LipCh6AdrenergicAgonists.txt

The adrenergic drugs affect receptors that are stimulated by norepineph-rine or epinephrine.

• Some adrenergic drugs act directly on the adrener-gic receptor (adrenoceptor) by activating it and are said to be
• 1. sympath-omimetic.

• Others, which will be dealt with in Chapter 7, block the action of the neurotransmitters at the receptors
• 2 (sympatholytics),

whereas still other drugs afect adrenergic function by interrupting the release of nor-epinephrine from adrenergic neurons.

This chapter describes agents that either directly or indirectly stimulate adrenoceptors (Figure 6.1)

II. THE ADRENERGIC NEURON

Adrenergic neurons release norepinephrine as the primary neuro trans-mitter.

• 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 efector organs.

The adrenergic neurons and receptors,

located either presynaptically on the neuron or postsynapti-cally on the efector organ,

are the sites of action of the adrenergic drugs (Figure 6.2

A. Neurotransmission at adrenergic neurons

Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons (see p. 43),

except that

norepinephrine is the neurotransmitter instead of acetylcholine.

Neurotransmission takes place at numerous bead-like enlargements called varicosities.

• The process involves fve steps:
• 1 synthesis,
• 2 storage,
• 3 release, and
• 4 receptor binding of norepinephrine, followed by 5 removal of the neurotransmitter from the synaptic gap (Figure 6.3).

1. Synthesis of norepinephrine:

• A Tyrosine
• is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to
• B dihydroxyphenylalanine (DOPA)
• by tyrosine hydroxylase.

1 This is the rate-limiting step in the formation of nor-epinephrine.

DOPA is then

decarboxylated

by the enzyme

dopa decarboxylase (aromatic l-amino acid decarboxylase) to form

dopamine in the cytoplasm of the presynaptic neuron.

2. Storage of norepinephrine in vesicles:

• A. 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 (see p. 90).

Dopamine is hydroxylated to form

B norepinephrine

by the enzyme,

dopamine β-hydroxylase.

[Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP), and β-hydroxylase, as well as other cotransmitters.]

In the adrenal medulla,

norepinephrine

is methylated to yield

epinephrine,

both of which are stored in chromafn cells.

On stimulation, the adrenal medulla releases about 80 percent epineph-rine and 20 percent norepinephrine directly into the circulation.

3. Release of norepinephrine:

An action potential arriving at the nerve junction triggers an infux of

calcium ions

from the extracel-lular fuid 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.

This release is blocked by drugs such as

guanethidine (see p. 91).

4. Binding to α receptor:

Norepinephrine released from the synaptic vesicles difuses across the synaptic space and binds to either

1. post-synaptic receptors on the efector organ or to

2. presynaptic receptors on the nerve ending.

The recognition of norepinephrine by the mem-brane 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 efector cell.

Adrenergic recep-tors use both the

1. cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the

2. phosphatidylinositol cycle,3 to trans-duce the signal into an efect.

5. Removal of norepinephrine:

Norepinephrine may

1) difuse out of the synaptic space and enter the general circulation,

2) be metabo-lized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or

3) 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
• 1. imipramine, or by
• 2 cocaine (see Figure 6.3).

Uptake of norepinephrine into the presyn-aptic neuron is the primary mechanism for termination of norepi-nephrine’s efect

6. Potential fates of recaptured norepinephrine:

Once norepi-nephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into

adrenergic vesicles via the amine transporter sys-tem 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 mito-chondria.

• The inactive products of norepinephrine metabolism are excreted in the urine as
• 1 vanillylmandelic acid,
• 2 metanephrine, and
• 3 normetanephrine.

n the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, des-ignated

1 α and

2 β,

were initially identif ed on the basis of their responses to the adrenergic agonists

1 epinephrine,

2 norepinephrine, and

3 isoprotere-nol.

The use of specif c blocking drugs and the cloning of genes have revealed the molecular identities of a number of receptor subtypes. \

These proteins belong to a multigene family.

Alterations in the primary structure of the receptors inf uence their affinity for various agents.

1. α1 and α2 Receptors:

The α-adrenoceptors show a weak response to the synthetic agonist

isoproterenol,

but they are responsive to the naturally occurring catecholamines

epinephrine and norepinephrine (Figure 6.4).

For α receptors, the rank order of potency is

ep inephrine ≥ norepinephrine >> isoproterenol.

The α-adrenoceptors are sub-divided into two subgroups,

α1 and α2,

based on their afnities for

α agonists and blocking drugs.

• For example, the α1 receptors have a higher afnity for
• 1. phenylephrine than do the α2 receptors. Conversely, the drug
• 2. clonidine selectively binds to α2 receptors and has less efect on α1 receptors.

a. α1 Receptors:

These receptors are present on the

post-synaptic membrane of the efector organs

and mediate many of the classic efects—originally designated as α-adrenergic—

involving constriction of smooth muscle.

Activation of α1 receptors initiates a series of reactions through a

G protein activation of phospholipase C,

resulting in the generation of

inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol.

IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and

DAG turns on other proteins within the cell (Figure 6.5).

b. α2 Receptors:

These receptors, located primarily on

presynaptic nerve endings and

on other cells, such as the β cell of the pancreas, and

on certain vascular smooth muscle cells,

control adrenergic neuromediator and insulin output, respectively.

When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors.

A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane (see Figure 6.5).

The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron.

This inhibitory action decreases further output from the adrenergic neuron and

serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity.

[Note: In this instance these receptors are acting as inhibitory autoreceptors.]

α2 Receptors are also found on presynpatic parasympathetic neurons.

Norepinephrine released from a presynaptic sympathetic neuron can difuse to and interact with these receptors, inhibiting acetylcholine release

[Note: In these instances these receptors are behaving as inhibitory heteroreceptors.]

This is another local modulating mechanism to control autonomic activity in a given area.

In contrast to α1 receptors, the efects of binding at α2 receptors are mediated by

inhibition of adenylyl cyclase and a fall in the levels of intracellular cAM

. Further subdivisions:

The α1 and α2 receptors are further divided into

• α1A,
• α1B,
• α1C, and
• α1D

and into

α2A,

α2B,

α2C, and

α2D.

This extended classifcation is necessary for understanding the selectivity of some drugs.

For example,

tamsulosin

is a selective α1A antagonist that is used to treat benign prostate hyperplasia.

The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland

β Receptors:

β Receptors exhibit a set of responses dif erent from those of the α receptors.

• These are characterized by a strong response to
• 1. isoproterenol,

• with less sensitivity to
• 2 epinephrine and
• 3 norepineph-rine (see Figure 6.4).

For β receptors, the rank order of potency is

isoproterenol > epinephrine > norepinephrine.

• The β-adrenoceptors can be subdivided into three major subgroups,
• β1,
• β2, and
• β3,
• based on their af nities for adrenergic agonists and antagonists,

although several others have been identif ed by gene cloning.

[It is known that β3 receptors are involved in lipolysis but their role in other specif c reactions are not known] .

β1 Receptors have approximately equal af nities for epinephrine and norepinephrine, whereas

β2 receptors have a higher af nity for epinephrine than for norepinephrine.

Thus,

tissues with a predominance of β2 receptors (such as the vascula-ture of skeletal muscle) are particularly responsive to the hormonal ef ects of circulating epinephrine released by the adrenal medulla.

Binding of a neurotransmitter at any of the three β receptors results in activation of

adenylyl cyclase and, therefore, increased concentra-tions of cAMP within the cell

Distribution of receptors:

Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor.

For example,

1 tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors,

but the β2 receptors predominate.

Other tissues may have one type of receptor exclusively, with practically no signif cant numbers of other types of adrenergic receptors.

For example,

• 2 the heart contains
• predominantly β1 receptors.

4. Characteristic responses mediated by adrenoceptors:

It is use-ful to organize the physiologic responses to adrenergic stimulation according to receptor type,

because many drugs preferentially stim-ulate or block one type of receptor.

Figure 6.6 summarizes the most prominent ef ects mediated by the adrenoceptors.

As a generaliza-tion,

1 stimulation of α1 receptors characteristically produces

vasocon-striction (particularly in skin and abdominal viscera)

and an increase in total peripheral resistance

and blood pressure.

Conversely, stimu-lation of β1 receptors characteristically causes

cardiac stimulation,

whereas stimulation of β2 receptors produces

vasodilation (in skel-etal vascular beds) and

bronchiolar relaxation

5. Desensitization of receptors:

Prolonged exposure to the cat-echolamines reduces the responsiveness of these receptors,

a phenomenon known as desensitization.

Three mechanisms have been suggested to explain this phenomenon:

1) sequestration of the receptors so that they are unavailable for interaction with the ligand;

2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis; and

3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase A or β-adrenergic receptor kinase.

Most of the adrenergic drugs are derivatives of

β-phenylethylamine (Figure 6.7).

Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities to dif erentiate between α and β receptors and to penetrate the CNS.

Two important struc-tural features of these drugs are the number and location of OH substitu-tions on the benzene ring and the nature of the substituent on the amino nitrogen