118 Cardiac Drug Therapy Advice, Adverse Effects, and Interactions CONTRAINDICATIONS • Hypersensitivity to thiazides or sulfonamides. • Anuria or severe renal failure. • Pregnancy and breastfeeding (see Chapter 20). • Concomitant lithium therapy. ADVERSE EFFECTS These include the following: 1. Dehydration and electrolyte imbalance are the most common adverse effects. The dose is too large if signs of dehydration or orthostatic hypotension develop, or if the patient has increased urea > 10.0 mmol/L or an increase of 7.0 mmol/L from baseline, chlorides < 94 mEq (mmol)/L, total carbon dioxide > 32 mEq (mmol)/L, and uric acid > 7 mg/dL (420 µmol/L). 2. Hypokalemia occurs in a significant number of patients receiving thiazides and contributes to increased risk of cardiac arrest (32). Chlorthalidone causes a greater loss of potassium (K + ) than for equivalent doses of HCTZ. The incidence of hypokalemia can be decreased by the use of low-dose thiazide regimens with K + -sparing diuretics. It is advisable to use the following: a. A thiazide-K + -sparing diuretic, such as amiloride with HCTZ (Moduretic, Moduret), if renal function is normal: for patients aged < 75 yr, serum creatinine level < 1.3 mg/dL (115 µmol/L); for patients aged > 75 yr, serum creatinine level < 1.0 mg/dL (88 µmol/L). *More common than angina in men >50 yr. **Statin and beta-blocker or ACE inhibitor, not alpha-blocker. †Not prone to hypoglycemia. ‡Not renovascular. Fig. 8-6. Choice of antihypertensive agent in patients with coexisting diseases. Chapter 8 / Hypertension 119 b. If mild renal dysfunction exists, hyperkalemia may occur with the use of K + -sparing diuretics; therefore, a plain thiazide is recommended without potassium supplements. 3. If the physician does not wish to use the combination of amiloride and HCTZ (Moduretic) or the combination of triamterene and HCTZ (Dyazide) when the serum creatinine concentration is normal, a thiazide can be used and the K + rechecked in months to evaluate whether the patient is a K + retainer or has a tendency to lose K + . If the serum K + level is less than 3.5 mEq (mmol)/L, the deficiency should be corrected with potassium chloride (KC1) and the thiazide replaced with the combination of amiloride and HCTZ (Moduretic). The possibility of alternate-day therapy may be considered because the antihypertensive effect is significant and the risk of electrolyte imbalance is greatly reduced. 4. Gastrointestinal effects include anorexia, gastric irritation, intrahepatic cholestatic jaun- dice, and pancreatitis. 5. Central nervous system effects include dizziness, vertigo, paresthesia, and headache. 6. Hematology and blood disturbances include leukopenia, rare agranulocytosis, thrombo- cytopenia, aplastic anemia and hemolytic anemia; increased serum cholesterol, decreased HDL cholesterol, and increased blood viscosity. 7. Cardiovascular effects include orthostatic hypotension, low cardiac output, and arrhyth- mias from hypokalemia, especially if the patient is taking digitalis. 8. Hepatic coma may be precipitated, so do not use in patients with impending hepatic coma or moderate to severe hepatic dysfunction. 9. In diabetes, insulin requirement may be increased; latent diabetes may become manifest; rarely, hyperosmolar, nonketotic hyperglycemic diabetic coma may be precipitated. If the patient has ever had this condition, avoid all diuretics. 10. For use in pregnant or nursing mothers, thiazides cross the placental barrier, appear in breast milk, and can cause fetal or neonatal jaundice, thrombocytopenia, decreased vas- cular volume and placental perfusion, and acute pancreatitis. 11. Precipitation of gout and hyperuricemia is a well-known complication of all diuretics. If gout or hyperuricemia occurs, this is treated in the usual fashion, and the diuretic is discontinued. There is no reason to add allopurinol to the regimen to prevent further episodes of gout. This is commonly done and adds to polypharmacy and expense. 12. Thiazides decrease calcium (Ca 2+ ) excretion, but hypercalcemia rarely occurs. 13. Acute allergic interstitial pneumonitis (33,34) is an extremely rare, but life-threatening, complication. 14. Drug interactions with lithium, steroids, and oral anticoagulants have been reported. Drug name: Bendrofluazide Trade names: UK Aprinox, Berkozide, Centyl, Neo-Naclex, Urizide Supplied: 2.5, 5 mg Dosage: 2.5–5 mg daily Advice and Adverse Effects Recommendations are the same as for HCTZ. Drug name: Triamterene and Hydrochlorothiazide Trade name: Dyazide Supplied: Tablets containing 50 mg triamterene and 25 mg hydrochlorothiazide Dosage: 1 tablet each morning 120 Cardiac Drug Therapy Advice and Adverse Effects Contraindications are the same as those outlined for HCTZ; special note should be made of the following: 1. Triamterene is a K + -sparing diuretic and is contraindicated in patients with past or present renal dysfunction or renal calculi (see Chapter 7). 2. The use of Dyazide (triamterene and HCTZ) is not recommended if the serum creatinine level is > 1.3 mg/dL (115 µmol/L) in patients aged < 70 yr. For patients > 70 yr of age, the lower creatinine value of not more than 1.0 mg/dL (88 µmol/L) should be used to prevent hyperkalemia. Do not use along with KC1, ACE inhibitor, or any other K + -sparing regimen. Do not use with indomethacin: renal failure may be precipitated. Drug name: Hydrochlorothiazide and Amiloride Trade names: Moduretic, Moduret (C) Supplied: Tablets containing 50 mg hydrochlorothiazide and 5 mg amiloride Dosage: Half a tablet daily; see text for further advice Dosage (Further Advice) The manufacturer indicates up to four tablets daily. The physician must insist on a lower dose of diuretics. A more appropriate combination, co-amilozide, available in the United Kingdom and Europe, contains amiloride 2.5 mg, HCTZ 25 mg. Advice and Adverse Effects Do not use along with potassium supplements. See Chapter 7 for amiloride, Aldacta- zide, eplerenone, spironolactone, and triamterene. Drug name: Furosemide; Frusemide Trade name: Lasix Supplied: Tablets: 20, 40, 80, 500 mg Injectable: 20 mg in 2-mL ampule; 100 mg in 10-mL ampule Advice and Adverse Effects Furosemide is less effective than thiazides in mild to moderate hypertension, and therefore it is not advisable to use this drug unless the patient has significant renal dys- function, such as a creatinine level > 2.3 mg/dL (203 µmol/L). Because furosemide inhibits the reabsorption of a very high percentage of filtered sodium, it is more effective than thiazides in patients with reduced glomerular filtration rate (GFR). As with thiazides, the combination with a K + -sparing diuretic has proved to be useful in causing further diuresis and in reducing K + loss. Ziac (US) or Monocor (UK) is a combination of bisoprolol 2.5, 5, and 10 mg with 6.25 mg HCTZ. This is an appropriate combination of a diuretic and a beta-blocker. BP is lowered to goal levels in about 80% of patients. This combination-type therapy with Ziac has shown consistently low discontinuation rates because of adverse effects, compared with enalapril. Drug name: Eplerenone Trade name: Inspra Dosage: 25 mg once daily, max. 50 mg Chapter 8 / Hypertension 121 ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS ACE inhibitors and ARBs play a major role in the management of hypertension, par- ticularly in patients with target organ damage and coexisting diseases (see Table 8-1). The major advantage of ARBs over ACE inhibitors is the absence of cough and very rare occurrence of angioedema; these agents are as effective as ACE inhibitors for the control of hypertension and HF. The failure of losartan, however, to control BP in scleroderma renal crisis with responsiveness to lisinopril has been reported (35). • In patients with target organ damage and coexisting conditions and special situations (see Table 8-6), particularly HF, LVH, diabetes with proteinuria, and selected cases of nephrop- athy (excluding renovascular hypertension), these agents are indicated. They are, however, not superior to other agents in diabetic patients, as is often claimed (see Chapter 9, Hyper- tension Controversies). Action ACE inhibitors prevent the conversion of angiotensin I to angiotensin II; ARBs block the effects of angiotensin II on blood vessel walls and do not interfere with the breakdown of bradykinin. These actions of ACE inhibitors and ARBs result in • Arteriolar dilation, which causes a fall in total systemic vascular resistance. • Attenuation of angiotensin potentiation of sympathetic activity and release of norepineph- rine. The diminished sympathetic activity causes vasodilation, reduction in afterload, and some decrease in preload. Also, heart rate is not increased by these agents, as opposed to other vasodilators. • Reduction in aldosterone secretion. The latter action promotes Na + excretion and K + reten- tion. • Blocking of angiotensin-mediated vasopressin release, which appears to be important in HF. • Converting enzyme (the same as kinase II), which causes degradation of bradykinin. The accumulation of bradykinin stimulates release of vasodilator prostaglandins that contrib- ute to the decrease in peripheral vascular resistance. Thus, indomethacin and other prosta- glandin inhibitors reduce the effectiveness of ACE inhibitors. Advice, Adverse Effects, and Interactions ACE inhibitors retain K + , so these drugs should not be given with potassium supple- ments or K + -sparing diuretics, Aldactazide (spironolactone and HCTZ), Dyazide (triam- terene and HCTZ), Maxzide (triamterene and HCTZ), or Moduretic (Moduret) (amiloride and HCTZ). Hyperkalemia may also occur with renal failure. Cough occurs in up to 20% of patients; angioedema is discussed in Chapter 3. Captopril causes proteinuria in about 1% of patients; this finding has occurred mainly in patients with preexisting renal disease who are taking doses of captopril in excess of 150 mg daily. Proteinuria caused by dia- betes is not a contraindication because the drug has been shown to diminish proteinuria in some diabetic patients (36,37). Adverse reactions reportedly include severe pruritus and rash in 10% and loss of taste in 7% of patients (38), as well as mouth ulcers, neuro- logic dysfunction, and gastrointestinal disturbances. Occasionally, tachycardia, increased angina, and precipitation of MI may occur. Neutropenia and agranulocytosis are rare and occur mainly in patients with serious intercurrent illness, particularly immunologic dis- turbances, and in those with an altered immune response, in particular collagen vascular disease. Precipitation of renal failure in patients with tight renal artery stenosis has been reported(39,40). Uncommon side effects include fatigue, Raynaud’s phenomenon, cough and/or wheeze, myalgia, muscle cramps, hair loss, angioedema of the face, mouth, or 122 Cardiac Drug Therapy larynx, impotence or decreased libido, pemphigus, hepatitis, and the occurrence of anti- nuclear antibodies. Contraindications The use of ACE inhibitors and ARBs should be avoided in the following clinical situations: • Hypotension: systolic pressures < 95 mmHg. • Moderate or severe aortic stenosis. • Severe renal failure; serum creatinine level > 2.3 mg/dL, 203 µmol/L. If the use of an ACE inhibitor is necessary, alter the dose and dosing interval. • Hyperkalemia or concomitant use of K + -sparing diuretics or potassium supplements. • Tight renal artery stenosis or stenosis in a solitary kidney. • Immune problems, in particular collagen vascular disease and autoimmune disease; ACE inhibitors are necessary. Discontinue the following drugs, which alter immune response: steroids, procainamide, hydralazine, probenecid, tocainide, allopurinol, acebutolol, pindolol, and others. • Patients known to have neutropenia or thrombocytopenia. • Severe carotid artery stenosis. • Restrictive, obstructive, or hypertrophic cardiomyopathies, constrictive pericarditis, cardiac tamponade, and hypertensive hypertrophic cardiomyopathy of the elderly with impaired ventricular relaxation (41). • Pregnancy and breastfeeding. • Women aged < 45 yr who may wish to become pregnant; these drugs should be avoided. • Chlorpromazine therapy because severe hypotension may occur. • Uric acid renal calculi: Captopril increases uric acid excretion. The drug has been proposed as strongly indicated in hypertensive patients with gout or hyperuricemia (42). However, excretion of increased uric acid may predispose to accretion of renal calculi. Further, the usual measures of alkalinizing the urine are not acceptable in hypertensive or cardiac patients; probenecid interacts with captopril and so may allopurinol. Drug name: Captopril Trade name: Capoten Supplied: 12.5, 25, 50 mg Dosage: Hypertension: 12.5 mg twice daily for a few days and then three times daily for about 1 wk, and then 25 mg three times daily; max. 75–100 mg daily; see text for further advice Dosage (Further Advice) The 75-mg dose appears to be as effective as higher doses. Do not exceed 150 mg daily. A twice-daily maintenance dose is effective for hypertension. If the BP is not excessively high (systolic > 180 mmHg, diastolic > 100 mmHg), it is advisable to discontinue diuret- ics 24–48 h before commencing the ACE inhibitor and to restart them a few days to weeks later, depending on BP response. In renal failure, increase the dose interval depending on creatinine clearance (GFR) (see Appendix II): GFR 75–35 mL/min dose every 12–24 h GFR 34–20 mL/min dose every 24–48 h GFR 9–6 mL/min dose every 48–72 h Chapter 8 / Hypertension 123 Drug name: Enalapril Trade names: Vasotec, Innovace (UK) Supplied: 2.5, 5, 10, 20 mg Dosage: Hypertension: 2.5 mg once daily for 1–2 d, and then 5 mg increasing over weeks or months to 10–20 mg; max. 30 mg (rarely 40 mg); see text for further advice Dosage (Further Advice) Occasionally, the daily dose must be given in two divided doses to achieve 24-h con- trol of BP. The usual recommended initial dose in patients not taking a diuretic is 5 mg once daily, except in the elderly or in those with renal impairment, and in suspected high renin states as seen with renal artery stenosis, prior diuretic use, and low-sodium diets. Here 2.5 mg is advisable. Note that the serum creatinine level may be normal in patients aged > 70 yr with renal impairment, and caution with dosage is necessary. The dosages of ACE inhibitors and ARBs are given in Tables 8-8 and 8-9, respectively. The maximum doses given in these tables are approximately 20% lower than those stated Table 8-8 ACE Inhibitors Drug Trade name Dosage (mg) a Max/d (mg) Benazepril Lotensin 5–30 30 Captopril Capoten 25–100 (2) 100 Cilazapril Inhibace, Vascase 1–5 5 Enalapril Vasotec, Innovace 5–20 (1–2) 30 Fosinopril Monopril 10–30 (1–2) 30 Lisinopril Prinivil, Zestril 5–30 (1) 30 Moexipril Perdix 7.5–15 (2) 15 Perindopril Coversyl 2–8 8 Quinapril Accupri, Accupro 5–40 (1–2) 40 Ramipril Altace, Tritace 1.25–15 (1) 15 Trandolapril Mavik, Gopten 1–4(1) 4 a See text: suggested maximum is slightly lower than manufacturer’s maximum. (1), once daily; (2), two divided doses. Table 8-9 Angiotensin II Receptor Blockers Drug Trade name Dosage (mg) a Max/d (mg) a Candesartan Atacand, Amias 4–10 32 Losartan Cozaar 25–100 (1, 2) 100 Valsartan Diovan 80–160 (1) 160 Irbesartan Avapro, Aprovel 75–225 (1) 300 Telmisartan Micardis 20–80 (1) 80 Eprosartan Teveten 300–400 (2) 800 a See text: suggested maximum is slightly lower than manufacturer’s maximum. (1), once daily; (2), two divided doses. Halve the initial dose in elderly patients and in the presence of hepatic or renal impairment. 124 Cardiac Drug Therapy by the manufacturer. The author does not recommend the use of the manufacturer’s maximum for BP control. The goal BP should be achieved with approximately 75% of the maximum dose; if this is not achieved, the drug should be combined with a small dose of another agent. For other ACE inhibitors, the action, pharmacokinetics, and adverse effects of ACE inhibitors, and ARBs, see Chapter 2. ACE Inhibitor-Diuretic Combination Capozide: 15–30 mg contains 15 mg captopril with 30 mg HCTZ for twice-daily dosage. These preparations carry the disadvantages of fixed combinations. Vaseretic: 10–25 mg contains enalapril 10 mg with HCTZ 25 mg and is effective when given once daily. The combinations are not recommended if there is moderate renal impairment: serum creatinine level > 2.3 mg/dL, 203 µmol/L. Hyzaar: This is a combination of losartan 50 mg and HCTZ 12.5 mg. This agent should not be prescribed as initial therapy but only after a trial of a diuretic or ACE inhibitor independently. This drug is contraindicated in patients with renal vascular hypertension. CALCIUM ANTAGONISTS (EXTENDED RELEASE) Calcium antagonists are recommended by the JNC for the following situations: • In older African Americans or if diuretics are contraindicated or cause adverse effects (see Table 8-4). • In younger African Americans if beta-blockers are contraindicated or not well tolerated. • In older white patients with isolated systolic hypertension if beta-blockers or diuretics are contraindicated or cause adverse effects (6) provided that left ventricular function is normal. • As second-line therapy in combination with beta-blockers or other agents in patients with angina or renal dysfunction. The calcium antagonists are used with caution in the following situations: • Patients with IHD, with silent ischemia, and after MI: diltiazem is indicated if beta-blockers are contraindicated. DHPs may be used in this subset of patients if a beta-blocker is being used concomitantly. • Patients with hypertension and diabetes: RCTs have shown an increase in mortality in patients treated with extended-release calcium antagonists. The isradipine and nisoldipine studies (7,8) confirm an increased risk of IHD events caused by calcium antagonists in dia- betic patients. ACE inhibitors and beta-blockers are preferred. • Patients with HF, LV dysfunction, or ejection fraction < 45%. Drug name: Amlodipine Trade names: Norvasc, Istin (UK) Supplied: Tablets 5, 10 mg Dosage: 5 mg, max. 10 mg once daily; initial 2.5 mg in the elderly Drug name: Nifedipine Trade names: Procardia XL, Adalat CC, Adalat LA (UK), Adalat XL (C) Dosage: 30 mg daily increasing to 60 mg, max. 60 mg Chapter 8 / Hypertension 125 DHPs cause a significant increase in sodium excretion, and a diuretic may not be necessary or may not lower BP further. The rapid-release capsule of nifedipine is no longer recommended. The extended- release preparation has been used worldwide since the 1980s. The drug has a role in reno- vascular hypertension and in the perioperative management of pheochromocytoma (43). Nifedipine and other DHPs may cause rebound hypertension. A case of an increase from 170/100 to 300/200 mmHg has been reported on sudden cessation of nifedipine therapy (44). The INSIGHT trial (10) showed nifedipine equivalent to diuretic in preventing stroke, but it increased the risk of HF significantly. Drug name: Diltiazem extended release Trade names: Cardizem CD, Tiazac, Adizem-XL (UK), Viazem XL Supplied: Cardizem CD, Tiazac: 120, 180, 240, 300 mg Dosage: 120 mg increasing to 240 mg daily, max. 300 mg Diltiazem is a weak vasodilator, 50% less potent than DHPs. Caution is needed when this drug is combined with a beta-blocker because bradycardia or LVF may ensue. Inter- actions occur with digoxin and amiodarone. A diltiazem-lithium interaction causing psy- chosis has been reported (45). The NORDIL trial (46) indicated that diltiazem was as safe as a beta-blocker or diuretic, but there was a small increase in the combined end point of MI and HF. Drug name: Verapamil extended release Trade names: Covera-HS*, Chronovera*, Isoptin SR, Securon SR (UK) Supplied: 120, 180, 240 mg Dosage: 120 mg once daily, max. 240 mg. *180–240 mg daily; reduce the dose in liver disease, renal failure, or the elderly Caution: Short-acting formulations are not recommended, Verapamil should not be used in patients with cardiomegaly or LV dysfunction. Also avoid in HF, conduction defects, and sick sinus syndrome. Constipation and bradycardia are limiting considerations, particularly in patients aged > 70 yr. Combination with a beta-blocker is contraindicated. Drug name: Felodipine Trade names: Plendil, Renedil Supplied: Extended-release tablets: 2.5, 5, 10 mg Dosage: 2.5–10 mg once daily Other calcium antagonists are discussed in Chapter 5. CENTRALLY ACTING DRUGS Drug name: Clonodine Trade name: Catapres Supplied: 0.1, 0.3 mg Dosage: 0.1 mg at bedtime; increase to twice daily with a larger dose at night; maintenance 0.2–0.8 mg 126 Cardiac Drug Therapy Caution:Clonidine is contraindicated in patients with depression. Rebound hyperten- sion can pose a major problem. Newer agents have rendered centrally acting drugs obsolete. Drug name: Methyldopa Trade name: Aldomet Supplied: 125, 250, 500 mg Dosage: 250 mg twice daily, increasing over days to weeks to 250 mg three times daily; max. 500 mg two or three times daily Caution: This drug should be avoided in patients with active liver disease, depression, or pheochromocytoma. Hemolytic anemia is a well-known complication, and myocardi- tis causing death has been reported (47). The drug has a role mainly in pregnancy (see Chapter 20) and in special situations as combination therapy when other agents have failed or are contraindicated. ALPHA 1 -BLOCKERS The ACC has issued a caution regarding the use of alpha-blockers. The author issued a caution in the second edition of this book in 1988. Drug name: Prazosin Trade names: Minipress, Hypovase (UK) Supplied: 1, 2, 5 mg Dosage: 0.5 mg test dose, then 1–2 mg twice daily, max. 10 mg daily; see text Dosage Withhold diuretics for 24 h. For mild hypertension, start a 0.5-mg test dose at bedtime. If no syncope or other adverse effects occur 24 h later, use 1 mg twice daily. If a dose > 6 mg is used, a beta-blocker and diuretic are usually necessary. Caution: Rare syncopal reactions after the first dose has been documented. Postural hypotension, dizziness, tachycardia, and palpitations with rare precipitation of angina have been documented. The drug is not recommended by the author. Prazosin may cause • Increase in heart rate. • Increase in pulsative force and cardiac peak ejection velocity. • Increase in circulating norepinephrine levels. • Activation of the renin-angiotensin system. Dosaxozin prazosin, terazosin, hydralazine, and vasodilators of this class do not sig- nificantly prevent or reduce LVH and have some nonbeneficial effects on the cardiovas- cular system (see Table 8-8). Drug name: Terazosin Trade name: Hytrin Supplied: 1, 2, 5, 10 mg Dosage: Discontinue diuretics and give a daily 1-mg dose at bedtime, increasing if needed to 2 mg in a few weeks; maintenance 2–5 mg daily Chapter 8 / Hypertension 127 The main advantage over prazosin is a half-life three to four times greater, which allows for once-daily dosing. The agent is widely used in men with benign prostatic hypertrophy. Caution is required in combination with calcium antagonists. Drug name: Phentolamine Trade name: Rogitine Supplied: 10 mg/dL; as 1- or 5-mL ampules Dosage: IV: 10–20 µg/kg/min; average 5–10-mg dose IV repeated as necessary Infusion: 5–60 mg over 10–30 min at rate of 0.1–2 mg/min Phentolamine and phenoxybenzamine block alpha 1 -receptors and especially alpha 2 - receptors. The drug is very expensive; action is rapid and lasts only minutes. Thus, nitro- prusside is preferred for control of most hypertensive crises including pheochromocytoma. Drug name: Phenoxybenzamine Supplied: 10-mg capsules Dosage: Pheochromocytoma: 10 mg every 12 h, increasing the dose every 2 days by 10 mg daily; usual dosage 1–2 mg/kg daily in divided doses; saline may be needed to prevent postural hypotension The drug is given for 1–2 wk before surgical removal of pheochromocytoma. Postop- erative hypotension may be avoided by discontinuing the drug several days before op- eration and limited use in selected patients. Beta-blockers may be added after 1 wk of alpha-blockade, but only if it is necessary to treat catecholamine-induced arrhythmias. Contraindications HF is a contraindication. HYPERTENSIVE CRISIS Hypertensive crisis is usually subclassified into either hypertensive emergency or urgency. • Hypertensive emergency is defined as a severe sudden elevation in BP, generally diastolic > 120–130 mmHg; some clinicians add: and/or systolic BP > 220 mmHg. The systolic pres- sures should reflect a knowledge of previous BPs, such as a rise within days from 160–170 to >220 mmHg systolic; the rate of rise of BP in relation to previous BP is more important than the absolute BP. Most important, the sudden excessive elevation in BP should be associated with acute organ damage or dysfunction, which confers an immediate threat to the integrity of the cardiovascular system and to life. In aortic dissection or acute pulmonary edema, a BP of 200/110 mmHg must be reduced. Conditions associated with emergencies are given in Table 8-10. Emergencies require reduction in BP within minutes by intravenous (IV) therapy. The emergencies and the drugs of choice are given in Table 8-11; because these are rare occur- rences and memory may elude the reader, I have provided a second approach (Table 8-12) that gives the drugs and their indications. For hypertensive emergencies, the goal is to produce an immediate but modest reduc- tion in BP. The objective, in most patients, is to achieve no greater than a 20% reduction from baseline of the mean arterial pressure or to reduce the diastolic BP to 110 mmHg [...]... vs 2 34 RR 0.87 103 vs 119 RR 0. 84 —c 108 vs 1 14 RR 0. 94 5 vs 4 NS 1 vs 7 RR 0.15 64 vs 58 RR 1.12 59 vs 75 RR 0.88 43 1 vs 383 RR 1.13 820 vs 738 RR 1.11 —c 45 vs 46 RR 0.97 — —c 96 vs 1 04 RR 0.92 — 6 vs 11 RR 0.56 52 vs 62 RR 0.85 17 vs 21 RR 0.90 309 vs 232 RR 1. 34 422 vs 327 RR 1.29 7 vs 6 RR 1.2 45 vs 40 RR 1. 14 46 vs 61 RR 0.84e 188 vs 198 RR 0.95 44 4 vs 390 RR 1.1 f 369 vs 742 RR 0.99 237 vs 42 2... Captopril Placebo 72 .4 A 62 .4 AB 59.6 AB 54. 8 B 53.7 B 50.0 B 31.0 C 70.3 57.5 84. 9 71.7 47 .5 68.8 57.8 73.3 51 .4 64. 9 44 .7 72 .4 47.9 32 .4 63.6 68.3 41 .9 54. 5 49 .0 69.0 43 .2 61.5 33.3 61.8 22.7 25.8 27.3 37.5 *Treatment was considered successful if the diastolic blood pressure was less than 90 mmHg at the end of the titration period and less than 95 mmHg at the end of 1 yr of maintenance therapy †Agents... UKPDS (41 ) Atenolol vs captopril LIFE (43 ) Atenolol vs losartan ASCOT-BPLA (25) Atenolol + diuretic Amlodipine + perindopril STOP-2 (7) Atenolol Pindolol d Metoprolol vs ACE inhibitor or calcium antagonist NORDIL (46 ) Any beta-blocker vs diltiazem CONVINCE ( 14) Atenolol vs verapamil Not assessed by Lindholm et al CAPP (47 ) Captopril vs atenolol or metoprolol 43 96 (5.8) 6357 (4) 106 (10) 3 04 (4) 147 3 (2.6)... difference 0.20 mmol/L; p < 0.0001) in the amlodipine/perindopril arm versus the atenolol/diuretic-based regimen • Baseline glucose concentration for amlodipine and the atenolol-based regimen was 6. 24 versus 6. 24 mmol/L  144 4 5 6 7 Cardiac Drug Therapy • The mean change in glucose levels attributed to atenolol therapy from baseline to final visit was only 0.2 mmol/L (25a) • Thus these trialists do not... alpha-blocker doxazosin (39) “HF risk was doubled ( 4- yr rates, 8.13% versus 4. 45%; RR, 2. 04; 95% CI, 1.79–2.32; p < 0.001).” I cautioned that the use of alpha-blockers should be curtailed in the second edition of this book (1988) as well as the fourth edition (1995) (53) 2 In the INSIGHT trial, a 46 % higher rate of HF was observed with calcium antagonist therapy versus older drug regimens (Table 9-2 )... process • Insulin secretion is partly beta-2 mediated, and glucose-sulfonyl-urea-stimulated insulin secretion is partially inhibited by beta-blockers (36) Clinically, however, there is no significant worsening of glycemic control when beta-blockers are combined with these agents Diabetes Incidence in Clinical Studies 1 In 1982 Murphy et al reported on the results of a 1 4- yr follow-up in hypertensive patients... Cardiology: Cardiac Drug Therapy, Seventh Edition M Gabriel Khan © Humana Press Inc., Totowa, NJ 137 138 Cardiac Drug Therapy Table 9-1 Clinical Trials Assessed in the Metaanalysis by Lindholm et al (1) and Relevant Effects Trial No of patients (yr of follow-up) MRC 1985 (8) Propranolola vs placebo Total mortality Stroke Myocardial infarction 120 vs 253 RR 0.93 120 vs 128 RR 0.91 42 vs 109 RR 0.76 42 vs... frequent in the patients on amlodipine than in those on valsartan (13.1% versus 16 .4% ; p < 0.0001) (45 ) 9 STOP-2 was a large RCT of 66 14 patients aged 70– 84 yr randomized to a beta-blocker group (mixed beta-blockers) or hydrochlorothiazide or newer drugs (enalapril or lisinopril, felodipine or isradipine) (7) At 5-yr follow-up, there were no differences in the prevention of cardiovascular mortality or... prediabetic state, beta-blockers and/or diuretics do not cause genuine diabetes mellitus  146 Cardiac Drug Therapy Table 9-2 Antihypertensive Agents and Risk for Heart Failure Drugs Doxazosin Amlodipine Lisinopril Nifedipine Carvedilol Trial Risk for heart failure ALLHAT (40 ) ALLHAT ALLHAT INSIGHT ( 54) CAPRICORN (18) 82% versus diuretic 32% versus diuretic 19% versus diuretic 46 % versus diuretic Significantly... and atenolol 140 Cardiac Drug Therapy or hydrochlorothiazide (88/2 74) groups It must be emphasized that atenolol does not provide a full 2 4- h action and fails to quell early morning catecholamine surge (15) It is not surprising, therefore, that the drug is only partially CVD protective Reasons for the Poor Cardiovascular Protective Effects of Atenolol • Atenolol is a hydrophilic beta-blocker that attains . 2003;289:2560–2572. 1 34 Cardiac Drug Therapy 21. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major out- comes in high-risk hypertensive patients randomized to angiotensin-converting. available beta-blocking drugs are discussed. • In addition, in the RCTs analyzed, atenolol monotherapy, or calcium antagonist, ACE inhib- itor monotherapy was the therapy in < ;45 % of treated. 24 h, 100–200 mg daily. If there is no contraindication to beta-blockers, propra- nolol is given IV 1 4 mg and then orally 120– 240 mg daily in addition (or the equivalent dose of another beta-blocker).