anticholinergics - drdhriti
DESCRIPTION
A power point presentation on "anticholinergics" suitable for medical undergraduate MBBS level students of Pharmacology.;TRANSCRIPT
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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