CATECHOLAMINES

1. HO HO HO b a HO CH CH NH2 HO HO CH2 CH2 NH2 HO HO CH CH2 NH2 OH HO CH CH2 NH HO OH CH3 CATECHOLAMINES CATECHOL CATECHOLAMINE DOPAMINE (DIHYDROXYPHENYL- ETHYLAMINE) NOREPINEPHRINE (NORADRENALINE) EPINEPHRINE (ADRENALINE)

2. CATECHOLAMINES NORADRENALINE– POSTGANGLIONIC FIBRES OF SYMPATHETIC NERVOUS SYSTEM (ADRENERGIC FIBRES) FOUND IN HIGHEST CONCENTRATION IN HYPOTHALAMUS AND CERTAIN ZONES OF LIMBIC SYSTEM. MOST NORADRENERGIC NEURONES ARISE IN LOCUS COERULEUS. INHIBITORY IN ACTION. ALSO IN ADRENAL MEDULLA. DOPAMINE– MAINLY IN CNS. FOUND IN BASAL GANGLIA ESP. CAUDATE NUCLEUS, NEOSTRIATUM, NUCLEUS ACCUMBENS, OLFACTORY TUBERCLE, CENTRAL NUCLEUS OF AMYGDALA, MEDIAN EMINENCE AND AND RESTRICTED FIELDS OF THE FRONTAL CORTEX. PREDOMINENT ACTION INHIBITORY ADRENALINE–CHROMAFFIN CELLS OF THE ADRENAL MEDULLA. IN CNS FOUND IN MEDULLARY RETICULAR FORMATION CONNECTING TO A FEW PONTINE AND DIENCEPHALIC NUCLEI. NORADRENALINE– DEFICIENCY – BEHAVIOURAL DEPRESSION - EXCESS – MANIA DOPAMINE– EXCESS – SCHIZZOPHRENIA & PSYCHOSES - DEFICIENCY – PARKINSON'S DISEASE HYPERTENSION -  CATECHOLAMINE  VASCULAR TONE  BP

3. HO HO CH2 CH NH2 HO CH2 CH NH2 CH2 CH NH2 COOH COOH COOH HO HO CH2 CH2 NH2 HO HO CH CH2 NH2 OH HO CH CH2 NH HO OH CH3 BIOSYNTHETIC PATHWAY PHENYLALANINE PHENYLALANINE HYDROXYLASE (DIHYDROBIOPTERIN) TYROSINE TYROSINE HYDROXYLASE (TETRAHYDROPTERIDINE, O2, Fe 2+ ) 5 –8x10-5 M IN BLOOD DYHYDROXYPHENYLALANINE (DOPA) DOPA DECARBOXYLASE L-AROMATIC AMINOACID DECARBOXYLASE (PYRIDOXAL PHOSPHATE) DOPAMINE (DIHYDROXYPHENYL- ETHYLAMINE) DOPAMINE-b-HYDROXYLASE (ASCORBIC ACID, O2, Cu2+ ) NOREPINEPHRINE (NORADRENALINE) PHENYLETHANOLAMINE-N- METHYL TRANSFERASE (S-ADENOSYLMETHIONINE) EPINEPHRINE (ADRENALINE)

4. HO CH2 CH2 CH2 CH2 NH2 NH2 HO CH CH CH2 CH2 NH2 NH2 OH OH DOPAMINE-b-HYDROXYLASE PHENYLETHANOLAMINE PHENYLETHYLAMINE TYRAMINE OCTOPAMINE a-METHYLDOPA a-METHYLNOREPINEPHRINE FALSE NEUROTRANSMITTER

5. TH TH TH P P ATP ATP 3'5'cAMP REGULATION OF TYROSINE HYDROXYLASE DIACYLGLYCEROL PROTEIN KINASE C TETRAMER 59000 M.WT FEEDBACK INHIBITION BY CATECHOLAMINES N-TERMINAL REGULATORY DOMAIN Ser40 cAMPPK Ser40 PHOSPHORYLATION BY cAMPPK OR PKC ON SERINE 40 DECREASES Km FOR PTERIDINE COFACTOR (CATECHOLAMINE RELEASED) ACase

6. TH TH TH A P P P P P TH TH A ATP ATP ATP ATP 3'5'cAMP A A ACTION POTENTIAL DEPOLARIZATION DIACYLGLYCEROL Ca2+ Cal +Ca2+ Cal.Ca2+ PROTEIN KINASE C Cal.Ca2+ KINASE Ser19 Ser40 ATP cAMPPK PHOSPHORYLATION ON SERINE 19 BY Ca2+-CAMODULIN PK RESULTS ON BINDING OF ACTIVATOR PROTEIN AND INCREASE IN THE Vmax OF THE ENZYME. DUAL PHOSPHORYLATION RESULTS IN FULLY ACTIVE ENZYME ACase

7. STORAGE CHROMAFFIN GRANULES LARGE VESICLES DOPAMINE-b- HYDROXYLASE ATP NE:ATP 12:1 EPI:ATP 4:1 NORADRENALINE (2 POOLS) POLYOPIOID PRECURSORS CHROMOGRANIN (GLYCOSYLATED/ SULPHATED PROTEIN) Ca2+/Mg 2+ ATPase SMALL VESICLES NO CHROMOGRANIN NODOPAMINE-b-HYDROXYLASE NO OPIOID PEPTIDES ONE POOL NE MICROTUBULES NEURONAL CELL X NERVE TERMINAL COLCHICINE

8. ACTION POTENTIAL DEPOLARIZATION DIACYLGLYCEROL Ca2+ Cal +Ca2+ Cal.Ca2+ PROTEIN KINASE C Cal.Ca2+ KINASE TH TH Ser19 TH A Ser40 ATP P P P P P TH TH A cAMPPK TUBULIN MAP-2 V V ATP ATP ATP ATP 3'5'cAMP A A A2 ADENOSINE ATP CATECHOLAMINE

9. 1. MONOAMINE OXIDASE -COOH MAO ALDEHYDE -CH-NH2 -CHODEHYDROGENASE AMINE ALDEHYDE ALDEHYDE REDUCTASE -CH2OH 2. CATECHOL-O-METHYL TRANSFERASE COMT S-ADENOSYLMETHIONINE HO CH3O HO HO CH CH CH2 CH2 NH2 NH2 OH OH 3. REUPTAKE INTO PRESYNAPTIC TERMINAL ACTIVE TRANSPORT LINKED TO Na+/K+ ATPase METABOLISM

10. TYROSINE TYROSINE 1 2 DOPA 9 3 NE DOPAMINE 4 POST- SYNAPTIC EFFECTOR CELL 10 NE 7 5 b NE NE NE 8 6 NE 1. UPTAKE BLOCKED BY AROMATIC AMINO ACIDS 2. a-METHYL-p-TYROSINE – INHIBITOR TYROSINE HYDROXYLASE 3. NON-SPECIFIC ENZYMES – FALSE NEUROTRANSMITTERS a-METHYL DOPA TO a-METHYLNOREPINEPHRINE 4. INHIBITION OF STORAGE – RAUWOLFIA ALKALOIDS (RESERPINE) 5. DISPLACEMENT OF CATECHOLAMINE – GUANETHIDINE 6. MAO INHIBITORS – PARGYLLINE & TRANYLCYPROMINE 7. INHIBITION OF RELEASE – BRETYLIUM 8. INHIIBTION OF RE-UPTAKE – TRICYCLIC ANTIDEPRESSANTS, COCAINE E.G. IMIPRAMINE, AMITRYPTYLINE 9. FACILITATION OF UPTAKE – LITHIUM 10. ADRENERGIC RECEPTOR BLOCKERS AND SYMPATHOMIMETIC AGONISTS MAO a a2 DRUG ACTION

11. SYMPATHETIC NERVE STIMULATION ACETYL CHOLINE NICOTINIC RECEPTOR  Na+ ENTRY DEPOLARISATION  VOLTAGE-DEPENDENT Ca2+ CHANNELS  INTRACELLULAR Ca2+ ADRENAL MEDULLA ACTIVE IN RESPONSE TO COLD, STRESS, FEAR, ANGER, LOW BLOOD SUGAR, CEREBRAL ANOXIA, ASPHYXIA, LOW BLOOD PRESSURE

12. PHENYLEPHRINE a CH CH NH2 HO OH CH3 HO CH CH2 NH HO OH CH3 ADRENERGIC AGONISTS HO CH3 ISOPROTERENOL b (ISOPRENALINE) CH CH2 NH+ HO OH CH3 EPINEPHRINE MIXED ANTAGONISTS ba PROPRANOLOL PHENTOLAMINE BUTOXAMINE (b2) PHENOXYBENZAMINE METOPROLOL (b1) ERGOT ALKALOIDS BUPRANOLOL (b3) PRAZOCIN (a1) YOHIMBINE (a2)

13. DISTRIBUTION a1 RECEPTORS – POSTSYNAPTIC EFFECTOR SITES ON SMOOTH MUSCLE, GLAND CELLS, LIVER ETC. a2 RECEPTORS – EXIST ON NERVE TERMINALS (PRE-SYNAPTIC FEEDBACK INHIBITION OF NOREPINEPHRINE RELEASE). POST-SYNAPTIC SITES IN NUMEROUS TISSUES INCLUDING CEREBRAL CORTEX, PLATELETS, UTERUS, LIVER ETC. b1-RECEPTORS – PREDOMINENTLY IN CARDIAC ANDADIPOSE TISSUE. PRE-SYNAPTIC FIBRES IN CNS, RBC's. b2-RECEPTORS – SMOOTH MUSCLE AND GLAND CELLS. MOST COMMON b3-RECEPTORS - ATYPICAL RECEPTORS. ADIPOSE TISSUE, LIVER AND HEART DIFFERENT TISSUES MAY POSSESS b1, b2 AND b3 RECEPTORS E.G. LIVER, ADIPOSE TISSUE.

14. FLIGHT OR FRIGHT RESPONSE SYSTEM ACTION RECEPTOR LIVER GLYCOGENOLYSIS a1  GLYCOGEN SYNTHESIS b2 & b3  GLUCONEOGENESIS  UREAGENESIS MUSCLE GLYCOGENOLYSIS b2  GLYCOGEN SYNTHESIS ADIPOSE LIPOLYSIS b1 & b3 TISSUE LIPOGENESIS b1 & b3  LIPOLYSIS a2 PANCREAS INSULIN SECRETION b2  INSULIN SECRETION a2 HEART RATE & FORCE b1 BLOOD  CONSTRICTION a1 VESSELS DILATION b2 GUT CONSTRICTION a1 SPHINCTERS DILATION b2 CATECHOL- RELEASE b1 AMINE RELEASE a2 RELEASE

15. P P P P P b-RECEPTORS ACTIVATES ADENYLATE CYCLASE ATP 3'5'cyclic AMP R2C2 + 4cAMP 2C + (R2.4cAMP) TRIGLYCERIDE LIPASE TRIGLYCERIDE LIPASE PYRUVATE KINASE PYRUVATE KINASE • GLUCONEO- GENESIS  LIPOLYSIS GLYCOGEN SYNTHASE GLYCOGEN SYNTHASE ACETYL CoA CARBOXYLASE ACETYL CoA CARBOXYLASE • GLYCOGEN SYNTHESIS  LIPOGENESIS PHOSPHORYLASE KINASE PHOSPHORYLASE KINASE  GLYCOGENOLYSIS

16. a1-RECEPTORS PtdINS-4,5-P2 INS-1,4,5-P3 + 1,2 DIACYLGLYCEROL Ca2+ RELEASE FROM INTERNAL STORES ACTIVATION OF DIACYLGLYEROL DEPENDENT PROTEIN KINASE C ACTIVATION OF Ca2+ AND CALMODULIN- DEPENDENT PROTEIN KINASES PROTEIN PHOSPHORYLATION a1A Ca2+ CHANNEL a1B IP3/DAG a1CIP3/DAG PHOSPHOLIPASE Cb

17. a2-RECEPTORS INHIBITS ADENYLATE CYCLASE AND ALTERS ION CHANNELS a2AcAMP, Ca2+ CHANNEL, K+ CHANNEL a2B cAMP, Ca2+ CHANNEL a2CcAMP