Table 1-1. Metric System Prefixes

Prefix

Meaning

mega-

one million times the base unit (10⁶)

kilo-

one thousand times the base unit (10³)

deci-

one-tenth the base unit (10^-1)

centi-

one-hundredth the base unit (10^-2)

milli-

one-thousandth the base unit (10^-3)

micro-

one-millionth the base unit (10^-6)

nano-

one-billionth the base unit (10^-9)

pico-

one-trillionth the base unit (10^-12)

Table 1-2. Apothecaries' System of Measure

Weight

Volume

20 grains = 1 scruple

60 minims = 1 fluidram

3 scruples = 1 dram

8 fluidrams = 1 fluid ounce

8 drams = 1 ounce

16 fluid ounces = 1 pint

12 ounces = 1 pound

2 pints = 1 quart

4 quarts = 1 gallon

Table 3-1. Typical Pharmaceutical Ingredients

Ingredient type

Definition

Examples

Antifungal preservative

Used in liquid and semisolid formulations to prevent growth of fungi

Benzoic acid, butylparaben, ethylparaben, sodium benzoate, sodium propionate

Antimicrobial preservative

Used in liquid and semisolid formulations to prevent growth of microorganisms

Benzalkonium chloride, benzyl alcohol, cetylpyridinium chloride, phenyl ethyl alcohol

Antioxidant

Used to prevent oxidation

Ascorbic acid, ascorbyl palmitate, sodium ascorbate, sodium bisulfate, sodium metabisulfite

Binder

Used to cause adhesion of powder particles in tablet granulations

Acacia, alginic acid, ethylcellulose, starch, povidone

Diluent

Used as fillers to create desired bulk, flow properties, and compression characteristics in tablet and capsule preparations

Kaolin, lactose, mannitol, cellulose, sorbitol, starch

Disintegrant

Used to promote disruption of solid mass into small particles

Microcrystalline cellulose, carboxymethylcellulose calcium, sodium alginate, sodium starch glycolate, alginic acid

Emulsifying agent

Used to promote and maintain dispersion of finely divided droplets of a liquid in a vehicle in which it is immiscible

Acacia, cetyl alcohol, glyceryl monostearate, sorbitan monostearate

Glidant

Used to improve flow properties of powder mixture

Colloidal silica, cornstarch, talc

Humectant

Used for prevention of dryness of ointments and creams

Glycerin, propylene glycol, sorbitol

Lubricant

Used to reduce friction during tablet compression and to facilitate ejection of tablets from the die cavity

Calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate

Plasticizer

Used to enhance coat spread over tablets, beads, and granules

Glycerin, diethyl palmitate

Surfactant

Used to reduce surface or interfacial tension

Polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate

Suspending agent

Used to reduce sedimentation rate of drug particles dispersed throughout a vehicle in which they are not soluble

Carbopol, hydroxymethylcellulose, hydroxypropyl cellulose, methylcellulose, tragacanth

Table 3-2. Examples of Sustained-Release Drug Delivery Products

Dosage forms

Manufacturer

Active ingredients

Indications

Controlled-release tablets

Theo-Dur

ALZA Corp.

Theophylline

Asthma

Abacavir (Ziagen)

GlaxoSmithKline

Nucleoside reverse transcriptase inhibitor

HIV-1 infection

Sinemet

Bristol-Myers Squibb

Carbidopa + levodopa

Parkinson's disease

Volmax

ALZA Corp.

Albuterol

Bronchospasm

Voltaren

Novartis

Diclofenac sodium

Osteoarthritis and rheumatoid arthritis

Efidac 24

ALZA Corp.

Chlorpheniramine

Allergy symptoms and nasal congestion

DynaCirc CR

Novartis

Isradipine

Hypertension

Capsules

Dexedrine Spansules

GlaxoSmithKline

Dextroamphetamine

Narcolepsy

Adderall XL

Shire Pharmaceuticals

Amphetamine + dextroamphetamine

Attention-deficit/hyperactivity disorder (ADHD)

Ritalin LA

Novartis

Methylphenidate hydrochloride

ADHD

Videx EC

Bristol-Myers Squibb

Didanosine

HIV-1 infection

Aerosols

Ventolin HFA

GlaxoSmithKline

Albuterol sulfate

Bronchodilator

Azmacort

Kos

Triamcinolone acetonide

Asthma

Serevent

GlaxoSmithKline

Salmeterol

Bronchodilator

Osmotic systems

Oros System

ALZA Corp.

Oral delivery of different drugs

Ditropan XL

ALZA Corp.

Oxybutynin chloride

Overreacting bladder

Covera-HS

Pfizer

Verapamil

Antihypertensive

Concerta

ALZA Corp.

Methylphenidate HCl

ADHD

DUROS implant systems

Viadur

ALZA Corp.

Leuprolide

Prostate cancer

Inserts

Pilocarpine Ocusert

ALZA Corp.

Pilocarpine

Glaucoma

Lacrisert

ALZA Corp.

Hydroxypropyl cellulose

Ophthalmic moisturizer

Progestasert

CollaGenex

Progesterone

Contraceptive

Atridox

ALZA Corp.

Doxycycline

Periodontal disease

Transdermal patches

Alora

Watson Pharma

Estradiol

Menopausal symptoms

CombiPatch

Novartis

Estradiol/norethindrone acetate

Vasomotor symptoms associated with menopause

Androderm

Watson Pharmaceuticals

Testosterone

Testosterone deficiency

Nicotine transdermal system

Watson Pharmaceuticals

Nicotine

Smoking cessation

PEGylated proteins

PEGIntron

Schering Corp.

PEGylated interferon

Hepatitis C

PEGASYS

Roche

PEGylated interferon + ribavirin

Hepatitis B, hepatitis C

Liposomes

Doxil

Ortho Biotech

Doxorubicin HCl

Kaposi's sarcoma

DaunoXome

NeXstar Pharmaceuticals

Daunorubicin

Kaposi's sarcoma

Poly(lactic-co-glycolic acid)/polylactic acid microspheres

Lupron Depot

TAP Pharmaceuticals

Luteinizing hormone-releasing hormone agonist

Prostate cancer, endometriosis

Zoladex Depot

AstraZeneca

Goserelin acetate

Prostate cancer, endometriosis

Nutropin Depot

Genentech

Recombinant human growth hormone

Growth deficiencies

Table 4-1. Levigating Agents by Type and Ointment Base Classification

Type of agent

Ointment base classification

Aqueous

Glycerin

Oil-in-water emulsion

Propylene glycol

Water soluble

Polyethylene glycol 400

Water washable

Oily

Mineral oil

Oleaginous or hydrocarbon

Castor oil

Absorption

Cottonseed oil

Water-in-oil emulsion

Note: Other agents may be useful for certain preparations, such as Tween 80 for incorporating coal tar. Castor oil is useful for incorporating ichthammol and peru balsam.

Table 6-1. IV Bolus Multiple Dose Regimen

Dose number

Equation

Maximum or peak concentration

Minimum or trough concentration at the end of the dosing interval

1

n

Steady state

Table 7-1. Milestones in Biotechnology

Event

Year

Identification of DNA as a genetic material

1940

Discovery of DNA double helix by James Watson and Francis Crick

1953

Elucidation of the genetic code (64 nucleic acid triplets, or codons, encode 20 amino acids)

1961

Cloning of DNA and the production of the first recombinant DNA-derived protein

1973

Introduction of monoclonal antibodies

1975

Production of the first human protein (somatostatin) from recombinant DNA technology

1977

Cloning of the human insulin gene

1978

Licensing in the United States of technology to derive human insulin from recombinant DNA

1982

Conception of the polymerase chain reaction for amplification of DNA

1983

Initiation of the Human Genome Project

1990

Sequencing of the human genome

2001

Table 7-2. Approved Biological Products

Generic name

Brand name (manufacturer)

Indications

Blood factors

Factor VII

NovoSeven (Novo Nordisk)

Hemophilia

Factor VIII

Bioclate, Recombinate, Advate (Baxter); Kogenate, Helixate (Bayer); ReFacto (Genetics Institute); Xyntha (Wyeth Pharmaceuticals)

Hemophilia A

Factor IX

BeneFIX (Genetics Institute)

Hemophilia B

Cytokines

Aldesleukin (IL-2)

Proleukin (Chiron)

Metastatic renal cell carcinoma and melanoma

Denileukin diftitox

Ontak (Ligand)

Cutaneous T-cell lymphoma

Interferon alfacon-1

Infergen (InterMune)

Hepatitis C

Interferon alfa-n1

Wellferon (GlaxoSK)

Chronic hepatitis C

Interferon alfa-2a

Roferon-A (Roche)

Hairy cell leukemia; AIDS-related Kaposi's sarcoma; chronic myelogenous leukemia

Interferon alfa-2b

Intron-A (Schering)

Hairy cell leukemia; AIDS-related Kaposi's sarcoma; chronic hepatitis B and C; condylomata acuminata; malignant melanoma

Interferon alfa-n3

Alferon-N (InterMune)

Condylomata acuminata

Interferon beta-1b

Betaseron (Berlex)

Acute relapsing-remitting multiple sclerosis

Interferon beta-1a

Avonex (Biogen); Rebif (Serono)

Acute relapsing-remitting multiple sclerosis

Interferon gamma-1b

Actimmune (InterMune)

Chronic granulomatous disease; osteoporosis

Oprelvekin (IL-11)

Neumega (Genetics Institute)

Thrombocytopenia from chemotherapy

Peginterferon alfa-2a

Pegasys (Roche)

Hepatitis C

Peginterferon alfa-2b

PegIntron (Schering)

Hepatitis C

Enzymes

Agalsidase beta

Fabrazyme (Genzyme)

Fabry disease

Alglucosidase alfa

Myozyme (Genzyme)

Lysosomal alpha-1,4-glucosidase deficiency

Alpha-1-proteinase inhibitor

Zemaira (Aventis)

Alpha-1-proteinase inhibitor deficiency

Alteplase

Activase (Genentech)

Acute myocardial infarction; pulmonary embolism; stroke

Bivalirudin

Angiomax (Medicines Co.)

Coronary angioplasty (PTCA); unstable angina

Dornase alfa

Pulmozyme (Genentech)

Respiratory complication from cystic fibrosis

Eptifibatide

Integrelin (Millennium)

Acute coronary syndromes; angioplasties

Galsulfase

Naglazyme (Biomarin Pharmaceutical Inc.)

Mucopolysaccharidosis

Idursulfase

Elaprase (Shire Human Genetic Therapies)

Mucopolysaccharidosis

Imiglucerase

Cerezyme (Genzyme)

Type 1 Gaucher's disease

Laronidase

Aldurazyme (Biomarin)

Mucopolysaccharidosis

Lepirudin

Refludan (Berlex)

Heparin-induced thrombocytopenia

Rasburicase

Elitek (Sanofi-Synthelabo)

Elevated plasma uric acid in pediatric malignancy

Reteplase

Retavase (Centocor/J&J)

Acute myocardial infarction

Tenecteplase

TNKase (Genentech)

Acute myocardial infarction

Tirobifan

Aggrastat (Merck)

Acute coronary syndromes

Growth factors

Becaplermin (PDGF)

Regranex (Ortho-McNeil)

Diabetic foot ulcer

Darbepoetin alfa

Aranesp (Amgen)

Anemia associated with end-stage renal disease and chronic renal insufficiency

Epoetin alfa

EPOGEN (Amgen); Procrit (Ortho Biotech)

Anemia attributable to chronic renal disease; zidovudine-induced anemia; anemia due to chemotherapy; surgery patients

Filgrastim

Neupogen (Amgen)

Neutropenia attributable to myelosuppressive chemotherapy; myeloid reconstitution after bone marrow transplant; severe chronic neutropenia; peripheral blood progenitor cell transplant; induction and consolidation therapy in acute myelogenous leukemia

Methoxy polyethylene glycol-epoetin beta

Mircera (Roche)

Anemia attributable to chronic renal failure

Palifermin

Kepivance (Biovitrum)

Oral mucositis; mucositis following chemotherapy

Pegfilgrastim

Neulasta (Amgen)

Febrile neutropenia attributable to myelosuppressive chemotherapy

Sargramostim

Leukine (Berlex)

Myeloid reconstitution after bone marrow transplant; bone marrow transplant failure; adjunct to chemotherapy in acute myelogenous leukemia; peripheral blood progenitor cell transplant

Hormones

Choriogonadotropin alfa

Ovidrel (Serono)

Fertility

Follitropin alfa

Gonal-F (Serono)

Ovulatory failure

Follitropin beta

Follistim (Organon)

Ovulatory failure

Human growth hormone

Protopin, Nutropin (Genentech)

Growth hormone deficiency in pediatric patients

Humatrope (Eli Lilly)

Growth retardation in chronic renal disease

Saizen, Serostim (Serono)

AIDS wasting

Norditropin (Novo Nordisk)

Turner's syndrome

Genotropin (Pharmacia); Biotropin (Sol Source Technologies)

Growth hormone deficiency in adults

Human insulin

Humulin; Humalog (Eli Lilly); Novolin (Novo Nordisk); Lantus (Aventis)

Insulin-dependent diabetes mellitus

Ganirelix

Antagon (Organon)

Luteinizing hormone surge during fertility therapy

Glucagon

GlucaGen (Novo Nordisk)

Hypoglycemia

Growth hormone-releasing hormone

Geref (Serono)

Growth hormone deficiency in pediatric patients

Thyrotropin

Thyrogen (Genzyme)

Thyroid cancer

Monoclonal antibodies

Abciximab

ReoPro (Centocor)

Prevention of blood clots following percutaneous coronary intervention; unstable angina prior to percutaneous coronary intervention

Adalimumab

Humira (Abbott)

Acute rheumatoid arthritis

Alemtuzumab

Campath (Berlex)

Chronic lymphocytic leukemia

Basiliximab

Simulect (Novartis)

Acute organ transplant rejection

Bevacizumab

Avastin (Genentech)

Colorectal cancer

Certolizumab pegol

Cimzia (UCB)

Crohn's disease

Cetuximab

Erbitux (ImClone Systems)

Colorectal cancer

Daclizumab

Zenapax (Roche)

Kidney transplant; acute rejection

Eculizumab

Soliris (Alexion)

Paroxysmal nocturnal hemoglobinuria

Efalizumab

Raptiva (Genentech)

Psoriasis

Gemtuzumab (ozogamicin)

Mylotarg (Wyeth/PDL)

Acute myeloid leukemia (CD33+)

Ibritumomab (tiuxetan)

Zevalin (IDEC)

B-cell non-Hodgkin's lymphoma

Infliximab

Remicade (Centocor)

Crohn's disease; rheumatoid arthritis

Natalizumab

Tysabri (Amgen)

Crohn's disease; multiple sclerosis

Omalizumab

Xolair (Genentech)

Asthma

Palivizumab

Synagis (MedImmune)

Prevention of respiratory syncytial virus and fatal pneumonia in pediatrics

Panitumumab

Vectibix (Amgen)

Metastatic colorectal cancer

Ranibizumab

Lucentis (Genentech)

Exudative age-related macular degeneration

Rituximab

Rituxan (IDEC/Genentech)

Low-grade non-Hodgkin's lymphoma

Tositumomab

Bexxar (Corixa)

CD20+ non-Hodgkin's lymphoma

Trastuzumab

Herceptin (Genentech/PDL)

Metastatic breast cancer (Her 2 Neu+)

Vaccines

Haemophilus b/hepatitis B

Comvax (Merck)

Prevention of Haemophilus influenzae and hepatitis B

Hepatitis B vaccine

Engerix-B (GlaxoSK); Recombivax HB (Merck)

Prevention of hepatitis B

Others

Abatacept

Orencia (BMS)

Rheumatoid arthritis

Anakinra

Kineret (Amgen)

Rheumatoid arthritis

BCNU polymer

Gliadel (Guilford)

Recurrent glioblastoma multiforme

Daunorubicin-liposomal

DaunoXome (Gilead)

Kaposi's sarcoma

Doxorubicin-liposomal

DOXIL (Alza)

Kaposi's sarcoma; ovarian cancer

Drotrecogin alfa

Xigris (Eli Lilly)

Sepsis

Etanercept

Enbrel (Amgen)

Rheumatoid arthritis; psoriatic arthritis

Fomivirsen

Vitravene (Isis)

Cytomegalovirus retinitis

Glatiramer

Copaxone (Teva)

Relapsing multiple sclerosis

Lipid-based amphotericin B

Abelcet (Elan); Amphotec (Sequus); AmBisome (Fujisawa/Gilead)

Aspergillosis; cryptococcal meningitis in HIV; systemic fungal infections

Nesiritide

Natrecor (Scios/Innovex)

Congestive heart failure

Rilonacept

Arcalyst (Regeneron)

Cryopyrin-associated periodic syndromes

Romiplostim

Nplate (Amgen)

Idiopathic thrombocytopenic purpura

AIDS, acquired immunodeficiency syndrome; BCNU, bis-chlorethylnitrosourea; HIV, human immunodeficiency virus; IL, interleukin; PDGF, platelet-derived growth factor; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty.

Table 7-3. Genetic Polymorphisms in Drug Target Genes That Can Influence Drug Response^a

Gene or gene product

Medication

Drug effect associated with polymorphism

Angiotensin-converting enzyme (ACE)

ACE inhibitors (e.g., enalapril)

Renoprotective effects; blood pressure reduction; reduction in left ventricular mass; endothelial function

Fluvastatin

Lipid changes (reductions in low-density lipoprotein cholesterol and apolipoprotein B); progression or regression in coronary atherosclerosis

Arachidonate 5-lipoxygenase

Leukotriene inhibitors

Improvement of FEV₁

β₂-adrenergic receptor

β₂-agonists

Bronchodilatation; susceptibility to agonist-induced desensitization; cardiovascular effects

Bradykinin B₂ receptor

ACE inhibitors

ACE inhibitor-induced cough

Dopamine receptors (D₂, D₃, D₄)

Antipsychotics (e.g., haloperidol and clozapine)

Antipsychotic response (D₂, D₃, D₄); antipsychotic-induced tardive dyskinesia (D₃); antipsychotic-induced acute akathisia (D₃)

Estrogen receptor-α

Conjugated estrogens

Increase in bone mineral density

Hormone replacement therapy

Increase in high-density lipoprotein cholesterol

Glycoprotein IIIa subunit of glycoprotein IIb/IIIa

Aspirin or glycoprotein IIb/IIIa inhibitors

Antiplatelet effect

Serotonin (5-hydroxytryptamine transporter)

Antidepressants (e.g., clomipramine, fluoxetine, and paroxetine)

Serotonin neurotransmission; antidepressant response

FEV₁, forced expiratory volume in 1 second.

a. The examples shown are illustrative and are not representative of all published studies. Reprinted by permission from Evans, McLeod, 2003.

Table 7-4. Genetic Polymorphisms in Disease-Modifying or Treatment-Modifying Genes That Can Influence Drug Response^a

Gene or gene product

Disease or response association

Medication

Influence of polymorphism on drug effect or toxicity

Adducin

Hypertension

Diuretics

Myocardial infarction or strokes

Apolipoprotein E

Progression of atherosclerosis; ischemic cardiovascular events

Statins (e.g., simvastatin)

Enhanced survival

Alzheimer's disease

Tacrine

Clinical improvement

Human leukocyte antigen

Toxicity

Abacavir

Hypersensitivity reaction

Cholesterol ester transfer protein

Progression of atherosclerosis

Statins (e.g., pravastatin)

Slowing of progression of atherosclerosis

Ion channels (HERG, KvLQT1, Mink, and MiRP1)

Congenital long-QT syndrome

Erythromycin; terfenadine; cisapride; clarithromycin; and quinidine

Increased risk of drug-induced torsade de pointes

Methylguanine methyltransferase

Glioma

Carmustine

Response of glioma to carmustine

Parkin

Parkinson's disease

Levodopa

Clinical improvement and levodopa-induced dyskinesias

Prothrombin and factor V

Deep-vein thrombosis; cerebral-vein thrombosis

Oral contraceptives

Increased risk of deep-vein thrombosis and cerebral-vein thrombosis with oral contraceptives

Stromelysin-1

Atherosclerosis progression

Statins (e.g., pravastatin)

Reduction in cardiovascular events by pravastatin (death, myocardial infarction, stroke, angina, and others); reduction in risk of repeated angioplasty

a. The examples shown are illustrative and are not representative of all published studies. Reproduced with permission from Evans, McLeod, 2003.

Table 7-5. Pharmacogenomics of Phase I Drug Metabolism^a

Drug-metabolizing enzyme

Frequency of variant poor-metabolism phenotype

Representative drugs metabolized

Effect of polymorphism

Butyrylcholinesterase (pseudocholinesterase)

Approximately 1 in 3,500 Europeans

Succinylcholine

Enhanced drug effect

Cytochrome P-450 2D6 (CYP2D6)

6.8% of Swedes

Debrisoquin

Enhanced drug effect

1% of Chinese

Sparteine

Enhanced drug effect

Nortriptyline

Enhanced drug effect

Codeine

Decreased drug effect

Cytochrome P-450 2C9 (CYP2C9)

Approximately 3% of English (those homozygous for the *2 and *3 alleles)

Warfarin

Phenytoin

Enhanced drug effect

Enhanced drug effect

Cytochrome P-450 2C19 (CYP2C19)

2.7% of white Americans; 3.3% of Swedes; 14.6% of Chinese; 18% of Japanese

Omeprazole

Enhanced drug effect

Dihydropyrimidine dehydrogenase

Approximately 1% of population is heterozygous

Fluorouracil

Enhanced drug effect

a. Examples of genetically polymorphic phase I enzymes that catalyze drug metabolism are listed, including selected examples of drugs that have clinically relevant variations in their effect.

Reproduced with permission from Weinshilboum, 2003.

Table 7-6. Pharmacogenomics of Phase II Drug Metabolism^a

Drug-metabolizing enzyme

Frequency of variant poor-metabolism phenotype

Representative drugs metabolized

Effect of polymorphism

N-acetyltransferase 2

52% of white Americans

Isoniazid

Enhanced drug effect

17% of Japanese

Hydralazine

Enhanced drug effect

Uridine diphosphate-glucuronosyltransferase 1A1 (TATA box polymorphism)

10.9% of whites

Procainamide

Enhanced drug effect

4% of Chinese

Irinotecan

Enhanced drug effect

1% of Japanese

Bilirubin

Gilbert's syndrome

Thiopurine S-methyltransferase

Approximately 1 in 300 whites

Mercaptopurine

Enhanced drug effect (toxicity)

Approximately 1 in 2,500 Asians

Azathioprine

Enhanced drug effect (toxicity)

Catechol O-methyltransferase

Approximately 25% of whites

Levodopa

Enhanced drug effect

a. Examples of genetically polymorphic phase II (conjugating) enzymes that catalyze drug metabolism are listed, including selected examples of drugs that have clinically relevant variations in their effects.

Reproduced with permission from Weinshilboum, 2003.

Table 8-1. Trends in Awareness, Treatment, and Control of High Blood Pressure in Adults Ages 18-74

National Health and Nutrition Examination Survey

Aspect

II, 1976-80 (%)

III, phase 1, 1988-91 (%)

III, phase 2 1991-94 (%)

1999-2000 (%)

2005-06 (%)

Awareness

51

73

68

70

78

Treatment

31

55

54

59

68

Control^a

10

29

27

34

64

Unpublished data for 1999-2000 computed by M. Woltz, National Heart, Lung, and Blood Institute; adapted from JNC-7 Express, National Heart, Lung, and Blood Institute. Information for 2005-06 comes from the most recent Nhanes data available.

High blood pressure is systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or it is evidenced by the taking of antihypertensive medication.

a. Those adults surveyed have systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg.

Table 8-2. Prevalence of Hypertension by Ethnic Group for Adults Ages 20-74 (percent)

Ethnic group

Male

Female

Caucasians

24

19

African Americans

35

34

Mexican Americans

25

22

Asian Americans

13

13

Table 8-3. Classification and Management of Blood Pressure for Adults

Initial drug therapy

Blood pressure classification

SBP^a(mm Hg)

DBP (mm Hg)

Lifestyle modification

Without compelling indication

With compelling indications^b

Normal

< 120

and < 80

Encouraged

Prehypertension

120-139

or 80-89

Yes

No antihypertensive drug indicated

Drug(s) for compelling indications.^c

Stage 1 hypertension

140-159

or 90-99

Yes

Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB, or combination

Drug(s) for compelling indications;^c other antihypertensive drugs (diuretics, ACEI, ARB, BB, or CCB) as needed

Stage 2 hypertension

≥ 160

or ≥ 100

Yes

Two-drug combination for most^d(usually thiazide-type diuretic and ACEI or ARB or BB or CCB)

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; CCB, calcium channel blocker; DBP, diastolic blood pressure; SBP, systolic blood pressure

a. Treatment is determined by highest blood pressure category.

b. See

Table 8-12.

c. Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.

d. Treat patients with chronic kidney disease or diabetes to blood pressure goal of < 130/80 mm Hg.

Table 8-4. Recommendations for Follow-Up Based on Initial BP Measurements for Adults

Initial BP (mm Hg)^a

Systolic

Diastolic

Recommended follow-up^b

< 130

< 85

Recheck in 2 years.

130-139

85-89

Recheck in 1 year.^c

140-159

90-99

Confirm within 2 months.^c

160-179

100-109

Evaluate or refer to source of care within 1 month.

~180

~110

Evaluate or refer to source of care immediately or within 1 week depending on clinical situation.

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. If systolic and diastolic readings are different, follow recommendations for shorter time to follow-up (e.g., a person with a reading of 160/86 mm Hg should be evaluated or referred to source of care within 1 month).

b. Modify the scheduling of follow-up according to reliable information about past BP measurements, other cardiovascular risk factors, or target organ disease.

c. Provide advice about lifestyle modifications.

Table 8-5. Identifiable Causes, Diagnostic Tests, and Clinical Findings for Secondary Hypertension

Cause or diagnosis

Diagnostic test (clinical finding)

Chronic kidney disease

Estimated GFR (abdominal or flank mass for polycystic kidney disease)

Coarctation of the aorta

CT angiography (delayed or absent femoral pulse)

Cushing's syndrome and other glucocorticoid excess states, including chronic steroid therapy

History; dexamethasone suppression test (truncal obesity, moon facies, buffalo hump, abdominal striae, and hirsutism)

Drug-induced or drug-related condition

History; drug screening

Pheochromocytoma

24-hour urinary metanephrine and normetanephrine (headache, palpitations, and sweating)

Primary aldosteronism and other mineralocorticoid excess states

24-hour urinary aldosterone level or specific measurements of other mineralocorticoids (hypokalemia)

Renovascular hypertension

Doppler flow study; magnetic resonance angiography (abdominal bruit)

Sleep apnea

Sleep study with oxygen saturation (obesity, snoring, and tired during wake time)

Thyroid or parathyroid disease

Thyroid-stimulating hormone; serum parathyroid hormone (goiter; hypercalcemia)

CT, computed tomography; GFR, glomerular filtration rate.

Table 8-6. Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

RECOMMENDED DRUGS

COMPELLING INDICATION*

DIURETIC

BB

ACEI

ARB

CCB

ALDO ANT

CLINICAL TRIAL BASIS

Heart failure

•

•

•

•

•

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES

Postmyocardial infarction

•

•

•

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

High coronary disease risk

•

•

•

•

ALLHAT, HOPE, ANBP₂, LIFE, CONVINCE

Diabetes

•

•

•

•

•

NKF-ADA Guideline, UKPDS, ALLHAT

Chronic kidney disease

•

•

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

Recurrent stroke prevention

•

•

PROGRESS

* Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP.

Drug abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; Aldo ANT, aldosterone antagonist; BB, beta-blocker; CCB, calcium channel blocker.

Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs.

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

Table 8-7. Lifestyle Modifications to Manage Hypertension

MODIFICATION

RECOMMENDATION

APPROXIMATE SBP REDUCTION (RANGE)

Weight reduction

Maintain normal body weight (body mass index 18.5-24.9 kg/m²).

5-20 mmHg/10 kg weight loss

Adopt DASH eating plan

Consume a diet rich in fruits, vegetables, and lowfat dairy products with a reduced content of saturated and total fat.

8-14 mmHg

Dietary sodium reduction

Reduce dietary sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium chloride).

2-8 mmHg

Physical activity

Engage in regular aerobic physical activity such as brisk walking (at least 30 min per day, most days of the week).

4-9 mmHg

Moderation of alcohol consumption

Limit consumption to no more than 2 drinks (1 oz or 30 mL ethanol; e.g., 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey) per day in most men and to no more than 1 drink per day in women and lighter weight persons.

2-4 mmHg³⁰

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

DASH, Dietary Approaches to Stop Hypertension. For overall cardiovascular risk reduction, stop smoking. The effects of implementing these modifications are dose and time dependent, and could be greater for some individuals.

Table 8-8. Dietary Suggestions for Hypertensive Patients

Food group

Daily servings

Serving sizes

Examples and notes

Significance of each food group to the DASH diet pattern

Grains and grain products

7-8

1 slice bread; 1/2 c dry cereal; 1/2 c cooked rice, pasta, or cereal

Whole wheat bread, english muffins, pita bread, bagel, cereals, grits, and oatmeal

Major sources of energy and fiber

Vegetables

4-5

1 c raw leafy vegetable; 1/2 c cooked vegetable; 6 oz vegetable juice

Tomatoes, potatoes, carrots, peas, squash, broccoli, turnip greens, collards, kale, spinach, artichokes, beans, and sweet potatoes

Rich sources of potassium, magnesium, and fiber

Fruits

4-5

6 oz fruit juice; 1 medium fruit; 1/4 c dried fruit; 1/4 c fresh, frozen or canned fruit

Apricots, bananas, dates, grapes, oranges, orange juice, grapefruit, grapefruit juice, mangoes, melons, peaches, pineapple, prunes, raisins, strawberries, and tangerines

Important sources of potassium, magnesium, and fiber

Low-fat or nonfat dairy foods

2-3

8 oz milk; 1 c yogurt; 1.5 oz cheese

Skim or 1% milk, skim or low-fat buttermilk, nonfat or low-fat yogurt, part-skim mozzarella cheese, and nonfat cheese

Major sources of calcium and protein

Meats, poultry, and fish

2 or fewer

3 oz cooked meats, poultry, or fish

Select only lean cuts; trim away visible fats; broil, roast, or boil, instead of frying; and remove skin from poultry

Rich sources of protein and magnesium

Nuts, seeds, and legumes

4-5 per week

1.5 oz or 1/3 c nuts; 1/2 oz or 2 T seeds; 1/2 c cooked legumes

Almonds, filberts, mixed nuts, peanuts, walnuts, sunflower seeds, kidney beans, and lentils

Rich sources of energy, magnesium, potassium, protein, and fiber

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

DASH, Dietary Approaches to Stop Hypertension.

Table 8-9. The DASH Diet Sample Menu Based on 2000 Calories per Day

Food

Amount

Servings provided

Breakfast

Orange juice

6 oz

1 fruit

1% lowfat milk

8 oz (1 c)

1 dairy

Cornflakes (with 1 tsp sugar)

1 c

2 grains

Banana

1 medium

1 fruit

Whole wheat bread (with 1 T jelly)

1 slice

1 grain

Soft margarine

1 t

1 fat

Lunch

Chicken salad

3/4 c

1 poultry

Pita bread

1/2 large

1 grain

Raw vegetable medley

Carrot and celery sticks

3-4 sticks each

1 vegetable

Radishes

2

1 vegetable

Loose-leaf lettuce

2 leaves

1 vegetable

Part-skim mozzarella cheese

1.5 slices (1.5 oz)

1 dairy

1% lowfat milk

8 oz (1 c)

1 dairy

Fruit cocktail in light syrup

1/2 c

1 fruit

Dinner

Herbed baked cod

3 oz

1 fish

Scallion rice

1 c

2 grains

Steamed broccoli

1/2 c

1 vegetable

Stewed tomatoes

1/2 c

1 vegetable

Spinach salad:

Raw spinach

1/2 c

1 vegetable

Cherry tomatoes

2

1 vegetable

Cucumber

2 slices

1 vegetable

Light Italian salad dressing

1 T

1/2 fat

Whole wheat dinner roll

1 small

1 grain

Soft margarine

1 t

1 fat

Melon balls

1/2 c

1 fruit

Snacks

Dried apricots

1 oz (1/4 c)

1 fruit

Minipretzels

1 oz (3/4 c)

1 grain

Mixed nuts

1.5 oz (1/3 c)

1 nuts

Diet ginger ale

12 oz

0

Total number of servings in 2000-calorie per day menu

Food group

Servings

Grains

8

Vegetables

4

Fruits

5

Dairy foods

3

Meats, poultry, and fish

2

Nuts, seeds, and legumes

1

Fats and oils

2.5

Tips on eating the DASH way

• Start small. Make gradual changes in your eating habits.

• Center your meal around carbohydrates, such as pasta, rice, beans, or vegetables.

• Treat meat as one part of the whole meal, instead of the focus.

• Use fruits or low-fat, low-calorie foods such as sugar-free gelatin for desserts and snacks.

Remember: If you use the DASH diet to help prevent or control high blood pressure, make it part of a lifestyle that includes choosing foods lower in salt and sodium; keeping a healthy weight; being physically active; and if you drink alcohol, doing so in moderation.

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

DASH, Dietary Approaches to Stop Hypertension.

Table 8-10. Considerations for Individualizing Antihypertensive Drug Therapy

Indication

Drug therapy

Compelling indications unless contraindicated

Diabetes mellitus (type 1) with proteinuria

ACEI

Heart failure

ACEI, diuretics

Isolated systolic hypertension (older patients)

Diuretics (preferred), calcium antagonists (long-acting dihydropyridine)

Myocardial infarction

β-blockers (nonintrinsic sympathomimetic activity), ACEI (with systolic dysfunction)

Possible favorable effects on comorbid conditions^b

Angina

β-blockers, calcium antagonists

Atrial tachycardia and fibrillation

β-blockers, calcium antagonists (nondihydropyridine)

Cyclosporine-induced hypertension (use caution with the dose of cyclosporine)

Calcium antagonists

Diabetes mellitus (types 1 and 2) with proteinuria

ACEI (preferred), calcium antagonists

Diabetes mellitus (type 2)

Low-dose diuretics

Dyslipidemia

α-blockers

Essential tremor

β-blockers (noncardioselective)

Heart failure

Carvedilol, losartan potassium

Hyperthyroidism

β-blockers

Migraine

β-blockers (noncardioselective), calcium antagonists (nondihydropyridine)

Myocardial infarction

Diltiazem hydrochloride, verapamil hydrochloride

Osteoporosis

Thiazides

Preoperative hypertension

β-blockers

Prostatism (benign prostatic hyperplasia)

α-blockers

Renal insufficiency (use caution in renovascular hypertension and if creatinine ≥ 265.2 micromole/L [3 mg/dL])

ACEI

Possible unfavorable effects on comorbid conditions^a

Bronchospastic disease

β-blockers^b

Depression

β-blockers, central α-agonist, reserpine^b

Diabetes mellitus (types 1 and 2)

β-blockers, high-dose diuretics

Dyslipidemia

β-blockers (nonintrinsic sympathomimetic activity), diuretics (high-dose)

Gout

Diuretics

Heart block (second- or third-degree)

β-blockers,^b calcium antagonists (nondihydropyridine)^b

Heart failure

β-blockers (except carvedilol), calcium antagonists (except amlodipine besylate and felodipine)

Liver disease

Labetalol hydrochloride, methyldopa^b

Peripheral vascular disease

β-Blockers

Pregnancy

ACEI,^b angiotensin II receptor blockers^b

Renal insufficiency

Potassium-sparing agents

Renovascular disease

ACEI, angiotensin II receptor blockers

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

ACEI, angiotensin-converting enzyme inhibitors.

For initial drug therapy recommendations, see

Tables 8-11 through

8-19.

a. These drugs may be used with special monitoring unless contraindicated.

b. Contraindicated.

Table 8-11. Thiazide Diuretics, Thiazide-Like Diuretics, Loop Diuretics, Potassium-Sparing Agents, and Aldosterone-Receptor Blocker

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

Thiazide diuretics

Bendroflumethiazide

Naturetin

2.5-5 (1)

Short-term: increased cholesterol and glucose

Benzthiazide

Aquatag, Exna

12.5-50 (1)

Biochemical: decreased potassium, sodium, and magnesium; increased uric acid and calcium

Chlorothiazide

Diuril

125-500 (1)

Chlorthalidone

Hygroton, Hylidone

12.5-25 (1)

Rare: blood dyscrasias, photosensitivity, pancreatitis, hyponatremia, and sulfonamide-type immune reactions

Hydrochlorothiazide

HydroDIURIL, Microzide

12.5-50 (1)

Other: impotence, fatigue, headache, rash, and vertigo

Hydroflumethiazide

Saluron, Diucardin

25-50 (1)

Methyclothiazide

Renese

2.5-5 (1)

Polythiazide

Metahydrin, Naqua

2-4 (1)

Trichlormethiazide

2-4 (1)

Thiazide-like diuretics

Metolazone

Mykrox

2.5-10 (1)

(Less or no hypercholesterolemia compared to other thiazides; decreased microalbuminuria in diabetes)

Metolazone

Zaroxolyn

2.5-5 (1)

(Less or no hypercholesterolemia compared to other thiazides; decreased microalbuminuria in diabetes)

Indapamide

Lozol

2.5-5 (1)

Loop diuretics

Bumetanide

Bumex

0.5-2 (2)

Ototoxicity at high doses

Furosemide

Lasix

20-80 (2)

(Short duration and no hypercalcemia)

Torsemide

Demadex

2.5-10 (1)

(Short duration and no hypercalcemia)

Potassium-sparing agents^b

Amiloride

Midamor

5-10 (1-2)

Hyperkalemia

Triamterene

Dyrenium

50-100 (1-2)

(Avoid with history of kidney stones or hepatic disease)

Aldosterone-receptor blocker

Spironolactone

Aldactone

25-50 (1-2)

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. Adverse events, or side effects, listed are for the class of drugs, except where noted for individual drugs (in parentheses).

b. See

Table 8-12 for combination products.

Table 8-12. Combination Drugs for Hypertension

Fixed-dose combination (mg)^a

Trade name

ACEIs and CCBs

Amlodipine/benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20)

Lotrel

Enalapril maleate/felodipine (5/5)

Lexxel

Trandolapril/verapamil (2/180, 1/240, 2/240, 4/240)

Tarka

ACEIs and diuretics

Benazepril/hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25)

Lotensin HCT

Captopril/hydrochlorothiazide (25/15, 25/25, 50/15, 50/25)

Capozide

Enalapril maleate/hydrochlorothiazide (5/12.5, 10/25)

Vaseretic

Lisinopril/hydrochlorothiazide (10/12.5, 20/12.5, 20/25)

Prinzide

Moexipril HCL/hydrochlorothiazide (7.5/12.5, 15/25)

Uniretic

Quinapril HCL/hydrochlorothiazide (10/12.5, 20/12.5, 20/25)

Accuretic

ARBs and CCBs

Amlodipine/valsartan (5/160, 5/320, 10/160, 10/320)

Exforge

Amlodipine/olmesartan (5/20, 5/40, 10/20, 10/40)

Azor

ARBs and diuretics

Candesartan cilexetil/hydrochlorothiazide (16/12.5, 32/12.5)

Atacand HCT

Eprosartan mesylate/hydrochlorothiazide (600/12.5, 600/25)

Teveten/HCT

Irbesartan/hydrochlorothiazide (150/12.5, 300/12.5)

Avalide

Losartan potassium/hydrochlorothiazide (50/12.5, 100/25)

Hyzaar

Telmisartan/hydrochlorothiazide (40/12.5, 80/12.5)

Micardis/HCT

Valsartan/hydrochlorothiazide (80/12.5, 160/12.5)

Diovan/HCT

BBs and diuretics

Atenolol/chlorothalidone (50/25, 100/25)

Tenoretic

Bisoprolol fumarate/hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25)

Ziac

Propranolol LA/hydrochlorothiazide (50/25, 80/25)

Inderide

Metoprolol tartrate/hydrochlorothiazide (50/25, 100/25)

Lopressor HCT

Nadolol/bendrofluthiazide (40/5, 80/5)

Corzide

Timolol maleate/hydrochlorothiazide (10/25)

Timolide

Centrally acting drug and diuretics

Methyldopa/hydrochlorothiazide (250/15, 250/25, 500/30, 500/50)

Aldoril

Reserpine/chlorothiazide (0.125/250, 0.25/500)

Diupres

Reserpine/hydrochlorothiazide (0.125/25,0.25/50)

Hydropres

RIs and diuretics

Aliskiren/hydrochlorothiazide (150/12.5, 150/25, 300/12.5, 300/25)

Tekturna HCT

Other combinations

Amiloride HCL/hydrochlorothiazide (5/50)

Moduretic

Spironolactone/hydrochlorothiazide (25/25, 50/50)

Aldactazide

Triamterene/hydrochlorothiazide (37.5/25, 50/25, 75/50)

Dyazide, Maxzide

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

Abbreviations: BB, β-blocker; RI, renin inhibitor.

a. Some drug combinations are available in multiple fixed doses. Each drug dose is reported in milligrams.

Table 8-13. Postganglionic Adrenergic Neuron Blockers

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments

Guanadrel

Hylorel

10-75 (2)

Postural hypotension and diarrhea

Guanethidine monosulfate

Ismelin

10-150 (1)

Postural hypotension and diarrhea

Reserpine^a

Serpasil

0.05-0.25 (1)

Nasal congestion, sedation, depression, activation of peptic ulcer, dizziness, lethargy, memory impairment, sleep disturbances, and weight gain

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. Reserpine also acts centrally.

Table 8-14. Centrally Active α₂-Agonists

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

Clonidine HCl^b

Catapres

0.1-0.8 (2)

Sedation, dry mouth, bradycardia, withdrawal hypertension, orthostatic hypotension, depression, impotence, and sleep disturbances

Guanabenz acetate

Wytensin

8-32 (2)

(More withdrawal)

Guanfacine HCl

Tenex

1-3 (1)

(Less withdrawal)

Methyldopa

Aldomet

250-1,000 (2)

(Hepatic and "autoimmune" disorders)

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. Adverse events, or side effects, listed are for the class of drugs, except where noted for individual drugs (in parentheses).

b. Clonidine HCl is also available as a once-weekly transdermal patch.

Table 8-15. Peripherally Acting α₁-Adrenergic Blockers

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments

Doxazosin mesylate

Prazosin HCl

Terazosin HCl

Cardura

Minipress

Hytrin

1-16 (1)

2-20 (2-3)

1-20 (1-2)

Postural hypotension, syncopal episode with first dose, postural hypotension, diarrhea, weight gain, peripheral edema, dry mouth, urinary urgency, constipation, priapism, nausea, dizziness, headache, palpitations, and sweating; no effects on glucose or cholesterol

Reprinted with permission from JNC-VII.

Table 8-16. β-Blockers and Combination α- and β-Blockers

Drug

Trade name

Lipid solubility/primary (secondary) routes of elimination

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

β-blockers

Acebutolol^b,c

Atenolol^b

Betaxolol^b

Bisoprolol fumarate^b

Carteolol HCl^c

Sectral

Tenormin

Kerlone

Zebeta

Cartrol

Low/H (R)

Low/R (H)

Low/H (R)

Low/R (H)

Low/R

200-800 (1)

25-100 (1)

5-20 (1)

2.5-10 (1)

2.5-10 (1)

Bronchospasm, bradycardia, and heart failure; may mask insulin-induced hypoglycemia; less serious: impaired peripheral circulation, insomnia, fatigue, decreased exercise tolerance, and hypertriglyceridemia, except agents with intrinsic sympathomimetic activity

Metoprolol tartrate^b

Lopressor

Moderate/H (R)

50-100 (2)

Metoprolol succinate^b

Toprol-XL

Moderate/H (R)

50-100 (1)

Nadolol

Corgard

Low/R

40-120 (1)

Penbutolol sulfate^c

Levatol

High/H (R)

10-20 (1)

Pindolol^c

Visken

Moderate/H (R)

10-60 (2)

Propranolol HCl

Inderal

High/H

40-160 (2)

Inderal LA

High/H

60-180 (1)

Timolol maleate

Blocadren

Low-moderate/H (R)

20-40 (2)

Combined α- and β-blockers

Carvedilol

Coreg

Moderate/bile into feces

12.5-50 (2)

Postural hypotension, bronchospasm

Labetalol

Normodyne, Trandate

Moderate/R (H)

200-800 (2)

Reprinted with permission from JNC-VII.

H, hepatic; R, renal.

a. Adverse events, or side effects, listed are for the class of drugs.

b. Cardioselective.

c. Intrinsic sympathomimetic activity.

Table 8-17. Direct Vasodilators

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

Headaches, fluid retention, tachycardia, peripheral neuropathy, and postural hypotension

Hydralazine HCl

Apresoline

25-100 (2)

(Lupus syndrome)

Minoxidil

Loniten

2.5-80 (1-2)

(Hirsutism)

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. Adverse events, or side effects, listed are for the class of drugs, except where noted for individual drugs (in parentheses).

Table 8-18. Calcium Antagonists

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

Nondihydropyridines

Diltiazem HCl

Cardizem SR, Cardizem CD, Dilacor XR, Tiazac

180-420 (1) 120-360 (1)

Conduction defects, worsening of systolic dysfunction, and gingival hyperplasia

Verapamil immediate-release

Calan, Isoptin

80-320 (2)

(Nausea and headache)

Verapamil long-acting

Calan SR, Isoptin SR

120-360 (1-2)

(Constipation)

Verapamil COER

Covera HS, Verelan PM

120-360 (1)

Dihydropyridines

Amlodipine besylate

Norvasc

2.5-10 (1)

Edema of the ankle, flushing, headache, and gingival hyperplasia

Felodipine

Plendil

2.5-20 (1)

Isradipine

DynaCirc

2.5-10 (2)

DynaCirc CR

5-20 (1)

Nicardipine

Cardene SR

60-120 (1)

Nifedipine

Procardia XL, Adalat CC

30-60 (1)

Nisoldipine

Sular

10-40 (1)

Adapted from JNC-7 Express, National Heart, Lung, and Blood Institute.

a. Adverse events, or side effects, listed are for the class of drugs, except where noted for individual drugs (in parentheses).

Table 8-19. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments^a

ACEIs

Benazepril HCl

Lotensin

10-40 (1-2)

Common: cough

Captopril

Capoten

25-100 (2-3)

Rare: angioedema, hyperkalemia, rash, loss of taste, and leucopenia

Enalapril maleate

Fosinopril

Lisinopril

Vasote

Monopril

Prinivil, Zestril

2.5-40 (1-2)

10-40 (1-2)

10-40 (1)

Other: vertigo; headache; fatigue; first-dose hypotension; minor GI disturbances; acute renal insufficiency in patients with predisposing factors such as renal stenosis and coadministration with thiazide diuretics; and proteinuria (especially in patients with history of renal disease)

Moexipril

Univasc

7.5-30 (1)

Perindopril

Aceon

4-8 (1-2)

Quinapril HCl

Accupril

10-40 (1-2)

Ramipril

Altace

1.25-20 (1)

Trandolapril

Mavik

1-4 (1)

ARBs

Candesartan

Atacand

8-32 (1)

Angioedema and hyperkalemia

Eprosartan

Teveten

400-800 (1-2)

Irbesartan

Avapro

150-300 (1)

Losartan

Cozaar

25-100 (1-2)

Olmesartan

Benicar

20 (1)

Telmisartan

Micardis

40-80 (1)

Valsartan

Diovan

80-320 (1)

Reprinted with permission from JNC-VII.

Table 8-20. Direct Renin Inhibitors

Drug

Trade name

Usual dose range, total mg/d (frequency per day)

Adverse events and comments

Aliskiren

Tekturna

150-300 mg (1)

Common: diarrhea

Rare: elevated uric acid, gout, renal stone, angioedema, and rash

Other: headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain, and cough

Drug product package insert.

Table 8-21. Parenteral Drugs for Treatment of Hypertensive Emergencies

Drug

Dose

Onset of action

Duration of action

Adverse effects^a

Special indications

Vasodilators

Sodium nitroprusside

0.25-10 mcg/kg/min IV infusion^b (maximal dose for 10 min only)

Immediate

1-2 min

Nausea, vomiting, muscle twitching, sweating, and thiocyanate and cyanide intoxication

Most hypertensive emergencies; caution with high intracranial pressure or azotemia

Nicardipine hydrochloride

5-15 mg/h IV

5-10 min

1-4 h

Tachycardia, headache, flushing, and local phlebitis

Most hypertensive emergencies, except acute heart failure; caution with coronary ischemia

Fenoldopam mesylate

0.1-0.3 mcg/kg/min IV infusion

< 5 min

30 min

Tachycardia, headache, nausea, and flushing

Nitroglycerin

5-100 mcg/min IV infusion^c

2-5 min

3-5 min

Headache, vomiting, methemoglobinemia, and tolerance with prolonged use

Coronary ischemia

Enalaprilat

1.25-5 mg every 6 h IV

15-30 min

6 h

Precipitous fall in pressure in high-renin states; response variable

Acute left ventricular failure; avoid in acute myocardial infarction

Hydralazine hydrochloride

10-20 mg IV; 10-50 mg IM

10-20 min; 20-30 min

3-8 h

Tachycardia, flushing, headache, vomiting, and aggravation of angina

Eclampsia

Diazoxide

50-100 mg IV bolus repeated, or 15-30 mg/min IV infusion

2-4 min

6-12 h

Nausea, flushing, tachycardia, and chest pain

Now obsolete; when no intensive monitoring available

Adrenergic inhibitors

Labetalol hydrochloride

20-80 mg IV bolus every 10 min;

0.5-2.0 mg/min IV infusion

5-10 min

3-6 h

Vomiting, scalp tingling, burning in throat, dizziness, nausea, heart block, and orthostatic hypotension

Most hypertensive emergencies, except acute heart failure

Esmolol hydrochloride

250-500 mcg/kg/min for 1 min, then 50-100 mcg/kg/min for 4 min; may repeat sequence

1-2 min

10-20 min

Hypotension and nausea

Aortic dissection, perioperative

Phentolamine

5-15 mg IV

1-2 min

3-10 min

Tachycardia, flushing, and headache

Catecholamine excess

Reprinted with permission from JNC-VII.

a. Hypotension may occur with all agents.

b. Requires special delivery system.

Table 8-22. Selected Agents for Specific Hypertensive Emergencies

Emergency

Recommended therapy

Comments

Encephalopathy

Labetalol, nicardipine, and nitroprusside

Avoid methyldopa (sedation), diazoxide (reduces cerebral blood flow), reserpine (sedation), and hydralazine (increases intracranial pressure).

Myocardial infarction or unstable angina

Nitroglycerin and esmolol

Reduce BP until pain is relieved, and use in conjunction with conventional therapy for MI/angina.

Avoid diazoxide and hydralazine (increases oxygen demand), dihydropyridines (may worsen angina), and nitroprusside (coronary steal).

Congestive heart failure

Nitroprusside, nitroglycerin, and enalaprilat

Avoid labetalol, esmolol, and other β-blockers (reduces cardiac output).

Subarachnoid hemorrhage, intracerebral hemorrhage, and stroke

Nitroprusside

BP reduction is controversial because it may cause hypoperfusion; generally recommended for severe hypertension (systolic blood pressure > 220 or diastolic blood pressure > 120 mm Hg).

Dissecting aortic aneurysm

Trimethaphan, esmolol, and nitroprusside

Avoid diazoxide and hydralazine (increase shear force).

Pheochromocytoma and cocaine overdose

Phentolamine and labetalol

Anecdotal reports suggest increased BP with labetalol; unopposed β blockade may worsen crisis.

Renal insufficiency

Nitroprusside, calcium channel blocker, and labetalol

Monitor cyanide and thiocyanate levels.

Postoperative hypertension

Nitroprusside, nicardipine, and labetalol

Blood pressure levels of >180/110 should be controlled before surgery. Contributing factors to postoperative hypertension may include pain and increased intravascular volume, which may require parenteral loop diuretics.

Table 8-23. Agents Used to Treat Hypertensive Urgencies

Drug

Dose

Onset

Duration

Adverse effects

Captopril

25 mg, repeat in 1-2 hours as needed

5-15 min

4-6 h

Hypotension, acute renal failure, and angioedema

Clonidine

0.1-0.2 mg, repeat in 1-2 hours as needed (up to 0.6 mg)

5-15 min

6-12 h

Hypotension, drowsiness, sedation, and dry mouth

Labetalol

100-400 mg, repeat in 2-3 hours as needed

15-30 min

4-6 h

Hypotension, heart block, and bronchoconstriction

Table 9-1. Loop Diuretics

Generic name

Trade name

Dosage form

Dosage range and frequency

Furosemide

Lasix

Oral tablet

20.0-160.0 mg qd bid

Bumetanide

Bumex

Oral tablet

0.5-5.0 mg qd bid

Torsemide

Demadex

Oral tablet

10.0-100.0 mg qd bid

Table 9-2. Angiotensin-Converting Enzyme Inhibitors

Generic name

Trade name

Dosage form

Dosage range and frequency

Captopril

Capoten

Oral tablet

6.25-50.0 mg tid

Enalapril

Vasotec

Oral tablet

2.5-20.0 mg bid

Fosinopril

Monopril

Oral tablet

5.0-40.0 mg qd

Lisinopril

Zestril, Prinivil

Oral tablet

2.5-40.0 mg qd

Quinapril

Accupril

Oral tablet

10.0-40.0 mg bid

Ramipril

Altace

Oral capsule

2.5-5.0 mg bid

Perindopril

Aceon

Oral tablet

2.0-16.0 mg qd

Trandolapril

Mavik

Oral tablet

0.5-4.0 mg qd

Table 9-3. Angiotensin Receptor Blockers

Generic name

Trade name

Dosage form

Dosage range and frequency

Candesartan

Atacand

Oral tablet

4-32 mg qd

Valsartan

Diovan

Oral tablet

20-160 mg bid

Table 9-4. β-Blockers

Generic name

Trade name

Dosage form

Dosage range and frequency

Bisoprolol

Zebeta

Oral tablet

1.25-10.0 mg qd bid

Carvedilol

Coreg

Oral tablet

3.125-50.0 mg bid

Carvedilol

Coreg CR

Oral capsule

10.0-80.0 mg qd

Metoprolol succinate extended-release

Toprol-XL

Oral tablet

12.5-200.0 mg qd

Table 9-5. Aldosterone Antagonists

Generic name

Trade name

Dosage form

Dosage range and frequency

Spironolactone

Aldactone

Oral tablet

12.5-50.0 mg qd or qod

Eplerenone

Inspra

Oral tablet

25.0-50.0 mg qd

Table 9-6. Digoxin

Generic name

Trade name

Dosage form

Dosage range and frequency

Digoxin

Lanoxin

Oral tablet, IV, elixir

0.125-0.25 mg qd

Digoxin

Lanoxicaps

Oral capsule

0.1-0.2 mg qd

Table 9-7. Digoxin Pharmacokinetics

Oral bioavailability

Tablets

0.50-0.90 (average 0.65)

Elixir

0.75-0.85 (average 0.80)

Capsules

0.90-1.00 (average 0.95)

Elimination half-life

Normal renal function

36 hours

Anuric patients

5 days

Volume of distribution

7 L/kg

Fraction excreted unchanged in urine

0.65-0.70

Table 9-8. Vasodilators

Generic name

Trade name

Mechanism of action

Dose^a

Adverse effects and comments

Nitroprusside

Nipride

Arterial and venous dilator

Initial dose 0.1-0.25 mcg/kg/min and titrate to response

Hypotension, headache, tachycardia, cyanide and thiocyanate toxicity, myocardial ischemia

Nitroglycerin

Nitro-Bid, Nitrostat

Venous dilator but also an arterial dilator at higher doses

Initial dose 5-10 mcg/min and titrate to response

Hypotension, headache, tachycardia, tolerance to hemodynamic effects

Nesiritide

Natrecor

B-type natriuretic peptide that increases diuresis and is an arterial and venous dilator

Initially 2 mcg/kg bolus followed by 0.01 mcg/kg/min infusion; can increase to 0.03 mcg/kg/min

Hypotension, headache when used in combination with diuretics

a. All are given by continuous IV infusion.

Table 9-9. Inotropes

Generic name

Trade name

Mechanism of action

Dose^a

Adverse effects and comments

Dopamine

Intropin

Dose-dependent agonist of dopamine, β-, and α_1--receptors

0-3 mcg/kg/min: stimulates dopamine receptors; may improve urine output

3-10 mcg/kg/min: stimulates β₁- and β₂-receptors to increase cardiac output

> 10 mcg/kg/min: stimulates α₁-receptors to increase blood pressure

Increases heart rate, contractility, myocardial oxygen demand, myocardial ischemia, arrhythmias, and systemic vascular resistance; should be used only in patients with marked systemic hypotension or cardiogenic shock

Dobutamine

Dobutrex

β₁- and β₂-receptor agonist and weak α₁ agonist; increases cardiac output and vasodilates

2.5-20.0 mcg/kg/min

Increases heart rate, contractility, myocardial oxygen demand, myocardial ischemia, arrhythmias; not useful to increase blood pressure in hypotensive patients

Milrinone

Primacor

Inhibits phosphodiesterase III, resulting in positive inotropic and vasodilating effects

50 mcg/kg loading dose over 10 min, followed by 0.375 mcg/kg/min; can titrate to 0.75 mcg/kg/min on basis of response

Arrhythmias, hypotension, and headache; is an alternative to patients not responding to dobutamine or dopamine; may be useful for patients receiving β-blockers because its positive inotropic effects are not mediated by β-receptors; adjust dose in patients with renal insufficiency; preferred over inamrinone because of decreased risk of thrombocytopenia

a. All are given by continuous IV infusion.

Table 10-1. Phases of Atrial and Ventricular Tissue Action Potential

Phase

Process

Ion flow

Corresponding ECG

0

Depolarization

Na⁺ fast channel opens; Na⁺ enters cell.

Atrial: P wave; ventricular: QRS

1

Initial repolarization

Na⁺ channel closes; passive Cl^- influx.

2

Prolongs depolarized state

Predominantly Ca²⁺ enters cell.

ST segment

3

Repolarization

Rapid efflux of K⁺ out of cell.

T wave, QT interval

4

Repolarization

Na⁺ leaks into cell; K⁺ pumped out of cell.

Table 10-2. Management of Elevated International Normalized Ratio

INR

Significant bleeding

Recommendations

< 5.0 but above therapeutic range

No

Lower dose or omit single dose and restart at lower dose when INR is therapeutic.

≥ 5.0 and < 9.0

No

Omit 1-2 doses and resume at lower dose when INR is therapeutic; if more rapid reversal desired, omit dose and give ≤ 5 mg vitamin K orally; restart warfarin at lower dose when INR is therapeutic or clinically appropriate.

> 9.0

No

Hold warfarin and give 2.5-5.0 mg vitamin K orally; use additional vitamin K if necessary; resume warfarin at lower dose when INR is therapeutic.

Serious bleeding at any elevation of INR

Yes

Hold warfarin; give 10 mg vitamin K IV via slow infusion (over at least 10 minutes); supplement with fresh-frozen plasma, rVIIa, or prothrombin complex concentrate if necessary; repeat vitamin K 10 mg IV q12h if necessary.

Life-threatening bleeding at any elevation of INR

Yes, life threatening

Hold warfarin; give fresh-frozen plasma, prothrombin complex concentrate, or rVIIa with vitamin K 10 mg via IV slow infusion; repeat as necessary

Table 10-3. Effects of Antiarrhythmic Drugs on Cardiac Electrophysiology

Drug class

Ion block

Conduction

Refractory period

Automaticity

Ia

Sodium

Ib

Sodium

0/

Ic

Sodium

II

Calcium (Indirect effect)

III¹

Potassium

0

0

IV

Calcium

Decreases

Increases

¹Sotalol also possesses β-blocking activity. Amiodarone also possesses sodium and calcium channel blockade.

Table 10-4. Antiarrhythmic Drug Availability and Standard Dosing Regimens

Generic name

Trade name

Dosage forms

Loading dose

Maintenance dose

Class Ia

Quinidine gluconate

Quinaglute Dura-Tabs, Duraquin, Quinalan, Quinatime

324, 330 mg tablets 80 mg/mL injection

IV: not recommended

328-648 mg PO tid

Quinidine sulfate

Quinidex Extentabs, Cin-Quin, Quinora

100, 200, 300 mg tablets

PO: 200 mg q 2-3 h for 5-8 doses (sulfate salt only)

200-400 mg PO qid

Quinidine polygalacturonate

Cardioquin

275 mg tablets

275 mg PO bid or tid

Procainamide

Pronestyl

100, 500 mg/mL injection Oral procainamide no longer available

IV: 15-18 mg/kg at 20-50 mg/min

IV: 1-6 mg/min

Disopyramide

Norpace, Norpace CR

100, 150 mg capsules 100, 150 mg capsules

150-300 mg q6h 300-600 mg q12h

Moricizine

Ethmozine

200, 250, 300 mg tablets

200-300 mg q8h

Class Ib

Lidocaine

10 mg/mL (5 mL and 10 mL)

20 mg/mL (5 mL)

IV: 100 mg repeat up to 2 times

IV: 1-4 mg/min

IV infusion: 2 (500 mL), 4 (250, 500, 1,000 mL), 8 (250, 500 mL) mg/mL in D₅W

Tocainide

Tonocard

400, 600 mg tablets

400-600 mg q8h

Mexiletine

Mexitil

150, 200, 250 mg capsules

100-300 mg q8h

Class Ic

Flecainide

Tambocor

50, 100, 150, 200 mg tablets

600 mg PO for conversion of atrial fibrillation to sinus rhythm

50-200 mg q12h

Propafenone

Rythmol, Rythmol-SR

150, 225, 300 mg tablets 225, 325, 425 mg capsules

150-300 mg q8h 225-425 mg q12h

Class II: β-blockers

Metoprolol

Lopressor, Toprol XL

25, 50, 100 mg tablets 25, 50, 100, 200 mg tablets; 1 mg/mL injection

IV: 2.5-5 mg up to 3 doses

25-450 mg PO daily

Propranolol

Inderal, Inderal LA

10, 20, 40, 60, 80 mg tablets

60, 80, 120, 160 mg capsules

20, 40 mg/mL oral solution 1 mg/mL (5 mL) injection

IV: 0.15 mg/kg IV: 0.5 mg/kg

PO: 80-240 mg daily

Esmolol

Brevibloc

10 and 250 mg/mL injection

0.5 mg/kg/min × 1 min

IV: 0.05-0.2 mg/kg/min

Class III

Amiodarone

Cordarone, Pacerone

100, 200, 400 mg tablets

800-1,600 mg/d in divided doses × 2-4 weeks

PO: 100-400 mg qd

5, 50 mg/mL IV solution

IV (VT/VF): 150 mg/10 min or 900 mg in 500 mL D₅W at 1 mg/min × 6 h IV (cardiac arrest): 300 mg

IV: 0.5 mg/min

Sotalol

Betapace, Betapace AF

80, 120, 160, 240 mg tablets

80-160 mg q12h

Ibutilide

Corvert

0.1 mg/mL (10 mL) injection

1.0 mg IV over 10 min; repeat × 1 if needed

Not applicable

Dofetilide

(Tikosyn)

125, 250, 500 mcg capsules

CrCl > 60 mL/min = 500 mcg bid; 40-60 mL/min = 250 mcg bid; 20-39 mL/min = 125 mcg bid; < 20 mL/min = not recommended

Class IV: calcium channel blockers

Verapamil

Calan, Calan SR, Isoptin SR, Covera-HS, Verelan, Verelan-PM

40, 80, 120 mg tablets 120, 180, 240 mg tablets 180, 240 mg tablets 120, 180, 240, 360 mg capsules 100, 200, 300 mg capsules 2.5 mg/ml injection

2.5-10 mg IV over 2 min

PO: 120-360 mg/d IV: 5-15 mg/h Calan, Isoptin: tid-qid Calan SR, Isoptin SR, Covera-HS, Verelan: qd

Diltiazem

Cardizem, Cardizem CD, Cardizem Monovial, Cardizem Lyo-Ject, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Tiazac, Cardizem LA

30, 60, 90, 120 mg tablets 5 mg/mL injection 120, 180, 240, 300, 360 mg capsules 100 mg/mL injection 25 mg injection 60, 90, 120 mg capsules 120, 180, 240, 300 mg capsules 120, 180, 240 mg capsules 120, 180, 240, 300 mg capsules 120, 180, 240, 300, 360, 420 mg tablets

20 mg IV over 2 min

IV: 5-15 mg/h PO: 120-360 mg/d Cardizem: qid Cardizem SR: bid Cardizem CD, Cardizem LA, Dilacor XR, Tiazac: qd

Miscellaneous

Atropine

0.1, 0.3, 0.4, 0.5, 0.6, 0.8, 1.0 mg/mL injection

0.5-1.0 mg q 5 min up to 3 mg total

Adenosine

Adenocard

3 mg/mL injection

Initial dose: 6 mg IV bolus; if necessary, can be followed by 12 mg q 2 min as IV bolus; flush IV line after each administration

Digoxin

Lanoxin, Lanoxicaps

125, 250, 500 mcg tablets

IV and PO: 0.25 mg q 2 h up to 1.5 mg

IV and PO: 0.125-0.375 mg qd

50 mcg/mL elixir 100, 250 mcg/mL injection 50, 100, 200 mcg capsules

Table 10-5. Pharmacokinetics of Antiarrhythmic Drugs

Drug

Bioavailability (%)

Protein binding (%)

Primary route of elimination

Substrate for

Inhibitor of

Half-life

Therapeutic range (mg/L)

Quinidine

70-80

80-90

Hepatic

CYP3A4

CYP2D6, CYP3A4, P-gp

5-9 h

2-6

Procainamide

75-95

10-20

Hepatic and renal

NAT

2.5-5.0 h

4-15

Disopyramide

70-95

50-80

Hepatic and renal

CYP3A4

4-8 h

2-6

Moricizine

34-38

92-95

Hepatic

1-6 h

Lidocaine

20-40

65-75

Hepatic

CYP3A4, CYP2D6, CYP1A2

CYP1A2

60-180 min

1.5-5.0

Tocainide

90-95

10-30

Hepatic

12-15 h

4-10

Mexiletine

80-95

60-75

Hepatic

CYP2D6, CYP1A2

CYP1A2

6-12 h

0.8-2.0

Flecainide

90-95

35-45

Hepatic and renal

CYP2D6

CYP2D6

13-20 h

0.2-1.0

Propafenone

11-39

85-95

Hepatic

CYP2D6, CYP1A2, CYP3A4

CYP2D6

3-25 h

Amiodarone

22-88

95-99

Hepatic

CYP3A4, CYP1A2, CYP2C19, CYP2D6

CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP2C19, P-gp

15-100 d

1.0-2.5

Sotalol

90-95

30-40

Renal

12-20 h

Ibutilide

40

Hepatic

3-6 h

Dofetilide

> 90

60-70

Renal

CYP3A4

6-10 h

Digoxin

60-85 (90-100) for Lanoxicaps

20-30

Renal

P-gp

34-44

0.5-2.2 ng/mL

Diltiazem

35-50

70-85

Hepatic

CYP3A4, CYP2C9, CYP2D6

CYP3A4, CYP2C9, CYP2D6, P-gp

4-10 h

Verapamil

20-40

95-99

Hepatic

CYP3A4, CYP1A2, CYP2C9

CYP3A4, CYP1A2, CYP2C9, CYP2D6, P-gp

4-12 h

Note: CYP = cytochrome P450 isoenzyme; NAT = N-acetyltransferase; P-gp = P-glycoprotein.

Table 10-6. Antiarrhythmic Drug Interactions and Significant Adverse Effects

Drug

Effect of disease/drugs on antiarrhythmic drug concentrations

Effect of antiarrhythmic on other drug concentrations

Common or severe adverse effects

Quinidine

Elevated: cimetidine, amiodarone, verapamil, diltiazem, ketoconazole, urine alkalinization

Reduced: enzyme inducers

Elevated: warfarin, digoxin, β-blockers, disopyramide, procainamide, propafenone, mexiletine, flecainide

QTc prolongation, torsades de pointes, diarrhea, fever, hepatitis, thrombocytopenia

Procainamide

Elevated: cimetidine, trimethoprim, amiodarone

Lupus-like syndrome, QTc prolongation, torsades de pointes, hypotension, gastrointestinal (GI) distress, agranulocytosis

Disopyramide

Reduced: enzyme inducers

Elevated: erythromycin, protease inhibitors, cimetidine

Anticholinergic side effects, decreased cardiac contractility, heart failure, QTc prolongation, torsades de pointes, hypoglycemia

Moricizine

Elevated: cimetidine

Elevated: theophylline

Dizziness, nausea, tremor, ataxia, paresthesias, proarrhythmia

Lidocaine

Increased: with decreased cardiac output

Central nervous system (CNS) toxicity: paresthesias, dizziness, muscle twitching, confusion, nausea and vomiting, slurred speech, seizures, sinus arrest

Tocainide

Decreased: cimetidine, enzyme inducers

GI distress; CNS: dizziness, paresthesias, confusion, seizures; pulmonary fibrosis or pneumonitis; agranulocytosis

Mexiletine

Reduced: enzyme inducers

Elevated: quinidine, amiodarone, ritonavir

Elevated: theophylline

GI distress; CNS: tremor, dizziness, confusion, vertigo, nystagmus, diplopia, tremor, ataxia; hypotension, sinus bradycardia, AV block

Flecainide

Elevated: cimetidine, amiodarone

Elevated: digoxin

Proarrhythmia, prolonged PR interval and QRS complex; dizziness, blurred vision, headache, tremor, heart failure

Propafenone

Reduced: enzyme inducers

Elevated: cimetidine, quinidine

Elevated: warfarin, digoxin, cyclosporine, theophylline

Metallic/bitter taste; CNS: dizziness, paresthesias, fatigue; GI distress; heart failure, liver injury, bradycardia, AV block, proarrhythmia

Amiodarone^a

Elevated: quinidine, procainamide, warfarin, digoxin, phenytoin, cyclosporine, lovastatin, simvastatin, atorvastatin

IV: phlebitis; general: corneal microdeposits, photophobia, increased liver enzymes, photosensitivity, blue-gray skin discoloration, pulmonary fibrosis, hyper- and hypothyroidism, polyneuropathy

Sotalol

β-blocking effects: bradycardia, fatigue, dyspnea, bronchospasm, heart failure; QTc prolongation, torsades de pointes

Ibutilide

QTc prolongation, torsades de pointes

Dofetilide

Elevated: verapamil, cimetidine, ketoconazole, trimethoprim, megestrol, prochlorperazine

QTc prolongation, torsades de pointes

Digoxin

Elevated: quinidine, amiodarone, verapamil, diltiazem

Diltiazem

Elevated: cimetidine

Elevated: cyclosporine, carbamazepine, digoxin

Hypotension, bradycardia, heart failure

Verapamil

Reduced: rifampin, phenobarbital

Elevated: theophylline, digoxin, carbamazepine, cyclosporine, simvastatin, lovastatin

Hypotension, bradycardia, heart failure, constipation

a. See

Table 10-7.

Table 10-7. Suggested Monitoring Guidelines for Amiodarone

Test

Baseline

6 months

12 months

Electrocardiogram

•

•

•

Pulmonary function tests

•

Routine monitoring is controversial; may repeat tests if patient becomes symptomatic.

Ophthalmologic examination

•

Periodic exam is recommended.

•

•

Chest x-ray

•

Repeat earlier if patient becomes symptomatic.

•

•

Thyroid function tests

•

•

•

Liver enzymes

•

•

•

Table 11-1. Cardiac Enzymes and ECG Changes: UA versus NSTEMI/STEMI

UA

NSTEMI/STEMI

Cardiac enzymes

Negative

Positive

ECG changes: ST-segment, T-wave changes

If present, are transient

Always present

Table 11-2. Morphine, Oxygen, Nitrates, and Aspirin Therapy

Medication

Details

Morphine

Vasodilatory properties on both arterial and venous sides decrease both preload and afterload. Pain relief decreases tachycardia, along with decrease in preload and afterload; all work to decrease myocardial O₂ demand.

Increments of 2-4 mg IV are given every 5-15 minutes until pain is relieved.

Nausea, vomiting, hypotension, sedation, and respiratory depression may occur.

Morphine produces a vagotonic effect that may be contraindicated in patients with bradycardia. Watch closely for hypotension, respiratory depression, and allergic reactions.

Meperidine

Meperidine can be used in patients who are intolerant of morphine. It has vagolytic effects, so it is the analgesic of choice in patients who are bradycardic; 25-75 mg IV.

Oxygen

Supplemental O₂ 2-4 L/min by nasal cannula is recommended to correct and avoid hypoxia, particularly within the first 2-3 hours. More aggressive ventilatory support should be considered and given as needed.

Nitroglycerin

All patients should receive NTG as a sublingual tablet or spray, followed by IV administration as needed for the relief of ischemia.

Long-acting nitrates (oral, transdermal) should be used as secondary prevention in patients who do not tolerate β-blockers and CCBs. These nitrates can be used in patients who have continual chest pain despite the use of β-blockers and CCBs.

Aspirin (ASA)

Nonenteric-coated aspirin 162-325 mg should be given at the onset of chest pain unless contraindicated. Chew and swallow the first dose.

A dose of 75-162 mg should be taken daily for life.

Poststent, aspirin 162-325 mg is used in combination with clopidogrel for at least 1 month after BMS, 3 months after sirolimus-eluting stents, and 6 months after paclitaxel-eluting stents. With the newer DES, everolimus, and zotarolimus, a minimum of 75 mg of aspirin daily is acceptable immediately after PCI. After this initial period, the dose of aspirin can be reduced to 75-162 mg daily.

Clopidogrel may be substituted if a true aspirin allergy is present or if the patient is considered unresponsive to ASA.

Table 11-3. STEMI versus UA or NSTEMI

STEMI

NSTEMI

Totally occlusive thrombus is found.

Platelet-rich thrombi, which do not completely block coronary blood flow, are found.

More extensive damage occurs.

Smaller, less extensive damage occurs.

STEMI results in an injury that affects the entire thickness of the myocardial wall.

NSTEMI involves only the subendocardial myocardium.

Occlusion persists long enough to compromise myocardial function and leads to myocardial necrosis.

Unstable angina is ischemia; NSTEMI may still result in necrosis, but not to the extent of STEMI.

ST-segment elevation on ECG is present.

ST depression or no ST elevation on ECG is present.

Lytic therapy or primary reperfusion is a main treatment strategy.

Antiplatelets and anticoagulants are used to target platelet-rich thrombus.

Table 11-4. Pharmacologic Properties and Doses of Nitrates

Drug

Route

Onset

Duration of action

Dose

Nitroglycerin sublingual tablet (Nitrostat, Nitroquick)

Sublingual

1-3 min

30-60 min

0.2-0.6 mg every 5 min. Seek emergency treatment if chest pain is unrelieved after 1 dose.

Nitroglycerin spray (Nitrolingual)

Translingual

2 min

30-60 min

0.4 mg every 5 min. Seek emergency treatment if chest pain unrelieved after 1 spray.

Nitroglycerin transmucosal tablets (Nitroguard)

Buccal

1-2 min

3-5 hours

Insert 1 tablet into cheek every 3-5 hours.

Nitroglycerin ointment (Nitrobid, Nitrol)

Topical

30-60 min

2-12 hours

1-2 inches every 8 hours up to 4-5 inches every 4 hours.

Nitroglycerin transdermal patches (Nitro-dur, Transderm Nitro, Nitrek, Nitrodisc, Deponit, Minitran)

Topical

30-60 min

Up to 24 hours

Starting dose: 0.2-0.4 mg/hour. Apply and allow patch to stay in place for 12 hours. Remove the patch after 12 hours to allow a nitrate-free interval.

Nitroglycerin sustained-release tablets or capsules (Nitrong, Nitroglyn, Nitro-Time)

Oral

20-45 min

3-8 hours

Starting dose: 2.5 mg tid-qid. Increase the dose by 2.5 mg two to four times daily to reach effective dose.

Nitroglycerin intravenous (Tridil, Nitro-Bid IV)

IV

1-2 min

3-5 min

Starting dose: 5 mcg/min. Titrate to response.

Isosorbide mononitrate (Ismo, Monoket)

Oral

30-60 min

No data

20 mg bid (given 7 hours apart). May need to start with 5 mg bid for low-weight patients.

Isosorbide mononitrate, extended-release (Imdur, Isotrate ER)

Oral

30-60 min

No data

Starting dose: 30-60 mg daily. Maximum dose: 240 mg daily.

Isosorbide dinitrate (Isordil Titradose, Sorbitrate)

Oral

20-40 min

4-6 hours

Starting dose: 5-20 mg q6h. Maintenance dose: 10-40 mg q6h.

Isosorbide dinitrate, sustained-release tablets or capsules (Isordil Tembids, Dilatrate-SR)

Oral

Up to 4 hours

6-8 hours

Initial dose: 40 mg q8h. Maintenance dose: 40-80 mg q8-12 h.

Table 11-5. Nitrate Adverse Reactions

Type

Reaction

Tolerance

Tolerance to the vasodilatory effects can develop if dosing does not allow for a nitrate-free interval (10-12 hours).

CNS

Headache (up to 50%), dizziness, anxiety, and nervousness can occur.

Cardiovascular

Hypotension, tachycardia, palpitations, and syncope can occur.

Gastrointestinal

Nausea, vomiting, and dyspepsia can occur.

Dermatologic

Rash or dermatitis can occur.

Other

Blurred vision, muscle twitching, perspiration, edema, and arthralgia can occur.

Table 11-6. Nitrate Drug-Drug Interactions

Interacting medication

Effect

Sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis)

Significant reduction of systolic and diastolic blood pressure may occur. Do not give sildenafil or vardenafil within 24 hours of nitrate use. Do not give tadalafil within 48 hours of nitrate use.

Calcium channel blockers

Marked symptomatic hypotension may occur.

Alcohol

Severe hypotension may occur.

Table 11-7. Ranolazine Adverse Drug Reactions

Type

Reaction

CNS

Dizziness, headache, asthenia

Cardiovascular

Bradycardia, palpitations, hypotension, orthostatic hypotension

Gastrointestinal

Nausea, abdominal pain, vomiting, dry mouth, constipation

Other

Tinnitus, vertigo, dyspnea, peripheral edema

Table 11-8. Ranolazine Drug-Drug Interactions

Interacting medication

Effect

Strong CYP3A inhibitors: ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, nelfinavir, indinavir, saquinavir

Medication increases average steady-state plasma concentration of ranolazine 3.2-fold, which can precipitate QTc prolongation. Concomitant use is contraindicated.

Moderated CYP3A inhibitors: diltiazem, verapamil, erythromycin, fluconazole, grapefruit juice

Medication increases ranolazine steady-state plasma concentrations about twofold, which can precipitate QTc prolongation. Concomitant use is cautioned.

P-glycoprotein inhibitors: cyclosporine

Increased ranolazine concentrations can occur; use lower doses of ranolazine.

CYP3A and P-glycoprotein inducers: rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, St. John's Wort

Medication decreases plasma concentrations of ranolazine by up to 95% (rifampin).

Simvastatin

Plasma levels of simvastatin, a CYP3A4 substrate, are increased approximately twofold.

Table 11-9. Aspirin Adverse Reactions

Type

Reaction

Cardiovascular

Hypotension, edema, tachycardia

CNS

Fatigue, nervousness, dizziness

Dermatologic

Rash, urticaria, angioedema

Gastrointestinal

Nausea, vomiting, dyspepsia, gastrointestinal ulceration, gastric erosion, duodenal ulcers

Hematologic

Bleeding, anemia

Otic

Hearing loss, tinnitus

Renal

Renal impairment, increased serum creatinine, proteinuria

Respiratory

Asthma, bronchospasm, dyspnea, tachypnea, respiratory alkalosis

Table 11-10. Thienopyridine Adverse Reactions

Type

Reaction

Clopidogrel

Chest pain, headache, dizziness, abdominal pain, vomiting, diarrhea, arthralgia, back pain, upper respiratory infections, flu-like symptoms; < 1% blood dyscrasias, bleeding, rash

Ticlopidine

Rash, nausea, dyspepsia, diarrhea; 2.4% neutropenia; < 1% blood dyscrasias, thrombotic thrombocytopenic purpura, bleeding

Table 11-11. Thienopyridine Drug-Drug Interactions

Interacting medication

Effect

Antiplatelet agents, anti-coagulants, NSAIDs, and celecoxib

Combination may increase the risk of bleeding.

CYP4502C9 substrates (phenytoin, fluvastatin, NSAIDs, losartan, irbesartan, valsartan)

Medication may increase serum levels.

Table 11-12. Pharmacologic Properties of Glycoprotein IIb/IIIa Receptor Inhibitors

Drug

Chemical nature

Duration of effect (hours)

Renal elimination

Renal dosing adjustment

Abciximab (ReoPro)

Antibody

>12^a

No

No

Eptifibatide (Integrilin)

Nonpeptide

4-8

Yes

Yes

Tirofiban (Aggrastat)

Peptide fragment

4

Yes

Yes

a. Action can be reversed by a platelet infusion.

Table 11-13. Indications and Doses of the Glycoprotein IIb/IIIa Receptor Inhibitors

Drug

Indication

Dose

Abciximab (ReoPro)

Adjunct to PCI or when PCI is planned within 24 hours

0.25 mg/kg IV bolus, 0.125 mg/kg infusion continued for 12 hours postprocedure; maximum length of infusion: 18-24 hours

Eptifibatide (Integrilin)

Adjunct to PCI

180 mcg/kg IV bolus × 2, 10 min apart; 2 mcg/kg/min infusion (creatinine clearance < 50 mL/min; 1 mcg/kg/min) started after the first bolus and continued for 18-24 hours postprocedure (minimum of 12 hours)

Patients with ACS managed with or without PCI

180 mcg/kg IV bolus, 2 mcg/kg/min infusion (creatinine clearance < 50 mL/min; 1 mcg/kg/min) continued until discharge, up to 72 hours; or if post-PCI for 18-24 hours; maximum length of infusion: 96 hours

Tirofiban (Aggrastat)

Adjunct to PCI

0.4 mcg/kg/min IV bolus for 30 min, 0.1 mcg/kg/min infusion (creatinine clearance < 30mL/min; bolus and infusion are reduced by 50%) for 12-24 hours postprocedure

Patients with ACS managed with or without PCI

10 mcg/kg IV bolus over 3 min followed by 0.15 mcg/kg/min infusion for 36 hours or 0.4 mcg/kg IV bolus over 30 min, 0.1 mcg/kg/min infusion for 72 hours (creatinine < 30 mL/min, bolus and infusion are reduced by 50%)

Table 11-14. Properties of Low Molecular Weight Heparin versus Unfractionated Heparin

Drug

Half-life (hours)

Molecular weight (daltons)

Anti-Xa: Anti-IIa

Renal elimination

Enoxaparin

4.5

4,500

2.7:1.0

Yes

UFH

1

15,000

1.0:1.0

No

Table 11-15. Thrombolytic Doses

Drug

Dose

Streptokinase (Streptase)

1.5 million units in 50 mL of normal saline or D₅W given over 60 min

Tissue plasminogen activator (Alteplase)

15 mg IV bolus, followed by 0.75 mg/kg IV infusion over 30 min (not to exceed 50 mg); then 0.5 mg/kg IV infusion over 1 hour (not to exceed 35 mg)

Reteplase (Retevase)

10 units IV push over 2 min, followed in 30 min by a repeat 10 units IV bolus over 10 min

Tenecteplase (TNKase)

< 60 kg, give 30 mg IV bolus; 60-69.9 kg, give 35 mg IV bolus; 70-79.9 kg, give 40 mg IV bolus; 80-89.9 kg, give 45 mg IV bolus; > 90 kg, give 50 mg IV bolus; each bolus given over 5 seconds

Table 12-1. Classification of Lipids

Type

Classification

LDL cholesterol (primary target of therapy)

< 100 mg/dL

Optimal

100-129 mg/dL

Near optimal or above optimal

130-159 mg/dL 3

Borderline high

160-189 mg/dL

High

≥ 190 mg/dL

Very high

Total cholesterol

< 200 mg/dL

Desirable

200-239 mg/dL

Borderline high

≥ 240 mg/dL

High

HDL cholesterol

< 40 mg/dL

Low

≥ 60 mg/dL

High

Triglycerides (secondary target of therapy)

< 150 mg/dL

Normal

150-199 mg/dL

Borderline high

200-499 mg/dL

High

> 500 mg/dL

Very high

Table 12-2. Risk Categories, Lipid Goals, and Risk of Event

Risk category

LDL goal

Risk of event

CHD and CHD risk equivalent^a

< 100 mg/dL

> 20% over 10 years

Multiple risk factors (2+)

< 130 mg/dL

10-20% over 10 years

0-1 risk factor

< 160 mg/dL

< 10% over 10 years

a. CHD risk equivalent = clinical CHD, symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, and diabetes.

Table 12-3. Drug Products and Dosage

Generic name

Trade name

Dosage range and schedule

Dosage form and strength

Statins

Atorvastatin

Lipitor

10-80 mg/d qhs

10-, 20-, 40-, and 80-mg tablet

Fluvastatin

Lescol

20-80 mg/d qhs

20- and 40-mg capsule; 80-mg XL tablet

Lovastatin

Mevacor

20-80 mg/d qhs

10-, 20-, 40-mg tablet

Lovastatin extended-release

Altoprev

10-60 mg/d qhs

10-, 20-, 40-, and 60-mg tablet

Pravastatin

Pravachol

20-80 mg/d qhs

10-, 20-, 40-, and 80-mg tablet

Simvastatin

Zocor

20-80 mg/d qhs

5-, 10-, 20-, 40-, and 80-mg tablet

Rosuvastatin

Crestor

5-40 mg/d hs

5-, 10-, 20-, and 40-mg tablet

Bile acid sequestrants

Cholestyramine

Questran

4-16 g/d divided

Powder

Colestipol

Colestid

5-20 g/d divided

Powder or tablet

Colesevelam

WelChol

2.6-3.8 g/d (once or bid)

625-mg tablet

Nicotinic acid

Immediate release

Niacor

1.5-3 g/d (divided tid)

500-mg tablet

Sustained release

Slo-Niacin

1-2 g/d qhs

250-, 500-, and 750-mg tablet

Extended release

Niaspan

1-2 g/d qhs

500-, 750-, and 1,000-mg tablet

Fibric acids

Gemfibrozil

Lopid

600 mg before meals bid

600-mg tablet

Fenofibrate

Tricor

48-145 mg/d

48- and 145-mg tablet

Cholesterol inhibitors

Ezetimibe (Zetia)

10 mg/d

10-mg tablet

Omega-3 fatty acids

Omega-3 fatty acid

Lovaza

4 g qd or 2 g bid

1-g capsule

Combinations

Aspirin + pravastatin^a

Pravigard PAC

81/20-325/80 mg qhs

81/20-, 81/40-, and 81/80-mg tablets; 325/20-, 325/40-, and 325/80-mg tablets

Ezetimibe + simvastatin

Vytorin

10/10-10/80 mg qhs

10/10-, 10/20-, 10/40-, and 10/80-mg tablets

Lovastatin + Niaspan

Advicor

20/500-40/2,000 mg/d

20/500-, 20/750-, and 20/1,000-mg tablets

a. Aspirin tablets and pravastatin tablets are separate tablets within the PAC.

Table 12-4. Efficacy of Drugs Used to Treat Hyperlipidemia

Drug class

Lipid and lipoprotein effect

Statins

LDL 18-55%

HDL 5-15%

TG 7-30%

Resins

LDL 15-30%

HDL 3-5%

TG (no change)

Nicotinic acid

LDL 5-25%

HDL 15-35%

TG 20-50%

Fibric acids

LDL 5-20%

HDL 10-20%

TG 20-50%

Cholesterol inhibitors

LDL 17%

HDL 1.3%

TG 6%

Omega-3 fatty acid (Lovaza)

LDL 25-31%

HDL 4-13%

TG 45%

Table 12-5. Pharmacotherapeutic Options for Treatment of Hyperlipidemia

Lipid target

Pharmacotherapy

LDL

Statin most potent and effective for large LDL reductions

Niacin and resins effective for moderate LDL reductions

Combination of statin + niacin

Combination of statin + ezetimibe

Combination of statin + resin

LDL + TG

Combination of statin + niacin

Combination of statin + fibric acid

TG

Fibric acid or niacin

Table 12-6. Nutrient Makeup of the TLC Diet

Nutrient

Recommended intake

Saturated fat

< 7% of total calories

Polyunsaturated fat

Up to 10% of total calories

Monounsaturated fat

Up to 20% of total calories

Total fat

25-35% of total calories

Carbohydrate

50-60% of total calories

Fiber

20-30 g/d

Protein

About 15% of total calories

Cholesterol

< 200 mg/d

Total calories

Individualize to balance energy intake and expenditure to maintain desirable weight or prevent weight gain.

Table 13-1. Summary of Recommendations for Adults with Diabetes

Area

Recommended goal

Glycemic control:

A_1C

< 7.0%^a

Preprandial capillary plasma glucose

70-130 mg/dL

Peak postprandial capillary plasma glucose^b

< 180 mg/dL

Blood pressure:

< 130/80 mmHg

Lipids:^c

LDL

< 100 mg/dL^d

Triglycerides

< 150 mg/dL

HDL

> 40 mg/dL^e

Key concepts in setting glycemic goals:

• A_1C is the primary target for glycemic control.

• Goals should be individualized.

• More or less stringent glycemic goals may be appropriate for individual patients.

• Postprandial glucose may be targeted if A_1C goals are not met despite reaching preprandial glucose goals.

a. Referenced to a nondiabetic range of 4.0-6.0% using a Diabetes Control and Complications Trial-based assay.

b. Postprandial glucose measurements should be made 1-2 hours after the beginning of the meal—generally peak levels in patients with diabetes.

c. Current National Cholesterol Education Program-Adult Treatment Panel III guidelines suggest that in patients with triglycerides ≥ 200 mg/dL, the "non-HDL cholesterol" (total cholesterol - HDL) be used. The goal is 130 mg/dL.

d. In individuals with overt cardiovascular disease, a lower LDL cholesterol goal of < 70 mg/dL is an option.

e. For women, it has been suggested that the HDL goal be increased by 10 mg/dL.

Source: Adapted from American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care. 2009: 32(suppl 1):S13-61.

Table 13-2. Sulfonylureas

Drug

Trade name

Strength

Daily dose

Duration of action

Comments

First generation

Acetohexamide

Dymelor

250, 500 mg

250-1,500 mg

Up to 16 hours

Active metabolite excreted by kidney

Chlorpropamide

Diabinese

100, 250 mg

100-500 mg

Up to 72 hours

Contraindicated in renal insufficiency

Tolazamide

Tolinase

100, 250, 500 mg

100-1,000 mg

Up to 10 hours

Tolbutamide

Orinase