Anticholinergic Drugs

Department of Pharmacology NEIGRIHMS, Shillong

 

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

Introduction

 Recall

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

Muscarinic (M) GPCR

Nicotinic (N) – ligand gated

Muscarinic Receptor Subtypes: M1, M2, M3, M4 and M5
M1
Location Autonomic ganglia, Gastric glands and CNS

M2
Heart and CNS

M3
SMs of Viscera, Eye, exocrine glands and endothelium Visceral SM contraction, Constriction of pupil, contraction of Cilliary muscle and vasodilatation

Functions

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

Less impulse generation, less velocity of conduction, decreased contractility, less Ach release Methacholine Methoctramine & Triptramine

Agonists Antagonist s

Oxotremorine and MCN and MCN-343A Pirenzepine

Bethanechol Darifenacin

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

Nicotinic (N) Receptors

Sites of Cholinergic transmission and types of Receptors
Site All Postganglionic Parasympathetic Postganglionic sympathetic to sweat gland & BV Ganglia (Both Para and sympathetic and also Adrenal Medulla Skeletal Muscle CNS Types Selective agonist Muscarine Selective antagonist Atropine

Muscarini c

NN

DMPP

Hexamethoniu m Curare Atropine

NM Muscarini c

PTMA Muscarine Oxotremorin e

 

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

Classification - Anticholinergics


 

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 stramonium

Atropa belladona

Atropine as Prototype


 

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 - Chemically

Atropine causes reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors

Atropine is highly selective for muscarinic receptors  Does not distinguish between the M1, M2, and M3  Some quaternary amine antimuscarinic agents have significant ganglion-blocking actions

◦ blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist

Atropine - Mechanism

Absorption:

Distribution:

◦ 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% ◦ 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 ◦ Atropine is metabolized in liver by conjugation and 60% excretes unchanged in urine ◦ Effects disappear quickly within 2 Hrs except eye

Metabolism:

Atropine - Pharmacokinetics

Central Nervous System: Overall CNS stimulant

Eye:

◦ 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) ◦ Topical atropine and other tertiary antimuscarinic drug - results in unopposed sympathetic dilator activity and mydriasis ◦ Cycloplegia: desirable in Ophthalmology ◦ Dry Eye: Not desirable
 but hazardous in narrow angle glaucoma

Pharmacological Effects - Atropine

Paralysis of accommodations Atropine

Effect of Scopolamine

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 ◦ However, No marked effect on BP
 But, histamine release cause direct vasodilatation

Pharmacological Effects of Atropine – contd.

Heart rate and salivary secretion after Atropine

Respiratory System:

Sweat glands:

◦ 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 asthma

Urinary:

◦ Suppresses thermoregulatory sweating – peripheral and central action ◦ May cause "atropine fever“ - children
◦ Slows voiding ◦ Useful in spasm conditions – inflammation ◦ Danger – Elderly (BHP)

Pharmacological Effects of 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

Pharmacological Effects of Atropine – contd.

Various Effects of Atropine

Mydriatic and Cycloplegic  Used 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)

Anticholinergics - Ophthalmic uses

Antisecretory: 1. Preanaesthetic medication:
 To reduce secretions  To prevent laryngospasm

2. Peptic ulcer 3. Pulmonary embolism 4. Hyperhidrosis Antispasmodic: ◦ Intestinal and renal colic – not in biliary colic ◦ Diarrhoea (nervous and drug induced) – Lomotil ◦ Pylorospasm, gastric hypermotility, gastritis, nervous dyspepsia etc.

Therapeutic Uses Anticholinergics

◦ 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

Uses Anticholinergics – contd.

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 reflexes

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

Anticholinergics – uses

  

Commonly occurring but of non serious type Mydriasis and cycloplegia – using as antisecretory or Preanaesthetic medication Poisoning:
◦ 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

Anticholinergic - ADRs

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

Atropine Poisoning – contd.

Glaucoma – Narrow angle (Precipitation of angle closure)  BHP – urinary retention  Acid peptic ulcer diseases (Nonselective ones) – precipitation of symptoms

Anticholinergic - Contraindications

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

Atropine Substitutes - Quarternary compounds

 

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

Tertiary Amines

Oxybutynin:

 

Tolterodine – M3 selective Flavoxate – similar to 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

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

Individual Drugs – Vasicoselective

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

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

Ganglion Blockers:
◦ Competitive blockers:  Quaternary compounds: Hexamethonium, Pentolinium  Secondary/tertiary: Mecamylamine, Pempidine ◦ Persistent depolarizers: Nicotine (large dose) and Anticholinesterases

Drugs acting in Autonomic ganglia

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 Poisoning  Ganglion Stimulants and Blockers Drugs

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