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

50
SECTION I
GENERAL PRINCIPLES
PRESCRIBED
DOSE
ADMINISTERED
DOSE
CONCENTRATION
AT SITE(S)
OF ACTION
DRUG
EFFECTS
• medication errors
• patient compliance
• rate and extent of absorption
• body size and composition
• distribution in body fluids
• binding in plasma and tissues
• rate of metabolism and excretion
• physiological variables
• pathological factors
• genetic factors
• interaction with other drugs
• development of tolerance and
desensitization
• drug-receptor interaction
• functional state of targeted system
• selectivity of drug, propensity to produce
unwanted effects
• placebo effects
• resistance (anti-microbial agents)
Figure 3–7. Factors that influence the relationship between prescribed
dosage and drug effects. (Modified with permission from
Koch-Weser J. Serum drug concentrations as therapeutic guides.
N Engl J Med, 1972, 287:227–231. Copyright © Massachusetts
Medical Society. All rights reserved.)
contribute significantly to the inter-individual variability of responsiveness
to many drugs (Chapter 7). Among the best examples of
a drug with significant inter-individual sensitivity due to genetic
factors affecting both pharmacokinetics and pharmacodynamics is
the anticoagulant drug warfarin (Chapter 30). In order to achieve
optimal anticoagulant therapy with minimal adverse effects (i.e.,
excessive clotting due to under dosing, or excessive bleeding due
to overdosing), it is necessary to stay within a very narrow dose
range (i.e., warfarin’s therapeutic index is very low). There is considerable
inter-individual variation in this optimal dose range,
on the order of 10-fold or more, and nearly 60% of the variability
is due to genetic variation in the primary metabolizing enzyme
(CYP2C9) and in the drug’s receptor, vitamin K epoxide reductase
complex, subunit 1 (VKORC1). Polymorphisms in CYP2C9 (especially
homozygosity in the *3/*3 allele) increase sensitivity
towards warfarin, whereas coding region polymorphisms in
VKORC1 result in a warfarin-resistant phenotype. In 2007, the
FDA recommended that pharmacogenetics be used to optimize
warfarin dosing, but did not provide specific protocols to be used.
Subsequently, an algorithm that incorporates clinical and pharmacogenetic
data was shown to be significantly better than algorithms
that lack genetic data in predicting the initial appropriate dose of
warfarin that is close to the required stable dose. The patients who
benefited most by the pharmacogenetic algorithm were the 46%
who required either low or high dosing to achieve optimal anticoagulation
(Klein et al., 2009).
Combination Therapy. Marked alterations in the effects of some
drugs can result from co-administration with other agents, including
prescription and non-prescription drugs, as well as supplements
and nutraceuticals. Such interactions can cause toxicity, or
inhibit the drug effect and the therapeutic benefit. Drug interactions
always should be considered when unexpected responses to
drugs occur. Understanding the mechanisms of drug interactions
provides a framework for preventing them. Drug interactions may
be pharmacokinetic (the delivery of a drug to its site of action is
altered by a second drug) or pharmacodynamic (the response of
the drug target is modified by a second drug). Examples of pharmacokinetic
interactions that can enhance or diminish the delivery
of drug to its site of action are provided in Chapter 2. In a patient
with multiple comorbidities requiring a variety of medications, it
may be difficult to identify adverse effects due to medication interactions,
and to determine whether these are pharmacokinetic,
pharmacodynamic, or some combination of interactions.
Combinations of drugs often are employed to therapeutic
advantage when their beneficial effects are additive or synergistic, or
because therapeutic effects can be achieved with fewer drug-specific
adverse effects by using submaximal doses of drugs in concert.
Combination therapy often constitutes optimal treatment for many
conditions, including heart failure (Chapter 28), hypertension
(Chapter 27), and cancer (Chapters 60-63). There are many examples
of pharmacodynamic interactions that can produce significant
adverse effects. Nitrovasodilators produce relaxation of vascular
smooth muscle (vasodilation) via NO-dependent elevation of cyclic
GMP in vascular smooth muscle. The pharmacologic effects of sildenafil,
tadalafil, and vardenafil result from inhibition of the type 5
cyclic nucleotide phosphodiesterase (PDE5) that hydrolyzes cyclic
GMP to 5′GMP in the vasculature. Thus, co-administration of an NO
donor (e.g., nitroglycerin) with a PDE5 inhibitor can cause potentially
catastrophic hypotension. The oral anticoagulant warfarin has
a narrow margin between therapeutic inhibition of clot formation and
bleeding complications and is subject to numerous important pharmacokinetic
and pharmacodynamic drug interactions. Alterations in
dietary vitamin K intake may also significantly affect the pharmacodynamics
of warfarin and dosing changes may be required if a
patient’s diet is inconsistent. Similarly, antibiotics that alter the intestinal
flora reduce the bacterial synthesis of vitamin K, thereby
enhancing the effect of warfarin. Nonsteroidal anti-inflammatory
drugs (NSAIDs) cause gastric and duodenal ulcers (Chapter 34), and
their concurrent administration with warfarin increases the risk of GI
bleeding almost 4-fold compared with warfarin alone. By inhibiting
platelet aggregation, aspirin increases the incidence of bleeding in
warfarin-treated patients. A subset of NSAIDs, including
indomethacin, ibuprofen, piroxicam, and cyclooxygenase (COX)-2
inhibitors, can antagonize antihypertensive therapy, especially with
regimens employing angiotensin-converting enzyme inhibitors,
angiotensin receptor antagonists, and β adrenergic receptor antagonists.
The effect on arterial pressure ranges from trivial to severe. In
contrast, aspirin and sulindac produce little, if any, elevation of blood
pressure when used concurrently with these antihypertensive drugs.
Anti-arrhythmic drugs such as sotalol and quinidine that block K +
channels can cause the polymorphic ventricular tachycardia known as
torsades de pointes (Chapter 29). The abnormal repolarization that
leads to this polymorphic ventricular tachycardia is potentiated by
hypokalemia, and diuretics that produce K + loss increase the risk of
this drug-induced arrhythmia.
Most drugs are evaluated in young and middle-aged adults,
and data on their use in children and the elderly are sparse. At the
extremes of age, drug pharmacokinetics and pharmacodynamics
can be altered, possibly requiring substantial alteration in the dose
or dosing regimen to safely produce the desired clinical effect.