Autonomics & Sympathetics
- 1. AUTONOMICS Ma. Janetth B. Serrano, MD, DPBA
- 2. NERVOUS SYSTEM CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM BRAIN SPINAL CORD EFFERENT Division AFFERENT Division AUTONOMIC N.S. SOMATIC N.S. Sympathetic N.S. Parasympathetic N.S. Enteric N.S.
- 3. NERVOUS SYSTEM SOMATIC N.S. Skeletal, motor, voluntary No ganglias or plexuses Motor n. to skeletal muscles myelinated Interruption of impulses paralysis & atrophy AUTONOMIC N.S. Visceral, vegetative, involuntary Efferent n. supply all except skeletal m. Peripheral ganglias & plexuses Postganglionic fibers unmyelinated Interruption of transmission spontaneous activity
- 4. NEUROTRANSMITTERS: Sympathetic: ADRENERGIC Central: EPINEPHRINE Peripheral: NOREPINEPHRINE Parasympathetic: CHOLINERGIC Acetylcholine
- 5. RECEPTORS: Sympathetic: ADRENOCEPTORS Alpha α 1 , α 2 Beta 1 , 2 , 3 Parasympathetic: CHOLINOCEPTORS Muscarinic Nicotinic Dopaminergic: D 1 , D 2
- 6. Stimulation of adenyl cyclase ↑ cAMP Postsynaptic effector cells esp. lipocytes Beta 3 Stimulation of adenyl cyclase ↑ cAMP Posynaptic effector cells esp. sm. m. & cardiac m. Beta 2 Stimulation of adenyl cyclase ↑ cAMP Postsynaptic effector cells esp.heart, lipocytes, brain Presyn cholinergic & adrenergic terminals Beta 1 Inhibition of adenyl cyclase ↓ cAMP Presynaptic adrenergic n. terminals, platelets, lipocytes, sm.m. Alpha 2 Formation of IP 3 and DAG ↑ IC calcium Postsynaptic effector cells esp. smooth m. Alpha 1 RESULT OF LIGAND BINDING TYPICAL LOCATIONS RECEPTOR NAME
- 7. Inhibition of adenyl cyclase Brain, Cardiovascular System D 4 Inhibition of adenyl cyclase Brain D 3 Inhibition of adenyl cyclase ↑ K + conductance Brain, effector tissues, esp. smooth m., presynaptic nerve terminals D 2 (DA 2 ) Stimulation of adenyl cyclase ↑ cAMP Brain, effector tissues esp. sm.m. of the renal vascular bed D 1 (DA 1 ), D 5 RESULT OF LIGAND BINDING TYPICAL LOCATIONS RECEPTOR NAME
- 8. MUSCARINIC RECEPTORS Na + , K + depolarizing ion channel Postganglionic cell body, dendrites N N Na + , K + depolarizing ion channel Skeletal muscle NMJ N M IP 3 , DAG cascade ? CNS M 5 Inhibition of cAMP production ? CNS M 4 IP 3 , DAG cascade Glands, smooth muscle, endothelium M 3 Inhibition of cAMP prod’n, activation of K + channels Heart, nerves, smooth muscles M 2 IP 3 , DAG cascade Nerves M 1 Postreceptor Mechanism Location Receptor Type
- 9. SUMMARY OF NEUROHUMORAL TRANSMISSION PROCESS: Synthesis and Storage of Neurotransmitter Release of Neurotransmitter Interaction with Postjunctional Cell and Initiation of Activity Deactivation
- 10. METYROSINE COCAINE, TCA, IMIPRAMINE RESERPINE
- 11. HEMICHOLINIUM VESAMICOL BOTULINUM TOXIN
- 13. EFFECTOR ORGANS Autonomic Nervous System
- 14. Autonomic Nervous System Some Sweat glds & some BV RVSM Acetylcholine Acetylcholine Acetylcholine Dopamine Nicotinic Receptor Nicotinic Receptor Muscarinic Receptor D 1 Receptor
- 15. Somatic Nervous System
- 16. Enteric Nervous System Third division of the ANS Innervates GIT, pancreas, gallbladder Includes: Myenteric plexus (Plexus of Auerbach) Submucous plexus (Plexus of Meissner)
- 17. Autonomic Nervous System
- 18. Sympathetic N. S. relaxation 2 Lung bronchial m. ↑ Heart rate ↑ conduction velocity ↑ contraction 1 1 1 Heart SA node AV node Contractility Contraction (mydriasis) Relaxation α 1 2 Eye radial m. (iris) ciliary m. Action Receptor Effector Organs
- 19. Sympathetic N. S. Constriction Relaxation Ejaculation α 1 2 α 1 GUT sphincter bladder wall Penis, seminal v. Constriction Decrease α 1 α , 2 GIT sphincter motility & tone Constriction Relaxation α 1 2 Blood Vessels most BV skeletal m. Action Receptor Effector Organs
- 20. Sympathetic N. S. Secretion of cathecolamines ↑ renin release Glycogenolysis ↓ insulin release Lipolysis N N 1 2 α 2 3 Metabolism adrenal medulla kidney skeletal m. Pancreas (B-cell) fat cells Localized secretion Inhibition - Moderate secretion α 1 α 2 - α Secretory glands sweat intestinal bronchial lacrimal Action Receptor Effector Organs
- 21. Parasympathetic N. S. contraction M 3 Lung bronchial m. ↓ Heart rate ↓ conduction velocity ↓ contraction M 2 M 2 M 2 Heart SA node AV node Contractility Contraction (miosis) Contraction (accomodation) M 3 M 3 Eye circular m. ciliary m. Action Receptor Effector Organs
- 22. Parasympathetic N. S. Relaxation Increase Erection M 3 M 3 M GUT trigone & sphincter m. bladder wall & detrusor m. Penis, seminal v. Relaxation Increase M 3 M 3 GIT sphincter motility & tone - - - - Blood Vessels most BV skeletal m. Action Receptor Effector Organs
- 23. Parasympathetic N. S. Generalized secretion ↑ secretion ↑ secretion Profuse secretion M M 3 M M Secretory glands sweat intestinal bronchial lacrimal Action Receptor Effector Organs
- 24. Site and Mode of Action: 1. Direct Acting - Epinephrine - Dobutamine - Phenylephrine - Norepinephrine - Isoproterenol - Clonidine 2. Indirect Acting Tyramine, Amphetamine, Cocaine 3. Mixed Acting Agonists - Dopamine - Ephedrine - Amphetamine - Metaraminol - Phenylpropanolamine SYMPATHETIC DRUGS
- 25. Sympathetic Agonists SYMPATHOMIMETICS
- 26. Sympathetic Agonists (Sympathomimetics) EPINEPHRINE NOREPINEPHRINE DOPAMINE IBOPAMINE AMPHETAMINE METHAMPHETAMINE EPHEDRINE PSEUDOEPHEDRINE DOBUTAMINE ISOPROTERENOL β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 27. Sympathetic Agonists (Sympathomimetics) PHENYLEPHRINE METHOXAMINE MEPHENTERMINE METARAMINOL MITODRINE β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 28. Sympathetic Agonists (Sympathomimetics) METHYLDOPA CLONIDINE GUANABENZ GUANFACINE β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 29. Sympathetic Agonists (Sympathomimetics) NAPHAZOLINE TETRAHYDROZOLINE β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 30. Sympathetic Agonists (Sympathomimetics) NAPHAZOLINE TETRAHYDROZOLINE OXYMETAZOLINE XYLOMETAZOLINE β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 31. Sympathetic Agonists (Sympathomimetics) METAPROTERENOL TERBUTALINE, ALBUTEROL RITODRINE ISOETHARINE, PILBUTEROL BITOLTEROL, FENOTEROL FORMOTEROL, SALMETEROL PROCATEROL β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 32. Special sympathomimetics: COCAINE Local anesthetic Inhibits uptake 1 Peripheral sympathomimetic action CNS inhibits reuptake of dopamine into neurons in the “pleasure centers” of the brain Sympathetic Agonists (Sympathomimetics)
- 33. Special sympathomimetics: TYRAMINE Normal by-product of tyrosine metabolism Fermented foods cheese, red wine Metabolized by MAO Release of stored catecholamines indirect sympathomimetic action Sympathetic Agonists (Sympathomimetics)
- 34. Sympathetic Antagonists SYMPATHOLYTICS
- 35. Adrenergic Neuron Blockers (ANB) Guanethedine, Reserpine Adrenergic Receptor Blockers (ARB) Reversible – Prazosin, Phentolamine, Tolazoline, Labetalol, Ergot alkaloids Irreversible – Phenoxybenzamine, Dibenamine Sympathetic Antagonists (Sympatholytics)
- 36. Sympathetic Antagonists (Sympatholytics) YOHIMBINE BUTOXAMINE LABETALOL CARVEDILOL Β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 37. Sympathetic Antagonists (Sympatholytics) PRAZOSIN, TERAZOSIN DOXAZOSIN, TRIMAZOSIN INDORAMIN, URADIPIL KETANSERIN, ALFUZOSIN BUNAZOSIN, TAMSULOSIN α 1 and α 2 β 1 and β 2 β 2 β 1 α and β α 2 α 1
- 38. Sympathetic Antagonists (Sympatholytics) PHENOXYBENZAMINE PHENTOLAMINE ERGOT ALKALOIDS NEUROLEPTIC DRUGS Β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 39. PHENOXYBENZAMINE irreversible noncompetetive blockade (14-48 hrs) inhibits NE reuptake Blocks H 1 , Ach and serotonin receptors Blocks catecholamine-induced vasoconstriction Epinephrine- reversal Cl. Indication: pheochromocytoma male erectile dysfunction peripheral vascular diseases Adv. Eff: postural hypotension, tachycardia
- 40. PHENTOLAMINE Competetive antagonist (4 hrs) Epinephrine- reversal reduce PVR Cardiac stimulation baroreflex & ↑ NE release Inhibits serotonin responses Indic: Pheochromocytoma, male erectile dysfunction Adv. Eff: severe tachycardia, arrhythmia, myocardial ischemia, GI stimulation
- 41. Beta-Adrenergic Blocking Agents BETA - BLOCKERS
- 42. Sympathetic Antagonists (Sympatholytics) METOPROLOL ATENOLOL ACEBUTOLOL BETAXOLOL CELIPROLOL ESMOLOL Β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 43. Sympathetic Antagonists (Sympatholytics) PROPRANOLOL NADOLOL, TIMOLOL PINDOLOL, LEVOBUNOLOL CARTEOLOL, BISOPROLOL Β 1 and β 2 α 1 and α 2 β 2 β 1 α and β α 2 α 1
- 44. Beta- blockers Pharmacokinetics: oral: peak in 1-3 hrs extensive first-pass metabolism half- lives: 3 to 10 hrs * Esmolol – 8 – 10 min * Nadolol – 24 hrs
- 45. PHARMACODYNAMICS: CVS: (-) chronotropic, (-) inotropic effects Respiratory: bronchoconstriction Eye: reduce IOP Metabolic & Endocrine: inhibits lipolysis partial inhibition of glycogenolysis ↑ VLDL and ↓ HDL ↓ HDL: LDL ratio ISA; MSA Beta- blockers
- 46. Properties of Beta-receptor blocking agents: 50 3-4 hrs Mod + - Metoprolol 70 4-5 hrs No data - + Celiprolol 0 8-10 min Low - - Esmolol 90 14-22 hrs Low Slight - Betaxolol 40 6-9 hrs Low - - Atenolol 50 3-4 hrs Low + + Acebutolol Selective β 1 blockers Approxi-mate Bioavai-lability Elimination Half-life Lipid Solu-bility Local Anesthetic Activity (MSA) Partial Agonist Activity ( ISA)
- 47. Properties of Beta-receptor blocking agents: 90 3-4 hrs Mod + + Pindolol 50 4-50 hrs Mod - - Timolol 33 14-24 hrs Low - - Nadolol 30 5 hrs Mod + + Labetalol 25-35 6-8 hrs No Data - - Carvedilol 85 6 hrs Low - + Carteolol 30 3.5-6 hrs High + - Propranolol NonSelective β 1 Blockers Approxi-mate Bioavai-lability Elimina-tion Half-life Lipid Solu-bility MSA (Local Anesthetic Activity) ISA (Partial Agonist Activity )
- 48. CLINICAL INDICATIONS: Hypertension Cardiac arrhythmias Angina CHF: Metoprolol, Bisoprolol, Carvedilol Glaucoma: Timolol, Betaxolol, Carteolol, Levobunolol, Metipranolol Neurologic: Migraine, somatic mgt. of anxiety, alcohol withdrawal Misc: reduce portal vein pressure in cirrhosis Beta- blockers
- 49. Clinical toxicities: Drug allergy – rare CNS effects – sedation, sleep disturbances, depression, psychotic rxns Worsening of preexisting asthma & airway obstruction Depress myocardial contractility & excitability Hypoglycemic episodes Beta- blockers
- 50. DRUG INTERACTION: Calcium- channel VERAPAMIL Severe hypotension Bradycardia CHF arrhythmia Beta- blockers
- 51. “ A heartfelt apology can’t change the past, but it can brighten the future.”
- 52. QUIZ Major neurotransmitter of the Sympathetic Nervous System Write A if Agonist or B if Antagonist: 2. Epinephrine 7. Phentolamine 3. Labetalol 8. Cocaine 4. Clonidine 9. Phenylephrine 5. Prazosin 10. Ephedrine 6. Terbutaline