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PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM

PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM. Sympathomimetics. Catecholamines compounds with different pharmacodynamic effects, but have a common structure group "catechol ” (ortho-diphenols). Catecholamines. Adrenalin e ( epinephrine )

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PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM

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  1. PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM Sympathomimetics

  2. Catecholaminescompounds with different pharmacodynamic effects, but have a common structure group "catechol” (ortho-diphenols)

  3. Catecholamines • Adrenaline (epinephrine) • is released from the adrenal medulla and other chromaffin tissues. • equally stimulates receptors12 şi 123 • Noradrenaline (norepinephrine) • is released from postganglionic sympathetic fibers, neurons of the CNS and adrenal medulla. • stimulates receptors12 and 12 • Dopamine • is released from peripheral autonomic endings and CNS neurons • stimulate receptorsD1= D2 D3D4D5 In the body, the synthesis of catecholamines from tyrosine and phenylalanine starts and stops depending on physiological needs at one of the three stages of training.

  4. Biosynthesis of adrenaline and noradrenaline

  5. Adrenergics Receptors

  6. Adrenergics Receptors • Catecholamine receptors are located on the surface of cell membranes and coupled to specific G protein (Gs and Gi). • Catecholamines exist in a polarized form, which allows the coupling of receptors and explains the very difficult crossing the blood-brain barrier.

  7. SETTING adrenergic receptor • presynaptic setting- 2, 1, D2 • receptors2inhibits release of noradrenalineperipheral sympathetic activity is inhibited • receptors1stimulates the release of noradrenalineperipheral sympathetic activity is stimulated • receptors D2inhibits release of noradrenaline • postsynaptic setting • sequestration in the membrane receptor • decreased receptor synthesis ("down regulation") • phosphorylation and thus inactivation of receptor

  8. NORADRENALINEPost receptor signal transmision 1.

  9. EFFECTS OF CATECHOLAMINES • NORADRENALINE (NA) • dominant action on the cardio-vascular • ↑ adrenergic receptor affinity on αşi β1 + β3 (↓β2 ) • ADRENALINE (A) • dominant action on smooth muscle and metabolism • adrenergic receptor affinity ↑ on αşi β1 + β2 (↓β3) • DOPAMINE • dominant action on the cardio-vascular: inotrop+ and ↓TPR • receptors types : DA1(excitators) and DA2(inhibitors)

  10. EFFECTSOF SYMPATHETIC STIMULATION • Pupillary diameter increased • (mydriasis) • Heart rate increased • (tachycardia or • positive chronotrop effect) • Myocardial contractility increased • (positive inotrop effect ) • Bronchial smooth muscle relaxation • Salivary secretion increased (increases viscosity of secretion) • Sweat secretion increased

  11. EFFECTSOF SYMPATHETIC STIMULATION • Gastro-intestinal motility decreased • Gastro-intestinal secretion decreased • Defecation ? • Skeletal muscle tone no effect • Urination decreased • Urinary frequency decreased • Bladder tone decreased

  12. PHARMACODYNAMICS OF CATECHOLAMINES eye • 2 – ciliary relaxation • 2 – mydriasis • use of adrenaline inglaucoma (promote drainage of aqueous humor) – eye drops heart • 1 – inotrop + • 1 – inotrop +, increases syno-atriale, A-V, Hiss fasc, Purkinje fibr driving

  13. PHARMACODYNAMICS OF CATECHOLAMINES vessels ADRENALINE • small and medium doses - vasodilation and decreased BP, reflex tachycardia (vascular 2 receptors stimulation - the most sensitive) • high doses of adrenaline - vasoconstriction – increasesystolic and diastolic BP, reflex bradycardia (1 a vascular receptor stimulation) NORADRENALINE • At all doses - vasoconstriction - increases blood pressure, increased peripheral vascular resistance, reflex bradycardia

  14. PHARMACODYNAMICS OF CATECHOLAMINES vessels DOPAMINE vasodilation in the territory of the kidneys, bowel, decreased peripheral resistance strong positive inotropic effect, increasing cardiac output remain unchanged BP and peripheral pulse Dopamine is the only catecholamine that may be indicated in cardiogenic shock!!! Adrenalineand noradrenalinearecontraindicated in cardiogenic shock în şocul cardiogen because they produce vasoconstriction in the mesenteric and renal vessels, increasing organs ischemia 16

  15. PHARMACODYNAMICS OF CATECHOLAMINES coronaro-dilatation (1, 1, 2, D1, D2) vasoconstriction in visceral vesselsexcept for liver and lung vessels that causes vasodilation effect Decrease capillary and post-capillary permeability(increased by pathological factors, type I allergy) - anaphylactic shock Anaphylactic shock is the only form of shock is indicated A and NA! 17

  16. PHARMACODYNAMICS OF CATECHOLAMINES Bronchial smooth muscle – bronhodilation (2) Gastro-intestinal smooth muscle - relaxation (2 and 2) Gastro-intestinal sphincters- contraction(1) inhibarea plexurilor mezenterice () Secretion is not influenced by SNV gastrointestinal sympathetic. Genito-urinary smooth muscle Bladder smooth muscle - relaxetion (2), bladder sphincter - contraction(1) uterine muscles - relaxation during pregnancy(2) andcontractionin labor (1) stimulation ejaculation(1) 18

  17. PHARMACODYNAMICS OF CATECHOLAMINES Metabolic effects Hyperglycemia (physiological doses) • 2stimulation– increaseglycogenolysisandinhibit glycogen synthesis • 1, 2stimulation– stimulates glyconeogenesis,decreases the glucose prelevation from periphery • 2stimulation– inhibit insulin secretion by the endocrine pancreas Metabolic acidosis (supraphysiological doses) • stimulation2– up-take of potassium into cells causes the decrease in extracellular potassium (this is a protective effect during stress increases the serum potassium can be dangerous)

  18. PHARMACODYNAMICS OF CATECHOLAMINES Metabolic effects hyperlipidemia 1 and 3stimulation ( 2 receptors inhibit lipolysis) renal release of renin 1 presynapticactivation - stimulates synthesys (2 presynapticstimulation - inhibition of renin release) increase basal metabolism (20-30%) noradrenaline has a role in defending the body against cold increasecardiac oxygen consumption 20

  19. PHARMACODYNAMICS OF CATECHOLAMINES • exocrineglands– inhibits salivary and pancreatic exocrine water secretion (2) • endocrineglands – increases synthesis of melatoninby pineal gland (1) • increases release of prostaglandins • platelet agregation - (2 A)

  20. FARMACOCINETICA CATECOLAMINELOR • rapidly inactivated in the digestive tract and liver (oral adm.) • form stable salts with acids - may be given by injection. • Metabolism is made by specific enzymes • COMT (catechol ortho-methyltransferase) - liver and intestine • MAO (monoamine oxidase) - liver and kidney • exogenous catecholamines and that released from adrenal medulla are inactivated first by COMT and then by MAO. • Catecolaminlele from nervous tissue are inactivated first by intraneuronaly MAO and than by extraneuronal COMT • Noradrenaline is re-up-taked in most of the nerve endings that released her. • Elimination of active metabolites of catecholaminesare excreted in the urine

  21. CLASIFICATION OF SYMPATHOMIMETICS •  şi  Sympathomimetics • direct • Adrenaline • Noradrenaline • Dopamine • Ibopamine • indirect (Noradrenaline release) and direct • Efedrine

  22. CLASIFICATION OF SYMPATHOMIMETICS  Sympathomimetics systemic administration Etilephrine Phenilephrine Metoxamine Midodrine Metaraminol  -metil-Noradrenaline local administration (topic) Naphazoline Oximetazoline Tetrizoline Xylometazoline 24

  23. CLASIFICATION OF SYMPATHOMIMETICS  Sympathomimetics non-selective 1 and2 Sympathomimetics Isoprenaline (Isoproterenol) Orciprenaline Bufenine Bametan Etil-Noradrenaline 25

  24. CLASIFICATION OF SYMPATHOMIMETICS 2 selective Sympathomimetics Salbutamol Fenoterol Terbutaline Salbutamol Clenbuterol Pirbuterol Procaterol Bambuterol Isoxuprine Isoetarine 1 selective Sympathomimetics Dobutamine Prenalterol 26

  25. CLASIFICATION OF SYMPATHOMIMETICS Catecholamines releasers (other than ephedrine, phenylephrine, naphazoline) Amfetamine Hidroxiamfetamine Fenmetrazine Pemolin Metilfenidat Fenilpropanolamine special Sympathomimetics Cocaine Tyramine 27

  26. THERAPEUTIC USE OF SYMPATHOMIMETICS Adrenaline (1 = 2, 1 = 2 =3 agonist) • Clinical uses: • diffuse bleeding from mucous membranes and skin surface (1/50000-1/10000) • is associated as a vasoconstrictor to local anesthetic • bronchial asthma with mucosa edema (0.3 -0.8 mg sc) • glaucoma (1-2% ophthalmic solution) • intracardiac administration as an alternative therapy in the cardiac arrest (the first alternative is isoproterenol) • Type I allergies (including anaphylactic shock)

  27. THERAPEUTIC USE OF SYMPATHOMIMETICS Adrenaline (1 = 2, 1 = 2 =3 agonist) Side effects: Pallor Anxiety Palpitations at higher doses arrhythmia, ventricular fibrillation, hypertension, acute pulmonary edema 29

  28. THERAPEUTIC USE OF SYMPATHOMIMETICS Adrenaline (1 = 2, 1 = 2 =3 agonist) Contraindication: HTA angina pectoris Tachyarrhythmias not associated with local anesthetics in anesthesia extremities (nose, ears, penis, fingers) - ischemic necrosis preparations is not associated with calcium - contributes tachyarrhythmias 30

  29. THERAPEUTIC USE OF SYMPATHOMIMETICS Noradrenaline (1 = 2, 1 2 agonist ) • Clinical use: • diffuse bleeding from mucous membranes and skin surface (1/500.000 - 1/10.000) • is associated as a vasoconstrictor to local anesthetic • Side effects: • Pallor • Anxiety • Palpitations • at higher doses arrhythmia, ventricular fibrillation, hypertension, acute pulmonary edema

  30. THERAPEUTIC USE OF SYMPATHOMIMETICS Noradrenaline (1 = 2, 1 2 agonist ) Contraindication: HTA angina pectoris Tachyarrhythmias not associated with local anesthetics in anesthesia extremities (nose, ears, penis, fingers) - ischemic necrosis preparations is not associated with calcium - contributes tachyarrhythmias 32

  31. THERAPEUTIC USE OF SYMPATHOMIMETICS Dobutamine Catecholamine is only indicated in cardiogenic shock. Side effects: can give you chest pain, nausea, vomiting It is given intravenously slowly infusion under medical supervision 33

  32. THERAPEUTIC USE OF SYMPATHOMIMETICS Ephedrine (NA releaser,  şi  agonist) is a natural alkaloid - structură non-catechol structure Crosses the blood-brain barrier and cause the release of catecholamines in the CNS psyhoanaleptic inducing effects (cortical awakening, increase the concentration of attention, memory, learning) anorexines, so the effect of "amphetamine" (much lower than amphetamines). 34

  33. THERAPEUTIC USE OF SYMPATHOMIMETICS Ephedrine (NA releaser,  şi  agonist) Pharmacodynamic effects: systolic and diastolic blood pressure increases positive inotropic effect, increase SA and AV drivind bronchodilation amphetamine-type effects at central decrease capillary permeability and increased postcapillary pathological factorslocal vasoconstriction (antiedema effect) 35

  34. THERAPEUTIC USE OF SYMPATHOMIMETICS Ephedrine (NA releaser,  şi  agonist) Side effects: tachyarrhythmias, ventricular fibrillation excessive blood pressure increases Tachyphylaxis psychological dependence Contraindication: high blood pressure arrhythmia endogenous psychoses angina pectoris 36

  35. THERAPEUTIC USE OF SYMPATHOMIMETICS Ephedrine (NA releaser,  şi  agonist) Clinical use: AV block astm bronşic cu edem al mucoasei (pentru iniţierea terapiei, bronchial asthma with mucosa edem (treatment initiation and then continues with two selective 2 stimulators) hTA (therapeutic alternative - increased BP for several hours local solutions in rhinitis, allergic conjunctivitis (antiedema effect) Etilefrina is indicated for the background treatment of hypotension. There are also forms of storage, slow release of active substance. 37

  36. THERAPEUTIC USE OF SYMPATHOMIMETICS Phenilephrine - 12 agonist non-catechol structure Cross blood-bain barrier Release noradrenaline from cell storage – can causetachyphylaxis Pharmacodynamic Effects increases systolic and diastolic blood pressure produce mydriasis of short duration (few minutes) reduce mucosal edema by reflex compensatory, increase in blood pressure occurs after a brief period of bradycardia (will be shown in PSVT) 38

  37. THERAPEUTIC USE OF SYMPATHOMIMETICS Fenilephrine - 12 agonist Clinical use Damage to the sympathetic cervical syndrome Claude Bernard HornerHTA produce diagnostic mydriasis the solutions applied locally - antiedematos of mucosal PSVT It is associated as a vasoconstrictor to local anesthetic 39

  38. THERAPEUTIC USE OF SYMPATHOMIMETICS Metoxamine not cross the blood-brain barrier, produces a long lasting increase in blood pressure (limits its clinical utility) It is indicated as an alternative in the treatment of hypertension. Midodrine N-acetamide derivative of metoxamine It is indicated for the background treatment of orthostatic hypertension It is administered orally.. Metaraminol Increase bloog preasure increase in venous tone pulmonary vessels produces vasoconstriction decreases renal blood flow and cerebral 40

  39. THERAPEUTIC USE OF SYMPATHOMIMETICS Naphasoline (1 şi 2 agonist) a small proportion is a deposits cell noradrenaline releaser - may produce tachyphylaxis In chronic administration (nasal instillation) - can lead to atrophy of nasal mucosa - atrophic rhinitis physiological barriers across immature children - carries significant systemic concentrations and stimulates CNS 2 presynaptic receptors resulting sympatholysis (TA and collapse) In adult at high doses - significant systemic concentrations stimulates the vascular 1 receptors and excitoconductor tissue (hypertension, ventricular fibrillation) 41

  40. THERAPEUTIC USE OF SYMPATHOMIMETICS Oxymetasoline atrophic rhinitis occurs less frequently. Isoprenaline (Isoproterenol)- (non-selectiv 12 agonist) AV block Indicated cardiac arrest asthma (initiation, then continues with 2 stimulators) Side effects: anginal pain nausea, vomiting Headache tachyarrhythmias, ventricular fibrillation 42

  41. THERAPEUTIC USE OF SYMPATHOMIMETICS Bufenineand Bametane - relatively selective 2 vascular receptors indicated in the treatment of intermittent claudication Raynaud's syndrome. Dobutamine – increased pozitivinotrop effect(and negligible influence heart rate and BP) It is indicated in congestive heart failure Cardiogenic shock. 43

  42. THERAPEUTIC USE OF SYMPATHOMIMETICS Prenalterol is1 agonist. Indicated in congestive heart failure Salbutamol, Fenoterol, Terbutaline, Salmeterol indicated in asthma / inhalator / injectable, orally way. Isoetarine, Isoxuprine (1 antagonists and inhibitors with direct action on uterinesmooth muscle) Indicated in premature labor 44

  43. THERAPEUTIC USE OF SYMPATHOMIMETICS Amphetamines rapidly crosses the blood-brain barrier to reach CNS where release noradrenaline and dopamine from central warehouses acts directly through stimulation of ascending activating reticulate fibers inhibit MAO 45

  44. THERAPEUTIC USE OF SYMPATHOMIMETICS Pharmacodynamic effects Central - psihoanaleptice effects, anorexines Peripheral - sympathomimetics type effects Clinical uses: stimulation of psychomotor performance Narcolepsy hyperkinetic syndrome in children adjunct in Parkinson's disease adjuvant seizures "petit mal“ nocturnal enuresis 46

  45. THERAPEUTIC USE OF SYMPATHOMIMETICS Contraindication: schizophrenia, bipolar psychosis mental instability SDR. Tourette Hypertension, tachyarrhythmiasCoronary sclerosis, cerebral Glaucoma Side effects: headache chest pain nausea, vomiting, constipation Hypertension, tachyarrhythmias Outbreak of acute episodes of endogenous psychoses Amphetamines cause psychological dependence,coherent thought disorder - "amphetamine psychosis" 47

  46. THERAPEUTIC USE OF SYMPATHOMIMETICS Acute intoxication with amphetamine - at doses above 100 mg. DL is less than 1 g. The patient presentes Hypertension, palpitations, tachyarrhythmias - fibrillated fibrillation or ventricular pallor, anxietychills, sweating, paranoid psychosis There is no antidote for acute poisoning with amphetamines. Treatment benzodiazepines, barbiturates Haloperidol ChlorpromazineClonidine, methyldopa, 1 –blockers loop-diuretic furosemide iv urine acidification (ammonium chloride) to spur removal 48

  47. THERAPEUTIC USE OF SYMPATHOMIMETICS COCAINE- natural alkaloid obtaned from din Eritroxilon coca leaves (Peru, Bolivia). It uses non-medical purposes for euforizante effects. It is a very fine powder, white. It is administered by smoking, snuff nasal injection. The therapy is indicated only as a surface anesthetic ENT oftalmolgie. Mechanism of action - inhibits the uptake of noradrenaline in nerve endings, increases norepinephrine turnover 49

  48. THERAPEUTIC USE OF SYMPATHOMIMETICS Effects Mydriasis Tachyarrhythmias high blood pressure Nasal septal perforation - the chronic administration by nasal snuff Cocainomanul is on alert (mydriatic) quickly earning their "followers" and provides the first dose entourage, with great pleasure, the following will be taken at doses voluntarily recruited. After intravenous administration of cocaine creates a sense of physical and mental strength, even orgasm (cocaine is called "girl" or "boy ").As there is no antidote for cocaine intoxication 50

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