Page 53 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 2 Drug Receptors & Pharmacodynamics 39

of biochemical processes in the responding cell and physiologic In some of these cases (eg, bleeding caused by anticoagulant
regulation by interacting organ systems. Clinically, changes in therapy; hypoglycemic coma due to insulin), toxicity may be
these postreceptor processes represent the largest and most impor- avoided by judicious management of the dose of drug adminis-
tant class of mechanisms that cause variation in responsiveness to tered, guided by careful monitoring of effect (measurements of
drug therapy. blood coagulation or serum glucose) and aided by ancillary mea-
Before initiating therapy with a drug, the prescriber should sures (avoiding tissue trauma that may lead to hemorrhage; regula-
be aware of patient characteristics that may limit the clinical tion of carbohydrate intake). In still other cases, the toxicity may
response. These characteristics include the age and general health be avoided by not administering the drug at all, if the therapeutic
of the patient and—most importantly—the severity and patho- indication is weak or if other therapy is available.
physiologic mechanism of the disease. The most important poten- In certain situations, a drug is clearly necessary and beneficial
tial cause of failure to achieve a satisfactory response is that the but produces unacceptable toxicity when given in doses that pro-
diagnosis is wrong or physiologically incomplete. Drug therapy is duce optimal benefit. In such situations, it may be necessary to add
most successful when it is accurately directed at the pathophysi- another drug to the treatment regimen. In treating hypertension, for
ologic mechanism responsible for the disease. example, administration of a second drug often allows the prescriber
When the diagnosis is correct and the drug is appropriate, to reduce the dose and toxicity of the first drug (see Chapter 11).
an unsatisfactory therapeutic response can often be traced to
compensatory mechanisms in the patient that respond to and B. Beneficial and Toxic Effects Mediated by Identical
oppose the beneficial effects of the drug. Compensatory increases Receptors but in Different Tissues or by Different
in sympathetic nervous tone and fluid retention by the kidney, for Effector Pathways
example, can contribute to tolerance to antihypertensive effects of Many drugs produce both their desired effects and adverse effects
a vasodilator drug. In such cases, additional drugs may be required by acting on a single receptor type in different tissues. Examples
to achieve a useful therapeutic result. discussed in this book include digitalis glycosides, which act by
+
+
inhibiting Na /K -ATPase in cell membranes; methotrexate,
Clinical Selectivity: Beneficial versus Toxic which inhibits the enzyme dihydrofolate reductase; and glucocor-
Effects of Drugs ticoid hormones.
Three therapeutic strategies are used to avoid or mitigate this
Although we classify drugs according to their principal actions, it sort of toxicity. First, the drug should always be administered at
is clear that no drug causes only a single, specific effect. Why is this the lowest dose that produces acceptable benefit. Second, adjunc-
so? It is exceedingly unlikely that any kind of drug molecule will tive drugs that act through different receptor mechanisms and
bind to only a single type of receptor molecule, if only because the produce different toxicities may allow lowering the dose of the
number of potential receptors in every patient is astronomically first drug, thus limiting its toxicity (eg, use of other immunosup-
large. Even if the chemical structure of a drug allowed it to bind pressive agents added to glucocorticoids in treating inflammatory
to only one kind of receptor, the biochemical processes controlled disorders). Third, selectivity of the drug’s actions may be increased
by such receptors would take place in many cell types and would by manipulating the concentrations of drug available to receptors
be coupled to many other biochemical functions; as a result, the in different parts of the body, for example, by aerosol administra-
patient and the prescriber would probably perceive more than tion of a glucocorticoid to the bronchi in asthma.
one drug effect. Accordingly, drugs are only selective—rather than
specific—in their actions, because they bind to one or a few types C. Beneficial and Toxic Effects Mediated by Different
of receptor more tightly than to others and because these receptors Types of Receptors
control discrete processes that result in distinct effects. Therapeutic advantages resulting from new chemical entities with
It is only because of their selectivity that drugs are useful in improved receptor selectivity were mentioned earlier in this chapter
clinical medicine. Selectivity can be measured by comparing and are described in detail in later chapters. Many receptors, such as
binding affinities of a drug to different receptors or by comparing catecholamines, histamine, acetylcholine, and corticosteroids, and
s for different effects of a drug in vivo. In drug development
ED 50 their associated therapeutic uses were discovered by analyzing effects
and in clinical medicine, selectivity is usually considered by sepa- of the physiologic chemical signals. This approach continues to be
rating effects into two categories: beneficial or therapeutic effects fruitful. For example, mis-expression of microRNAs (miRNAs),
versus toxic or adverse effects. Pharmaceutical advertisements small RNAs that regulate protein expression by binding to protein-
and prescribers occasionally use the term side effect, implying coding (messenger) RNAs, was linked recently to Duchenne
that the effect in question is insignificant or occurs via a pathway muscular dystrophy. Current preclinical investigations include the
that is to one side of the principal action of the drug; such implica- utility of RNA-based therapy for this and other diseases.
tions are frequently erroneous. Other drugs were discovered by exploiting therapeutic or toxic
effects of chemically similar agents observed in a clinical context.
A. Beneficial and Toxic Effects Mediated by the Same Examples include quinidine, the sulfonylureas, thiazide diuretics,
Receptor-Effector Mechanism tricyclic antidepressants, opioid drugs, and phenothiazine anti-
Much of the serious drug toxicity in clinical practice represents a psychotics. Often such agents turn out to interact with receptors
direct pharmacologic extension of the therapeutic actions of the drug. for endogenous substances (eg, opioids and phenothiazines for