Class anticholinergic drugs

this class is in brief for under graduate understanding and examination purpose

1. AUTONOMIC NERVOUS SYSTEM- ANTICHOLINERGIC DRUGS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1

2. Autonomic Nervous System Central Nervous System (CNS) - Brain and spinal cord Peripheral Nervous System (PNS) - Located outside the brain & spinal cord  Autonomic Nervous System (ANS) & the somatic The PNS receives stimuli from the CNS & initiates responses to the stimuli after it’s interpreted by the brain

3. Parasympathomimetic receptors Acetylcholine – preganglionic Post ganglionic Ach Exception-post ganglionic sympathetic fibres to apocrine glands Cholinergic fibres  All somatic motar neurons All preganglionic fibres Post ganglionic parasympathetic fibres

4. Parasympathetic system 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

5. Classification Natural alkaloids: Atropine (spasmolytic, mydriatic ), Hyoscine (Scopolamine), ( antiemetic) 2 . Semisynthetic derivatives Mydriatics : Homatropine , Tropicamide GI spasmolytics : Hyoscine butyl bromide 3 . Synthetic compounds GI spasmolytics : Oxyphenonium Antiulcer drugs: Pirenzepine (M1-blockers) Antiasthmatics : Ipratropium and Tiotropium Urinary system: Flavoxate , Oxybutynyne , Trospium Antiparkinsonian (central M- cholinolytics ): Benztropine , Biperiden , Trihexyphenidyl

6. Anticholinergics 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.

7. 50 100 150 200 A B C D 1 min ATROPINE BLOCKS M-EFFECTS OF ACH Blood pressure [mm Hg] ACh 2 mcg i.v. ACh 50 mcg ACh 50 mcg ACh 5 mg M- effect M- effect N- effect Atropine 2 mg i.v. ACh

8. Atropine A belladonna alkaloid has a high affinity for muscarinic receptors , it is a competitive inhibitor of muscarinic receptors preventing ACH from binding to that site. Atropine

9. Action of 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 vas о motor. 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.

10. Atropine on CVS Low dose-M2 receptor on cholinergic N auto- inhibitary cholinergic action bradycardia Moderate dose- M2 receptor on post junctional SAN, AVN blkescape the heart from inhibitiontachycardia+Unopposed adrenegic action chronotropic , dronotropic Toxic dose-M3 receptor-endothelium blockade NO release is blockedsmooth muscle donot relaxprevention of cholinergic mediated dialation

11. Atropine action on eye 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

12. Atropine action on smooth muscles All visceral smooth muscles with parasympathetic innervation are relaxed (M 3 -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 other neurotransmitters (serotonin, encephalin, etc.).

13. Atropine action on smooth muscles 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.

14. Atropine action on glands Glands. Atropine decreases sweat, salivary, tracheo - bronchial, and lacrimal secretion (M3-blockade). Skin and eyes become dry, talking, and swallowing my be very 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 at higher 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.

15. Atropine other actions Local anaesthetic action. Atropine has a mild anaesthetic action on the cornea. The sensitivity of different organs and tissues to atropine varies and can be graded as Saliva , sweat, bronchial secretion > eye > bronchial muscles > heart > intestinal and bladder smooth muscles > gastric glands and gastric smooth muscles

16. Pharmacokinetics Atropine and hyoscine are rapidly absorbed from GIT. 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 t 1/2 3–4 h. Hyoscine is more completely metabolized and has better BBB penetration . Some rabbits have a specific atropine esterase which degrades atropine very rapidly.

17. Scopalamine ( hyoscine ) 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 .

18. Ipratropium bromide 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.

19. Centrally Acting Anticholinergics 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.

20. Urinary Antispasmodics 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, antimuscuranic anticholinergic that inhibits contraction. More selective for this area than elsewhere in the body.

21. Ganglionic blockers - 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)B lood pressure falls because of ganglionic blockade B)Activity both in GIT and UB musculature decrease .

22. Trimethaphan 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.  

23. Neuromuscular blocking drugs - 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.

24. Clinical Uses 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

25. Clinical uses 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

26. Clinical uses CNS- Parkinson’s Disease- Useful in those with minimal side effects Those who cannot take Levodopa Helpful in decreasing salivation, spasticity and tremors

27. Drug interactions Absorption of other drugs is slowed because atropine delays 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 effects MAO inhibitors interfere with the metabolism of central antiparkinsonian drugs ( biperiden and others ) delirium may occur.

28. Contraindications BPH Myasthenia gravis Hyperthyroidism Glaucoma Tachydysrhythmias

29. Toxicity of Anticholinergics 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

30. Toxicity of Anticholinergics -treatment Diagnosis : 1 mg neostigmine s.c. fails to induce typical M-effects. Treatment: Gastric lavage with tannic acid (KMnO4 is ineffective in oxidation of atropine). The patient must be kept in a dark quiet room. Galantamine or physo - stigmine (1-3 mg s.c. / i.v. ), diazepam against convulsion.

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