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SYMPATHETIC SYSTEM Sympathomimetic Agents

SYMPATHETIC SYSTEM Sympathomimetic Agents. SYMPATHETIC SYSTEM Mostly activated during stressful situations Actions can be identified by reactions during “fright, fight, flight” Neurotransmitter at most post-ganglionic terminals is Noradrenaline Others: Adrenaline ( Brain, adrenal)

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SYMPATHETIC SYSTEM Sympathomimetic Agents

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  1. SYMPATHETIC SYSTEM Sympathomimetic Agents

  2. SYMPATHETIC SYSTEM • Mostly activated during stressful situations • Actions can be identified by reactions during “fright, fight, flight” • Neurotransmitter at most post-ganglionic terminals is Noradrenaline • Others: • Adrenaline (Brain, adrenal) • Adrenaline from adrenal medulla augments • function during sympathetic activation • Dopamine : Basal ganglia, other parts of brain, • ? Periphery

  3. Synthesis Storage and Release and degradation of NA, DA, Adr

  4. Storage and release of Catecholamines • Storage in vesicles along with ATP and other substances • Released by exocytosis • Release is modified by presynapticautoreceptors & heteroreceptors • α2 ↓ • β2 ↑

  5. Termination of action of Catecholamines • Re-Uptake • Enzymatic degradation • Diffusion • Extra synaptic uptake

  6. Receptors are located PRE and POST-synaptically Pre-synaptic receptors modify release from the terminal

  7. Transduction mechanisms and actions of adrenergic receptor subtypes

  8. Organ system effects of sympathetic activation

  9. Organ system effects of sympathetic activation

  10. Organ system effects of sympathetic activation

  11. Targets for Pharmacological Interference Tyrosine hyhroxylase  MPT  NA DOPA decarboxylase  Methyldopa Pseudotransmitter* Dopamine  hydroxylaseDisulfiram Release of NATyramine Sympathomimetic Amphetamine Release of NA Guanethidine Sympatholytic Bretylium Reuptake Cocaine,  effect of NT Imipramine  indirect mimetics Reuptake into granules Reserpine Release Depletion

  12. Targets for Pharmacological Interference Presynaptic 2 Catecholamines  release Presynaptic 2 Catecholamines  release Presynaptic M ACh  release  MAO Several  metabolism  Extrasynaptic uptake PBZ, Steroids  Effect  COMTPyrogallol --- Talcapone Entacapone

  13. Sympathomimetic drugs Mixed Directly acting Indirectly acting Ephedrine Tyramine Amphetamine Non-Catecholamines Catecholamines α2 agonists β2 agonists α1 agonists Clonidine Methyldopa* Apraclonidine Guanfacine Guanabenz Endogenous Methoxamine Phenylephrine Terbutaline Albuterol Fenoterol Pirbuterol Long Acting Procaterol Salmeterol DA, NA, Adr Synthetic Isoprenaline (β1 & β2) Dobutamine (β1) Isoetharine Prenalterol Oxymetazoline Xylometazoline Naphazoline

  14. ENDOGENOUS CATECHOLAMINES Adrenaline Noradrenaline Dopamine

  15. ENDOGENOUS CATECHOLAMINES • ADRENALINE (Epinephrine): Mainly from adrenal medulla (Also some neurons in brain) • Receptor actions: Both  and ; Potency for >  • All effects of stimulation of  and  receptors; but some are more evident. • Heart:  rate, force, arrhythmias (high dose, rapid • administration)

  16. Blood Pressure: Adrenaline is one of the most potent vasoconstrictors • Pharmacological dose: ↑Force and rate of ventricular contraction (β1) +↑Vascular resistance (skin, mucosa, kidney) (α) + ↑Marked venoconstriction • Lower dose:  B.P. ( 2 more sensitive) • Cutaneous blood flow  ; Skeletal muscle blood flow  • Nett effect:  C.O. & B.P. (systolic ; diastolic ±)

  17. Dale’s Reversal Phenomenon Mean arterial blood pressure PBZ Adr

  18. Respiratory system: Bronchodilatation ( specially when constriction +nt) CNS: Not marked ( poor BBB penetration) Large doses: Restlessness, apprehension, headache, tremor Metabolic:  Blood glucose (  insulin (2); glucose uptake; glycogenolysis) (glucagon secretion - ) Mast cells : Stabilized

  19. Absorption fate and excretion Orally ineffective (hydrolyzed by liver and gut) Absorption I.M > S.C. ; Given I.V. in emergencies ; Inhalation (nebulized) Toxicity : due to  and  stimulation Mainly CVS: BP, vasoconstriction, tachycardia, arrhythmia Therapeutic uses: Anaphylaxis ( I.M / I.V.) ( 0.3 – 0.5 ml of 1:1000) Cardiac arrest (May have to be given intra-cardiac ) With local anaesthetics ( 1: 200000) Topical haemostatic :bleeding from mouth, peptic ulcer, nose Bronchial asthma – s.c. or inhalation (nebulized)

  20. 2.NORADRENALINE (Norepinephrine) Released from post-ganglionic sympathetic nerves 10-20% of content of adrenal medullary secretion Receptor action: α1 ,α2 & β1  >  No effect on β2

  21. Comparison of effects of Epinephrine and NE

  22. Other effects: Similar to Epinephrine Metabolic effects seen with larger doses Toxicity: Similar to Epinephrine but greater  in BP Greater vasoconstriction : sloughing and necrosis can occur at site of administration Uses : Hardly used now except sometimes in peripheral vascular failure (eg. Septic shock).

  23. DOPAMINE Immediate precursor of NE Neurotransmitter in CNS (? Periphery) CVS effects: Low conc. : D1 - Renal, mesenteric and coronary vasodilatation  glomerular filteration renal blood flow, Na excretion Moderate Conc. : 1 - Positive inotropic effect on heart  in systolic BP and pulse pressure, ± on diastolic pressure High Conc. : 1 - Generalized vasoconstriction

  24. Other effects : Not significant. Therapeutic Uses:- Severe CHF (sp. with oliguria) Cardiogenic and septic shock Major Actions of DA are within the CNS Five receptor subtypes (D1 to D5) D1 – excitatory D2 – inhibitory Involved in behavioural functions, endocrine regulation

  25. Sympathomimetic Catecholamines

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