Page 156 - Basic _ Clinical Pharmacology ( PDFDrive )

142 SECTION II Autonomic Drugs

transporter, SERT), and other neurotransmitters. The NET, sur-
Therapeutic Potential of Biased prisingly, has equivalent affinity for dopamine as for norepineph-
Agonists at Beta Receptors rine, and it can sometimes clear dopamine in brain areas where
DAT is low, like the cortex.
Traditional β agonists like epinephrine activate cardiac Blockade of the NET, eg, by the nonselective psychostimulant
β 1 receptors, increasing heart rate and cardiac workload cocaine or the NET selective agents atomoxetine or reboxetine,
through coupling with G proteins. This can be deleterious in impairs this primary site of norepinephrine removal and thus syn-
situations such as myocardial infarction. Beta 1 receptors are aptic norepinephrine levels rise, leading to greater stimulation of
also coupled through G protein-independent signaling path- α and β adrenoceptors. In the periphery this effect may produce a
ways involving β-arrestin, which are thought to be cardio- clinical picture of sympathetic activation, but it is often counter-
protective. A “biased” agonist could potentially activate only balanced by concomitant stimulation of α 2 adrenoceptors in the
the cardioprotective, β-arrestin–mediated signaling (and not brain stem that reduces sympathetic activation.
the G protein-coupled–mediated signals that lead to greater However, the function of the norepinephrine and dopamine
cardiac workload). Such a biased agonist would be of great transporters is complex, and drugs can interact with the NET to
therapeutic potential in situations such as myocardial infarc- actually reverse the direction of transport and induce the release of
tion or heart failure. Biased agonists potent enough to reach intraneuronal neurotransmitter. This is illustrated in Figure 9–3.
this therapeutic goal have not yet been developed. Under normal circumstances (panel A), presynaptic NET (red)
inactivates and recycles norepinephrine (NE, red) released by
vesicular fusion. In panel B, amphetamine (black) acts as both an
NET substrate and a reuptake blocker, eliciting reverse transport
Adrenoceptor Polymorphisms and blocking normal uptake, thereby increasing NE levels in and
beyond the synaptic cleft. In panel C, agents such as methylphe-
Since elucidation of the sequences of the genes encoding the α ,
1
α , and β subtypes of adrenoceptors, it has become clear that nidate and cocaine (hexagons) block NET-mediated NE reuptake
2
there are relatively common genetic polymorphisms for many of and enhance NE signaling.
these receptor subtypes in humans. Some of these may lead to
changes in critical amino acid sequences that have pharmacologic
importance. Often, distinct polymorphisms occur in specific com- ■ MEDICINAL CHEMISTRY OF
binations termed haplotypes. Some polymorphisms are clinically SYMPATHOMIMETIC DRUGS
relevant and have been shown to alter susceptibility to diseases
such as heart failure, modify the propensity of a receptor to desen- Phenylethylamine may be considered the parent compound from
sitize, or modulate therapeutic responses to drugs in diseases such which sympathomimetic drugs are derived (Figure 9–4). This
as asthma. In many other cases, studies have reported inconsistent compound consists of a benzene ring with an ethylamine side
results as to the pathophysiologic importance of polymorphisms. chain. The presence of –OH groups at the 3 and 4 positions of the
benzene ring yields sympathomimetic drugs collectively known as
The Norepinephrine Transporter catecholamines. Additional substitutions made on (1) the benzene
ring, (2) the terminal amino group, and (3) the α or β carbons pro-
When norepinephrine is released into the synaptic cleft, it binds duce catechols with different affinity for α and β receptors, from
to postsynaptic adrenoceptors to elicit the expected physiologic almost pure α agonists (methoxamine) to almost pure β agonists
effect. However, just as the release of neurotransmitters is a tightly (isoproterenol).
regulated process, the mechanisms for removal of neurotransmit- In addition to determining relative affinity to receptor subtypes,
ter must also be highly effective. The norepinephrine transporter chemical structure also determines the pharmacokinetic properties
(NET) is the principal route by which this occurs. It is particu- and bioavailability of these molecules.
larly efficient in the synapses of the heart, where up to 90% of
released norepinephrine is removed by the NET. Remaining
synaptic norepinephrine may escape into the extrasynaptic space A. Substitution on the Benzene Ring
and enter the bloodstream or be taken up into extraneuronal cells Maximal α and β activity is found with catecholamines, ie, drugs
and metabolized by catechol-O-methyltransferase. In other sites having –OH groups at the 3 and 4 positions on the benzene ring.
such as the vasculature, where synaptic structures are less well The absence of one or the other of these groups dramatically
developed, removal may still be 60% or more by NET. The NET, reduces the potency of these drugs. For example, phenylephrine
often situated on the presynaptic neuronal membrane, pumps the (Figure 9–5) is much less potent than epinephrine; its affinity to
synaptic norepinephrine back into the neuron cell cytoplasm. In α receptors is decreased approximately 100-fold, but because its
the cell, this norepinephrine may reenter the vesicles or undergo β activity is almost negligible except at very high concentrations,
metabolism through monoamine oxidase to dihydroxyphenylgly- it is a selective α agonist.
col (DHPG). Elsewhere in the body similar transporters remove On the other hand, the presence of –OH groups make catechol-
dopamine (dopamine transporter, DAT), serotonin (serotonin amines subject to inactivation by catechol-O-methyltransferase