pharmacodynamics

Lecture 6
Pharmacodynamics
describes the actions of a drug on the body and the
influence of drug concentrations on the magnitude of the response. Most
drugs exert their effects, both beneficial and harmful, by interacting with
receptors (that is, specialized target macromolecules) present on the cell
surface or within the cell. The drug–receptor complex initiates alterations
in biochemical and/or molecular activity of a cell by a process called signal
transduction
The drug–receptor complex
Cells have many different types of receptors, each of which is specific
for a particular agonist and produces a unique response. Cardiac cell
membranes, for example, contain ? receptors that bind and respond to
epinephrine or norepinephrine, as well as muscarinic receptors specific
for acetylcholine. These different receptor populations dynamically
interact to control the heart’s vital functions.
The magnitude of the response is proportional to the number of drug–
receptor complexes. This concept is closely related to the formation of
complexes between enzyme and substrate or antigen and antibody.
These interactions have many common features, perhaps the most noteworthy
being specificity of the receptor for a given agonist. Most receptors
are named for the type of agonist that interacts best with it. For example,
the receptor for histamine is called a histamine receptor. Although much
of this chapter centers on the interaction of drugs with specific receptors,
it is important to know that not all drugs exert their effects by interacting
with a receptor. Antacids, for instance, chemically neutralize excess gastric
acid, thereby reducing the symptoms of “heartburn.”
Receptor states
Receptors exist in at least two states, inactive (R) and active (R*),
that are in reversible equilibrium with one another, usually favoring the
inactive state. Binding of agonists causes the equilibrium to shift from
R to R* to produce a biologic effect. Antagonists occupy the receptor
but do not increase the fraction of R* and may stabilize the receptor in
the inactive state. Some drugs (partial agonists) cause similar shifts in
equilibrium from R to R*, but the fraction of R* is less than that caused
by an agonist (but still more than that caused by an antagonist). The
magnitude of biological effect is directly related to the fraction of R*.
Agonists, antagonists, and partial agonists are examples of ligands,
or molecules that bind to the activation site on the receptor.
. Major receptor families
Pharmacology defines a receptor as any biologic molecule to which
a drug binds and produces a measurable response. Thus, enzymes,
nucleic acids, and structural proteins can act as receptors for drugs or
endogenous agonists. However, the richest sources of therapeutically
relevant pharmacologic receptors are proteins that transduce extracellular
signals into intracellular responses. These receptors may be
divided into four families: 1) ligand-gated ion channels, 2) G protein–
coupled receptors, 3) enzyme-linked receptors, and 4) intracellular
receptors . The type of receptor a ligand interacts with
depends on the chemical nature of the ligand. Hydrophilic ligands
interact with receptors that are found on the cell surface
. In contrast, hydrophobic ligands enter cells through the
lipid bilayers of the cell membrane to interact with receptors found
inside cells
Transmembrane ligand-gated ion channels: The extracellular
portion of ligand-gated ion channels usually contains the ligandbinding
site. This site regulates the shape of the pore through which
ions can flow across cell membranes . The channel is
usually closed until the receptor is activated by an agonist, which
opens the channel briefly for a few milliseconds. Depending on
the ion conducted through these channels, these receptors mediate
diverse functions, including neurotransmission, and cardiac
or muscle contraction. For example, stimulation of the nicotinic
receptor by acetylcholine results in sodium influx and potassium
outflux, generating an action potential in a neuron or contraction
in skeletal muscle. On the other hand, agonist stimulation of the
?-aminobutyric acid (GABA) receptor increases chloride influx
and hyperpolarization of neurons. Voltage-gated ion channels
may also possess ligand-binding sites that can regulate channel
function. For example, local anesthetics bind to the voltage-
gated
sodium channel, inhibiting sodium influx and decreasing neuronal
conduction
Transmembrane G protein–coupled receptors: The extracellular
domain of this receptor contains the ligand-binding area, and
the intracellular domain interacts (when activated) with a G protein
or effector molecule. There are many kinds of G proteins (for
example, Gs, Gi, and Gq), but they all are composed of three protein
subunits. The ? subunit binds guanosine triphosphate (GTP),
and the ? and ? subunits anchor the G protein in the cell membrane
Binding of an agonist to the receptor increases
GTP binding to the ? subunit, causing dissociation of the ?-GTP
complex from the ?? complex. These two complexes can then
interact with other cellular effectors, usually an enzyme, a protein,
or an ion channel, that are responsible for further actions within
the cell. These responses usually last several seconds to minutes.
Sometimes, the activated effectors produce second messengers
that further activate other effectors in the cell, causing a signal
cascade effect
A common effector, activated by Gs and inhibited by Gi, is adenylyl
cyclase, which produces the second messenger cyclic adenosine
monophosphate (cAMP). Gq activates phospholipase C, generating
two other second messengers: inositol 1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG). DAG and cAMP activate different
protein kinases within the cell, leading to a myriad of physiological
effects. IP3 regulates intracellular free calcium concentrations, as
well as some protein kinases
Enzyme-linked receptors: This family of receptors consists of
a protein that may form dimers or multisubunit complexes. When
activated, these receptors undergo conformational changes
resulting in increased cytosolic enzyme activity, depending on
their structure
and function . This response lasts
on the order of minutes to hours. The most common enzymelinked
receptors (epidermal growth factor, platelet-derived
growth factor, atrial natriuretic peptide, insulin, and others) possess
tyrosine kinase activity as part of their structure. The activated
receptor phosphorylates tyrosine residues on itself and
then other specific proteins . Phosphorylation can
substantially modify the structure of the target protein, thereby
acting as a molecular switch. For example, when the peptide
hormone insulin binds to two of its receptor subunits, their
intrinsic tyrosine kinase activity causes autophosphorylation of
the receptor itself. In turn, the phosphorylated receptor phosphorylates
other peptides or proteins that subsequently activate
other important cellular signals. This cascade of activations
results in a multiplication of the initial signal, much like that with
G protein– coupled receptors
Intracellular receptors: The fourth family of receptors differs
considerably from the other three in that the receptor is
entirely intracellular, and, therefore, the ligand must diffuse into
the cell to interact with the receptor (Figure 2.5). In order to
move across the target cell membrane, the ligand must have
sufficient lipid solubility. The primary targets of these ligand–
receptor complexes are transcription factors in the cell nucleus.
Binding of the ligand with its receptor generally activates the
receptor via dissociation from a variety of binding proteins.
The activated ligand–receptor complex then translocates to the
nucleus, where it often dimerizes before binding to transcription
factors that regulate gene expression. The activation or inactivation
of these factors causes the transcription of DNA into RNA
and translation of RNA into an array of proteins. The time course
of activation and response of these receptors is on the order
of hours to days. For example, steroid hormones exert their
action on target cells via intracellular receptors. Other targets
of intracellular ligands are structural proteins, enzymes, RNA,
and ribosomes. For example, tubulin is the target of antineoplastic
agents such as paclitaxel (see Chapter 46), the enzyme
dihydrofolate reductase is the target of antimicrobials such as
trimethoprim , and the 50S subunit of the bacterial
ribosome is the target of macrolide antibiotics such as erythromycin
Some characteristics of signal transduction
Signal transduction has two important features: 1) the ability to amplify
small signals and 2) mechanisms to protect the cell from excessive
stimulation.
1. Signal amplification: A characteristic of G protein–linked and
enzyme-linked receptors is their ability to amplify signal intensity
and duration. For example, a single agonist–receptor complex
can interact with many G proteins, thereby multiplying the
original signal manyfold. Additionally, activated G proteins persist
for a longer duration than does the original agonist–receptor
complex. The binding of albuterol, for example, may only exist
for a few milliseconds, but the subsequent activated G proteins
may last for hundreds of milliseconds. Further prolongation and
amplification of the initial signal are mediated by the interaction
between G proteins and their respective intracellular targets.
Because of this amplification, only a fraction of the total receptors
for a specific ligand may need to be occupied to elicit a
maximal response. Systems that exhibit this behavior are said
to have spare receptors. Spare receptors are exhibited by insulin
receptors, where it is estimated that 99% of receptors are
“spare.” This constitutes an immense functional reserve that
ensures that adequate amounts of glucose enter the cell. On
the other hand, in the human heart, only about 5% to 10% of
the total ?-adrenoceptors are spare. An important implication of
this observation is that little functional reserve exists in the failing
heart, because most receptors must be occupied to obtain
maximum contractility.
2. Desensitization and down-regulation of receptors: Repeated
or continuous administration of an agonist (or an antagonist) may
lead to changes in the responsiveness of the receptor. To prevent
potential damage to the cell (for example, high concentrations of
calcium, initiating cell death), several mechanisms have evolved
to protect a cell from excessive stimulation. When a receptor is
exposed to repeated administration of an agonist, the receptor
becomes desensitized resulting in a diminished
effect. This phenomenon, called tachyphylaxis, is due to either
phosphorylation or a similar chemical event that renders receptors
on the cell surface unresponsive to the ligand. In addition,
receptors may be down-regulated such that they are internalized
and sequestered within the cell, unavailable for further agonist
interaction. These receptors may be recycled to the cell surface,
restoring sensitivity, or, alternatively, may be further processed
and degraded, decreasing the total number of receptors available.
Some receptors, particularly ion channels, require a finite time following
stimulation before they can be activated again. During this
recovery phase, unresponsive receptors are said to be “refractory.”
Similarly, repeated exposure of a receptor to an antagonist may
result in up-regulation of receptors, in which receptor reserves
are inserted into the membrane, increasing the total number of
receptors available. Up-regulation of receptors can make the cells
more sensitive to agonists and/or more resistant to the effect of
the antagonist.