Autonomic nervous system Cholinergic antagonists (CHOLINOBLOCKERS) PhD. A.V. Aleksandrova

1. Autonomic nervous system Cholinergic antagonists (CHOLINOBLOCKERS)PhD. A.V. Aleksandrova

2. Cholinergic receptor types • Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (N-cholinoceptors). At least 5 subtypes of muscarinic receptors (M1 – M5) have been distinguished. • There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes. MUSCARINIC NICOTINIC M1 NM M5 NN M2 M4 M3 • Ganglions • Carotid sinus • Skeletal muscles • Adrenal glands • CNS • Eye • Heart • Smooth muscles • Exocrine glands • CNS

3. Muscarinic receptors • High affinity to muscarine • M1 – gastric parietal cells, saliva, CNS • M2 - cardiac cells, smooth muscle, CNS • M3 - bladder, exocrine glands, smooth muscle, eye, CNS • M1&M3 – Gq • M2 - Gi Amanita muscaria

4. Nicotinic receptors • High affinity to nicotine • NM- neuro-muscular junction • NN – ganglion, adrenal gland CNS, carotid sinus

5. Mechanisms of impulse transmission • Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses throughM1, M3, M5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol • Stimulation of M2 and M4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular cAMP. • N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization.

6. M-cholinoceptors

7. N-cholinoceptors

8. Classification of cholinoblockers • I. M-cholinoblockers (Muscarinic antagonists) • Natural agents • Atropine • Hyoscine /Scopolamine/ • Plathyphylline • Dry extract of Beladonna • Semisynthetic and synthetic • Homatropine • Propantheline • Methacinum • Ipratropium bromide /Atrovent/ • Cyclopentolate • Pirenzepine

9. Classification of N-cholinoblockers • 1. Ganglion blocking drugs • Hexamethonium /Benzohexonium/ • Hygronium • Pempidine tosilate • Trimethaphan • Pentaminum • Pirilenum • 2. Neuromuscular blockers • a) Nondepolarizing • Atracurium • Pancuronium • Tubocurarine • Vecuronium • b) Depolarizing • Succinylcholine • (Dithylinum)

10. Mechanism of action

11. Cholinoblockers • Eye • inability to focus for near vision, mydriasis, IOP ↑ • Saliva • xerostomia • Bronchi • bronchodilation, secretion ↓ • Heart • Rate ↑ • GIT • secretion, peristalsis ↓ sphincter tone ↑ • Bladder • detrusor ↓ sphincter tone ↑

12. Clinical uses of M-cholinoblockers • A-V block – Atropine • Colic, abdominal cramps – Atropine, Plathyphylline • Urinary frequency - Oxybutinin • Preanesthetic medication – Atropine, Hyoscine • Peptic ulcer – Pirenzepine (selective M1 cholinoblocker) • Bronchial asthma - Ipratropium bromide

13. Clinical uses of M-cholinoblockers • Therapeutic uses in ophthalmology: in iritis, keratitis and other inflammatory diseases and trauma of eye - Atropine • Diagnostics in ophthalmology – Atropine, Homatropine, Cyclopentolate • Prevention of motion sickness - Hyoscine • Muscarinic poisoning – Atropine • Organophosphate poisoning - Atropine

14. Pharmakokinetics ATROPINE • Tertiary nitrogen • Good adsorbtion • Penetrate BBB Atropa belladonna

15. Main effects ATROPINE • Smooth muscle relaxation • Antisecretory Influence on an eye Dilation of a pupil (midriasis) Increasing of intraocular pressure Paralysis of accomodation (cycloplegia) Dose-dependent effects of atropine

16. Therapeutic uses ATROPINE • Ophtalmological tests • Spasmolythic (as an antispasmodic agent to relax the GIT and bladder) • Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery) • Mushroom poisoning • Organophosphates poisoning • Heart block, bradycardia • Resuscitation (asystole)

17. Therapeutic uses 8. Trauma of the eye, inflammation in the eye (cycloplegia and midriasis are “pharmacological bandage” producing eye immobilization) 9. Premedication 10. Enuresis

18. Adverse effects ATROPINE 1. Dilated pupils resulting in photophobia 2. Blurred vision 3. An increase in intraocular pressure, an attack of glaucoma in someone with latent condition prostate 4. Tachycardia 5. Dry mouth 6. Constipation 7. Retention of urine 8. Flushed skin 9. A rise in body temperature.

19. Contraindications ATROPINE • Narrow-angle glaucoma • Pyloricstenosis • Prostatichypertrophy • Drivers • 5. Hepatic insufficiency • 6. Hyperthyroidism • 7. High body temperature • 8. Toxicosis of pregnancy • 9. Cerebral pathology in children • 10. Childhood or old age.

20. Belladonna poisoning • Dry mouth, difficulties in swallowing and talking • Dilated pupil, photophobia, blurred vision • Dry, flushed and hot skin • Difficulties in micturation • Constipation • Hypotension, weak and rapid pulse • Excitement, psychotic behavior,delirium, hallucination Death is caused by paralysis of breath center • ANTICHOLINESTERASE DRUGS ARE ANTIDOTES

21. TREATMENT OF ACUTE POISONING • wash out of stomach with0,5 % Tannin solution, laxative agents, sorbents, forced diuresis • Specific antagonists – anticholinesterase drugs: repeated introduction ofproserinum, galantaminum, hydrobromidumuntil symptoms of disappearance of M-cholinoblockersblockade • removal of psychomotor excitement - aminasinum, sybazon, barbiturates • removal of tachycardia –anapryline • for relief of photophobia patient is transferred to a dark room • for decreasing of body temperature ice-cube bottles are placed around the patient • In case of considerable depressing of breathing - artificial ventilation with oxygen inhalation

22. Pharmakokinetics SCOPOLAMINE • Tertiary nitrogen • Good adsorbtion • Penetrate BBB Solanaceae family

23. Therapeutic uses SCOPOLAMINE • the central action • Is greater and longer than that of atropine; • inhibits activity of VIII pair of cranial • nerves and decreases motion sickness, • produces sedation and short-memory blocking, • has antiparkinsonian effect; • has a strong and short (5-6 hrs) action on the eye;

24. USES • is used for the prevention and treatment of motion sickness, • for the complex therapy • of psychic diseases, • Parkinson’s disease, • for premedication; • has side-effects similarto those of atropine.

25. Platyphylline • is an alkaloid from Senecioplatyphylus • has the central action lessthan that of atropine; has a short (5-6 hrs) action on the eye; • causes inhibition of thevasomotor center and a direct myotropic action on blood vessels, • Dilatesblood vessels and lowers BP; • may be used to treat spasms of cerebral and coronaryblood vessels, as well as to treat hypertension.

26. Methacinum • is a synthetic preparation, non-selective M-cholinoblocker; • Is more potent than atropine in dilation of bronchi, the inhibition of gasrtric secretion, and a decrease of the uterus tone; • it does not penetrate CNS, • does not act on the eye, • has poor influence on the heart rate; is used • in bronchial asthma, • ulcer of the stomach, colic, premedication, and the danger of miscarriage.

27. Therapeutic uses TROPICAMIDE Eye examination

28. Therapeutic uses IPRATROPIUM • non-selectiveM-cholinoblocker in the form of aerosol; • is not absorbed in the lungs and acts onM-cholinoreceptors only in bronchi; • dilates bronchi; • is used for the prevention of a • bronchial asthma attack; • has not significant side-effects

29. Therapeutic uses TRIHEXYPHENIDYL Parkinson’s disease

30. Pirenzepine • is selective M-cholinoblocker inhibiting gastric secretion; • Isadministered orally, IM, IV; produces maximal concentration in blood plasma • does not penetrateCNS and placenta; USES • is used for the treatment of ulcer of the stomach and duodenum, • Zollinger-Ellison’s syndrome, • the prevention of peptic ulcers caused by stress; • Maycause dry mouth, blurred vision, retention of urine, but side-effects are minimal incomparison with atropine.

31. Nicotine • Dose-dependent effect

32. Acute poisoning with nicotine Clinical picture nausea, vomiting, salivation, abdominal pain, diarrhea, dizziness, headache, cold sweat, weakness, loosing of consciousness, tachy- or bradycardia, cardiac arrhythmias, seizures, breathing depression Death is caused by acute depression of respiratory center and paralysis of breathing musculature

33. Chronic poisoning with nicotine Chronic diseases of respiratory system, Lung cancer, Malignant tumors of other etiology, Ischemic heart disease, Obliterating endarteritis, Gastric and duodenal ulcer disease • Women Depression of female sex hormones production, yellowface, early wrinkles, damaging of teeth, harsh voice, sometimes male type hair growth • Men Deep, irreversible changes of spermatozoids

34. Ganglion blocking drugs • Benzohexonium • Hygronium • Mecamylamine • Trimethaphan • Pentaminum • Pirilenum Interfere with postsynaptic transmission ofAch Block action of Ach on nicotinic receptors Usedrarely severe adverse effects: Orthostatic(postural) hypotension, tachycardia, dry-mouth, GIT atony, urine retention, digestive problems, sexual dysfunction: failure of erection and ejaculation

35. PHARMACODYNAMICS • Dilation of peripheralvessels • Decreasing ofblood pressure • Decreasing ofsmooth muscle toneof inner organs (bronchi, GI tract, urinary and bile tracts) • Decreasing of gland secretion: bronchial, gastric, salivary

36. Benzohexonium • The drug blocks N-cholinoreceptors in sympathetic and parasympatheticganglia and disturbs the autonomic regulation of internal organs • It inhibits the propagation of the nervous impulses running to effector organsalong both sympathetic and parasympathetic fibres. • The main result of sympathetic ganglia blockade is a decrease of BP, parasympathetic ganglia is manifested by sympatholyticand antisecretory effects.

37. Benzohexonium • the dilation of blood vessels, redistribution of blood in the body, loweringof BP • the dilation of bronchi • decrease in secretion and motility of the bowels, • spasmolytic action • a decrease in the tone of the urinary bladder and urinary pathways • an increase in the sensitivity of myometrium to oxytocin resulting in the • stimulation of uterus contractions in the labor • a decrease in'sweat secretion Pharmacodynamics

38. Benzohexonium Does nor penetrate through blood-brain barrier Duration of action varies from 3 to 6 hours Usage Hypertensive crisis Obliterating endarteritis Spasm of peripheral vessels Intestinal, hepatic, kidney colic Gastric ulcer Bronchial asthma, lung emphysema, lung edema

39. Pentaminum Duration of action– 2-4 hours Usage Hypertensive crisis Obliterating endarteritis Spasm of peripheral vessels Intestinal, hepatic, kidney colic Gastric ulcer Bronchial asthma, lung emphysema

40. Hygronium Effect develops after 2-3 min, and lasts for 10-15 min after stopping of infusion Usage For controlled hypotonic For treatment of nephropathy and eclampsia For complex therapy of hypertensive crisis, brain edema, lung edema

41. Pirilenum Penetrates through blood-brain barrier and blocks central N-cholinergic systems Effect is observed after 1-2 hours and lasts for 6-8 hours if administered orally Usage Heavy form of arterial hypertension Trophic disorders

42. Side effects and complicationsof ganglionblockers Orthostatic collapse (postural hypotension) Dryness of mucous membranes Disturbance of accommodation General weakness Dizziness Tachycardia Atonia of urinary bladder, intestines (paralytic ileus)

43. Neuromuscular Blocking Drugs Depolarizing (non-competitive) Nondepolarizing (competitive) Succinylcholine Dithylinum Atracurium Pancuronium Tubocurarine

44. Skeletal muscles relax in such turn Small muscles of fingers,toes, ears, eyes, head, neck, muscles of extremities, trunk, Intercostals muscles and diaphragm Restoring of tone is performed in reversed sequence

45. Tubocurarine

46. Tubocurarine Relaxation begins after 1-1,5 min after introduction and lasts for 25-40 min Usage • For prolonged relaxation of striped muscles during surgical operations • For relaxation of muscles while repositioning fractured bones and complicated dislocations • For prevention of traumatic injuries during seizure therapy of schizophrenia, during epileptic status, seizures of other etiology PROSERINE is introduced to overcome action of the drug

47. Decurarization • The duration of the action of d-tubocurarine can be shortened by the administration of neostigmine. Inhibition of acetylcholine esterase causes the concentration of acetylcholine released at the endplate to rise. • Competitive “displacement” by acetylcholine of tubocurarine from the receptors allows transmission to be restored.

48. Side effects of nondepolarizing myorelaxants • Stimulation of histamine release, • Hypotension, • Flushing, • Tachycardia • Arrest of breathing. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

49. Succinylcholine Phase I: depolarization, fasciculation, prolong depolarization, flaccid paralysis Phase II: desensitization

50. Phase 1 • has the principal paralytic effect. Binding of Succinylcholine to the N-Ch receptor results in opening of the receptor's monovalentcation channel; a disorganized depolarization of the motor end-plate occurs and calcium is released from the sarcoplasmic reticulum. • Calcium is removed from the muscle cell cytoplasm independent of repolarization. As the calcium is taken up by the sarcoplasmic reticulum, the muscle relaxes. This explains muscle flaccidityrather than tetany following fasciculations. • The results are membrane depolarization and transient fasciculations, followed by paralysis.