Presentation on theme: "PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM Sympathomimetics."— Presentation transcript:
PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM Sympathomimetics
2 Catecholamines compounds with different pharmacodynamic effects, but have a common structure group "catechol” (ortho-diphenols)
5 Catecholamines Adrenaline (epinephrine) is released from the adrenal medulla and other chromaffin tissues. equally stimulates receptors 12 şi 123 Noradrenaline (norepinephrine) is released from postganglionic sympathetic fibers, neurons of the CNS and adrenal medulla. stimulates receptors 12 and 12 Dopamine is released from peripheral autonomic endings and CNS neurons stimulate receptors D1= D2 D3D4D5 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.
Biosynthesis of adrenaline and noradrenaline
7 Adrenergics Receptors
8 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.
9 SETTING adrenergic receptor presynaptic setting - 2, 1, D2 receptors 2 inhibits release of noradrenaline peripheral sympathetic activity is inhibited receptors 1 stimulates the release of noradrenaline peripheral sympathetic activity is stimulated receptors D2 inhibits release of noradrenaline postsynaptic setting sequestration in the membrane receptor decreased receptor synthesis ("down regulation") phosphorylation and thus inactivation of receptor
10 NORADRENALINE Post receptor signal transmision 1.
EFFECTS OF CATECHOLAMINES NORADRENALINE (NA) dominant action on the cardio-vascular ↑ adrenergic receptor affinity on α şi β1 + β3 ( ↓ β2 ) ADRENALINE (A) dominant action on smooth muscle and metabolism adrenergic receptor affinity ↑ on α şi β1 + β2 ( ↓ β3) DOPAMINE dominant action on the cardio-vascular : inotrop+ and ↓ TPR receptors types : DA1(excitators) and DA2 (inhibitors)
Gastro-intestinal motilitydecreased Gastro-intestinal secretion decreased Defecation? Skeletal muscle tone no effect Urination decreased Urinary frequencydecreased Bladder tone decreased EFFECTS OF SYMPATHETIC STIMULATION
14 PHARMACODYNAMICS OF CATECHOLAMINES eye 2 – ciliary relaxation 2 – mydriasis use of adrenaline in glaucoma (promote drainage of aqueous humor) – eye drops heart 1 – inotrop + 1 – inotrop +, increases syno-atriale, A-V, Hiss fasc, Purkinje fibr driving
15 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 – increase systolic and diastolic BP, reflex bradycardia (1 a vascular receptor stimulation) NORADRENALINE At all doses - vasoconstriction - increases blood pressure, increased peripheral vascular resistance, reflex bradycardia
16 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!!! Adrenaline and noradrenaline are contraindicated in cardiogenic shock în şocul cardiogen because they produce vasoconstriction in the mesenteric and renal vessels, increasing organs ischemia
17 PHARMACODYNAMICS OF CATECHOLAMINES coronaro-dilatation (1, 1, 2, D1, D2) vasoconstriction in visceral vessels except 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!
18 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) and contraction in labor (1) stimulation ejaculation (1)
19 PHARMACODYNAMICS OF CATECHOLAMINES Metabolic effects Hyperglycemia (physiological doses) 2 stimulation– increase glycogenolysis and inhibit glycogen synthesis 1, 2 stimulation– stimulates glyconeogenesis, decreases the glucose prelevation from periphery 2 stimulation– 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)
20 PHARMACODYNAMICS OF CATECHOLAMINES Metabolic effects hyperlipidemia 1 and 3 stimulation ( 2 receptors inhibit lipolysis) renal release of renin 1 presynaptic activation - stimulates synthesys ( 2 presynaptic stimulation - inhibition of renin release) increase basal metabolism (20-30%) noradrenaline has a role in defending the body against cold increase cardiac oxygen consumption
21 PHARMACODYNAMICS OF CATECHOLAMINES exocrine glands– inhibits salivary and pancreatic exocrine water secretion (2) endocrine glands – increases synthesis of melatonin by pineal gland (1) increases release of prostaglandins platelet agregation - (2 A)
22 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 catecholamines are excreted in the urine
23 CLASIFICATION OF SYMPATHOMIMETICS şi Sympathomimetics direct Adrenaline Noradrenaline Dopamine Ibopamine indirect (Noradrenaline release) and direct Efedrine
27 CLASIFICATION OF SYMPATHOMIMETICS Catecholamines releasers (other than ephedrine, phenylephrine, naphazoline) Amfetamine Hidroxiamfetamine Fenmetrazine Pemolin Metilfenidat Fenilpropanolamine special Sympathomimetics Cocaine Tyramine
28 THERAPEUTIC USE OF SYMPATHOMIMETICS Adrenaline (1 = 2, 1 = 2 =3 agonist) Clinical uses: diffuse bleeding from mucous membranes and skin surface (1/ /10000) is associated as a vasoconstrictor to local anesthetic bronchial asthma with mucosa edema ( 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)
29 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
30 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
31 THERAPEUTIC USE OF SYMPATHOMIMETICS Noradrenaline (1 = 2, 1 2 agonist ) Clinical use : diffuse bleeding from mucous membranes and skin surface ( 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
32 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
33 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
34 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).
35 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 factors local vasoconstriction (antiedema effect)
36 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
37 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.
38 THERAPEUTIC USE OF SYMPATHOMIMETICS Phenilephrine - 12 agonist non-catechol structure Cross blood-bain barrier Release noradrenaline from cell storage – can cause tachyphylaxis 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)
39 THERAPEUTIC USE OF SYMPATHOMIMETICS Fenilephrine - 12 agonist Clinical use Damage to the sympathetic cervical syndrome Claude Bernard Horner HTA produce diagnostic mydriasis the solutions applied locally - antiedematos of mucosal PSVT It is associated as a vasoconstrictor to local anesthetic
40 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
41 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)
42 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
43 THERAPEUTIC USE OF SYMPATHOMIMETICS Bufenine and Bametane - relatively selective 2 vascular receptors indicated in the treatment of intermittent claudication Raynaud's syndrome. Dobutamine – increased pozitiv inotrop effect (and negligible influence heart rate and BP ) It is indicated in congestive heart failure Cardiogenic shock.
44 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 uterine smooth muscle) Indicated in premature labor
45 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
46 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
47 THERAPEUTIC USE OF SYMPATHOMIMETICS Contraindication: schizophrenia, bipolar psychosis mental instability SDR. Tourette Hypertension, tachyarrhythmias Coronary 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"
48 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, anxiety chills, sweating, paranoid psychosis There is no antidote for acute poisoning with amphetamines. Treatment benzodiazepines, barbiturates Haloperidol Chlorpromazine Clonidine, methyldopa, 1 –blockers loop-diuretic furosemide iv urine acidification (ammonium chloride) to spur removal
49 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
50 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
51 THERAPEUTIC USE OF SYMPATHOMIMETICS Tyramine - blocks reuptake of norepinephrine and causes the release of norepinephrine from storage. It is a substance found in fermented foods: cheese, beer, wines. Results from normal metabolism of tyrosine in the body. Practical conclusion: fermented foods are not eated during treatment with MAO inhibitors (antidepressants) These foods are contraindicated or are take them with caution by people with hypertension.