Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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Central Nervous System (CNS) - Brain and spinalcord

Peripheral Nervous System (PNS) - Located outsidethe brain & spinal cord Autonomic NervousSystem (ANS) & the somatic

The PNS receives stimuli from the CNS & initiatesresponses to the stimuli after it’s interpreted by thebrain

Acetylcholine –preganglionicPost ganglionicAchException-post ganglionic sympathetic fibres toapocrine glandsCholinergic fibresAll somatic motar neuronsAll preganglionic fibresPost ganglionic parasympathetic fibres

75% of all parasympathetic nerve fibers are in thevagus nervesThese nerves supply the thoracic and abdominalorgans, which innervate the heart, lungs, esophagus,stomach, small intestine, proximal half of the colon,liver , gallbladder, pancreas and upper portions of theureters

Natural alkaloids: Atropine, Hyoscine (Scopolamine),2. Semisynthetic derivativesMydriatics: Homatropine,Antiasthmatics: Iprotropium, Tiotropium bromideGI spasmolytics: Hyoscine butyl bromide3. Synthetic compoundsMydriatic-Tropicamide, cyclopentolateGI spasmolytics:Quaternary - Oxyphenonium, clidinium, pipenzolate,isopropamide, glycopyrolate,Tertiary -Dicyclomine

Antiulcer drugs: Pirenzepine (M1-blockers), telenzapinevasicoselective: Flavoxate, Oxybutynin, TolteridineAntiparkinsonian (central M-cholinolytics): Benztropine,Biperiden, Trihexyphenidyl (benzhexol)

A belladonna alkaloid has ahigh affinity for muscarinicreceptors, it is a competitiveinhibitor of muscarinic receptorspreventing ACH from

binding to that site.

Atropine

Antimuscarinic agents:These agents block muscarinic receptors and

inhibit muscarinic functions, they are useful indifferent clinical situations, they have no actions onskeletal neuromuscular junctions or autonomicganglia because they do not block nicotinicreceptors.

Low dose-M1 receptor on cholinergic Nauto-inhibitarycholinergic actionbradycardiaModerate dose- M2 receptor on postjunctional SAN, AVN blkescape the heartfrom inhibition tachycardia+Unopposedadrenergic action chronotropic, dronotropicToxic dose-M3 receptor-endotheliumblockade NO release is blocked smoothmuscle donot relax prevention ofcholinergic mediated dilation

Blood pressure-tachycardia and vasomotar centre stimulation tends to increase bloodpressure, while histamine release and direct vasodilation tends to decrease BP

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A B C D1 min

ATROPINE BLOCKSM-EFFECTS OF ACH

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ACh2 mcg i.v.

ACh50 mcg

ACh50 mcg

ACh5 mg

M-effect

M-effect

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Atropine2 mg i.v.

ACh

CNS. Atropine has an overall stimulant action. Its stimulanteffects are not appreciable at low doses which produceperipheral effects because of restricted entry into the brain.Hyoscine produces central depressant effects even at lowdoses.Medullar centers - vagal, respiratory, and vasоmotor.By blocking the relative cholinergic over activity inbasal ganglia, it suppresses tremor and rigidityin parkinsonism.

High doses cause cortical excitation, restlessness,disorientation, hallucinations, and deliriumfollowed by respiratory depression and coma.

Autonomic control of pupil (A) and site ofaction of mydriatics (B) and miotics (C)Topical instillation of atropine (0.1%)causes mydriasis, abolition of light reflex,and cycloplegia, lasting 7–10 days.This results in photophobia and blurringof near vision.The intraocular tension rises, specially innarrow angle glaucoma

All visceral smooth muscles with parasympatheticinnervation are relaxed (M3-blokade).Tone and amplitude of GIT are reduced.Spasm may be reduced, constipation may occur.Peristalsis is only incompletely suppressed because it isprimarily regulated by local reflexes and otherneurotransmitters (serotonin, encephalin, etc.).

Atropine causes bronchodilation and reduced airwayresistance, especially in asthma patients.Inflammatory mediators (histamine, PGs, and kinins)increase vagal activity in addition to their direct actionon bronchial muscle and glands. Atropine attenuatestheir action by antagonizing the reflex vagal component.It has a relaxant action on the ureter and urinarybladder. Urinary retention can occur in older men withprostatic hyperplasia.

Glands. Atropine decreases sweat, salivary, tracheo-bronchial, and lacrimal secretion (M3-blockade). Skinand eyes become dry, talking, and swallowing may bevery difficult.Atropine decreases the secretion of acid and pep-sin and increases mucus in the stomach.Body temperature- Rise in body temperature occurs athigher doses, and is due to both inhibition of sweatingas well as stimulation of the temperature regulatingcentre in the hypothalamus. Children are highlysusceptible.

Local anaesthetic action. Atropine has a mildanaesthetic action on the cornea.The sensitivity of different organs and tissuesto atropine varies and can be graded as

Saliva, sweat, bronchial secretion > eye >bronchial muscles > heart > intestinal andbladder smooth muscles > gastric glandsand gastric smooth muscles“

Atropine and hyoscine are rapidly absorbed fromGIT. Applied to the eyes they penetrate the cornea.Passage across BBB is somewhat restricted.50% of atropine is metabolized in the liver andexcreted unchanged in urine.It has t1/2 3–4 h.Hyoscine is more completely metabolized and hasbetter BBB penetration.Some rabbits have a specific atropineesterase which degrades atropine very rapidly.

Scopalamine (hyoscine): A belladdona alkaloidproduce peripheral effects similar to atropine, it hasgreater actions on CNS and longer duration ofaction.Most effective in motion sickness, it is effective alsoin blocking short term memory, it produce sedationbut at higher doses cause excitement.

Depresses CNS and causes amnesia, drowsiness,euphoria, relaxation and sleep.

Given parenterally, orally and transdermally.

It is inhalational derivative of atropine useful intreating asthma and COPD in patients unable to takeadrenergic agonist. Useful in rhinorrhea. Alsoexcellent bronchodilator.

Opthalmic Agents- like homatropine, cyclopentolate,and tropicamide used mainly in ophthalmology.

Benztropine-used in drug induced Parkinson’sdisease. Useful for dystonic reactions caused byantipsychotics.

Trihexyphenidyl -also used for treating ExtraPyramidal Symptoms caused by some antipsychotics.

Flavoxate-relieves dysuria, urgency, frequency and painwith genito-urinary infectionsOxybutynin -has direct antispasmodic effects onsmooth muscle and anticholinergic effects. Decreasesfrequency of voiding.Tolterodine -is competitive, Antimuscarinicanticholinergic that inhibits contraction. Moreselective for this area than elsewhere in the body.

Trimethaphan- They act on nicotinic receptors of theautonomic ganglia.

- They have no selectivity toward the parasympatheticor sympathetic ganglia .

- The effect of these drugs is complex andunpredictable so rarely used therapeutically,

- Used mainly in experimental pharmacology.- Increase peristalsis and secretions.- On large dose of nicotine- A)Blood pressure falls because of ganglionic blockade- B)Activity both in GIT and UB musculature decrease.

Short acting competitive nicotinic ganglionic blockerthat must be given by i.v infusion

It is used for the emergency lowering of the bloodpressure in hypertension caused by pulmonaryedema or dissecting aortic aneurysm, when otheragents cannot be used.

Neuromuscular blocking drugs-- Drugs that block cholinergic transmission between

motor nerve ending and the nicotinic receptors onthe neuromuscular end plate of the skeletal muscle.

- They are structural analogs of ACH.

Mydriatic and cycloplegic agent in the eye to permitmeasurement of refractive errors. Mydriasis andcycloplegia for surgeryRS-In bronchospasm whether related to asthma orCOPD bronchodilating effectsCVS-Atropine is used to increase heart rate insymptomatic bradycardias and higher blocksGIT-Antispasmodic agent: Relax GIT and bladder.Helpful in treating irritable colon or colitis

Useful in gastritis, pylorospasm and ulcerative colitis asthey slow motilityAntispasmotic effects seen in overactive bladder and inurinary incontinenceAntidote for cholinergic agonists: To treatorganophsphorus poisoning (present in insecticides),and mushroom poisoning.Antisecretory agent: To block the secretion of upperand lower respiratory tracts prior to surgery.Helps to prevent vagal stimulation and potentialbradycardia

CNS- Parkinson’s Disease-Useful in those with minimal side effectsThose who cannot take LevodopaHelpful in decreasing salivation, spasticity and tremors

Absorption of other drugs is slowed because atropinedelays gastric emptying. So dose of levodopa, inparkinsonism may have to be increased. But the extent ofdigoxin and tetracyclines absorption may be increased.Antacids interfere with the absorption of anticholinergics.Antihistaminics, tricyclic antidepressants, phenothiazines,pethidine have anticholinergic property additive sideeffectsMAO inhibitors interfere with the metabolism of centralantiparkinsonian drugs (biperiden and others) deliriummay occur.

BPHMyasthenia gravisHyperthyroidismGlaucomaTachydysrhythmias

Dry mouth, difficulty in swallowing and talking;Difficulty in micturitionDilated pupils, photophobia, blurring of near vision;palpitation; excitement, psychotic behavior,Ataxia, delirium, hallucinations; hypotension, weak andrapid pulse, cardiovascular collapse with respiratorydepression;Convulsion and coma (in very high doses).It is very risky in individuals with glaucoma and BPH

Diagnosis: 1 mg neostigmine s.c. fails to inducetypical M-effects.Treatment: Gastric lavage with tannic acid (KMnO4 isineffective in oxidation of atropine). The patient mustbe kept in a dark quiet room. Galantamine or physo-stigmine (1-3 mg s.c./i.v.), diazepam againstconvulsion.

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