PPM2 Antihypertensive Agents

Required Reading:

Brenner          Chp. 9:   “Adrenergic Receptor Antagonists”

                        Chp. 10:  "Antihypertensive Drugs"

CMDT 2003    Chp. 11:  “Systemic Hypertension”

“Drugs for Hypertension,” Medical Letter, Vol. 43, #1099 (March 5, 2001), pp. 17-22.

Note:  Learning all of the numerous antihypertensive drugs can be very confusing. All of the above references cover essentially the same information, and can be used in answering the learning objectives below.  The CMDT chapter is very well written, and may be the best place to start. The Medical Letter article is a handy summary of the most essential information when you are reviewing.

Objectives:

1.         Categorize the major classes of antihypertensive agents according to the following scheme: diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor blockers, calcium-channel blockers, alpha-one blockers, centrally acting sympatholytics, and direct vasodilators.  (Terminology for these classes will vary slightly from source to source, but these are probably the most commonly used terms in clinical practice.)

Megan B.  Brenner 90-100, CMDT 416-429

Diuretics: Reduce BP by two mechanisms, both stemming from their ability to increase sodium and water excretion.  They lower BP by decreasing blood volume-by suppressing tubular reabsorption of sodium, thus increasing the excretion of sodium and water and thereby decreasing cardiac output.  During chronic therapy their major hemodynamic effect is reduction of peripheral vascular resistance.  Diuretics are more potent in blacks, older individuals, the obese, and other sub groups with increased plasma volume or low plasma rennin activity and they are more effective in smokers than nonsmoker.

Sympatholytics

Beta blockers:  Widely employed in the treatment of HTN because they are relatively safe and effective in most patients and are particularly useful in patients who suffer from angina or have a history of MI.  The drugs are cardioprotective and only rarely cause orthostatic hypostension or produce hepatic, renal, or hematopoietic toxicity.  Β-blockers provide effective single-drug therapy for mild HTN and can be combined with other drugs to treat more severe HTN.  

Angiotensin Inhibiters:  Increasingly used as the  initial medication in mild to moderate HTN.  Primary mode of action is inhibition of the rennin-angiotensin-alderstone system, but they also inhibit bradykinin degredation, stimulate the synthesis of vasodialationg prostoglandins and may reduce sympathetic nervous system activity.  Ace inhibitors can be used as single drug therapy or with a diuretic or calcium channel blocker.

Angiotensin II receptor blockers:  Primarily used for patients who develop cough when taking ACE inhibitors.  Mechanism of action similar to ACE inhibitors, block AT₁ receptors in smooth muscle and in the adrenal cortex and therefore cause vasodilation and decrease aldesterone secretion.

Calcium channel blockers:  Cause peripherial vasodialtion, which is associated with less reflex tachycardia and fluid retention than other vasodilators.  They are effective as a single drug therapy in all demographic groups and all grades of HTN.  May be preferable to β-blockers and ACE inhibitors.

Alpha-one blockers: Relax smooth muscle and reduce blood pressure by lowering peripheral vascular resistance.

Centrally acting sympatholytics: Lower blood pressure by stimulating alpha adrenergic receptors in the CNS, thus reducing efferent peripheral sympathetic outflow.

Direct vasodiators:  relax vascular smooth muscle and produce peripheral vasodilation.

Kim R.  Brenner pg 90-100

Diuretics-

            Thiazides- HCTZ (hydorchlorathiazide) metolazone, Indapamide.

            Loop diuretics- bumetanide, furosemide.

            K+ sparing diuretics- amiloride, spironolactone, triamterene.

Sympatholytics include adrenergic antagonists, centrally actng drugs, neuronal blocking agents, and ganglionic blocking agents.

            Adrenergic receptor antagonists

                        Beta-blockers- (selective) atenolol, metoprolol.  (nonselective) nadolol,

                                                Pinolol, propanolol.

                        Beta adrenergic antagonists-Labetolol. Which is a combined alpha and

                                                Beta blocker.

                        Alph-blockers- (selective) doxazosin, prazosin, terazosin.  

(nonselective) phenoxybenzamine.

            Centrally acting

                        Alpha2 agonists- clonidine, guanabenz, guanfacine, methyldopa.

            Neuronal blocking agents

                        guanethidine, reserpine.

            Ganglionic blocking agent

                        Trimethaphan

ACE Inhibitors

            Benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril.

Angiotensin II receptor blockers

            Losartan, valsartan

Ca channel blockers

            Diltiazem, verapamil, amlodipine, felodipine, isradipine, nicardipine, nifedipine.

Other vasodilators

            Hydralazine, minoxidil, nitroprusside.

Anonymous Brenner 88-100    

•        Diuretics- Diuretics are used in the management of edema associated with cardiovascular, renal, and endocrine abnormalities, as well as in the treatment HTN, glaucoma, and several other clinical disorders.  The drugs act various sites in the nephron to cause diuresis.

•        Beta-blockers- The Beta-blockers are widely employed in the treatment of hypertension because they are relatively safe and effective in most patients and are particularly useful in patients who suffer from angina or have a history of MI.

•        ACE inhibitors- The antihypertensive action of ACE inhibitors is primarily due to a reduction in Peripheral vascular resistance (PVR), with little or no change in cardiac output or blood volume.  ACE inhibitors decrease both arterial pressure and venous pressure, and this in turn reduces cardiac afterload and cardiac preload, respectively.

•        Angiotensin-receptor antagonist- These drugs block angiotensin 1 receptors in the vascular smooth muscle and in the adrenal cortex, thereby causing vasodilatation and decreasing aldosterone secretion.  They don't seem to cause the typical cough associated with ACE inhibitors.

•        Calcium channel blockers- By blocking calcium channels in the plasma membrane of smooth muscle, the calcium channel blockers (CCB) relax vascular smooth muscle and thereby cause vasodilatation.  CCB have a greater effect on the arteriolar smooth muscle, and their effect on blood pressure is primarily due to a reduction in PVR, with relatively little impact on venous capitance, cardiac filling pressure, or cardiac output.

•        Alpha-one blockers- The alpha-blockers act to inhibit sympathetic stimulation of arteriolar contraction.  Selective alpha-one blockers are preferred for the treatment of chronic essential hypertension because they produce less tachycardia than do nonselective alpha-blockers.

•        Centrally acting sympatholytics- These agents are alpha-two adrenergic receptor agonists that reduce sympathetic outflow from the brain stem to the heart, blood vessels, and other tissues.  They lower the blood pressure primarily by causing a reduction in the PVR while the heart rate and cardiac output are either reduced or remain unchanged.  Should not be used with tricyclic antidepressants.

•        Direct vasodilators- They are primarily used in combination with other antihypertensive drugs for the treatment of moderate to severe HTN.  When used alone, they often evoke reflex tachycardia and cause fluid retention, and they may precipitate angina in susceptible patients.

Anonymous  pg. 88 Brenner

Diuretics

Beta-Blockers – Atenolol, Metoprolol, Nadolol, Propranolol

ACE inhibitors – Benazepril, captopril, enalapril, enalaprilat, fosinopril, lisinopril, quinapril, ramipril.

Angiotensin-Receptor antagonists – Losartan and valsartan

Calcium-Channel blockers – Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, and verapamil

Alpha-one blockers – Doxazosin, prazosin, and terazosin

Centrally Acting Sympatholytics – Clonidine, guanabenz, guanfacine, and methyldopa

Direct Vasodilators – Amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin

2.         Distinguish between thiazide diuretics, loop diuretics, and potassium-sparing diuretics in the treatment of hypertension.  List or recognize specific adverse effects of each group.  (representative drugs: hydrochlorothiazide, furosemide, spironolactone, triamterene)

Megan B. Brenner 91-92

Kim R. Brenner pg 90-92

Thiazide diuretics reduce blood pressure by 2 mechanisms, both stemming from their ability to increase Na and H2O excretion.  

            Adverse Effects-blood cell deficiencies, hyperlipidemia, hyperuricemia, hypokalemia, and other electrolyte changes.  Also aggravates diabetes.

Loop diuretics- usually less effective than thiazide diuretics in the TX of HTN pts, with normal renal function.  Loop diuretics are usually reserved for use in hypertensive pts who have poor renal function and a serum creatinine > 2.3mg/dl.

            Adverse effects- same as Thiazides.

K+ sparing diuretics-exert mild naturemic and antihypertensive effects.  Also decrease renal K+ excretion and thereby prevent hypokalemia, a common problem caused by other diuretics.

            Adverse effects- Hyperkalemia

Anonymous Brenner 90-92

•        Hydrochlorothiazide- Is the thiazide diuretic that is most commonly used for the treatment of HTN.  The thiazide and related diuretics reduce blood pressure by two mechanisms, both stemming from their ability to increase sodium and water excretion.  With continued administration over weeks and months, they also decrease PVR, and this appears to account for much of their long-term antihypertensive effect.

•        Furosemide- Despite their greater natriuretic effect of the loop diuretics, they usually are less effective than thiazide diuretics in patients with normal renal function.  In patients with poor renal function, loop diuretics like furosemide continue to function while thiazide diuretics lose their effect.

•        Spironolactone/triamterene- These potassium-sparing diuretics exert mild natiuretic and antihypertensive effect.  They reduce renal potassium excretion and thereby prevent hypokalemia, a common problem caused by other diuretics.

Anonymous  Brenner pg. 90 and 93

Thiazide diuretics (hydrochlorothiazide) have a moderate natriuretic effect and are the diuretics most frequently used for HTN.

Loop diuretics (furosemide) have the greatest natriuretic effect, may be used for HTN when a thiazide is not effective or contraindicated.

Potassium-sparing diuretic (spironolactone, triamterene) have a relatively low natriuretic effect and are generally used in combo. with a thiazide or loop diuretic, to reduce potassium excretion and prevent hypokalemia.

Adverse effects: (Both loop and thiazide diuretics) - blood cell deficiencies, hyperlipidemia, hyperuricemia, hypokalemia, other electrolyte changes and aggravation of DM.  Potassium sparing diur. - hyperkalemia

3.         Describe the role of beta-blockers in the treatment of hypertension.  (representative drugs: propranalol, atenolol)   (Note: beta-blockers are also used for the treatment of angina, cardiac arrhythmias, and reduction of post-MI mortality; see objectives for CHF/Angina Drugs.  

Megan B. Brenner 94

Β-blockers produce their therapeutic effects in patients with HTN and other C/V diseases by blocking

β₁-adrenergic receptors in the heart and other tissues.  This reduces cardiac output by decreasing the heart rate and contractility.  The β-blockers inhibit rennin secretion from renal juxtaglomerular cells, and this in turn reduces the formation of angiotensin II and the subsequent release of aldosterone.  The drugs also appear to reduce sympathetic outflow from the CNS.  Β-blockers have multiple actions affecting blood pressure.

Atenolol- cardioselective β₁

Propranalol- non-selective β blocker

Kim R. Brenner pg 94

These are relatively safe and effective in most pts and are particularly useful in pts who suffer from angina or a hx of MI.  These drugs are cardioprotective and only rarely cause orthostatic hypotension or produce hepatic, renal, or hematopoietic toxicity.

**Beta-blockers provide effective single-dose therapy for many pts with mild HTN and can be combined with other drus to TX more severe forms of HTN.  Decreased cardio output, decreased HR, decreased contractility.

**inhibit rennin secretion from renal juxtaglomerular cells, and this in turn reduces the formation of angiotensin II and the subsequent release of aldonsterone.

Anonymous Brenner 81,82,94

            The Beta-blockers are widely employed in the treatment of hypertension because they are relatively safe and effective in most patients and are particularly useful in patients who suffer from angina or have a history of MI.  The drugs are cardioprotective and only rarely cause orthostatic hypotension or produce hepatic, renal, or hemopoietic toxicity.  The nonselective beta-blockers were in clinical use first.  In addition to blocking Beta 1 receptors in the heart and other tissues, they block beta 2 receptors in smooth muscle, liver, and other tissues. An example of this is propranolol.  Selective beta-blockers like atenolol (blocks beta one receptors) have become more useful in patients with diabetes and asthma. Antagonism of beta 2 receptors may cause bronchoconstriction in the asthmatic and slow the recovery of blood glucose after a hypoglycemic episode in a diabetic.  For this reason, Beta-blockers should be used cautiously in diabetics and particularly in those who are insulin dependant.

Anonymous  

The non-selective beta-blocker –propanolol blocks both beta 1 and beta 2 receptors. Beta 1 blockade reduces sympathetic stimulation of the heart and reduces heart rate and contractility. In the kidneys-beta 1 blockade reduces renin secretion. Blockade of beta 2 receptors in the lungs reduces the vasodilating effects of epinephrine( this is why non-selective beta blockers are not good in pts. with asthma) Brenner 82-83

Atenolol is a selective beta 1 blocker and therefore has all the same properties of propanolol w/o the effects on beta 2 receptors. Both of these drug work by decreasing cardiac output(sympathetic stimulation blockade) and reducing the formation of angiotensin II which increases peripheral resistance. These drugs are considered good single-drug therapy for mild hypertension. They are also cardio-protective because they decrease the cardiac workload.( Brenner 94)

4.         List or recognize important adverse effects of beta-blockers.

Megan B. Brenner 93

Common adverse effects: Bradycardia, bronchoconstriction, depression, fatigue, impaired glycogenolysis, and vivid dreams

Kim R. Brenner pg 93

Bradycardia, bronchconstriction, depression, fatigue, impaired glycogenolysis, and vivid dreams.

Anonymous Brenner 93

Anonymous  Archives of Internal Med p.2425

More serious: Bronchospasm, bradycardia, Heart failure, may mask insulin-induced hypoglycemia, and may promote developmental of type 2 diabetes in some pts w/ HTN.

Less serious: impaired peripheral circulation, insomnia, fatigue, impotence, Raynaud’s phenomenon, delirium, decreased exercise tolerance, hypertriglyceridemia (except – agents w/ intrinsic sympathomimetics activity)

Common Adverse effects: Bradycardia, bronchoconstriction, depression, fatigue, impaired glycogenolysis, and vivid dreams. Brenner p. 93

5.         Discuss the advantages and disadvantages of combination alpha- and beta- blockers.  (representative drug: labetalol)

Megan B. Brenner 94 CMDT 419

Labetalol- a combined α and β adrenergic receptor antagonist is used to treat both chronic HTN and hypertensive emergencies.  Because of its α- adrenergic receptor- blocking activity, it may cause orthostatic hypotension.

α:β blocking activity 1:3; more orthostatic hypotension, fever, hepatotoxicity

Kim R.  Brenner pg 94

Used to TX both chronic HTN and HTN emergencies.  May cause orthostatic hypotension due to alpha adrenergic blocking activity.

Anonymous  Brenner 84,94

            Labetalol is a nonselective beta-blocker and a selective alpha-one blocker that is primarily used in the treatment of HTN.  It is 5-10 times more potent as a beta-blocker than as an alpha-blocker.  Both actions are believed to contribute to its antihypertensive effect.  Labetalol decreases the heart rate and cardiac output as a result of beta-one receptor blockade, and it decreases PVR as a result of alpha-one receptor blockade.  Because of its alpha-one receptor blocking ability, it may cause orthostatic hypertension.

Anonymous  Brenner, p.84-85

Labetalol is a nonselective B-blocker and a selective A1-blocker that is used mostly for hypertension.  It is 5-10 x more potent as a B-blocker than an A-blocker, but both actions are believed to contribute to its antihypertensive effects by decreasing the heart rate and cardiac output as a result of B1 receptor blockade, and it decreases peripheral vascular resistance as a result of A1 receptor blockade.

6.         Describe the role of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension.  (representative drugs: captopril, enalapril, lisinopril Added 2004)  (Note:  ACE inhibitors are also used for the treatment of  CHF and nephroprotection in diabetes mellitus; see objectives for CHF/Angina Drugs.)

Stephen Brenner pg. 97

Drugs that inhibit ACE (angiotensin-converting enzyme) exert hypotensive effects by blocking the formation of a vasoconstrictor (angiotensin II) and by blocking the degradation of a vasodilator (bradykinin). Increased renal prostaglandin synthesis may also contribute to the hypotensive effects of these drugs.

The antihypertensive action of ACE inhibitors is primarily due to a reduction in PVR, with little or no change in cardiac output or blood volume. ACE inhibitors decrease both arterial and venous pressure.

…By reducing angiotensin-stimulated aldosterone secretion, ACE inhibitors prevent the compensatory increase in sodium retention…

Anonymous Brenner 97

            The antihypertensive action of ACE inhibitors is primarily due to a reduction in PVR, with little or no change in cardiac output or blood volume.  ACE inhibitors decrease both arterial pressure and venous pressure, and this in turn reduces cardiac afterload and cardiac preload, respectively.  Adverse effects- Ace inhibitors may cause fetal and neonatal morbidity and mortality when administered to pregnant women, particularly during the second and third trimesters.  They may cause renal failure in patients who have bilateral renal artery stenosis.  The most common side effect is a dry, irritating, and nonproductive cough, which occur in about 20% of patients.  10% of patients develop a pruritic rash.

Anonymous  Brenner 97

Remember that renin is released from the kidneys and acts to convert angiotensinogen to angiotensin I.  Angiotensin I is converted to the active vasoconstrictor angiotensin II by means of an enzyme appropriately called angiotensin-converting enzyme (ACE).  So, ACE inhibitors prevent the conversion of angiotensin I to angiotensin II which has a vasodilating (hypotensive) effect.  The antihypertensive action of ACE inhibitors is primarily due to a reduction in peripheral vascular resistance (PVR), with little or no change in cardiac output or blood volume.  ACE inhibitors decrease both arterial pressure and venous pressure, and this in turn reduces cardiac afterload and cardiac preload, respectively.  Angiotensin II will also stimulate aldosterone secretion at the adrenal cortext.  Remember that aldosterone will increase sodium plasma concentration and decrease potassium plasma concentration.  So, if there is no angiotensin II, there is no aldosterone, which means in patients treated with ACE inhibitors, renal sodium retention is decreased, renal potassium retention is increased (about 0.5mEq/L).  

7.         List or recognize important adverse effects, contraindications, and drug interactions of the ACE inhibitors.

Stephen Brenner pg 97

ACE inhibitors may cause fetal and neonatal morbidity and mortality when administered to pregnant women, especially during the second and third trimesters.

…may cause renal failure in patients who have bilateral renal stenosis, because these patients depend on angiotensin II to maintain renal blood flow and glomerular filtration.

In most other patients, ACE’s are well tolerated, andepidemiologic studies have shown that they do not adversely affect the life-style of patients as much as some other types of anti-hypertensive drugs do. The most common side effect is a dry, irritating, and non-productive cough, which occurs in up to 20% of patients and may be due to increased bradykinin levels.

Pg 98 Thiazide and loop diuretics augment the action of ACE inhibitors.

…may also interact with K+-sparing diuretics and K+ supplements to increase serum K+ levels significantly and cause hyperkalemia.

…may increase serum levels of lithium and produce lithium toxicity…

…ibuprofen may impede effects of ACE inhibitors.

Anonymous Brenner 93

Anonymous  

Adverse effects- most common is dry, irritating, nonproductive cough. Most serious are fetal/neonatal morbidity/mortality (in preg.). renal failure in pts with bilateral renal artery stenosis, angoiedema, neutropenia. Rare are pruritic rash and abnormal taste sensation.

Contraindications- pregnancy, bilateral renal artery stenosis.

Drug interactions- diuretics (increased risk of hypotension and renal failure), potassium supplements or potassium-sparing diuretics (increased risk of hyperkalemia), lithium (increased serum lithium level), NSAIDS (decreased effectiveness of ACE inhibitor). Brenner, pp 97-98

8.         Describe the potential advantages and disadvantages of angiotensin II receptor blockers (ARBs) in the treatment of hypertension.  (representative drug: losartan)

Stephen Brenner pg 98

ARBs, like Losartan, appear to be as effective as the ACE inhibitors but only rarely cause the chronic cough that is frequent with ACE’s.

ARBs are relatively free of other adverse effects, and the vast majority of patients tolerate them well.

They do not increase serum glucose, uric acid, or cholesterol levels.

Occasional…results of…hyperkalemia, neutropenia, and elevated hepatic aminotransferase enzymes.

Like the ACE’s, ARB’s may cause fetal injury and death and should not be used during pregnancy.

Anonymous Brenner 98

            Angiotensin receptor antagonists block the angiotensin II Type I receptors in vascular smooth muscle and in the adrenal cortex, thereby causing vasodilatation and decreasing aldosterone secretion.  In the treatment of HTN, these drugs appear to be as effective as the ACE inhibitors but rarely cause the chronic cough that is a frequent problem with ACE inhibitors.  These drugs are tolerated vary well by the vast majority of patients.  Some side effects include hyperkalemia, neutropenia, and elevated serum levels of hepatic aminotransferase enzymes.  Like the ACE inhibitors, they should not be given to pregnant women

Anonymous  

Advantages- appear as effective as ACE inhibitors, but without the cough. Fewer side effects and better tolerated by patients. (Brenner, p. 98)

Disadvantages- Hyperkalemia, neutropenia and elevated AST (Brenner, p. 99). According to JNC VI, angiotensin II receptor antagonists lack data regarding long-term cardiac and renal protection and therefore should only be used in patients who cannot tolerate ACE inhibitors. (Archives of Internal Medicine, The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, p 2424)

9.         Describe the role of calcium-channel blockers in the treatment of hypertension. (Note:  calcium channel blockers are also used for the treatment of angina and cardiac arrhythmias; see objectives for CHF/Angina Drugs.)

Stephen Brenner pg 99

By blocking CA++ ion channels in the plasma membranes of smooth muscle, the CA++ channel blockers relax vascular smooth muscles and thereby cause vasodilation. CA++ channel blockers have a greater effect on arterial smooth muscle than on venous smooth muscle, and their effect on BP is primarily due to a reduction in the PVR, with relatively little impact on venous capacitance, cardiac filling pressure, and cardiac output. Some studies indicate that CA++ channel blockers have a natriuretic effect that may contribute to their ability to lower BP.

Anonymous Brenner 99, Goroll- management of hypertension

By blocking calcium ion channels in the plasma membranes of smooth muscle, the calcium channel blockers relax vascular smooth muscle and thereby cause vasodilation. Calcium channel blockers have a greater effect on arteriolar smooth muscle than on venous smooth muscle, and their effect on blood pressure is primarily due to a reduction in PVR (peripheral vascular resistance), with relatively little impact on venous capacitance, cardiac filling pressure, and cardiac output. Their mild natriuretic (anti-sodium retention) effect makes them useful for African-American and elderly patients.

Goroll says calcium channel blockers are useful in patients with volume overload hypertension (African-americans, elderly) and those with angina (though not proven cardioprotective). Brenner says they are useful in all forms of hypertension particularly African heritage and those with asthma.  Use cautiously in patients with heart failure or conduction defects, especially if already taking a beta-blocker.  Avoid in patients bothered by peripheral edema. Prescribe a sustained release preparation except in patients with concurrent coronary disease to reduce costs.

Anonymous   Brenner p. 99

By blocking calcium ion channels in the plasma membranes of smooth muscle, the calcium channel blockers relax vascular smooth muscle and thereby cause vasodilation (arteriolar > venous) and their effect on BP is primarily d/t a reduction in PVR, with very little impact on venous capacitance, cardiac filling pressure, and CO. Possible natriuretic effect that may contribute to lowering of BP. They are effective in all forms of HTN. They do not alter levels of serum glucose, lipids, uric acid, or electrolytes and are relatively free of adverse effects and therefore are particularly useful in treating patients with asthma and African Americans. diltiazem and verapamil also have a significant effect on cardiac tissue and reduce HR in some patients.

10.       Distinguish between dihydropyridines and nondihydropyridines, and describe their most important adverse effects.  (representative drugs:  nifedipine, amlodipine, diltiazem, verapamil)  

Stephen Brenner pg 99

Nifedipine and amlodipine belong to the dihydropyridine class, and have relatively little effect on cardiactissue at usual therapeutic levels; however, they may evoke reflex tachycardia, and some of them have been reported to suppress cardiac contractility in patients with heart failure.

Diltiazem and verapamil belong to the nondihydropyridine class a have a significant effect on cardiac tissue, as well as reduce the heart rate in some patients.

Anonymous Brenner 99

Non-dihydropyridines include diltiazem and verapamil (these have a greater direct effect on the cardiac tissue and reduces the heart rate).  Adverse effects include AV block, bradycardia, dizziness, nausea, HA, and heart failure.  Drugs increase serum levels of tegretol, digoxin, and theophylline; decrease lithium levels.  Verapamil can cause constipation

Dihydropyridine class (amlodipine, felodipine, isradipine, nicardipine, and nifedipine).  This class may evoke reflex tachycardia and suppress cardiac contractility in patients with heart failure.  Adverse effects include dizziness, edema, HA, and tachycardia.  Levels can be increased by azole antifungal agents, cimetidine, and grapefruit juice.

Anonymous   goroll 157

Dihydropyridines-

Nifedipine- is a  potent vasodilator but causes little net reduction in inotropy.  Main drawbacks- reflex tachycardia and peripheral edema secondary to venodilating effects, headache, flushing and esophageal reflux

Amlodipine—newer,promoted as cardiofriendly. Produce little reflex tachycardia , negative inotropy or peripheral edema

Nondihydropyridines-  

Verapamil—main disadvantage is negative inotropy and conduction system disturbances leading to arterioventricular nodal block and bradycardia.  It should not be used in pts. with heart failure or suspected conduction system disease.  Constipation, headache and dizziness can occur.  Leg edema is usuaaly not a problem unless heart failure worsens.

Diltiazem- falls between nifedipine and verapamil having negative effects on inotropy and conduction but less likely than nifedipine to cause leg edema.

11.       Describe why short-acting calcium-channel blockers are not recommended for treatment of hypertension.

Jennyb Current 342, Brenner 107

            Current states that short acting CC blockers like nifedipine actually may increase ischemia and mortality.  Brenner states T-type CC blockers or transient type CC blockers are low voltage and are rapidly inactivated.  The only T-type approved was Mibefredil and that was pulled due to potentially dangerous drug interactions.

Anonymous

Immediate-release nifedipine has precipitated ischemic events and may increase cardiac mortality in patients who’ve had an MI…so use with great caution, if at all.  There have been inconsistent reports regarding adverse health effects of short-acting or immediate-release formulations of nifedipine, diltiazem HCL, and verapamil HCL.

Anonymous  Brenner, Ch 11, pp. 107

In retrospective case-control studies, investigators found a higher incidence of myocardial infarction, congestive heart failure, and deaths due to coronary heart disease in the group of patients who took immediate-release forms of nifedipine and other short-acting CCBs than in the control groups.

12.       Describe the role of alpha₁-blockers in the treatment of hypertension.  (representative drug: prazosin)

Jennyb Current 428

            These drugs block postsynaptic alpha receptors, relax smooth muscle, and reduce blood pressure by lowering peripheral vascular resistance.

Anonymous

Alpha blockers act to inhibit sympathetic stimulation of arteriolar contraction. Selective alpha 1-blockers are preferred for the treatment of chronic essential hypertension because they produce less tachycardia than do nonselective alpha blockers. They may cause fluid retention and are frequently given in combination with a diuretic. Because they affect both the arterial and venous systems they cause less reflex tachycardia than pure arterial vasodilators. They are useful in patients with concomitant BPH and  hypercholesterolemia

Anonymous  Brenner Chp. 9, 10

Alpha1-blockers such as prazosin are selective adrenergic receptor antagonists. They relax vascular + other smooth muscle such as urinary bladder + prostate. They are vasodilators decreasing BP, + are used in the treatment of chronic primary hypertension. They cause less reflex tachycardia than non-selective a1-blockers. They are second-line drugs used when preferred beta-blockers are ineffective or contraindicated. They are often given in combination w/ a diuretic because a1-blockers activate the renin-angiotensin-aldosterone system + may cause fluid retention.

FYI: prazosin is also used in treating urinary retension due to benign protatic hyperplasia. Brenner p.80

13.       Identify the first dose phenomenon that can be seen with alpha₁-blockers.

Jennyb Current 428

            First dose phenomenon may cause marked hypotension and syncope.

Anonymous

The first dose phenomenon is profound postural hypotension leading to syncope occurring one to three hours after the initial dose, especially in elderly patients and those taking diuretics. This can be avoided by starting with a low dose at bedtime and instructing the patient to stay supine for at least three hours. If the patient is on a diuretic this can be prevented by beginning treatment with a low dose of the blocker at bedtime and withholding the diuretic for one day.  

Anonymous  

The selective alpha1 blockers (doxazocin, prazocin, and terazocin) causes:

-Vasodilatation

-Decrease vascular resistance

-Decrease blood pressure

-Relaxes bladder neck and prostate

-Are preferred to treat chronic essential hypertension because they produce less tachycardia than do nonselective alpha-blockers

First dose phenomenon:

Alpha 1- blockers activate the renin-angiotensin –aldosterone system and may cause some fluid retention. So, they are frequently given in combination with a diuretic. The use of selective alpha1- blocker and a diuretic cause first-dose syncope in some patients, but beginning treatment with a low dose of the blocker at bedtime and withholding the diuretic for one day can prevent this.

14.       Recognize methyldopa and clonidine as examples of centrally acting sympatholytic drugs.  List or recognize important adverse effects of these drugs.

Jennyb Current 428

            Adverse effects include:  sedation, fatigue, dry mouth, postural hypotension, and impotence.

Anonymous Brenner94

Sympatholytics are alpha 2 agonists that reduce CNS outflow.  They lower the blood pressure primarily by causing a reduction in PVR while the heart rate and cardiac output are either reduced or remained unchanged. Can cause sedation, dry mouth, and other CNS side effects as well as heart block and bradycardia. Sedative effects may subside after a few weeks.

Anonymous    Brenner, pgs. 94-6

            Examples of centrally acting sympatholytics that are used in the treatment of HTN are clonidine and methyldopa.  These agents are a₂-adrenergic receptor agonists that reduce sympathetic outflow from the brain stem to the heart, blood vessels, and other tissues.  They lower blood pressure primarily by causing a reduction in PVR while the heart rate and cardiac output are either reduced or remain unchanged.  Since tricyclic antidepressant drugs can block the effects of centrally acting sympatholytic drugs, the two classes of drugs should not be used concurrently.

            Sedation, dry mouth, and other CNS side effects of centrally acting sympatholytics may be problematic in HTN patients whose work requires mental alertness, as well as in those who are elderly or have neurologic diseases.  In many cases, the sedative effects subside after a few weeks of treatment, so discontinuation of the drug is not necessary.  Because severe rebound HTN may occur if the drug is discontinued abruptly, the dosage should be tapered gradually over 1-2 weeks if treatment is to be stopped.

            Methyldopa is well known for its ability to cause immunologic effects, including a Coombs-positive hemolytic anemia (reported in up to 2% of patients), autoimmune hepatitis, and other organ dysfunction.  Methyldopa is often preferred for the treatment of HTN in pregnant women, since long experience has shown that it does not harm the fetus.

15.       Identify hydralazine, minoxidil, and sodium nitroprusside as direct vasodilators.  Identify the latter as a parenteral agent used in the treatment of hypertensive emergencies.

Jennyb Brenner 100, Current 432

            These drugs relax vascular smooth muscle and produce peripheral vasodilation.  Sodium nitroprusside lowers the blood pressure within seconds once given by direct arterial and venous dilation.

Anonymous.Brenner100

Hydralazine and minoxidil are orally effective vasodilators that are primarily used in combination with other anti-hypertensive drugs (diuretic plus either a β-blocker or other sympatholytic agent) for the treatment of moderate to very severe HTN.  When used alone, they evoke reflex tachycardia and cause fluid retention; they can also precipitate angina.

            Nitroprusside is used parenterally in the management of hypertensive emergencies because it effectively reduces the patient’s blood pressure to a safe level.  It has a short half-life and is rapidly metabolized to cyanide and then thiocyanate, which can become toxic.

Anonymous    Brenner pg. 100

Hydralazine and minoxidil are primarily used in combination with other antihypertensive drugs for the treatment of moderate to very severe hypertension.  When used alone, they often evoke reflex tachycardia, cause fluid retention, and may precipitate angina in patients who are susceptible. To prevent these problems, they are usually given in combination with either a diuretic plus either a B-adrenergic receptor antagonist or another sympatholytic agent.   Hydralazine has been assoc. with a lupuslike syndrome. Minoxidil may cause hypertrichosis (excessive hair growth), especially in women.

Nitropusside is commonly used in the management of hypertensive emergencies because it effectively reduces the patient’s blood pressure to a safe level.  The duration is limited to only a few days.

16.       Discuss the reasons why either a thiazide diuretic or a beta-blocker are the usual first choice drugs for patients who need pharmacologic therapy for hypertension.

Zen Seeker

Summary

            CMDT 2003 429

Because the most extensive and most favorable experience in randomized control trials has been with diuretic-based and, to a lesser extent, beta-blocker-base regimes, these should be the initial agents for the majority of uncomplicated hypertensives.  Figure 11-1 summarizes results achieved with these agents in clinical trials.        

Thiazide Brenner 90-92

            The thiazide and related diuretics reduce blood pressure by two mechanisms, both stemming from their ability to increase sodium and water excretion.  When they are first administered to a patient, the drugs decrease blood volume and thereby decrease cardiac output (fig 10-2 and table 10-2) continued administration over weeks and months, they also decrease PVR (peripheral vascular resistance), and  this appears to account for much of their long-term antihypertensive effect.  The decreased PVR may be due to a reduction in the sodium content of arteriolar smooth muscle cells, which decreases muscle contraction in response to vasopressor agents such as norepinephrine and angiotensin.  This relationship is supported by the finding that the effect of a thiazide on PVR is reduced if patients ingest enough dietary sodium to counteract the natriuetic effect of the drug.

            Use of a thiazide typically reduces the blood pressure by 10-15 mm Hg.  Hydrochlorothiazide is the thiazide diuretic that is most often used for treating hypertension.  Indapamide, metolazone, and other thiazide-related diuretics have equivalent efficacy in the treatment of hypertension and differ primarily in their pharmacokinetic properties.  Indapamide may also cause vasodilation via calcium channel blockade.

            For may patients with mild hypertension, single-drug therapy with a thiazide provides ecumenical and effective treatment.  For patients with moderate to severe hypertension, a thiazide diuretic may be used in combination with another type of antihypertensive agent (such as a sympatholytic, an angiotensin inhibitor, or a vasodilator).  The two drugs usually have a additive effect, and the thiazide prevents the compensatory fluid retention that may otherwise be evoked by the other agent.

Β-blocker Brenner 94

            The β-blockers are widely employed in the treatment of hypertension because they are relatively safe and effective in most patients and are particularly useful in patients who suffer from angina or have a history of myocardial infarction.  The drugs are cardioprotective and only rarely cause orthostatic hypotension or produce hepatic, renal, or hematopoietic toxicity.  For these reasons, β-blockers provide effective single-drug therapy for many patients with mild hypertension and can be combined with other drugs to treat more severe forms of hypertension.

            The β-blockers produce their therapeutic effects in patients with hypertension and other cardiovascular diseases by blocking β₁-adrenergic receptors in the heart and other tissues.  This reduces cardiac output by decreasing the heart rate and contractility.  The β-blockers inhibit rennin secretion from renal juxtaglomerular cells, and this in turn reduces the formation of angiotensin II and the subsequent release of aldosterone.  The drugs also appear to reduce sympathetic outflow from the central nervous system (CNS).  Hence, β-blockers have multiple actions affecting blood pressure.

            “Drugs for Hypertension,” Medical Letter, Vol. 43, #1099 March 5, 2001, pp. 17-22.

CHOICE OF DRUGS — The best tolerated drugs for treatment of hypertension are diuretics (particularly in low doses) and angiotensin II receptor antagonists. Beta-adrenergic blockers, ACE inhibitors and calcium-channel blockers generally have mild adverse effects. Diuretics alone and together with beta-blockers have been shown in large-scale clinical trials to decrease mortality in patients with hypertension (JNC VI, Arch Intern Med 1997; 157:2413). Some Medical Letter consultants believe calcium-channel blockers should be reserved for patients who do not respond to or cannot tolerate diuretics, beta-blockers, ACE inhibitors or angiotensin II receptor antagonists.

            In special categories of patients, one type of drug may offer advantages. ACE inhibitors should be considered in patients with diabetes, particularly with nephropathy, and in those with heart failure or left ventricular dysfunction. A beta-blocker may be the best choice for hypertensive patients with angina pectoris or migraine, for those who have had a myocardial infarction and for some patients with heart failure. For patients with hyperlipidemia, an ACE inhibitor, alpha-blocker or calcium-channel blocker might be a good choice. Diuretics and calcium-channel blockers are more effective than beta-blockers, ACE inhibitors or angiotensin II receptor antagonists in African-Americans. A diuretic with or without a beta-blocker, or a long-acting dihydropyridine calcium-channel blocker, is preferred in older patients with isolated systolic hypertension.

DIURETICS — Diuretics have been shown to decrease mortality in patients with hypertension. Thiazide diuretics have been shown to reduce the incidence of stroke and cardiovascular events in elderly patients with isolated systolic hypertension (SHEP Cooperative Research Group, JAMA 1991; 265:3255). Many thiazide-type diuretics are used to treat hypertension; hydrochlorothiazide and chlorthalidone are the most widely used. Metolazone and indapamide may be effective in patients with impaired renal function when thiazides are not. Many patients, particularly older ones, can be treated with small doses of diuretics equivalent to 12.5 mg to 25 mg of hydrochlorothiazide once daily. Doses as low as 6.25 mg are now used to enhance the effectiveness of other drugs while minimizing adverse effects such as hypokalemia. Loop diuretics can be used to treat hypertension in patients with renal insufficiency (creatinine clearance below 30 to 50 ml/min). In patients without renal insufficiency, they may be less effective than thiazides for treatment of hypertension.

BETA-ADRENERGIC BLOCKING DRUGS — Beta-blockers are effective for treatment of hypertension, but, like ACE inhibitors, may be less effective in African-American patients. A beta-blocker alone appears to be less effective than a diuretic alone for the treatment of hypertension in the elderly.

            Propranolol, timolol, nadolol, pindolol, penbutolol, and carteolol are ‘‘nonselective’’ beta-blockers; in low doses bisoprolol, atenolol, metoprolol, acebutolol and betaxolol are ‘‘cardioselective,’’ with a greater effect on cardiac (beta1) adrenergic receptors than on beta2-adrenergic receptors in bronchi and blood vessels. These drugs become less selective as dosage is increased, and even low doses may cause bronchospasm. Pindolol, acebutolol, penbutolol, and carteolol have intrinsic sympathomimetic activity (ISA) and unlike other beta-blockers generally do not increase serum triglyceride concentrations or decrease HDL cholesterol. In addition, beta-blockers with ISA can lower blood pressure with less decrease in heart rate at rest and may be preferred for patients who develop symptomatic bradycardia or postural hypotension with other beta-blockers. Beta-blockers without ISA are preferred in patients with angina pectoris or a history of myocardial infarction.

            Labetalol combines nonselective beta-blockade and minimal ISA with alpha-adrenergic receptor blockade. It decreases blood pressure more promptly than other beta-blockers, is equally effective in African-American and Caucasian patients, and does not affect serum lipids. Carvedilol is also both an alpha- and a nonselective beta-blocker, but has no ISA. It has been promoted more for treatment of heart failure than for treatment of hypertension (Medical Letter 1999; 41:13).

Anonymous Goroll, 151

These agents are the only drugs to date demonstrating significant reductions in cardiovascular morbidity and mortality in large-scale, prospective, randomized, controlled trials.  Not only are they of proven efficacy, but their cost is low.

Anonymous  

Based on evidence from several random control trials, there have been shown a significant reduction in morbidity and mortality with these agents. Very low doses of a diuretic can potentiate the effect of the other agent without producing adverse metabolic effects. They state there needs to be a compelling or specific indication for another drug if a different therapy is to be chosen.

17.       List or recognize common causes of failure to respond to drug therapy of hypertension.

Zen Seeker CMDT 2003 431

Patients who are compliant with their medications and who do not respond to these combinations should usually be evaluated for secondary hypertension before proceeding to more complex regimens.

            Brenner 100

A large number of effective antihypertensive medications are available, and their selection is primarily based on their adverse effect profile, contraindications, cost and convenience to the patient.  Because hypertension is usually asymptomatic, even minor side effects may decrease the patient’s compliance and blood pressure control.  For this reason, it is important to select a drug that is both effective and well tolerated.

            Noble 524 http://home.mdconsult.com/das/book/body/0/959/405.html#top

Resistant Hypertension

Almost all patients with hypertension can achieve good blood pressure control with minimal side effects, although a few patients may persistently have unacceptably high diastolic pressures (diastolic blood pressure greater than 105 mm Hg). For these patients, consider the following:

Poor Adherence to Drug Regimen.

Nonadherence to drug therapy is probably the major cause of poor blood pressure control. An estimated 50% of patients take less than 80% of their prescribed antihypertensive pills (see below).

Sodium Retention.

Patients who take one or more nondiuretic antihypertensive agents often have reflex sodium retention. Adding a diuretic (or using a more potent one) and reemphasizing the need for a low-sodium diet may improve blood pressure control.

Excessive Alcohol Intake.

If the hypertensive patient has a substantial alcohol intake, physicians should encourage total abstention from alcohol for 4 to 6 weeks while monitoring changes in blood pressure.

Secondary Hypertension.

Refer to the previous section on secondary hypertension for screening evaluations and taking a medication history.

Substitute More Potent Antihypertensive Agents.

For example, substitute minoxidil or an ACE inhibitor for hydralazine.

Close observation is essential for patients with resistant hypertension. Physicians should evaluate these patients for causes of secondary hypertension and carefully monitor the drug regimen and diet. A few patients may require hospitalization to control their blood pressure. Most patients experience a fall of 5 to 15 mm Hg in diastolic blood pressure during hospitalization, but this does not necessarily reflect increased drug effect. Occasionally, poor adherence can be diagnosed if there is a substantial blood pressure fall to almost hypotensive levels when the patient is hospitalized and continued on the prescribed medication.

Noncompliance with Treatment

Diagnosing poor compliance can be difficult and requires a frank, nonjudgmental exploration with the patient about pill-taking habits. Physicians may preface this discussion by acknowledging that pills are expensive, symbolic of illness, sometimes accompanied by unpleasant side effects, and, for many people, including physicians, difficult to take as prescribed. Another helpful approach is to identify the time of day when the patient takes medications and to review the exact number of pills taken during the previous 24 hours. Compliance occasionally may be assessed clinically or biochemically because some antihypertensive agents cause predictable physiologic effects. For example, beta-blockers consistently decrease pulse, and thiazide diuretics consistently increase uric acid and usually decrease serum potassium.

Some methods that may improve adherence include:

1. Educating patients. Communicate clear target goals for blood pressure and discuss in a nonthreatening way the consequences of high blood pressure and the benefits of treatment. Emphasize that treating high blood pressure does not generally make patients feel better but, rather, is designed to prevent morbidity and mortality.

2. Encouraging patients to report side effects. Acknowledge that unpleasant side effects can occur during drug therapy and select an acceptable treatment regimen. Ask patients specifically about side effects they may be reluctant to voluntarily discuss, such as sexual dysfunction or the expense of treatment.

3. Simplifying drug regimens. Ask if once-a-day therapy would be easier than twice-a-day therapy. If so, use long-acting preparations that provide adequate 24-hour control.

4. Providing simple, written instructions about dosage and side effects. Review pill-taking habits with the patient. Recommend keeping pill bottles in a convenient location and emphasize the need to take pills at set times.

5. Improving the convenience of office visits and using other health care providers (e.g., nurses, physicians' assistants) to help with case management if feasible. Sending appointment reminders, having flexible scheduling hours, and contacting patients who have missed appointments help to improve adherence. Emphasize that high blood pressure may be a lifelong problem and that patients are responsible for returning for follow-up appointments and promptly refilling their medication. Give the patient shared responsibility for treatment and monitoring.

Anonymous Goroll, 158

• poor compliance

• excess alcohol intake

• obesity

• secondary causes of hypertension

• renal failure

• renovascular disease

Anonymous  

*noncompliance with drug regimen

*failure to sufficiently alter life style:

            i.e. --continued tobacco use

                 --insufficient weight reduction

                 --continued ETOH consumption

                 --sedentary

*failure of provider to prescribe an adequate drug regimen—i.e. ACEI + diuretics + B-blocker

18.       Based on comorbid conditions, identify drug classes that would be compelling or reasonable first choices in the following patient groups: (See CMDT, Table 11-10)

                        diabetes mellitus with proteinuria

                        heart failure

                        post-MI

                        isolated systolic hypertension

                        angina

                        atrial tachycardia, fibrillation

                        prostatism (BPH)

Zen Seeker CMDT 430

diabetes mellitus with proteinuria

            ACE I

heart failure

            ACE I, diuretics, β-Blockers

post-MI

            β-Blockers (non-ISA), ACE I (with systolic dysfunction)

isolated systolic hypertension

            Diuretics (preferred), calcium antagonists

angina

            β-Blockers, calcium antagonists

atrial tachycardia, fibrillation

            β-Blockers, calcium antagonists (nondihydropyridine)

prostatism (BPH)

            α-Blockers

Anonymous See JNC VI, Table 10

*Note – this is actually Table 9, Pg. 34 on this document; http://www.nhlbi.hih.gov/guidelines/hypertension/jnc6.pdf

• diabetes mellitus with proteinuria

  • ACE I

• heart failure

  • ACE I

  • diuretics

• isolated systolic hypertension

  • Diuretics (preferred)

  •  CA (long-acting DHP)

• myocardial infarction

  • Beta-blockers (non-ISA)

  • ACE I (with systolic dysfunction)

• Angina

  • Beta-blockers

  •  CA

• prostatism (BPH)

  • Alpha-blockers

Anonymous  See JNC VI, Table 10

diabetes mellitus with proteinuria                       ACE 1

heart failure                                                       ACE 1, diuretics

isolated systolic hypertension                 diuretics (preferred), CA (=calcium antagonists)

                                                                        example of CA: long acting DHP (dihydropyridine)

myocardial infarction                                         beta-blockers (non-ISA), ACE 1 (with systolic dysfunction)

angina                                                               beta-blockers, CA

prostatism (BPH)                                              alpha-blockers

*In general, hypertension in African Americans is more responsive to monotherapy with diuretics and calcium antagonists than to beta-blockers or ACE inhibitors.  However, if a beta-blocker or ACE inhibitor is needed for other therapeutic benefits, differences in efficacy usually can be overcome with reduction of salt intake, higher doses of the drug, or addition of a diuretic.  

- from JNC VI, 2427

19.       Based on comorbid conditions, identify drug classes that may have unfavorable effects in the following patient groups:  (See CMDT, Table 11-10)

                        bronchospastic disease

                        depression

                        diabetes mellitus

                        dyslipidemia

                        gout

                        second or third degree heart block

                        CHF

                        pregnancy

                        renovascular disease

Zen Seeker CMDT 430

bronchospastic disease

            β-Blockers⁴

depression

            β-Blockers, central α-agonists, rserpine⁴

diabetes mellitus

            β-Blockers, high-dose diuretics

dyslipidemia

            β-Blockers, (non-ISA), diuretics (high-dose)

gout

            Diuretics

second or third degree heart block

            β-Blockers,⁴ calcium antagonists (nondihydropuridine)⁴

CHF

            Calcium antagonist (except amlodipine), α-blockers, β-Blockers⁵

pregnancy

            ACE I,⁴ angiotensin II receptor blackers⁴

renovascular disease

            ACE I, angiotensin II receptor blockers

diabetes mellitus with proteinuria

            ACE I

***read:

⁴ Contraindicated

⁵ β-Blockers may worsen heart failure initially but are indicated in stable patients

Anonymous See JNC VI, Table 10

*Note – this is actually Table 9, Pg. 34 on this document; http://www.nhlbi.hih.gov/guidelines/hypertension/jnc6.pdf

• bronchospastic disease

  • Beta-blockers (contraindicated)

• Depression

  • Beta-blockers

  • Central alpha-agonists

  • Reserpine (contraindicated)

• Dyslipidemia

  • Beta-blockers (non-ISA)

  • Diuretics (high dose)

• Gout

  • diuretics

• second or third degree heart block

  • beta-blockers (contraindicated)

  • CA (non-DHP) contraindicated

• Pregnancy

  • ACE I (contraindicated)

  • Angiotensin II receptor blockers (contraindicated)

Anonymous  See JNC VI, Table 10

bronchospastic disease- Beta-Blockers

depression- Beta-blockers, central alpha-antagonists, reserpine

dyslipidemia- Beta-blockers (non-ISA), diuretics (high dose)

gout- diuretics

second or third degree heart block- Beta-blockers, calcium channel blockers (non-DHP)

pregnancy- ACE I, angiotensin II receptor blockers