Drugs affecting adrenergic synapses

1. Drugs affecting adrenergic synapses

Adrenomimetics
lecture of associate professor of
pharmacology
Goldobina Galina

2.

3.

In the adrenergic synapses the transmission is
mediated by noradrenaline or norepinephrine
(NE). The biosynthesis of NE from tyrosine
occurs in the adrenergic neurons (varicosities).
Formation of DOPA and dopamine takes place in
the cytoplasm of neurons. Dopamine is converted
to norepinephrine under the influence of
dopamine hydroxylase in the vesicles.
Norepinephrine in the adrenal medulla turns into
adrenaline
under
the
influence
of
methyltransferase

4.

• Noradrenaline (NE), dopamine and
adrenaline are called catecholamines.
• In presynaptic endings noradrenaline is in a
free state (mobile pool) and in vesicles.
• Inactivation of NE via monoamine oxidase
(MAO) may regulate prejunctional levels
of transmitter in the mobile pool.
• Nerve impulses induce the release of NE
into the synaptic gap. And NE interacts
with its receptors.

5.

6.

• The action of NE on receptors is shortterm. It is mainly caused by the swift
uptake (70-80%) by the terminals of the
anrenergic fibres. Small amounts of NE
undergo extraneuronal uptake by the
effector cells (smooth muscles).
• Catabolism of NE is controlled by MAO
and catechol O-methyltransferase.
• Adrenoreceptors are divided into α- and
β-subtypes.

7.

• The main α-adrenoreceptors include α1 and
α2R.
• Adrenoreceptors α1 have postsynaptic
localization
and
α2R
are
located
presynaptically and beyond the synapses.
• The main role of the presynaptic α2R is their
involvement in the system of negative
feedback, controlling the release of NE.
• Stimulation of these receptors by NE or
other drugs inhibits release of NE from the
varicosities.

8.

• Among β-R there are also post-, pre-, and
extrasynaptic receptors.
• Presynaptic β2-R perform positive reverse
feedback, stimulating NE release. So, it
can be confirmed that β-agonists facilitate
the release of the NE and β-antagonists
inhibit it.

9.

10.

The main effects associated with the stimulation of
post-and extrasynaptic adrenoreceptors
α1 - adrenoreceptors:
Constriction of vessels of the skin, kidneys,
intestines;
Contraction of the radial muscle of iris (mydriasis);
Contraction of myometrium;
Contraction of sphincters of the gastrointestinal
tract;
Contraction in the capsule of the spleen;
Decrease of motility and tone of the intestine.

11.

α2 –adrenoceptor (extrasynaptic):
Vasoconstriction;
Increased platelet aggregation;
Decrease in insulin secretion.

12.

β1 - receptors:
Heart
↑ HR – heart rate (positive chronotropy)
↑ Conduction velocity (positive
dromotropy)
↑ Force of contraction (positive
inotropy), cardiac output and oxygen
consumption
Kidneys ↑ Renin release

13.

β2 - receptors:
Dilation of vessels of the skeletal muscles,
liver, coronary;
Decrease in muscle tone of the bronchi;
Decrease in intestinal motility and tone;
Decrease in the tone of myometrium;
Activation of glycogenolysis and lipolysis;
Increase in insulin secretion.

14.

15.

Classification
Drugs of presynaptic action, affecting
release and storage of NE or
sympathomimetics or adrenomimetics
of indirect action: Ephedrine

16.

• α and β adrenomimetics: Epinephrine,
Norepinephrine;
• α1: Phenylephrine;
• α2: Naphazoline, Xylometazoline,
Oxymetazoline;
• β1, 2: Isoprenaline;
• β1: Dobutamine;
• Β2: Salbutamol, Salmeterol, Fenoterol,
Berodual (ipratropium bromide +fenoterol).

17.

• Epinephrine stimulates all types of AR.
• It increases the force and rate of cardiac
contractions, increases the stroke and minute
volume of the heart, systolic blood pressure.
The consumption of oxygen by myocardium
is increased also. Hypertensive reaction
usually induces reflex bradycardia from the
mechanoreceptors of the blood vessels.
• E. increases peripheral resistance of the
blood vessels because it stimulates α AR,
but dilates vessels via stimulation βAR.

18.

• Mean
arterial
pressure increases.

19.

• E. relaxes smooth muscles of bronchi,
eliminates bronchospasm. E. reduces the
secretion of the bronchial glands, reduces the
release of inflammatory mediators
(histamine) from mast cells.
• E. reduces the tone and motility of
gastrointestinal tract, but increases the tone
of sphincters.
• E. induces the contraction of the splenic
capsule.
• E. increases neuromuscular transmission.

20.

E. stimulates
• glycogenolysis
(hyperglycemia
occurs, blood
concentration of lactic
acid and potassium
increases) and
• lipolysis
(concentration of free
fatty acids increases).

21.

Local effects:
• E. dilates the pupils (mydriasis) due to the
contraction of the radial muscles of the iris
and decreases intraocular pressure
(production of the intraocular fluid is
decreased).
• Epinephrine causes spasm of blood vessels
of the skin and mucous membranes,
reduces exudation and inflammation.

22.

Duration of action: intravenously - 5-10 min.,
subcutaneous injections - up to 30 minutes.
Indications for use:
to prolong the effect and reduce the
toxicity of local anesthetics;
anaphylactic shock, allergic laryngeal
edema;
relief of bronchospasm;
insulin overdose, hypoglycemia;
cardiac arrest, acute heart failure,
hypotension.

23.

Side effects: headache, fear,
anxiety,
tremor,
vomiting,
tachycardia, extrasystoles.

24.

• Norepinephrine stimulates predominantly αadrenergic receptors and to a small extent β-AR.
• It causes severe vasospasm and increases blood
pressure (5-10 times stronger than epinephrine).
Norepinephrine increases force of heart
contractions, stroke volume of the heart, causes a
reflex bradycardia (activation of the vagus
nerve).
• Norepinephrine is administered intravenously
with vascular collapse during surgery,
intoxication, injuries.

25.

26.

• Norepinephrine can not be administered
subcutaneously due to the possibility of
necrosis.
• It is contraindicated in hemorrhagic and
cardiogenic shock because it causes
spasm of arterioles and increases the
load on the heart.
• Side effects: arrhythmias, headache,
breathing disorders.

27.

• Phenylephrine stimulates α1-AR but
acts weaker than norepinephrine.
• It increases arterial pressure and causes
reflex bradycardia. But it does not affect
the heart.
• It is more stable (duration of action
after intravenous administration – 20
min; after subcutaneous – 40-50 min). It
is effective after oral administration.

28.

Indications for the use:
relief and prevention of
shock and collapse,
to potentiate the action and
reduce the toxicity of local
anesthetics,
open-angle glaucoma,
conjunctivitis, rhinitis,
hemorrhoids (in
suppositories).

29.

• Naphazoline, Oxymetazoline and
Xylometazoline constrict the vessels of
the nasal mucosa, reduce inflammatory
response, exudation.
• They are used in rhinitis.
• Side effects: irritant effect, atrophy of
the nasal mucosa, tolerance.
• Naphazoline has an inhibitory effect on
the CNS.

30.

31.

• Isoprenaline stimulates all types of β-AR.
• It stimulates β1-AR of the heart and
increases the force and rate of cardiac
contractions; systolic pressure.
• Isoprenaline activates β2-AR of the
skeletal muscles vessels. This leads to a
decrease in diastolic pressure. The mean
arterial pressure is also decreased.

32.

33.

• The drug facilitates atrioventricular
conduction and increases heart
automatism.

34.

• I. decreases the tone of bronchi, muscles
of gastrointestinal tract; causes
hyperglycaemia.
• Indications for use: bronchial spasm,
atrioventricular block.
• Routes of administration: sublingual,
inhalation, intravenous, SC.
• Adverse affects: tachycardia, cardiac
arrhythmias, headache, tremor.

35.

• Salbutamol,
fenoterol,
salmeterol
stimulate B2-AR. They expand the
bronchi and are used for the prevention
and relief of bronchospasm.
• They cause relaxation of the uterus,
prevent premature labor. They are used in
threatened preterm labor.
• They cause hyperglycemia, vasodilation,
low blood pressure.

36.

Drug
Route of
Inhalation
administration onset of duration
action
Salbutamol By inhalation,
4 min
4-6 h
orally, IV
Fenoterol
By inhalation,
4 min
5-6 h
orally, IV
Salmeterol
By inhalation
30 min
12 h
Formoterol
By inhalation
˃6 min
8-10 h

37.

• Dobutamine stimulates β1-AR.
• It moderately increases heart rate, stroke
and minute volume of the heart.
• It improves atrioventricular conduction,
increases
myocardial
oxygen
consumption.
• It is used intravenously drip in acute
heart failure.

38.

39.

Ephedrine
Violates the reverse neuronal uptake of NE;
Inhibits MAO; Facilitates and increases the
release of the mediator in the synaptic gap
Increases the effect of sympathetic nerves on
the organs

40.

• Effects: It stimulates heart function,
increases blood pressure, causes a
broncholytic effect, inhibits intestinal
peristalsis, dilates pupils.
• It acts longer and weaker than epinephrine.
• It is absorbed from the gastrointestinal tract
and penetrates through the BBB, resistant to
MAO action.
• Indication for the use: spasm of bronchi, to
increase arterial pressure, atrioventricular
block, rhinitis, narcolepsy.

41.

Side effects:
• tachyphylaxis with frequent use
(reduction in norepinephrine storage in
the varicosities),
• tachycardia, increased blood pressure,
hyperglycemia,
• mental dependence (causes euphoria),
excitation, insomnia, tremor, doping
effect.

42.

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