ADRENERGIC AGONISTS
I. Overview
- Affect receptors (AKA: adrenergic receptors or adrenoceptors) that are
stimulated by norepinephrine (noradrenaline) or epinephrine
(adrenaline).
- Activate: sympathomimetics, Block activation: sympatholytics.
- Some sympathomimetics directly activate adrenergic receptors (direct-
acting agonists), while others act indirectly by enhancing release or
blocking reuptake of NE (indirect-acting agonists)
II. The Adrenergic Neuron
- Release norepinephrine as the primary neurotransmitter. Found in the
CNS and in the sympathetic nervous system, and serves as links
between ganglia and the effector organs.
- Located either presynaptically: neuron or postsynaptically: effector
organ.
A. Neurotransmission at Adrenergic Neurons
o Neurotransmission: closely resembles that described for the cholinergic
neurons, except that norepinephrine is the neurotransmitter instead of
acetylcholine.
o Neurotransmission involves the following steps: SSRBRP
1. Synthesis of norepinephrine
▪ Tyrosine is transported by a carrier into the adrenergic neuron, where
it is hydroxylated to dihydroxyphenylalanine (COPA) by tyrosine
hydroxylase. This is the rate-limiting (shortest step) step in the
formation of norepinephrine.
▪ DOPA is then decarboxylated by the enzyme aromatic L-amino acid
decarboxylase to form dopamine in the presynaptic neuron.
2. Storage of norepinephrine in vesicles
▪ Dopamine is then transported into synaptic vesicles by an amine
transporter system
▪ Dopamine is hydroxylated to form NE by the enzyme dopamine β-
hydroxylase
3. 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  in calcium = synaptic vesicles to fuse with the cell membrane and
to undergo exocytosis and expel their contents (NE) in to the synapse.
4. Binding to receptors
▪ Norepinephrine released from the synaptic vesicles diffuses into the
synaptic space and binds to postsynaptic receptors on the effector
organ or to presynaptic receptors on the nerve ending.
▪ Binding of norepinephrine to 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.
5. Removal of norepinephrine
▪ Norepinephrine may:
o Diffuse out of the synaptic space and enter the systemic
circulation
o Be metabolized to inactive metabolites by catechol-O-
methyltransferase (COMT) in the synaptic space, or
o Undergo reuptake back into the neuron
o Reuptake of norepinephrine in to the presynaptic neuron is the
primary mechanism for termination of its effects
6. Potential fates of recaptured norepinephrine
▪ Once norepinephrine re-enters the adrenergic neuron, it may be taken
up into synaptic vesicles via the amine transporter system and be
sequestered for release by another action potential, or it may persist in
a protected pool in the cytoplasm.
▪ Alternatively, norepinephrine can be oxidized by monoamine oxidase
(MAO) present in neuronal mitochondria
B. Adrenergic Receptors (Adrenoceptors)
▪ Two main families of receptors, designated α and β, are classified based
on response to the adrenergic agonists’ epinephrine, norepinephrine,
and isoproterenol. Both the α and β receptors types have a number of
specific receptor subtypes
1. α-Adrenoceptors
▪ Show a weak response to the synthetic isoproterenol, but they are
responsive to naturally occurring catecholamines epinephrine, NE and
isoproterenol.
▪ Potency: Epinephrine > Norepinephrine > Isoproterenol
Isoproterenol is a drug used for heart failure.
a. α1 Receptors
▪ Present on the postsynaptic membrane of the effector organs and
mediate many of the classic effects, originally designated as α-
adrenergic, involving constriction of smooth muscle.
b. α2 Receptors
▪ Located primarily on sympathetic presynaptic nerve endings and
control the release of NE
▪ When sympathetic adrenergic nerve is stimulated, a portion of the
released NE “circles back” and reacts with α2 receptors on the
presynaptic membrane.
2. β-Adrenoceptors
o Have strong response to isoproterenol with less sensitivity to
epinephrine and norepinephrine
o Potency: Isoproterenol > epinephrine > norepinephrine
a. β1 - Have approximately equal affinities for epinephrine and NE
b. β2 – Have  affinity for epinephrine than for NE
c. β3
3. Desensitization of Receptors
o Prolonged exposure to the catecholamines the responsiveness of
these receptors.
III. Characteristics of Adrenergic Agonists
A. Catecholamines
o Sympathomimetic amines that contain the 3,4-dihydroxybenzene
group (such as epinephrine, norepinephrine, isoproterenol and
dopamine) are called catecholamines
o Show the highest potency in directly activating  and β receptors
o Have only brief period of action when given parenterally, and they are
inactivated (ineffective) when administered PO.
o Are polar, and therefore, do not readily penetrate into the CNS. But,
have some clinical effects (anxiety, tremor and headaches) that are
attributable to action on the CNS.
B. Non-catecholamines
o Lack catechol hydroxyl groups have longer-half-lives (E.g. Cadmium
has a 10-year half-life), because they are not inactivated by COMT
o Include phenylephrine, ephedrine and amphetamine
o Poor substrates for MAO, and thus, show prolonged duration of action
o  lipid solubility of many noncatecholamines (due to lack of polar
hydroxyl groups) permits greater access to the CNS
 C. Mechanism of Action of Adrenergic Agonists o Also  systemic absorption of the local anesthetic and promotes local
1. Direct-Acting Agonists (PINED) hemostasis.
o These drugs act directly on  or β receptors, producing effects similar
to those that occur following stimulation of sympathetic nerves or v. Intraocular surgery
release of epinephrine from the adrenal medulla o Used in the induction and maintenance of mydriasis during intraocular
o E.g.: Epinephrine, Norepinephrine, isoproterenol, dopamine and surgery
phenylephrine
c. Adverse effects (CCPHD)
[1] Epinephrine • CNS effects – anxiety, fear, tension, HA and tremor
a. Actions (CRHL) • Can trigger cardiac arrhythmias, particularly if px is receiving digoxin
i. Cardiovascular • Can induce pulmonary edema due to increased overload caused by
o Major actions are on the cardiovascular system vasoconstrictive properties of the drug
o Strengthens the contractility of the myocardium (positive inotrope: β1 • Patients with hyperthyroidism may have an  production of adrenergic
action) and  its rate of contraction (positive chronotrope: β1 action). receptors in the vasculature, leading to an enhanced response to
Therefore, cardiac output increases. These effects  oxygen demands epinephrine, and the dose must be reduced in these individuals
on the myocardium. • In diabetic patients, dosages of insulin may have to be .
o Activates β1 receptors on the kidney = renin release. Renin is an
enzyme involved in the production of angiotensin II, a potent
vasoconstrictor (HTN).
o Constricts arterioles in the skin, mucus
membranes and viscera (α effects), and
dilates vessels going to the liver and
skeletal muscle (β2 effects). These
combined effects = decrease in renal blood
flow.
o Therefore, the cumulative effect is an  in systolic BP, coupled with a
slight  in diastolic pressure due to β2 receptor-mediated
vasodilation in the skeletal muscle vascular bed.

ii. Respiratory
o Causes powerful bronchodilation (for patients’ w/ asthma) by acting
directly on bronchial smooth muscle (β2 action).
o It also inhibits the release of allergy mediators (IV for emergency-
Epipen) such as histamine from mast cells

iii. Hyperglycemia
o Significant hyperglycemic effect because of  glycogenolysis in the liver
(β2 effect),  release of glucagon (β2 effect), and a  release of insulin
(α2 effect).

iv. Lipolysis
o Epinephrine initiates lipolysis through agonist activity on the β receptors
of adipose tissue.  levels of cAMP stimulate a hormone-sensitive
lipase, which hydrolyxes triglycerides → free fatty acids and glycerol.

b. Therapeutic uses (BACLI)

i. Bronchospasm
o Primary drug used in the emergency treatment of respiratory
conditions when bronchoconstriction has resulted in diminished
respiratory function.
o DOC: Tx of anaphylactic shock (Type I hypersensitivity reaction),
o Within a few minutes after subcutaneous administration, respiratory
function greatly improves

ii. Anaphylactic shock

o DOC: Tx of type I hypersensitivity reactions (including anaphylaxis) in
response to allergies.

iii. Cardiac arrest

o Used to restore cardiac rhythm in px with cardiac arrest

iv. Local anesthesia

o Local anesthetic solutions may contain low concentrations of
epinephrine
o Epinephrine greatly  the duration of local anesthesia by producing
vasoconstriction at the site of injection