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Autonomics & Sympathetics

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Pharmacology

Pharmacology

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  • 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
  • 12.  
  • 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