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Adrenoceptor agonists

Jiang Junlin

Department of Pharmacology,
School of Pharmaceutical Science, Central South University

AdrenergicNervousSystem:Overview
OH
HO

NH2

HO

Norepinephrine
(Noradrenaline)
OH
HO

NHMe

HO

Epinephrine
(Adrenaline)

Types of -adrenergic receptor


They are subdivided into two types:
1 adrenergic Receptor-Located on postsynaptic effector cells
in vessel, eye, heart, and liver, with effects including
vasoconstriction, uterine contraction and pupillary dilation,
2-adrenergic receptor-Located on presynaptic nerve terminals, with
effects controlling the release of neurotransmitters (negative
feedback-inhibition of norepinephrine release.)
Predominant -adrenergic agonist responses---Vasoconstriction

-receptor types
They are subdivided into three types:
1-Adrenergic receptors are located mainly in heart and kidney.
2-Adrenergic receptors are located mainly in bronchial tract,
liver, uterus, vascular smooth muscle in skeletal muscle.
3-receptors are located in fat cells.

Adrenergic Drugs
Drugs that stimulate the sympathetic nervous
system (SNS)
Adrenergic agonists
Sympathomimetics
Mimic the effects of the SNS neurotransmitters:
norepinephrine (NE)
epinephrine (EP)

Basic Pharmacology of
Sympathomimetics
Phenylethylamine is the parent compound for
sympathomimetic drugs.
This compound consists of a benzene ring with
an ethylamine side chain.

Substitutions
may be of
made
(1) on the terminalchange
amino the
The modification
phenylethylamine
group,
(2) onofthe
(3) on the the
or -carbons.
affinity
thebenzene
drugs ring,
for receptors,
intrinsic
Substitutionability
by -OHand
group
at the 3 and 4 positions yield
pharmacokinetics.
catecholamines.

Structure-Activity Relationship (SAR) of


Adrenomimetics
Responsible for
different receptor selecitvity of
sympathomimetics --> different actions
different distribution of drugs -->
different actions
different duration

According to the chemical structure


5

6
1

4
3

catecholamines

CH

CH

NH

R1

R2

R3

non-catecholamines

phenylethylamine
HO

HO

Catechol amine

Catecholamine drugs

Structure-Activity Relationship
1) different chemical groups on the

benzene ring
Catecholamines-high polarity
poor oral absorption
easy to be inactivated by COMT, shorter duration
not easily cross the blood brain barrier ( weak role in the central ,
strong role in peripheral )
Non-catecholamines-high lipophila
Go to a hydroxyl group (metaraminol) - increased oral
bioavailability, prolonged duration of action, reduced role in peripheral
To two hydroxyl (ephedrine) - reduced role in peripheral, strong
role in central

2) the hydrogen atom of the amino group (-NH-) is substituted


by various groups:
Substituted groups from methyl, tertiary and butyl, the role of
weakened, role of receptor enhanced
(epinephrine isoproterenol, salbutamol).
norepinephrine epinephrine

isoproterenol

salbutamol

6
1

4
3

CH

CH

NH

R1

R2

R3

3 -H replaced by methyl (-CH3):


Not easily be MAO destruction, prolonged duration of
action,
and
promote
norepinephrine
(ephedrine,
metaraminol, etc.).

4) -H replaced by hydroxy (-OH):


The central role is weak, peripheral effect is obvious.

6
1

4
3

CH

CH

NH

R1

R2

R3

Classification
According to the affinity for different
groups of receptor:
-adrenoceptor agonists
-adrenoceptor agonists
, -adrenoceptor agonists

-adrenoceptor agonists
Norepinephrine
Metaraminol
1 -adrenoceptor agonists
phenylephrine and methoxamine

receptor agonist
norepinephrin
Potent effect of receptor
Relative little effect on 1
receptor
weak effect on 2 receptor

Pharmacodynamics
1. Cardiovascular system
Heart : receptor

an increase in heart rate, contractions and conduction


velocity
Vessel : receptor
constrict vessels of skin, cutaneous,
visceral(splanchnic), lung, kidney
a rise in BP and an increase in peripheral vascular
resistance (PVR)

Net effect: BP heart


rate
a reflex increase in vagal outflow
(BP increase) --> reflex bradycard
ia

2. Metabolism (high dose)


Blood glucose increased (glycogenolysis and
gluconeogenesis, 2, 1)
Free fatty acids increased (2, 1, 3)

Clinical uses:
1) early shock:
Drug induced hypotension
Pheochromocytoma resection
Resection of sympathetic nerve
Application of the principles

early, low-dose, short-term use


(long-term heavy use: vasoconstriction, increased peripheral
resistance, increased the burden on the heart, decreased cardiac output,
reduced pressure, decreased in perfusion of heart, brain, kidney and
lung.

Shock
is a complex acute cardiovascular syndrome that
results in a critical reduction in perfusion of vital
tissues, and usually associated with hypotension,
oliguria.
The major mechanisms are hypovolemia, cardiac
insufficiency, and altered vascular resistance.
sympathomimetic drugs have been used in the
treatment of all forms of shock.

2)cardiac arrest adjuvant therapy (to help cardiac


resuscitation)
3) upper gastrointestinal bleeding: oral (local effects)
Side effects
1) local tissue necrosis
2) Acute renal failure: renal vasoconstriction, oliguria,
anuria, renal damage

Contraindication
Hypertension, arteriosclerosis

Metaraminol
Characteristics: non-catecholamine, stable,
maintaining for a long time, not easily damaged by
COMT and MAO.
Effects:
(1) a direct role: mainly act on 1 receptors, beta
receptors weak.
indirect role: promoting the release of NA.

Clinical uses:
1) replace NA for shock in the early
2) Hypotension or shock induced by
operation or spinal anesthesia

1receptor agonist
Phenylephrine

1) shock, or anesthesia-induced hypotension


2) paroxysmal supraventricular tachycardia
3) Examining the retina is facilitated by

mydriasis.
increase peripheral resistance and venous capacitance and rise the
BP. The rise in BP increases baroreceptor-mediated vagal tone with
slowing of the heart rate.

and agonist
Epinephrine
Dopamine
ephedrine

Epinephrine
adrenal medulla EP85% NA 15%
At low concentration, effects predominate ;
at high concentration, effects predominate.
-R are more sensitive to EP than the -R.

Pharmacological properties
Cardiovascular System

A. Heart
The heart are determined
largely by 1 receptors.
-receptor activation increase
calcium influx in cardiac cells.
Contractility is increased, heart rate is
accelerated.

B. Blood Vessels
Regulate vascular tone.
Alpha receptors increase arterial resistance,
B1recptors in kidney induce the release of renin,
2 receptors relax smooth muscle.
There are differences in receptor
types in the various vascular beds.

Blood Pressure

The effects of sympathomimetic drugs on BP is


based on their effects on the heart, the
peripheral vascular resistance, and the venous
return
Cummulative effect is
an increase in systolic BP,
a slight decrease diastolic BP

Epinephrine (E)
Vasoconstriction in
systemic arteries ()

The overall response


At low concentrations, epinephrine decreases
Vasodilation
in skeletal
BP.
muscle
arteries
(
2);
At high concentrations, epinephrine increases BP
because vasoconstriction of -receptors offsets
the 2-receptor mediated vasodilation.

Respiratory Tract
Bronchial smooth muscle contains 2
receptors that cause bronchodilation.
The blood vessels of the respiratory tract
mucosa contains receptors;
The decongestant action of adrenoceptor
stimulants is clinically useful.
Blocks the release of histamine (2 in mast
cell of bronchial tract)
snuffle

Metabolic effects
increase in glucoses and lactate production via
glycogenolysis (-R)
inhibition of insulin secretion (-R)
increase in free fatty acid and oxygen
consumption .

Therapeutic uses
1 cardiac arrest

cardiac arrest due to electric shock, severe electrolyte


imbalance, drug allergies, drug toxicity, acute asthma,
drowning, anesthesia accidents, infectious diseases

2) Anaphylactic shock
death in minutes if left untreated.

will usually lead to

Adrenaline is a first choice drug for treatment of


anaphylactic shock. Why?

Characteristics:

dilated small blood vessels, increased peripheral


resistance, increased capillary permeability, and decreased
blood pressure.
bronchial smooth muscle spasm, mucosal edema,
laryngeal edema, difficulty in breathing
Cardiac function depression

Effect of Adrenaline

Constrict blood vessels, increase blood pressure ;

Stimulate heart, dilate coronary artery, improve heart


function

Dilate bronchial, constrict bronchial mucosa, reduce


bronchial mucosal edema, relieve breathing difficulties;

Inhibit the release of allergic mediators (histamine),


improve breathing difficulties.

3) Bronchial asthma-Control acute bronchial asthma,


subcutaneous or intramuscular injection can work within minutes.

stimulate 2 receptor in bronchial smooth muscle, relax


bronchial smooth muscle.
stimulate 2 receptor in mast cell of bronchial mucosa
and submucosa, inhibit the release of allergic mediators
(histamine and other substances )
constrict bronchial mucosal vascular ( receptor ), reduce
asthma mucosal edema and capillary permeability.

Palpitations, irritability
Headache, elevated BP

Side effects

Cerebral hemorrhage
Ventricular fibrillation
Arrhythmia

contradiction

hypertension,
diabetic mellius
Cerebral arteriosclerosis

Dopamine
Be metabolized by MAO and COMT
quickly
No effect on CNS
activate 1 and dopa-receptor

Pharmacological properties
heart: act on 1 receptor, positive
inotropic effect on the myocardium,
increase cardiac output
blood vessels
At low or intermediate concentration: act on
D1 receptor, dilate
At high concentration : act on -receptor,
constrict

Pharmacological Effects
Kidney
At low or intermediate concentration: reduce
arterial resistance in the mesentery and kidney
At high concentration: cause vasoconstriction
with consequent reduction in renal function

The effect on renal blood flow is of clinical


value.

Clinical uses
Shock
Acute renal failure

Adverse reaction
Arrhythmia
Reduction in renal function

Ephedrine
Ephedrine occurs in plants and has been used in
China for over 2000 years.
Ephedrine can activate both and receptors
Because ephedrine is a noncatechol, it has high
bioavailability and a long duration of action
hours rather than minutes.

Clinical Uses
bronchial asthma
nasal decongestant
hypotension without crisis
Adverse reactions: CNS

-receptor agonist-isoproterenol
A very potent -receptor
agonist.
It activates 1 and causes
positive chronotropic and
inotropic actions; leading to a
marked increase in cardiac
output and an increase in
It
activates
systolic
BP.2, results in vasodilation, which associate
with a fall in diastolic and mean arterial pressure.

Cardiac Applications
Isoproterenol and epinephrine have been
utilized in the management of complete heart
block and cardiac arrest.

Heart failure may respond to the positive


inotropic effects of drugs such as dobutamine.

Pulmonary Applications
The most important use is in the therapy of
bronchial asthma.
Nonselective drugs, agents, and 2-selective
agents are all available for this indication.
2-selective drugs have less adverse effects.

ANS - Adrenergic Drugs


Responses to Stimulation
Location
Cardiovascular:
Blood vessels
Cardiac muscle
AV Node
SA Node
Gastrointestinal:
Muscle:
Sphincters:

Receptor

Response

1
2
1

Constriction
Dilation
Increased contractility

1
heart rate
1
heart rate

Increased

2
1

Decreased motility
Constriction

Increased

ANS - Adrenergic Drugs


Responses to Stimulation
Location

Receptor

Response

Genitourinary:
Bladder sphincter

Constriction

Penis

Ejaculation

Uterus

1
2

Contraction
Relaxation

Respiratory:
Bronchial muscles

Dilation

Liver

Glycogenolysis

Pupils

Dilation

Adrenoceptor Antagonist Drugs


Jiang Junlin

Department of Pharmacology,
School of Pharmaceutical Science, Central South University

50

Drugs blocking adrenoceptors are classified


according to the drugs selectivity for and
receptors.
Their major effect is to occupy either , or
receptors and prevent their activation by
catecholamines and
related agonists.

51

BASIC PHARMACOLOGY OF THE RECEPTOR ANTAGONIST DRUGS


Cardiovascular Effects
- antagonist drugs block receptors, dilate vascular
smooth muscle, lower peripheral resistance and BP; reflex
tachycardia.
Epinephrine reversal
The fall in blood pressure produced by
epinephrine following the
administration of alpha-blockers.
( due to cancel alpha1 role, retain beta2 role)
Reversal of epinephrine is a phenomenon that is
usually seen in people who are being treated for high blood pressure. Administration52of
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Alpha 1-receptor blockade of


base of the bladder and the
prostate is associated with
decreased resistance to the
flow of urine.

Benign Prostatic Hyperplasia


(BPH)
53

Minor effects in other tissues


miosis and nasal stuffiness.

The radial muscle is


innervated by alpha
receptor. Its blockade
by antagonists results
in miosis.

The smooth muscles of the iris

stuffiness

receptor antagonists-phentolamine
a potent competitive antagonist at both 1 and 2
receptors.
Pharmacological properties
1.Vessel-reduces peripheral resistance by blockade of .
2. heart-stimulate the heart due to baroreflex
mechanisms; stimulate the heart by exciting receptors ;
block 2 receptors, enhance release of NE from
sympathetic nerves
3. multiple potential actions: inhibit responses to
serotonin (5-HT) ; activate M and histamine (H)
receptors.
55

Therapeutic effects
1. Pheochromocytoma
phentolamine is most useful in the
pre-operative management of
pheochromocytoma. it can control
hypertension and reverse cardiac
effects of excessive catecholamines.

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2. Peripheral Vascular Spasm Diseases

3. Local Vasoconstrictor Excess


Phentolamine has been used to
reverse the vasoconstriction caused
by infiltration of NE
into subcutis during intravenous administration.
57

Adverse effects:
The principal adverse effects are cardiac
stimulation, such as tachycardia, postural
hypotension, arrhythmias, myocardial ischemia
and nasal congestion as well as headache.

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1-selective antagonist drugs

Prazosin is highly selective for 1 receptors, leads to


vasodilation.
It is effective in the management of hypertension.

Terazosin is another reversible 1-selective antagonist


that is effective in hypertension.
First-dose effect-orthostatic hypotensive response, fainting
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Chronic Hypertension
Prazosin family of 1-selective antagonists are
efficacious in the treatment of hypertension.
However, their efficacy in preventing heart failure
for hypertension has been questioned.
The adverse effect is postural hypotension,
which may be severe after the first dose.
Nonselective antagonists are not used in
primary hypertension.
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Urinary Obstruction

Prazosin can improve urine


flow in BPH.
The mechanism involves
reversal of smooth muscle
contraction in the enlarged
prostate and in the bladder
base.
Prazosin is efficacious,
particularly in patients with
hypertension.
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III. Basic Pharmacology of the Beta-ReceptorAntagonist Drugs


Beta-blocking drugs occupy receptors and reduce
receptor occupy by catecholamines and other agonists.
major difference among the -receptor-blocking drugs is
their relative affinities for 1 and 2 receptors.
Some of these antagonists have a higher affinity for 1
than for 2 receptors
The selectivity is dose-related, and it tends to diminish at
higher concentrations.
Other major differences among antagonists relate to
their pharmacokinetics.

62

Pharmacodynamics of the antagonist Drugs


1) Effects on the Cardiovascular System
Beta-adrenoceptor-blocking drugs are of major clinical
importance in the treatment of hypertension.
The mechanisms include
effects on the heart and
.
blood
vessels, the
rennin-angiotensin
system, and the CNS
Conventional doses do not cause hypotension in healthy
individuals with normal BP.

Vascular System
Blocking 1-mediated contraction of heart
cardiac output
Blocking 1-mediated release of rennin
Blocking2-mediated vasodilation

decreased

dilating vessel

contracting vessel

Heart
Decreased cardiac output due to negative inotropic
and chronotropic effects.
Cardiac output, work, oxygen consumption are
decreased, which is useful in treating angina.
Attenuating superventricular cardiac arrhythmias, no
useful in ventricular arrhythmias

2)Effects on the Respiratory Tract


Blockade of the 2 receptors in
bronchus increases airway
resistance, particularly in asthma.
1 antagonists have advantage over nonselective
antagonists when blockade of 1 in the heart is
desired and 2 blockade is undesirable .
However, no available 1-selective antagonist is
sufficiently specific to completely avoid interactions
with 2 adrenoceptors.
They should be avoided in patients with asthma.

3) Effects on the Eye


Several -blocking agents reduce intraocular
pressure, especially in glaucomatous eyes.

The mechanism usually


is due to a decrease in
cAMP levels, which
results in a reduction of
aqueous humor
production

4) Metabolic and Endocrine Effects


Beta-receptor antagonists such as propranolol
inhibit lipolysis.
The chronic use of -adrenoceptor antagonists has
been associated with increased plasma VLDL and
decreased concentrations of HDL cholesterol.
Beta-receptor antagonists lead to decreased
glycogenolysis, and they should be used with
caution in insulin-dependent diabetic patients.

Clinical Application
Hypertension
The -adrenoceptor-blocking
drugs are effective and well
tolerated in hypertension.
The drug is often used with either a diuretic
or a vasodilator.

Ischemic Heart Disease


Beta-adrenoceptor blockers
reduce the frequency of anginal
episodes and improve exercise
tolerance in patients with angina.
These actions relate to the blockade of cardiac
receptors, resulting in decreased cardiac work and
reduction in oxygen demand. Slowing of the heart rate
may contribute to clinical benefits.

Cardiac Arrhythmias
Beta antagonists are effective in
supraventricular arrhythmias by
increasing the atrioventricular nodal
refractory period.

Glaucoma
-blocking drugs can reduce production
of aqueous humor and decrease
intraocular pressure in glaucoma.

Timolol, Betaxolol, carteolol, levobunolol and metipranolol


are used for treatment of glaucoma.

Hyperthyroidism
Excessive catecholamine action is an
important aspect of hyperthyroidism.
The antagonists have salutary effects
in this condition.
These beneficial effects is to inhibition of peripheral
conversion of thyroxine to triiodothyronine.
Propranolol has been used extensively in patients
with thyroid storm.

Neurologic Diseases
Propranolol reduce the frequency
and intensity of migraine headache.
Other -receptor antagonists with preventive
efficacy include metoprolol and probably
also atenolol, timolol, and nadolol.
The mechanism is not known.

Propranolol
Propranolol is the standard against.
It is a safe and effective drug for many
indications

(1924 )

1964

1988 Nobel Prize


Sir James W. Black
The Nobel Prize in Physiology
or Medicine 1988

CLINICAL TOXICITY OF THE BETARECEPTOR ANTAGONIST DRUGS


A variety of minor toxic effects have been reported.
Beta-receptor blockade depresses myocardial
contractility and excitability.
Caution must be exercised in using -receptor
antagonists in compensated heart failure.

Beta-blockers may interact with the calcium


antagonist (hypotension, bradycardia, heart failure,
conduction abnormalities have all been described).
These adverse effects may even arise in susceptible
patients taking a topical (ophthalmic) -blocker
and oral verapamil.
Patients with ischemic heart disease may be at
increased risk if -blockade is suddenly
interrupted, which might involve up-regulation of
the -receptors.

Thanks a lots

Key points of efferent nervous


drugs
1.
2.
3.
4.
5.
6.
7.

Pharmacodynamics and therapeutic application of


atropine
The toxicology and treatment of organophosphorate
cholinesterase inhibitor
Drugs on eye effects (M-R agonist, M-R antagonist and
anticholinesterase inhibitor)
Cycloplegia or spasm of accomodation
Therapeutic applications of beta receptor blocker
Adrenaline reversal
Adrenaline is a first choice drug for treatment of
anaphylactic shock. Why?

Practice Questions
Which of the following drugs does
stimulate mainly b receptors
NE
EP
Isoproterenol
Dopamine

80

Which of the following drugs, when


administrated intravenously, can decrease
blood flow to the skin, increase blood flow
to skeletal muscle, an increase the force and
rate of cardiac contraction?
NE
EP
Phenylephrine
Isoproterenol

81

Which of the following catecolamines may


cause reflex bradycardia due to stimulation
of a1 receptors?
NE
EP
Dopamine
Isoproterenol

82

What is the treatment of choice for


anaphylactic shock
NE
EP
Isoproterenol
Dobutamine

83