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

appetite suppressant

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