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Liliana Tarţău , MD, PhD 20 13

AUTONOMIC. NERVOUS. SYSTEM. Liliana Tarţău , MD, PhD 20 13. ADRENERGIC. SYSTEM. Catec h olamine s. “catec h ol” group (ort h o-diphenol); Epinephrine (E) – adrenal medulla , other c h roma ff in tissues. Agonist on R  1  2 şi  1  2  3.

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Liliana Tarţău , MD, PhD 20 13

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  1. AUTONOMIC NERVOUS SYSTEM Liliana Tarţău, MD, PhD 2013

  2. ADRENERGIC SYSTEM

  3. Catecholamines • “catechol” group (ortho-diphenol); Epinephrine (E) – adrenal medulla, other chromaffin tissues. Agonist on R 12 şi 123. Norepinephrine (NE) – peripheral postganglionic sympathetic neurons, CNS neurons and adrenal medulla. Agonist on R 12 şi 12. Dopamine (D) – peripheral autonomic endings, CNS neurons. Agonist on R D1= D2 D3D4D5.

  4. Adrenergic receptors • presynaptic setting(2, 1, D2) • - receptors2inhibits release of NEperipheral sympathetic activity is inhibited; • - receptors1stimulates the release of NEperipheral sympathetic activity is stimulated; • receptors D2inhibits release of NE; • postsynaptic setting (α1, α1, β1, β2, β3, D1, D2, D3, D4, D5) • - sequestration in the membrane receptor; • - decreased receptor synthesis ("down regulation"); • - phosphorylation and thus inactivation of receptor;

  5. Postsinaptic adrenergic receptors • alfa-1: - vascular smooth muscles (vasoconstriction), - genito-urinarysmooth muscle (contraction, oxytocic effect), • eye smooth muscle (contraction, mydriasis), • intestinal smooth muscle (relaxation), • myocard ( force of muscular contraction and excitability, arrhythmia), • liver (glycogenolysis, hyperglicemia); • alfa-2: - endocrine pancreas gland ( insulin secretion, hyperglicemia), - thrombocytes (platelets adhesion);

  6. Postsinaptic adrenergic receptors • beta-1: - myocard ( force of muscular contraction, rhythmicity,A-V conduction speed), - renal juxtaglomerular apparatus ( renin secretion); • beta-2: - vascular, bronchial, gastrointestinal, genito-urinary smooth muscles (vasodilation, bronhodilation, relaxation,tocolytic effect), - liver, skeletal muscles (glycogenolysis, hyperglicemia); • beta-3: - adipose tissue (lipolysis, hyperlipidemia).

  7. Presinaptic adrenergic receptors • alfa-2A: - NE release in synaptic cleft, sympathetic tonus; • beta-2: - NE release in synaptic cleft amplification of sympathetic tonus;

  8. Effects of catecholamines • NOREPINEPHRINE (NE) • dominant action on the cardio-vascular system • ↑ adrenergic receptor affinity on αand β1 + β3 (↓β2). • EPINEPHRINE (E) • dominant action on smooth muscle and metabolism • adrenergic receptor affinity ↑ on αand β1 + β2 (↓β3). • DOPAMINE (D) • dominant action on the cardio-vascularsystem: inotropic + effect and ↓ of total peripheral resistance. • receptors type : D1 (excitatory) and D2(inhibitory).

  9. Pharmacodinamic effects • heart - 1 – inotrop + - 1 – inotrop +, syno-atrial, A-V conduction; • vessels - R 2 are the most sensitive to the catecholamine actions: - E - low doses- vasodilation, blood pressure, reflex tachycardia (R 2); medium and high doses - sistolic and diastolic blood pressure, reflex bradycardia (R1). • - NE – in all doses - blood pressure, vascular peripheral resistance, reflex bradycardia (vagal riposte); • - D – vasodilation in renal, mezenteric territory, vascular peripheral resistance, intense inotrop positive effect, cardiac output (without blood pressure and peripheral pulse modification)the unique catecholamine indicated in cardiogenic shock. - E şi NE - contraindicated in cardiogenic shock (vasoconstriction in mesenteric and renal territory, increasing organs ischemia). - coronary level (1, 1, 2, D1, D2) - coronarodilation, - visceral level – prevalent vasoconstriction (exception: liver, lung vessels - vasodilation).

  10. Pharmacodinamic effects • decrease capillary and post-capillary permeability (increased by pathological factors, allergic reactions type I) - anaphylactic shock (unique form of shock in which E and NE are indicated !) • bronchial smooth muscle (R 2) – bronchodilation; • gastro-intestinal smooth muscle (R 2 and 2) – relaxation; - sphincters contraction (R1). • - inhibition of mesenteric plexus (R). - gastro-intestinal secretion is not influenced by sympathetic system. • genito-urinary smooth muscle • urinary bladder wall – relaxation (R2), • vesical sphincter – contraction (R1); • uterine muscle– relaxation during pregnancy (2) and contraction in labor (1); • increase ejaculation (R1).

  11. Pharmacodinamic effects • eyes - 2 – ciliary relaxation - 2 – mydriasis E - indicated in glaucoma (aqueous humor drainage) – eye drops. Hyperglycemia (physiological doses) - 2stimulation– increaseglycogenolysisandinhibit glycogen synthesis; - 1, 2stimulation– stimulateglyconeogenesis, decrease the glucose prelevation from periphery; - 2stimulation– inhibit insulin secretion from endocrine pancreas; Metabolic acidosis (supra physiological doses) • stimulation2– up-take of potassium into cells causes the decrease in extracellular potassium (protective effect during stress, when the increasing of serum potassium level can be dangerous).

  12. Pharmacodinamic effects • hyperlipidemia- 1 and 3 stimulation (2 receptors inhibit lipolysis); • renal release of renine- 1 pre synapticactivation - stimulates synthesis (2 pre synapticstimulation - renine release inhibition) • increase basal metabolism (20-30%) - NE has a role in body defending against cold. • increasecardiac oxygen consumption, • exocrine glands– inhibits salivary and pancreatic exocrine water secretion (2); • endocrineglands – increases synthesis of melatonin by pineal gland (1) ; • increases release of prostaglandins; • platelet agregation - (2 A).

  13. SYMPATHOMIMETIC DRUGS

  14. Classification •  and  sympathomimetics - direct action - E, NE, D; - indirect (NE release) and direct action – Ephedrine •  sympathomimetics - systemic administration - Ethylephrine, Phenylephrine, - topic administration - Naphazoline, Oxymetazoline, Xylometazoline, Tetryzoline. • α1 agonists (Phenylephrine, Methoxamine,Metaraminol) – antihypotensive, vasoconstrictors; • α2 agonists- neurosympatholytics – presinaptici  agonists or/and central imidazoline receptors agonists- Clonidine, Apraclonidine, Brimonidine, Tizanidine, Moxonidine.

  15. Classification •  sympathomimetics - 1 şi 2 nonselective - Isoprenaline, Orciprenaline - 2 selective: • bronchial level: Salbutamol, Fenoterol, Terbutaline, Salmeterol, Formoterol, Bambuterol, • uterine level: Isoxuprine, Ritodrine. - 1 selective – Dobutamine – cardiogenic shock, cardiac failure. • Catecholaminereleasers sympathomimetics -Amphetamine, Hidroxyamphetamine, Methylphenidat, Phenylpropanolamine. • special sympathomimetics – Cocaine, Tyramine – affect presynaptic reuptake of NE, D, Serotonin.

  16. Therapeutic use of sympathomimetics • general vasoconstrictors–acute and chronic hypotension (NE, E, Ephedrine, Phenylephrine); • local vasoconstrictors – nasal, ocular decongestive drugs (E, Ephedrine, Naphazoline, Xylometazoline) – eye drops, nasal drops (1-2%); • cardiac stimulants – cardiogenic shock, cardiac block (E, D, Isoprenaline, Dobutamine) - intracardiac administration; • peripheral vasodilators – peripheral circulatory insufficiency (Bamethan, Isoxsuprine, Buphenine);

  17. Therapeutic use • tocolytic drugs – preterm labor (Isoxsuprine, Hexoprenaline, Ritodrine); • bronhodilators – bronchial asthma (E, Ephedrine, Isoprenaline, Orciprenaline, Terbutaline, Salbutamol, Salmeterol); • diffuse bleeding on skin and mucosal surfaces (1/50000-1/10000); • association with local anaesthetics; • allergic reactions type I (also anaphylactic shock).

  18. Contraindications of sympathomimetics • HTA • angina pectoris • tachyarrhythmias • !Will not be associated with local anaesthetics for local anaestesia of: nose, ears, penis, fingers – risk of ischemic necrosis. • ! Will not be associated with compounds containing calcium –tachyarrhythmias.

  19. Epinephrine • Indications: • diffuse bleeding on skin and mucosal surfaces (1/50000-1/10000) • - association with local anaesthetics • - bronchial asthma • - glaucoma • - intracardiac administration – therapeutic alternative in heart stop (first alternative is Isoproterenol) • - allergic reaction type I (also anaphylactic shock) Norepinephrine • Side effects: • - pallor • anxiety, palpitations • in higher doses arrhythmia, ventricular fibrillation, hypertension, acute pulmonary edema. Dobutamine • Contraindicaţii: • HTA, angina pectoris, tachyarrhythmias • will not be associated with local anesthetics in anesthesia of extremities (nose, ears, penis, fingers) - ischemic necrosis. • will not be associated with calcium - tachyarrhythmias. Indication: cardiogen shock. Side effects: - cardiac pain, emesis.

  20. non catecholic structure, by-passes blood brain barrier. • agonist 12, release NE. Ephedrine • Pharmacodinamic effects • increase blood pressure (α1), tachycardia (β1), bronhodilatation(β2); • local decongestion on the mucose, • psyhoanaleptic inducing effects (cortical awakening, increase the concentration attention, memory, learning). • Indications: • hypotension (orthostatic, during rachianaestesia), • general vasoconstrictor (allergy), local vasoconstrictor – nasal decongestiv(topic); • bradycardia, A-V block; • bronchoconstriction; • in association with local anaestetics. • Side effects: • tachyphylaxia, chronic atrophic rhinitis (loosing the smell); • hypertension, tachycardia, • psychological dependence, • pseudoamphetaminic effect.

  21. Naphazoline • 1 and2 agonist, in small proportion induces the release of NE, • topic administration. • chronic use (topic ) – atrophic rhinitis. • tachyphylaxis. • in children – hypotension (action on pre synaptic αRs) • in adults – hypertension, arrhythmias. Xylometazoline Oxymetazoline

  22.  stimulants 1. 1selective(Dobutamine – inotrop +, Prenalterol) Indications: congestive cardiac failure, cardiogenic shock. • 3. nonselective 12 • Isoprenaline, Orciprenaline • Indications: A-V block, cardiac stop, bronchial asthma • Side effects: • tachyarrhitmia, • cardiac pain, • cardiac ischemia. • Contraindication: angina pectoris. • - Buphenine, Bamethan (R2 on the vessels) • Indications: • - Raynaud syndrome, intermittentclaudication. • 2. selective2 • bronchodilators • a. short action - Salbutamol, Formoterol - Terbutaline b. medium action - Salmeterol, Fenoterol c. long action - Bambuterol • Isoxuprine (also1antagonist), Isoetharine, Ritodrine • Indication: preterm labor

  23. Pharmacodinamic effects: • central • peripheral. Amphetamine • Indications: • - psycho-motor performances stimulation • narcolepsia • hyperkinetic syndrome in children, • - adjuvant in Parkinson disease, • - adjuvant in “petit mal” seizures crisis, • - enurezis. • Mecanism of action: • - releasing of NE and D on the CNS; • direct action – stimulation of the ascending reticular activating system. • inhibition of MAO. Side effects: - headache, - digestive disturbances, - HTA, tachyarrhythmias,cardiac pain, - acute crisis of endogenous psychosis, - psychological dependence, psychiatric disturbances – “amphetaminic psychosis” • Contraindications: • - schizophrenia, bipolar psychosis • HTA, tachyarrhythmias, • - coronary and cerebral sclerosis, • - glaucoma.

  24. Eritroxilon cocaleaves (Peru, Bolivia). • non-medical use (euphoria). • indications: local anaesthetic in ORL, ophtalmology. Cocaine • Mecanism of action: - inhibition of NE re-uptake from nervous endings, • increase the NE turn-over. • mydriasis, tachyarrhythmias, hypertension. • Side effects: • nasal septum perforation - chronic administration by nasal snuff, • psychological dependence. • Cocaine addicted is on alert (mydriatic), quickly earning his "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.

  25. THANK YOU !

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