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

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Central Nervous System (CNS) - Brain and spinal cord

Peripheral Nervous System (PNS) - Located outside the brain & spinal cordAutonomic Nervous System (ANS) & the somatic

The PNS receives stimuli from the CNS & initiates responses to the stimuli after it’s interpreted by the brain

Acetylcholine –preganglionic Post ganglionicAch Exception-post ganglionic sympathetic fibres to

apocrine glands Cholinergic fibres All somatic motar neurons All preganglionic fibres Post ganglionic parasympathetic fibres

75% of all parasympathetic nerve fibers are in the vagus nerves

These nerves supply the thoracic and abdominal organs, which innervate the heart, lungs, esophagus, stomach, small intestine, proximal half of the colon, liver , gallbladder, pancreas and upper portions of the ureters

Natural alkaloids: Atropine (spasmolytic, mydriatic), Hyoscine (Scopolamine), (antiemetic)2. Semisynthetic derivativesMydriatics: Homatropine, TropicamideGI spasmolytics: Hyoscine butyl bromide 3. Synthetic compoundsGI spasmolytics: OxyphenoniumAntiulcer drugs: Pirenzepine (M1-blockers)Antiasthmatics: Ipratropium and TiotropiumUrinary system: Flavoxate, Oxybutynyne, TrospiumAntiparkinsonian (central M-cholinolytics): Benztropine, Biperiden, Trihexyphenidyl

Antimuscarinic agents: These agents block muscarinic receptors and

inhibit muscarinic functions, they are useful in different clinical situations, they have no actions on skeletal neuromuscular junctions or autonomic ganglia because they do not block nicotinic receptors.

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ATROPINE BLOCKS M-EFFECTS OF ACH

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ACh2 mcg i.v.

ACh50 mcg

ACh50 mcg

ACh5 mg

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Atropine2 mg i.v.

ACh

A belladonna alkaloid has a high affinity for muscarinic receptors, it is a competitive inhibitor of muscarinic receptorspreventing ACH from

binding to that site.

Atropine

CNS. Atropine has an overall stimulant action. Its stimulant effects are not appreciable at low doses which produce peripheral effects because of restricted entry into the brain. Hyoscine produces central depressant effects even at low doses.

• Medullar centers - vagal, respiratory, and vasоmotor.• By blocking the relative cholinergic overactivity in basal ganglia, it suppresses tremor and rigidity in parkinsonism.• High doses cause cortical excitation, restlessness,

disorientation, hallucinations, and delirium followed by respiratory depression and coma.

Low dose-M2 receptor on cholinergic N auto-inhibitarycholinergic action bradycardia

Moderate dose- M2 receptor on post junctional SAN, AVN blkescape the heart from inhibitiontachycardia+Unopposed adrenegicaction chronotropic, dronotropic

Toxic dose-M3 receptor-endothelium blockade NO release is blockedsmooth muscle donotrelaxprevention of cholinergic mediated dialation

Autonomic control of pupil (A) and site of action 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 blurring of near vision. The intraocular tension rises, specially in narrow angle glaucoma

All visceral smooth muscles with parasympathetic innervation 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 is primarily regulated by local reflexes and otherneurotransmitters (serotonin, encephalin, etc.).

Atropine causes bronchodilation and reduced airway resistance, especially in asthma patients. Inflammatory mediators (histamine, PGs, and kinins) increase vagal activity in addition to their direct action on bronchial muscle and glands. Atropine attenuates their action by antagonizing the reflex vagal component.It has a relaxant action on the ureter and urinary bladder. Urinary retention can occur in older men with prostatic hyperplasia.

Glands. Atropine decreases sweat, salivary, tracheo-bronchial, and lacrimal secretion (M3-blockade). Skin and eyes become dry, talking, and swallowing my bevery difficult.Atropine decreases less the secretion of acid and pep-sin and more of the mucus in the stomach. Body temperature. Rise in body temperature occurs athigher doses, and is due to both inhibition of sweating as well as stimulation of the temperature regulating centre in the hypothalamus. Children are highly susceptible.

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 and bladder 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 and excreted unchanged in urine. It has t1/2 3–4 h. Hyoscine is more completely metabolized and has better BBB penetration. Some rabbits have a specific atropineesterase which degrades atropine very rapidly.

Scopalamine (hyoscine): A belladdona alkaloid produce peripheral effects similar to atropine, it has greater actions on CNS and longer duration of action.Most effective in motion sickness, it is effective also in blocking short term memory, it produce sedation but 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 in treating asthma and COPD in patients unable to take adrenergic agonist. Useful in rhinorrhea. Also excellent bronchodilator.

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

Benztropine-used in drug induced Parkinson’s disease. Useful for dystonic reactions caused by antipsychotics.

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

Flavoxate-relieves dysuria, urgency, frequency and pain with genito-urinary infections

Oxybutynin -has direct antispasmodic effects on smooth muscle and anticholinergic effects. Decreases frequency of voiding.

Tolterodine -is competitive, antimuscuranicanticholinergic that inhibits contraction. More selective for this area than elsewhere in the body.

- They act on nicotinic receptors of the autonomic ganglia.

- They have no selectivity toward the parasympathetic or sympathetic ganglia .

- The effect of these drugs is complex and unpredictable 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 blocker that must be given by i.v infusion

It is used for the emergency lowering of the blood pressure in hypertension caused by pulmonary edema or dissecting aortic aneurysm, when other agents cannot be used.

- Drugs that block cholinergic transmission between motor nerve ending and the nicotinic receptors on the neuromuscular end plate of the skeletal muscle.

- They are structural analogs of ACH.

Mydriatic and cycloplegic agent in the eye to permit measurement of refractive errors. Mydriasis and cycloplegia for surgery

RS-In bronchospasm whether related to asthma or COPD bronchodilating effects

CVS-Atropine is used to increase heart rate in symptomatic bradycardias and higher blocks

GIT-Antispasmodic agent: Relax GIT and bladder.Helpful in treating irritable colon or colitis

Useful in gastritis, pylorospasm and ulcerative colitis as they slow motility

Antispasmotic effects seen in overactive bladder and in urinary incontinence

Antidote for cholinergic agonists: To treat organophsphorus poisoning (present in insecticides), and mushroom poisoning. Antisecretory agent: To block the secretion of upper and lower respiratory tracts prior to surgery.

Helps to prevent vagal stimulation and potential bradycardia

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, in parkinsonism may have to be increased. But the extent of digoxin and tetracyclines absorption may be increased.Antacids interfere with the absorption of anticholinergics.Antihistaminics, tricyclic antidepressants, phenothiazines, pethidine have anticholinergic property additive side effectsMAO inhibitors interfere with the metabolism of central antiparkinsonian drugs (biperiden and others) delirium may occur.

BPH Myasthenia gravis Hyperthyroidism Glaucoma Tachydysrhythmias

Dry mouth, difficulty in swallowing and talking; Difficulty in micturition Dilated pupils, photophobia, blurring of near vision;

palpitation; excitement, psychotic behavior, Ataxia, delirium, hallucinations; hypotension, weak

and rapid pulse, cardiovascular collapse with respiratory depression;

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 induce typical 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 against convulsion.

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