Loretta Walker, Ph.D.

ADRENERGIC AGENTS
Reading:

Rang & Dales Pharmacology, 6th Edition, Chapter 11

Objectives:
1. To define adrenergic drugs and categorize them based on
mechanism of action: alpha-selective; beta-selective; non-selective;
indirect acting; mixed acting; endogenous sympathomimetics
2. To describe the pharmacological effects of adrenergic agents
DRUGS
Norepinephrine
Phenylephrine
Methoxamine
Clonidine

Isoproterenol
Dobutamine
Albuterol
Terbutaline
Epinephrine

Tyramine
Cocaine
Phenelzine

Amphetamine
Methylphenidate
Ephedrine

Norepinephrine

Dopamine

Definitions: Sympathomimetic is often used to denote adrenergic; however, they

are not necessarily interchangeable. Sympathomimetic agents evoke responses
similar to some or all of those expected to result from sympathetic nerve
activation or from epinephrine secreted from the adrenal medulla. Adrenergic
agents encompass a wider group of compounds that nonetheless largely act on
targets of the sympathetic nervous system
Overview of synthesis, storage, release and inactivation of endogenous
catecholamines:
The catecholamines dopamine, norepinephrine (noradrenaline), or epinephrine
(adrenaline) are synthesized from tyrosine in a series of enzymatic modifications
that occur in a nerve terminal, or in the case of epinephrine, in a chromaffin cell.
They are stored in vesicles (synaptic vesicles or chromaffin granules), available for
secretion by exocytosis on stimulation by a variety of means. After binding to
target receptors, the action of the released neurotransmitters - dopamine and
norepinephrine- is largely terminated by diffusion and uptake into different
compartments. Subsequently, the catecholamines are metabolized.
TH
DDC
DH
PNMT
TyrosineDOPA Dopamine Norepinephrine Epinephrine
(DA)
(NE)
(E)
TH=tyrosine hydroxylase; DDC=Dopa decarboxylase;
DBH=dopamine beta hydroxylase;

Synthesis:

PNMT=phenylethanolamine N-methyltransferase
Action:

DA acts on D1 = D2 receptors >> Beta1 receptors>>Alpha-adrenoceptors

NE acts on Alpha1 = Alpha2 > Beta1 >> Beta2
E acts on Beta1 = Beta2 > Alpha1 = Alpha2
(Rang et al. states that E has little selectivity; however, at low doses
it is decidedly selective for Beta2 receptors; NE and E are about
equivalent at Beta1)
Removal:

Uptake 1 via carrier into the nerve terminal

Uptake 2 via carrier into postsynaptic and/or glial cell

Metabolism: Monoamine oxidase (MAO) - high concentrations in nerve terminal

MAO-A: degrades NE (and tyramine and serotonin)
MAO-B: degrades DA
Catechol-O-methyltransferase (COMT) - postsynaptic;
present in gut and liver

Direct-Acting Agonists:
Act directly on Alpha- or Beta-adrenoceptors or on dopamine receptors
(action: usually sympathomimetic)
Alpha agonists
Beta agonists
norepinephrine
Alpha1 agonists
phenylephrine
methoxamine

isoproterenol

Alpha2 agonists
clonidine

Beta1 agonists
dobutamine

Beta2 agonists
terbutaline
albuterol

Indirect-Acting Agents:
Act indirectly by blocking reuptake, blocking degradation or by inducing
release of endogenous catecholamines
Uptake 1 blocker: cocaine

MAO-I:

phenelzine

Releaser:

tyramine

Mixed-Acting Agents:
Act indirectly to induce release of catecholamines and directly as agonists
Ephedrine; pseudoephedrine
[Amphetamine; methyphenidate]
(amphetamine and amphetamine-like compounds have very weak agonist
activity, and as such are sometimes listed only as indirect-acting agents)

Endogenous sympathomimetics:
All poorly absorbed on oral administration due to degradation by COMT.
Predominant effect of intravenous administration is on cardiovascular system
-

Epinephrine:
low dose - largely vasodilation leading to drop in blood pressure due
to high potency at vessel Beta2 receptors

high dose - increased in systolic blood pressure via action on vessel

Alpha receptors; maintained decrease in diastolic pressure via Beta2
receptors (hence, mean arterial pressure may not be greatly elevated, but it
is); increased cardiac output and rate due to potent action on Beta1
receptors (rate somewhat blunted due to vagal reflex)

Norepinephrine:
sharp increase in diastolic and systolic blood pressure via action on
vessel Alpha receptors; increase in cardiac contraction; small if any increase
in heart rate via Beta1 receptors (effect counteracted by vagal reflex)

Dopamine:
low dose - vasodilation leading to drop in blood pressure via D1
receptors; enhanced renal perfusion due to pronounced renal vasodilation
high dose - small increase in cardiac output via Beta1 receptors;
vasocontriction due to activation of vessel Alpha receptors

Other sympathomimetics:
-

Isoproterenol (Isoprenaline):
strong vasodilator and cardiac stimulant due to very selective action
on Beta receptors, resulting in sharp drop in blood pressure with
concomitant increase in cardiac output and rate

Phenylephrine:
vasocontrictor due to selective action on Alpha (mainly Alpha1)
receptors; effective mydriatic and decongestant due to action on Alpha1
receptors. (Why a decongestant? Answer can be found below)
-

Clonidine:
short-term action as vasocontrictor due to direct action on Alpha2
receptors in blood vessels; long-term vasodilation likely resulting from action
on presynaptic Alpha2 receptors in brain reducing sympathetic discharge
-

Dobutamine:
increase cardiac output via selective action on Beta1 receptors

Albuterol:
effective bronchodilator, whether via inhalation or oral
administration, due to highly selective action on Beta2 receptors and long
duration of action
-

Ephedrine:
effective decongestant due to action on Alpha1 receptors on vessels in
nasal mucosa, decreasing fluid output, and long duration of action; mild CNS
stimulation

[Modified after notes prepared by: Robert A. Nichols, Ph.D.]