1

Sympatholytic Drugs
.., .. ()

Sympatholytic Drugs

Sympathetic nervous system

preganglionic nerves synapse

sympathetic ganglions
post-ganglionic
nerves
( 1)
post-ganglionic
nerves norepinephrine
adrenergic receptors (
alpha1, alpha2 beta1)

sympathetic nervous system
post-ganglionic nerves
dopamine acetylcholine

pre-ganglionic nerves
adrenal medulla
norepinephrine epinephrine
(
, )
neurotransmitters
adrenergic receptors
receptors
norepinephrine adrenergic
receptors
epinephrine adrenergic
receptors alpha1, alpha 2, beta1
beta 2

sympathetic nervous system

1. Centrally Acting Sympatholytic

Agents
alpha2adrenergic receptors
sympathetic outflow

methyldopa clonidine
2. Autonomic Ganglion Blocking
Agents
acetylcholine
nicotinic receptors postganglionic neurons sympathetic
( parasympathetic) ganglions

ganglions
3. Post-Ganglionic Neuron Blocking
Agents

norepinephrine transmitter vesicles

post-ganglionic neurons
guanethidine reserpine
4. Adrenergic Receptor Blockers
adrenergic
receptors
alpha receptors (alpha-blockers)
beta receptors (betablockers)
1

 1 neurotransmitters autonomic
somatic motor nerves (Ach, acetylcholine; D, dopamine; E, epinephrine; NE, norepinephrine; N,
nicotinic receptors; M, muscarinic receptors) [ Katzung BG.4]

METHYDOPA

1. CENTRALLY ACTING
SYMPATHOLYTIC AGENTS

analog L-dopa
alpha-methyldopamine
alpha-methylnorepinephrine
( L-dopa
dopamine norepinephrine
) alpha-methyldopamine
alpha-methylnorepinephrine
alpha2 receptors
sympathetic
outflow
methyldopa total
peripheral resistance (TPR)
cardiac
output

alpha2
receptor
sympathetic outflow

receptors presynaptic
sites ( norepinephrine
) postsynaptic sites

baroreceptor reflex
postural hypotension
2 methyldopa
clonidine
2

CLONIDINE

Pharmacokinetics
oral bioavailability
25% first-pass
metabolism ( Osulfate conjugation gastrointestinal
mucosa)
halflife 2

antihypertensives
4-6
half-life
24
metabolite (alphamethylnorepinephrine)
methyldopa parent drug

1-2

Clonidine alpha2
receptors
sympathetic outflow

parasympathetic nervous
system

Clonidine antihypertensives
2

alpha-1 receptors

(
)

clonidine
hemodymamics
cardiac output

(

)
TPR
TPR
(upright position)
sympathetic nervous system

clonidine imidazoline receptor
( I1) rostral ventrolateral
medulla (RVLM)
( rilmenidine, moxonidine) I1 receptor
RVLM ( affinity alpha2

,
,
extrapyramidal movement
galactorrhea
dopamine

positive Coombs test ( 10-20%
12
) drug
fever

receptor I1 receptor)

clonidine

ganglions
sympathetic nerve
fibers
sympathetic
nervous system

( sympathetic
ganglions sympathetic nerve fibers )
(
parasympathetic ganglions
SA AV node parasympathetic
nerve fibers )

hypertension


trimethaphan

hypertensive crisis



(
)

hypotension

sympathetic
nervous system ( postural hypotension sexual dysfunction )
parasympathetic
nervous system ( ,
, glaucoma ,
)

Pharmacokinetics
Clonidine oral bioavailability
75% half-life 812

,


( 1 )

hypertensive crisis
withdrawal hypertension

sympathetic nervous system (
)
clonidine
alpha- beta-blockers


antihypertensives

2. AUTONOMIC GANGLION
BLOCKING AGENTS
acetylcholine nicotinic receptors
post-ganglionic neurons sympathetic ( parasympathetic) ganglions

4

3. POST-GANGLIONIC
NEURON BLOCKING
AGENTS

50 % volume of
distribution half-life (5 )
2
sympathetic nervous system

norepinephrine post-ganglionic
neurons

guanethidine reserpine

sympathetic nervous
system (pharmacologic
sympathectomy)
postural hypotension
(
parasympathetic nervous system
)

GUANETHIDINE

sympathetic nerve membrane
transmitter vesicles
norepinephrine (
uptake-1
norepinephrine nerve
membrane)
norepinephrine
transmitter vesicles
norepinephrine
transmitter vesicles
sympathetic nerve endings

(local anesthetics)
sympathetic nerve endings
norepinephrine
sympathetic nerve endings
nerve action potentials

( TPR)
cardiac output

TPR
salt-water retention

RESERPINE

Resepine alkaloid
(Rauwolfia
sperpentina) neurotransmitters transmitter1
vesicles sympathetic nerve endings
norepinephrine
sympathetic nerve endings
cardiac
output TPR

neurotransmitters
transmitter vesicles
(
)

Pharmacokinetics
Bioavailability
3-50 %

neurotransmitters
biogenic amines serotonin
dopamine

4.1 ALPHA-BLOCKERS

baroreceptor reflex
postural hypotension

Alpha-blockers 2

1. Reversible Alpha-Blockers
alpha receptors
receptors

half-life receptors
prasosin, terazosin,
doxazosin phentolamine
2. Irreversible Alpha-Blockers
alpha
receptors covalent bond
receptors

alpha receptors (
)
phenoxybenzamine
Alpha-blockers
selectivity alpha1 alpha2
receptors
1

Pharmacokinetics
pharmacokinetics

adrenergic vesicles (irreversible)
vesicle membrane

1.

neurotransmitters
,
serotonin

dopamine
extrapyramidal movement

(0.25 )

2.
,

1.

alpha receptors

(tone)
arterioles
alpha-blockers
TPR
postural
hypotension reflex tachycardia

salt-water
retention
postural hypotension
alpha1 receptors

4. ADRENERGIC
RECEPTOR BLOCKERS
alphablockers beta-blockers

 1 Selectivity alpha receptors alpha-blockers [ Hoffman BB.2]

Affinity receptors
Prazosin*, terazosin*, doxazosin*
alpha1 >>>> alpha2
Phenoxybenzamine*
alpha1 > alpha2
Phetolamine**
alpha1 = alpha2
Yohimbine
alpha2 > alpha1
* Alpha1-selective blockers
**nonselective alpha-blockers

hypotension ( )
nonselective alphablockers

2. Benign Prostatic Hypertrophy

(BPH)
BPH
alpha1selective blockers

prazosin, terazosin
doxazosin

BPH
hypertension


alpha1A receptors

alpha1B
receptors alpha-blockers
alpha1A receptors (
tamsulosin)
BPH
tamsulosin
BPH alphablockers
postural hypotension

(
) postural
hypotension (syncope)

first dose phenomenon
first dose syncope

reflex tachycardia
alpha2
receptors (
Prazosin Phentolamine )
2.
alpha receptors

receptors

(prostate gland)

benign prostatic hypertrophy
(BPH)

1. Hypertension
Alpha1-selective blockers (
prazosin)
hypertension

postural
7

BPH alpha-blockers
finasteride (5 alpha-reductase inhibitor)

3. Pheochromocytoma
Pheochromocytoma
adrenal medulla
epinephrine norepinephrine

catecholamines
hypertension, tachycardia cardiac
arrhythmia
Phentolamine phenoxybenzamine

phenoxybenzamine

antihypertensives
sodium nitroprusside, revesible alpha1blockers calcium antagonists
alpha-blockers
beta-blockers
catecholamines
beta-blockers alphablockers ( ) betablockers
(
Beta-blockers )
4. Peripheral Vascular Disease

phentolamine, prazosin phenoxybenzamine
Raynauds phenomenon
vasospasm
calcium
antagonists

5.
phentolamine
nonspecific vasodilator ( papaverine)

hypotension
phenolamine

ALPHA-BLOCKERS

PRAZOSIN

Prazosin alpha1-selective
blocker venules
arterioles arterioles
TPR
alpha2 receptors
sympathetic nerve endings (presynaptic
alpha2 receptors) norepinephrine
sympathetic nerve endings
presynaptic alpha2
receptors
negative feedback mechanism
norepinephrine sympathetic nerve endings
( alpha1-selective blockers )
tachycardia
prazosin

bioavailability 50% half-life
3
antihypertensive drug
3-4

TERAZOSIN

alpha1-selective blocker
hypertension

BPH
bioavailability

 half-life 9-12

receptors (irreversible blockade)

14-48
alpha1-selective blocker selectivity
alpha1 receptors prazosin
( 1)
reflex tachycardia
alpha2 receptors
sympathetic nerve endings

bioavailability
pharmacokinetics




pheochromocytoma (
)
postural
hypotension tachycardia



,

DOXAZOSIN

alpha1-selective blocker
half-life 22
half-life prazosin terazosin
bioavailability



hypertension
BPH

PHENTOLAMINE

nonselective alpha-blocker
alpha1 receptors

alpha2 receptors sympathetic
nerve endings negative
feedback mechanism (
norepinephrine sympathetic nerve
ending)
norepinephrine sympathetic nerve
endings

phentolamine prazosin
alpha1-selective blockers
Phentolamine


pharmacokinetics

(
) tachycardia, cardiac arrhythmias
angina
pectoris

YOHIMBINE

indole alkaloid
alpha2-selective blocker


autonomic insufficiency
alpha2 receptors sympathetic
nerve endings
neurotransmitters

(painful
diabetic neuropathies)
()

alpha2 receptors

PHENOXYBENZAMINE

alpha receptors
covalent bound
9

 2 pharmacokinetics beta-blockers [ Hoffman BB.2]

Oral bioavailability
Beta-blockers
Lipid solubility
Half-life
(%)
Propranolol

3.5-6
30
Nadolol

14-24
33
Timolol

4-5
50
Carvedilol 1

6-8
25-35
Metoprolol

3-4

50
Atenolol11

6-9
40
Esmolol2

10 *
0
Pindolol

3-4
90
Acebutolol1,2

3-4
50
1
Beta1-selective blockers 2Beta-blockers with ISA (partial agonists)
* esterase supraventricular arrhythmia,
perioperative hypertension acute myocardial infarction

( clonidine)
hypertension
yohimbine

genous catecholamines
beta-blockers
pindolol
3.2 Beta1-selective blockers with
ISA acebutolol

4.2 BETA-BLOCKERS

Pharmacokinetics
.

peak plasma
concentration
1-3 propranolol
metoprolol sustained-release
preparation
. Bioavailability
Propranolol first
pass metabolism
bioavailability ( 2)
saturation

(systemic circulation)
propanolol

first pass metabolism
bioavailability 30-50%
( pindolol)
bioavailability 90% ( 2)

Beta-blockers
affinity beta
receptors
1. Nonselective Beta-Blockers
beta1
beta2 receptors propranolol timolol
2. Beta1-Selective Blockers
beta1
receptors beta2 receptors
cardioselective beta-blockers
metoprolol atenolol
3. Beta-Blockers with Intrinsic
Sympathomimetic Activity (ISA)
Partial Agonists
3.1 Nonselective beta-blockers
with ISA beta receptors
beta1 beta2
beta receptors full agonists
( epinephrine norepinephrine)
endo10

.
Beta-blockers
volume of distribution
( propanolol)
blood-brain-barrier
half-life 3-6
( 2) esmolol
hydrolyzed half-life
10 propranolol
metoprolol

atenolol pindolol
betablockers
,
liver
enzyme nadolol

half-life betablockers half-life
nadolol
beta-blockers
half-life

beta1 receptor
renin
renin-angiotensin-aldosterone system

2.
beta2 receptors

bronchospasm
asthma chronic obstructive pulmonary disease
3.
beta-blockers
aqueous humor ciliary epithelium

(intraocular pressure)
open-angle
glaucoma
4. Metabolisms
Beta-blockers
beta2 receptors
glucogenolysis gluconeogenesis

hypoglycemia


beta-blockers
hypoglycemia

hypoglycemia

insulin
hypoglycemia
beta1-selective blockers
glucogenolysis gluconeogenesis
beta2 receptors

beta-blockers
very-lowdensity lipoproteins (VLDL)

1.
beta receptors


reflex
( TPR)
beta2 receptors

(
beta2 receptors
)


()
TPR
cardiac output


11

high-density lipoproteins (HDL)

low-density lipoproteins
(LDL)
HDL LDL

beta1-selective nonselective betablockers
beta-blockers with ISA (partial agonists)

with rapid ventricular response

premature atrial contraction
(PAC) premature ventricular contraction (PVC)
catecholamines

4. Open-Angle Glaucoma
betablockers
aqueous humor ciliary epithelium
intraocular pressure
beta-blockers
( timolol, betaxolol, carteolol, levobunolol metipranolol)


timolol
1 mg

hypertension angina
10-60 mg

beta-blockers

5. Hyperthyroidism

sympathetic nervous system (
)
beta-blockers


tetraiodothyronine (T4) triiodothyronine (T3)
(T3 potency
T4 4 )

thyroid hormone
antithyroids, radioactive iodine
(131I)

1. Hypertension

TPR
renin

( Beta-blockers
Drug therapy of hypertension )
2. Angina Pectoris
Beta-blockers

myocardial oxygen demand

( Betablockers Antianginal drugs
)
3. Cardiac Arrhythmia
Beta-blockers
phase 4 action potential SA
node SA node
sinus
tachycardia

( hyperthyroidism )
refractoriness
AV node
supraventricular tachycardia
paroxysmal supraventricular tachycardia, atrial flutter atrial fibrillation
12

6. Neurological Diseases
Beta-blockers ( propranolol)

migraine

beta-blockers
(tremor)
sympathetic nervous
system, (somatic
manifestation)
alcohol
withdrawal

5.

Beta-blockers

, , ,

6. Withdrawal hypertension
beta receptors

receptors (upregulation)
catecholamines
receptors

sympathetic overactivity hypertension tachycardia
angina pectoris

7.
beta-blockers
VLDL HDL

beta-blockers with ISA (partial agonists)
beta-blockers

1.
beta receptor

congestive heart
failure, bradycardia heart block
2.

peripheral vascular disease
3. Brochospasm
Nonselective beta-blockers (
beta2 receptors )
bronchospasm
asthma chronic obstructive pulmonary disease
4.
Hypoglycemia
beta-blockers

hypoglycemia nonselective
beta-blockers glycogenolysis gluconeogenesis

hypoglycemia
beta-blockers
insulin
hypoglycemia

Beta-blockers

PROPANOLOL

Propranolol prototype
beta-blockers
nonselective beta-blocker
first-pass metabolism
bioavailability bioavailability
alpha muscarinic
receptors
partial agonist beta receptors

METOPROLOL & ATENOLOL

beta1-selective
blockers
13


bronchoconstriction
propranolol beta1
selectivity
(
)
beta2 receptors
asthma
chronic obstructive pulmonary disease

diabetes peripheral
vascular disease
beta-blockers beta2
receptors

hypoglycemia beta2 receptors

beta2 selectivity

nonselective betablockers

beta-blockers with
ISA angina pectoris

beta-blockers
pure antagonists
ISA myocardial oxygen demand

beta-blockers with ISA

nonselective
beta-blockers ( pindolol) beta1selective blockers ( acebutolol)

LABETALOL

Labetalol revesible adrenoceptor blocker alpha

beta receptors selectivity
receptors beta-1 = beta2 > alpha-1 > alpha-2

isomers SS RS isomers
SR isomer
alpha receptors RR isomer
beta receptors
labetalol beta receptors
alpha receptors
beta:alpha antagonism
3:1
labetalol affinity
alpha receptors phentolamine
potency beta receptors
propranolol

nonselective alpha-blockers
hypertension
pheochromocytoma hypertensive
emergencies

NADOLOL & TIMOLOL

Nadolol
timolol
nonselective beta-blockers
(local anesthetic
activity)2
intraocular
pressure glaucoma

PINDOLOL & ACEBUTOLOL

partial
agonists beta-blockers with ISA

betablockers pure antagonists

CARVEDILOL

local anesthetic activity cornea

nonselective beta-blocker
alpha1 receptors
14

 Beta-Blockers
propranolol
prototype
propranolol (
nonselective beta-blockers)

beta-blockers
asthma
beta1-selective blockers (
metoprolol atenolol)

beta2 receptor (
)
bronchospasm

beta-blockers
with ISA (partial agonists)
peripheral vascular disease
beta-blockers with ISA
beta1-selective blockers
betablockers with ISA angina pectoris

betablockers pure antagonist
ISA myocardial
oxygen demand

beta-blockers
( atenolol)

catecholamines
beta receptors alpha receptors
half-life 6-8

Carvedilol
antioxidant oxygen
free radical-initiated lipid peroxidation
vascular smooth
muscle mitogenesis
adrenergic receptors

congestive heart failure

ESMOLOL

beta1-selective blocker

ester linkage
esterase
half-life 10
continuous infusion
steady state

esmolol
(
)
beta-blockers

supraventricular arrhythmias,

myocardial ischemia

1. Benowitz NL. Antihypertensive agents. In: Katzung BG, editor. Basic & Clinical
Pharmacology. 8th ed. New York: The McGraw-Hill Companies, Inc; 2001. p.155-80.
2. Hoffman BB. Adrenoceptor antagonist drugs. In: Katzung BG, editor. Basic & clinical
pharmacology. 8th ed. New York: The McGraw-Hill Companies, Inc; 2001. p.138-54.
3. Hoffman BB. Catecholamines, sympathetic dugs, and adrenergic receptor
antagonists. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilmans
15

the pharmacological basis of therapeutics. 10th ed. New York: The McGraw-Hill
Companies, Inc; 2001. p.215-68.
4. Katzung BG. Introduction to autonomic pharmacology. In: Katzung BG, editor. Basic
& clinical pharmacology. 8th ed. New York: The McGraw-Hill Companies, Inc; 2001.
p.75-91.
5. Oates JA, Brown NJ. Antihypertensive agents and the drug therapy of hypertension.
In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilmans the
pharmacological basis of therapeutics. 10th ed. New York: The McGraw-Hill
Companies, Inc; 2001. p.871-900.

16