Adrenergic drugs
Adrenergic drugs
Adrenergic transmission:
catecholamines (norepinephrine,
epinephrine, dopamine) are the
neurotransmitters
terminating action is by membrane
reuptake of the transmitter or metabolism
by catechol-O-methyltransferase (COMT)
and monoamine oxidase (MOA) in some
tissues.
vasoconstriction
uterine contractions
platelet aggregation
mydriasis
contraction of the urethral
sphincter
Stimulation of
postsynaptic alpha-1
receptors results in
Alpha-2 receptors:
are mainly presynaptic
stimulation results in a decrease of
noradrenaline release
there are postsynaptic alpha-2
receptors whose stimulation
induces platelet aggregation.
Alpha-2 receptors:
central alpha-2 adrenergic receptor
stimulation results in sedation,
analgesia, decreased sympathetic
outflow, tranquilization
indirectly affects cardiac function
by decreased sympathetic tone
Beta-1 receptors
postsynaptic localized in the heart
stimulation results in a positive
inotropic effect (increase the strength of
contractions)
positive chronotropic effect (rate)
positive dromotropic effect (conduction)
positive bathmotropic effect (increase of
excitability)
Beta-2 receptors
their stimulation induces:
vasodilation
bronchodilatation
uterus relaxation
cardiac stimulation (20% of beta-2 receptors)
the stimulation of beta-2 receptors increases
potassium uptake by muscles and lead to a
decrease of its plasma concentration.
beta-3 receptors in
adipocytes
present in adipocytes act by activation
adenylcyclase
lipolysis and stimulation of
mitochondrial respiration with
dissipation of heat
certain obese patients could have a
deficiency of beta- 3 lipolytic activity
the use of bêta-3 agonists in the
treatment of obesity is considered
Dopaminergic effects
Peripheral effects
In low doses dopamine has specific
peripheral effects:
renal, mesenteric, coronary and cerebral
vasodilation (by effect on D1 receptors) with
lowering of arterial pressure
decrease of tubular reabsorption of Na+ (D2)
decrease of aldosterone and renin release
inhibition of gastroduodenal motility, nausea
and vomiting by blood-brain barrier.
Dopaminergic effects
during iv. administration of high
dose of dopamine, stimulation of the
adrenergic alpha and beta receptors
occour (release of endogenous
noradrenaline)
Drugs
Agonists: mimic the effects of a transmitter
at receptors, due to structural similarities
sympathomimetic
Antagonists: bind the receptor but do not
activate it, preventing the transmission of
any signal via the receptor sympatholytics
Catecholamines
noradrenaline (norepinephrine)
adrenaline (epinephrine)
dopamine
endogenous transmitters
Mixed alpha and beta
adrenergic agonists
Agonists like norepinephrine and
epinephrine stimulate both alpha and beta
receptors.
norepinephrine stimulates alpha-1, alpha-
2 and (beta-1) adrenergic receptors
epinephrine - stimulates alpha-1, beta-1
and beta-2 adrenergic receptors
Epinephrine (adrenaline)
Cardiovascular effects
accelerates and reinforces cardiac
contractions and cardiac output
vascular effects: adrenaline has both
alpha-1 (vasoconstriction) more potent
and beta-2 (vasodilation) effects
Inversion of effect after administration of
an alpha-1 adrenolytic drug
Epinephrine (adrenaline)
Other effects:
Adrenaline has bronchodilator, mydriatic
effets and inhibits peristaltic activity of the
digestive tract
it has metabolic effects: increase of plasma
glucose, free fatty acids and glycerol
reduces the production of aqueous humor
and increases its elimination.
it raises the temperature and increases
oxygen uptake
Epinephrine (adrenaline)
Use
adrenaline is used, in injectable
formulation in the treatment of
-anaphylactic shocks
-andcardiac arrest
it is very often combined with local
anesthetics to reduce their
diffusion from their injection site
reduces the production of aqueous
humor and in addition it increases
its elimination
it can be used in the treatment of
asthma attack
Norepinephrine
(Noradrenaline)
norepinephrine (administered in
perfusion) increase systolic and
diastolic arterial pressure proportional
to the dose
it induces a decrease of blood flow rate
in the majority of organs: kidney, liver,
brain
Norepinephrine
(Noradrenaline)
On intestine: decrease of tone,
suppression of peristaltic contractions.
Mydriatic action on the eye.
Uterotonic action (alpha-1): contraction.
Metabolic effects less than those of
adrenaline and isoprenaline:
These effects are not useful in therapeutics
because of its potent hypertensive action
Norepinephrine
(Noradrenaline)
Use
Norepinephrine is used ( intravenous
perfusion) in the treatment of
collapse
severe hypotension with peripheral
vasodilation and normal blood
volume (refractory vasodilation)
Norepinephrine
(Noradrenaline)
Side effects:
hypertension
vasoconstriction which reduces
organs blood flow
necrosis in the site of
administration
Dopamine
Use
acute heart failure as occurs in cardiogenic
shock and myocardial infarction
low cardiac output syndrome
It is administered by intravenous perfusion
under monitoring of various parameters:
arterial pressure, heart rate…
adverse effects are observed especially in
case of overdose: nausea, vomiting, rise in
blood pressure, heart rate disorders
Mixed beta-1 and beta-2
adrenergic agonists
Isoprenaline (isoproterenol), orciprenaline (metaproterenol)
The effect on smooth muscles consists of bronchodilatation,
inhibition of uterine contractions and vasodilation (beta-2)
On the heart, positive inotropic, chronotropic, bathmotropic
and dromotropic effects and increases cardiac output.
Its effect on blood pressure results in ↑systolic and
↓diastolic bp
It raises glycemia and plasma free fatty acids levels
Mixed beta-1 and beta-2
adrenergic agonists
Only therapeutic indications for
Isoprenaline, orciprenaline are
cardiovascular:
Bradycardia
Stokes-Adams syndrome
(atrioventricular block)
Shocks
Alpha-1 agonists with
central effects
Stimulation of alpha-1adrenergic receptors
of the central nervous system has a
psychostimulant effect, increases vigilance,
decreases the requirement of sleep.
Modafinil
Modafinil potent CNS stimulant. It is used
in the treatment of idiopathic hypersomnia
and narcolepsy.
adverse effects are: nervousness, anxiety,
anorexia, tremor, headache…
Alpha-1 agonists with
peripheral effects
Ergot derivatives:
Dihydroergotamine has an alpha-1-
mimetic effect particulary on veins
It has also serotonergic effects
It is used in preventive and curative
treatment of migraine and is proposed in
the treatment of postural hypotension
Methylergometrine is used to induce
uterine contractions after postpartum
it has also a vasoconstrictive effect.
Alpha-1 agonists with
peripheral effects
Nasal congestion treatment (local use)
phenylephrine, naphazoline and tymazoline
by vasoconstriction relieve congestion of
mucous membranes and increase air routes
they give only a momentary improvement
Phenylephrine in the form of ophthalmic solution
is used as a mydriatic for optic examination and
during someocular surgical operations.
Beta-1 adrenergic agonists
Dobutamine causes cardiac stimulation,
positive inotropic and chronotropic
effects with increase in cardiac output.
is used in management of congestive
heart failure, shock with low cardiac
output
it increases also cardiac excitability and
can cause rhythm disorders
contraindications for its employment are
mechanical obstacles to blood circulation
Beta-2 adrenergic agonists
The two main pharmacological
properties of beta-2 stimulants,
used in therapeutics are their:
bronchodilator effect
uterine relaxant effect
Beta-2 stimulants in the
treatment of asthma
salbutamol, terbutaline, pirbuterol
and fenoterol - curative and preventive
in the treatment of asthma attacks
Salmeterol, formoterol and
bambuterol are prescribed in
prevention of attacks because they have
a sustained effect, not fast enough nor
intense for acute state
preferably given by bronchial route
Beta-2 stimulants in the
treatment of preterm delivery
Salbutamol, terbutaline and
ritodrine
are used to prevent premature
labour.
Beta-2 stimulants adverse
effects:
tachycardia secondary to peripheral
vasodilation and cardiac stimulation,
tremor, sweating, agitation.
more severe effects, pulmonary edema,
myocardial ischemia, cardiac arrythmia
asthma aggravation (hyperreactivity)
loss of the bronchodilator activity of beta-
2-mimetic (both attenuated by
glucocorticoid intake)
With high doses, certain beta-2-
agonists showed muscular anabolic
properties.
Clenbuterol, used by athletes to
induce muscular development
Its principal adverse effects are
tremors and tachycardia.
Dopaminergic agonists
Dopamine
The effects depend on the administered dose:
In low doses, it stimulates specific dopaminergic
receptors and induces renal, mesenteric and coronary
vasodilation and an increase in diuresis and natriuresis.
In moderate doses, it stimulates beta receptors
resulting in a positive inotropic effect and a vasodilation
In large doses, it can stimulate alpha- adrenergic
receptors inducing a vasoconstriction and cause a
release of norepinephrine.
Dopaminergic agonists
with central effects
Dopaminergic agonists which cross the
blood-brain barrier have central effects
of neurological and endocrine types
They are used in the treatment of
Parkinson's disease and
hyperprolactinemia
These agonists are bromocriptine,
lisuride, pergolide, ropinirol
Indirectly acting
sympathomimetic drugs
number of drugs act indirectly via
endogenous catecholamines by
increasing their concentration in
synaptic clefts and are called
indirectly acting
Indirectly acting
sympathomimetic drugs
The increase of dopamine and
noradrenaline concentration can be
obtained by different mechanisms
Increase of synthesis.
Increase of release.
Decrease of reuptake.
Decrease of catabolism.
Indirectly acting
sympathomimetic drugs
Drugs with indirect sympathomimetic
activity are used as
vasoconstrictors
CNS stimulants and anorexiants
antidepressants
antiparkinsonians
Indirectly acting
sympathomimetic drugs
Amphetamine
Amphetamine increases release and inhibits
reuptake of dopamine and noradrenaline,
perhaps also of serotonin.
In moderate and high doses, amphetamine
stimulates vigilance, decreases sleep
requirement and fatigue, reduces appetite
(appetite suppressant effect).
it was withdrawn from the market because
of its cardiovascular, neuropsychiatric
adverse effects and especially because of the
risk of addiction.
Amphetamine and derivatives such as
methamphetamine (“ice”), methylene
dioxymethamphetamine (MDMA or
“ecstasy”), are used by abusers
can induce true psychotic states with
absence of sleep and loss of weight
Indirectly acting
sympathomimetic drugs
Sibutramine
an inhibitor of the reuptake of monoamines,
noradrenaline, serotonin and dopamine. It
was not active as an antidepressant but is
active as an
facilitating the loss of weight
The most frequent adverse effects of
sibutramine are insomnia, constipation,
mouth dryness, headache, tachycardia,
palpitations, hypertension
Indirectly acting
sympathomimetic drugs
Cocaine
Cocaine inhibits the reuptake of catecholamines, dopamine and
noradrenaline. It has moreover a local anesthetic effect but is
not used in therapeutics. Cocaine is a substance of abuse. It is
taken by oral, nasal, pulmonary and intravenous routes. Cocaine
base, called crack when smoked, is as active and toxic as
intravenous preparations. Intensity of psychic effects depends on
the rate at which its cerebral concentration increases. In fast
administration, it induces an intense state of euphoria of short
duration followed by a dysphoric state which pushes to repeat
intakes several times per day. Its action resembles that of
amphetamine but is of much shorter duration, half an hour
instead of approximately ten hours.
Immediate toxic effects of cocaine are tachycardia, ventricular
arrhythmia, chest pain, myocardial infarction, arterial
hypertension, hyperthermia and seizures.
Addiction to cocaine is very strong in human beings and in
animal experiments