (hyoscine) occurs in Hyoscyamus niger Many antihistaminics: Histamine, Serotonin, & Ergots

alkaloids, Antipsychotic Agents & Lithium and antidepressant drugs have similar structures and, predictably, significant antimuscarinic effects

Datura stramoniumAtropa belladona

Atropine - ChemicallyAtropine - Chemically

Atropine: Ester of tropic acid (aromatic acid) + tropine

Scopolamine: Ester of tropic acid (aromatic acid) + scopine

Chemically tropine and scopine are closely similar Most of the actions of both are similar

Atropine - MechanismAtropine - Mechanism

Atropine causes reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors◦ blockade by a small dose of atropine can be overcome

by a larger concentration of acetylcholine or equivalent muscarinic agonist

Atropine is highly selective for muscarinic receptors

Does not distinguish between the M1, M2, and M3Some quaternary amine antimuscarinic agents

have significant ganglion-blocking actions

Atropine - PharmacokineticsAtropine - Pharmacokinetics

Absorption:◦ The natural alkaloids and most tertiary antimuscarinic drugs are well

absorbed from the gut and conjunctival membranes – some even over the skin (scopolamine)

◦ Quaternary ones – only upto 30% Distribution:

◦ Atropine and the other tertiary agents are widely distributed in the body

◦ Scopolamine is rapidly and fully distributed into the central nervous system where it has greater effects than most other antimuscarinic drugs

◦ Quaternary derivatives are poorly taken up by the brain Metabolism:

◦ Atropine is metabolized in liver by conjugation and 60% excretes unchanged in urine

◦ Effects disappear quickly within 2 Hrs except eye

Pharmacological Effects - AtropinePharmacological Effects - Atropine

Central Nervous System: Overall CNS stimulant◦ Atropine has only peripheral effects and minimal minimal

stimulant effect on CNS – low entry◦ Atropine stimulates many medullary centres – vagal,

respiratory and vasomotor◦ Depresses vestibular excitation – antimotion sickness property◦ Scopolamine has more marked central effects – amnesia and

drowsiness ◦ Parkinson's disease is reduced by centrally acting

antimuscarinic drugs – acting on Basal ganglia (atropine) Eye:

◦ Topical atropine and other tertiary antimuscarinic drug - results in unopposed sympathetic dilator activity and mydriasis

◦ Cycloplegia: desirable in Ophthalmology but hazardous in narrow angle glaucoma

◦ Dry Eye: Not desirable

Paralysis of accommodations - Atropine

Effect of Scopolamine

Pharmacological Effects of Pharmacological Effects of Atropine – contd.Atropine – contd.

CVS:◦ Moderate and high doses: TACHYCARDIA◦ More In young adults - Because of Vagotonia◦ MOA: SAN, AVN are richly supplied by Parasympathetic Nerves

Atropine produces PS blockade in SAN – tachycardia AVN – Atropine produces PS blockade – higher AV conduction rate

(reduced PR interval in ECG)◦ IM/SC injection initially – transient BRADYCARDIA – may

be due to inhibition of presynaptic M1 autoreceptor inhibition (not due to stimulation of vagal centre) Evidenced by Pirenzepine injection does not cross BBB

◦ BP: Parasympathetic nerve stimulation dilates coronary arteries, and sympathetic cholinergic nerves (predominant) cause vasodilatation in the skeletal muscle vascular bed - Atropine can block this vasodilatation But, histamine release cause direct vasodilatation

◦ However, No marked effect on BP

Heart rate and salivary secretion Heart rate and salivary secretion after Atropineafter Atropine

Pharmacological Effects of Pharmacological Effects of Atropine – contd.Atropine – contd.

Respiratory System:◦ Smooth muscles and secretor glands receive

innervations from parasympathetic system ◦ Bronchodilatation and reduction in secretion in asthma◦ Particularly used in COPD and prior to initiation of

inhalation therapy in asthmaSweat glands:

◦ Suppresses thermoregulatory sweating – peripheral and central action

◦ May cause "atropine fever“ - childrenUrinary:

◦ Slows voiding◦ Useful in spasm conditions – inflammation◦ Danger – Elderly (BHP)

Pharmacological Effects of Pharmacological Effects of Atropine – contd.Atropine – contd.

GIT:◦Decrease in GI motility◦Gastric emptying time is prolonged, and

intestinal transit time is lengthened◦Dry mouth occurs frequently in patients taking

antimuscarinic drugs◦Gastric secretion is blocked with larger doses –

blocks acid, pepsin and mucus secretion◦Pirenzepine is more effective

Various Effects of Atropine

Anticholinergics - Ophthalmic usesAnticholinergics - Ophthalmic uses

Mydriatic and CycloplegicUsed as eye drop or ointment:

◦Diagnostic: Atropine 1% ointment is used

◦Measurement of refractive error◦Ophthalmic examination of retina - fundoscopy◦Preferred ones: Homatropine, Tropicamide and

cyclopentolate – shorter action

◦Therapeutic Uses: For resting eye: Iritis, iridocyclitis, keratitis, corneal

ulcer etc. Alternating with miotics (prevention of synechia)

Therapeutic Uses AnticholinergicsTherapeutic Uses Anticholinergics

Antisecretory:1. Preanaesthetic medication:

To reduce secretions To prevent laryngospasm

2. Peptic ulcer3. Pulmonary embolism4. Hyperhidrosis

Antispasmodic:◦ Intestinal and renal colic – not in biliary colic◦ Diarrhoea (nervous and drug induced) – Lomotil◦ Pylorospasm, gastric hypermotility, gastritis, nervous

dyspepsia etc.

Uses Anticholinergics – contd.Uses Anticholinergics – contd.

◦Parkinsonism: Mild cases of parkinsonism (early cases), Drug induced Parkinsonism and adjunct to Levodopa

◦Motion sickness: Hyoscine (scopolamine) is the drug used – Oral,

injection and transdermal patch 0.2 mg orally given as prophylaxis before journey Not effective in other type of vomiting

◦Twilight sleep: sedation and amnesia To antagonize Muscarinic effects of Drugs and Poisons: Anti-

ChE, Mushroom poisoning, and to block Muscarinic effects of Neostigmine, Cobra envenometion

Anticholinergics – usesAnticholinergics – uses

CVS:CVS:◦ Vagolytic - Marked reflex vagal discharge in myocardial

infarction - depression of SA or AV node function to impair cardiac output - Parenteral atropine or a similar antimuscarinic drug

◦ Hyperactive carotid sinus reflexesRespiratory:

◦ Ipratropium Bromide – in COPD and chronic bronchitis Improves mucociliary clearance and bronchodilatation

Anticholinergic - ADRsAnticholinergic - ADRs

Commonly occurring but of non serious typeMydriasis and cycloplegia – using as antisecretory or

Preanaesthetic medicationPoisoning:

◦ Causes: Drug overdose Consumption of Belladona and Datura seeds

◦ Symptoms: Dry mouth, difficulty in swallowing and talking Dry, flushed and hot skin, fever, decreased bowel sound,

photophobia Excitement, psychotic behavior, delirium and hallucinations Hypotension and cardiovascular collapse

Atropine Poisoning – contd.

Diagnosis: Methacholine 5 mg or Neostigmine 1 mg SC – no muscarinic effects

Treatment:◦Gastric lavage in case of ingestion – KMNO4◦Dark Room◦Cold sponging and ice bags◦Physostigmine 1–3 mg SC or IV◦Maintenance of blood volume, assisted

respiration and Diazepam to control convulsions

Anticholinergic - ContraindicationsAnticholinergic - Contraindications

Glaucoma – Narrow angle (Precipitation of angle closure)

BHP – urinary retentionAcid peptic ulcer diseases (Non-

selective ones) – precipitation of symptoms

Atropine Substitutes - Quarternary Atropine Substitutes - Quarternary compoundscompounds

Incomplete Oral absorption, Poor penetration in Eye and CNS, Longer acting than Atropine, Higher Nicotinic Blocking Property, NM Blockade

Drugs:◦ Hyoscine Butylbromide: Oesophageal and GIT spastic conditions

– Buscopan◦ Atropine methonitrate: Abdominal colics and hypercidity◦ Ipratropium Bromide: Selective action on Bronchial SM

Enhanced mucocilliary clearance (contrast to Atropine) Slowly acting Bronchodilator - 1-2 Hrs (prophylactic use) Acts mainly on larger Central airways (contrast to sympoathomimetics) More effective in COPD than Asthma Other Drugs – Tiotropium bromide, Propantheline, Oxyphenonium,

Clidinium and Glycopyrrolate

Tertiary AminesTertiary Amines

Dicyclomine and valethamate Dicyclomine: Direct SM relaxant and weak antispasmodic

◦ Lesser side effects than Atropine◦ Atropine toxicity in infants (not recommended below 6

months) Valethmate: Dilatation of Cervix in delayed labour

Individual Drugs – Vasicoselective

Oxybutynin:◦ Specific selectivity for receptors in Urinary bladder and salivary

gland (M1/M3)◦ Additional smooth muscle relaxation property◦ Uses:

Bladder surgery after urologic surgery Spina bifida and nocturnal enuresis Involuntary voiding in patients with neurologic disease -

children with meningomyelocele Dose: 5 mg BD/tds or local instillation

Tolterodine – M3 selectiveFlavoxate – similar to Oxybutynin Drotaverine: Newer Drug - Non anticholinergic smooth

muscle relaxant – elevation of cAMP/cGMP◦ Renal colic, biliary colic, IBS, uterine spasms etc.◦ Dose: 40 – 80 mg tds

MydriaticsMydriaticsHomatropine, Cyclopentolate and Tropicamide – various ophthalmological procedures as substitutes of Atropine

Drugs acting in Autonomic ganglia

Ganglion stimulants:◦ Selective agonists: Nicotine, Lobeline, DMPP and TMA◦ Non-selective: Acetylcholine, carbachol, Pilocarpine,

AnticholinesterasesGanglion Blockers:

◦ Competitive blockers: Quaternary compounds: Hexamethonium,

Pentolinium Secondary/tertiary: Mecamylamine, Pempidine

◦ Persistent depolarizers: Nicotine (large dose) and Anticholinesterases

Remember !!!

Atropine and its Pharmacological Effects◦Therapeutic uses of Atropine◦Mechanism of Mydriasis and Cycloplegia

Names of Atropine Substitutes with their Uses◦Details of Atropine Substitutes – Ipratropium

bromide Treatment of Atropine PoisoningGanglion Stimulants and Blockers Drugs

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