[Cholinoceptor antagonists]

CHOLINORECEPTOR ANTAGONISTS

Competitive antagonists of acetylcholine at cholinergic sites

Cholinoreceptor antagonists

NM Blockers NM

Antimuscarinics M123

Anticholinergic drugs[Antimuscarinic] [Classification]

Atropine substitutes

Natural alkaloids

Semisynthetic derivatives

Synthetic compounds

Atropine Scopolamine [Hyoscine]

Homatropine Atropine methonitrate Hyoscine butyl bromide Ipratropium bromide Tiotropium bromide

Mydriatics
Cycclopentolate& Tropicamide

Antisecretoryantispasmodics
Quaternary

Propatheline, Glycopyrrolate
Tertiary

Dicyclomine, Pirenzepine

Antiparkinsonian
Trihexyphenydyl, Biperiden, Benztropine

Vasicoselective
Oxybutynin, Flavoxate

SOURCE AND CHEMISTRY

Atropine -Atropa belladonna Or Datura stramonium-tertiary amine Scopolamine (hyoscine) -Hyoscyamus niger, Tertiary derivatives- used -effects on the eye or the CNS[mydriatrics or antiparkinsonians] Quaternary amines -more peripheral effects with reduced CNS effects[Antispasmodics] Antihistaminic -antipsychotic -antidepressant - have similar structures Hence antimuscarinic side effects.

Pharmacokinetics
ABSORPTION
Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes. Even absorbed across the skin (transdermal route-scopolamine). Only 1030% of a dose of a quaternary drug is absorbed after oral administration,

Pharmacokinetics
DISTRIBUTION
Atropine and tertiary agents are widely distributed in the body.
Significant levels in CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. Scopolamine is rapidly and fully distributed into the CNS where it has greater effects than most other antimuscarinic drugs. Quaternary derivatives are poorly taken up by the brain and therefore are relatively freeat low dosesof CNS effects.

Pharmacokinetics
METABOLISM AND EXCRETION Atropine-Rapid phase is 2 hours and that of the slow phase is approximately 13 hours. About 50% of the dose is excreted unchanged in the urine.

The drug's effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for 3-7 days

Atropine-MOA Competitive inhibition of acetylcholine at muscarinic sites

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

Tissue selectivity
Most sensitive to atropine are the salivary, bronchial, and sweat glands. Secretion of acid by the gastric parietal cells is the least sensitive. Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, Atropine does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors. Differences between Atropine and Scopolamine????

Systemic Effects
CNS Excitation[Atropine] Depression[Scopolamine] Vestibular-depression Basal ganglion-Cholinergic activity High doses-Disorientation, hallucination, coma Eye[topical] Passive mydriasis Cycloplegia IOT increased Reduce lachrymal secretion

Belladona!!!
The name belladonna derives from the alleged use of this preparation by Italian women to dilate their pupils Modern-day fashion models are known to use this same device for visual appeal

Active and Passive Mydriasis

ADRENERGIC STIMULANT DILATOR PUPILLAE MUSCLE CONTRACTS LEADING TO MYDRIASIS. ACTIVE MYDRIASIS. [No cycloplegia] [Light reflex ++] ANTICHOLINERGICSUN-OPPOSED ACTION OF THE DILATOR PUPILLAE -MYDRIASIS. -PASSIVE MYDRIASIS [Cycloplegia++] [No light reflex]

Active Mydriasis Drug Muscles Cycloplegia Light reflex Conjuctival vessels Adrenergic Contraction of dilator Absent Present Constricted

Passive Passive mydriasis Anticholinergic Paralysis of constrictor Present Absent No effect

IOT

Decreased or no change

Increased

Systemic Effects
CVS Tachycardia-M2 blockade [SA] Transient initial bradycardia[Not central action][M1 auto]

Most blood vessels receive no direct innervation from the parasympathetic system.

At toxic doses, and in some individuals at normal doses, antimuscarinic agents cause cutaneous vasodilation, especially in the upper portion of the body. The mechanism is unknown.

M1
Atropine ACh M2

Systemic Effects
RS

GIT

Bronchodilation and decreased secretions COPD and preanesthesia

Salivary secretion effectively blocked Gastric-only basal secretion Volume reduced, HCO3 reduced. Not pH Not intestinal and pancreatic secretions [Hormonal control] Antispasmodic

GUT

Systemic Effects

Sweat glands

Relaxes smooth muscle of the ureters and bladder wall and slows voiding Can precipitate urinary retention in men who have prostatic hyperplasia

Atropine suppresses sweating Stimulates thermoregulatory center Body temperature is elevated-therapeutic doses in children

Hierarchy of relative sensitivities of atropine

Small doses depress salivary and bronchial secretion and sweating. Larger doses, the pupil dilates, accommodation of the lens to near vision is inhibited, and vagal effects on the heart are blocked Larger doses antagonize parasympathetic control of the urinary bladder and GI tract, Still larger doses are required to inhibit gastric motility and particularly secretion. Thus, doses of atropine and most related muscarinic antagonists that depress gastric secretion also almost invariably affect salivary secretion, ocular accommodation, micturition, and GI motility.

Atropine toxicity
Hot as hell, Hyperthermia-No sweating Blind as a bat, Dilated pupils Dry as a bone, No secretions Red as a beet, Vasodilataion-face & neck Mad as a hatter [hen]. CNS affect Bowel and bladder lose their tone, and the heart runs alone I cant pee, I cant ***t [Rhymes with spit]

Toxicity and DI

Management of Toxicity Gastric lavage [if ingested] with KMNO4 Cold sponging Dark room Physostigmine i.v. Diazepam

Anticholinergics Clinical applications

Mydriatic & Cycloplegic Respiratory disorders-COPD CVS disorders GIT disorders Disorders of urinary system Parkinsonism Motion sickness Preanesthetic OP poisoning

Mydriasis-Anticholinergics

Drug
Atropine Homatropine Cyclopentolate

Onset
30-40 Mts 45-60 Mts 30-60 Mts

Duration
1 week 1-3 days 1 day

Remarks
Useful in children High ciliary tone [Diseases of eye]

Unsatisfactory in children Behavioral abnormalities in children[Absorption]

Tropicamide

20-40 Mts

3-6 H

Unreliable cycloplegic

Mydriasis
To test errors of refraction For fundoscopy Iritis, iridocyclitis, keratitis Rest to iris, anodyne, reduces spasm To prevent/break adhesions[Synechiae]

Respiratory disorders [Ipratropium & Tiotropium]

Not absorbed COPD & Bronchitis Less effective in B.Asthma Atropine-dries secretions, Mucociliary clearance is not affected Inhalational route [MDI] Combined with adrenergic agonists Only prophylactic

Cardiovascular disorders
Increased vagal tone- BradycardiaMI, Digitalis toxicity

GIT & Genito-urinary disorders [Antispasmodic]

Peptic ulcer-not common[Propantheline, oxyphenonium] Travellers diarrhoea Intestinal colic, dysmenorrhoea [Dicyclomine] Urinary incontinence [Oxybutynin, Darifenacin , solifenacin, Tolterodine and fesoterodine ] Valethamate-Cx dialation delayed labour

Preanesthetic
Prior admin.with irritant GA[Ether] To reduce secretions & prevent laryngospasm With Halothane To reduce vasovagal reflexes Atropine & Glycopyrrolate

Atropine

CNS action
Motion sickness Hyoscine-oral & Transdermal Prophylactically Not effective in other vomiting Parkinsonism Trihexyphenydyl, procyclidine,Biperiden In mild cases Lie detector

CI, DI & Cautions

DI Delays gastric emptying-delays absorption Antihistaminics, TCA-additive effects CI in closed angle glaucoma Elderly-urinary retention

 Ref. text books for individual drugs and dosages