27 Principles of Pharmacology - Drug Receptor Interactions
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Prof. Gary Strichartz
HST-151 1
DRUG-RECEPTOR INTERACTIONS
OBJECTIVES: This lecture will introduce the qualitative and
quantitative vocabulary of pharmacology. Drugs interact with
specific receptors to produce or block biochemical and physiological
effects. These interactions can be modeled by applying the
principle of mass-action to agonist and antagonist dose-response
relationships. The concept of a full agonist, a partial agonist, a
reversible antagonist, and an irreversible antagonist will be
explored.
The identification of receptor molecules by structural, functional, and
ligand binding criteria will also be discussed.
I. Introduction
A drug receptor is any biological component capable of binding a drug
molecule and generating a cellular effect. When P. Erlich introduced the
term “receptor” around 1900, he was considering the mechanism of
action of agents toxic to invading microorganisms but not to the host.
Even before Ehrlich’s studies, pharmacologists and physiologists
examining the effect of poisons on animals and man concluded that
specific receptors probably exist that mediate information transfer from
nerve to muscle. Between 1880 and 1900 J. N. Langley and others
examined the actions on the vertebrate peripheral nervous system of a
variety of plant alkaloids. In one study Langley examined the effects on
skeletal muscle of nicotine and of tubocurarine. Nicotine applied to the
neuromuscular junction caused a muscle contraction similar to that
elicited by stimulation of the nerve, while tubocurarine blocked the
action of both applied nicotine and of nerve stimulation. Langley
concluded that there was probably a “receptive substance” for nicotine
and for turocurarine.
Since both agents affected muscle contraction in the absence of nerve, he
concluded that the function of the nerve was closely related or identical
to stimulation of the “nicotine receptive substance” of muscle.
In initial studies the existence of agents that mimic nerve (agonists) and
of agents that block agonist action (antagonists) was crucial. The
identity of the neurotransmitter substances and receptors themselves
was unknown. A clue concerning the chemical nature of those receptors
was found in a comparison of the activity of substances that exist as
pairs of optically active stereoisomers: L-epinephrine was found to be at
least 15 times as potent as D-epinephrine in controlling the rate of
, HST-151 2
beating of an isolated heart; the analgesic activity of morphine derivatives
also demonstrated stereospecificity. The stereospecificity of the action of
many agonists and antagonists suggested that the binding sites of
receptors would be similar to the active sites of enzymes. The analysis of
drug actions in terms of specifc receptors depends upon the systematic
analysis of the dose-dependence of agonist and antagonist actions. In
the following lectures we will consider families or classes of drugs that
exert their therapeutic action as a result of interactions with specific
receptors.
In this lecture we introduce the general principals of agonist and
antagonist dose-response relations, as well as the biochemical criteria
used to identify drug receptors.
II. Agonist Dose-Response Relations
A. Dose-response relations can be established whenever a drug
produces a graded response, for example, a change in heart rate or
systemic blood pressure. Doses can be expressed as mg drug/kg body
weight or, for isolated organ preparations, directly in terms of
concentration (moles drug/liter; M). Responses can be plotted as a linear
function of agonist dose:
Fig 1
Linear
100
75
Response (%)
50
25
0
0.10 100.00
Dose (M x 10 -7)
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