pharmacology of cholinergic system 4 anti-muscarinics
TRANSCRIPT
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
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Cholinoreceptor antagonists
Antimuscarinics
M123
NM BlockersNM
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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
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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.
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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,
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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.
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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
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Atropine-MOACompetitive inhibition of acetylcholine at
muscarinic sites
Atropine causes reversible (surmountable) blockade of cholinomimetic actions at
muscarinic receptors;
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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????
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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
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•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
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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
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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
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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
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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
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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.
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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
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Toxicity and DI
Management of Toxicity
• Gastric lavage [if ingested] with KMNO4
• Cold sponging
• Dark room
• Physostigmine i.v.
• Diazepam
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Anticholinergics – Clinical
applications
• Mydriatic & Cycloplegic
• Respiratory disorders-COPD
• CVS disorders• GIT disorders
• Disorders of urinary system
• Parkinsonism• Motion sickness
• Preanesthetic
• OP poisoning
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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
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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
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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
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Cardiovascular disorders
• Increased vagal tone- Bradycardia-MI, Digitalis toxicity
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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
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Preanesthetic
• Prior admin.with irritant GA[Ether]
• To reduce secretions & prevent
laryngospasm
• With Halothane• To reduce vasovagal reflexes
• Atropine & Glycopyrrolate
Atropine
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CNS action
Motion sickness
• Hyoscine-oral & Transdermal
• Prophylactically
• Not effective in other vomiting
Parkinsonism
• Trihexyphenydyl, procyclidine,Biperiden• In mild cases
Lie detector
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CI, DI & Cautions
DI
Delays gastric emptying-delays absorption
Antihistaminics, TCA-additive effects• CI in closed angle glaucoma
• Elderly-urinary retention