AUTONOMICAUTONOMICSS

MA. JANETTH B. SERRANO, M.D. DPBA

Site and Mode of Action:Site and Mode of Action:1. Direct Acting1. Direct Acting

– EpinephrineEpinephrine - 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 - -

PhenylpropanolaminePhenylpropanolamine– MetaraminolMetaraminol

SYMPATHETIC DRUGSSYMPATHETIC DRUGS

Sympathetic Sympathetic AgonistsAgonists

SYMPATHOMIMETICSYMPATHOMIMETICSS

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

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 inhibits reuptake of

dopamine into neurons in the dopamine into neurons in the “pleasure centers” of the brain“pleasure centers” of the brain

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 cheese, red

winewine– 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 Adrenergic Receptor Blockers (ARB)(ARB)

ReversibleReversible – – Prazosin, Phentolamine, Prazosin, Phentolamine,

Tolazoline, Labetalol, Tolazoline, Labetalol, Ergot alkaloidsErgot alkaloids

IrreversibleIrreversible – – 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 AnesthetAnesthet

ic ic Activity Activity (MSA)(MSA)

Lipid Lipid Solu-Solu-bilitybility

EliminatioElimination n

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 AnesthetAnesthet

ic ic Activity)Activity)

Lipid Lipid Solu-Solu-bilitybility

Elimina-Elimina-tion 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