Autonomicssympa 090916062947 Phpapp01

AUTONOMICS Ma. Janetth B. Serrano, MD, DPBA

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.

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

NEUROTRANSMITTERS:
Sympathetic: ADRENERGIC
Central: EPINEPHRINE
Peripheral: NOREPINEPHRINE
Parasympathetic: CHOLINERGIC
Acetylcholine

RECEPTORS:
Sympathetic: ADRENOCEPTORS
Alpha  α 1 , α 2
Beta   1 ,  2 ,  3
Parasympathetic: CHOLINOCEPTORS
Muscarinic
Nicotinic
Dopaminergic: D 1 , D 2

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

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

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

SUMMARY OF NEUROHUMORAL TRANSMISSION PROCESS:
Synthesis and Storage of Neurotransmitter
Release of Neurotransmitter
Interaction with Postjunctional Cell and Initiation of Activity
Deactivation

METYROSINE COCAINE, TCA, IMIPRAMINE RESERPINE

HEMICHOLINIUM VESAMICOL BOTULINUM TOXIN

EFFECTOR ORGANS Autonomic Nervous System

Autonomic Nervous System Some Sweat glds & some BV RVSM Acetylcholine Acetylcholine Acetylcholine Dopamine Nicotinic Receptor Nicotinic Receptor Muscarinic Receptor D 1 Receptor

Somatic Nervous System

Enteric Nervous System
Third division of the ANS
Innervates GIT, pancreas, gallbladder
Includes:
Myenteric plexus
(Plexus of Auerbach)
Submucous plexus
(Plexus of Meissner)

Autonomic Nervous System

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

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

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

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

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

Parasympathetic N. S. Generalized secretion ↑ secretion ↑ secretion Profuse secretion M M 3 M M Secretory glands sweat intestinal bronchial lacrimal Action Receptor Effector Organs

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

Sympathetic Agonists SYMPATHOMIMETICS

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

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

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

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

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

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

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)

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)

Sympathetic Antagonists SYMPATHOLYTICS

Adrenergic Neuron Blockers (ANB)
Guanethedine, Reserpine
Adrenergic Receptor Blockers (ARB)
Reversible – Prazosin, Phentolamine,
Tolazoline, Labetalol, Ergot alkaloids
Irreversible – Phenoxybenzamine,
Dibenamine
Sympathetic Antagonists (Sympatholytics)

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

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

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

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

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

Beta-Adrenergic Blocking Agents
BETA - BLOCKERS

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

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

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

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

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)

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 )

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

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

DRUG INTERACTION:
Calcium- channel VERAPAMIL
Severe hypotension
Bradycardia
CHF
arrhythmia
Beta- blockers

“ A heartfelt apology can’t change the past, but it can brighten the future.”

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

Autonomicssympa 090916062947 Phpapp01

by axix on Sep 16, 2009

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