Page 1758 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 125: Critical Care Pharmacology 1227

Interindividual Response Variability (Sensitivity): Another point to note
is the variability between individual responses to a given plasma drug Choice of drug:
level; sensitivity to drug action may differ between individuals or groups. Drug-disease
Drug-patient
For example, elderly subjects are more sensitive to the sedative effects Drug-drug
of benzodiazepines (and many other sedatives) than younger subjects ;
12
American subjects of Chinese descent are twice as sensitive as American
white men to the β-blocking effects of propranolol ; black subjects are
13
less sensitive to the vasodilatory effect of isoproterenol than are white
Americans. Recent evidence implicates pharmacogenomics as the Route of administration
14
Bioavailability
cause of variability of drug effect between races, and even individuals Feeding status of patient
within races. Pharmacogenomics is the study of the role of inherited Convenience
15
and acquired genetic variation in drug response. It can facilitate the Titratability
identification of biomarkers that can help physicians optimize drug selec-
tion, dose, and treatment duration and avert adverse drug reactions.
16
An example is an association between the presence of HLA-B*5701 and
hypersensitivity reactions to Abacavir, a nucleoside analogue used to treat Loading dose necessary?
HIV infection. This resulted in the FDA modification of the abacavir Volume of distribution
17
label to include a recommendation that patients undergo genotyping Urgency in observing desired
for HLA-B*5701 before the initiation of therapy. Despite significant drug effect
advances in research relating to pharmacogenomics as well as FDA
guidelines, the use of these tests is not widespread due to limitations
in the availability of tests, lack of cost-effective analyses, and the need
to establish clinical utility. Current information regarding the known Maintenance dosing
specific drug gene interactions can be obtained through the National Half-life
Institute of Health Pharmacogenetics Research Network’s PharmGKB: Ability to titrate
The Pharmacogenomics Knowledge base (www.pharmgkb.org). 18
Dose-Dependent Effects: The predominant drug-receptor complex
mediating a drug’s effect may change according to drug concentration,
resulting in variable pharmacologic responses at different plasma levels. Adjustments for
For example, dopamine predominantly activates dopaminergic receptors Drug-drug, drug-patient, and
(and causes mesenteric and renal vasodilation) only at infusion rates of Drug-disease interactions
up to 2 µg/kg per minute. β -Adrenergic (inotropic) and α-adrenergic
1
(vasoconstrictor) activation occur at doses as low as 2 to 4 µg/kg per
minute and 5 to 10 µg/kg per minute, respectively; as a result, the hemo-
dynamic effect of dopamine infusion changes with increasing dose. Therapeutic drug monitoring
15
Despite such concerns, we expect the attainment of drug levels in the
usual therapeutic range to elicit the desired effect in most patients.
Most drugs used in the ICU are dosed according to broadly applicable FIGURE 125-5. Flowchart for a suggested method of design for a rational drug dosing
population-based PK and PD parameters and titrated to pharmacologic regimen. This illustration serves to depict the process of drug prescription and dosing as a
response only if this is readily quantifiable, rather than being subjected to perpetual cycle of actions. Individualization of drug therapy involves careful consideration of
rigorous PK modeling with therapeutic drug-level monitoring. The latter the patient’s unique clinical status for each step along the path of drug prescription and dosing.
approach is applied to drugs that have a low therapeutic index and plasma The initial choice of drug, route of administration, loading dose, and maintenance dose calcula-
drug concentrations that correlate with drug effect. The intermediate- tions involve consideration of desired drug effects, titratability, and convenience. Modifications
complexity approach of monitoring physiologic parameters (PD monitor- of the dosing regimen may be required to accommodate the individual characteristics of
ing) of drug effect is more readily applied in the ICU (and operating room) the patient, including allergies, age, sex, and race; potential drug-drug interactions; and
than in other patient care settings because of the routine use of monitoring potentially confounding disease states. Once a drug regimen is designed and implemented,
devices. Sedation, neuromuscular paralysis, seizure suppression, diuretic therapeutic drug monitoring is indicated to ensure adequate drug effect and to minimize
agent action, and the effects of cardiovascular drugs (antiarrhythmic, chro- potential adverse events. The results of therapeutic drug monitoring may indicate the need for
notropic, inotropic, vasodilator, and vasoconstrictor actions) and broncho- further modification of the drug regimen.
dilators are commonly assessed in this fashion, in conjunction with formal
PK monitoring using drug levels for appropriate agents.
What follows is a framework for drug administration based on physi- a series of questions can provide a framework for therapeutic individu-
ologic modeling of the patient and application of known drug charac- alization. Individualization of drug therapy requires consideration of the
teristics to this patient model, in order to optimize ICU therapeutics effects of multiple factors responsible for variability in drug response
and minimize the potential for iatrogenic adverse events. Furthermore, (aside from disease severity); these include (1) drug-patient interac-
this approach includes routine surveillance to prevent adverse drug tions (including body habitus, age, gender, comorbidities, and race) and
reactions, and to assess the potential for such a phenomenon to be the (2) drug-drug interactions. This approach only yields an approximation
underlying cause of a change in patient status. of ideal therapeutics, because information addressing drug disposition
in this population is often incomplete, and its interpretation is further
INDIVIDUALIZATION OF DRUG THERAPY complicated by the dynamic physiology of critical illness. This method
IN THE ICU: AN APPROACH TO RATIONAL DRUG simply attempts to maximize the potential for rational therapy based
DOSING IN CRITICALLY ILL PATIENTS on available information. As a result, any drug regimen in critically ill
patients requires early and frequent reassessment. The customary pru-
The PK and PD principles outlined above may be applied routinely to dent approach to drug dosing in settings in which altered disposition
attempt optimal design of drug regimens for ICU patients. As shown in is anticipated but poorly quantifiable, embodied in the phrase “start
Figure 125-5, focused consideration of PK and PD parameters to answer low and go slow,” is generally inappropriate in this setting, in which

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