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ADRENERGIC TRANSMISSION

ADRENERGIC TRANSMISSION. Adrenergic transmission is restricted to the sympathetic nervous system Norepinephrine is the transmitter at post-ganglionic sympathetic nerves – except sweat glands Epinephrine is secreted by the adrenal medulla. ADRENERGIC TRANSMISSION.

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ADRENERGIC TRANSMISSION

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  1. ADRENERGIC TRANSMISSION • Adrenergic transmission is restricted to the sympathetic nervous system • Norepinephrine is the transmitter at post-ganglionic sympathetic nerves – except sweat glands • Epinephrine is secreted by the adrenal medulla

  2. ADRENERGIC TRANSMISSION • Dopamine is the transmitter in basal ganglia, limbic system, CTZ and anterior pituitary . • Naturally occurring catecholamines - Epinephrine, Norepinephrine, Dopamine.

  3. ADRENERGIC TRANSMISSION • SYNTHESIS : Catecholamines like Epinephrine, Norepinephrine, and Dopamine are synthesized from Tyrosine • Tyrosine hydroxylases is the rate limiting step in the synthesis of CA

  4. ADRENERGIC TRANSMISSION STORAGE : • The granules take up dopamine from the cytoplasm and synthesis of NE occurs within the granules. • NE is stored in the granules within the adrenergic terminal . • Released by exocytosis

  5. ADRENERGIC TRANSMISSION RELEASE : • The release of CA takes by exocytosis . • Indirectly acting amines (tyramine and amphetamine) induce the release of NE by displacing it from the nerve endings.

  6. ADRENERGIC TRANSMISSION UPTAKE OF CA : It is an efficient mechanism after the release of NE – • Axonal uptake (Uptake 1 ) : Transports NE at a higher rate than E. • It is the most important mechanism for the termination of the NE. • Cocaine, Imipramineinhibits this uptake 1.

  7. ADRENERGIC TRANSMISSION • METABOLISM : by two enzyme systems – MAO and COMT. • NE after uptake -1 into the axoplasm is acted upon by MAO. • NE which diffuses into the circulation is acted upon by COMT, mainly in the liver • The major metabolites excreted in urine is VMA (Vanillyl mandelic acid)

  8. ADRENERGIC TRANSMISSION • Adrenergic receptors are G protein coupled receptors which acts by increasing or decreasing the production of c AMP ADRENERGIC RECEPTORS • ALPHA – 1 -- A , B , D • ALPHA – 2 -- A , B , C

  9. ADRENERGIC TRANSMISSION ALPHA 1 : • Acts by activating Phospholipase C – production of inositol triphosphate (IP3) and DAG • IP3 promotes the release of calcium from the intracellular stores ---increase cytoplasm calcium

  10. Adrenergic System ALPHA 1 receptors • EYE– radial fibers – contraction –mydriasis • Arterioles and veins – contraction – can increase peripheral resistance. • Bladder trigone and sphincter – contraction – urinary retention • Liver – Glycogenolysis. • Vas deferens – ejaculation.

  11. Adrenergic System ALPHA 2 : acts by inhibiting adenylyl cyclase – cAMP • Platelets- aggregation • Prejunctional receptors – decrease release of transmitter (NE) • Pancreas -- decrease insulin release (predominant)

  12. Adrenergic System BETA: beta receptors stimulate adenylyl cyclase – increasing the cAMP Beta 1 • Heart • JG cells in kidney (increase renin release).

  13. Adrenergic System Beta 2 receptors : cAMP • Blood vessels to skeletal muscle – Vasodilation • Uterus– Relaxation • Bronchioles – Dilatation • Skeletal muscles – tremors • Liver- Glycogenolysis

  14. Adrenergic System Dopamine 1 receptors : Acts by stimulation of adenylyl cyclase and increased cAMP • Renal and mesenteric vasculature – vasodilation and increase blood flow and Na excretion. Dopamine 2 receptors : Acts by inhibition of adenylyl cyclase, decrease cAMP, open potassium channels, • Brain

  15. Adrenergic System Adrenergic Drugs: • Directly acting : Epinephrine, Norepinephrine, Phenylephrine, Albuterol • Indirectly acting : acts by release of NE : Tyramine, Amphetamine • Mixed : Ephedrine

  16. Adrenergic System • Epinephrine acts on alpha 1, 2 beta 1, 2 • Norepinephrine acts on alpha 1, 2 beta 1 • Isoprenaline acts on beta 1 , 2 • Dopamine 1 receptors agonist : Dobutamine, Fenoldopam

  17. Adrenergic System AGENTS ACTING AT DIFFERENT SITES • INTERFERE WITH THE SYNTHESIS : Metyrosine • BLOCKADE OF UPTAKE 1 AT NERVE TERMINAL :Cocaine, Imipramine • BLOCKADE OF STORAGE IN GRANULE OR GRANULAR UPTAKE :Reserpine • PROMOTION OF RELEASE : Amphetamine • PREVENTION OF RELEASE : Bretylium, Guanethidine

  18. Adrenergic System MAO MAO –A present in the nerves /intestine/ liver or Anywhere • Metabolizes NE, 5-HT and tyramine • Inhibitors are Phenelzine, Tranylcypromine MAO – B • Present mainly in the Brain • Metabolizes preferentially dopamine • Inhibitors are Selegiline

  19. Adrenergic System COMT INHIBITORS :Tolcapone -- Long acting Entacapone -- Short acting

  20. Adrenergic System Agonist acting on Alpha 1receptors Phenylephrine, Methoxamine • Given systemically they increase the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP). • The increase in BP can elicits reflex bradycardia.

  21. Adrenergic System Phenylephrine

  22. Adrenergic System Agonist acting specifically on • Alpha 2receptors : Clonidine, Alpha Methyldopa • Beta 1 and beta 2 :Isoproterenol • Beta 1 : Dobutamine • Beta 2 :Terbutaline, Albuterol, Ritodrine, Metaproterenol

  23. Adrenergic System • Beta agonists :Beta 1 and Beta 2 • Isoproterenol • It cause a decrease in peripheral resistance, a decrease in mean BP due to beta 2 receptor action and a reflex increase in heart rate. Systolic blood pressure does not fall significantly as diastolic, due to beta 1 receptor action, so the pulse pressure increases .

  24. Adrenergic System Isoproterenol

  25. Adrenergic System Norepinephrine : • It has little effect on beta 2 receptors. • It increases TPR and both diastolic and systolic blood pressure. • Positive inotropic action results in increase of pulse pressure. • Compensatory vagal reflexes tend to overcome the direct chronotropic action of NE -- reflex bradycardia may occur.

  26. Adrenergic System

  27. Adrenergic System Epinephrine : • Acts on alpha 1, 2 and beta 1 and 2. • Epinephrine increase the HR, systolic BP and PP. • Its effects on diastolic blood pressure depends on dose.

  28. Adrenergic System Epinephrine : • At low dose, beta 2 activation predominates resulting in decrease of diastolic pressure and TPR, although mean BP may not decrease significantly. • At medium dose,increase in heart rate, increase in mean blood pressure and increase in pulse pressure due to both beta 1 and 2 receptor action.

  29. Adrenergic System Epinephrine at low dose resulting in decrease diastolic pressure and increase in heart rate. Low dose Epinephrine

  30. Adrenergic System Epinephrine at medium dose increase the mean blood pressure, heart rate and pulse pressure Medium dose

  31. Adrenergic System Epinephrine : At high dose, increase in blood pressure and reflex bradycardia similar to norepinephrine. Epinephrine at high dose

  32. Adrenergic System ALPHA BLOCKERS: Non-selective • Phenoxybenzamine, Phentolamine Alpha -1 selective • Prazosin, Terazosin, Tamsulosin Alpha-2 selective • Yohimbine

  33. Adrenergic System BETA BLOCKERS: Non selective : Propranolol, Nadolol, Timolol With Partial agonist :Pindolol Beta 1 selective :Atenolol, Metoprolol Beta and alpha 1 blocker : Labetolol, Carvedilol

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