DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

MECHANISMS OF DRUG ACTION
Receptors That Affect Concentrations
of Endogenous Ligands
A large number of drugs act by altering the synthesis,
storage, release, transport, or metabolism of endogenous
ligands such as neurotransmitters, hormones, and
other intercellular mediators. For instance, there are
many examples of drugs that act on neuroeffector junctions
by altering neurotransmitter synthesis, storage of
neurotransmitter in vesicles, release of neurotransmitters
into the synaptic cleft, and subsequent removal of
the neurotransmitter from the synaptic cleft by hydrolysis
or transport into the pre-synaptic or post-synaptic
neuron. The effects of these drugs can either enhance or
diminish the effects of the neurotransmitter in order to
achieve the desired therapeutic effect. For instance,
some of the drugs acting on adrenergic neurotransmission
(Chapters 8 and 12) include α-methyltyrosine
(inhibits synthesis of norepinephrine (NE)), cocaine
(blocks NE reuptake), amphetamine (promotes NE
release), and selegeline (inhibits NE breakdown). There
are similar examples for other neurotransmitter systems
including acetylcholine (ACh; Chapters 8 and 10),
dopamine (DA), and serotonin (5HT; Chapters 13-15).
Drugs that affect the synthesis of circulating mediators
such as vasoactive peptides (e.g., angiotensin-converting
enzyme inhibitors; Chapter 26) and lipid-derived
autocoids (e.g., cyclooxygenase inhibitors; Chapter 33)
are also widely used in the treatment of hypertension,
inflammation, myocardial ischemia, and other disease
states.
Receptors That Regulate the Ionic Milieu
A relatively small number of drugs act by affecting the
ionic millieu of blood, urine, and the GI tract. The
receptors for these drugs are ion pumps and transporters,
many of which are expressed only in specialized
cells of the kidney and GI system. Drug effects on
many of these receptors can have effects throughout
the body due to changes in blood electrolytes and pH.
For instance, most of the diuretics (e.g., furosemide,
chlorothiazide, amiloride) act by directly affecting ion
pumps and transporters in epithelial cells of the
nephron that increase the movement of Na + into the
urine, or by altering the expression of ion pumps in
these cells (e.g., aldosterone). Chapter 25 provides a
detailed description of the mechanisms of action of
diuretic drugs. Another therapeutically important target
is the H + ,K + -ATPase (proton pump) of gastric parietal
cells. Irreversible inhibition of this proton pump by
drugs such as esomeprazole reduces gastric acid secretion
by 80-95% (Chapter 45) and is a mainstay of
therepy for peptic ulcer.
Cellular Pathways Activated by
Physiological Receptors
Signal Transduction Pathways. Physiological receptors
have at least two major functions, ligand binding and
message propagation (i.e., signaling). These functions
imply the existence of at least two functional domains
within the receptor: a ligand-binding domain and an
effector domain. The structure and function of these
domains in many families of receptors have been
deduced from high-resolution crystal structures of the
receptor proteins and/or by analysis of the behavior of
intentionally mutated receptors. Many drugs target the
extracelluar ligand-binding domain of physiological
receptors. Examples include the widely used β adrenergic
antagonists. However, drugs can affect the receptor by
targeting either domain, as in the case of anticancer
drugs used to target the epidermal growth factor
receptor (EGFR; Chapters 60-62). Cetuximab is a monoclonal
antibody that targets the extracellular ligandbinding
domain of the EGFR and inhibits epidermal
growth factor (EGF) signaling, whereas the small molecule
drugs gefitinib and erlotinib bind the intracellular
effector domain and block the protein tyrosine kinase
activity of the activated EGFR.
The regulatory actions of a receptor may be
exerted directly on its cellular target(s), on effector protein(s),
or may be conveyed by intermediary cellular
signaling molecules called transducers. The receptor,
its cellular target, and any intermediary molecules are
referred to as a receptor-effector system or signal transduction
pathway. Frequently, the proximal cellular
effector protein is not the ultimate physiological target
but rather is an enzyme, ion channel, or transport protein
that creates, moves, or degrades a small molecule
(e.g., a cyclic nucleotide, inositol trisphosphate, or NO)
or ion (e.g., Ca 2+ ) termed a second messenger. If the
effector is an ion channel or ion pump, the effect of ligand
binding can be a change in membrane potential that
alters the excitability of the cell. Second messengers
can diffuse in the proximity of their synthesis or release
and convey information to a variety of targets, which
may integrate multiple signals. Even though these second
messengers originally were thought of as freely diffusible
molecules within the cell, imaging studies
show that their diffusion and intracellular actions are
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CHAPTER 3
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION