Chapter 1

DRUGS ACTING ON THE SYMPATHETIC

NERVOUS SYSTEM
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

ACh NA
Sympathetic
nervi ANS
nerve
simptic innervated
tissue
Preganglionic
fibra
fiber
preganglionar

Postganglionic
fibra
fiber
posganglionar
GANGLION

PHYSIOLOGY OF THE CATECHOLAMINERGIC TRANSMISSION

ADRENERGIC = ADRENOCEPTORS (AR) & DOPAMINERGIC RECEPTORS

CLASSIFICATION & LOCALIZATION
MOLECULAR MECHANISMS

SYMPATHOMIMETIC DRUGS
CLASSIFICATION
DIRECT-ACTING = ADRENERGIC AGONISTS
INDIRECT-ACTING
MIXED-ACTION AGENTS

PHARMACOLOGIC EFFECTS

THERAPEUTIC USES
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

Catechol Ethylamine
PHYSIOLOGY OF THE CATECHOLAMINERGIC TRANSMISSION

1. Synthesis
Tirosina
Tyrosine

CNS, ANS &

Adrenal Medulla
Tyrosine hydroxylase a-methyltyrosine

DOPA

Cytoplasm a-methylDOPA
DOPA decarboxylase
Carbidopa
Dopamine

Vesicle Dopamine -hydroxylase Disulfiram

Noradrenaline

Phenylethanolamine
N-methyltransferase

Adrenaline
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

PHYSIOLOGY OF THE CATECHOLAMINERGIC TRANSMISSION

2. Storage
3. Release

CNS & ANS

 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

PHYSIOLOGY OF THE CATECHOLAMINERGIC TRANSMISSION

4. Uptake CNS & ANS
Uptake 1: neuronal
high affinity
slow Dopamine depolarization

active transport
saturable &
stereospecific Na+
NET = neuronal noradrenaline transporter Ca2+ amphetamines
cocaine
imipramine

Uptake 2: extraneuronal
low affinity
fast EMT

active transport
non-saturable &
non-stereoespecific NA
metabolites
O-methylated
EMT = extraneuronal monoamine transporter COMT
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

PHYSIOLOGY OF THE CATECHOLAMINERGIC TRANSMISSION

5. Metabolism

MAO: Monoaminoxydase
COMT
Mitochondrial oxidative enzyme
MAO
MAO A intraneuronal
selective for NA, DA, 5-HT Aldehyde

MAO B extraneuronal dehydrogenase

(liver, kidney, intestine)

Aldehyde reductase

COMT: Catechol-O-methyltransferase
Cytoplasmic/plasma membrane enzyme
Methylates an OH of catechol COMT
Aldehyde
reductase
Both: neuronal or extraneuronal

Aldehyde
dehydrogenase
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DRUGS AFFECTING THE NORADRENERGIC TRANSMISSION

CNS & ANS
- SYNTHESIS:
METHYLTYROSINE

- STORAGE:
RESERPINE

- RELEASE:
TYRAMINE
EPHEDRINE
AMPHETAMINES

- UPTAKE 1:
COCAINE
TRICYCLIC ANTIDEPRESSANTS

- ENZYMATIC INACTIVATION:

- MAO: ANTIDEPRESSANTS
ANTIPARKINSONIAN DRUGS

- COMT: ANTIPARKINSONIAN DRUGS

 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
ADRENERGIC RECEPTORS: ADRENOCEPTORS (AR)
Membrane glycoproteins (64-68 Kda)

Amino acids involved in ligand-binding

Amino acids involved in coupling to G-protein
Amino acids involved in desensitization
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
ADRENERGIC RECEPTORS: ADRENOCEPTORS (AR)
Classification & localization

a (A > NA >> ISO) b (ISO > A NA)

Classification a1 a2 b1 b2 b3
Potency order A NA > Clonidine > A NA >> ISO > A = ISO > A >> NA ISO = NA > A
clonidina>>ISO ISO NA
Localization POSTSYNAPTIC POSTSYNAPTIC POST- POSTSYNAPTIC POST-
vascular s.m., liver, PRESYNAPTIC SYNAPTIC PRESYNAPTIC SYNAPTIC
heart, salivary EXTRASYNAPTIC heart EXTRASYNAPTIC adipose
glands, kidney, vascular s.m. vascular s.m., tissue
gastrointestinal m. platelets, pancreas skeletal m.
blood vessels, airways,
uterus, mast cells
Subtypes a1A, a1B, a1D a2A, a2B, a2C

a1 a2 b1 b2 vascular smooth muscle a1 > a2, b2

Vascular sm Kidney
pancreas a2
hepatocytes a1
b3
skeletal muscle b2
uterus, airways b2
heart b1 > b2
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

MOLECULAR MECHANISMS OF ADRENERGIC RECEPTOR ACTIVATION

Ca2+

Feedback control of noradrenaline release: The

presynaptic 2 receptor inhibits adenylyl cyclase, thereby
reducing intracellular cAMP. cAMP acts to promote Ca2+
influx in response to membrane depolarisation, and
hence to promote the release of noradrenaline and ATP
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
ADRENERGIC RECEPTORS: ADRENOCEPTORS (AR)

a (A > NA >> ISO) b (ISO > A NA)

Classification a1 a2 b1 b2 b3
Coupled Gq PLC IP3 Gi Adenylate
Gs Adenylate cyclase AMPc
G-protein Ca2+ cyclase AMPc
Localization POSTSYNAPTIC POSTSYNAPTIC POST- POSTSYNAPTIC POST-
vascular s.m., liver, PRESYNAPTIC SYNAPTIC PRESYNAPTIC SYNAPTIC
heart, salivary glands, EXTRASYNAPTIC heart EXTRASYNAPTIC Adipose
gastrointestinal m. kidney, vascular s.m. vascular s.m., tissue
platelets, pancreas skeletal m.
blood vessels,
airways, uterus,
mast cells
Main effects Vasoconstriction Inhibition of insulin Tachycardia Vasodilation lipolysis
peripheral release myocardial peripheral
resistance Inhibition of contractility resistance
arterial pressure neurotransmitters lipolysis Bronchodilation
Mydriasis release (CNS & release of glycogenolysis
ANS) renin
urinary retention glucagon release
Platelet aggregation
Relaxed uterine
smooth muscle
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
RESPONSES TO PERIPHERAL ADRENERGIC RECEPTORS ACTIVATION
TISSUES & EFFECTS a1 a2 b1 b2 b3
Smooth muscle
blood vessels contraction contraction/dilatation dilatation
bronchia (contraction) dilatation
digestive system relaxation (presynaptic) relaxation
digestive sphincters contraction
uterus contraction relaxation
bladder contraction relaxation
seminal system contraction relaxation
iris contraction (mydriasis)
Heart conduction velocity
frequency increase (increase)
contraction force increase
Skeletal muscle increased release tremor thermogenesis
of ACh in motor plate increased
muscle mass and
contraction velocity
glycogenolysis
Liver glycogenolysis glycogenolysis
Fat inhibition of lipolysis lipolysis
thermogenesis
Pancreatic islets reduction of
insulin secretion
Nerve endings
Adrenergic reduced released increased released
Cholinergic reduced released
Salivary gland K+ release amylase secretion

Platelets aggregation
Mast cells inhibition of histamine release
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
DOPAMINERGIC RECEPTORS:

Family D1 Family D2
Classification D1 D5 D2 D3 D4
Coupled
Gs Adenylate cyclase AMPc Gi Adenylate cyclase AMPc
G-protein
Localization POSTSYNAPTIC CNS POSTSYNAPTIC CNS CNS
CNS, peripheral PRESYNAPTIC Cardiovascular
mesenteric and renal CNS
vascular beds peripheral mesenteric
and renal vascular
beds, presynaptic
adrenergic neurons

Main effects Renal vasodilation, NA release

diuresis
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

SYMPATHOMIMETIC DRUGS
CLASSIFICATION

NON-SELECTIVE Responses may be

DIRECT-ACTING potentiated by prior
AGONISTS
SELECTIVE treatment with
cocaine or reserpine

Responses are
abolished by prior
RELEASE STIMULATION
treatment with
reserpine
INDIRECT-ACTING UPTAKE INHIBITION

DEGRADATION INHIBITION

Responses are
diminished by prior
MIXED-ACTION AGONISTS + INDIRECT-ACTING
treatment with
reserpine
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

CLASSIFICATION OF SYMPATHOMIMETIC DRUGS

A) DIRECT-ACTING
CATECHOLAMINES: ADRENALINE (Epinephrine) (a & b)
NORADRENALINE (Norepinephrine) (a & b1)
DOPAMINE (weak adrenergic agonist, dopaminergic system D1 & D2)
ISOPRENALINE (Isoproterenol) (b)

a agonists: a1: PHENYLEPHRINE

METHOXAMINE
PHENYLPROPANOLAMINE
MIDODRINE NAPHAZOLINE
OXYMETAZOLINE
a2: CLONIDINE TETRIZOLINE
TIZANIDINE (central myorelaxant)

b agonists: b1: DOBUTAMINE (catecholamine)

b2: SALBUTAMOL (Albuterol) SALMETEROL
TERBUTALINE FENOTEROL
RITODRINE FORMOTEROL

OTHER agonists: ETHYLEPHRINE (a1 & b1 > b2)

B) INDIRECT-ACTING: TYRAMINE
C) MIXED-ACTION: EPHEDRINE
COCAINE
PSEUDOEPHEDRINE
IMAOs
AMPHETAMINE
ENTACAPONE
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS ADRENALINE (Epinephrine)

PHARMACOLOGIC EFFECTS

CARDIOVASCULAR
a1: Vascular smooth muscle contraction
Use: Local anesthesia (+ local anesthetic)
Cardiac hypertrophy

b1: rate of contraction (positive chronotropic)

contraction force (positive inotropic)
automaticity
Heart
A-V nodal conductivity
cardiac output
oxygen demand of the myocardium
Use: Shock
( release of renin)

b2: Vasodilation
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS ADRENALINE (Epinephrine)

PHARMACOLOGIC EFFECTS
RESPIRATORY b2 : Bronchodilation
Uses: Bronchospasm & anaphylactic shock

DIGESTIVE b2 : Motility

UTERUS b2 : Relaxation

SKELETAL MUSCLE
a1 : acetylcholine in neuromuscular motor plate
b2 : fine tremor

EYE a1 : Mydriasis
Vasoconstriction
a1 & a2 aqueous humor production
intraocular pressure

URINARY BLADDER a1 : Contraction of sphincter

b2 : Relaxation of detrusor
Urinary retention

PLATELETS a2 : Aggregation
NEUROTRANSMISSION IN THE AUTONOMIC NERVOUS SYSTEM

EYE a1 : Mydriasis
Pupil size Vasoconstriction
a1 & a2 aqueous humor production
intraocular pressure

constrictor dilatator S
PS
III
ACh

NE
ACh
(Epi)
Circulating
Epinephrine

MIOSIS MYDRIASIS
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS ADRENALINE (Epinephrine)

PHARMACOLOGIC EFFECTS

PANCREATIC ISLETS
a2: Inhibition of insulin release Glycogenolysis

METABOLISM
Mobilization of
glycogen and fat stores

HYPERGLYCEMIA!!

Lipolysis
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS ADRENALINE (Epinephrine)

PHARMACOKINETICS

No oral bioavailability
Rapid metabolism
Very short half-life

ADVERSE EFFECTS

Generalized adrenergic hyperactivity

Arterial blood pressure
Arrhythmias
Palpitations
Hyperglycemia
Fine tremor
INTERACTIONS

LOCAL ANESTHETICS
TRICYCLIC ANTIDEPRESSANTS
COCAINE & AMPHETAMINE
DIGOXIN
b-BLOCKERS
 Receptor Desensitization

Laboratory of Cornelius Krasel, Philipps Universitt Marburg

Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS PHARMACOLOGIC EFFECTS

NORADRENALINE (Norepinephrine) CARDIOVASCULAR
a1: Vascular smooth muscle contraction
Cardiac hypertrophy

b1: moderated
Uses: cardiac arrest & acute hypotension
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS PHARMACOLOGIC EFFECTS

NORADRENALINE (Norepinephrine) CARDIOVASCULAR
a1: Vascular smooth muscle contraction
Cardiac hypertrophy

b1: moderated
Uses: cardiac arrest & acute hypotension
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS PHARMACOLOGIC EFFECTS

ISOPRENALINE (Isoproterenol)

CARDIOVASCULAR
b1: rate of contraction
contraction force
automaticity
A-V nodal conductivity
cardiac output
oxygen demand
Uses: heart block & shock
b2: Vasodilation
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

ISOPRENALINE (Isoproterenol)

PHARMACOLOGIC EFFECTS
RESPIRATORY
b2: Bronchodilation

DIGESTIVE
b2: Motility

UTERUS
b2: Relaxation

SKELETAL MUSCLE
b2: fine tremor

METABOLISM
Mobilization of glycogen and fat stores
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

DOPAMINE

PHARMACOLOGIC EFFECTS
CARDIOVASCULAR

D1: renal vasodilation, diuresis

D2: NA

Weak agonist:
b1: rate of contraction
contraction force
cardiac output

a: Vasoconstriction total peripheral resistance

Use: cardiogenic and septic shock correction of hemodynamic imbalances present in

given by continuous infusion the shock syndrome due to myocardial infarctions,
trauma, endotoxic septicemia, open heart surgery,
ADVERSE REACTIONS??? renal failure, and chronic cardiac decompensation
as in congestive failure
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

a1 AGONISTS
PHENYLEPHRINE
METHOXAMINE
PHENYLPROPANOLAMINE
MIDODRINE

PHARMACOLOGIC / ADVERSE EFFECTS

EYE: Mydriasis, vasoconstriction Decongestant, eye fundus examination

URINARY BLADDER Contraction of sphincter

Urinary retention
CARDIOVASCULAR
VASOCONSTRICTION Decongestant REBOUND EFFECT
arterial pressure Reflex bradycardia
peripheral resistance
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

a2 AGONISTS ADVERSE EFFECTS
CLONIDINE TIZANIDINE
Partial agonist Sedation
Dry mouth
Sexual dysfunction
Hyperglycemia

EFECTOS FARMACOLGICOS
CARDIOVASCULAR
Paradoxical hypotension
acting at CNS sympathetic vasomotor centers
i.v. First arterial pressure followed by
hypotension
oral
topical: Use: Decongestant
EYE: intraocular pressure
topical: Use: Glaucoma / laser surgery
PANCREATIC ISLETS: insulin release
CNS: NT release Sedation
Use: Withdrawal syndrome
from opiates and BZD
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

a AGONISTS
TOPICAL
NAPHAZOLINE
OXYMETAZOLINE a1 / a2
TETRIZOLINE OXYMETAZOLINE

NAPHAZOLINE
PHARMACOLOGIC / ADVERSE EFFECTS

LOCAL VASOCONSTRICTION

Local Decongestant REBOUND EFFECT!!

Local treatment of hemorrhages of skin & mucosae

Mydriasis
Cardiovascular & CNS alterations if systemic absorption
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

DIRECT-ACTING ADRENERGIC AGONISTS

b1 AGONISTS b2 AGONISTS
DOBUTAMINE TERBUTALINE SALMETEROL
SALBUTAMOL (Albuterol) FENOTEROL
RITODRINE FORMOTEROL

PHARMACOLOGIC EFFECTS
PHARMACOLOGIC EFFECTS
HEART: rate of contraction
contraction force RESPIRATORY: Bronchodilation
automaticity Use: Asthma
A-V nodal conductivity UTERUS: Relaxation
cardiac output Use: to stop premature labor
oxygen demand DIGESTIVE: Motility
Use: Congestive heart failure
CARDIOVASCULAR
Vasodilation
ADVERSE EFFECTS
Arrhythmias SKELETAL MUSCLE
Fine Tremor
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

INDIRECT-ACTING SYMPATHOMIMETIC DRUGS

1. RELEASE STIMULATION

Neuronal uptake system &

Indirect ag.
displacement of NA from vesicles
TYRAMINE

2. UPTAKE INHIBITION

COCAINE
TRICYCLIC ANTIDEPRESSANTS
3
3. DEGRADATION INHIBITION
indirect ag. 2 1
IMAOs indirect ag.
ENTACAPONE
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

MIXED-ACTING SYMPATHOMIMETIC DRUGS

Agonists of adrenergic receptors
Uptake inhibition
Neuronal uptake system &
displacement of NA from vesicles

EPHEDRINE

PSEUDOEPHEDRINE

AMPHETAMINE
Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM

ADRENERGIC AGONISTS

ADVERSE EFFECTS
PALPITATIONS
HYPERTENSION
HYPERGLYCEMIA
 Chapter 1. DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM
THERAPEUTIC USES OF ADRENERGIC AGONISTS
A. Cardiac Pathologies : ADRENALINE, b-adrenergic agonists (ISOPRENALINE, DOBUTAMINE),
DOPAMINE
Atrioventricular (A-V) block
Cardiac arrest
Cardiopulmonary Resuscitation
Atrial (auricular) bradycardia
Heart failure
Shock: cardiogenic: DOPAMINE
neurogenic
hypovolemic
anaphylactic: ADRENALINE
septic: DOPAMINE
B. Hypotension: MIDODRINE, ETHYLEPHRINE, DOPAMINE, NORADRENALINE
C. Hypertension: CLONIDINE
D. Local vasoconstriction & decongestant: PSEUDOEPHEDRINE, PHENYLEFPHRINE, EPHEDRINE
OXYMETAZOLINE, METHOXAMINE
E. Local hemorrhages in skin & mucosae: OXYMETAZOLINE
F. Asthma: SALBUTAMOL, TERBUTALINE, SALMETEROL, FORMOTEROL
G. Ophthalmic uses
Mydriatics: PHENYLEFPHRINE, EPHEDRINE, PHENYLPROPANOLAMINE
Glaucoma treatment / laser surgery: APRACLONIDINE
I. CNS pathologies: CLONIDINE, AMPHETAMINES
J. SPASTICITY: TIZANIDINE
K. Inhibition of uterine contractions in premature labor: RITODRINE
L. Urologic disorders: EPHEDRINE, PSEUDOEPHEDRINE, PHENYLPROPANOLAMINE
M. Renal failure: DOPAMINE
(------------------------------------)
N. Obesity: AMPHETAMINES