SympatheticNervous System

BrainSpinal Cord

CNS

SomaticNS

PNS

Nervous System

Autonomic NS

Sympathetic

Parasympathetic

AChNEN

1

2

1

N

ACh

MACh

CNS

C

T

L

SSMACh

NE

N

AChNEN

ACh

EPIN 1

2

1

N

ACh

MACh

CNS

C

T

L

SACh

NE

SMN

AChNEN

1

2

1

N

ACh

MACh

CNS

C

T

L

SACh

NE

SGAChN

ACh

SMN

M

AChNEN

ACh

EPIN 1

2

1

M

C

T

L

S

NE

2

CNS(-)

Sympathetic Nervous System

Dual Innervation

Predominant Tone

Exceptions

Primarily parasympathetic NS

- blood vessels

Exceptions

- blood vessels (sympathetic)

- sweat glands (sympathetic cholinergic)

(only sympathetic)

- bronchioles (only parasympathetic)

- ciliary muscles (only parasympathetic)

Denervation Supersensitivity

Before Denervation After Denervation

+ Effect+ Effect +++ Effect+++ Effect

NTNT NTNT

NENE

EPIEPI

DADA

Catecholamines

PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC

NE

Re-uptake 1Re-uptake 1

Metabolic RemovalMetabolic Removal

ActionAction /

ReceptorBinding

ReceptorBinding

NE synthesisNE synthesis

NE

COMTCOMT

MAOMAO

Re-uptake 2

(-)

NE - predominately removed from synapse via ‘re-uptake 1’

2

Drug actions at presynaptic autonomic nerve terminals

NE

EPI 1, 2, 1, 2

1, 2, 1

Adrenergic Receptors

NE

EPI 1, 2, 1, 2

1, 2, 1

Adrenergic Receptors

DA 1, 1, DA1

SITE EFFECT

EFFECTS OF STIMULATING ADRENERGIC RECEPTORS

BRONCHORELAXATION (2)

TACHYCARDIA and INCREASED CONTRACTILITY (1)

VASODILATION

DECREASED URINATION (2)

DECREASED GI MOTILITY and SECRETIONS (2)

GI TRACT

BLADDER

IRIS

AIRWAYS

VASCULATURE

HEART

(2)VASOCONSTRICTION

(1, 2)

UTERUS RELAXATION (2)

MYDRIASIS (1)

1, 2 vasoconstrictionTPR

contractile forceheart rate

1

2 vasodilation, TPR

renin release

Drugs and Adrenergic Synapses

AChNEN

1

2

1

N

ACh

MACh

CNS

C

T

L

SACh

NE

SMN

Adrenergic Agonists

EPIN

ACh

MIXED ADRENERGIC AGONISTSMIXED ADRENERGIC AGONISTS

NorepinephrineNorepinephrine

EpinephrineEpinephrine

1, 2, 1, 2

1, 2, 1

DopamineDopamine

DA1, 1, 1

HR

BP

TPR

MIXED ADRENERGIC AGONISTSMIXED ADRENERGIC AGONISTS

Norepinephrine Norepinephrine ((1, 2, 1)

Epinephrine Epinephrine ((1, 2, 1, 2)

Dopamine Dopamine ((DA, 1, 1)

Tx: ● Asthma (but there are better drugs)

Tx: ● CHF

● Anaphylactic shock

● Cardiogenic shock

● Prolong action of local anesthetics

● Topical hemostatic agent

ALPHA AGONISTSALPHA AGONISTS

- - PhenylephrinePhenylephrine ( (11))

- - Oxymetazoline Oxymetazoline ( (11 and and 2 in periphery2 in periphery))

- - Ephedrine/PseudoephedrineEphedrine/Pseudoephedrine ( (11))

- - Clonidine Clonidine ( (22, Tx site of action is CNS), Tx site of action is CNS)

- - MethoxamineMethoxamine ( (1)1)

- - Tetrahydrozoline Tetrahydrozoline ((1)1)

- - NaphazolineNaphazoline ((1)1)

Alpha-1 agonistsAlpha-1 agonists

Alpha-2 agonists Alpha-2 agonists

Tx: ● Nasal decongestion

Tx: ● Hypertension

● Hypotensive states

● Used in eye drops to ‘get the red out’

Tx uses for ALPHA AGONISTSTx uses for ALPHA AGONISTS

BETA AGONISTS BETA AGONISTS and Tx usesand Tx uses

Non-selective 1/2

- - Isoproterenol

Selective 1

- - Dobutamine

Non-selective 1/2

- - Isoproterenol

Selective 1

- - Dobutamine

Selective Selective 22

- - Albuterol- - Albuterol

- - Terbutaline- - Terbutaline

- - Isoetharine

- - Metaproterenol

- - Bitolterol

- - Ritodrine

Tx: Cardiac stimulant

Tx: Inotropic agent

Tx: COPD, Asthma

Tx: Uterine

relaxation

HR

BP

TPR

NE EPI ISO

Dose-response effects produced by dopamine at different receptors

CNS ADRENERGIC AGENTSCNS ADRENERGIC AGENTS

- - Clonidine Clonidine ((2 agonist)2 agonist)

- - MethyldopaMethyldopa

- - GuanfacineGuanfacine ( (2 2 agonist)agonist)

CNS : Tx antihypertensive effectCNS : Tx antihypertensive effect

Converted in CNS to methylnorepinephrine Converted in CNS to methylnorepinephrine (low efficacy (low efficacy 2 agonist)2 agonist)

- - Guanabenz Guanabenz ( (2 agonist)2 agonist)

AChNEN

ACh

EPIN 1

2

1

M

C

T

L

S

NE

2

CNS(-)Sympathetic Nervous System

(-)

(-)

2

AChNEN

1

2

1

N

ACh

MACh

CNS

C

T

L

SACh

NE

SMN

Adrenergic Antagonists

EPIN

ACh

XX

XXXX

ALPHA ANTAGONISTS ALPHA ANTAGONISTS and Tx usesand Tx uses

- - PhentolaminePhentolamine

- - PrazosinPrazosin - - Terazosin Terazosin (water soluble)(water soluble)

- - PhenoxybenzaminePhenoxybenzamine Non-competitive actionNon-competitive action

Tx: - DOC for overdose of alpha agonists Tx: - DOC for overdose of alpha agonists - Management of pheochromocytoma- Management of pheochromocytoma - Dental use for reversal of local anesthetic action- Dental use for reversal of local anesthetic action

Nonselective Nonselective 1 and 1 and 2 receptor antagonists2 receptor antagonists

Selective Selective 1 receptor antagonists1 receptor antagonists

Tx: Antihypertensive agents,Tx: Antihypertensive agents,Management of benign prostatic hypertrophy Management of benign prostatic hypertrophy

Competitive action Competitive action

NE VasoconstrictionVasoconstriction1

NE

(-)

Adrenergic Influence onVascular Smooth Muscle Tone

2

VSMCVSMC

2

NE VasoconstrictionVasoconstriction1

NE

(-)2

VSMCVSMC

2

EPI

VasoconstrictionVasoconstriction

Adrenergic Influence onVascular Smooth Muscle Tone

NEVasodilationVasodilation

1

NE

(-)

Marked hypotensive response produced by dual 1 and 2 - Receptor Blockade on VSMC

2

VSMCVSMC

2

EPI

VasodilationVasodilation

Phentolamine - 11 and 2 2 blockade blockade

X

XX

VasodilationVasodilation1

NE

(-)

Moderate hypotensive response produced by dual 1 and 2 - Receptor Blockade 0n VSMC

2

VSMCVSMC

2

EPI

Prazosin - selective 11 blockade ockade

XNE

VasoconstrictionVasoconstriction

● ● Non-selective Non-selective 1, 1, 22

BETA ANTAGONISTSBETA ANTAGONISTS

● ‘● ‘Cardio’- Cardio’- Selective Selective 11

PropranololPropranolol

NadololNadolol

TimololTimolol

PindololPindolol

CarteololCarteolol Intrinsic Intrinsic Sympathomimetic Sympathomimetic

ActivityActivity

AtenololAtenolol

MetropololMetropolol

EsmololEsmolol

AcebutololAcebutolol (ISA)(ISA)

●● Non-selective1, 1, 2, 2, 11

LabetalolLabetalol

CarvedilolCarvedilol

Beta Blocker Tx Uses:Beta Blocker Tx Uses:

● Hypertension

● Migrane ● Arrhythmias

● Anxiety

● Angina

● Congestive heart failure

● Stage fright

● Myocardial infarction

AmphetamineAmphetamine

INDIRECT ACTING ADRENERGICINDIRECT ACTING ADRENERGICAGONISTSAGONISTS

TyramineTyramine (dietary substance)(dietary substance)

PseudoephedrinePseudoephedrine

EphedrineEphedrine

PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC

NE

Re-uptake 1Re-uptake 1

ActionAction /

ReceptorBinding

ReceptorBinding

NE

AmphetamineAmphetamine

PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC

Re-uptake 1Re-uptake 1

ActionAction /

ReceptorBinding

ReceptorBinding

NE

AmphetamineAmphetamine

NE

amphetamineamphetamine

(+)

• CocaineCocaine

• Tricyclic AntidepressantsTricyclic Antidepressants

Uptake BlockersUptake Blockers

PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC

NE

Re-uptake 1Re-uptake 1

ActionAction /

ReceptorBinding

ReceptorBinding

NE

CocaineCocaine

PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC

Re-uptake 1Re-uptake 1

ActionAction /

ReceptorBinding

ReceptorBinding

NE

CocaineCocaine

NE

XXcocainecocaine

• GuanethadineGuanethadine

Neuronal BlockersNeuronal Blockers

• ReserpineDepletes NE stores by inhibiting Depletes NE stores by inhibiting vesicular uptake of NE; NE then vesicular uptake of NE; NE then metabolized by intra-neuronal metabolized by intra-neuronal MAOMAO

Inhibits NE release, also causes Inhibits NE release, also causes NE depletion, and can damage NE NE depletion, and can damage NE neuronsneurons

• PargylinePargyline

Monoamine Oxidase (MAO) InhibitorsMonoamine Oxidase (MAO) Inhibitors

• Tranylcypromine• Tranylcypromine

Tyramine (or other drugs that promote NE release) Tyramine (or other drugs that promote NE release) may cause markedly increased blood pressure in may cause markedly increased blood pressure in patients taking MAO inhibitorspatients taking MAO inhibitors