1. Lady Ann L. Francisco

2. Objectives: Steps of Biosynthesis of Catecholamine Distribution of adrenergic receptors Individual Functions of Adrenergic receptors All aspects of adrenaline – Dale`s Phenomenon

3. Neurotransmission in ANS

4. Noradrenergic transmission Nor-adrenaline is the major neurotransmitter of the Sympathetic system Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia They have long axons which end in varicosities where NA is synthesized and stored

5. Adrenergic transmission Catecholamines: Natural: Adrenaline, Noradrenaline, Dopamine Synthetic: Isoprenaline, Dobutamine Non-Catecholamines: Ephedrine, Amphetamines, Phenylepherine, Methoxamine, Mephentermine Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group

6. • Catecholamines: Compounds containing a catechol nucleus (Benzene ring with 2 adjacent OH groups) and an amine containing side chain • Non-catecholamines lack hydroxyl (OH) group

7. Biosynthesis of Catecholamines Phenylalanine PH Rate limiting Enzyme 5-HT, alpha Methyldopa Alpha-methyl-p- tyrosine

8. Storage of Noradrenaline

9. Release of NA – Feedback Control

10. Regulators of NA release

11. Uptake of Catecholamines

12. Reuptake Sympathetic nerves take up amines and release them as neurotransmitters Uptake I is a high efficiency system more specific for NA Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines Uptake 2 is less specific for NA Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

13. Metabolism of CAs Mono Amine Oxidase (MAO) Intracellular bound to mitochondrial membrane Present in NA terminals and liver/ intestine MAO inhibitors are used as antidepressants Catechol-o-methyl-transferase (COMT) Neuronal and non-neuronal tissue Acts on catecholamines and byproducts VMA levels are diagnostic for tumours

14. Metabolism of CAs (Homovanillic acid) (Vanillylmandelic acid)

15. Adrenergic neurotransmission

16. Adrenergic Receptors Adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors that are the target of catecholamines Adrenergic receptors specifically bind their endogenous ligands – catecholamines (adrenaline and noradrenline) Increase or decrease of 2nd messengers cAMP or IP3/DAG Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight- fight manner. For instance, the heart will start beating quicker and the pupils will dilate

17. How Many of them ???? Alpha (α) Beta (β) Adenoreceptors α 1 β3β 2β1α 2 α 2B α 2Cα 2A α 1A α 1B α 1D

18. Differences - Adrenergic Receptors (α and β) ! Alpha (α) and Beta (β) Agonist affinity of alpha (α): adrenaline > noradrenaline > isoprenaline Antagonist: Phenoxybenzamine IP3/DAG, cAMP and K+ channel opening Agonist affinity of beta (β): isoprenaline > adrenaline > noradrenaline Propranolol cAMP and Ca+ channel opening

19. Potency of catecholamines on Adrenergic Receptors Adr NA Iso Iso Adr NA Log Concentration Aortic strip contraction Bronchial relaxation α β

20. Molecular Effector Differences - α Vs β α Receptors: ○ IP3/DAG ○ cAMP ○ K+ channel opening β Receptors: ○ cAMP ○ Ca+ channel opening

21. Recall: Adenylyl cyclase: cAMP pathway PKA Phospholamban Increased Interaction with Ca++ Faster relaxation Troponin Cardiac contractility Other Functional proteins PKA alters the functions of many Enzymes, ion channels, transporters and structural proteins. Faster sequestration of Ca++ in SR

22. PKc Also Recall: Phospholipase C: IP3-DAG pathway

23. Differences between β1, β2 and β3 Beta-1 Beta-2 Beta-3 Location Heart and JG cells Bronchi, uterus, Blood vessels, liver, urinary tract, eye Adipose tissue Agonist Dobutamine Salbutamol - Antagonist Metoprolol, Atenolol Alpha-methyl propranolol - Action on NA Moderate Weak Strong

24. Clinical Effects of β-receptor stimulation β1: Adrenaline, NA and Isoprenaline: Tachycardia Increased myocardial contractility Increased Lipolysis Increased Renin Release β2: Adrenaline and Isoprenaline (not NA) Bronchi – Relaxation SM of Arterioles (skeletal Muscle) – Dilatation Uterus – Relaxation Skeletal Muscle – Tremor Hypokalaemia Hepatic Glycogenolysis and hyperlactiacidemia β3: Increased Plasma free fatty acid – increased O2 consumption - increased heat production

25. Differences between α1 and α2 Alpha-1 Alpha-2 Location Post junctional – blood vessels of skin and mucous membrane, Pilomotor muscle & sweat gland, radial muscles of Iris Prejunctional Function Stimulatory – GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Agonist Phenylephrine, Methoxamine Clonidine Antagonist Prazosin Yohimbine

26. α1 adrenoceptors Clinical effects Eye -- Mydriasis Arterioles – Constriction (rise in BP) Uterus -- Contraction Skin -- Sweat Platelet - Aggregation Male ejaculation Hyperkalaemia Bladder Contraction α2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release

27. Molecular Basis of Adrenergic Receptors Also glycogenolysis in liver Inhibition of Insulin release and Platelet aggregation Gluconeogen esis

28. Dopamine receptors D1-receptors are post synaptic receptors located in blood vessels and CNS D2-receptors are presynaptic present in CNS, ganglia, renal cortex

29. Summary of agents modifying adrenergic transmission Step Actions Drug Synthesis of NA Inhibition α - methyl-p-tyrosine Axonal uptake Block Cocaine, guanethidine, ephedrine Vesicular uptake Block Reserpine Vesicular NA Displacement Guanethidine Membrane NA pool Exchange diffusion Tyramine, Ephedrine Metabolism MAO-A inhibition MAO-B inhibition COMT inhibition Moclobemide Selegiline Tolcapone Receptors α 1 α 2 β1 + β2 β1 Prazosin Yohimbine Propranolol Metoprolol

30. Adrenaline as prototype Potent stimulant of alpha and beta receptors Complex actions on targets: Heart, Blood vessel, Blood pressure(dale’s phenomenon)

31. Dale`s Vasomotor Reversal Phenomenon

32.  CNS Skeletal Muscle Uterus Bladder GIT Respiratory Actions of Adrenaline

33. Metabolic effects Increases concentration of glucose and lactic acid Calorigenesis (β-2 and β-3) Inhibits insulin secretion (α-2) Decreases uptake of glucose by peripheral tissue Simulates glycogenolysis - Beta effect Increases free fatty acid concentration in blood Hypokalaemia – initial hyperkalaemia

34. ADME All Catecholamines are ineffective orally Absorbed slowly from subcutaneous tissue Faster from IM site Inhalation is locally effective Not usually given IV Rapidly inactivated in Liver by MAO and COMT

35. ADRs Restlessness, Throbbing headache, Tremor, Palpitations Cerebral hemorrhage, cardiac arrhythmias Contraindicated in hypertensives, hyperthyroid and angina poctoris Halothane and beta-blockers – not indicated