‫معهد واكادميية النهال‬ DR.

Marwan Imad

Adrenergic Agents
Biosynthesis

Catecolamines are the endogenous adrenergic agents which include dopamine,

epinephrine and norepinephrine.

Metabolism
The major mammalian enzymes of importance in the CA metabolism are monoamine
oxidase (MAO) and catechol-O-methyltransferase (COMT).
MAOs oxidatively deaminate CAs to their corresponding aldehydes, which are rapidly
oxidized to the corresponding acid.
The second enzyme of importance in the metabolism of CAs is COMT that O-methylates
3!-OH group of CAs and renders them inactive.

Adrenergic Receptor Subtypes

Which includes ɑ1, ɑ2, ᵦ1 & ᵦ2 all are G-protein coupled receptor.

Drugs Affecting Catecholamine Biosynthesis

metyrosine is a much more effective competitive inhibitor of E and NE production (inhibit

TH) than agents that inhibit any of the other enzymes involved in CA biosynthesis. It is
often possible to “fool” the enzymes into accepting a structurally similar and unnatural
substrate such as metyrosine.
‫معهد واكادميية النهال‬ DR.Marwan Imad

Drugs Affecting Catecholamine Storage and Release

Reserpine, a prototypical and historically important drug, is an indole alkaloid, It depletes
the vesicle storage of NE in sympathetic neurons in PNS, neurons of the CNS, and E in the
adrenal medulla. It is used as antihypertensive agent.

Direct-Acting Sympathomimetics
STRUCTURE–ACTIVITY RELATIONSHIPS

Norepinephrine

it is polar and rapidly metabolized by both COMT and MAO, resulting in poor oral
bioavailability and short DOA.

Epinephrine
Like the other CAs, E is light sensitive and easily oxidized on exposure to air because of
the catechol ring system. The development of a pink-to-brown color indicates oxidative
breakdown. To minimize oxidation, solutions of the drug are stabilized by the addition of
reducing agents such as sodium bisulfite.
‫معهد واكادميية النهال‬ DR.Marwan Imad

Like NE, it lacks oral activity and has short DOA. However, it is much more widely used
clinically than NE. NE has, in general, greater "-activity caused by an additional N-methyl
group. Therefore, E is used to stimulate the heart in cardiac arrest.

Dipivefrin
To overcome several of the pharmacokinetic and pharmaceutical shortcomings of E as an
ophthalmic agent, the prodrug approach has been successfully applied. Dipivefrin is a
prodrug of E that is formed by the esterification of the catechol OH groups of E with pivalic
acid. Most of the advantages of this prodrug over E stem from improved bioavailability.

ɑ-ADRENERGIC RECEPTOR AGONISTS

All selective !1-agonists have therapeutic activity as vasoconstrictors. Structurally, they include
(a) phenylethanolamines such as phenylephrine, metaraminol, and methoxamine and
(b) 2-arylimidazolines such as xylometazoline, oxymetazoline, tetrahydrozoline,
and naphazoline.

Phenylephrine

used is in the treatment of severe hypotension resulting from either shock or drug
administration. It also has widespread use as a nonprescription nasal decongestant in both
oral and topical preparations.

Naphazoline (Privine), tetrahydrozoline (Tyzine,Visine), xylometazoline (Otrivin),

and oxymetazoline (Afrin)
are 2-aralkylimidazolines ɑ1-agonists. These agents are used for their vasoconstrictive effects as
nasal and ophthalmic decongestants. Although nearly all ᵦ-agonists are phenylethanolamine
derivatives, ɑ-receptors accommodate more diverse chemical structures.
Xylometazoline and oxymetazoline have been used as topical nasal decongestants
because of their ability to promote constriction of the nasal mucosa.
‫معهد واكادميية النهال‬ DR.Marwan Imad

Methyldopa (L-!-methyldopa, Aldomet)

acts on ɑ2-receptors in the CNS in the same manner as clonidine, to decrease

sympathetic outflow and lower blood pressure.

ᵦ-ADRENERGIC RECEPTOR AGONISTS

Isoproterenol
is a nonselective and prototypical ᵦ-agonist. After oral administration, the absorption of ISO
is rather erratic and undependable. The principal reason for its poor absorption
characteristics and relatively short DOA is its facile metabolism by sulfate and glucuronide
conjugation of the phenolic OH groups and o-methylation by COMT. Because it is a
catechol, it is sensitive to light and air. Aqueous solutions become pink on standing.

Albuterol
example of selective ᵦ2- agonists whose selectivity results from replacement of the
meta-OH group of the aromatic ring with a hydroxymethyl moiety.

Indirect-Acting Sympathomimetics
Indirect-acting sympathomimetics act by releasing endogenous NE. They also enter the nerve
ending by way of the active-uptake process and displace NE from its storage granules.

Pseudoephedrine
Is the (S,S) diastereoisomer of ephedrine. Whereas ephedrine has a mixed mechanism of
action, L-(+)-pseudoephedrine acts mostly by an indirect mechanism and has virtually no
direct activity.
‫معهد واكادميية النهال‬ DR.Marwan Imad

Sympathomimetics with a Mixed Mechanism of Action

Those phenylethylamines considered to have a mixed mechanism of action usually have no hydroxyls
on the aromatic ring but do have a ᵦ-hydroxyl group.

D-()-Ephedrine.
The pharmacological activity of (1R,2S)-D-()-ephedrine resembles that of E. The drug acts on both ɑ-
and ᵦ-receptors. Its ability to activate ᵦ-receptors probably accounted for its earlier use in asthma. It
is the classic example of a sympathomimetic with a mixed mechanism of action.

ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS)

ɑ-Blockers

Because ɑ-agonists cause vasoconstriction and raise blood pressure, ɑ-blockers should be
therapeutically used as antihypertensive agents, the ɑ-blockers consist of several
compounds of diverse chemical structure.

SELECTIVE ɑ1-BLOCKERS
Prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura)
are quinazoline ɑ1-blockers. As a result, in part, of its greater ɑ1-receptor selectivity, the
quinazoline class of ɑ-blockers exhibits greater clinical utility. Structurally, these agents
consist of three components: the quinazoline ring, the piperazine ring, and the acyl moiety.
The 4-amino group on the quinazoline ring is very important for ɑ1-receptor affinity.
Although they possess a piperazine moiety attached to the quinazoline ring, this group can
be replaced with other heterocyclic moieties (e.g., piperidine moiety) without loss of affinity.
The nature of the acyl group has a significant effect on the pharmacokinetic properties.
‫معهد واكادميية النهال‬ DR.Marwan Imad

ᵦ-Blockers
STRUCTURE–ACTIVITY RELATIONSHIPS (SAR)

ᵦ-Blockers are among the most widely employed antihypertensives and are also
considered the first-line treatment for glaucoma. Most of ᵦ-blockers are in the chemical
class of aryloxypropanolamines.
This simple structural modification, involving the replacement of the aromatic OH groups,
has provided the basis for nearly all of the approaches used in subsequent efforts to
design and synthesize therapeutically useful ᵦ-blockers.

Propranolol belongs to the group of ᵦ-blockers known as aryloxypropanolamines. This term

reflects the fact that an OCH2 group has been incorporated into the molecule between the
aromatic ring and the ethylamino side chain. Because this structural feature is frequently
found in ᵦ-blockers, the assumption is made that the OCH2 group is responsible for the
antagonistic properties of the molecules. However, this is not true; in fact, the OCH 2 group
is present in several compounds that are potent ᵦ-agonists. This latter fact again leads to
the conclusion that it is the nature of the aromatic ring and its substituents that is the
primary determinant of ᵦ-antagonistic activity. The aryl group also affects the absorption,
excretion, and metabolism of the ᵦ-blockers.

The nature of the aromatic ring is also a determinant in their ᵦ1-selectivity. One common
structural feature of many cardioselective ᵦ1-blockers is the presence of a parasubstituent
of sufficient size on the aromatic ring along with the absence of meta-substituents. Practolol
is the prototypical example of a ᵦ1-blocker of this structural type. It was the first
cardioselective ᵦ1-blocker to be used extensively in humans. Because it produced several
toxic effects, however, it is no longer in general use in most countries.

For ᵦ-blockers, the ᵦ-OH-substituted carbon must be in the S absolute configuration for
maximal ᵦ-blocking activity.
‫معهد واكادميية النهال‬ DR.Marwan Imad

ᵦ1-SELECTIVE BLOCKERS
The discovery that ᵦ-blockers are useful in the treatment of cardiovascular disease, such as
hypertension, stimulated a search for cardioselective ᵦ-blockers. Cardioselective ᵦ1-blockers are
drugs that have a greater affinity for the ᵦ1-receptors of the heart than for ᵦ2-receptors in other
tissues. Such cardioselective agents should provide two important therapeutic advantages. The first
advantage should be the lack of a blocking effect on the ᵦ2-receptors in the bronchi. Theoretically,
this would make ᵦ1-blockers safe for use in patients who have bronchitis or bronchial asthma. The
second advantage should be the absence of blockade of the vascular ᵦ2-receptors, which mediate
vasodilation. This would be expected to reduce or eliminate the increase in peripheral resistance
that sometimes occurs after the administration of nonselective ᵦ-blockers. Unfortunately,
cardioselectivity is usually observed with ᵦ1-blockers at only relatively low doses. At normal
therapeutic doses, much of the selectivity is lost.

At present, the following "1-selective blockers are used therapeutically: acebutolol

(Sectral), atenolol (Tenormin), betaxolol (Kerlone, Betoptic), bisoprolol (Zebeta), esmolol
(Brevibloc), and metoprolol (Lopressor).