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Pharmacodynamics
Mark Marino; Zohaib Jamal; Patrick M. Zito.
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Last Update: August 26, 2020.

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Introduction
“Did we but know the mechanical affections of the particles of rhubarb,
hemlock, opium, and a man... we should be able to tell beforehand that
rhubarb will purge, hemlock kill and opium make a man sleepy...”
John Locke Essay Concerning Human Understanding
Pharmacodynamics is the study of a drug's molecular, biochemical, and
physiologic effects or actions. It comes from the Greek
words "pharmakon" meaning "drug" and "dynamikos" meaning "power." All
drugs produce their effects by interacting with biological structures or targets
at the molecular level to induce a change in how the target molecule
functions in regards to subsequent intermolecular interactions. These
interactions include receptor binding, post-receptor effects, and chemical
interactions. Examples of these types of interactions include (1) drugs
binding to an active site of an enzyme, (2) drugs that interact with cell surface
signaling proteins to disrupt downstream signaling, and (3) drugs that act by
binding molecules like tumor necrosis factor (TNF).[1]  Subsequent to the
drug-target interaction occurring downstream, effects are elicited which can
be measured by biochemical or clinical means. Examples of this include the
(1) inhibition of platelet aggregation after administering aspirin, (2) the
reduction of blood pressure after ACE inhibitors, and (3) the blood-glucose-
lowering effect of insulin.[2][3][2] While these examples seem obvious, the
administration of the preceding drug examples should be kept in mind so
practitioners do not administer these drugs to inhibit platelet aggregation,
lower blood pressure or lower blood glucose but to reduce the risks of
cerebrovascular accident, myocardial infarction, and renal and eye
complications through the drug's pharmacodynamic effects.[4]
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Issues of Concern
Pharmacodynamic Concepts
There are a few key concepts and terms used in the description of
pharmacodynamics that describe the extent and duration of a drug's action.
 Emax is the maximal effect of a drug on a parameter that is measured.
For example, this could be a measure of platelet inhibition as an ex-
vivo test or the maximum lowering of blood pressure
 EC50 is the concentration of the drug at a steady-state that produces
half of the maximum effect
 Hill coefficient is the slope of the relationship between drug
concentration and drug effect. Hill coefficients above 2 indicate a steep
relationship (i.e., small changes in concentration produce large changes
in effect), and hill coefficients above 3 indicate an almost instantaneous
"all or none" effect.[5]
General Mechanisms of Drug Actions
Drugs produce their effects by interacting with biologic targets, but the time
course of the pharmacodynamic effect is dependent on the mechanism and
biochemical pathway of the target. Effects can be classified as direct or
indirect and immediate or delayed. Direct effects are usually the result of
drugs interacting with a receptor or enzyme that is central to the pathway of
the effect. Beta-blockers inhibit receptors that directly modulate cAMP levels
in smooth muscle cells in the vasculature. Indirect effects are the result of
drugs interacting with receptors, proteins of other biologic structures that
significantly upstream from the end biochemical process that produces the
drug effect. Corticosteroids bind to nuclear transcription factors in the cell
cytosol which translocate to the nucleus and inhibit transcription of DNA to
mRNA encoding for several inflammatory proteins.[6] Immediate effects are
usually secondary to direct drug effects. Neuromuscular blocking agents such
as succinylcholine, which consists of two acetylcholine (ACh) molecules
linked end to end by their acetyl groups, interact with the nicotinic
acetylcholine receptor (nAChR) on skeletal muscle cells and leave the
channel in an open state, resulting in membrane depolarization and
generation of an action potential, muscle contraction and then paralysis
within 60 seconds after administration.[7] Delayed effects can be secondary
to direct drug effects. Chemotherapy agents that interfere with DNA
synthesis, like cytosine arabinoside which is used in acute myeloid leukemia,
produce bone marrow suppression that occurs several days after
administration.
Dosing Principles-Based Upon Pharmacodynamics
Kd: The pharmacologic response depends on the drug binding to its target as
well as the concentration of the drug at the receptor site. Kd measures how
tightly a drug binds to its receptor. Kd is defined as the ratio of rate constants
for association (kon) and dissociation (koff) of the drug to and from the
receptors. At equilibrium, the rate of receptor-drug complex formation is
equal to the rate of dissociation into its components receptor + drug. The
measurement of the reaction rate constants can be used to define an
equilibrium or affinity constant (1/Kd). The smaller the Kd value, the greater
the affinity of the antibody for its target. For example, albuterol has a Kd of
100 nanomolar (nM) for the beta-2 receptor while erlotinib has a Kd of 0.35
nM for the estimated glomerular filtration rate (EGFR) receptor indicating
that erlotinib has approximately 300 times the receptor interaction than
albuterol.[8]
Receptor Occupancy: From the law of mass action the more receptors that are
occupied by the drug, the greater the pharmacodynamic response; but all
receptors do not need to be occupied in order to get a maximal response. This
is the concept of spare receptors and occurs commonly to include muscarinic
and nicotinic acetylcholine receptors, steroid receptors, and catecholamine
receptors. Maximal effects are obtained by less than maximal receptor
occupancy by signal amplification.
Receptor Up- and Downregulation: Chronic exposure of a receptor to an
antagonist typically leads to upregulation, or an increased number of
receptors, while chronic exposure of a receptor to an agonist causes
downregulation or a decreased number of receptors. [9]Other mechanisms
involving alteration of downstream receptor signaling may also be involved
in up- or downmodulation without altering the receptor number on the cell
membrane. [10]The insulin receptor undergoes downregulation to chronic
exposure to insulin. The number of surface receptors for insulin is gradually
reduced by receptor internalization and degradation brought about by
increased hormonal binding. An exception to the rule is the receptor for
nicotine that demonstrates upregulation in receptor numbers upon extended
exposure to nicotine, despite nicotine being an agonist, which explains some
of its addictive properties.
Effect compartment and indirect pharmacodynamics: A delay between the
appearance of drug in the plasma and its intended effect may be due to
multiple factors to include transfer into the tissue or cell compartment in the
body or a requirement for the inhibition or stimulation of a signal to be
cascaded through intracellular pathways. These effects can be described by
either using an effect compartment or using indirect pharmacodynamic
response models, which describe the effect of the drug through indirect
mechanisms such as inhibition or stimulation of the production or elimination
of endogenous cellular components that control the effect pathway.[11]
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Clinical Significance
Several issues in drug dosing can be explained in terms of Kd, receptor
occupancy, and up/downregulation. Tolerance to a drug, where the effects
seem to diminish with continued dosing, frequently occurs with prolonged
dosing of opioids. Activation of opioid receptors stimulates the production of
intracellular proteins called arrestins. Arrestins bind to the intracellular
portion of the opioid receptor, block G-protein signaling and induce receptor
endocytosis. This results in less "signaling" or tolerance. The activity of
arrestins, which produce receptor down-regulation, is one of the many
pathways that lead to opioid tolerance.[10]
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Continuing Education / Review Questions

 Access free multiple choice questions on this topic.
  Earn continuing education credits (CME/CE) on this topic.
 Comment on this article.
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References
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