Adrenergic Agonists

Dr. M.S Fageyinbo

 Introduction
• The adrenergic drugs affect receptors that are stimulated
by norepinephrine or epinephrine.
• Some adrenergic drugs act directly on the adrenergic
receptor (adrenoceptor) by activating it and are said to be
sympathomimetic.
• Adrenergic neurons release norepinephrine as the primary
neurotransmitter.
• These neurons are found in the central nervous system (CNS)

and also in the sympathetic nervous system, where they serve

as links between ganglia and the effector organs.

• The adrenergic neurons and receptors, located either

presynaptically on the neuron or postsynaptically on the

effector organ, are the sites of action of the adrenergic drugs

 Sympathomimetic Drugs
• These drugs increase the activity of adrenergic system
and may be divided into directly acting, indirectly
acting and mixed action sympathomimetics.
• Directly acting drugs stimulates alpha and beta
receptors directly whereas indirectly acting drugs
increase the amount of Na+ in the synapse.
• Mixed action sympathomimetics possess both of these
actions.
 Neurotransmission at adrenergic neurons
• Neurotransmission in adrenergic neurons closely resembles that
already described for the cholinergic neurons except that
norepinephrine is the neurotransmitter instead of acetylcholine.
• Neurotransmission takes place at numerous bead-like enlargements
called varicosities.
• The process involves five steps:
 Synthesis, storage, release, and receptor binding of norepinephrine,
followed by removal of the neurotransmitter from the synaptic gap.
• Synthesis of norepinephrine:

 Tyrosine is transported by a Na+-linked carrier into the axoplasm of the

adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine

(DOPA) by tyrosine hydroxylase.

 This is the rate-limiting step in the formation of norepinephrine.

 DOPA is then decarboxylated by the enzyme dopa decarboxylase

(aromatic l-amino acid decarboxylase) to form dopamine in the

cytoplasm of the presynaptic neuron.

Storage of norepinephrine in vesicles:
 Dopamine is then trans-ported into synaptic vesicles by an amine

transporter system that is also involved in the reuptake of preformed

norepinephrine. This carrier system is blocked by reserpine

 Dopamine is hydroxylated to form norepinephrine by the enzyme,

dopamine ẞ-hydroxylase.

[Note: Synaptic vesicles contain dopamine or norepinephrine plus

adenosine triphosphate (ATP), and ẞ-hydroxylase, as well as other

cotransmitters.]
 In the adrenal medulla, norepinephrine is methylated to yield
epinephrine, both of which are stored in chromaffin cells.
 On stimulation, the adrenal medulla releases about 80
percent epinephrine and 20 percent norepinephrine directly
into the circulation.
Release of norepinephrine:
 An action potential arriving at the nerve junction triggers an
influx of calcium ions from the extracellular fluid into the
cytoplasm of the neuron.
 The increase in calcium causes vesicles inside the neuron to
fuse with the cell membrane and expel (exocytosis) their
contents into the synapse.
 This release is blocked by drugs such as guanethidine

Binding to a receptor:
 Norepinephrine released from the synaptic vesicles diffuses
across the synaptic space and binds to either postsynaptic
receptors on the effector organ or to presynaptic receptors on
the nerve ending.
 The recognition of norepinephrine by the membrane receptors
triggers a cascade of events within the cell
 resulting in the formation of intracellular second
messengers that act as links (transducers) in the
communication between the neurotransmitter and the action
generated within the effector cell.
 Adrenergic receptors use both the cyclic adenosine
monophosphate (cAMP) second-messenger system, and the
phosphatidylinositol cycle, to transduce the signal into an effect.
Removal of norepinephrine:
• Norepinephrine may:
 diffuse out of the synaptic space and enter the general
circulation;
 be metabolized to O-methylated derivatives by
postsynaptic cell membrane “associated catechol O-
methyltransferase (COMT) in the synaptic space,
 be recaptured by an uptake system that pumps the
norepinephrine back into the neuron.
• The uptake by the neuronal membrane involves a
sodium/potassium-activated ATPase that can be
inhibited by tricyclic antidepressants, such as
imipramine, or by cocaine.
• Uptake of norepinephrine into the presynaptic neuron is
the primary mechanism for termination of
norepinephrine's effects.
Potential fates of recaptured norepinephrine:
• Once norepinephrine re-enters the cytoplasm of the
adrenergic neuron, it may be taken up into adrenergic
vesicles via the amine transporter system and be
sequestered for release by another action potential, or it
may persist in a protected pool.
• Alternatively, norepinephrine can be oxidized by
monoamine oxidase (MAO) present in neuronal
mitochondria.
• The inactive products of norepinephrine
metabolism are excreted in the urine as
vanillylmandelic acid, metanephrine, and
normetanephrine.
 Catecholamines

• Sympathomimetic amines that contain the 3,4-

dihydroxybenzene group (such as epinephrine, norepinephrine,
isoproterenol, and dopamine) are called catecholamines. These
compounds share the following properties:

High potency:
• Drugs that are catechol derivatives (with OH groups in the 3
and 4 positions on the benzene ring) show the highest potency
in directly activating α or β receptors.
Rapid inactivation:
• Not only are the catecholamines metabolized by COMT
postsynaptically and by MAO intraneuronally, they are also
metabolized in other tissues.
• For example, COMT is in the gut wall, and MAO is in the
liver and gut wall.
• Thus, catecholamines have only a brief period of action
when given parenterally, and they are ineffective when
administered orally because of inactivation.
Poor penetration into the CNS:
• Catecholamines are polar and, therefore, do not readily
penetrate into the CNS. Nevertheless, most of these
drugs have some clinical effects (anxiety, tremor, and
headaches) that are attributable to action on the CNS.
 Non-catecholamines

• Compounds lacking the catechol hydroxyl groups have

longer half-lives, because they are not inactivated by
COMT.
• These include phenylephrine, ephedrine, and amphetamine.
• Phenylephrine, an analogue of epinephrine, has only a
single OH at position 3 on the benzene ring, whereas
ephedrine lacks hydroxyls on the ring but has a methyl
substitution at the α carbon.
• These are poor substrates for MAO and, thus, show a
prolonged duration of action, because MAO is an
important route of detoxification.
• Increased lipid solubility of many of the non-
catecholamines (due to lack of polar hydroxyl groups)
permits greater access to the CNS.

[Note: Ephedrine and amphetamine may act indirectly

by causing the release of stored catecholamines.]
 Mechanism of action of the adrenergic agonists

• Direct-acting agonists:

 These drugs act directly on α or β receptors, producing

effects similar to those that occur following stimulation
of sympathetic nerves or release of the hormone
epinephrine from the adrenal medulla.
 Examples of direct-acting agonists include:

 epinephrine, norepinephrine, isoproterenol, and

phenylephrine.
• Indirect-acting agonists:

 These agents, which include amphetamine, cocaine and tyramine,

may block the uptake of norepinephrine (uptake blockers) or are taken
up into the presynaptic neuron and cause the release of norepinephrine
from the cytoplasmic pools or vesicles of the adrenergic neuron.

 As with neuronal stimulation, the norepinephrine then traverses the

synapse and binds to the α or β receptors.

 Examples of uptake blockers and agents that cause norepinephrine

release include cocaine and amphetamines, respectively.
• Mixed-action agonists:
 Some agonists, such as ephedrine,
pseudoephedrine and metaraminol, have the
capacity both to stimulate adrenoceptors
directly and to release norepinephrine from the
adrenergic neuron
 Direct-Acting Adrenergic Agonists

• Direct-acting agonists bind to adrenergic receptors

without interacting with the presynaptic neuron.
• The activated receptor initiates synthesis of second
messengers and subsequent intracellular signals.
• As a group, these agents are widely used clinically.
Epinephrine
• Epinephrine is one of four catecholamines; epinephrine,
norepinephrine, dopamine, and dobutamine commonly
used in therapy.
• The first three catecholamines occur naturally in the
body as neurotransmitters; the latter is a synthetic
compound.
• Epinephrine is synthesized from tyrosine in the adrenal
medulla and released, along with small quantities of
norepinephrine, into the bloodstream.
• Epinephrine interacts with both α and β receptors.
• At low doses, β effects (vasodilation) on the vascular
system predominate, whereas at high doses, α effects
(vasoconstriction) are strongest.
Actions:
Cardiovascular: The major actions of epinephrine are on
the cardiovascular system.
– Epinephrine strengthens the contractility of the myocardium
(positive inotropic: β1 action) and increases its rate of
contraction (positive chronotropic: β 1 action).
• Cardiac output therefore increases.

• With these effects comes increased oxygen demands on the

myocardium.

• Epinephrine constricts arterioles in the skin, mucous membranes,

and viscera (α effects), and it dilates vessels going to the liver and

skeletal muscle (β2 effects).

• Renal blood flow is decreased.

• Therefore, the cumulative effect is an increase in systolic blood

pressure, coupled with a slight decrease in diastolic pressure
 Respiratory:
– Epinephrine causes powerful bronchodilation by acting
directly on bronchial smooth muscle (β2 action).
– This action relieves all known allergic- or histamine-
induced bronchoconstriction.
– In the case of anaphylactic shock, this can be lifesaving.
– In individuals suffering from an acute asthmatic attack,
epinephrine rapidly relieves the dyspnoea (laboured
breathing) and increases the tidal volume (volume of
gases inspired and expired).
– Epinephrine also inhibits the release of allergy
mediators such as histamines from mast cells.
Hyperglycaemia:
– Epinephrine has a significant hyperglycaemic effect
because of increased glycogenolysis in the liver (β2 effect),
increased release of glucagon (β2 effect), and a decreased
release of insulin (α2 effect).
– These effects are mediated via the cAMP mechanism.
Lipolysis:
– Epinephrine initiates lipolysis through its agonist activity
on the β receptors of adipose tissue, which upon
stimulation activate adenylyl cyclase to increase cAMP
levels.
– Cyclic AMP stimulates a hormone-sensitive lipase, which
hydrolyzes triacylglycerols to free fatty acids and glycerol.
Biotransformations:
• Epinephrine, like the other catecholamines, is metabolized
by two enzymatic pathways:
 MAO, and COMT, which has S-adenosylmethionine as a
cofactor.
 The final metabolites found in the urine are metanephrine
and vanillylmandelic acid.
[Note: Urine also contains normetanephrine, a product of
norepinephrine metabolism.]
• Therapeutic uses
– Bronchospasm: Epinephrine is the primary drug used
in the emergency treatment of any condition of the
respiratory tract when bronchoconstriction has
resulted in diminished respiratory exchange.
– Thus, in treatment of acute asthma and anaphylactic
shock, epinephrine is the drug of choice; within a few
minutes after subcutaneous administration, greatly
improved respiratory exchange is observed.
• Administration may be repeated after a few hours. However,
selective β2 agonists, such as albuterol, are presently favoured
in the chronic treatment of asthma because of a longer duration
of action and minimal cardiac stimulatory effect.
– Glaucoma: In ophthalmology, a two-percent epinephrine
solution may be used topically to reduce intraocular
pressure in open-angle glaucoma.
– It reduces the production of aqueous humour by
vasoconstriction of the ciliary body blood vessels.
 – Anaphylactic shock: Epinephrine is the drug of choice for the
treatment of Type I hypersensitivity reactions in response to
allergens.
– Cardiac arrest: Epinephrine may be used to restore cardiac
rhythm in patients with cardiac arrest regardless of the cause.

• Anaesthetics: Local anaesthetic solutions usually contain

1:100,000 parts epinephrine.
• The effect of the drug is to greatly increase the duration of
the local anaesthesia
• It does this by producing vasoconstriction at the site
of injection, thereby allowing the local anaesthetic to
persist at the injection site before being absorbed into
the circulation and metabolized.

• Very weak solutions of epinephrine (1:100,000) can

also be used topically to constrict mucous membranes
to control oozing of capillary blood.
Pharmacokinetics:
• Epinephrine has a rapid onset but a brief duration of action (due to
rapid degradation).
• In emergency situations, epinephrine is given intravenously for the
most rapid onset of action.
• It may also be given subcutaneously, by endotracheal tube, by
inhalation, or topically to the eye.
• Oral administration is ineffective, because epinephrine and the
other catecholamines are inactivated by intestinal enzymes.
• Only metabolites are excreted in the urine.
Adverse effects:
– CNS disturbances: Epinephrine can produce adverse CNS
effects that include anxiety, fear, tension, headache, and tremor.
– Haemorrhage: The drug may induce cerebral haemorrhage as a
result of a marked elevation of blood pressure.
– Cardiac arrhythmias: Epinephrine can trigger cardiac
arrhythmias, particularly if the patient is receiving digitalis.
– Pulmonary oedema: Epinephrine can induce pulmonary
oedema.
• Interactions:
– Hyperthyroidism: Epinephrine may have enhanced cardio-
vascular actions in patients with hyperthyroidism.
– If epinephrine is required in such an individual, the dose must
be reduced.
– The mechanism appears to involve increased production of
adrenergic receptors on the vasculature of the hyperthyroid
individual, leading to a hypersensitive response.
– Cocaine: In the presence of cocaine, epinephrine produces
exaggerated cardiovascular actions.
• This is due to the ability of cocaine to prevent reuptake of
catecholamines into the adrenergic neuron; thus, like
norepinephrine, epinephrine remains at the receptor site for
longer periods of time.
– Diabetes: Epinephrine increases the release of endogenous
stores of glucose. In the diabetic, dosages of insulin may
have to be increased.
– β-Blockers: These agents prevent epinephrine's effects on β
receptors, leaving α-receptor stimulation unopposed.
– This may lead to an increase in peripheral
resistance and an increase in blood pressure.
– Inhalation anaesthetics: Inhalational anaesthetics
sensitize the heart to the effects of epinephrine,
which may lead to tachycardia.
Norepinephrine
• Because norepinephrine is the neuromediator of adrenergic
nerves, it should theoretically stimulate all types of adrenergic
receptors.
• In practice, when the drug is given in therapeutic doses to
humans, the α-adrenergic receptor is most affected.
• Cardiovascular actions:
– Vasoconstriction: Norepinephrine causes a rise in peripheral resistance
due to intense vasoconstriction of most vascular beds, including the
kidney (α1 effect).
– Both systolic and diastolic blood pressures increase.
– The weak β2 activity of norepinephrine also explains why it is not useful
in the treatment of asthma.]
– Baroreceptor reflex: In isolated cardiac tissue,
norepinephrine stimulates cardiac contractility; however, in
vivo, little of any cardiac stimulation is noted.
– This is due to the increased blood pressure that induces a
reflex rise in vagal activity by stimulating the baroreceptors.
– This reflex bradycardia is sufficient to counteract the local
actions of norepinephrine on the heart, although the reflex
compensation does not affect the positive inotropic effects of
the drug.
Therapeutic uses:
• Norepinephrine is used to treat shock, because it increases
vascular resistance and, therefore, increases blood pressure.
• However, metaraminol is favoured, because it does not reduce
blood flow to the kidney, as does norepinephrine.
• Other actions of norepinephrine are not considered to be
clinically significant.
• It is never used for asthma or in combination with local
anaesthetics.
• Norepinephrine is a potent vasoconstrictor and will cause
extravasation (discharge of blood from vessel into tissues) along
the injection site.
[Note: When norepinephrine is used as a drug, it is sometimes
called levarterenol
Pharmacokinetics:

• Norepinephrine may be given IV for rapid onset of

action.

• The duration of action is 1 to 2 minutes following the

end of the infusion period.

• It is poorly absorbed after subcutaneous injection and is

destroyed in the gut if administered orally.

• Metabolism is similar to that of epinephrine

Adverse effects:
• These are similar to those of epinephrine.

• In addition, norepinephrine may cause blanching and sloughing of skin

along injected vein (due to extreme vasoconstriction).

Isoproterenol

• Isoproterenol is a direct-acting synthetic catecholamine that

predominantly stimulates both β1- and β2-adrenergic receptors.

• Its nonselectivity is one of its drawbacks and the reason why it is rarely
used therapeutically.

• Its action on α receptors is insignificant.

• Actions:
– Cardiovascular: Isoproterenol produces intense
stimulation of the heart to increase its rate and force of
contraction, causing increased cardiac output.
– It is as active as epinephrine in this action and,
therefore, is useful in the treatment of atrioventricular
block or cardiac arrest.
– Isoproterenol also dilates the arterioles of skeletal
muscle (β2 effect), resulting in decreased peripheral
resistance.
– Because of its cardiac stimulatory action, it may
increase systolic blood pressure slightly, but it greatly
reduces mean arterial and diastolic blood pressure.
– Pulmonary: A profound and rapid bronchodilation is produced by
the drug (β2 action).

– Isoproterenol is as active as epinephrine and rapidly alleviates an

acute attack of asthma when taken by inhalation (which is the
recommended route).
– This action lasts about 1 hour and may be repeated by subsequent
doses.
– Other effects: Other actions on β receptors, such as increased
blood sugar and increased lipolysis, can be demonstrated but are
not clinically significant.
• Therapeutic uses: Isoproterenol is now rarely used as a
bronchodilator in asthma. It can be employed to stimulate the
heart in emergency situations.
• Pharmacokinetics: Isoproterenol can be absorbed systemically
by the sublingual mucosa but is more reliably absorbed when
given parenterally or as an inhaled aerosol. It is a marginal
substrate for COMT and is stable to MAO action.
• Adverse effects: The adverse effects of Isoproterenol are
similar to those of epinephrine.
Dopamine

• Dopamine, the immediate metabolic precursor of norepinephrine, occurs naturally in

the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the
adrenal medulla.

• Dopamine can activate α and β-adrenergic receptors.

• For example, at higher doses, it can cause vasoconstriction by activating α1 receptors,

whereas at lower doses, it stimulates β1 cardiac receptors.

• In addition, D1 and D2 dopaminergic receptors, distinct from the α- and β-adrenergic

receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of
dopamine produces vasodilation.

• D2 receptors are also found on presynaptic adrenergic neurons, where their activation

interferes with norepinephrine release.

• Actions:
– Cardiovascular: Dopamine exerts a stimulatory effect on the β1
receptors of the heart, having both inotropic and chronotropic
effects.

– At very high doses, dopamine activates α1 receptors on the

vasculature, resulting in vasoconstriction.
– Renal and visceral: Dopamine dilates renal and splanchnic
arterioles by activating dopaminergic receptors, thus increasing
blood flow to the kidneys and other viscera.
– These receptors are not affected by α- or β-blocking drugs.
 – Therefore, dopamine is clinically useful in the treatment of shock, in
which significant increases in sympathetic activity might compromise
renal function.
[Note: Similar dopamine receptors are found in the autonomic ganglia
and in the CNS.]
Therapeutic uses:
 Dopamine is the drug of choice for shock and is given by continuous
infusion.

It raises the blood pressure by stimulating the β1 receptors on the heart to

increase cardiac output, and α1 receptors on blood vessels to increase total

peripheral resistance.
• In addition, it enhances perfusion to the kidney and splanchnic areas
• An increased blood flow to the kidney enhances the glomerular
filtration rate and causes sodium diuresis.

• In this regard, dopamine is far superior to norepinephrine, which

diminishes the blood supply to the kidney and may cause renal

shutdown.
Adverse effects:
• An overdose of dopamine produces the same effects as sympathetic
stimulation.
• Dopamine is rapidly metabolized to homovanillic acid by MAO or
COMT, and its adverse effects (nausea, hypertension, arrhythmias) are
therefore short-lived.
Dobutamine

• Actions: Dobutamine is a synthetic, direct-acting catecholamine

that is a β1-receptor agonist.

• It is available as a racemic mixture. One of the stereoisomers has a

stimulatory activity.
• It increases cardiac rate and output with few vascular effects.
 Therapeutic uses:

• Dobutamine is used to increase cardiac output in congestive heart

failure as well as for inotropic support after cardiac surgery.
• The drug increases cardiac output with little change in heart
rate, and it does not significantly elevate oxygen demands of
the myocardium a major advantage over other
sympathomimetic drugs.
Adverse effects:
• Dobutamine should be used with caution in atrial fibrillation,
because the drug increases atrioventricular conduction.
• Other adverse effects are the same as those for epinephrine.
Tolerance may develop on prolonged use.
Oxymetazoline
• Oxymetazoline is a direct-acting synthetic adrenergic
agonist that stimulates both α1- and α2-adrenergic receptors.

• It is primarily used locally in the eye or the nose as a

vasoconstrictor.
• Oxymetazoline is found in many over-the-counter short-
term nasal spray decongestant products as well as in
ophthalmic drops for the relief of redness of the eyes
associated with swimming, colds, or contact lens.
• The mechanism of action of oxymetazoline is direct stimulation
of α receptors on blood vessels supplying the nasal mucosa and
the conjunctiva to reduce blood flow and decrease congestion.
• Oxymetazoline is absorbed in the systemic circulation regardless
of the route of administration and may produce nervousness,
headaches, and trouble sleeping.
• When administered in the nose, burning of the nasal mucosa and
sneezing may occur.
• Rebound congestion is observed with long-term use.
Phenylephrine

• Phenylephrine is a direct-acting, synthetic adrenergic drug that binds

primarily to α receptors and favours α1 receptors over α2 receptors.

• It is not a catechol derivative and, therefore, not a substrate for COMT.

• Phenylephrine is a vasoconstrictor that raises both systolic and diastolic

blood pressures.

• It has no effect on the heart itself but rather induces reflex bradycardia
when given parenterally.

• It is often used topically on the nasal mucous membranes and in

ophthalmic solutions for mydriasis.
• Phenylephrine acts as a nasal decongestant and
produces prolonged vasoconstriction.
• The drug is used to raise blood pressure and to
terminate episodes of supraventricular tachycardia
(rapid heart action arising both from the
atrioventricular junction and atria).
• Large doses can cause hypertensive headache and
cardiac irregularities.
Methoxamine
• Methoxamine is a direct-acting, synthetic adrenergic drug
that binds primarily to α receptors, with α1 receptors
favoured over α2 receptors.
• Methoxamine raises blood pressure by stimulating α1
receptors in the arterioles, causing vasoconstriction.
• This causes an increase in total peripheral resistance.
• Because of its effects on the vagus nerve, methoxamine is
used clinically to relieve attacks of paroxysmal
supraventricular tachycardia.
• It is also used to overcome hypotension during surgery
involving halothane anaesthetics.
• In contrast to most other adrenergic drugs, methoxamine does not
tend to trigger cardiac arrhythmias in the heart, which is
sensitized by these general anaesthetics.
• Adverse effects include hypertensive headache and vomiting.
Clonidine
• Clonidine is an α2 agonist that is used in essential hypertension to
lower blood pressure because of its action in the CNS.
• It can be used to minimize the symptoms that accompany
withdrawal from opiates or benzodiazepines.
• Clonidine acts centrally to produce inhibition of sympathetic
vasomotor centres, decreasing sympathetic outflow to the
periphery.
Metaproterenol
• Metaproterenol, although chemically similar to isoproterenol, is
not a catecholamine, and it is resistant to methylation by COMT.
• It can be administered orally or by inhalation. The drug acts
primarily at β2 receptors, producing little effect on the heart.

• Metaproterenol produces dilation of the bronchioles and

improves airway function.
• The drug is useful as a bronchodilator in the treatment of asthma
and to reverse bronchospasm
Albuterol, pirbuterol, and terbutaline

• Albuterol, pirbuterol, and terbutaline are short-acting β2

agonists used primarily as bronchodilators and

administered by a metered-dose inhaler.

• Compared with the nonselective β-adrenergic agonists,

such as metaproterenol, these drugs produce equivalent
bronchodilation with less cardiac stimulation.
Salmeterol and formoterol
• Salmeterol and formoterol are β2-adrenergic selective, long-acting
bronchodilators.
• A single dose by a metered-dose inhalation device, such as a dry
powder inhaler, provides sustained bronchodilation over 12 hours,
compared with less than 3 hours for albuterol.
• Unlike formoterol, however, salmeterol has a somewhat delayed
onset of action.
• These agents are not recommended as monotherapy and are highly
efficacious when combined with a corticosteroid.
• Salmeterol and formoterol are the agents of choice for treating
nocturnal asthma in symptomatic patients taking other asthma
medications.
 Indirect-Acting Adrenergic Agonists
• Indirect-acting adrenergic agonists cause norepinephrine
release from presynaptic terminals or inhibit the uptake of
norepinephrine.
• They potentiate the effects of norepinephrine produced
endogenously, but these agents do not directly affect
postsynaptic receptors.
Amphetamine
• The marked central stimulatory action of amphetamine is often
mistaken by drug abusers as its only action.
• However, the drug can increase blood pressure significantly by α-agonist action

on the vasculature as well as β-stimulatory effects on the heart.

• Its peripheral actions are mediated primarily through the blockade of

norepinephrine uptake and cellular release of stored catecholamines; thus,

amphetamine is an indirect-acting adrenergic drug.

• The actions and uses of amphetamines are discussed under stimulants of the CNS.

• The CNS stimulant effects of amphetamine and its derivatives have led to their use

for treating hyperactivity in children, narcolepsy, and appetite control.

• Its use in pregnancy should be avoided because of adverse effects on development

of the foetus.
Tyramine

• Tyramine is not a clinically useful drug, but it is important because it

is found in fermented foods, such as ripe cheese and Chianti wine.

• It is a normal by-product of tyrosine metabolism.

• Normally, it is oxidized by MAO in the gastrointestinal tract, but if

the patient is taking MAO inhibitors, it can precipitate serious
vasopressor episodes.

• Like amphetamines, tyramine can enter the nerve terminal and

displace stored norepinephrine.

• The released catecholamine then acts on adrenoceptor.

Cocaine

• Cocaine is unique among local anaesthetics in having the

ability to block the Na+/K+-activated ATPase (required for
cellular uptake of norepinephrine) on the cell membrane of
the adrenergic neuron.

• Consequently, norepinephrine accumulates in the synaptic

space, resulting in enhancement of sympathetic activity and
potentiation of the actions of epinephrine and norepinephrine.
• Therefore, small doses of the catecholamines produce greatly

magnified effects in an individual taking cocaine as compared

to those in one who is not.

• In addition, the duration of action of epinephrine and

norepinephrine is increased.

• Like amphetamines, it can increase blood pressure by α-

agonist actions and β-stimulatory effects.

 Mixed-Action Adrenergic Agonists
• Mixed-action drugs induce the release of norepinephrine from presynaptic
terminals, and they activate adrenergic receptors on the postsynaptic
membrane.
Ephedrine and pseudoephedrine
• These drugs are mixed-action adrenergic agents. They not only release stored
norepinephrine from nerve endings but also directly stimulate both α and β
receptors.
• Thus, a wide variety of adrenergic actions ensue that are similar to those of
epinephrine, although less potent.
• Ephedrine and pseudoephedrine are not catechols and are poor substrates for
COMT and MAO; thus, these drugs have a long duration of action.
• Ephedrine and pseudoephedrine have excellent absorption orally and
penetrate into the CNS; however, pseudoephedrine has fewer CNS
effects.
• Ephedrine is eliminated largely unchanged in the urine, and
pseudoephedrine undergoes incomplete hepatic metabolism before
elimination in the urine.
• Ephedrine raises systolic and diastolic blood pressures by
vasoconstriction and cardiac stimulation.
• Ephedrine produces bronchodilation, but it is less potent than
epinephrine or isoproterenol in this regard and produces its action more
slowly.
• It is therefore sometimes used prophylactically in chronic
treatment of asthma to prevent attacks rather than to treat the
acute attack.

• Ephedrine enhances contractility and improves motor function

in myasthenia gravis, particularly when used in conjunction
with anticholinesterases.

• Ephedrine produces a mild stimulation of the CNS.

• This increases alertness, decreases fatigue, and prevents sleep.

It also improves athletic performance.
• Ephedrine has been used to treat asthma, as a nasal
decongestant (due to its local vasoconstrictor action),
and to raise blood pressure.

• Pseudoephedrine is primarily used to treat nasal and

sinus congestion or congestion of the Eustachian tubes.

[Note: The clinical use of ephedrine is declining due to the

availability of better, more potent agents that cause fewer
adverse effects
 Study Questions
Choose the ONE best answer.

• A 68-year-old man presents to the emergency department

with acute heart failure. You decide that this patient requires
immediate drug therapy to improve his cardiac function.
Which one of the following drugs would be most beneficial?
A. Albuterol.
B. Dobutamine.
C. Epinephrine.
D. Norepinephrine.
E. Phenylephrine.
Remedies for nasal stuffiness often contain which one of the
following drugs?
A. Albuterol.
B. Atropine.
C. Epinephrine.
D. Norepinephrine.
E. Phenylephrine.

.
• Which one of the following drugs, when administered
intravenously, can decrease blood flow to the skin, increase
blood flow to skeletal muscle, and increase the force and rate
of cardiac contraction?
A. Epinephrine.
B. Isoproterenol.
C. Norepinephrine.
D. Phenylephrine.
E. Terbutaline.