Autonomics & Sympathetics
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Transcript of Autonomics & Sympathetics
AUTONOMICSAUTONOMICS
Ma. Janetth B. Serrano, MD, DPBAMa. Janetth B. Serrano, MD, DPBA
NERVOUS SYSTEMNERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM
PERIPHERAL NERVOUS SYSTEM
BRAINSPINAL CORDEFFEREN
T DivisionAFFERENT Division
AUTONOMIC N.S.
SOMATIC N.S.
Sympathetic N.S.
Parasympathetic N.S.
Enteric N.S.
NERVOUS SYSTEMNERVOUS SYSTEM
SOMATIC N.S.SOMATIC N.S. Skeletal, motor, Skeletal, motor,
voluntary voluntary No ganglias or No ganglias or
plexusesplexuses Motor n. to skeletal Motor n. to skeletal
muscles myelinatedmuscles myelinated Interruption of Interruption of
impulses impulses paralysis paralysis & atrophy& atrophy
AUTONOMIC N.S.AUTONOMIC N.S. Visceral, vegetative, Visceral, vegetative,
involuntaryinvoluntary Efferent n. supply all Efferent n. supply all
except skeletal m.except skeletal m. Peripheral ganglias & Peripheral ganglias &
plexusesplexuses Postganglionic fibers Postganglionic fibers
unmyelinatedunmyelinated Interruption of Interruption of
transmission transmission spontaneous activityspontaneous activity
NEUROTRANSMITTERS:NEUROTRANSMITTERS: Sympathetic: ADRENERGICSympathetic: ADRENERGIC
Central: EPINEPHRINECentral: EPINEPHRINE Peripheral: NOREPINEPHRINEPeripheral: NOREPINEPHRINE
Parasympathetic: Parasympathetic: CHOLINERGICCHOLINERGIC
AcetylcholineAcetylcholine
RECEPTORS:RECEPTORS: Sympathetic: Sympathetic: ADRENOCEPTORSADRENOCEPTORS
Alpha Alpha αα1 1 , , αα2 2
Beta Beta 1 1 , , 2 2 , , 33
Parasympathetic: Parasympathetic: CHOLINOCEPTORSCHOLINOCEPTORS
MuscarinicMuscarinic NicotinicNicotinic
Dopaminergic: Dopaminergic: DD11, D, D22
RECEPTOR NAME TYPICAL LOCATIONS RESULT OF LIGAND BINDING
Alpha 1 Postsynaptic effector cells esp. smooth m.
Formation of IP3 and DAG↑ IC calcium
Alpha 2 Presynaptic adrenergic n. terminals, platelets, lipocytes, sm.m.
Inhibition of adenyl cyclase↓ cAMP
Beta 1 Postsynaptic effector cells esp.heart, lipocytes, brainPresyn cholinergic & adrenergic terminals
Stimulation of adenyl cyclase↑ cAMP
Beta 2 Posynaptic effector cells esp. sm. m. & cardiac m.
Stimulation of adenyl cyclase↑ cAMP
Beta 3 Postsynaptic effector cells esp. lipocytes
Stimulation of adenyl cyclase↑ cAMP
RECEPTOR NAME TYPICAL LOCATIONS RESULT OF LIGAND BINDING
D1 (DA1), D5Brain, effector tissues esp. sm.m. of the renal vascular bed
Stimulation of adenyl cyclase↑ cAMP
D2 (DA2)Brain, effector tissues, esp. smooth m., presynaptic nerve terminals
Inhibition of adenyl cyclase↑ K+ conductance
D3Brain Inhibition of adenyl
cyclase
D4Brain, Cardiovascular System
Inhibition of adenyl cyclase
MUSCARINIC RECEPTORSMUSCARINIC RECEPTORSReceptor
TypeLocation Postreceptor Mechanism
M1Nerves IP3, DAG cascade
M2Heart, nerves, smooth muscles
Inhibition of cAMP prod’n, activation of K+ channels
M3Glands, smooth muscle, endothelium
IP3, DAG cascade
M4? CNS Inhibition of cAMP
production
M5? CNS IP3, DAG cascade
NMSkeletal muscle NMJ Na+, K+ depolarizing ion
channel
NNPostganglionic cell body, dendrites
Na+, K+ depolarizing ion channel
SUMMARY OF NEUROHUMORAL SUMMARY OF NEUROHUMORAL TRANSMISSION PROCESS:TRANSMISSION PROCESS:
I.I. Synthesis and Storage of Synthesis and Storage of NeurotransmitterNeurotransmitter
II.II. Release of NeurotransmitterRelease of Neurotransmitter
III.III. Interaction with Interaction with Postjunctional Cell and Postjunctional Cell and Initiation of ActivityInitiation of Activity
IV.IV. DeactivationDeactivation
METYROSINE
COCAINE, TCA, IMIPRAMINE
RESERPINE
HEMICHOLINIUM
VESAMICOL
BOTULINUM TOXIN
EFFECTOR ORGANS
Autonomic Autonomic Nervous SystemNervous System
Autonomic Autonomic Nervous SystemNervous System
Some Sweat glds & some BV
RVSM
AcetylcholineAcetylcholine
Acetylcholine Dopamine
Nicotinic Receptor
Nicotinic Receptor
Muscarinic Receptor
D1 Receptor
Somatic Nervous System
Enteric Nervous Enteric Nervous System System
Third division of the ANSThird division of the ANS Innervates GIT, pancreas, gallbladderInnervates GIT, pancreas, gallbladder Includes:Includes:
• Myenteric plexusMyenteric plexus
(Plexus of Auerbach)(Plexus of Auerbach)
• Submucous plexus Submucous plexus
(Plexus of Meissner)(Plexus of Meissner)
Autonomic Autonomic Nervous SystemNervous System
Effector Organs
Receptor Action
Eye radial m. (iris) ciliary m.
α1
2
Contraction (mydriasis)Relaxation
Heart SA node AV node Contractility
1
1
1
↑ Heart rate↑ conduction velocity↑ contraction
Lung bronchial m. 2 relaxation
Sympathetic N. S.Sympathetic N. S.
Effector Organs Receptor Action
Blood Vessels most BV skeletal m.
α1
2
ConstrictionRelaxation
GIT sphincter motility & tone
α1
α, 2
ConstrictionDecrease
GUT sphincter bladder wallPenis, seminal v.
α1
2
α1
ConstrictionRelaxationEjaculation
Sympathetic N. S.Sympathetic N. S.
Sympathetic N. S.Sympathetic N. S.Effector Organs Receptor Action
Secretory glands sweat
intestinal bronchial lacrimal
α1
α2 -α
Localized secretionInhibition
-Moderate secretion
Metabolism adrenal medulla
kidney skeletal m. Pancreas (B-cell) fat cells
NN
1
2
α2
3
Secretion of cathecolamines↑ renin releaseGlycogenolysis↓ insulin releaseLipolysis
ParasympatheParasympathetic N. S.tic N. S.Effector Organs
Receptor Action
Eye circular m. ciliary m.
M3
M3
Contraction (miosis)Contraction(accomodation)
Heart SA node AV node Contractility
M2
M2
M2
↓ Heart rate↓ conduction velocity↓ contraction
Lung bronchial m. M3 contraction
Effector Organs Receptor Action
Blood Vessels most BV skeletal m.
--
--
GIT sphincter motility & tone
M3
M3
RelaxationIncrease
GUT trigone & sphincter m. bladder wall & detrusor m.Penis, seminal v.
M3
M3
M
Relaxation
Increase
Erection
Parasympathetic N. Parasympathetic N. S.S.
Effector Organs Receptor Action
Secretory glands sweat intestinal bronchial lacrimal
M
M3
MM
Generalized secretion↑ secretion↑ secretionProfuse secretion
Parasympathetic N. Parasympathetic N. S.S.
Site and Mode of Action:Site and Mode of Action:
1. Direct Acting1. Direct Acting- Epinephrine- Epinephrine - Dobutamine- Dobutamine
-- PhenylephrinePhenylephrine - Norepinephrine - Norepinephrine
-- IsoproterenolIsoproterenol - Clonidine- Clonidine
2. Indirect Acting2. Indirect Acting• Tyramine, Amphetamine, CocaineTyramine, Amphetamine, Cocaine
3. Mixed Acting Agonists3. Mixed Acting Agonists-- DopamineDopamine - Ephedrine- Ephedrine
-- AmphetamineAmphetamine - Metaraminol - Metaraminol
-- PhenylpropanolaminePhenylpropanolamine
SYMPATHETIC DRUGSSYMPATHETIC DRUGS
Sympathetic Sympathetic AgonistsAgonists
SYMPATHOMIMETICSSYMPATHOMIMETICS
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22 ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists
(Sympathomim(Sympathomimetics) etics)
EPINEPHRINE
NOREPINEPHRINE
DOPAMINE
IBOPAMINE
AMPHETAMINE
METHAMPHETAMINE
EPHEDRINE
PSEUDOEPHEDRINE
DOBUTAMINE
ISOPROTERENOL
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22 ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists(Sympathomi(Sympathomimetics) metics)
PHENYLEPHRINE
METHOXAMINE
MEPHENTERMINE
METARAMINOL
MITODRINE
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22 ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists(Sympathomi(Sympathomimetics) metics)
METHYLDOPA
CLONIDINE
GUANABENZ
GUANFACINEGUANFACINE
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22 ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists
(Sympathomi(Sympathomimetics) metics)
NAPHAZOLINE
TETRAHYDROZOLINE
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22 ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists
(Sympathomi(Sympathomimetics) metics)
NAPHAZOLINE
TETRAHYDROZOLINE
OXYMETAZOLINE
XYLOMETAZOLINE
αα11 αα22 αα and and ββ ββ11 ββ22
αα11 and and αα22
ββ1 1 and and ββ22
Sympathetic Sympathetic AgonistsAgonists
(Sympathomi(Sympathomimetics) metics) METAPROTERENOL
TERBUTALINE, ALBUTEROL
RITODRINE
ISOETHARINE, PILBUTEROL
BITOLTEROL, FENOTEROL
FORMOTEROL, SALMETEROL
PROCATEROL
Special sympathomimetics:Special sympathomimetics:
COCAINECOCAINE• Local anestheticLocal anesthetic• Inhibits uptake 1 Inhibits uptake 1 Peripheral Peripheral
sympathomimetic actionsympathomimetic action• CNS CNS inhibits reuptake of dopamine into inhibits reuptake of dopamine into
neurons in the “pleasure centers” of the neurons in the “pleasure centers” of the brainbrain
Sympathetic Sympathetic AgonistsAgonists
(Sympathomi(Sympathomimetics) metics)
Special sympathomimetics:Special sympathomimetics:
TYRAMINETYRAMINE• Normal by-product of tyrosine Normal by-product of tyrosine
metabolismmetabolism• Fermented foods Fermented foods cheese, red wine cheese, red wine• Metabolized by MAOMetabolized by MAO• Release of stored catecholamines Release of stored catecholamines
indirect sympathomimetic action indirect sympathomimetic action
Sympathetic Sympathetic AgonistsAgonists
(Sympathomi(Sympathomimetics) metics)
Sympathetic Sympathetic AntagonistsAntagonists
SYMPATHOLYTICSSYMPATHOLYTICS
1.1. Adrenergic Neuron Blockers (ANB)Adrenergic Neuron Blockers (ANB)- Guanethedine, ReserpineGuanethedine, Reserpine
2.2. Adrenergic Receptor Blockers (ARB)Adrenergic Receptor Blockers (ARB) Reversible – Reversible – Prazosin, Phentolamine, Prazosin, Phentolamine,
Tolazoline, Tolazoline, Labetalol, Labetalol, Ergot alkaloidsErgot alkaloids
Irreversible – Irreversible – Phenoxybenzamine, Phenoxybenzamine,
DibenamineDibenamine
Sympathetic Sympathetic AntagonistsAntagonists
(Sympatholytics(Sympatholytics) )
Sympathetic Sympathetic AntagonistsAntagonists
(Sympatholytics(Sympatholytics) )
αα11 αα22 αα and and ββ ββ11 ββ22
αα1 1 and and αα22 ΒΒ1 1 and and ββ22
YOHIMBINE BUTOXAMINELABETALOL
CARVEDILOL
αα11 αα22αα and and ββ ββ11 ββ22
ββ11 and and ββ22
αα1 1 and and αα22
Sympathetic Sympathetic AntagonistsAntagonists(Sympatholytics(Sympatholytics) ) PRAZOSIN, TERAZOSIN
DOXAZOSIN, TRIMAZOSIN
INDORAMIN, URADIPIL
KETANSERIN, ALFUZOSIN
BUNAZOSIN, TAMSULOSIN
αα11 αα22 αα and and
ββββ11 ββ22
αα1 1 and and αα22 ΒΒ1 1 and and ββ22
Sympathetic Sympathetic AntagonistsAntagonists(Sympatholytics) (Sympatholytics)
PHENOXYBENZAMINE
PHENTOLAMINE
ERGOT ALKALOIDS
NEUROLEPTIC DRUGS
PHENOXYBENZAMINEPHENOXYBENZAMINE
irreversible noncompetetive blockade (14-48 hrs)
inhibits NE reuptake Blocks H1, Ach and serotonin receptors Blocks catecholamine-induced vasoconstriction Epinephrine- reversal Cl. Indication: pheochromocytoma
male erectile dysfunctionperipheral vascular diseases
Adv. Eff: postural hypotension, tachycardia
PHENTOLAMINEPHENTOLAMINE Competetive antagonist (4 hrs)Competetive antagonist (4 hrs) Epinephrine- reversal Epinephrine- reversal reduce PVRreduce PVR Cardiac stimulation Cardiac stimulation baroreflex & baroreflex & ↑ NE ↑ NE
releaserelease Inhibits serotonin responsesInhibits serotonin responses Indic: Pheochromocytoma, male erectile Indic: Pheochromocytoma, male erectile
dysfunctiondysfunction Adv. Eff: severe tachycardia, arrhythmia, Adv. Eff: severe tachycardia, arrhythmia,
myocardial ischemia, GI stimulationmyocardial ischemia, GI stimulation
Beta-AdrenergicBeta-AdrenergicBlocking AgentsBlocking Agents
BETA - BLOCKERSBETA - BLOCKERS
αα11 αα22 αα and and ββ ββ11 ββ22
αα1 1 and and αα22 ΒΒ1 1 and and ββ22
Sympathetic Sympathetic AntagonistsAntagonists
(Sympatholytics(Sympatholytics) )
METOPROLOL
ATENOLOL
ACEBUTOLOLBETAXOLOL
CELIPROLOL
ESMOLOL
αα11 αα22 αα and and ββ ββ11 ββ22
αα1 1 and and αα22 ΒΒ1 1 and and ββ22
Sympathetic Sympathetic AntagonistsAntagonists
(Sympatholytics(Sympatholytics) )
PROPRANOLOL
NADOLOL, TIMOLOL
PINDOLOL, LEVOBUNOLOL
CARTEOLOL, BISOPROLOL
Beta- Beta- blockersblockers
Pharmacokinetics:Pharmacokinetics:
• oral: peak in 1-3 hrsoral: peak in 1-3 hrs• extensive first-pass extensive first-pass
metabolismmetabolism• half- lives: 3 to 10 hrshalf- lives: 3 to 10 hrs
* Esmolol – 8 – 10 min* Esmolol – 8 – 10 min
* Nadolol – 24 hrs* Nadolol – 24 hrs
PHARMACODYNAMICS:PHARMACODYNAMICS:
• CVS: (-) chronotropic, (-) inotropic CVS: (-) chronotropic, (-) inotropic effectseffects
• Respiratory: bronchoconstrictionRespiratory: bronchoconstriction• Eye: reduce IOPEye: reduce IOP• Metabolic & Endocrine:Metabolic & Endocrine:
inhibits lipolysisinhibits lipolysis partial inhibition of glycogenolysispartial inhibition of glycogenolysis ↑ ↑ VLDL and ↓ HDLVLDL and ↓ HDL ↓ ↓ HDL: LDL ratioHDL: LDL ratio
• ISA; MSAISA; MSA
Beta- Beta- blockersblockers
Properties of Beta-receptor Properties of Beta-receptor blocking agents:blocking agents:
Partial Partial Agonist Agonist Activity Activity
((ISA)ISA)
Local Local Anesthetic Anesthetic
Activity Activity (MSA)(MSA)
Lipid Lipid Solu-Solu-bilitybility
Elimination Elimination
Half-lifeHalf-life
Approxi-Approxi-mate mate
Bioavai-Bioavai-labilitylability
Selective Selective ββ11
blockersblockers
AcebutolAcebutololol
++ ++ LowLow 3-4 hrs3-4 hrs 5050
AtenololAtenolol -- -- LowLow 6-9 hrs6-9 hrs 4040
BetaxololBetaxolol -- SlightSlight LowLow 14-22 hrs14-22 hrs 9090
EsmololEsmolol -- -- LowLow 8-10 8-10 minmin
00
CeliprololCeliprolol ++ -- No No datadata
4-5 hrs4-5 hrs 7070
MetoprolMetoprololol
-- ++ ModMod 3-4 hrs3-4 hrs 5050
ISAISA
(Partial (Partial Agonist Agonist ActivityActivity))
MSAMSA
(Local (Local Anesthetic Anesthetic
Activity)Activity)
Lipid Lipid Solu-Solu-bilitybility
Elimina-tion Elimina-tion
Half-lifeHalf-life
Approxi-Approxi-mate mate
Bioavai-Bioavai-labilitylability
NonSelective NonSelective ββ1 1 BlockersBlockers
PropranolPropranololol
-- ++ HighHigh 3.5-6 hrs3.5-6 hrs 3030
CarteololCarteolol ++ -- LowLow 6 hrs6 hrs 8585
CarvedilolCarvedilol -- -- No No DataData
6-8 hrs6-8 hrs 25-3525-35
LabetalolLabetalol ++ ++ ModMod 5 hrs5 hrs 3030
NadololNadolol -- -- LowLow 14-24 14-24 hrshrs
3333
PindololPindolol ++ ++ ModMod 3-4 hrs3-4 hrs 9090
TimololTimolol -- -- ModMod 4-50 hrs4-50 hrs 5050
Properties of Beta-receptor Properties of Beta-receptor blocking agents: blocking agents:
CLINICAL INDICATIONS:CLINICAL INDICATIONS: HypertensionHypertension Cardiac arrhythmiasCardiac arrhythmias AnginaAngina CHF: Metoprolol, Bisoprolol, CarvedilolCHF: Metoprolol, Bisoprolol, Carvedilol Glaucoma: Timolol, Betaxolol, Carteolol, Glaucoma: Timolol, Betaxolol, Carteolol,
Levobunolol, MetipranololLevobunolol, Metipranolol Neurologic: Migraine, somatic mgt. of Neurologic: Migraine, somatic mgt. of
anxiety, alcohol withdrawalanxiety, alcohol withdrawalMisc: reduce portal vein pressure in Misc: reduce portal vein pressure in
cirrhosiscirrhosis
Beta- Beta- blockersblockers
Clinical toxicities:Clinical toxicities:
1.1. Drug allergy – rareDrug allergy – rare
2.2. CNS effects – sedation, sleep CNS effects – sedation, sleep disturbances, depression, psychotic rxnsdisturbances, depression, psychotic rxns
3.3. Worsening of preexisting asthma & Worsening of preexisting asthma & airway obstructionairway obstruction
4.4. Depress myocardial contractility & Depress myocardial contractility & excitabilityexcitability
5.5. Hypoglycemic episodesHypoglycemic episodes
Beta- Beta- blockersblockers
DRUG DRUG INTERACTION:INTERACTION:• Calcium- channel Calcium- channel
VERAPAMILVERAPAMIL Severe Severe
hypotensionhypotension BradycardiaBradycardia CHFCHF arrhythmiaarrhythmia
Beta- Beta- blockersblockers
“A heartfelt apology can’t change the past, but it can brighten the future.”
QUIZQUIZ1.1. Major neurotransmitter of the Major neurotransmitter of the
Sympathetic Nervous SystemSympathetic Nervous System
Write A if Agonist or B if Write A if Agonist or B if Antagonist:Antagonist:
2. Epinephrine2. Epinephrine7. Phentolamine7. Phentolamine
3. Labetalol3. Labetalol 8. Cocaine8. Cocaine
4. Clonidine4. Clonidine 9. 9. PhenylephrinePhenylephrine
5. Prazosin5. Prazosin 10. Ephedrine10. Ephedrine
6. Terbutaline6. Terbutaline