Adrenergic transmission

• Transmission is restricted to sympathetic division of ANS.

• Three closely related endogenous catecholaminses (CAs) as a neurotransmitter.
– Noradrenaline (NA)
– Adrenaline (Adr)
– Dopamine (DA)
• Catecholamines are compounds containing a catechol moiety ( a benzene ring with two adjacent hydroxyl groups)
and an amine side chain.
• Pharmacologically the most important ones are :
- Noradrenaline (norepinephrene)
- Adrenaline (epinephrine)
- Dopamine
- Isoprenaline
ENDOGENOUS CATECHOLAMINES
 Norepinephrine -sites: Postganglionic sympathetic sites (except sweat glands , erector pili muscle, hair
follicles, )
 Epinephrine- secreted by adrenal medulla
 Dopamine- major transmitter in basal ganglia, CTZ, imbic system, anterior pituitary. Limited in periphery
 ADRENOMIMETICS
• These are the drugs which act similar to that of adrenaline or sympathetic stimulation.

• Adrenergic pharmacology involves the study of agents that act on the pathways mediated by endogenous
catecholamine's norepinephrine , epinephrine and dopamine.
• These neurotransmitters modulate many functions , including the rate and force of contraction , the
resistance ( constriction and dilation) of blood vessels and bronchioles , release of insulin , and the
breakdown of fats .
• Drugs that targets the synthesis , storage , release and reuptake of norepinephrine and epinephrine and that
target the postsynaptic receptors for those neurotransmitters are frequent therapies for hypertension ,
depression , shock , asthma , angina , and many other disorders.
Steps in neurohumoral transmission
A. Synthesis and storage of norepinephrine
 Start with the amino acid tyrosine, which enters the neuron by active transport.
 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.
 DOPA is then decarboxylated by the enzyme dopadecarboxylase (aromatic l-amino acid decarboxylase)
to form dopamine in the cytoplasm of the presynaptic neuron.
Steps in neurohumoral transmission
B. Storage and release
 Dopamine is then trans-ported into synaptic vesicles by an amine transporter system that is also involved in
the reuptake of preformed norepinephrine.
 Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine -hydroxylase.
 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% epinephrine and 20% norepinephrine directly into the
circulation.
Steps in neurohumoral transmission
C. Release of NE
 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
(exocytose) their contents into the synapse
 Release is modulated by presynaptic receptors, of which alpha2 inhibitory control is dominant.
 Indirectly acting sympathomimetic amines (tyramine etc) also induce the release of NA, by displacing NA from
the nerve ending binding sites and by diffusion utilizing amine carrier of uptake-1.
D. Binding to the receptors
 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.
E. Removal of norepinephrine

• Norepinephrine may:
1. diffuse out of the synaptic space and enter the general circulation,
2. be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-
methyltransferase (COMT) in the synaptic space, 3) be recaptured by an uptake system that pumps the
norepinephrine back into the neuron.
 The uptake by the neuronal membrane involves a sodium/potassiumactivated ATPase that can be inhibited by
tricyclic antidepressants, such as imipramine, or by cocaine
 Where are the adrenergic receptors?
Receptor: α1 α2 β1 β2 β3

localization blood vessels pancreas heart lungs adipose tissue

vas deferens g.i. tract kidney g.i. tract

uterus CNS uterus adipose tissue

(pregnant) (nonpregnant)

ureter stomach salivary glands

 ALPHA(α2)
Acts by inhibiting adenyl cyclase – cAMP

• Aggregation Platelets -

Prejunctional • Decrease release of receptors – transmitter (NE)

• Decrease insulin release Pancrease -- (predominant)

Beta (β1)
Beta receptors stimulate adenyl cyclase–
 cAMP
Heart :

• Increase in heart rate, Force of

contraction & conduction velocity

JG cells in kidney

• Increase renin release.

Beta (β2)receptors : cAMP

Blood vessels to • Vasodilation

skeletal muscle

Uterus • Relaxation

Bronchioles • Dilatation

Skeletal muscles • Tremors

Liver - • Glycogenolysis
Types and subtypes of adrenoceptors
 • Two subtypes of adrenoceptors (a and b)

 a excitatory in most tissues

(except - intestinal smooth muscle) b inhibitory in most tissues

(except - heart)
Types and subtypes of adrenoceptors
Rank Order of Potency a Receptors Epi > NE >> Iso b Receptors
Iso > Epi > NE

Type of adrenoceptor

 a 1, a 2

 b 1, b 2, b 3

 DA1, DA2

List of Adrenomimetic Drugs

Selective agonists

a 1 , a 2 , b 1 : Norepinephrine* a 1 > a 2 : Phenylephrine*,

methoxamine, metaraminol, midodrine
 a 2 > a 1 : Clonidine*,
methylnorepinephrine, apraclonidine, brimonidine b 1 = b 2 :
Isoproterenol*
List of Adrenomimetic Drugs

Selective agonists b 1 > b 2 : Dobutamine* b 2 > b 1 : Terbutaline*, albuterol,

metaproterenol, ritodrine

Dopamine agonist: Dopamine*, bromocriptine

Adrenergics or Sympathetic Agonists
(Sympathomimetics)
A. Directly Acting
1. Acting on both α– and β- receptors:- Epinephrine, Nor-Epinephrine, Dipivefrine

2. Acting on α- receptors

a. Non-Subtype selective:- Oxymetazoline, Xylometazoline

b. α1- selective:- Phenylephrine, Methoxamine, Medodrine, Desglymedodrine,

Napazoline
c. α2- selective:- Clonidine, Apraclonidine, Methyldopa, Guanabenz, Guanafacine,
3. Acting on β- receptors
a. Non-selective:- Isoproterinol

b. β1-selective:- Dobutamine , Prenalterol

c. β2-selective:- Salbutamol, Terbutaline, Metaproterinol, Femoterol, Fenoterol, Bitolterol, Isoetherine, Retodrine

 Major effects mediated by adrenoceptors

SITE OF ACTION

1 April 2018 17
1 April 2018 18
 SITE OF ACTION

1 April 2018 19
 DRUGS UNDER ADRENERGIC AGONISTS

DRUGS UNDER ADRENERGIC AGONISTS

DIRECT-ACTING INDIRECT-ACTING DIRECT & INDIRECT ACTING (mixed
action)

 Albuterol  Amphetamine  Ephedrine

 Clonidine  Cocaine  Pseudophrine
 Dobutamine  Tyramine

 Dopamine
 Epinephrine
 Isoproterenol
 Metaproterenol
 Methoxamine
 Norepinephrine
 Phenylphrine
 Piruterol
 Salmeterol
 Terbutaline
Adrenergics or Sympathetic Agonists (Sympathomimetics)
 PHARMACOLOGICAL ACTIONS

• Adrenaline stimulates both the α and β adrenergic receptors .

• Its effect on cardiovascular system and smooth muscles are particularly prominent.
1.Heart

 Adrenaline is a powerful cardiac stimulant (β1 receptors) .

 Force of myocardial contraction is increased.

 Heart rate is increased due to increased conduction velocity and decreased refractory period.

 Cardaic output is increased. Work load of the heart is increased along with increased oxygen
consumption.

 Excitability of heart is increased leading to extrasystoles (tachyarrhythmias)

2.Blood pressure

 adrenaline is a very potent vasopressor drug.

 It caused marked rise in systemic blood pressure due to myocardial stimulation (positive ionotropic
effect) increased heart rate (positive chronotropic effect) and vasoconstriction in skin , mucosa , and kidney.

 Diastolic blood pressure falls.

 TPR decreases because vascular β2 receptors are more sensitive than α receptors.

 There is increased pulse pressure.

 Noradrenaline causes rise in systolic , diastolic and mean BP, it doesnot causes vasodialtion (no β2
action), peripheral resistance increases consistently due to α2 action.

 It acts on two types of receptors α and β receptors.

 α-receptors causes vasoconstriction whereas βreceptors mediate vasodilatation.

 β receptors are more sensitive.

 3. Respiration

• Adrenaline and isoprenaline but not noradrenaline are potent bronchodialtors (β2).
• This action is more marked when the bronchi are constricted.
• Adrenaline given by aerosol additionally decongests bronchial mucosa by alpha action.
• Very large dose may cause death due to pulmonary edema caused by adrenaline.
• Given IV adrenaline may cause brief apnea before stimulation of respiration. Apnea is probably due to
transient reflex inhibition of respiratory centre through baroreceptor mechanism
4. GI tract

• smooth muscles of the GI tract is generally relaxed by adrenaline .

• Stomach and intestine are relaxed; pyloric and ileocecal sphincters are contracted . Both α and β receptors
are involved in these actions.

• In the smooth muscle of GIT wall.

– β2 stimulation cause relaxation of the wall leading to decreased peristalsis
• α2-agonist decrease tone and motility of GI smooth muscles indirectly (by presynaptically reducing
release of Ach and other stimulant within enteric nervous system)

• β2-agonist directly relaxes GI smooth muscles hyperpolarization and decrease spike activity of the cells.
5.Urinary bladder

• Adrenaline relaxes the detrusor muscles of the bladder ( β receptors ) and contracts the trigone and sphincter
muscles ( α receptors).

• α1-agonist cause contraction of trigone muscle of blaldder, urethral sphincter contributing to

resistance to outflow of urine

• α1- agonist increase motility and tone of ureter

• β2- agonist cause relaxation of detrusor muscle of bladder wall
• Both the action hinder micturition
6. Uterus

• Adr can both contract and relax uterine muscle, resp. through α and β receptor.
• Human uterus is relaxed by Adr at term of pregnancy, but at other times, its concentrations are
enhanced.
8. CNS

• Adrenaline, in clinically used doses does not produces marked CNS effect because of poor penetration
in brain , but restlessness and tremor may occur.

• activation of α2 receptors in brainstem results in decreased sympathetic outflow fall in BP and

bradycardia.
9. Metabolic

• Adrenaline produces glycogenolysis hyperglycaemia (action on liver tissue); lipolysis rise

in plasma free fatty acids (action on adipose tissue)

• transient hyperkalaemia followed by hypokalemia due to initial release of K+ from liver

10. Eye

 Mydraisis occurs due to contraction of radial muscles of iris (α 1) but this is minimal after topical
instillation, because Adr penetrates cornea poorly.

 The intraocular pressure tends to fall especially in wide angle glaucoma.

DIRECT-ACTING ADRENERGIC AGONISTS Epinephrine
 • 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 OF EPINEPHRINE
CARDIOVASCULAR RESPIRATORY HYPERGLYCEMIA LIPOLYSIS
Epinephrine strengthens the
contractility of the
myocardium (positive
inotropic: β1 action) and
increases its rate of
contraction (positive
chronotropic: β1 action).
Epinephrine causes
powerful bronchodilation by
acting directly on bronchial
smooth muscle (β2 action).
Epinephrine has a significant
hyperglycemic effect
because of increased
glycogenolysis in the liver (β2
effect), increased release of
glucagon (β2 effect), and a
decreased release of insulin
(α2 effect).
Epinephrine initiates
lipolysis through its agonist
activity on the β receptors
of adipose tissue, which
upon stimulation activate
adenylyl cyclase to increase
cAMP levels.

THERAPEUTIC USES OF EPINEPHRINE

BRONCHOSPASM GLAUCOMA CARDIAC ARREST ANESTHETICS
ANAPHYLACTIC SHOCK
Epinephrine is the In ophthalmology, Epinephrine is the drug Epinephrine may be The effect of the drug
primary drug used in the 2% epinephrine of choice for the used to restore cardiac is to greatly increase
emergency treatment of solution may be treatment of Type I rhythm in patients the duration of the
any condition of the used topically to hypersensitivity with cardiac arrest local anesthesia.
respiratory tract when reduce intraocular reactions in response regardless of the
bronchoconstriction has pressure in to allergens. cause.
resulted in diminished openangle
respiratory exchange. glaucoma.
CNS DISTURBANCE HEMORRHAGE CARDIAC PULMONARY EDEMA
ARRYTHMIAS

Includes: anxiety, fear, tension, headache, and

tremor.

ADVERSE EFFECTS OF EPINEPHRINE

 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 OF NOREPINEPHRINE

VASOCONSTRICTION BARORECEPTOR REFLEX EFFECTS OF ATROPINE PRE-
TREATMENT
Norepinephrine causes a rise in In isolated cardiac tissue,
peripheral resistance due to intense norepinephrine stimulates cardiac
vasoconstriction of most vascular contractility; however, in
beds, including the kidney (α1 effect). vivo, little if any cardiac stimulation is
noted.
If atropine, which blocks the
transmission of vagal effects, is given
before norepinephrine, then
norepinephrine stimulation
of the heart is evident as tachycardia.

Isoproterenol

• Isoproterenol is a direct-acting synthetic catecholamine that predominantly stimulates both β - and β -

1 2

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 OF ISOPROTERENOL

CARDIOVASCULAR PULMONARY OTHER EFFECTS

Isoproterenol produces intense Isoproterenol is as active as Other actions on β receptors, such as

stimulation of the heart to increase epinephrine and rapidly alleviates an increased blood sugar and increased
its rate and force of contraction, acute attack of asthma when taken by lipolysis, can be demonstrated but
causing increased cardiac output. inhalation (which is the are not clinically significant.
recommended route).
 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.

ACTIONS OF DOPAMINE
CARDIOVASCULAR RENAL & VISCERAL
Dopamine exerts a stimulatory effect on the β1 receptors
of the heart, having both inotropic and chronotropic
effects.
Dobutamine
• Dobutamine is a synthetic, direct-acting catecholamine that is a β -receptor
agonist.
• One of the stereoisomers has a stimulatory activity.
Dopamine dilates renal and splanchnic arterioles by
activating dopaminergic receptors, thus increasing blood
flow to the kidneys and other viscera.
Therefore, dopamine is clinically useful in the treatment
of shock, in which significant increases in sympathetic
activity might compromise renal function.
1
• It increases cardiac rate and output with few vascular effects.
• Dobutamine is used to increase cardiac output in congestive heart failure as well as for inotropic support
after cardiac surgery.

Oxymetazoline

• Oxymetazoline is a direct-acting synthetic adrenergic agonist that stimulates both α - and α -adrenergic
1 2

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.
 Phenylephrine

• Phenylephrine is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors and favors α 1

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.
 Methoxamine

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

to α-receptors, with α1 receptors favored over α2 receptors.

• Methoxamine raises blood pressure by stimulating α receptors in the

1

arterioles, causing vasoconstriction.

• This causes an increase in total peripheral resistance.

Clonidine

• Clonidine is an α agonist that is used in essential hypertension to lower blood pressure because of its action
2

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 centers, 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.

• 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 shortacting β2 agonists used primarily as bronchodilators and
administered by a metered-dose inhaler.

Salmeterol and formoterol

• Salmeterol and formoterol are β -adrenergic selective, longacting bronchodilators.

2

• Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in symptomatic patients
taking other asthma medications.
 INDIRECT-ACTING ADRENERGIC AGONISTS
Amphetamine

• The marked central stimulatory action of amphetamine is often mistaken by drug abusers as its only action.
• 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 fetus.
 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.

Cocaine

• Cocaine is unique among local anesthetics 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.

• Like amphetamines, it can increase blood pressure by αagonist actions and β-stimulatory effects.
 MIXED-ACTION ADRENERGIC AGONISTS
Ephedrine and pseudoephedrine

• Ephedrine, and pseudoephedrine are plant alkaloids, that are now made synthetically.
• 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.
Therapeutic Uses of Ephedrine and Pseudoephedrine

• Ephedrine enhances contractility and improves motor function in myasthenia gravis.

• 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.