3. 3
Synthesis, action and fate of
norepinephrine
Tyrosine is transported into the
axoplasm (A) and is converted to
DOPA and then to dopamine (DA).
DA is transported into the vesicles of
the varicosity, where the synthesis and
the storage of norepinephrine (NE)
take place (C).
An action potential causes an influx of
Ca2+ into the nerve terminal (not
shown) with subsequent exocytosis of
NE (D).
The NE activates - and -
adrenergic receptors in the
membrane of the postsynaptic cell (E).
NE that penetrates into these cells
(uptake 2) probably is rapidly
inactivated by catechol-O-
methyltransferase (COMT) to
normetanephrine (NMN). The most
important mechanism for termination
of the action of NE in the junctional
space is active reuptake (80%) into
the nerve (uptake 1) and the storage
vesicles (F).
8. 8
Characteristics of adrenoreceptors
# Tissue and organ Receptor Effect
1 Skin, kidney vessels 1,2, constrict
2 Vessels of skeletal muscles,
liver, and coronary vessels
2 dilation
3 Veins 1А constriction
4 Heart 1 increase of rate
and force of
contraction
5 Bronchi 1
2
constriction
dilation
6 Iris (radial musscle) 1 contract
midriasis
7 GI
- smooth musscle
- sphincters
1,2,2
1
relaxation
contraction
9. 9
# Tissue and organ Receptor Effect
8 Uterus
- myometrium
- sphincters
2
1
relaxation
contraction
9 Bladder sphincter 1А contraction
10 Juxtaglomerular cells of the
kidney
1 2 increase of rennin
secretion
11 Splin capsule 1 contract
12 Pancreatic islets 2 decrease of insulin
secretion
13 Platelets 2 aggregation
14 Liver 1, 2 glycogenolysis
15 Fat 3 lipolysis
Characteristics of adrenoreceptors
10. Effect of adrenoreceptors stimulation
The stimulation of certain postsynaptic
adrenoreceptors is associated with effects
that are typical for their activation
The stimulation of -adrenorecetrors leads to
an increase of the effectors function (except
for the intestine)
The stimulation of -adrenorecetrors usually
leads to a decrease in the innervated organ
function (except for the heart)
13. 13
Pharmacologic action of epinephrine
1
2
vessels
1
vagus
1. is due to 1 AR activation
(cause ventricular contraction)
2. is due to vagal discharge
3. is due to 1 AR stimulation
(cause vasoconstriction)
4. is due to 2 (vasodilator)-
receptors activation
Effects on the heart produced by epinephrine include:
Slight initial increase in heart rate (1-receptors)
Increased stroke volume
Increased cardiac output
A propensity toward arrhythmias
Effects on smooth muscle include:
Bronchiolar smooth muscle relaxes (2).
Gastrointestinal smooth muscle relaxes (2- and -receptor stimulation)
Sphincter contraction (- stimulation),
Metabolic effects of epinephrine include:
Hyperglycemia via liver and muscle glycogenolysis
Inhibition of insulin secretion (1)
An increase in free fatty acids
14. 14
Clinical application of epinephrine
It’s used only parenterally (S.C., I.M., rarely I.V.) and local
I.V. effect lasts for 5` whereas S.C. – up to 30`
Clinical usage
severe bronchospasm, anaphylaxis (primary treatment for
anaphylactic shock)
severe hypotension
cardiogenic shock
AV block and cardiac arrest
nasal decongestant
ophthalmic vasoconstrictor and mydriatic
chronic open-angle glaucoma
to prolong the duration of anesthesia in conjunction with local
anesthetic
Unwanted effects
anxiety, headache
can precipitate angina, myocardial infarction ( cardiac work)
arrhythmias
15. 15
Clinical application of
norepinephrine
Clinical usage
severe hypotension
septic shock
Unwanted effects
can precipitate angina, myocardial infarction ( cardiac
work)
arrhythmias
If extravasates, can cause tissue necrosis
16. 16
Clinical application of sympathomimetics
Ephedrine is used:
In the treatment of bronchial asthma
As a nasal decongestant
As a pressor agent in spinal anesthesia
As a mydriatic
Adverse effects
These are similar to the adverse effects seen with
epinephrine.
In addition, CNS effects may occur.
17. 17
1-stimulating drugs
Phenylephrine (mesatone) (1)
severe hypotension
nasal decongestant
to prolong the duration of anesthesia in conjunction with
local anesthetic
open-angle glaucoma
Naphazoline (naphtizine), xylometazoline (2)
nasal decongestant
oral cavity surgery
18. 18
1-stimulating bronchodilators
Dobutamine is used
to improve myocardial function in congestive heart
failure (it causes minimal changes in heart rate and
systolic pressure).
Adverse effects
Dobutamine increases atrioventricular conduction and
must, therefore, be used with caution in atrial fibrillation.
Other adverse effects are similar to those of other
catecholamines.
19. 19
2-stimulating bronchodilators
such as salbutamol, terbutaline, fenoterol, salmeterol,
albuterol
are used therapeutically for the treatment of bronchial
asthma or bronchospasm
they are chiefly used as aerosol inhalants
20. 20
Clinical application of antiadrenergic
agents
-ADRENOBLOCKERS
Phentolamine (1, 2)
has been used to control acute hypertensive episodes
caused by use of sympathomimetics.
Tolazoline (1, 2)
can be used in the treatment of neonates with persistent
pulmonary hypertension, despite use of oxygen therapy
and mechanical ventilation.
has been used experimentally to relieve vasospasm and
in the treatment of Raynaud's phenomenon.
25. 25
Clinical application of antiadrenergic
agents
Drugs affecting NE synthesis and release
Reserpine (a rauwolfia alkaloid)
It acts via catecholamine depletion. It inhibits the uptake
of norepinephrine into vesicles, and intraneuronal
degradation of norepinephrine by MAO then occurs. This
action takes place both centrally and peripherally.
Therapeutic use of reserpine is in:
the treatment of hypertension
Adverse effects include:
Sedation
Psychic depression that may result in suicide
Abdominal cramps and diarrhea
Gastrointestinal ulceration
Possible increased incidence of breast carcinoma
26. 26
Clinical application of antiadrenergic
agents
Guanethidine (Octadine)
acts presynaptically. It inhibits the release of NE from
peripheral adrenergic neurons.
It displaces norepinephrine from intraneuronal storage
granules.
Much of the norepinephrine released from the adrenergic
nerve terminals is deaminated by intraneuronal MAO.
Therapeutic use
as a potent, long-acting antihypertensive agent
Adverse effects include:
Postural hypotension
Syncope, especially with strenuous exercise
Diarrhea
Edema
Guanethidine is contraindicated in patients taking
MAO inhibitors.
27. NEXT LECTURE
The CNS affecting drugs:
Introduction, targets for drug’s action.
Antiepileptics. Drugs for treatment of
Parkinson’s disease.
27
