C/Vascular meds and enzyme polymorphisms

[Guest guest]

I hope you don't mind me clogging the board up with this. I found it

very interesting, considering so many of us have different

intolerances to different meds. Maybe it is down to our cultural

backgrounds.

Cultural Competence: Cardiovascular Medications

[Prog Cardiovasc Nurs 16(4):152-160,169, 2001. © 2001 CHF, Inc.]

Connelly Kudzma, DNSc, MPH, RNC

Abstract and Introduction

Abstract

Interethnic or racial differences are associated with enzyme

polymorphisms, which are tiny variations in individuals in the

physiology, absence, or presence of drug-metabolizing enzymes. The

largest class of cardiovascular drugs investigated in pharmacogenetic

studies is the antihypertensives. A number of studies have examined

the best choices of antihypertensives for individuals within selected

racial and ethnically defined populations. There is a fairly strong

consensus about the pattern of antihypertensive treatment for black

patients, but clear treatment directives for antihypertensive

patients with other cultural affiliations have not emerged. Less

information is reported about racial, ethnic, or cultural differences

in effectiveness for other cardiovascular drugs. Nurses should

consider whether the ethnic or racial affiliation of the patient

places him or her more at risk for impaired drug metabolism. This

article contains a guide for nursing assessment of culturally

important factors related to polymorphisms.

Introduction

An emerging body of investigation suggests that interethnic or racial

differences have an influence on the pharmacokinetics

(biotransformation) and pharmacodynamics (concentration-response

relationship) of commonly prescribed cardiovascular drugs. Minority

and ethnic populations have been under-represented[1,2] within drug

and nursing studies. As the United States population becomes less

Caucasian, the relationship of genetics, ethnicity, race, and

variable response to medications will have to be factored into

prescribing and health care decisions.

Ethnicity encompasses variations in humans derived from interactions

of geography and heredity.[3] Patterns of genetic inheritance formed

when individuals intermarried within closely located groups.[3,4]

Inherited DNA differences among family members and within ethnic

groups are <0.2%, which indicates why individuals who are related or

of the same ethnic heritage have common traits. Within a smaller

portion of this tiny DNA difference, medication response variation

occurs.[5] These subtle differences are of increasing importance as

drug metabolism theory becomes better understood.

Genes controlling patterns of metabolic enzymes are formed under

different selection processes from those predicting physical

characteristics. Sickle cell trait developed through selection

factors in parts of the world where resistance to malaria favored

chances for survival. Similarly, glucose-6-phosphate dehydrogenase

(G6PD) deficiency is related to malarial resistance, but causes drug-

related red blood cell hemolysis when affected individuals are

administered certain drugs. Both disorders favor malarial resistance

and their common evolution favors a common incidence in African

Americans, Southeast Asians, and individuals of Mediterranean descent.

Drug Polymorphisms

Pharmacogenetics investigates the relationship be-tween genetic

factors and responses to drugs in various ethnic groups. These

differing responses are caused by polymorphisms -- tiny differences

in the construction, absence, or presence of drug-catabolizing

enzymes.

The first drug-related enzyme polymorphism re-ported (Table I) was in

the acetylation metabolism of isoniazid (INH). Early studies

indicated that large numbers of Caucasians were slow acetylators,

meaning that they metabolized INH at a slow rate. More studies

extended these variances to other ethnic groupings. Slow acetylators

cleared the drug more slowly and were more prone to develop toxic

drug reactions; in the case of INH, tuberculosis patients were more

likely to develop peripheral neuropathy and chemical hepatitis.

However, rapid acetylators, who cleared the drug rapidly, were more

likely to have a diminished clearing of the mycobacteria and

increased risk of development of drug resistance.

Two other model polymorphisms have been identified. Debrisoquine

hydroxylase (CYP2D6) is an oxidizing enzyme within the cytochrome P-

450 system that detoxifies and metabolizes modern therapeutic agents.

When the enzyme behaves in a polymorphic manner, it has a bimodal, or

dual, metabolic population distribution. These enzymes are believed

to be nonselective; that is, each enzyme can oxidize chemicals/drugs

that are structurally dissimilar.[3] The importance of this pathway

resides in the number of commonly prescribed medications that are

oxidized by this route, including antidepressants, ß blockers,

codeine, and dextromethorphan (used as a probe drug for enzyme

absence or presence). Slow oxidators of debrisoquine are called poor

metabolizers (PMs); rapid debrisoquine oxidators are termed extensive

metabolizers.

The metabolism of mephenytoin hydroxylase (CYP2Cmp) is a model for

another set of oxidation enzymes that predict response to

phenobarbital, diazepam, propranolol, and warfarin. Fewer Caucasians

than Asians are deficient in these enzymes, and individuals deficient

in pathway enzymes are at higher risk for drug intoxication. Future

investigations (based on human genome research) may identify more

enzymes involved in each drug's metabolism. Meanwhile, it is

clinically useful to organize behaviorally similar drugs in

association with the pathway. Table I summarizes data for the three

pathways and reported population ranges of PMs[3] (poor acetylators

and oxidizers) based on 60 studies worldwide. The largest class of

cardiovascular drugs investigated via pharmacogenetic studies are the

antihypertensives.

One of the most significant questions in primary care surrounds the

selection of the most effective initial agent for each patient with

hypertension. The research on differences in drug metabolism/drug

polymorphisms of antihypertensives has largely been conducted with ß

blockers, hydralazine, procainamide, and common stimulants (e.g.,

caffeine). The literature has been extended by studies that

demonstrate differences emanating from such causes as salt and renin

sensitivity. As there have been fewer studies that include ethnic

populations and drugs used in the studies are not always the same, it

is not easy to determine if the source of the variation is drug

polymorphism or another physiologic difference. Table II provides an

historical view of significant studies investigating

antihypertensives in ethnic populations.[6-12]

Hypertension in Black Patients

Hypertension is a serious issue in black populations because this

group has the highest incidence of hypertensive morbidity and

comorbid conditions (greater risk of stroke and heart and renal

disease). Using the drug hydrochlorothiazide, Freis[13] reported that

67% of younger (<55 years) black patients and 80% of older (55-65

years) black patients achieved blood pressure control (diastolic

blood pressure of <90 mm Hg). In 1993, Materson et al.[8] reported

the similar finding that 40% of younger and 58% of older blacks

achieved blood pressure control using hydrochlorothiazide as a single

agent. Studies like these supported the position of the Joint

National Committee on Prevention, Detection, Evaluation, and

Treatment of High Blood Pressure (JNC V), which advised low doses of

a thiazide diuretic (12.5-25 mg hydrochlorothiazide) as the agent of

first choice for hypertensive black patients. JNC VI[14,15] currently

advises that diuretics be used for initial therapy unless there are

contraindications or coexisting conditions that might be treated by

another agent. In the presence of renal disease, a loop diuretic

should be used, as thiazide diuretics become less effective.[16] JNC

VI also allows for initial therapy with ß blockers. However, ß

blockers as first-line therapy have been shown to be less predictable

than diuretics in black patients; labetalol, a combined blocker,

might be recommended as equally effective in both black and Caucasian

populations.[17,18]

Recent studies of antihypertensive agent efficacy in black and white

comparison populations have sought to determine whether differences

in salt sensitivity and renin levels could further explain noted

racial differences in drug response. A number of studies have

suggested that black patients tend toward low-renin profiles, while

white patients tend toward moderate to high renin levels. Weir et al.

[10] investigated the influence of dietary salt on antihypertensive

medication effectiveness and concluded that treatment with both

enalapril (Vasotec®) and isradipine (Dynacirc®) lowered blood

pressure in the presence of high salt intake, but that greater blood

pressure control was achieved overall in all racial populations on a

low-salt diet. On the high-salt diet, blacks had better blood

pressure control with isradipine. Preston et al.[11] investigated the

influence of plasma renin levels on the patient's response to

antihypertensive agents. In this study, age and race more

significantly predicted response to the antihypertensive agent than

the renin profile, and clonidine (Catapres®) and diltiazem

(Cardizem®) were the most effective agents overall, independent of

renin levels. Bakris et al.[19] investigated the use of

antihypertensive agents in black Americans with diabetic nephropathy.

An antihypertensive agent (verapamil) that reduced arterial pressure

and proteinuria slowed the progression of diabetic renal disease to a

greater extent than an agent (atenolol) without that effect.

Studies of hypertensive pathophysiology in black patients indicate

that low renin levels, salt sensitivity, and impaired salt excretion

are more prevalent. Obesity is more prevalent in black women as

compared to other black or white adults, and dietary intake of

potassium is often lower in blacks as compared to whites.[16] These

facts suggest that lifestyle modifications might be the most

effective strategy to lower blood pressure in this population.

Reductions in body weight of as little as 7 lb and use

of oral potassium supplements can significantly reduce blood pressure.

[16] A high proportion of this group is overweight and has a higher-

than-reported intake of sodium, which is unknown to both the patient

and health care provider. For these patients precise dietary

counseling and monitoring are indicated. Part of the increased risk

for hypertension and cardiovascular disease in black Americans may be

mediated through differing vascular responses. Wood[20] indicated

that black Americans have an impaired vascular response to the ß

receptor drug isoproterenol (Isuprel®) and an impairment of

vasodilation in response to nitric oxide-mediated drugs (nitrates).

Calcium channel blockers are also an excellent choice for black

patients8 with salt sensitivity, especially those who are not

responsive to diuretics. Treatment with diltiazem produced the best

blood pressure control for black patients in a study of six classes

of agents, with a 64% rate of response.[8] For black patients who

cannot take hydrochlorothiazide or calcium channel blockers, other

antihypertensive classes -- specifically, angiotensin-converting

enzyme (ACE) inhibitors and ß blockers -- may be useful to lower

blood pressure even though studies indicate that these agents may not

be quite as effective. If a diuretic is combined with an ACE

inhibitor or ß blocker as primary or secondary therapy, the two

together produce similar lowering of blood pressure,[21] probably due

to better stimulation of renin secretion.

JNC VI also provides support for use of antihypertensive medication

choices in the presence of known coexisting conditions. Minority

patients who have coexisting conditions are especially at risk for

undertreatment. Beta blockers are specifically indicated for patients

who have a history of myocardial infarction and ACE inhibitors are

recommended for patients with an ejection fraction of <40% (heart

failure) and diabetes with proteinuria. Most hypertensive black

patients will need two or more medications to attain adequate blood

pressure control, as only 46% of black patients achieved a diastolic

blood pressure <90 mm Hg on one antihypertensive medication.[8] More

attention should be given to black patients with a history of

myocardial infarction, who should receive a ß blocker, and those with

heart failure or diabetic nephropathy, who should take an ACE

inhibitor. These drugs may protect the patient by more mechanisms

than solely lowering blood pressure. Bakris et al.[19] reported that

in diabetic black hypertensive patients with demonstrated

nephropathy, drug treatment that reduced arterial pressure and

proteinuria also appeared to slow the progression of renal disease.

Table III summarizes therapeutic nursing considerations for black

hypertensive patients.

Hypertension in Asian and Hispanic Patients

There are fewer reports of described variations in antihypertensive

drug response in other ethnic or racial populations. Zhou et al.[7]

investigated the therapeutic response of Chinese patients who were

given propranolol. Chinese men metabolized propranolol more quickly

than white men and the drug had significantly greater effects on

heart rate and blood pressure reduction. Differences in the rate of

metabolism of propranolol and other drugs in Asian populations may

explain why dosing patterns are different in China, with lower doses

prescribed and more careful titration of dosage according to blood

pressure measurements. The increased sensitivity of Asian patients to

propanolol has been confirmed by later studies.[20,22] Asian

Americans are reported to have better hypertension control with

calcium antagonists, diuretics, and ß blockers,[4] as adult

hypertension in Asians is more likely to be preceded by onset of

hypertension during childhood.

There is little information to indicate that the treatment of

Hispanic hypertensive patients should be different from that of

Caucasian hypertensive patients.[4] The Hispanic population

experiences the highest mortality rate in the United States, next to

black patients, and hypertension is more likely to be undiagnosed.

Current evidence available for Hispanic Americans supports no

hierarchy of medication choice in response to the various

antihypertensive drug classifications.[4]

To assure adequate monitoring of blood pressure, JNC VI recommends

that blood pressure be taken during each health visit.[14]

Hypertension is defined as a systolic blood pressure of >140 mm Hg or

diastolic blood pressure of >90 mm Hg.[14] Patients with blood

pressures in the high normal area are advised about lifestyle changes

(weight loss if overweight, increased physical activity, reduction of

dietary fat/cholesterol intake, limiting of alcohol ingestion,

reduction of sodium intake, adequate intake of dietary potassium,

calcium, and magnesium, and smoking cessation) and are usually asked

to return within the year for another check. However, lifestyle

modifications may be difficult to address if the patient has a less

than adequate understanding of what hypertension is, and language or

communication impediments exist.

For individuals with elevated blood pressure, measurements to

determine if treatment or further monitoring is required should be

repeated sooner than 1 year. Patients with persistent high blood

pressure must be evaluated within 1 month for further treatment,

including drug therapy. Patients may not return for therapy if they

have no symptoms or are not experiencing adverse effects. When

patients fail to observe treatment recommendations or to adhere to

medication protocols, it is prudent to carefully assess their

understanding of the disease. In interviews with 54 black women

receiving treatment for hypertension,[23] a majority mistakenly

believed that the disease could be explained as a folk illness

related to " hot, rich, or thick blood " or " anxiety, stress, and

worry. " Those who interpreted the disease as a folk illness

demonstrated less treatment compliance than those who believed in

hypertension as a biomedical model. Also interesting was the

observation that their health providers were largely ignorant of the

women's health beliefs, attributing their use of the folk descriptive

terms to misuse of the biomedical diagnostic terms. Ensuring that

patients understand what is prescribed and that nurses understand the

patient's perception of illness requires thorough nursing dialogue

and assessment.

Other Cardiovascular Drugs

Less information has been reported on racial or ethnic differences

for other cardiovascular drugs. A considerable number of US adults

eligible for cholesterol-lowering therapy do not receive treatment,

[24] with only about 35% reporting that they have been prescribed

diets or medications. This undertreatment exists despite the evidence

supporting the relationship between high low-density lipoprotein

(LDL) cholesterol levels, increased cardiac mortality, and overall

mortality. Hoerger et al.[24] reported that members of minority

populations are more underserved within the undertreated group, with

24.5% of blacks and 18% of Mexican Americans in treatment as compared

with 29% of whites. American Indians appear to have lower cholesterol

levels than the US population as a whole.[24] The lower cholesterol

levels translate to a lower incidence of coronary heart disease

despite an increased prevalence of diabetes and obesity. These

factors suggest that dietary/exercise treatment might be more useful

than lipid-lowering medications in American Indian populations.[25]

Another study[26] noted that familial hypercholesterolemia, which is

caused by a chromosome deletion, is more frequent in the French

Canadian population of Quebec and that as many as 9% of patients with

this disorder have a poor response to lovastatin.

A recent study[27] of three apolipoprotein (apo) E polymorphisms,

which are determinants of blood lipid levels, indicated that the apo

E3 form had the highest incidence, ranging from 68.2% in black

Americans to 80.3% in non-Hispanic Caucasians. The apo E2 form is

associated with lower LDL or protective cholesterol levels,

particularly in non-Hispanic whites and black Americans. The

prevalence of the apo E4 form, which has been shown in many clinical

studies to be associated with increases in LDL and coronary heart

disease, was higher in black Americans (20.4%). (The apo E4 form was

less prevalent in older subjects,[27] suggesting that some may have

died earlier.) More study is needed to determine specifically whether

the apo E2 isoform is protective for cardiovascular disease, whether

the racial differences noted in this study can be replicated, and

what implications these differences might have for drug treatment

within specific racial or ethnic groups.

Aplastic anemia is a potentially life-threatening condition

associated with genetic causes. If it develops in response to medical

drugs, it tends to be idiosyncratic and affects small numbers of

individuals. Therefore, genetic variation in debrisoquine metabolism

might provide a rationale to explain the cause of aplastic anemia

seen in individuals who contract this disease subsequent to clinical

drug exposure. Marsh et al.[28] sought to determine if poor

debrisoquine metabolism was associated with the development of

aplastic anemia in 54 patients. Although the percentage of PM

patients in the aplastic anemia group was similar to that in the

controls, because of the small size of the study sample no inferences

could be made about the development of aplastic anemia in PMs who had

drug exposure. Larger samples will be needed to more specifically

describe the relationships between drug polymorphisms and genetically

based susceptibility to drug-induced aplastic anemia.

Estimating the correct heparin dose is important for drug efficacy

and safety. In a study by Yu et al.,[29] Chinese subjects were shown

to require lower heparin doses than those usually recommended for

Caucasians. Only part of this lower dose requirement was attributed

to weight. Underdosing can lead to potential risks of recurrent

thrombosis, and overdosing increases the risk of bleeding. An earlier

report by the same investigators[29] indicated that warfarin

requirements are lower in Chinese patients.

Codeine is known to be one of the drugs using the debrisoquine

pathway. Through histographic comparisons of metabolic ratios of

codeine, Yue et al.[30] indicated that more Caucasians are PMs of

codeine (also morphine products). This tends to confirm observations

that Asians are prone to be rapid metabolizers of codeine and to

suffer more adverse effects. Other investigators[18] indicate that

the Chinese are more sensitive to morphine's emetic effect and less

sensitive to respiratory depression and hypotensive drug actions.

Alcohol consumption has cardiovascular implications and is implicated

in the etiology of hypertension. The alcohol dehydrogenase enzyme is

known to be absent in about 50% of Asians. This leads to build-up of

the toxic chemical aldehyde, which probably plays a significant role

in the pathophysiology of alcoholic hepatic damage. This increased

sensitivity produces a flushing syndrome with tachycardia, facial

heat, palpitations, headache, vomiting, and even shock after alcohol

ingestion. Tsuritani et al.[31] reported that among 403 Japanese

individuals, those who possessed both the normal and defective

metabolic aldehyde gene consumed more alcohol than individuals who

had only the defective gene. These investigators speculated that

alcoholic liver metabolite build-up is related to hepatic steatosis,

an early manifestation of alcoholic liver damage. This supports the

prevalent belief that the discomfort that accompanies alcohol

consumption in Asians leads to lower consumption.

Educating Patients About Drugs

When patients fail to take their regularly prescribed medications,

consider whether the patient's ethnic or racial affiliation contains

a high percentage of PMs or slow metabolizers. A possible alternative

explanation for decreased medication adherence may be that they have

stopped or reduced their medication because of adverse side effects.

Patients should be carefully instructed to telephone their physician

if they think they are experiencing medication-induced adverse

effects. For these patients, downward titration of the dosage might

reduce the undesirable effects. In other situations, it might be

prudent to start the patient on a lower dose and titrate the dose

upward until the peak effect has occurred; dosing in Japan and other

Asian countries tends to follow this pattern.

Consider the need to more carefully explain the importance of taking

the drug. Hearing a similar message from other health providers or

family members can help, so consider enlisting the assistance of

others who might be more culturally influential. Filling

prescriptions with smaller amounts of medication allows the patient

to try medications on a temporary basis so that the patient's

response to the medication can be determined. Patients are

justifiably concerned about spending money on costly prescription

drugs that cannot be tolerated or are not effective.[32] Starting

medication on a trial basis may be problematic for insurance programs

that require patients on long-term therapy to fill a minimum of 3

months' medication by mail. Dispensing samples, starting medication

on a temporary basis, ascertaining the patient's response, and

refilling the prescription as required are practical responses to

overcoming difficulties when choosing the most effective

antihypertensive preparation.

Relevance to Clinical Practice

An understanding of clinical polymorphisms is most practically

significant when a drug has a narrow therapeutic range, uses an

identified enzyme pathway, and is commonly used (Table IV). It would

also be important if the drug were used globally, had few substitutes

in its class, or was likely to be a substitute for a drug not known

for genetic polymorphisms. Practitioners should also be aware of

generic substitutions because, while only 10% of the active drug

component can differ, there is greater range allowed in the filler.

For example, lactose, a common filler constituent, may be relied on

to a greater degree and may cause unpleasant side effects in

susceptible populations. Changes in allowed drugs listed in an

insurance company's prescribing formulary may not take into account

drug polymorphisms.[32]

Individuals who do not inherit essential drug-metabolizing enzymes

are considered PMs; they are more subject to drug build-up and toxic,

adverse, or idiosyncratic drug effects (Table IV). Those who inherit

the full complement of enzymes are rapid metabolizers. Since dosing

strategies take into account doses known for efficacy in average

populations or perhaps only limited populations, those who metabolize

the drug more rapidly may also be subject to toxic effects caused by

rapid uptake and high initial titers of the drug. However, in rapid

metabolizers, drug levels may drop too soon, leaving lapses in drug

coverage between doses.

As noted before, drug polymorphisms have been best studied in drugs

that are extensively available, heavily prescribed, and used

worldwide. However, new drugs are being developed at a rapid rate and

some of these are taking the place of drugs that have been used for

decades. In addition, improved drugs are being substituted for older

drugs and there has not been sufficient time to study the second- or

third-generation editions to see if they are prone to the same

metabolic differences. While improved drugs may act similarly, it

cannot be presumed that a new drug will have identical

pharmacokinetic effects.

Nursing Medication Evaluation

A comprehensive history assists the nurse in delivering

individualized, sensitive, and effective nursing care. The quality of

nursing care is related to the comprehensiveness and sophistication

entailed in the nursing assessment. The nurse should be able to

question the patient specifically about all trans- cultural issues

that might relate to pharmacokinetics. Questions such as those

outlined in Table V may be helpful in evaluating the patient's

ethnic, cultural, and/or racial background. These probes are drawn

from the author's familiarity with transcultural and pharmacology

literature and its application to known variations in drug response

related to ethnicity. Most nursing assessments do not contain

specific enough information about race, culture, or ethnicity to

formulate diagnostic indicators or cues that might contribute to the

perception of an alteration in medication absorption or utilization.

The reader should be cautious about the applicability, utility, and

generalizability of the reported studies. These studies, to date,

range from comparative/descriptive to randomized, controlled trials;

many offer important insights, but few are definitive. The purpose of

ethnicity-related investigations should be to determine the variation

in disease expression in human populations and to spotlight at-risk

groups for the most efficacious treatment. The clinician must be wary

of stereotyping or cultural profiling, as ethnicity alone is not a

sufficient indicator for predicting response to drug therapy but is

one of many factors that must be considered within the nursing

assessment. For example, with antihypertensives, most patients will

respond favorably to standard doses, since PMs are in a minority even

within each ethnic group. Preference for the use of specific drugs

for the treatment of cardiovascular disease in any individual should

be made only after considering other important factors in the

profiling of the cardiovascular disease, such as the presence of

cardiovascular risk factors, the nature and extent of target organ

involvement, and coexisting diseases.

Of major concern in many of these studies is the homogeneity of the

sampled populations.[33] For example, there are tendencies to group a

number of ethnic populations (Chinese, Japanese, Thais, Filipinos,

and others) broadly under the classification of " Asians. " Some

studies use Asian subjects who reside in the United States and it is

unknown how long they have been in residence and what characteristics

they have adopted from US exposure. " Caucasian " is a broad term

encompassing genetically and culturally different individuals with

Northern European, Mediterrean, Middle and Near Eastern, and Jewish

heritage. Cultural factors can affect drug metabolism through

differential exposure to lifestyle behaviors, such as diet, caffeine,

smoking, and environmental toxins. Lastly, while some studies seem to

agree that Asians may require lower drug doses, this finding should

be viewed with reservation because such factors as age, body weight,

medical diagnostic consistency, severity of illness, and coexisting

liver and renal impairments also affect drug metabolism. Genome

studies and tests with probe drugs may ultimately determine a

patient's responsiveness to and metabolism of specific drugs.[5]

Nurses have many concerns about cultural competence. As individuals,

we are prone to ethnocentrism -- a disposition to view others through

our own perception of socially constructed reality. There is a

tendency toward cultural imposition, that is, transplanting the

nurse's cultural beliefs and practices onto patients while denying or

trivializing theirs. Lack of cultural competency in medication

administration can lead to the waste of millions of dollars in unused

prescriptions and misdiagnoses, often with preventable dangerous

consequences. Some nurses might even be fearful that singling out

various ethnic groups with drug polymorphisms may be perceived as a

type of discrimination or prejudice.

In 1998, racial and ethnic minority groups comprised only 28% of the

US population; by 2030 this percentage will grow to an estimated 40%.

[34] The increasing diversity of the US population has strong

implications for delivery of health care. One of the two major goals

of Healthy People 2010 is to eliminate health disparities among

different segments of the population.[35] " These disparities are

believed to be the result of the complex interaction among genetic

variations, environmental factors, and specific health

behaviors. " [35] While the diversity of the US population may be one

of its greatest assets, it is also one of its greatest health

challenges -- a challenge that must addressed by nurses and all

health professionals. If nursing is to truly address diversity in

delivery of care, nurses must apprehend that cultural competence

requires, " ...a respect for difference, an eagerness to learn, and a

willingness to accept that there are many ways of viewing the

world. " [36] Nurses who sensitively assess patients for all of their

individual medication dosing requirements are those who positively

integrate cultural competence into their practice.

Table I. Brief Summary of Investigated Drug Polymorphisms

ACETYLATION

Isoniazid, antitubercular drug, used worldwide since WWII,

illustrated that individuals metabolize isoniazid differently

Acetylation polymorphic metabolism includes:

Slow acetylators

Rapid acetylators

Common drugs using acetylation pathway:

Clordiazepam, hydralazine, procainamide, caffeine

DEBRISOQUINE

Debrisoquine hydroxylase (CYP2D6) uses cytochrome P-450 isoenzyme

pathway

P-450 isoenzyme pathway evolved in animals as a protection against

toxic foreign substances

Debrisoquine polymorphism includes:

Poor metabolizers; deficient in metabolism

Extensive metabolizers; oxidize large amounts of the drug

Reported population estimates of poor metabolizers:[3]

Caucasian, 3%-9.2%; Asian, 0%-32%; Black, 0%-19%; Hispanic, 0%-

5.2%

Common drugs that use the debrisoquine pathway:

Amitriptyline, imipramine, perphenazine, haloperidol,

propranolol, metoprolol, codeine, morphine

MEPHENYTOIN

Mephenytoin hydroxylase (CYP2Cmp) also uses P-450 cytochrome pathway

Pattern of incidence is distinct from debrisoquine

Mephenytoin polymorphism includes:

Poor metabolizers

Reported population estimates of poor metabolizers:[3]

Caucasian, 2.4%-6.7%; Asian, 5%-18%; Black, 18.5%; Hispanic,

14.8%

Common drugs employing mephenytoin pathway:

epam, imipramine, barbiturates, warfarin

Table II. Selected Studies of Antihypertensive Drug Effectiveness in

Ethnic Populations

STUDY SUBJECTS/METHODOLOGY MEDICATION(S) RESULTS

Moser & Lunn[6] (1982) 38 Blacks compared to 185 black and white

subjects Hydrochlorothiazide, captopril Response in blacks to

hydrochlorothiazide was greater than that to captopril; in whites the

responses to hydrochlorothiazide and captropril were equal.

Zhou et al.[7] (1989) 10 Chinese men; 10 American white men; random

order drug doses Propranolol Chinese subjects had two times or

greater sensitivity to propranolol than white subjects, as indicated

by a reduction in BP and heart rate. Chinese subjects were more

sensitive to hypotensive effects.

Materson et al.[8] (1993) 1292 Hypertensive males: 647 whites, 621

blacks; randomized Hydrochlorothiazide, atenolol, captopril,

clonidine, diltiazem, prazosin Diltiazem lowered BP best in younger

and older blacks (64% success rate). Captopril success rate was 55%

in younger whites. Atenolol success rate was 68% in older whites.

Sowinski et al.[9] (1995) 13 Black men; 13 white men Propranolol

Racial differences in response to propranolol were more related to

hypertensive pathophysiology than to normal physiology.

Weir et al.[10](1998) 232 White subjects; 96 black subjects;

randomized, double-blind, placebo-controlled Isradipine, enalapril

Reduction in dietary salt aided BP reduction with either an ACE

inhibitor (enalpril/Vasotec®) or calcium channel blocker

(isradipine/Dynacirc®) in salt-sensitive black, Hispanic, and white

hypertensives. BP control achieved with the low-salt diet was better

in all races independent of antihypertensive employed.

Preston et al.[11] (1998) 1031 Younger/older white men and

younger/older black men; randomized (placebo and 6 treatment groups)

Clonidine, diltiazem Age and race more significantly predicted

response to antihypertensive therapy than renin levels. Clonidine

(Catapres®) and diltiazem (Cardizem®) were the most effective,

independent of renin levels. Diuretics worked best in patients with

low-level renin hypertension.

Hall et al.[12] (1998) 192 African American men and women;

randomized, double-blind, parallel, 4-group comparison Amlodipine

besylate, nifedipine CC, nifedipine GITS Effectiveness, safety, and

tolerance for 3 types of calcium channel blockers were equivalent in

African American men and women with hypertension (stages 1, 2)

(Norvasc®, Adalat CC®, Procardia XL®)

BP=blood pressure; ACE=angiotensin-converting enzyme;

GITS=gastrointestinal treatment system

Table III. Nursing Management Considerations for Hypertensive Black

Patients

Hypertension in black patients is more likely to be accompanied by

salt sensitivity and low renin levels.

Health education regarding weight reduction, lowering of sodium

intake, and maintenance of a high potassium intake may be more

effective.

Unless there are contraindications, the first medication recommended

is a thiazide diuretic.

Calcium channel blockers may be equally effective.

Adding a diuretic to a ß blocker or ACE inhibitor augments

effectiveness.

ß blockers are recommended after myocardial infarction.

ACE inhibitors are recommended for those with heart failure or

diabetes.

ACE inhibitors may slow the progression of renal disease in black

diabetic, hypertensive patients.

ACE=angiotensin-converting enzyme

Table IV. Clinical Nursing Implications

CLINICAL IMPORTANCE OF DRUG POLYMORPHISMS

Metabolizing polymorphisms have more practice implications when:

The drug has been studied and is known to exhibit significant

polymorphism.

Differences between poor and rapid metabolizers are clinically

significant for drug clearance and elimination.

The drug has a narrow, tight prescribing range, so that variances in

drug metabolism are quickly evidenced by ineffectiveness,

overeffectiveness, or adverse reactions.

The drug associated with genetic polymorphisms is used as a

substitute for one that is not.

The drug is commonly prescribed.

The drug is used worldwide.

CLINICAL IMPLICATIONS FOR SLOW METABOLIZERS

The drug is more slowly utilized.

Assess for less drug effectiveness.

Assess for higher plasma concentrations.

Monitor patient for possible drug toxicity.

CLINICAL IMPLICATIONS FOR RAPID METABOLIZERS

Assess for faster maximum effectiveness.

Assess for high early drug build-up and possible overdosage.

Monitor for possible adverse reactions due to high drug levels.

Assess for gaps in dosing coverage.

Table V. Nursing Assessment: Drug Polymorphisms

ASSESS ETHNIC/CULTURAL AFFILIATION

How does the patient report his/her ethnic/cultural background (e.g.,

Hispanic, Japanese, Chinese, or combinations)?

How closely does the patient identify with this affiliation (e.g.,

immigrant, third generation, fully assimilated)?

Does the patient have characteristics of a particular ethnic or

cultural group? Observe skin color, hair texture, other features.

Does the patient have anatomical characteristics of a particular

ethnic or cultural group? Observe height, weight, bone structure,

structure of upper and lower extremities, face, and hands.

Where was the patient born? What other countries has the patient

lived in? When?

What language is spoken at home? What language(s) does the patient

read?

What is the fluency level in English? This is important in describing

adverse effects.

ASSESS CULTURAL ASPECTS OF DISEASE INCIDENCE AND MEDICATION USE

Does the patient know of any specific genetic conditions in his

family that have a higher incidence in specific ethnic groups (e.g.,

sickle cell disease, G6PD deficiency, lactose intolerance)?

What diseases/disorders does the patient believe he/she is more

unlikely to have (e.g., sunburning, cancer, malaria)?

What are the patient's views of traditional or Western medicine?

Does the patient use any homeopathic, herbal, or cultural remedies?

How is nutritional intake influenced by the client's culture?

What foods are eaten, and what are the timing and sequence of meals?

Are any specific nutritional differences noted that might impact drug

absorption or metabolism (fat intake, food supplements)?

Does the patient smoke? Use alcohol? Use other drugs?

What are the patient's expectations regarding the effectiveness of

the prescribed medication?

ASSESS CULTURAL ASPECTS OF MEDICATION EVALUATION

Does the patient demonstrate signs that the medication is effective

or ineffective? (For example, a reduction of blood pressure in a

patient taking antihypertensive medication is a demonstration of

effectiveness.)

If medications are ineffective, is this reported so that

modifications can be made?

Is the patient experiencing secondary effects? Secondary effects

include:

Adverse effects: unwanted effects of medication usage that can be

coped with, but might be undesirable, such as nausea, vomiting, or

fatigue

Toxic effects: effects that result in harm to the patient, such as

hepatotoxicity, nephrotoxicity, aplastic anemia, or ototoxicity.

Adverse effects may be an indication of toxic effects, and both

should be reported.

Drug allergies: drug hypersensitivity might include skin reactions,

rashes, urticaria, and anaphylactic reactions.

Idiosyncratic reactions: any unexpected abnormal reaction.

Can the patient accurately describe any adverse, toxic, or

idiosyncratic reaction?

Can the patient comprehend all the information taught about the

medications prescribed?

Is the patient taking the prescribed medication as ordered?

G6PD=glucose-6-phosphate dehydrogenase

References

Svensson E. Representation of American blacks in clinical trials of

new drugs. JAMA. 1989;261:263-265.

Larsen E. Exclusion of certain groups from clinical research. Image.

1994;26:185-190.

Lin K, Poland R, Silver B. Overview: The interface between

psychobiology and ethnicity. In: Lin K, Poland R, Nakasaki G, eds.

Psychopharmacology and Psychobiology. Washington, DC: American

Psychiatric Press; 1993:11-35.

Jamerson K, DeQuattro V. The impact of ethnicity on response to

antihypertensive therapy. Am J Med. 1996;101(suppl 3A):22S-32S.

Wick J. Culture, ethnicity, and medications. J Am Pharm Assoc.

1996;36:556-564.

Moser M, Lunn J. Responses to captopril and hydrochlorothiazide in

black patients with hypertension. Clin Pharmacol Ther. 1982;32:307-

312.

Zhou H, Koshakji R, Silberstein D, et al. Racial differences in drug

response: altered sensitivity to and clearance of propranolol in men

of Chinese descent as compared with American whites. N Engl J Med.

1989;320:565-570.

Materson B, Reda D, Cushman W, et al. Veterans Affairs ative

Study Group on antihypertensive agents. Single drug therapy for

hypertension in men. N Engl J Med. 1993;328:914-921.

Sowinski KM, Burles BS, JA. Pharmacodynamics and drug action:

racial differences in sensitivity to the

negative chronotropic effects of propranolol in healthy men. Clin

Pharmacol Ther. 1995;57:678-683.

Weir M, Chrysant SG, McCarron D, et al. Influence of race and dietary

salt on the antihypertensive efficacy of an angiotensin-converting

enzyme inhibitor or a calcium channel antagonist in salt-sensitive

hypertensives. Hypertension. 1998;31:1088-1096.

Preston R, Materson B, Reda D, et al. Age-race subgroup compared with

renin profile as predictor of blood pressure response to

antihypertensive therapy. JAMA. 1998;280:1168-1172.

Hall WD, J, Flack J, et al. ISHIB Investigators Group.

Comparison of the efficacy of dihydropyridine calcium blockers in

African American patients with hypertension. Arch Intern Med.

1998;158:2029-2034.

Freis ED. Age and antihypertensive drugs (hydrochlorothi-azide,

bendroflumethiazide, nadolol and captopril). Am J Cardiol.

1998;61:117-121.

Sixth Report of the Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High blood Pressure. Arch

Intern Med. 1997;157:2413-2446.

Special report: A review of the sixth report of the Joint National

Committee on Prevention, Detection, Evaluaton, and Treatment of High

Blood Pressure. Washington, DC: American Pharmaceutical Association;

1998:1-18.

Hall WD. A rational approach to the treatment of hypertension in

special populations. Am Fam Phys. 1999;60:156-162.

s HW. Racial, ethnic and gender differences in response to

medicines. Drug Metabol Drug Interact. 1995; 12:77-91.

L. Acceptability of foreign data: genetic, cultural and

environmental differences -- do they matter? In: S, Lumley C,

McAuslane N, eds. Relevance of Ethnic Factors in the Clinical

Evaluation of Medicines. Boston, MA: Kluwer Academic Publishers;

1994:3-11.

Bakris G, Mangrum A, Copley JB, et al. Effect of calcium channel or ß-

blockade on the progression of diabetic nephropathy in African

Americans. Hypertension. 1997:29:744-750.

Wood AJ. Ethnic differences in drug disposition and response. Ther

Drug Monit. 1998;20:525-526.

B, Frohlich E, Elliott W, et al. Selected factors that

influence responses to antihypertensives. Arch Fam Med. 1994;3:528-

535.

Wood AJ, Zhou HH. Ethnic differences in drug disposition and

responsiveness. Clin Pharmacokinet. 1991;20:350-373.

Topics in minority health. Health beliefs and compliance with

prescribed medication for hypertension among black women-New Orleans,

1985-86. Morb Mortal Wkly Rep. 1990;39:701-704.

Hoerger T, Bala M, Bray J, et al. Treatment patterns and distribution

of low-density lipoprotein cholesterol levels in treatment-eligible

United States adults. Am J Cardiol. 1998;82: 61-65.

Robbins D, Welty T, Wang W, et al. Plasma lipids and lipoprotein

concentrations among American Indians: comparison with the US

population. Curr Opin Lipidol. 1996;7:188-195.

Yu L, Qiu S, Genest J. Abnormal regulation of the LDL-R and HMG CoA

reductase genes in subjects with familial hypercholesterolemia with

the " French Canadian Mutation. " Atherosclerosis. 1996;124:103-117.

Pablos-Mendez A, Mayeux R, Ngai C, et al. Association of apo E

polymorphism with plasma lipid levels in a multiethnic elderly

population. Arterioscler Thromb Vasc Biol. 1997;17:3534-3541.

Marsh JC, Chowdry J, Parry- N, et al. Study of the association

between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug

and chemical induced idiosyncratic aplastic anaemia. Br J Haematol.

1999;104:266-270.

Yu CM, Chan TY, Tsoi WC, et al. Heparin therapy in the Chinese --

lower doses are required. Q J Med. 1997;90:535-543.

Yue QY, Iselius L, Sawe J. Indices and graphical approaches

for the detection of interindividual and interethnic variations in

codeine metabolism. Br J Clin Pharmacol. 1997;44:239-244.

Tsuritani I, Ikai E, Date T, et al. Polymorphism in ALDH2-genotype in

Japanese men and the alcohol-blood pressure relationship. Am J

Hypertens. 1995;8:1053-1059.

Levy RA. Ethnic and Racial Differences in Response to Medicines:

Preserving Individualized Therapy in Managed Pharmaceutical Programs.

Reston, VA: National Pharmaceutical Council; 1993.

Frackiewicz E, Stramek J, Herrera J, et al. Ethnicity and

antipsychotic response. Ann Pharmacother. 1997:31:1360-1369.

US Department of Commerce, Bureau of Census. Resident population,

1980 to 1998 and projections, 1999 to 2050 (Table 19). In:

Statistical Abstracts of the United States: National Data Book. 119th

ed. Washington, DC: US Government Printing Office; 1999.

US Department of Health and Human Services. Healthy People 2010.

Conference ed. Washington, DC: US Government Printing Office; 2000.

R, Gooden M, Porter C. Eliminating racial and ethnic

disparities in health care. Am J Nurs. 2000;100:56-58

Reprint Request

Address for correspondence/reprint requests: Connelly

Kudzma, DNSc, MPH, RNC, 1071 Blue Hill Avenue, Milton, MA 02186

Author from: the Division of Nursing and Health Studies, Curry

College, Milton, MA