Pharmacology of cholinergic system 4 Anti-muscarinics

8/3/2019 Pharmacology of cholinergic system 4 Anti-muscarinics

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[Cholinoceptor antagonists]

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CHOLINORECEPTORANTAGONISTS

Competitive antagonists of acetylcholine at cholinergic sites



Cholinoreceptor antagonists

Antimuscarinics

M123

NM BlockersNM



Semisyntheticderivatives

•Homatropine

•Atropine

methonitrate•Hyoscine butylbromide

•Ipratropiumbromide

•Tiotropiumbromide

Synthetic compounds

•MydriaticsCycclopentolate& Tropicamide

•Antisecretory-antispasmodicsQuaternary

Propatheline, Glycopyrrolate

Tertiary

Dicyclomine, Pirenzepine

•AntiparkinsonianTrihexyphenydyl, Biperiden,Benztropine

•VasicoselectiveOxybutynin, Flavoxate

Natural alkaloids

•Atropine

•Scopolamine

[Hyoscine]

Anticholinergic drugs[Antimuscarinic]

[Classification]Atropine substitutes



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 10 –

30% 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 thiscan limit the dose tolerated when the drug is taken for its

peripheral effects.

• Scopolamine is rapidly and fully distributed into the CNS where ithas greater effects than most other antimuscarinic drugs.

• Quaternary derivatives are poorly taken up by the brain and

therefore are relatively free —

at low doses —

of 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-MOACompetitive 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



•ADRENERGIC STIMULANT•DILATOR PUPILLAE MUSCLE

CONTRACTS LEADING TO• MYDRIASIS.

•

ACTIVE MYDRIASIS.•[No cycloplegia]

•[Light reflex ++]•ANTICHOLINERGICS-

•UN-OPPOSED ACTION OFTHE DILATOR PUPILLAE

-MYDRIASIS.

-PASSIVE MYDRIASIS

•[Cycloplegia++]

•[No light reflex]

Active and PassiveMydriasis



Active

Mydriasis

Passive

Passive mydriasis

Drug Adrenergic Anticholinergic

Muscles Contraction of

dilator

Paralysis of constrictor

Cycloplegia Absent Present

Light reflex Present Absent

Conjuctival

vessels

Constricted 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 theparasympathetic system.

• At toxic doses, and in someindividuals at normal doses,

antimuscarinic agents cause

cutaneous vasodilation,

especially in the upper portionof the body. The mechanism is

unknown.

M1

M2

ACh

Atropine



Systemic EffectsRS

• Bronchodilation and

decreased secretions

• COPD and

preanesthesia

• Salivary secretioneffectively blocked

• Gastric-only basal secretion

Volume reduced, HCO3

reduced. Not pH

• Not intestinal and

pancreatic secretions

[Hormonal control]• Antispasmodic

GIT



Systemic EffectsGUT

• Relaxes smooth

muscle of the ureters

and bladder wall and

slows voiding

• Can precipitate

urinary retention inmen who have

prostatic hyperplasia

• Atropine suppressessweating

• Stimulates

thermoregulatory center• Body temperature is

elevated-therapeutic

doses in children

Sweat glands



Hierarchy of relative sensitivities of atropine

• Small doses depress salivary and bronchial secretion andsweating.

• 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 urinarybladder and GI tract,

• Still larger doses are required to inhibit gastric motility and

particularly secretion.

• Thus, doses of atropine and most related muscarinic antagoniststhat depress gastric secretion also almost invariably affect

salivary secretion, ocular accommodation, micturition, and GI

motility.



Atropine toxicity

• Hot as hell,

• Blind as a bat,

• Dry as a bone,• Red as a beet,

• Mad as a hatter [hen].

• ‘Bowel and bladder lose their tone, and the heart runs alone’

• ‘I can’t pee, I can’t ***t [Rhymes with ‘spit’]

Hyperthermia-No sweating

Dilated pupils

No secretions

Vasodilataion-face & neck

CNS affect



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



Drug Onset Duration Remarks

Atropine 30-40 Mts 1 week Useful in children

High ciliary tone

[Diseases of eye]

Homatropine 45-60 Mts 1-3 days Unsatisfactory in

children

Cyclopentolate 30-60 Mts 1 day Behavioral

abnormalities inchildren[Absorption]

Tropicamide 20-40 Mts 3-6 H Unreliable cycloplegic

Mydriasis-Anticholinergics



Mydriasis

• To test errors of refraction• For fundoscopy

• Iritis, iridocyclitis, keratitis

• Rest to iris, anodyne, reduces spasm• To prevent/break adhesions[Synechiae]

R i t di d



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- Bradycardia-MI, Digitalis toxicity



GIT & Genito-urinary disorders

[Antispasmodic]

• Peptic ulcer-not common[Propantheline,

oxyphenonium]

• Traveller’s 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

Pharmacology of cholinergic system 4 Anti-muscarinics

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