Handbook of clinical drug data - part 4 pptx

A syndrome similar to SLE with joint pain andskin rash only rarely with cerebritis and nephritis has been reported at an overallfrequency of 6.7% in 281 patients over 51 months; daily do

congestion, and flushing occur A syndrome similar to SLE with joint pain andskin rash (only rarely with cerebritis and nephritis) has been reported at an overallfrequency of 6.7% in 281 patients over 51 months; daily dosage affects the fre-quency, with none at 50 mg/day, 5.4% at 100 mg/day, and 10.4% at 200 mg/day.Women had a higher overall frequency than men (11.6 and 2.8%, respectively),and women taking 200 mg/day had a 19.4% rate; slow acetylator phenotype alsocan increase the risk; the syndrome is reversible with drug discontinuation, al-though residual effects can be detected years later.187 An immune complexglomerulonephritis has been reported in patients with hydralazine-induced SLE.188

Contraindications Coronary artery disease, mitral valvular rheumatic disease Precautions Reflex tachycardia can precipitate anginal attacks or ECG evidence

rou-Notes Reflex increases in heart rate, cardiac output, and stroke volume and

in-creases in plasma renin activity and retention of sodium and water can attenuatethe antihypertensive action of hydralazine; therefore, long-term regimens for hy-pertension should include a diuretic and a sympatholytic drug When hydralazine

is used as an afterload-reducing drug in the treatment of CHF in patients on tenance diuretics, the increase in cardiac output usually prevents the development

main-of reflex tachycardia; likewise, hypotension is usually prevented by the increasedcardiac output but can occur if myocardial reserves are inadequate or if the heartcannot respond by increasing output (eg, severe cardiomyopathy or aortic steno-sis).185

Pharmacology Labetalol is an adrenergic receptor blocking drug that has

selec-tive 1- and nonselective -adrenergic receptor blocking actions Although itspharmacologic profile resembles that of other -blockers and the postsynaptic

1-adrenergic blocking action of prazosin, its -blocking activity is approximately

3 times greater than the -blocking activity after oral administration and 7 timesgreater after IV administration During long-term treatment, -blocking activity isreduced even more.189,190

Administration and Adult Dosage PO for hypertension 100 mg bid initially,

in-creasing at 2- to 3-day intervals in 100 mg bid increments until blood pressure is

controlled Usual maintenance dosage is 200–400 mg bid, to a maximum of 1.2–2.4 g/day for severe hypertension IV for hypertension 20 mg by slow

(2 min) injection, followed by 40–80 mg at 10-min intervals until blood pressure

is controlled or to a total of 300 mg Alternatively, administer a dilute solution bycontinuous infusion at a rate of 2 mg/min, to a maximum total dosage of 300 mg;the usual effective cumulative dosage is 50–200 mg; the infusion can be repeated

q 6–8 hr.173,189,190

Special Populations Pediatric Dosage Safety and efficacy not established, but

the following has been used: IV for hypertension 0.2–1 (average 0.55) mg/kg

initially, followed by a continuous infusion of 0.25–1.5 (average 0.8) mg/kg/hr.191

Geriatric Dosage PO Initiate therapy with 50 mg bid.189

Other Conditions Titrate dosage to blood pressure control No dosage adjustment

is required in renal impairment Patients with hepatic dysfunction might requirelower than usual dosages

Dosage Forms Tab 100, 200, 300 mg; Inj 5 mg/mL.

Patient Instructions (See Antihypertensives Class Instructions.) Do not

discon-tinue medication abruptly except under medical supervision Do not sit up or standfor 3 hours after intravenous administration

Pharmacokinetics Onset and Duration PO onset is within 2 hr, peak in 3 hr, and

duration of 8–12 hr; can be longer with higher dosages IV injection onset <10min, peak in 5–15 min, duration 3–6 hr.173,190

Fate Almost completely absorbed, but bioavailability is only 18 ± 5% because of

extensive first-pass metabolism, with the higher values reported in the elderly andpatients with cirrhosis.10,192Peak serum levels occur within 1–2 hr after oral ad-ministration; food delays the time to peak but can increase bioavailability Plasmaprotein binding averages 50% There is little distribution into the brain because oflow lipid solubility Vdis 9.4 ± 3.4 L/kg; Cl is 1.5 ± 0.6 L/hr/kg, lower in younghypertensive patients and the elderly and unchanged in cirrhosis The drug is me-tabolized extensively primarily in the liver and possibly gut wall to inactive com-pounds Unchanged drug (<5%) and metabolites are excreted in urine andfeces.10,189,190,192

t¹⁄₂.  phase 4.9 ± 2 hr, independent of route of administration; increased in theelderly.10,189,192

Adverse Reactions These are generally related to - and -adrenergic blockadeand usually occur during the first few weeks of therapy Frequently, dizziness, fa-tigue, headache, scalp tingling, nausea, dyspepsia, and nasal congestion occur.Occasionally, postural hypotension, edema, taste disturbance, impotence, rash,and blurred vision occur IV administration causes ventricular arrhythmias rarely

Contraindications Bronchial asthma; overt cardiac failure; greater than

first-degree heart block; cardiogenic shock; bradycardia

Precautions Lower dosages might be required in patients with impaired hepatic

function

Drug Interactions Cimetidine can increase the bioavailability of oral labetalol.

Glutethimide can decrease the effect of labetalol by inducing hepatic enzymes.Concurrent use with halothane can produce myocardial depression Labetalol de-creases the reflex tachycardia induced by nitroglycerin and the bronchodilator ef-fects of 2-agonist bronchodilators

Parameters to Monitor Monitor blood pressure regularly and hepatic and renal

function as indicated

Notes Labetalol injection is incompatible with 5% sodium bicarbonate,

furosemide, or other alkaline products

Pharmacology Losartan is a selective, reversible, nonpeptide, competitive

antag-onist of the angiotensin II receptor (AT1), which is responsible for the physiologiceffects of angiotensin II including vasoconstriction, aldosterone secretion, sympa-thetic outflow, and stimulation of renal sodium reabsorption Losartan and otherangiotensin II receptor antagonists are highly selective for the AT1receptor overthe AT2receptor, whose physiologic function is unknown Angiotensin II receptorantagonists have no inhibitory effects on ACE and therefore decrease blood pres-sure with no appreciable effect on kinin metabolism.193

Administration and Adult Dosage PO for hypertension 50 mg/day initially;

25 mg/day in patients on diuretics or volume depleted The usual dosage is 25–100 mg/day given without regard to meals once daily; may increase to bid inpatients not adequately controlled with once-daily administrations Most patientsrespond to 50 mg/day, although further reductions in blood pressure are possiblewith 100 mg/day.194Patients who do not respond to 50 mg/day might benefit morewith the addition of hydrochlorothiazide than an increased dosage Dosages above

100 mg/day offer little added benefit.193

Special Populations Pediatric Dosage Safety and efficacy not established.

Geriatric Dosage Same as adult dosage.

Other Conditions No dosage adjustment is necessary in patients with renal

impair-ment or on dialysis Patients with hepatic insufficiency might require lower doses(eg, starting dose of 25 mg/day) because of decreased losartan clearance

Dosage Forms Tab 25, 50, 100 mg (Cozaar); Tab 50 mg with 12.5 mg

hy-drochlorothiazide, 100 mg with 25 mg hydrochlorothiazide (Hyzaar)

Patient Instructions (See Antihypertensives Class Instructions.) This medication

can cause dizziness, especially with the first few doses; do not drive or operatedangerous machinery until you know how you will react to this medicine Do notuse this medicine if you are pregnant or planning to become pregnant If you be-come pregnant while taking this medicine, contact your prescriber immediately.Report any skin rash or signs or symptoms of angioedema (eg, swelling of face,eyes, lips, tongue, larynx, extremities, or hoarseness or difficulty in swallowing)immediately to your prescriber

Pharmacokinetics Onset and Duration PO onset <2 hr; peak 6 hr; duration >24

hr, can be less with doses ≤25 mg/day.195 Maximum antihypertensive effect occursafter 1 week in most patients but can take 3–6 weeks

Serum Levels Large interindividual variability, with IC50for AT1inhibition curring at losartan concentrations of 1.4–200 nmol/L.196

oc-Fate Oral absorption is rapid, but extensive first-pass metabolism results in a

bioavailability of 33%, which might be doubled in hepatic insufficiency About14% of an oral dose is converted to an active carboxylic acid metabolite Peakconcentrations of losartan occur in 1 hr and those of its metabolite in 3–4 hr The

metabolite is approximately 10–40 times more potent than the parent compoundand is believed to be responsible for most of the antihypertensive effects of losar-tan.197Losartan and its metabolite are about 99% bound to proteins, mainly to al-bumin Vds of losartan and its active metabolite are 34 and 12 L, respectively Me-tabolism of losartan occurs through CYP2C9 and CYP3A4 to the activecarboxylic acid metabolite and several inactive metabolites Cl is about 36 L/hrfor losartan (12–15% renal Cl) and 3 L/hr for the active metabolite (50% renalCl) Losartan Cl can be 50% less with hepatic insufficiency.197About 4% of anoral losartan dose is excreted unchanged in the urine and 6% of the dose as activemetabolite After oral administration, 60% of a losartan dose is excreted in thefeces.

t¹⁄₂ (Losartan) 2 hr; (metabolite) 6–9 hr.

Adverse Reactions Angiotensin II receptor antagonists are generally well

toler-ated, with adverse reactions occurring at frequencies similar to those of placebo;adverse events are not related to dose The most frequent reactions are headache(10–20%) and upper respiratory tract infection (1–12%).198 Nasal congestion,cough, and fatigue occur in fewer than 6% of patients.198,199Unlike ACE in-hibitors, angiotensin II receptor antagonists induce cough about as frequently asplacebo, probably because bradykinin concentrations are not elevated as they arewith ACE inhibitors Angiotensin II receptor antagonists are effective alternatives

in patients who experience cough with ACE inhibitors.200,201Like ACE inhibitors,angiotensin II receptor antagonists can induce reversible renal dysfunction as aconsequence of affecting the renin–angiotensin–aldosterone system Increases in

Crsand BUN also can occur in patients with unilateral or bilateral renal arterystenosis Hypersensitivity reactions (eg, angioedema, rash) have been reported in

patients receiving losartan or valsartan Angiotensin II receptor antagonists can

decrease hemoglobin and hematocrit and increase serum bilirubin, but thesechanges are rarely of clinical importance Neutropenia has been reported in 1.8%

of patients taking valsartan (0.9% for placebo) Hyperkalemia has been reported in1.5% of losartan-treated patients (1.3% for ACE inhibitor) and 4.4% of valsartan-treated patients (2.9% for placebo).199

Contraindications Hypersensitivity to any product components.

Precautions Use of drugs affecting the renin–angiotensin–aldosterone system

can cause injury and even death to the developing fetus if used in the second orthird trimester of pregnancy Increase dosage slowly in patients with liver dys-function because of reduced drug clearance (losartan, valsartan) in these patients.Patients taking angiotensin II receptor antagonists whose renal function is depen-dent on the renin–angiotensin–aldosterone system (eg, CHF patients) can experi-ence oliguria, progressive azotemia, and (rarely) acute renal failure or death Re-versible increases in Crsand/or BUN can occur in patients with unilateral orbilateral renal artery stenosis

Drug Interactions Inhibitors of the CYP3A4 or 2C9 isoenzymes (eg, zole) can impair the conversion of losartan to the active metabolite Telmisartan

ketocona-can increase digoxin serum concentrations No important interactions have beenreported with other drugs in this class

Parameters to Monitor Monitor for hypersensitivity reactions (eg, flushing,

dys-pnea, facial swelling, rash) at the start of therapy Monitor blood pressure larly Monitor patients on dietary salt restriction, diuretic therapy, or dialysis (salt

regu-or volume depletion) fregu-or hypotensive episodes after the initial dose Obtain line and periodic Crsand BUN to assess the potential for adverse effects Obtainbaseline serum potassium, WBC count, hemoglobin, and hematocrit Monitor pe-riodically for hyperkalemia, neutropenia, and anemia

base-Notes Although the guidelines of the sixth report by the Joint National

Commit-tee on Prevention, Detection, Evlauation, and Treatment do not promote this,many clinicians consider AT1antagonists first-line therapy for hypertension be-cause of their efficacy, safety, and ease of administration.173,198Losartan is a uri-cosuric, which can lower plasma uric acid concentration and increase the risk ofacute uric acid nephropathy or acute gout.197Losartan has been shown to improvecardiac output and reduce peripheral vascular resistance and pulmonary capillarywedge pressure in patients with CHF.202The ELITE II study found losartan to becomparable but not superior to captopril in improving survival in elderly patientswith CHF, although this study was not designed to test equivalence.203(See An-

giotensin II Receptor Antagonists Comparison Chart.)

Pharmacology The action of methyldopa is thought to be mediated through

stimulation of central -adrenergic receptors in a manner similar to that of dine Stimulation is caused primarily by the metabolite -methylnorepinephrine

cloni-Administration and Adult Dosage PO for hypertension 250 mg bid–tid initially,

increasing at intervals of no less than 48 hr to the usual daily dosage of 500 mg–

2 g/day in 2–4 divided doses IV for hypertension usual dosage is 250–500 mg

over 30–60 min in 100 mL D5W q 6 hr, to a maximum of 1 g q 6 hr

Special Populations Pediatric Dosage PO 10 mg/kg/day in 2–4 doses initially,

to a maximum of 65 mg/kg/day or 3 g/day, whichever is less IV 20–

40 mg/kg/day in divided doses q 6 hr, to a maximum of 65 mg/kg/day or 3 g/day,whichever is less

Geriatric Dosage Use lower dosages to avoid causing syncope.

Other Conditions Patients with renal failure might respond to smaller dosages of

methyldopa

Dosage Forms Tab 125, 250, 500 mg; Tab 250 mg with chlorothiazide 150 or

250 mg (Aldoclor); Tab 250 mg with hydrochlorothiazide 15, 25 mg, 500 mg with hydrochlorothiazide 30, 50 mg (Aldoril, various); Susp 50 mg/mL; IV

50 mg/mL

Patient Instructions (See Antihypertensives Class Instructions.) Report changes

in mood (depression), loss of appetite, yellowing of eyes or skin, abdominal pain,

or unexplained fever or joint pains This drug can cause your urine to darken if it

is exposed to air after voiding

Pharmacokinetics Onset and Duration PO onset 2 hr, peak within 4–6 hr,

dura-tion 12–24 hr IV onset 4–6 hr, duradura-tion 10–16 hr

Serum Levels No correlation between serum levels and therapeutic effect Fate Oral bioavailability is 42 ± 16%.10Peak serum levels occur in 2–4 hr butcorrelate poorly with the hypotensive effect IV bioavailability is similar to oral,apparently because a large portion of methyldopate ester is not hydrolyzed tomethyldopa From 10 to 15% is bound to plasma proteins Vdis 0.46 ± 0.15 L/kg;

Cl is 0.22 ± 0.06 L/hr/kg and is decreased in uremia The drug is excreted in theurine as metabolites, sulfate conjugate, and unchanged drug About 49% (IV) and70% (PO) of a dose are excreted in urine as sulfate conjugate and unchangeddrug.10,204

t¹⁄₂.  phase 0.21 hr (range 0.16–0.26);  phase 1.8 ± 0.6 hr, increased in uremiaand in neonates.10,204

Adverse Reactions Frequently, drowsiness, headache, weight gain, nasal

stuffi-ness, postural hypotension, or dry mouth occur A positive Coombs’ test develops

in 10–20% of patients, usually between 6 and 12 months of therapy; hemolyticanemia is rare Occasionally, depression, sexual dysfunction, diarrhea, or night-mares occur Rarely, hepatitis, drug fever, lupus-like syndrome, leukopenia, throm-bocytopenia, or granulocytopenia occur

Contraindications Active hepatic disease such as acute hepatitis and active

cir-rhosis or liver dysfunction associated with previous methyldopa therapy; rent MAOI therapy

concur-Precautions Use with caution in patients with histories of liver disease A

previ-ously positive Coombs’ test does not preclude methyldopa use, but early tion of hemolytic anemia can be more difficult in such patients

recogni-Drug Interactions Methyldopa can potentiate the effect of tolbutamide and

lithium It also can cause confusion or disorientation when used with haloperidol

An increase in the pressor response of norepinephrine can occur with concurrentuse Iron products reduce methyldopa absorption Amphetamines and heterocyclicantidepressants can decrease the efficacy of methyldopa Levodopa and methyl-dopa can enhance each other’s effects

Parameters to Monitor Obtain direct Coombs’ test initially and at 6 and 12

months Obtain baseline and periodic CBC and liver function tests to monitor forhemolytic anemia, blood dyscrasias, and hepatic dysfunction

Notes Methyldopa is not a first-line drug because of its frequent side effects, but

it can be useful in those with ischemic heart disease or diastolic dysfunction cause it reduces left ventricular mass.205

be-Pharmacology Minoxidil is a potent vasodilator that acts by direct relaxation of

arteriolar smooth muscle, thereby reducing total peripheral resistance The lation and associated reduction in blood pressure lead to reflex sympathetic activa-tion, vagal inhibition, and altered renal homeostatic mechanisms manifested as in-creases in heart rate and cardiac output, increase in renin secretion, and salt and

water retention Because these responses can attenuate the hypotensive actions,give minoxidil with a sympatholytic drug and a diuretic Topically, minoxidilstimulates vertex hair growth by an unknown mechanism.

Administration and Adult Dosage PO for hypertension 5 mg/day initially as a

single daily dose, increasing to 10, 20, and then 40 mg/day q 3 days in single or vided doses based on blood pressure response, to a maximum of 100 mg/day; usualdosage is 10–40 mg/day If a single dose reduces supine diastolic blood pressure by

di-more than 30 mmHg, divide the total daily dosage into 2 equal doses Top for male pattern baldness or female alopecia androgenetica 1 mL to affected areas bid.

Special Populations Pediatric Dosage PO for hypertension 0.2 mg/kg as a

sin-gle daily dose, increasing in 50–100% increments q 3 days until optimum bloodpressure control or a total daily dosage of 50 mg is achieved; usual dosage is0.25–1 mg/kg/day

Geriatric Dosage Same as adult dosage.

Other Conditions In renal impairment, lower dosages might be required.

Dosage Forms Tab 2.5, 10 mg (Loniten, various); Top 20, 50 mg/mL (2, 5%)

(Rogaine, various)

Patient Instructions (See Antihypertensives Class Instructions.) If a dose is

missed, wait until the next regularly scheduled dose and continue with your lar dose; do not double the next dose Report any of the following: increase inresting heart rate of greater than 20 beats per minute, rapid weight gain of morethan 5 pounds, or the development of edema, increased difficulty in breathing,new or worsening angina, dizziness, lightheadedness, or fainting

regu-Pharmacokinetics Onset and Duration PO single dose onset 30 min; peak 2–3 hr;

duration up to 75 hr with a gradual return to baseline at a rate of about 30% per day.Time to maximum effect with repeated administration is a function of dose and av-erages 7 days at 10 mg/day, 5 days at 20 mg/day, and 3 days at 40 mg/day Toponset 4 or more months; relapse can occur 3–4 months after drug discontinuation

Serum Levels No correlation between serum levels and effects.

Fate Oral absorption is at least 90%, but bioavailability is probably lower

Pro-tein binding is negligible Vdis 2.7 ± 0.7 L/kg; Cl is 1.4 ± 0.4 L/hr/kg The drug isprimarily metabolized and renally excreted, with about 20% unchanged drug inthe urine The major metabolite, a glucuronide conjugate, is active and might con-tribute to the drug’s effect.10,205,206

t¹⁄₂ 3.1 ± 0.6 hr.10

Adverse Reactions Frequently, hypertrichosis (elongation, thickening, and

en-hanced pigmentation) (80%), transient ECG T-wave changes (60%), temporaryedema (7%), or tachycardia occur Occasionally, pericardial effusion with or with-out tamponade (3%), CHF, or angina occur Rarely, breast tenderness and rashes(including Stevens–Johnson syndrome) occur Minor dermatologic reactionsoccur occasionally after topical application

Contraindications (Oral) pheochromocytoma, caused by possible stimulation of

catecholamine release from the tumor; acute MI; dissecting aortic aneurysm

Precautions For hypertension, minoxidil must usually be administered with a

di-uretic to prevent fluid retention; a loop didi-uretic is almost always required Drugs

or regimens that provide around-the-clock sympathetic suppression are usually quired to prevent tachycardia, which can precipitate or worsen existing angina.Degenerative myocardial lesions reported in animal studies have yet to be con-firmed in humans

re-Drug Interactions Concomitant therapy with guanethidine can result in profound

orthostatic hypotension; discontinue guanethidine 1–3 weeks before initiation oforal minoxidil therapy or initiate therapy in the hospital

Parameters to Monitor Blood pressure, pulse rate, body weight, cardiac and

pul-monary function regularly

Notes Minoxidil is reserved for use in severe hypertension in combination with

other drugs, usually a diuretic and a sympatholytic drug (eg, -blocker).205

Pharmacology Nitroprusside is a potent vasodilator that has direct action on

vas-cular smooth muscle to reduce arterial pressure and produce a slight increase inheart rate, a mild decrease in cardiac output, and a moderate reduction in total pe-ripheral resistance The decrease in total peripheral resistance suggests arteriolardilation (afterload reduction), whereas the reduction in cardiac output might becaused by peripheral pooling of blood (preload reduction) Nitroprusside is some-what more active on veins than on arteries The active component of sodium nitro-prusside is the free nitroso (NO−) group

Administration and Adult Dosage IV 0.3 g/kg/min by continuous infusion tially, increasing to an average rate of 3 g/kg/min based on blood pressure re-sponse with a range of 0.5–10 g/kg/min Infusion at the maximum rate shouldnever exceed 10 min Patients receiving other antihypertensives can usually be con-trolled with smaller dosages Control administration rates carefully with a micro-drip regulator or an infusion pump; avoid too rapid reduction in blood pressure In-fusion rates greater than 2 g/kg/min generate more cyanide ion (CN−) than thebody can metabolize or eliminate Maintain infusions at the lowest possible dosagefor the shortest possible duration to avoid toxicity.207(See Adverse Reactions.)

ini-Special Populations Pediatric Dosage IV same as adult dosage.

Geriatric Dosage Initiate therapy with low infusion rates and carefully titrate the

rate and degree of lowering blood pressure to avoid coronary and cerebral perfusion

hypo-Other Conditions Patients with CHF, stroke, or receiving other antihypertensive

drugs might be particularly sensitive to the blood-pressure–lowering effects of troprusside sodium; initiate therapy with low infusion rates and carefully titratethe rate and degree of lowering blood pressure to avoid coronary and cerebral hy-poperfusions Limit the total dosage in renal failure to avoid accumulation of thio-cyanate Use caution in hepatic insufficiency

ni-Dosage Forms Inj 50 mg.

Pharmacokinetics Onset and Duration Onset within 1 min; peak 1–2 min; blood

pressure usually returns to pretreatment levels in 2–10 min.173

Serum Levels Therapeutic and toxic levels are not established for nitroprusside

because of rapid metabolism to cyanide and thiocyanate Thiocyanate levels

>60 mg/L (1 mmol/L) are associated with toxicity

Fate Nitroprusside is distributed in a volume that approximates the extravascular

space, from which it is rapidly metabolized by a reaction with hemoglobin, yieldingcyanmethemoglobin and an unstable intermediate that dissociates, releasing cyanideion Cyanide is converted to thiocyanate by the enzyme thiosulfate–cyanide sulfurtransferase (rhodanese) in the liver and the kidney The rate of conversion is deter-mined principally by the availability of sulfur, usually as thiosulfate Thiocyanate isexcreted largely by the kidneys and can accumulate with high infusion rates for pro-longed periods or renal dysfunction

t¹⁄₂ (Nitroprusside) 2 min; (thiocyanate) 2.7 days, up to 9 days in patients with

renal dysfunction.208

Adverse Reactions Most adverse reactions are related to excessive or too rapid

re-duction of blood pressure and include nausea, retching, diaphoresis, apprehension,restlessness, headache, retrosternal discomfort, palpitations, dizziness, and abdomi-nal pain, all of which resolve when the infusion rate is reduced or the infusion istemporarily discontinued Thiocyanate is not particularly toxic and usually accumu-lates to toxic levels only with prolonged (>48 hr) or high-dosage (>10 g/kg/min)infusions, when cyanide elimination is increased by the administration of thiosul-fate, or in the presence of renal dysfunction To limit the risk of thiocyanate toxicity,infuse at <3 g/kg/min Manifestations of thiocyanate toxicity include fatigue,anorexia, nausea, disorientation, toxic psychosis, and hallucinations Cyanide toxic-ity usually occurs only when large dosages (>10 g/kg/min) are infused rapidly orfor longer than 1 hr An early manifestation of cyanide toxicity can be apparent ni-troprusside resistance, so increasing dosage requirements to achieve the same level

of blood pressure control is an indication to look for metabolic acidosis, an indicator

of cyanide toxicity, that might not be evident for more than 1 hr after accumulation

of dangerous cyanide levels Other symptoms of cyanide toxicity include dyspnea,vomiting, dizziness, loss of consciousness, weak pulse, distant heart sounds, are-flexia, dilated pupils, shallow breathing, convulsions, and the occasional smell of

bitter almonds on the breath Hydroxocobalamin (25 mg/hr by continuous

infu-sion) can facilitate the conversion of cyanide to cyanocobalamin,209but an

appropri-ate hydroxocobalamin dosage form is unavailable Concurrent sodium thiosulfappropri-ate

administration also can prevent cyanide toxicity, but thiocyanate levels can crease.210Management of cyanide toxicity includes immediate discontinuation of ni-troprusside and the administration of sodium nitrite (0.2 mL/kg of a 3% solution IVover 2–4 min), followed by 12.5 g of sodium thiosulfate infused over 10 min.Methemoglobinemia can develop in patients congenitally unable to convertnitroprusside-induced methemoglobin back to hemoglobin Management consists of

in-IV administration of methylene blue 1–2 mg/kg over several minutes.

Contraindications Compensatory hypertension (eg, arteriovenous shunt or

coarctation of the aorta); controlled hypotension during surgery in patients with

inadequate cerebral circulation; congenital (Leber’s) optic atrophy; use of

silde-nafil (See Drug Interactions.)

Precautions If an adequate hypotensive response is not achieved after the

maxi-mum recommended infusion rate of 10 g/kg/min for a maximum of 10 min, stopthe infusion because these dosages increase the risk of toxicity Use with caution

in renal, hepatic, or thyroid disease, and in vitamin B12deficiency or elevated tracranial pressure

in-Drug Interactions Use during general anesthesia can impair the capacity to

com-pensate for hypovolemia and anemia and cause abnormal perfusion:ventilationratio Use in patients taking sildenafil can result in profound hypotension with se-rious consequences, including death

Parameters to Monitor Monitor blood pressure frequently (ie, every few

min-utes) because of the rapid onset and offset of effects Monitor thiocyanate levelsafter 24–48 hr in patients with normal renal function and daily in patients with im-paired renal function or receiving large dosages However, these levels are of novalue in detecting cyanide toxicity Monitoring of serum cyanide concentrationshas been recommended, but the assay is technically difficult and not readily inter-pretable if fluids other than packed RBCs are analyzed Frequent monitoring ofacid–base balance, particularly in patients with hepatic dysfunction, is consideredadequate by most clinicians

Notes Protect from light and discard solution after 24 hr or if the color changes

from the usual faint brownish tint to blue, green, or dark red Do not administer IVpush medications through the same line or use the solution for the simultaneousadministration of any other drug

Pharmacology Omapatrilat is the first of a new class of drugs called

vasopepti-dase inhibitors Omapatrilat inhibits ACE and neutral endopeptivasopepti-dase, leading toblockades of the formation of angiotensin II and the breakdown of vasodilatoryhormones such as natriuretic peptides, bradykinin, and adrenomedullin This re-sults in vasodilation, natriuresis, and diuresis.211

Adult Dosage Not established.

Pharmacokinetics Oral absorption is rapid, with peak plasma concentrations

oc-curring 0.5–2 hr postdose Biotransformation of the thiol group produces inactivemetabolites; half-life is 14–19 hr; dosage adjustments are not necessary in renaldysfunction.211

Adverse Reactions Omapatrilat is well tolerated, with an adverse event profile

similar to that of placebo The most commonly reported adverse reactions are potension (11%) and cough (about 10%) Flushing and syncope (about 1%) alsohave been reported, and angioedema is rare.211

hy-Notes Omapatrilat produces greater blood pressure reductions than lisinopril in

hypertensive patients and in one study reduced morbidity and mortality (not theprimary endpoint) to a greater extent than lisinopril in patients with CHF.212,213

ACE INHIBITORS COMPARISON CHART

DOSAGE DAILY ADULT INDICATED PEAK EFFECT DURATION HALF-LIFE ELIMINATION

Various

ACE INHIBITORS COMPARISON CHART (continued )

DOSAGE DAILY ADULT INDICATED PEAK EFFECT DURATION HALF-LIFE ELIMINATION

Mavik

a Usual maintenance dosage range for hypertension Initial dosage is often lower, and higher dosages are sometimes effective.

b Half-life of active drug.

c Indicated for CHF post-MI.

From references 214 and 215 and product information.

ANGIOTENSIN II RECEPTOR ANTAGONISTS COMPARISON CHART

USUAL DAILY

Micardis

Diovan

a Occasionally, the daily dosage can be given in 2 divided doses.

b For active metabolite, which is responsible for most or all pharmacologic effects.

1 -ADRENERGIC–BLOCKING DRUGS COMPARISON CHART

DAILY ADULT PEAK EFFECT DURATION HALF-LIFE ELIMINATION

a Usual maintenance dosage range for hypertension; higher dosages are sometimes effective Dosage is the same in the elderly.

b Not for hypertension; for symptoms of benign prostatic hypertrophy only.

From references 147, and 218 and product information.

SECOND-LINE ANTIHYPERTENSIVES COMPARISON CHART

Guanabenz Tab 4, 8 mg PO 4 mg bid, increasing 12 hr See clonidine monograph See clonidine

Various

Guanadrel Tab 10, 25 mg PO 5 mg bid, increasing 4–14 hr Orthostatic hypotension, diarrhea, Postganglionic

Sulfate q 1–4 weeks to 20–75 drowsiness, sexual dysfunction, adrenergic

Guanethidine Tab 10, 25 mg PO 10 mg/day, increasing 1–3 weeks Same as guanadrel, but more f Postganglionic

Guanfacine Tab 1, 2 mg PO 1 mg/day, increasing 2–4 days See clonidine monograph See clonidine

Various

Reserpine Tab 0.1, 0.25 mg PO 0.5 mg/day for 1–2 24 hr Drowsiness, weakness, GI Depletes

sexual dysfunction, bradycardia from

DRUGS FOR HYPERTENSIVE URGENCIES AND EMERGENCIES COMPARISON CHART

ONSET

ORAL DRUGS FOR HYPERTENSIVE URGENCIES

Captopril PO, SL 12.5–25 mg 10–30 2–6 hr Hypotensive effect is particularly large in patients on a diuretic or in

Clonidine PO 0.1–0.2 mg initially, then 0.1 30–120 6–8 hr Rate of onset is slower after a meal; drowsiness or dry mouth can occur

dosage of 0.8 mg.

Labetalol PO 200–400 mg, may repeat 30–120 6–12 hr Orthostatic hypotension, bronchoconstriction, and heart block can occur.

Trandate

Various

Prazosin PO 1–2 mg, may repeat q 1 hr 30–90 1–10 hr Useful in presence of increased circulating catecholamines First-dose

Various

DRUGS FOR HYPERTENSIVE URGENCIES AND EMERGENCIES COMPARISON CHART (continued )

ONSET

INTRAVENOUS DRUGS FOR HYPERTENSIVE EMERGENCIES

Diazoxide IV 1–3 mg/kg (up to 150 mg) over 2–4 3–12 hr Now obsolete, but can be useful in hypertensive encephalopathy,

furosemide IV 40 mg before sequent doses.

sub-Enalaprilat IV 0.625–1.25 mg (See monograph.) 15–30 4–6 hr Useful in CHF and those at risk for cerebral hypotension Avoid in acute

may occur.

Esmolol IV 250–500 µg/kg/min for 1–2 min, 1–2 10–20 min Useful in perioperative patients with aortic dissection Does not cause

may repeat sequence.

Fenoldopam IV 0.1–0.3 µg/kg/min initially by <5 30 min Useful in patients with renal insufficiency who risk cyanide toxicity with

Hydralazine IM or IV 10–40 mg q 3–6 hr 10–20 (IV) 3–8 hr Limited to treatment of severe pre-eclampsia and eclampsia Increases

excessive hypotension.

Labetalol IV push 20 mg initially, then 40– 10 3–6 hr Hypotensive effect is predictable; contraindicated in CHF, head trauma,

Alternatively, IV infusion 0.5–2 mg/min.

DRUGS FOR HYPERTENSIVE URGENCIES AND EMERGENCIES COMPARISON CHART (continued )

ONSET

Nicardipine IV infusion 5–15 mg/hr 5–15 1–4 hr Predictable effect Useful in coronary, cerebral, or peripheral artery disease and in

ischemia.

Nitroglycerin IV 0.3–6 mg/hr by continuous 1–5 3–5 min Useful in myocardial ischemia and hypertension associated with MI Hypotension,

pericardial tamponade, or intracranial hypertension.

Nitroprusside IV 0.3–10 µg/kg/min by con- 0.5–1 1–2 min Especially useful in ischemic heart disease Continuous monitoring required;

Sodium tinuous infusion Infuse at maximal arterial pressure response adjusted by changing infusion rate; hypotensive effect

3 µg/kg/min.

Adapted from references 173, 195, 219 and 220.

-Adrenergic Blocking Drugs

Pharmacology Esmolol is an ultrashort-acting, cardioselective, 1-adrenergicblocking agent It is effective in controlling ventricular response in patients withatrial fibrillation and other supraventricular tachycardias and in slowing heart rate

in patients with sinus tachycardia associated with acute MI or cardiac surgery molol is useful for treating hypertensive emergencies, particularly in patients withtachycardia, because it has a rapid onset, short duration of action, and reducesheart rate It also can be effective in perioperative hypertension.173,195,221,222

Es-Adult Dosage Dilute injection to a final concentration of 10 mg/mL IV loading

dose is 500 g/kg/min for 1 min and then 50 g/kg/min The IV loading dose can

be repeated as often as q 5 min, with a concomitant increase of infusion rate in

50 g/kg/min increments, titrated to ventricular response, heart rate, and/or bloodpressure Most patients respond to infusions of 100–200 g/kg/min Once the de-sired endpoint is obtained, the infusion rate can be decreased in 25–50 g/kg/minincrements at 5- to 10-min intervals Infusions up to 48 hr are well tolerated

Pediatric Dosage IV 500 g/kg/min for 1 min and then 25–200 (average 120) g/kg/min.222Weight-adjusted dosages can be higher than in adults because

of its more rapid elimination in children; infusion rates as high as 1 mg/kg/minhave been required to achieve complete  blockade.223

Dosage Forms Inj 10, 250 mg/mL.

Pharmacokinetics Effective plasma levels are about 1–1.5 mg/L (3.4–

5.1 mol/L) The  half-life is about 2 min; Vdaverages 3.5 L/kg (range 2–5) Esmolol is rapidly hydrolyzed by plasma and blood esterases to a metabolite withweak, clinically unimportant -blocking activity and small amounts of methanol

No unchanged esmolol appears in the urine The elimination half-life is about

9 min in adults and 3 min in children.221,222

Adverse Reactions The side effect profile is similar to that of other 1-selective

-blockers Dose-related hypotension is frequent; IV site phlebitis occurs sionally Concurrent IV morphine can increase serum levels by 46%

occa-Pharmacology Propranolol is a nonselective -adrenergic blocker used in rhythmias, hypertension, angina pectoris, and CHF It is also effective in decreas-ing post-MI mortality The antiarrhythmic mechanism is caused by decreased AVnodal conduction in supraventricular tachycardias and blockade of catecholamine-induced dysrhythmias Propranolol and other -blockers are effective in prevent-ing postoperative atrial fibrillation The antihypertensive mechanism is unknown,but contributing factors are a CNS mechanism, renin blockade, and decreases inmyocardial contractility and cardiac output Propranolol also lowers myocardialoxygen demand by decreasing contractility and heart rate, which symptomaticallyalleviates anginal pain and increases exercise tolerance in coronary artery disease

ar-Metoprolol and carvedilol (and perhaps other -blockers) are effective in

ing mortality and improving quality of life in patients with CHF by blocking terious neurohumoral compensatory factors -Blockers and diuretics are recom-mended as first-line drugs for hypertension because of demonstrated reductions inmorbidity and mortality.173 (See -Adrenergic Blocking Drugs ComparisonChart.)

dele-Administration and Adult Dosage PO 10–20 mg q 6 hr initially, increasing

grad-ually to desired effects In hypertension, more than 1 g/day has been used; ever, consider adding another drug if 480 mg/day is ineffective In angina pec-toris, the dosage is titrated to pain relief and exercise evidence of -blockade(bradycardia) The endpoint for dosage escalation in acute arrhythmias is the re-turn to sinus rhythm or, in atrial fibrillation or flutter, to a ventricular rate below

how-100 beats/min with hemodynamic stability Twice-daily administration is

effec-tive in angina pectoris and hypertension Administer SR Cap in the same daily dosage once or twice daily (not indicated post-MI) PO for post-MI prophylaxis (non-SR) 180–240 mg/day in 2–3 divided doses IV slow push 1 mg q 5 min, to a

maximum of 0.15 mg/kg; some investigators have recommended that the firstdose be given over 2–10 min

Special Populations Pediatric Dosage PO for hypertension 0.5–1 mg/kg/day in

2–4 divided doses, increasing to a maximum of 8 mg/kg/day IV slow push

0.01–0.1 mg/kg/dose over 10 min up to 1 mg (infants) or 3 mg (children); may peat in 6–8 hr.4

re-Geriatric Dosage Bioavailability is increased in the elderly, necessitating lower

initial doses

Other Conditions Therapeutic endpoints can be achieved with lower dosages in

hypothyroidism or liver disease Begin with lower dosages and titrate to clinicalresponse Patients with thyrotoxicosis require higher dosages to achieve the de-sired effect.224

Dosage Forms Soln 4, 8, 80 mg/mL; Tab 10, 20, 40, 60, 80, 90 mg; SR Cap 60,

80, 120, 160 mg; Inj 1 mg/mL.

Patient Instructions Report any symptoms such as shortness of breath, swelling,

wheezing, fatigue, depression, nightmares, or inability to concentrate Do not stoptherapy abruptly Do not crush or chew SR capsule A sustained-release capsulecore in the stool does not indicate lack of absorption

Missed Doses Take this drug at regular intervals If you miss a dose take it as

soon as you remember If it is about time for the next dose, take that dose only.Leave at least 4 hours between regular tablet doses and 6–8 hours between extended-release capsule doses Do not double the dose or take extra

Pharmacokinetics Onset and Duration PO onset is variable; the duration varies

from 6 to longer than 12 hr.224

Serum Levels No definite relation has been established between serum

concen-trations and therapeutic effect in the treatment of arrhythmias, angina pectoris, orhypertension -Blockade is associated with serum concentrations >100 g/L (340 nmol/L).225

Fate Propranolol is rapidly and completely absorbed after oral administration;

however, a large hepatic first-pass effect occurs, limiting systemic availability to

26 ± 10% First-pass elimination is saturable with an oral dose greater than about

30 mg.225The drug is 87 ± 6% bound to 1-acid glycoprotein and other plasmaproteins.10,224Vdis 4.3 ± 0.6 L/kg; Cl is 0.96 ± 0.3 L/hr/kg Unlike most otherdrugs, displacement from plasma proteins increases elimination half-life and Vd

because of high tissue affinity (nonrestrictive elimination) An active metabolite,4-hydroxypropranolol, is formed after oral, but not IV, administration Less than0.5% of a dose is excreted unchanged in urine.10

t¹⁄₂. phase is about 10 min;224 phase after a single PO dose is 3.9 ± 0.4 hr.10

With long-term oral therapy,  phase is 4–6 hr but can be as long as 10–20 hr inpatients with liver disease.226

Adverse Reactions Adverse effects often are not related to dose Depression,

nightmares, insomnia, fatigue, and lethargy occur frequently; less often, psychoticchanges have been reported CNS side effects probably occur more often with thelipophilic -blockers (eg, propranolol) The drug can cause occasional life-threat-ening reactions when therapy (especially IV) is initiated, and acute CHF with pul-monary edema and hypotension or symptomatic bradycardia and heart block canoccur Acute drug cessation in patients with coronary artery disease can precipi-tate unstable angina pectoris or MI The drug can precipitate hypoglycemia, butprobably more important in diabetics is its ability to mask hypoglycemic symp-toms (except for sweating) It can exacerbate symptoms of peripheral vascular dis-ease or Raynaud’s disease -Blockers can exacerbate previously stable asthma orchronic airway obstruction by causing bronchospasm or renal dysfunction by fur-ther depressing GFR

Contraindications Severe obstructive pulmonary disease, asthma or active

aller-gic rhinitis; cardiogenic shock or severe CHF; second- or third-degree heart block;severe sinus node disease

Precautions In coronary artery disease, discontinue drug by tapering the dosage

over 4–7 days Use cautiously in patients with Prinzmetal’s vasospastic angina toprevent worsening of chest pain Use caution in peripheral vascular disease orCHF and in patients with brittle diabetes or history of hypoglycemic episodes.Can worsen atrial fibrillation associated with accessory AV pathway

Drug Interactions Concurrent digoxin therapy can lessen the -blocker bation of CHF When taken with oral hypoglycemics, nonselective -blockerssuch as propranolol prolong hypoglycemic episodes and inhibit tachycardia andtremors, which are signs of hypoglycemia (sweating is not inhibited); hyperten-sion can occur during hypoglycemia Epinephrine can produce hypertensive reac-tions in patients on propranolol (and probably other nonselective -blockers); thiscan occur with other sympathomimetics such as phenylephrine and phenyl-propanolamine Barbiturates and rifampin can increase the metabolism of hepati-cally eliminated -blockers such as propranolol Cimetidine can increase propra-nolol effects Combined use of clonidine and propranolol can result in

exacer-hypertensive reactions, especially if clonidine is abruptly discontinued

ers can increase the first-dose hypotensive effect of prazosin and similar drugs.NSAIDs can blunt the hypotensive response of -blockers.

Parameters to Monitor During IV administration, obtain blood pressure and

pulse q 5 min with constant ECG monitoring for signs of AV nodal block ened PR interval) or bradycardia Evaluate vital signs routinely for hemodynamicendpoints (eg, blood pressure in hypertension and heart rate or pressure rate prod-uct in angina pectoris) Question the patient about subjective complaints such asnightmares or fatigue When a patient at risk for adverse reactions is first givenpropranolol, evaluate signs and symptoms of toxicity (eg, CHF, shortness ofbreath or edema; bronchospasm, wheezing or shortness of breath; diabetes, bloodglucose; peripheral vascular disease, painful or cold extremities)

(length-Notes Propranolol can be beneficial for treatment of symptomatic hypertrophic

obstructive cardiomyopathy by increasing end-diastolic volume, producing tricular relaxation, and relieving ventricular outflow obstruction Other uses in-clude migraine prophylaxis, prevention of GI bleeding in patients with esophagealvaricies, prevention of sudden death in congenital long-QT syndromes, and as acardiac protectant in patients with heart disease undergoing noncardiac surgery If

ven-a -blocker must be used in lung disease, 1-selective drugs (eg, acebutolol, atenolol, or metoprolol) cause alterations in pulmonary function that are more

easily reversed by bronchodilators; these drugs are probably a better choice thanpropranolol or other nonselective -blockers (See -Adrenergic Blocking DrugsComparison Chart.)

-ADRENERGIC BLOCKING DRUGS COMPARISON CHART

β HALF- EXCRETED

Acebutolol a Cap 200, + 3–4 30–40% 25% Hypertension, PO 400 PO 1.2 g/day.

Atenolol Tab 25, 50, + 6–7 85% 10% Hypertension PO 50 mg/day PO 200 mg/day.

-ADRENERGIC BLOCKING DRUGS COMPARISON CHART (continued )

β HALF- EXCRETED

Carteolol a Tab 2.5, 0 6–11 60% 15% Hypertension PO 2.5 mg/day PO 10 mg/day.

Carvedilol b Tab 3.125, 6.25, 0 6–8 1% 95% Hypertension, PO 3.125 mg bid, PO (<85 kg)

q 2 weeks (>85 kg)

100 mg/day.

Labetalol b Tab 100, 200, 0 4–9 5% 50% Hypertension PO 100 mg/day PO 2.4 g/day.

Metoprolol Tab 50, 100 mg + 3–7 39% 10% Hypertension PO 100 mg/day PO 450 mg/day.

-ADRENERGIC BLOCKING DRUGS COMPARISON CHART (continued )

β HALF- EXCRETED

Nadolol Tab 20, 40, 80, 0 17–24 70% 25% Hypertension, PO 40 mg/day PO 320 mg/day.

Propranolol (See monograph.) 0 4–6 <0.5% 87% Hypertension, PO 40–80 mg/day PO 480 mg/day.

Post-MI prophylaxis PO 180 mg/day PO 240 mg/day.

Sotalol c Tab 80, 120, 160, 0 7–15 80–90% 0% Life-threatening PO 160 mg/day PO 640 mg/day.

Timolol b Tab 5, 10, 0 4–5 20% <10% Hypertension PO 20 mg/day PO 60 mg/day.

a Acebutolol, carteolol, penbutolol, and pindolol have intrinsic agonist (sympathomimetic) activity (ISA).

b Carvedilol has α 1 -blocking actions Labetalol has potent α 1 -blocking actions (ratio of α- to ß-blockade 1:3 and 1:7 with PO and IV, respectively).

c Sotalol also has type III antiarrhythmic properties.

Calcium-Channel Blocking Drugs

Pharmacology Diltiazem is a calcium-channel blocking drug that decreases

heart rate, prolongs AV nodal conduction, and decreases arteriolar and coronaryvascular tone It also has negative inotropic properties Diltiazem is effective insymptomatic angina pectoris, essential hypertension, and supraventricular tachy-cardias It also can reduce early reinfarction rates in patients with non–Q-wave MI

and normal left ventricular functions (See Calcium-Channel Blocking Drugs

Comparison Chart.)

Administration and Adult Dosage IV loading dose 0.25 mg/kg (about 20 mg) over 2 min; can repeat in 15 min with 0.35 mg/kg (about 25 mg) IV infusion 5–15 mg/hr, titrated to ventricular response PO for angina 30–60 mg q 6–8 hr

initially; dosages up to 480 mg/day may be required for symptomatic relief ofangina;233,234180–300 mg once daily with Cardizem CD PO for hypertension

120–240 mg/day initially in 2 divided doses using Cardizem SR, or 180–300 mg

once daily using Cardizem CD or Dilacor XR, titrated to clinical response; tenance dosages of 180–480 mg/day are usually necessary.

main-Special Populations Pediatric Dosage Safety and efficacy are not established.

PO 1.5–2 mg/kg/day in 3–4 divided daily doses up to a maximum of

3.5 mg/kg/day.4

Geriatric Dosage Same as adult dosage but titrate dosage slowly.

Other Conditions Patients with liver disease may require lower dosages; titrate to

clinical response

Dosage Forms Tab 30, 60, 90, 120 mg; SR Cap (12 hr; Cardizem SR, various)

60, 90, 120 mg; SR Cap (24 hr; Cardizem CD) 120, 180, 240, 300 mg; (24 hr; lacor XR) 120, 180, 240 mg; (24 hr; Tiazac) 120, 180, 240, 300, 360 mg; SR Tab

Di-120, 180, 240 mg (Tiamate); Inj 5 mg/mL; SR Tab 180 mg with enalapril 5 mg

(Teczem)

Patient Instructions Report dizziness, leg swelling, or shortness of breath (For

angina) Maintain a diary to document the numbers of episodes of chest pain andsublingual nitroglycerin tablets used

Missed Doses Take this drug at regular intervals If you miss a dose, take it as

soon as you remember If it is about time for the next dose, take that dose only Donot double the dose or take extra

Pharmacokinetics Onset and Duration PO onset 0.5–3 hr, duration 6–10 hr;235

12–24 hr with SR cap, depending on the product

Serum Levels Levels >95 g/L (230 nmol/L) are necessary to cause namic changes, but their clinical usefulness is questionable.236Levels of desace-tyldiltiazem are similar to those of diltiazem.237

hemody-Fate Oral bioavailability is 38 ± 11% with the first dose and 90 ± 21% with

long-term therapy.237 The drug is 78 ± 3% bound to plasma proteins; Vdis 5.3 ±1.7 L/kg;237Cl is 0.72 ± 0.3 L/hr/kg.10Enterohepatic recycling occurs The drug is

almost entirely metabolized by the liver, with only 1–3% excreted unchanged inurine One metabolite, desacetyldiltiazem, has 40–50% the activity of diltiazem.Metabolites are excreted primarily in the feces.

t¹⁄₂. phase 2–5 min;  phase 4.9 ± 0.4 hr,235,237longer in the elderly.234 phase(desacetyldiltiazem) 6.1 ± 1.2 hr.237

Adverse Reactions Frequency of side effects is dose related Headache, flushing,

dizziness, and edema occur frequently Sinus bradycardia and AV block occur quently, often in association with concomitant -blockers.234CHF can worsen inpatients with underlying left ventricular dysfunction A variety of skin reactionshave been occasionally reported.234Hepatitis occurs rarely

fre-Contraindications Second- or third-degree block or sick sinus syndrome without

a ventricular pacemaker; symptomatic hypotension or severe CHF, acute MI, orpulmonary congestion; atrial fibrillation with accessory AV pathway

Precautions Use caution with concomitant use of -blockers in patients with derlying CHF, especially those with poor left ventricular function.234

un-Drug Interactions Cimetidine and propranolol increase diltiazem serum

lev-els.234Diltiazem inhibits CYP3A4 and the metabolism of many drugs, includingcarbamazepine, cyclosporine, and theophylline.234 It also inhibits P-glyco-protein.238

Parameters to Monitor Monitor blood pressure, heart rate, and ECG, especially

when initiating therapy Watch for symptoms of hypotension and CHF Serialtreadmill exercise tests can assess efficacy in angina Monitor the number ofepisodes of chest pain and SL nitroglycerin used

Pharmacology Nifedipine is a dihydropyridine calcium-channel blocking drug

with potent arterial and coronary vasodilating properties A reflex increase insympathetic tone (in response to vasodilation) counteracts the direct depressant ef-fects on SA and AV nodal conduction This renders nifedipine ineffective in thetreatment of supraventricular tachycardias It is used for vasospastic and chronic

stable angina and in the treatment of hypertension (See Calcium-Channel

Block-ing Drugs Comparison Chart.)

Administration and Adult Dosage PO for angina (Cap) 10 mg tid initially,

in-creasing to a usual maximum of 20–30 mg tid or qid; dosages above 180 mg/day

are not recommended PO for hypertension (SR Tab only) 30–60 mg/day tially, increasing up to 120 mg/day prn PO for severe hypertension (non-SR)

ini-10 mg, may repeat prn in 20 min The capsule can be punctured or bitten andswallowed, usually resulting in a more rapid onset than SL administration.239

Special Populations Pediatric Dosage Safety and efficacy not established PO

for hypertensive crisis 0.25–0.5 mg/kg q 4–6 hr.4

Geriatric Dosage Same as adult dosage.

Other Conditions Patients with liver disease might require lower dosages;240titrate

to clinical response

Dosage Forms Cap 10, 20 mg; SR Tab 30, 60, 90 mg.

Patient Instructions Report flushing, edema, dizziness, or increased frequency

of chest discomfort Do not split, chew, or crush sustained-release tablets A sustained-release tablet core in the stool does not indicate lack of absorption.Maintain a diary to document the number of episodes of chest pain and sublingualnitroglycerin tablets used

Missed Doses Take this drug at regular intervals If you miss a dose, take it as

soon as you remember If it is about time for the next dose, take that dose only Donot double the dose or take extra

Pharmacokinetics Onset and Duration PO onset 0.5–2 hr; duration (Cap) 4–8

hr; (SR Tab) 12–24 hr PO (punctured capsule) onset 10–20 min; duration 3–4 hr

Serum Levels (Therapeutic) >90 g/L (260 nmol/L), although clinical utility isquestionable.241

Fate Bioavailability is 52 ± 37% in normals and 91 ± 26% in cirrhosis because of

extensive and variable first-pass hepatic elimination.240It is 96 ± 1% bound toplasma proteins; Vdis 0.8 ± 0.2 L/kg;241,242Cl is 0.42 ± 0.12 L/hr/kg.10Nifedipine

is almost entirely eliminated by hepatic metabolism via the CYP3A4 isozyme,which is present in variable amounts (but is not a true polymorphism).243Onlytraces of drug are excreted unchanged in urine.241

t¹⁄₂.  phase 4–7 min;  phase 2 ± 0.4 hr.241,242

Adverse Reactions Most side effects relate to vasodilatory actions and occur

fre-quently; symptoms include dizziness (with or without hypotension), flushing, andheadache These types of side effects seem less frequent with SR dosage forms.244

Avoid long-term treatment of hypertension with immediate-release products cause they can increase mortality.173,245Edema occurs frequently and is related tovenous pooling and usually not exacerbation of CHF Nifedipine paradoxicallycan worsen anginal chest pain, possibly because of a reflex increase in sympa-thetic tone or redistribution of coronary blood flow away from ischemic areas.Acute, reversible renal failure can occur in patients with chronic renal insuffi-ciency;246rare reactions include hepatitis and hyperglycemia

be-Contraindications Symptomatic hypotension.

Precautions Use with caution in unstable angina pectoris when used alone

(ie, without a -blocker) and in patients with CHF caused by systolic dysfunctionbecause mortality can be increased.245,247Do not use immediate-release products

to treat hypertension Nifedipine has an antiplatelet action and can increase ing time.248Nifedipine can worsen symptoms of obstructive cardiomyopathy

bleed-Drug Interactions Barbiturates increase nifedipine metabolism Cimetidine can

increase nifedipine serum levels Nifedipine occasionally increases PT in patients

on oral anticoagulants Nifedipine and IV magnesium sulfate can cause cular blockade and hypotension

neuromus-Parameters to Monitor Monitor blood pressure and heart rate, especially when

initiating therapy Observe for symptoms of hypotension and edema Serial mill exercise tests can assess efficacy

tread-Notes Other potential uses for nifedipine are migraine prophylaxis, achalasia,

and Raynaud’s phenomenon

Pharmacology Verapamil is a calcium-channel blocking drug that prolongs AV

nodal conduction It is used to convert re-entrant supraventricular tachycardiasand slow ventricular rate in atrial fibrillation or flutter Because it decreases con-tractility and arteriolar resistance, it is used in angina caused by coronary obstruc-tion or vasospasm Verapamil also is effective in the treatments of hypertension,

hypertrophic obstructive cardiomyopathy, and migraine prophylaxis (See

Calcium-Channel Blocking Drugs Comparison Chart.)

Administration and Adult Dosage PO for angina 80–120 mg tid initially,

in-creasing at daily (for unstable angina) or weekly intervals to a maximum of 480

mg/day PO for hypertension usually 240 mg/day using SR tablet; SR dosages of

120 mg/day to 240 mg bid have been used Covera HS is designed to be taken hs

PO for migraine prophylaxis 160–320 mg/day IV for supraventricular rhythmias 5–10 mg (0.075–0.15 mg/kg) over at least 2 min (3 min in elderly);

ar-can repeat with 10 mg (0.15 mg/kg) in 30 min if arrhythmia is not terminated or

desired endpoint is not achieved IV constant infusion 5–10 mg/hr.249

Special Populations Pediatric Dosage PO 4–8 mg/kg/day in 3 divided doses IV

(<1 yr) 0.1–0.2 mg/kg; (1–15 yr) 0.1–0.3 mg/kg, to a maximum of 5 mg over 2–3min.4

Geriatric Dosage Same as adult dosage but administer over 3 min.

Other Conditions Dosage might need to be decreased in patients with liver

dis-ease; titrate to clinical response

Dosage Forms Tab 40, 80, 120 mg; SR Tab 120, 180, 240 mg; SR Cap 100,

120, 180, 200, 240, 300 mg; Inj 2.5 mg/mL; SR Tab 180 mg with trandolapril

2 mg, 240 mg with trandolapril 1, 4 mg (Tarka)

Patient Instructions Report any dizziness, shortness of breath, or edema

Consti-pation occurs often Maintain a diary to document the number of episodes of chestpain and sublingual nitroglycerin tablets used

Missed Doses Take this drug at regular intervals If you miss a dose, take it as

soon as you remember If it is about time for the next dose, take that dose only Donot double the dose or take extra

Pharmacokinetics Onset and Duration IV onset immediate; duration 2–6 hr, up

to 12 hr with long-term use.250

Serum Levels 50–400 g/L (100–800 nmol/L), although therapeutic range is notwell established

Fate Although the drug is well absorbed orally, only 22 ± 8% is bioavailable

be-cause of extensive first-pass elimination; bioavailability increases in liverdisease.251Covera-HS provides a 4- to 5-hr delay before releasing the drug Ver-apamil has stereospecific pharmacology and pharmacokinetics; L-verapamil is amore potent AV nodal blocking drug, but it undergoes greater first-pass metabo-lism.252Norverapamil is an active metabolite Verapamil is about 90 ± 2% bound

to plasma proteins, with the more active L-isomer having a greater unbound tion.251,253Vdis 5 ± 2 L/kg and increases in liver disease;10,251 Cl is 0.9 ±0.36 L/hr/kg About 1% is excreted unchanged in urine.10

frac-VERAPAMIL HYDROCHLORIDE Calan, Covera-HS, Isoptin, Verelan, Various

t¹⁄₂ (Verapamil)  phase 5–30 min;  phase 4 ± 1.5 hr; can increase during term use; 13.6 ± 3.9 hr in severe liver disease; (norverapamil) 8 ± 1.9 hr.10,251,253

long-Adverse Reactions Constipation occurs frequently (5–40%), particularly in

el-derly patients CHF can occur in patients with left ventricular dysfunction Serioushemodynamic side effects (eg, severe hypotension) and conduction abnormalities(eg, symptomatic bradycardia or asystole) have been reported; these reactionsusually occur when the patient is concurrently receiving a -blocker or has under-lying conduction disease.254Infants appear to be particularly susceptible to ar-

rhythmias IV calcium (gluconate or chloride salts, 10–20 mL of a 10% solution) and/or isoproterenol can, in part, reverse these adverse effects.254The administra-tion of IV calcium before verapamil can prevent hypotension without abolishingthe antiarrhythmic actions.255

Contraindications Shock or severely hypotensive states; second- or third-degree

AV nodal block; sick sinus syndrome, unless functioning ventricular pacemaker is

in place; hypotension or CHF unless caused by supraventricular tachyarrhythmiasamenable to verapamil therapy; atrial fibrillation and an accessory AV pathway

Precautions Use caution with any wide-QRS tachycardia; severe hypotension

and shock can ensue if the tachycardia is ventricular in origin Use with caution incombination with oral -blockers and poor left ventricular function

Drug Interactions Verapamil can increase serum levels of several drugs,

includ-ing carbamazepine, cyclosporine, digoxin (probably by inhibitinclud-ing protein238), and theophylline Barbiturates and rifampin can increase verapamilmetabolism

P-glyco-Parameters to Monitor Monitor blood pressure and ECG continuously during

IV administration Pay particular attention to signs and symptoms of CHF and potension Also, monitor the ECG for PR prolongation and bradycardia

CALCIUM-CHANNEL BLOCKING DRUGS COMPARISON CHART

Cardizem

Dilacor XR

Inj 2.5 mg/mL 30–60 mg q 12 hr.

IV for hypertension 5–15 mg/hr.

CALCIUM-CHANNEL BLOCKING DRUGS COMPARISON CHART (continued )

hr for 21 days.

Calan

Isoptin

Verelan

↑ = increase; ↓↓ = marked decrease, ↓ = decrease, 0 = no change.

a Selective vascular actions.

b Complex pharmacology with probable sodium- and potassium-channel blockade (quinidine-like).

c Vascular and eletrophysiologic actions.

d Predominantly vascular actions.

From reference 256 and product information.

Hypolipidemic Drugs

Class Instructions Hypolipidemics There is a strong relationship between

ele-vated serum cholesterol and death caused by coronary heart disease (CHD) ering cholesterol decreased events related to CHD and can slow or even reverseatherosclerosis These effects are associated with a decrease in CHD mortality Ingeneral, each 1% decrease in serum cholesterol results in a 2% decrease in the risk

Low-of coronary events Hypolipidemic drugs must be taken daily to achieve these sults Drug therapy does not eliminate the need for appropriate diet and other mea-sures such as weight reduction (if appropriate), smoking cessation, and physicalactivity Use of estrogen and progestin in postmenopausal women also has benefi-cial effects on lipoprotein levels, but the overall risk/benefit assessment ofhormone-replacement therapy remains controversial Depending on their overallstate of health, elderly patients can benefit from secondary prevention with hy-polipidemic therapy Hypolipidemic drug therapy (with the exception of niacin)has been associated with an increase in cancer in animals, but it is not known ifthey have this effect in humans

re-Missed Doses Take this drug at regular intervals If you miss a dose, take it as

soon as you remember If it is about time for the next dose, take that dose only Donot double the dose or take extra

Pharmacology Cholestyramine is a bile acid sequestrant that acts as an anion

ex-change resin; it releases chloride ions and adsorbs bile acids in the intestine toform a nonabsorbable complex that is excreted in feces The resulting increase inactivity of hepatic low-density lipoprotein cholesterol (LDL-c) receptors leads tothe oxidation of cholesterol to form new bile acids Despite a compensatory in-crease in hepatic cholesterol synthesis, total serum cholesterol and LDL-c levelsare reduced by 15–30% The increase in cholesterol synthesis sometimes results in

an increase in VLDL cholesterol levels, which can increase triglyceride levels by10–50%.257,258Cardioprotective HDL-c levels can increase by 3–8%.258

Administration and Adult Dosage PO for hyperlipidemia 4 g daily–bid

ini-tially, increasing slowly to a maintenance dosage of 8–16 g/day in 1–6 (usually 2)divided doses, to a maximum of 24 g/day Compliance appears to be best in the

range of 8–10 g/day in 1–2 divided doses PO for treatment of cholestatic tus 4–8 g/day is usual PO for treatment of relapsing enterocolitis caused by

pruri-Clostridium difficile 4 g tid or qid (with or without vancomycin) has been used.

Special Populations Pediatric Dosage Limited data are available, especially

concerning long-term use Drug therapy is generally reserved for children at least

10 yr old, initiated at the lowest possible dosage, and gradually increased until thedesired response is achieved Base initial dosage on serum LDL-c level rather than

body weight, and adjust dosage based on response: PO for hyperlipidemia

(LDL-c <195 mg/dL) 4 g/day; (LDL-c 195–235 mg/dL) 8 g/day; (LDL-c 236–

280 mg/dL) 12 g/day; (LDL-c >280 mg/dL) 16 g/day.259,260(See Precautions.)

Geriatric Dosage Initiate therapy at lowest possible dosage and slowly titrate to

desired effect Maximum dosage might not be required or tolerated

Other Conditions In patients with histories of constipation, start at the low end of

the dosage range In patients with GI intolerance, reduce dosage and increase

gradually (See Adverse Reactions.)

Dosage Forms Pwdr 4 g resin/9 g powder (Questran); 4 g resin/5, 5.5, 5.7 g powder (Questran Light, various); Tab 1 g.

Patient Instructions (See Hypolipidemics Class Instructions.) It is preferable to

take this drug before meals, but you can adjust the time of the dosages around thescheduling of other oral medications Take other oral medications at least 1 hourbefore or 4–6 hours after taking cholestyramine Do not take dry; mix each packet

or level scoopful with at least 60–180 mL (2–6 fluid ounces) of water or bonated beverage, highly fluid soup, or pulpy fruit such as applesauce or crushedpineapple You can experiment with different products and vehicles to determineyour preference based on taste, cost, and caloric restrictions Mixtures can be re-frigerated to improve palatability but do not cook because the drug can be inacti-vated This drug frequently causes constipation If this becomes a problem, con-tact your physician or pharmacist to discuss measures to minimize constipation Itcan cause other gastrointestinal symptoms that usually decrease over time

noncar-Pharmacokinetics Onset and Duration Reduction in cholesterol begins the first

month

Fate It is not absorbed from the GI tract Resin and complex are excreted in the

feces

Adverse Reactions Almost 70% of patients experience at least one GI side

ef-fect.261Constipation frequently occurs, especially with higher dosages, in the derly and patients with previous constipation; fecal impaction is rare Nausea,heartburn, abdominal pain, bloating, steatorrhea, and belching also occur fre-quently but tend to decrease over time.257GI side effects tend to be milder in chil-dren than in adults Hemorrhoids can be aggravated or develop Rash can occur.Chloride absorption in place of bicarbonate can lead to hyperchloremic acidosis,especially in children, and calcium excretion can increase Absorption of vitamins

el-D and K can be impaired, leading to osteomalacia and bleeding, respectively sorption of folic acid also can be impaired, especially in children Alimentary can-cers in rats are somewhat more prevalent with cholestyramine treatment because

Ab-of enhancement Ab-of other carcinogens, but the importance Ab-of this in humans is known.262

un-Contraindications Complete biliary obstruction.

Precautions Pregnancy and lactation because of possible malabsorption of

fat-soluble vitamins Avoid constipation in patients with symptomatic coronary arterydisease Constipation can be controlled by reducing dosage, slowly titratingdosage, increasing dietary fiber, or using stool softeners Avoid use in the pres-ence of diverticular disease and local intestinal tract lesions because constipationcan be a problem.263 Discontinue if a clinically important elevation in serumtriglycerides occurs Vitamin supplementation might be needed with high dosage

or long-term therapy Children in particular might need multivitamins with folate

and iron.260Patients with osteoporosis might need to restrict dietary chloride tolimit calcium excretion.264Phenylketonurics should avoid Questran Light because

it contains aspartame

Drug Interactions Absorption of many drugs can be delayed or reduced,

includ-ing acetaminophen, coumarin anticoagulants, digoxin, furosemide, gemfibrozil,hydrocortisone, oral hypoglycemic drugs,265 iron, loperamide, methotrexate,naproxen, penicillin G, phenobarbital, oral phosphate supplements, pravastatin,propranolol, tetracyclines, thyroid hormones, thiazides, and vancomycin Monitorfor concurrent drug therapy effects when initiating and altering sequestrant ther-apy, particularly for drugs with a narrow therapeutic index

Parameters to Monitor Monitor LDL-c and triglycerides 4 weeks and 3 months

after initiation of therapy If therapy goals are achieved, monitor q 4 months less adverse effects are suspected Periodically monitor hemoglobin and serumfolic acid during long-term therapy Monitor efficacy of and appropriate tests forconcurrent drug therapy that might be affected by cholestyramine In children,monitor serum concentrations of vitamins A, D, and E and erythrocyte folate, liverfunction tests, and CBC annually.260

un-Notes Bile acid sequestering resins are indicated as an adjunct to diet for primary

hypercholesterolemia (types IIa and IIb) in patients for whom eridemia is not a primary concern (triglyceride levels <300 mg/dL).264Bile acidsequestrants moderately lower LDL-c compared with some of the other hypolip-idemic drugs but are considered safer because they are not absorbed These drugscan be particularly useful with moderately elevated LDL-c and when the risk ofCHD is low and long-term safety is of concern (eg, primary prevention and inyoung men and premenopausal women).257,266They can be used in combinationwith other hypolipidemic drugs for additive effects when a larger decrease inLDL-c is required Long-term use reduces cardiovascular morbidity and mortality,including the incidence of first heart attacks Because over one-third of patientsdiscontinue bile acid sequestrants in the first year, primarily because of adverseeffects, conservative dosage titration, education, and support are needed to man-age and avoid adverse effects.261,267Maximum dosage is rarely needed.258Low-dose therapy (8–10 g/day) appears to be best tolerated257and the most cost effec-tive, alone or in combination therapy.268Increased dosage can increase adverseeffects without meaningful decreases in cholesterol Resins are not effective in pa-tients with homozygous familial hypercholesterolemia.258(See Recommendations

hypertriglyc-for Initiation of Drug Therapy in Hypercholesterolemia Chart.)

The resins also are used to reduce pruritus caused by dermal deposition ofbile acids in patients with partial biliary obstruction, and cholestyramine has been

used to treat relapsing Clostridium difficile colitis.269,270Interference with digoxinabsorption suggests a possible role in the management of the mild intoxicationcaused by these drugs; however, do not rely on cholestyramine alone in cases ofsevere digoxin toxicity.265Questran contains 14 kcal/9 g packet or scoop; Ques-tran Light is flavored with aspartame and contains 1.6 kcal and 16.8 mg of phenyl-alanine/5 g packet or scoop

Pharmacology Colesevelam is a nonabsorbed, polymeric, lipid-lowering agent

that binds intestinal bile acids, resulting in the increased clearance of LDL-c and areduction of total cholesterol Unlike cholestyramine and colestipol, colesevelam

is not an anion exchange resin but binds bile acids and impedes their reabsorption.Clinical trials have demonstrated a mean LDL-c reduction of 15–18% after 24weeks of therapy HDL-c was increased by approximately 3% and triglyceridelevels were elevated 4–5% compared with placebo

Administration and Adult Dosage PO for hyperlipidemia 3 tablets bid with

meals or 6 tablets once daily with a meal.271 PO combination therapy for lipidemia 4–6 tablets/day is safe and effective when coadministered with an

hyper-HMG-CoA reductase inhibitor The drugs can be administered together or rately.271

sepa-Special Populations Pediatric Dosage Safety and efficacy not established.

Geriatric Dosage Same as adult dosage.

Dosage Forms Tab 625 mg.

Patient Instructions Take this drug with meals for maximum benefit.

Pharmacokinetics Onset and Duration Maximum effect occurs after 2 weeks.271

Fate Colesevelam is not absorbed orally It is excreted unchanged in the feces.

Adverse Reactions Unlike cholestyramine and colestipol, colesevelam is

gener-ally well tolerated GI effects, including flatulence, constipation, diarrhea, nausea,and dyspepsia, are the most common side effects, but the frequency is similar tothat of placebo.271,272

Contraindications Bowel obstruction.

Precautions Caution in patients with elevated triglyceride levels or GI disorders

(ie, GI motility disorders, dysphagia, swallowing disorders, or recent GI surgery)

Drug Interactions Colesevelam does not affect the bioavailability of digoxin,

lovastatin, metoprolol, quinidine, valproic acid, or warfarin The bioavailability of

SR verapamil can be reduced by colesevelam Colesevelam does not interferewith the lipid-lowering activity of the HMG-CoA reductase inhibitors Coles-evelam did not appear to affect the bioavailability of vitamin A, D, E, or K duringclinical trials of up to 1 yr.271The manufacturer states that caution should be exer-cised when treating patients with a susceptibility to vitamin K or fat-soluble vita-min deficiencies

Parameters to Monitor Monitor serum total cholesterol, LDL-c, and triglyceride

levels initially and periodically during therapy

Notes The tolerability and the apparent lack of GI side effects can make

coles-evelam a good alternative to other bile acid binding agents and potentially thedrug of choice in this class.271It is a good choice for use with an HMG-CoA re-ductase inhibitor in patients with inadequate responses to the maximal HMG-CoAdose

Pharmacology Colestipol is a bile acid sequestrant similar to cholestyramine,

with equivalent lipid-lowering effects in most patients Selection of a bile acid questrant is generally based on patient preference and cost The palatability ofcholestyramine–vehicle combinations is often preferred over colestipol granules,although colestipol tablets are well tolerated A 5 g dose of colestipol lowers cho-lesterol in an amount equivalent to 4 g of cholestyramine; a 4 g dose of colestipoltablets is about equivalent to 5 g of the granules.273–279(See Hypolipidemic Drugs

se-Comparison Chart and Recommendations for Initiation of Drug Therapy in cholesterolemia Chart.)

Hyper-Adult Dosage PO for hypercholesterolemia (Granules) 5 g bid initially,

in-creasing in 5 g/day increments at 1- to 2-month intervals to a maximum of

30 g/day in 1–4 doses; (tablets) 2 g bid initially, increasing in 2 g/day increments

at 1- to 2-month intervals to a maximum of 16 g/day (See Adverse Effects.) PO for relapsing enterocolitis caused by Clostridium difficile 5 g q 12 hr has been

used with oral vancomycin but avoid coadministration with vancomycin to vent vancomycin binding

pre-Dosage Forms Granules 5 g resin/7.5 g packets and bulk containers; Tab 1 g Adverse Effects Adverse effects, precautions, monitoring instructions, and drug

interactions are similar to those of cholestyramine Patients with moderate cholesterolemia who cannot tolerate colestipol granules due to GI side effects can

hyper-benefit from one-half the colestipol dose mixed with 2.5 g of psyllium.

Pharmacology Fenofibrate is a fibric acid derivative indicated for the treatment

of type IV and V hyperlipidemias It reduces serum LDL-c by 17–35% andtriglycerides by 15–43% and increases HDL It appears to act by enhancinglipoprotein lipase activity, inhibiting VLDL synthesis, and reducing cholesterolsynthesis, possibly by inhibiting acyltransferase activity It also can reduceplatelet aggregation and decrease serum uric acid.280–282

Adult Dosage PO for type IV or V hyperlipidemia in those at risk of atitis 67 mg/day initially, increasing q 4–8 weeks to a maximum of 201 mg/day.

pancre-Take doses with a meal

Dosage Forms Cap 67, 134 mg.

Pharmacokinetics After absorption, fenofibrate is hydrolyzed to the active drug,

fenofibric acid, which is more than 99% bound to plasma proteins It is excretedpredominantly unchanged in urine with a half-life of 20 hr, which is prolonged inrenal dysfunction

Adverse Reactions Side effects include GI disturbances, skin rash, muscle pain,

and headache Elevations in serum transaminases and CPK have occurred.Cholelithiasis has been reported, but it is not clear if the frequency is as great aswith clofibrate Avoid fenofibrate in those with liver, gallbladder, or kidney dis-ease

Pharmacology Gemfibrozil is a fibric acid derivative that decreases triglyceride

and VLDL-c concentrations and increases HDL-c concentrations Effects onLDL-c are variable LDL-c can increase in some patients, especially those withtype IV hyperlipoproteinemia Its exact mechanism is unclear, but it appears to actthrough many mechanisms There is increased secretion of cholesterol into bile,increased affinity of LDL receptors for LDL particles, activation of lipoproteinlipase, inhibition of triglyceride synthesis, suppression of free fatty acid releasefrom adipose tissue, and a change in LDL-c toward a potentially less atheroscle-rotic form.258,282

Administration and Adult Dosage PO as a hypolipidemic 600 mg bid.

Special Populations Pediatric Dosage Safety and efficacy not established.

Geriatric Dosage Initiate therapy at lowest possible dosage and slowly titrate to

desired effect Maximum dosage might not be required or tolerated

Other Conditions Some investigators advise decreasing dose by one-half with Clcr

of 20–50 mL/min

Dosage Forms Tab 600 mg.

Patient Instructions (See Hypolipidemics Class Instructions.) Take doses 30

minutes before morning and evening meals Gemfibrozil can slightly increase therisk of cancer and is similar to another medication that increases the risk of can-cer, gallstones, and pancreatitis You and your physician might decide that thebenefit of reducing the risk of coronary heart disease is worth these other risks.Promptly report any muscle pain, tenderness, or weakness, especially if you alsoare taking lovastatin or a similar drug

Pharmacokinetics Onset and Duration The maximum decrease in serum

triglyc-eride and total cholesterol occurs within 4–12 weeks; lipids return to pretreatmentlevels after drug discontinuation

Fate The drug is rapidly and completely absorbed after oral administration Mean

peak serum concentrations of 15–25 mg/L (60–100 mol/L) occur 1–2 hr afteradministration of 600 mg bid Serum concentrations are directly proportional todose The drug is 97–98.6% bound to albumin Cl appears to be independent ofrenal function Gemfibrozil is metabolized in the liver to a number of compounds.Approximately 70% of a dose is excreted in the urine, primarily as glucuronideconjugates of the drug and metabolites; less than 2% is excreted renally as un-changed drug.283–285

t¹⁄₂ Reportedly 1.5–2 hr but might be longer.283

Adverse Reactions Dyspepsia (20%), abdominal pain (10%), diarrhea (7%),

fa-tigue (3%), and nausea and vomiting (3%) are frequent; acute appendicitis, ness, eczema, rash, vertigo, constipation, headache, paresthesia (all 1–2%) alsooccur Occasional side effects include atrial fibrillation and elevations in liverfunction tests (AST, ALT, LDH, bilirubin, and alkaline phosphatase) that return tonormal with drug discontinuation Occasional mild decreases in WBC count,hematocrit, and hemoglobin occur but usually stabilize However, there have beenrare reports of severe blood dyscrasias Serum glucose can be slightly elevated, as

can LDL-c in some patients with high triglyceride levels Gemfibrozil can crease biliary lipogenicity and possibly increase long-term risk of cholelithiasis.258

in-Cholelithiasis requiring gallbladder surgery developed in 0.9% of treated patients, compared with 0.5% of patients in a placebo group This excess

gemfibrozil-was similar to that which occurred with clofibrate (See Notes.) An acute

infection-like syndrome characterized by arthralgias, myalgia, and myositis has occurredduring therapy Rhabdomyolysis with elevated CPK levels can precipitate acuterenal failure, especially with the combination of gemfibrozil and lovastatin.263

This has occurred as early as several weeks to months after initiating therapy.Routine monitoring of CPK might not detect rhabdomyolysis in a timely manner.Many have recommended avoiding the combination of gemfibrozil and anyHMG-CoA reductase inhibitor.265Worsening of renal insufficiency has been re-ported with an initial Crs>2 mg/dL Carcinogenesis, impairment of fertility, and

development of cataracts occur in rats (See Precautions and Notes.)

Contraindications Hepatic or severe renal dysfunction; primary biliary cirrhosis;

pre-existing gallbladder disease

Precautions Pregnancy, lactation Evaluate any reports of muscle pain,

tender-ness, or weakness for myositis, including a determination of serum CPK tinue if an adequate effect does not occur after 3 months, if cholelithiasis is sus-pected, or if liver function tests remain elevated

Discon-Drug Interactions Gemfibrozil can potentiate the effect of oral anticoagulants.

Cholesterol-binding resins can decrease absorption of gemfibrozil Insulin or anoral hypoglycemic might be required.283,285 Displacement of glyburide fromplasma protein binding sites, an action that produces hypoglycemia, has been re-ported.286Gemfibrozil and lovastatin (and possibly other HMG-CoA reductase in-

hibitors) together might increase the risk of myotoxicity (See Adverse Reactions.)

Parameters to Monitor Serum lipids, initially every few weeks, and then about

q 3 months.266Liver function tests and CBC q 3–6 months Monitor serum cose if the patient is receiving insulin or an oral hypoglycemic and prothrombintime if patient is taking an oral anticoagulant

glu-Notes Gemfibrozil is not considered a major treatment for hypercholesterolemia

because of its effects on LDL-c, but it does increase HDL-c and decrease erides, so it is useful in some patients.257Gemfibrozil is indicated for the treatment

triglyc-of type IV and V hyperlipidemias with very high serum triglycerides (usually

>2000 mg/dL) in patients at risk for pancreatitis and not responding to diet It isalso indicated in type IIb patients (only those without history or symptoms ofCHD) with low HDL-c and an inadequate response to weight loss, diet, exercise,and other drugs that raise HDL-c (eg, bile acid sequestrants, niacin), but is not in-dicated in type I or IIa hyperlipidemias or in those patients who have low HDL-conly The Helsinki Heart Study showed a 34% reduction in the incidence of CHD

in middle-aged men (initially without CHD symptoms) treated with gemfibrozil in

a 5-yr study, although total death rate was no different between treated andplacebo groups.287,288A substudy of the Helsinki Heart Study showed an increase

in gallstone and gallbladder surgery in gemfibrozil-treated patients After a 3.5-yrextension of this study, all-cause mortality was slightly higher in the original gem-

fibrozil group, primarily because of cancer deaths.288An ancillary study of theHelsinki Heart Study investigated the use of gemfibrozil in patients with signs orsymptoms of CHD.289The rate of serious adverse cardiac advents and total mor-tality with gemfibrozil treatment did not significantly differ from that of placebo;however, information on key prognostic indicators and their distribution was notknown.289Gemfibrozil is chemically and pharmacologically similar to clofibrate.

A 44% relative increase in age-adjusted, all-cause mortality occurred in a study oflong-term clofibrate use related to a 33% increase in noncardiovascular diseasesuch as malignancy, gallbladder disease, and pancreatitis Because of the smallersize of the gemfibrozil studies, the increase in mortality in the gemfibrozil grouprelative to placebo might not be statistically significantly different from the excessmortality associated with clofibrate use

Pharmacology Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors

competitively inhibit conversion of HMG-CoA to mevalonate, an early limiting step in cholesterol synthesis A compensatory increase in LDL receptors,which bind and remove circulating LDL-c, results Production of LDL-c also candecrease because of decreased production of VLDL or increased VLDL removal

rate-by LDL receptors These drugs produce dose-dependent, maximum reductions inLDL of 30–40% (up to 60% with atorvastatin) and triglycerides of 10–30% andincreases in HDL levels of 2–15% Drug effects are dose dependent until the fol-lowing doses are reached: 80 mg for atorvastatin, 0.3 mg for cerivastatin, 20 mgfor fluvastatin and simvastatin, and 40 mg for lovastatin and pravastatin Fluva-statin is about 30% less effective in lowering lipids than the other drugs Thesedrugs stabilize arterial plaques, which might be an important factor in their reduc-tion of MI risk They also appear to reduce the risk of bone fracture by increasingbone density, the risk of DVT and the risk of becoming diabetic.258,290-292

Administration and Adult Dosage Adjust dosage at no less than 4-week vals PO for hyperlipidemia (Atorvastatin) 10 mg/day initially, increasing to a

inter-maximum of 80 mg/day (Cerivastatin) 0.2–0.8 mg/day in the evening statin) 20 mg hs initially, increasing up to 80 mg/day; a slight increase in fluva-statin LDL-c lowering occurs with a bid schedule (Lovastatin) 20 mg (40 mg withserum cholesterol >300 mg/dL) with the evening meal initially Start with

(Fluva-10 mg/day in patients requiring <20% decrease in LDL-c or when concurrent usewith cyclosporine is unavoidable Increase to a maintenance dosage of 20–

80 mg/day Do not exceed a lovastatin dosage of 20 mg/day when used with

HMG-COA REDUCTASE INHIBITORS: