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