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
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
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
Muscarini c
NN
DMPP
NM Muscarini c
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
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 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
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
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
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)
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
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)
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.
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
To antagonize Muscarinic effects of Drugs and Poisons: Anti-ChE, Mushroom poisoning, and to block Muscarinic effects of Neostigmine, Cobra envenometion
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
Gastric lavage in case of ingestion KMNO4 Dark Room Cold sponging and ice bags Physostigmine 13 mg SC or IV Maintenance of blood volume, assisted respiration and Diazepam to control convulsions
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
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:
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
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
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