SYMPATHETIC SYMPATHETIC NERVOUS NERVOUS SYSTEMSYSTEM

(ADRENERGICS)(ADRENERGICS)

SYMPATHOMIMETICSYMPATHOMIMETIC

Sympathomimetic drugs mimic the Sympathomimetic drugs mimic the

effects of sympathetic nerve stimulation effects of sympathetic nerve stimulation

Also adrenergic agonistsAlso adrenergic agonists

Adrenergic receptorsAdrenergic receptors

Adrenergic AgonistsAdrenergic Agonists Chemical classificationChemical classification

CatecholaminesCatecholamines Non-catecholaminesNon-catecholamines

Adrenergic AgonistsAdrenergic AgonistsDifferences Differences

CatecholamineCatecholamine

Cannot use orallyCannot use orally Cannot cross BBBCannot cross BBB

Short- Short-half livehalf live

Examples:Examples:

NorepinephrineNorepinephrine

EpinephrineEpinephrine

IsoproteronolIsoproteronol

DopamineDopamine

DobutamineDobutamine

NoncatecholaminesNoncatecholamines Can use orallyCan use orally Can cross BBBCan cross BBB

Longer half lifeLonger half life

Examples:Examples:

EphedrineEphedrine

PhenylephrinePhenylephrine

TerbutalineTerbutaline

ENDOGENOUS ENDOGENOUS CATECHOLAMINESCATECHOLAMINES

Naturally occurring in body:Naturally occurring in body: Norepinephrine -Norepinephrine -Sites:Sites: postganglionic postganglionic

sympathetic sites (except sweat glands , sympathetic sites (except sweat glands , erector pillorie, hair follicles, )erector pillorie, hair follicles, )

Epinephrine- Epinephrine- Secreted by adrenal medullaSecreted by adrenal medulla Dopamine- Dopamine- Major transmitter in basal Major transmitter in basal

ganglia, CTZ, limbic system, anterior ganglia, CTZ, limbic system, anterior pitutory.pitutory.

SYNTHESISSYNTHESIS

Catecholamine sCatecholamine s

TyrosineTyrosine

↓↓

DopaDopa

↓↓

DopamineDopamine

↓↓

NorepinephrineNorepinephrine

↓↓

EpinephrineEpinephrine

In dopaminergic In dopaminergic neurons, synthesis neurons, synthesis stops herestops here

In noradrenergic neurons, synthesis stops here

Final step only in adrenal medulla and CNS neurons

STORAGE, RELEASE, STORAGE, RELEASE, UPTAKEUPTAKEL-L-

PhenylalaninePhenylalanine Hepatic Hepatic hydroxylase hydroxylase

Adrenergic ReceptorsAdrenergic Receptors

These are mainly 2 typesThese are mainly 2 types

((αα) Alfa) Alfa

((ββ) Beta) Beta

These are again subdivided into These are again subdivided into various typesvarious types

ADRENERGIC ADRENERGIC RECEPTORSRECEPTORS

ADRENERGIC DRUGSADRENERGIC DRUGSSymphathomimeticsSymphathomimetics

DIRECT SYMPHATHOMIMETICSDIRECT SYMPHATHOMIMETICS AdrenalineAdrenaline NoradrenalineNoradrenaline IsoprenalineIsoprenaline PhenylephrinePhenylephrine MethoxamineMethoxamine SalbutamolSalbutamol XylometazolineXylometazoline

INDIRECT SYMPHATHOMIMETICSINDIRECT SYMPHATHOMIMETICS TyramineTyramine AmphetamineAmphetamine

MIXED SYMPHATHOMIMETICSMIXED SYMPHATHOMIMETICS EphedrineEphedrine DopamineDopamine MephenteramineMephenteramine

Pressor agentsPressor agentsNoradrenalineNoradrenaline PhenylephrinePhenylephrine

Ephedrine Ephedrine MethoxamineMethoxamine

DopamineDopamine MephentermineMephentermine

Cardiac stimulantsCardiac stimulantsAdrenalineAdrenaline DobutamineDobutamineIsoprenalineIsoprenaline

BronchodilatorsBronchodilatorsAdrenalineAdrenaline TerbutalineTerbutalineIsoprenalineIsoprenaline SalmeterolSalmeterolSalbutamolSalbutamol FormoterolFormoterol(Albuterol) Bambuterol(Albuterol) Bambuterol

THERAPEUTIC CLASSIFICATION THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGSOF ADRENERGIC DRUGS

Nasal decongestantsNasal decongestantsPhenylephrine NaphazolinePhenylephrine NaphazolineXylometazoline PseudoephedrineXylometazoline PseudoephedrineOxymetazoline Phenyl propanolamineOxymetazoline Phenyl propanolamine

CNS stimulantsCNS stimulantsAmphetamine Dexamphetamine Amphetamine Dexamphetamine MethamphetamineMethamphetamine

Anorectics Anorectics Fenfluramine Dexfenfluramine SibutramineFenfluramine Dexfenfluramine Sibutramine

Uterine relaxant and vasodilatorsUterine relaxant and vasodilatorsRitodrineRitodrine SalbutamolSalbutamol

IsoxsuprineIsoxsuprine TerbutalineTerbutaline

PHARMACOLOGICAL PHARMACOLOGICAL ACTIONSACTIONS

Cardiac effectsCardiac effects Positive chronotropic effectPositive chronotropic effect

An action that increases heart rateAn action that increases heart rate Positive dromotropic effectPositive dromotropic effect

An action that speeds conduction of An action that speeds conduction of electrical impulses (electrical impulses (↑ conduction ↑ conduction velocityvelocity through AV node) through AV node)

Positive inotropic effectPositive inotropic effect An action that increases the force of An action that increases the force of

contraction of cardiac musclecontraction of cardiac muscle

Cardiac effects of Cardiac effects of epinephrineepinephrine

Cardiac output is determined by heart Cardiac output is determined by heart rate and stroke volumerate and stroke volume

EpiEpi→ → ββ11receptors at SA node→↑HRreceptors at SA node→↑HR

Epi→ Epi→ ββ11receptors on ventricular receptors on ventricular myocytes→ myocytes→

↑↑ force of contractionforce of contraction

CO = HR x SVCO = HR x SV

vascular smooth musclevascular smooth muscle

In blood vessels In blood vessels supplying skin, supplying skin, mucous membranes, mucous membranes, viscera and kidneys, viscera and kidneys, vascular smooth vascular smooth muscle has almost muscle has almost exclusively alphaexclusively alpha11--adrenergic receptorsadrenergic receptors

Also biphasic Also biphasic response response

αα11

αα1+1+ββ1 effect1 effect

ββ2 effect (at low 2 effect (at low doses)doses) Mainly Mainly αα - -

actionaction

ββ Blocker Blocker ββ2 effect2 effect

αα Blocker Blocker EEEE

(A)(A)

(B)(B)

Biphasic Biphasic Response Response

vascular smooth musclevascular smooth muscle

In blood vessels supplying skeletal In blood vessels supplying skeletal muscle, vascular smooth muscle has both muscle, vascular smooth muscle has both alphaalpha11 and beta and beta22 adrenergic receptors adrenergic receptors

αα11

ββ22

α1 stimulation β2 stimulation

Effects of epinephrine on blood Effects of epinephrine on blood vessel calibervessel caliber

Blood vessels to Blood vessels to skin, mucous skin, mucous membranes, membranes, viscera and viscera and kidneyskidneys

Stimulation of Stimulation of αα11-adrenergic -adrenergic receptors causes receptors causes constriction of constriction of vascular smooth vascular smooth musclemuscle

αα11

Effects of epinephrine on blood vessel Effects of epinephrine on blood vessel caliber: skeletal musclecaliber: skeletal muscle

At low plasma concentrations of Epi, At low plasma concentrations of Epi, ββ22 effect predominates→ vasodilationeffect predominates→ vasodilation

At high plasma concentrations of Epi, At high plasma concentrations of Epi, αα11 effect predominates→ vasoconstrictioneffect predominates→ vasoconstriction

αα11

ββ22

Effects of Epi on arterial blood Effects of Epi on arterial blood pressurepressure

Arterial BP = CO x PVRArterial BP = CO x PVR

Epinephrine: Epinephrine: ↑ ↑ COCO Low doses ↓ PVR (arteriolar Low doses ↓ PVR (arteriolar

dilation in skeletal muscle)dilation in skeletal muscle) High doses ↑PVRHigh doses ↑PVR

Effects of epinephrine on Effects of epinephrine on airwaysairways

Epi→Epi→ββ22-adrenergic -adrenergic

receptors on receptors on

airway smooth airway smooth

muscle→ rapid, muscle→ rapid,

powerful powerful

relaxation→ relaxation→

bronchodilationbronchodilation

Effects of epinephrine in the eyeEffects of epinephrine in the eye Epi at Epi at αα11--

adrenergic adrenergic receptors receptors on radial on radial smooth smooth muscle → muscle → contractioncontraction→ mydriasis→ mydriasis

Epi at B2-Epi at B2-adrenergic adrenergic receptors→ receptors→ relaxation relaxation of ciliary of ciliary musclemuscle

αα11

ββ22

OTHER SYSTEMSOTHER SYSTEMS

GITGIT: Peristalsis is reduced, sphincters are : Peristalsis is reduced, sphincters are contracted.contracted.

BladderBladder : Detrusors relaxed, trigone contracted : Detrusors relaxed, trigone contracted Splenic capsuleSplenic capsule : Contracts (alpha action), RBCs are : Contracts (alpha action), RBCs are

poured poured Skeletal muscleSkeletal muscle : : Neuromuscular transmission is Neuromuscular transmission is

facilitated. (Tremors due to beta 2 actions)facilitated. (Tremors due to beta 2 actions) CNSCNS: Restlessness , tremors , fall in BP and : Restlessness , tremors , fall in BP and

bradycardiabradycardia MetabolicMetabolic : Hyperglycemia, lipolysis : Hyperglycemia, lipolysis

Mnemonic for Mnemonic for therapeutic uses of therapeutic uses of adrenaline adrenaline ABCDEGABCDEG

AA-- Anaphylactic shock Anaphylactic shock

BB-- Bronchial asthma Bronchial asthma

CC-- CardiacCardiac arrestarrest

DD- - Delay absorption of local anestheticsDelay absorption of local anesthetics

EE-- Epistaxis, Elevate BPEpistaxis, Elevate BP

GG-- GlaucomaGlaucoma

OthersOthers : : Reduce nasal congestion, Reduce nasal congestion, Induces mydriasisInduces mydriasis

Epinephrine (contd..)Epinephrine (contd..)

Adverse effects of Adverse effects of epinephrineepinephrine

Hypertensive crisis Hypertensive crisis DysrhythmiasDysrhythmiasAngina pectorisAngina pectorisNecrosis following Necrosis following extravasationextravasation

HyperglycemiaHyperglycemia

DopamineDopamine (DA)(DA)

Dopaminergic neurons in brain, Dopaminergic neurons in brain,

enteric nervous system and kidneyenteric nervous system and kidney

Dopaminergic receptors in brain, Dopaminergic receptors in brain,

mesenteric and renal vascular beds mesenteric and renal vascular beds

DopamineDopamine

Moderate doses DA:Moderate doses DA: Stimulate DA receptors in Stimulate DA receptors in

mesenteric and renal vascular beds mesenteric and renal vascular beds → → vasodilationvasodilation

Stimulate Stimulate ββ11 receptors in heart → receptors in heart → ↑HR and ↑force of contraction↑HR and ↑force of contraction

High doses DA:High doses DA: Stimulate Stimulate αα11 receptors → receptors →

vasoconstrictionvasoconstriction

Therapeutic usesTherapeutic uses

Shock (moderate doses)Shock (moderate doses) ↑ ↑ blood flow to kidney and blood flow to kidney and

mesenterymesentery ↑ ↑ cardiac outputcardiac output

Refractory congestive heart Refractory congestive heart failurefailure Moderate doses ↑ cardiac output Moderate doses ↑ cardiac output

without ↑PVRwithout ↑PVR

ββ11SA nodal cellsSA nodal cells→→↑↑HHRR

ββ11AV nodal cellsAV nodal cells→↑→↑

conduction velocityconduction velocity

ββ11 Ventricular muscle Ventricular muscle cellscells→ ↑ → ↑ force of force of contractioncontraction

Synthetic Catecholamines: Synthetic Catecholamines: IsoproterenolIsoproterenol

Very powerfully Very powerfully stimulates stimulates ββ11- - and and ββ22--adrenergic adrenergic receptorsreceptors No significant No significant

effect at effect at αα11--adrenergic adrenergic receptorsreceptors

Very powerful Very powerful ββ-adrenergic receptor agonist; -adrenergic receptor agonist; no effect at no effect at αα-adrenergic receptors-adrenergic receptors

αα11

ββ22

α1 stimulation β2 stimulation

Synthetic Catecholamines: Synthetic Catecholamines: IsoproterenolIsoproterenol

IsoproterenolIsoproterenol

↓↓arterial BP = ↑CO x ↓↓PVRarterial BP = ↑CO x ↓↓PVR

Decreased arterial blood pressure Decreased arterial blood pressure triggers autonomic reflex arctriggers autonomic reflex arc

Autonomic reflex arc: baroreceptor Autonomic reflex arc: baroreceptor reflexreflex

Carotid and aortic baroreceptors

↓BP

Cardiovascular control center in medulla

↑ ↑ SympatheticSympathetic

outflow→↑NEpioutflow→↑NEpi

↓ ↓ Parasympathetic Parasympathetic outflow→↓AChoutflow→↓ACh

↓↓BPBP

Carotid and aortic baroreceptors

ββ11

IsoproterenolIsoproterenol

↑↑↑↑HRHR

↑↑↑↑SVSV

+ dromo-+ dromo-tropic effecttropic effect

Reflex tachycardiaReflex tachycardia

Effects of isoproterenol on Effects of isoproterenol on airwaysairways

Powerfully Powerfully stimulates stimulates ββ22--adrenergic adrenergic receptors on receptors on airway smooth airway smooth muscle→ rapid, muscle→ rapid, powerful powerful relaxation→ relaxation→ bronchodilationbronchodilation

Therapeutic uses: Therapeutic uses: isoproterenolisoproterenol

BronchodilatorBronchodilator Complete AV block (3Complete AV block (3rdrd degree heart degree heart

block)block)

Synthetic Catecholamines: Synthetic Catecholamines: DobutamineDobutamine

It’s a derivative of DA but not a D1 It’s a derivative of DA but not a D1 or D2 receptor agonist or D2 receptor agonist

Stimulates Stimulates ββ11- and - and ββ22-adrenergic -adrenergic receptors, but at therapeutic doses, receptors, but at therapeutic doses, ββ11-effects-effects predominatepredominate

Increases force of contraction more Increases force of contraction more than increases heart ratethan increases heart rate

↑↑CO = ↑HR x ↑ ↑ SVCO = ↑HR x ↑ ↑ SV

Dobutamine: Therapeutic Dobutamine: Therapeutic usesuses

ShockShock MIMI Cardiac surgery Cardiac surgery Refractory congestive heart failureRefractory congestive heart failure

Major toxic effects of Major toxic effects of catecholaminescatecholamines

All are potentially arrhythmogenicAll are potentially arrhythmogenic Epi and isoproterenol more Epi and isoproterenol more

arrhythmogenic than dopamine and arrhythmogenic than dopamine and dobutaminedobutamine

Some can cause hypertensionSome can cause hypertension Epinephrine, in particular, can cause Epinephrine, in particular, can cause

CNS effects – fear, anxiety, CNS effects – fear, anxiety, restlessnessrestlessness

Dobutamine can cause vomiting and Dobutamine can cause vomiting and seizures in cats – must be used at very seizures in cats – must be used at very low doseslow doses

Adverse effectsAdverse effects

CNS: CNS: RestlessnessRestlessness PalpitationPalpitation Anxiety, tremorsAnxiety, tremors

CVS: CVS: Increase BP….cerebral haemmorrhageIncrease BP….cerebral haemmorrhage Ventricular tachycardia, fibrillationVentricular tachycardia, fibrillation May precipitate angina or AMIMay precipitate angina or AMI

Non-catecholamine Non-catecholamine direct-acting adrenergic direct-acting adrenergic

agonistsagonistsEphedrineEphedrine

Stimulates Stimulates αα11-, -, ββ1 1 and and ββ22-adrenergic -adrenergic receptors and ↑ NE release from receptors and ↑ NE release from noradrenergic fibersnoradrenergic fibers

Repeated injections produce Repeated injections produce tachyphylaxistachyphylaxis

It is resistant MAO, orally It is resistant MAO, orally Longer acting (4-6), cross BBBLonger acting (4-6), cross BBB

Marketed as dietary supplement Marketed as dietary supplement promoted to aid weight loss, ↑ sports promoted to aid weight loss, ↑ sports performance and ↑ energy. Ingredient performance and ↑ energy. Ingredient in OTC nasal decongestants and in OTC nasal decongestants and bronchodilatorsbronchodilators

Uses : Uses : Mild chronic Bronchial asthma, Mild chronic Bronchial asthma, hypotension during spinal anaesthesia hypotension during spinal anaesthesia ,occasionally for postural hypotension ,occasionally for postural hypotension

Sale prohibited by FDA in 2004 Sale prohibited by FDA in 2004 due to risks of life-threatening due to risks of life-threatening cardiac arrhythmias, stroke and cardiac arrhythmias, stroke and deathdeath

Non-catecholamine direct-acting Non-catecholamine direct-acting adrenergic agonists: adrenergic agonists:

Phenylpropanolamine (PPA)Phenylpropanolamine (PPA) Actions much like ephedrine in the Actions much like ephedrine in the

PNSPNS In veterinary medicine, used to treat In veterinary medicine, used to treat

urinary incontinence in dogsurinary incontinence in dogs Available in OTC products for Available in OTC products for

treatment of nasal decongestion and treatment of nasal decongestion and as appetite suppressantas appetite suppressant

FDA has requested all companies FDA has requested all companies discontinue marketing products discontinue marketing products containing PPA due to risk of containing PPA due to risk of hemorrhagic strokehemorrhagic stroke

αα11 ––adrenergic adrenergic receptor receptor agonist- agonist- contraction contraction urethral urethral smooth smooth muscle muscle

ββ2 2 ––adrenergic adrenergic receptor receptor agonist –agonist –relaxation relaxation detrusor detrusor musclemuscle

ββ22-selective adrenergic -selective adrenergic agonistsagonists

β2-adrenergic receptors on bronchial smooth muscle

Preferential affinity for β2-adrenergic receptors, but at sufficiently high doses, can stimulate β1

terbutaline , albuterol inhalation aerosolRelax bronchial smooth muscle→bronchodilationTreatment of asthma, chronic bronchitis

Due to selectivity for Due to selectivity for ββ22 receptors at receptors at

recommended doses, little-to-no direct recommended doses, little-to-no direct

stimulation of stimulation of ββ11 receptors in heart receptors in heart

Inhalant administration maximizes local Inhalant administration maximizes local

effect and minimizes systemic effectseffect and minimizes systemic effects

ββ22-selective adrenergic -selective adrenergic agonistsagonists

MephenteramineMephenteramine

It is mixed sympathomimeticIt is mixed sympathomimetic

COP, BP, heart rate are increasedCOP, BP, heart rate are increased

Active orally with longer DOA (2-6 hrs),can Active orally with longer DOA (2-6 hrs),can

crosses BBBcrosses BBB

UsesUses: : To treat hypotension due to spinal anesthesia and To treat hypotension due to spinal anesthesia and

surgical proceduressurgical procedures Shock in MI and other hypotensive states Shock in MI and other hypotensive states

USESUSES

VascularVascular Hypotensive statesHypotensive states

Shock: hemorrhagic/ hypovolemic, Shock: hemorrhagic/ hypovolemic, spinal, neurogenic, cardiogenic, spinal, neurogenic, cardiogenic, anaphylactic shock.anaphylactic shock.

Postural hypotension- in parkinsonism, Postural hypotension- in parkinsonism, diabetes mallitusdiabetes mallitus

Along with local anaestheticsAlong with local anaesthetics To control local bleedingTo control local bleeding Nasal decongestantsNasal decongestants Peripheral vascular diseasesPeripheral vascular diseasesCardiacCardiac Cardiac arrestCardiac arrest Partial AV blockPartial AV block Congestive heart failureCongestive heart failure

Bronchial asthmaBronchial asthma AcuteAcute severe bronchial asthmasevere bronchial asthmaAllergic disordersAllergic disorders Urticaria, angiodema, anaphylaxisUrticaria, angiodema, anaphylaxisMydriaticsMydriatics Fundus examinationFundus examination Wide angle glaucomaWide angle glaucomaCNS usesCNS uses ADHDADHD NarcolepsyNarcolepsy EpilepsyEpilepsy ParkinsonismParkinsonism ObesityObesityUterine relaxantUterine relaxant

Adrenergic AgonistsAdrenergic Agonists Indirect:Indirect:

Cause NE release Cause NE release onlyonly

Example:Example: AmphetamineAmphetamine

CNS stimulantCNS stimulant Increases BP by Increases BP by

alpha effect on alpha effect on vasculature, beta vasculature, beta effect on hearteffect on heart