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

2. www.company.com 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 M2 M3 M4 M5  Eye  Heart  Smooth muscles  Exocrine glands  CNS NMNM N  Ganglions  Carotid sinus  Skeletal muscles  Adrenal glands  CNS

3. www.company.com Muscarinic receptors High affinity to muscarine M 1 – gastric parietal cells, saliva, CNS M 2 - cardiac cells, smooth muscle, CNS M 3 - bladder, exocrine glands, smooth muscle, eye, CNS M 1 &M 3 – G q M 2 - G i Amanita muscaria

4. www.company.com Nicotinic receptors High affinity to nicotine N M - neuro-muscular junction N N – ganglion, adrenal gland CNS, carotid sinus

5. www.company.com Mechanisms of impulse transmission Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses through M1, 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. www.company.com M-cholinoceptors Pharmacological actionsLocationsReceptor CNS excitation Gastric acid secretion CNS gastric parietal cells M1 Excitatory Cardiac inhibition (Bradycardia) HeartM2 Inhibitory Secretion of glands Smooth muscle contraction Vasodilatation (via nitric oxide) Exocrine glands Smooth muscles Vascular endothelium M3 Excitatory memory, arousal, attention andCNSM4 & M5

7. www.company.com N-cholinoceptors Cholinoc eptors LocalizationEffects of stimulation NNAutonomic ganglia (parasympatheti c and sympathetic) Increase in parasympathetic and sympathetic reactions NNAdrenal medullaIncrease in adrenaline release, increase in BP NMSkeletal muscleIncrease in tone, contraction Carotid sinusReflex respiratory centre stimulation NNCNSStimulation

8. www.company.com 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. www.company.com 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. www.company.com Mechanism of action

11. www.company.com 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. www.company.com 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. www.company.com 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. www.company.com Pharmakokinetics ATROPINE 1.Tertiary nitrogen 2.Good adsorbtion 3.Penetrate BBB Atropa belladonna

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

16. www.company.com Therapeutic uses ATROPINE 1.Ophtalmological tests 2.Spasmolythic (as an antispasmodic agent to relax the GIT and bladder) 3. Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery) 4.Mushroom poisoning 5.Organophosphates poisoning 6.Heart block, bradycardia 7.Resuscitation (asystole)

17. www.company.com 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. www.company.com 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. www.company.com Contraindications ATROPINE 1.Narrow-angle glaucoma 2.Pyloricstenosis 3.Prostatichypertrophy 4.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. www.company.com 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 ANTICHOLINESTERASE DRUGS ARE ANTIDOTES Death is caused by paralysis of breath center

21. www.company.com TREATMENT OF ACUTE POISONING wash out of stomach with 0,5 % Tannin solution, laxative agents, sorbents, forced diuresis Specific antagonists – anticholinesterase drugs: repeated introduction of proserinum, galantaminum, hydrobromidum until symptoms of disappearance of M-cholinoblockers blockade 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. www.company.com Pharmakokinetics SCOPOLAMINE Solanaceae family 1.Tertiary nitrogen 2.Good adsorbtion 3.Penetrate BBB

23. www.company.com 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. www.company.com 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 similar to those of atropine.

25. www.company.com Platyphylline is an alkaloid from Senecioplatyphylus has the central action less than that of atropine; has a short (5-6 hrs) action on the eye; causes inhibition of the vasomotor center and a direct myotropic action on blood vessels, Dilates blood vessels and lowers BP; may be used to treat spasms of cerebral and coronary blood vessels, as well as to treat hypertension.

26. www.company.com 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. www.company.com Therapeutic uses TROPICAMIDE Eye examination

28. www.company.com Therapeutic uses IPRATROPIUM non-selective M-cholinoblocker in the form of aerosol; is not absorbed in the lungs and acts on M-cholinoreceptors only in bronchi; dilates bronchi; is used for the prevention of a bronchial asthma attack; has not significant side-effects

29. www.company.com Therapeutic uses TRIHEXYPHENIDYL Parkinson’s disease

30. www.company.com Pirenzepine is selective M-cholinoblocker inhibiting gastric secretion; Is administered orally, IM, IV; produces maximal concentration in blood plasma does not penetrate CNS 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; May cause dry mouth, blurred vision, retention of urine, but side-effects are minimal in comparison with atropine.

31. www.company.com Nicotine Dose-dependent effect

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

35. www.company.com PHARMACODYNAMICS Dilation of peripheral vessels Decreasing of blood pressure Decreasing of smooth muscle tone of inner organs (bronchi, GI tract, urinary and bile tracts) Decreasing of gland secretion: bronchial, gastric, salivary

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

37. www.company.com Benzohexonium the dilation of blood vessels, redistribution of blood in the body, lowering of 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. www.company.com 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. www.company.com 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. www.company.com 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. www.company.com 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. www.company.com Side effects and complications of ganglionblockers Orthostatic collapse (postural hypotension) Dryness of mucous membranes Disturbance of accommodation General weakness Dizziness Tachycardia Atonia of urinary bladder, intestines (paralytic ileus)

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

44. www.company.com 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. www.company.com Tubocurarine

46. www.company.com 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. www.company.com 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. www.company.com 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. www.company.com Succinylcholine Phase I: depolarization, fasciculation, prolong depolarization, flaccid paralysis Phase II: desensitization

50. www.company.com Phase 1 has the principal paralytic effect. Binding of Succinylcholine to the N-Ch receptor results in opening of the receptor's monovalent cation channel; a disorganized depolarization of the motor end-plate occurs and calcium is released from the sarcoplasmic reticulum.monovalentcationdepolarizationmotor end-platecalciumsarcoplasmic 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 flaccidity rather than tetany following fasciculations.cytoplasmflacciditytetanyfasciculations The results are membrane depolarization and transient fasciculations, followed by paralysis.

51. www.company.com Phase 2 This phase is not abnormal and is a part of its mechanism of action. It is caused by the blood concentration of Succinylcholine exceeding the therapeutic window. Desensitization occurs at the nerve terminal, and the myocyte becomes less sensitive to acetylcholine; the membrane repolarizes and cannot be depolarized again.

52. www.company.com Succinylcholine It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). Used before such manipulations as tracheal intubation, broncho and esophagoscopia, cystoscopia for reposition of fractures bones, dislocations It cause side effects: fasciculations (a sudden twitch just before paralysis occurs). post-operative pain

53. www.company.com Insufficiency of buthyrilcholinesterase (genetic pathology) In this pathology action of dithylinum can last for several hours, and all this time the patient should be connected to artificial respiration device TREATMENT Introduction of fresh-citrate blood Direct blood infusion from donnor Introduction of buthyrilcholinesterase

54. www.company.com TOXICITY 1.RESPIRATORY PARALYSIS - neuromuscular blockers induce a respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate. 2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia susceptibility, an autosomal dominant disorder of skeletal muscle, is one of the main causes of death due to anesthesia. Depolarizing neuromuscular blocking drugs (succinylcholine) can trigger malignant hyperthermia. Malignant hyperthermia is a result of excessive release of Ca2+ from sarcoplasmic reticulum. The clinical features of malignant hyperthermia are hyperthermia, metabolic acidosis, tachycardia, accelerated muscle metabolism and contructures.

55. www.company.com