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A. Angiotensin Physiology [26,27]

  1. Angiotensinogen is produced in the liver and other areas
    1. Converted to angiotensin I (10-mer) by renin, produced in the kidney
    2. Converted to angiotensin II (AT2; 8-mer) primarily by angiotensin converting enzyme (ACE)
    3. ACE is mainly produced in the kidney and lung
    4. ACE is also a potent bradykinin and Substance P degrading enzyme
    5. ACE is the primary, but not the only, enzyme capable of producing AT2
    6. Chymase in the heart produces significant local AT2 [1]
    7. ACE2, a carboxypeptidase, leads to production of angiotensin1-7 (7-mer; see below) [50]
  2. ACE Polymorphisms
    1. Insterion (I) and Deletion (D) alleles of ACE gene well described
    2. I allele confers low blood activity of ACE, D high blood activity
    3. Increased frequency of I alleles in people with enhanced endurance abilities
    4. Alleles are not linked to myocardial infarction or other coronary disease [25,30]
    5. Type I diabetic (DM1) patients with DD genotype have >3X risk of hypoglycemia [28]
    6. D allele correlated with increased risk for restenosis
    7. D allele associated with increased risk for systemic sclerosis [4]
    8. Quinapril given to DD patients after coronary stenting increased restenosis rates [29]
  3. AT2 is the Active Peptide [49]
    1. Three important receptors, AT2-R1, AT2-R2, AT2-R4 have been discovered
    2. Most vascular effects of AT2 (8 amino acids) are mediated through AT2-R1
    3. AT2-R1 found in kidney, heart, vascular smooth muscle, brain, platelets, placenta
    4. AT2-R1 also found in adrenal glands in the zona glomerulosa
    5. Binding to adrenal glands stimulates aldosterone secretion
    6. AT2-R2 important in fetal development, but levels decrease during growth
    7. AT2-R2 receptors may counterbalance AT2-R1 effects, inhibit cell proliferation
    8. AT2-R2 may stimulate nitric oxide induced vasodilation, block smooth muscle growth
    9. AT2 levels increased in congestive heart failure (CHF), some hypertension (HTN)
    10. AT2-R4 appears to be a growth factor receptor and may play a role in memory
  4. AT2 also regulates potassium (K+) homeostasis
    1. Aldosterone is the major hormone responsible for stimulating renal K+ excretion
    2. Hyperkalemia stimulates angiotensin II and aldosterone secretion
    3. Hypokalemia inhibits aldosterone secretion
  5. AT2 and Stress Pathways [1,37]
    1. AT2 increases oxidative stress in vasculature and target organs
    2. Interleukin 6 (IL6) and nuclear factor kappa B (NF-kB) increased
    3. Oxidative stress also increases transforming growth factor ß (TGFß) levels
    4. IL6 stimulates monocyte chemotactic protein 1 which is proinflammatory
    5. AT2 directly stimulates plasminogen activator inhibitor (PAI)-1 which is prothrombotic
    6. These effects lead to endothelial damage and enhance atherosclerotic damage
    7. They are particularly marked in patients with diabetes mellitus (DM)
    8. Prothrombotic and proinflammatory effects may also increase acute coronary events
  6. ACE Degrades Bradykinin (BK) [32]
    1. Kinins are peptide mediators of acute and subacute inflammation
    2. Stimulate production of nitric oxide and vasodilatory prostaglandins
    3. Cause vasodilation, vascular leak, pain and neurotransmitter release
    4. BK is degraded by ACE (preferred substrate)
    5. BK interacts with the angiotensin system to conteract AT2 effects
    6. BK may be protective against development of left ventricular (LV) hypertrophy (LVH) [33]
    7. Low expressor alleles of BK receptor (B2BKR) combined with ACE polymorphisms associated with specific levels of exercise induced LV hypertrophy
    8. Increased levels of BK with ACE inhibitors (ACE-I) likely cause associated cough
    9. ARB (angiotensin receptor blockers) also lead to increased BK, through feedback
  7. ACE Involved in Hematopoietic Stem Cell Proliferation [38]
    1. ACE degrades N-acetyl-Seryl-Aspartyl-Lysyl-Proline (NASDKP)
    2. NASDKP is a natural inhibitor of hematopoietic stem cell growth
    3. ACE-I may lead to increased NASDKP
    4. This may be beneficial in patients with polycythemia
    5. Anemia or other bone marrow effect is not a side effect of ACE-I
  8. ACE-I have clear cardio- and renal protective activities that have not all been demonstrated in AT2 blockers [21,27]
  9. Second ACE: ACE2 [50]
    1. Enzyme related to ACE, converts AT1 to angiotensin 1-9
    2. Angiotensin 1-9 converted to angiotensin 1-7 by ACE
    3. Angiotensin 1-7 is a blood vessel vasodilator
    4. ACE2 involved in cardiac development
  10. ACE-I combined with AT2 blockers safe and effective for maximal blockade [52,54]

B. Overview of ACE Inhibitors (ACE-I) [2,3,19]

  1. Primary Effects of ACE-I
    1. Reduction in AT2 levels
    2. Reduction in aldosterone levels
    3. Increase in bradykinin (BK) and Substance P (SP) and other peptides
    4. Blockade of BK receptors in ACE-I treated patients reverses hypotensive effects [1]
    5. Also reduces sympathetic overactivity in chronic renal failure [20]
    6. Unclear if this is related solely to AT2 level effects or other effects
    7. Minor differences between agents, although FDA approved labelling may differ
  2. Physiological Effects of ACE-I [27]
    1. Vasodilation: combination of reduced AT2 levels and increased BK
    2. BK probably plays as great a role as AT2 in blood pressure (BP) reduction with ACE-I [1]
    3. BK is also anti-atherogenic and stimulates nitric oxide production by endothelium [27]
    4. Reduction in aldosterone leads to reduced sodium but increased K+ retention
    5. Variable effects on volume: reduction in renal filtration versus reduced aldosterone
    6. May exacerbate renal artery stenosis, precipitating renal failure [8]
  3. Clinical Benefits
    1. Hypertension (HTN)
    2. Post-myocardial infarction (MI)
    3. Congestive heart failure (CHF)
    4. Left ventircular (LV) systolic dysfunction
    5. High risk cardiovascular (CV) disease
    6. Renal protection in diabetics with or without clinical renal dysfunction [81]
    7. Renal protection in some forms of non-diabetic renal dysfunction
    8. Atherosclerosis
    9. Proven mortality benefits in HTN [53], post-MI patients, and chronic CHF [16]
    10. ACE-I and ARB are similarly effective but ARB better tolerated, in HTN, CHF and after MI [13,45,56,80]
  4. HTN
    1. All agents are FDA approved for treatment of HTN
    2. ACE-I and ARB have similar efficacy in HTN
    3. Combinations of ACE-I and ARB show more BP reduction than either alone []
    4. ACE-I have higher incidence of cough and angioedema than ARB [80]
  5. Post- or Peri-MI
    1. Enalapril also reduces mortality in general LV systolic dysfunction [55]
    2. ACE-I given early or late after MI clearly reduce 30-day and 1 year mortality [67]
  6. CHF and LV Dysfunction
    1. Reduces deleterious ventricular remodelling
    2. Improves outcomes in CHF patients with LV systolic dysfunction
    3. Good reduction in LV mass in patients with LVH [1,58]
  7. High Risk for CV Disease
    1. Reduce serious vascular events in patients with atherosclerosis and normal systolic function [57]
    2. Probably reduce risk for atherosclerotic progression and acute coronary events [37]
    3. Ramipril reduced mortality in patients with high risk of cardiovascular (CV) disease [23]
    4. Telmisartan (ARB) equivalent to ramipril in reducing mortality and CV events in patients at high risk for vascular events; no benefit to combination of both [58]
    5. In patients with CHF, ARB or ACE-I reduced development of atrial fibrillation (AFib) [1]
    6. ACE-I associated with ~18% reduced risk of aortic aneurysm rupture versus other antihypertensives including AT2 blockers [11]
  8. Renal Protective Activities
    1. Provide renal protection in diabetes mellitus (DM1 and DM2) [81]
    2. Clear slowing of progression in non-diabetic chronic renal failure (CRF) [6]
    3. ACE-I (or ARB) should be given to any patient with type 2 DM [22]
    4. Beneficial on renal disease in sickle cell anemia
  9. Monitoring ACE-I Therapy
    1. In some patients, high BK/SP levels lead to a cough (may have to stop drug)
    2. All patients initiating ACE-I therapy should have renal functioning monitoring
    3. All patients initiating ACE-I therapy should have K+ levels measured
    4. Serum B-type Natriuretic Peptide levels can be used to follow cardiac function in patients with heart failure receiving ACE-I [43]
    5. ACE-I + aspirin is safe and effective and is not contraindicated [48]
  10. ACE-I or ARB Use in CRF
    1. Use caution with glomerular filtration rate (GFR) < 20mL/min [54]
    2. Clear benefit on slowing progressin of CRF with GFR >15mL/min [6]
    3. Monitoring renal function is critical (as above)
    4. K+ levels and renal function should be evaluated within 1 week of ACE-I initiation

C. Specific ACE-I [2,3]

  1. Captopril (Capoten®) [18]
    1. Half life (T1/2) ~ 6-8 hours
    2. Usual dose 12.5-100mg bid-tid orally only
    3. Mortality benefit overall in HTN equivalent to ß-blockers, thiazides
    4. Clearly reduces mortality in diabetics with HTN compared with standard anti-HTN
    5. FDA approved for CHF, post-MI, and for diabetic nephropathy
  2. Enalapril (Vasotec®)
    1. T1/2 ~ 12 hours
    2. Initial dosing usually 5-10mg qd-bid po (enalaprilate available iv 0.625mg dosing)
    3. Maintenance dose is 5-40mg po qd in 1-2 divided doses
    4. Cautious use in renal insufficiency
    5. Combinations with: hydrochlorothiazide (Vasoretic®), diltiazem (Teczem®)
    6. FDA approved for treatment of CHF and for asymptomatic LV dysfunction
  3. Lisinopril (Prinivil®, Zestril®)
    1. Lysine derivative of enalapril, may be used IV
    2. T1/2 ~ 18 hrs. qd (or bid) dosing
    3. Begin with 10mg qd, usually 20-40mg total qd (usually divided dosing for >20mg total)
    4. Dose reductions in renal insufficiency required ([Cr]>2-3mg/dL)
    5. Combinations with hydrochlorothiazide (Zestoretic®, Prinizide®)
    6. FDA approved for treatment of CHF
  4. Fosinopril (Monopril®)
    1. 10mg qd initial; 20-40mg in one or two divided doses
    2. Minimal reduction with renal insufficiency because excretion is 50% via liver
    3. In addition, there is increased hepatic excretion in renal disease
    4. Penetrates cardiac tissue and may be very effective in LVH
    5. This agent may be preferred in some patients with renal insufficiency
    6. FDA approved for treatment of CHF
  5. Benazepril (Lotensin®)
    1. 10mg qd initial; 20-40mg in one or two divded doses
    2. Reduction with renal insufficiency may be required
    3. Benazepril 20mg qd showed good reduction in CRF progression in non-diabetics with creatinines as high as 5.0mg/dL (GFR >15mL/min) [6]
    4. Available as combination with amlodipine (as Lotrol®)
  6. Quinapril (Accupril®)
    1. Initial dosing10-40mg qd initial
    2. T1/2 ~18 hours
    3. Maximal dosing 20-80mg qd or divided
    4. Slight decrease with renal insufficiency
    5. FDA approved for treatment of CHF
  7. Ramipril (Altace®)
    1. Dosing: 2.5mg qd initial; 5-10mg qd or bid
    2. Ramipril reduced mortality and CV events in high risk patients without previous CV events [23]
    3. Ramipril has significant cardioprotective and renoprotective effects in Type II diabetics with at least one additional CV risk factor [24]
    4. Ramipril reduced risk of developing DM in vascular disease patients >55 by >30% [34]
    5. Ramipril may be indicated in ANY patient with at least two CV risk factors [23,37]
    6. Ramipril 10mg po qd for 24 weeks significantly improved walk distance and pain- free time in patients with peripheral vascular disease without HTN or DM [74]
    7. In patients without CV disease and with impaired glucose tolerance, did not prevent progression to frank DM, but did increase regression to normoglycemia [10]
    8. Reduce to 1.25-5mg qd with serum creatinine >2.5
  8. Moexipril (Univasc®) [42]
    1. Dosing: 7.5-15mg po qd
    2. Reduce in renal insufficiency
    3. Efficacy apparently equal to others
  9. Trandolapril (Mavik®) [41]
    1. Dosing: 1-2mg po qd initial; 2-4mg qd maintenance
    2. Reduce only for creatinine clearance <30cc/min
    3. Efficacy apparently equal to others
    4. Has shown benefit 3-7 days post-MI on both CHF generation and mortality
    5. Safe and effective in patients with CAD and hypertension [76]
    6. Clear benefit in preventing microalbuminuria in Type 2 DM with HTN [71]
  10. Perindopril (Aceon®) [21]
    1. Initial dose 4mg po qd
    2. Maintenance dose 4-8mg po qd
    3. Reduced risk of recurrent stroke 28% or any CV event in patients with previous stroke [31]
    4. Reduction 20% in CV events in patients with stable coronary atherosclerosis, no CHF [66]
    5. Maximum dose 16mg po as 8mg po bid
    6. Indapamide, a diuretic, combines well with perindopril to reduce BP [31]
    7. Pancreatitis and pneumonitis have been reported

D. Side Effects of ACE-I

  1. Cough
    1. Probably due to increased BK levels
    2. May be more common with captopril than other agents [7]
    3. Overall ~2% of patients
  2. Renal Insufficiency
    1. Elevation in BUN and Creatinine
    2. Increased serum K+ and frank hyperkalemia
    3. Acute renal failure may be precipitated in patients with renal artery stenosis [8]
    4. ACE-I may be cautiously increased in patients with CrCl<30mL/min
    5. Presence of single functioning kidney is major contraindication
  3. Hyperkalemia
    1. Due to reduction in filtered load in kidney
    2. Reduce aldosterone production
    3. Severe hyperkalemia is rare in persons <70 years old with normal renal function
    4. Increased risk with ACE-I or ARB in combination with aldosterone inhibitor [70]
  4. Angioedema [7]
    1. Much less common than cough
    2. May be due to BK increases [44]
  5. Hypotension
    1. First dose hypotension is seen with ACE-I
    2. Especially in patients with renal insufficiency or those already taking diuretics
  6. Strongly consider AT2RB in patients intolerant of ACE-I
  7. Cannot be used in pregnancy at ANY time: cardiovascular, nervous system, renal problems [75]

E. Angiotensin II Receptor Blockers (ARB) [26]

  1. Agents which directly block vasoconstrictive effects of AT2
  2. May also block development of ventricular hypertrophy in patients with ATN
  3. Pathophysiology
    1. Block AT2 Receptor Type 1 (AT2-R1) only
    2. Block AT2 function only at AT2-R1 and induce elevated ACE levels
    3. Allow AT2 to bind to AT2-R2 and this may be beneficial (see above) [49]
    4. Do not have effects on bradykinin (BK) and substance P (SP) metabolism
    5. BK and SP may play a role in renal and cardioprotective effects of ACE-I only
  4. Utility
    1. As effective as ACE-I for HTN reduction with lower rates of cough [80]
    2. At least as good as ACE-I for reduction in LV mass in LVH [58]
    3. As beneficial as ACE-I in CHF and post-MI when used alone or in combination with ACE-I [13,16]
    4. Incidence of angioedema or cough similar to placebo (lower than ACE-I)
    5. First dose hypotension is not seen with ARB, even those on diuretics
    6. ARBs reduced development of new AFib in patients with HTN and CHF [1]
    7. Do not use with GRF <20 mL/min; caution with GFR 20-30mL/min [54]
    8. ARB no better than standard therapy in treatment of patients with HTN and diastolic dysfunction [79]
    9. All currently approved ARB have similar anti-HTN efficacy
  5. ARB may be combined cautiously with ACE-I to achieve maximal AT2 blockade [54]
  6. ARB can be combined with renin inhibitor with some additive effects [9,78]
  7. ARB should not be used in pregnancy

F. Specific ARB [26]

  1. Losartan (Cozaar®) [12]
    1. Approved for use in HTN; shows efficacy in CHF (may be as good as ACE inhibitors)
    2. Losartan reduces CVascular mortality and death more than atenolol in 55-80 year olds with or without DM or LVH and is better tolerated [39,40,47,60]
    3. Reduces microalbuminuria in normotensive DM2 [59]
    4. Very low side effect profile (no cough)
    5. Dose reduced in renal failure (25mg po qd)
    6. Normal dose is 50-100mg po qd in single or divided doses
    7. Combination with diuretic HCTZ (Hyzaar®) improves efficacy
  2. Candesartan (Atacand®) [17]
    1. Comprehensive demonstration of efficacy across many subpopulations with CHF [61]
    2. Reduced CV death in CHF when added to ACE-I [62] or in ACE-I intolerant patients [63]
    3. Also reduced hospital admissions for CHF patients with LV EF >40% [64]
    4. Initial dose is 16mg po qd (target 16mg qd in most patients)
    5. Maintenance dose of 8-32mg in most patients
    6. No change in dosage for hepatic or mild renal insufficiency
    7. Approved for HTN treatment and very effective in CHF; well tolerated
    8. Has shown activity for prophylaxis against migraine [51]
  3. Valsartan (Diovan®) [14]
    1. Approved for use in HTN; 80mg/day is as effective as 20mg/day enalapril
    2. BP reduction slightly less than amlodipine but similar protection on cardiac outcomes [68]
    3. Valsartan added to ACE-I reduces CHF related hospitalizations [65]
    4. Reduced risk of new development of DM compared with amlodipine [68]
    5. Dose is 80-160mg po qd; dose similar with liver or renal disease
    6. Very low side effect profile (rare or absent cough)
  4. Irbesartan (Avapro®) [15]
    1. Dose is 150-300mg po qd
    2. Longer half life than other agents
    3. Reduced diabetic nephropathy progression but had no effect on cardiovascular endpoints when added to standard antihypertensive therapy in normal LV function [77]
  5. Tasosartan (Verdia®)
    1. Dose is ~100mg po qd
    2. Mild elevations in liver function tests (AST, ALT) found in ~2% of patients
    3. No clear association with serious liver disease; mechanism unknown
    4. Consider monitoring AST and ALT in patients on this agent
  6. Telmisartan (Micardis®) [21]
    1. Dose is 40-80mg in one dose
    2. Lowest price AT2 blocker as of Nov 1999 [21]
    3. As effective as enalapril for HTN
    4. As effective as analapril for preventing microalbuminuria in Type 2 DM with HTN [72]
    5. Well tolerated therapy
  7. Eprosartan (Teveten®) [21]
    1. Dose is 400-800mg daily in 1 or 2 doses
    2. As or more effective than enalapril in treatment of HTN
    3. Very well tolerated
  8. Olmesartan (Benicar®) [46]
    1. Starting dose 20mg qd; maximum 40mg po qd
    2. Lower initial dose (5-10mg qd) in patients with volume depletion
    3. Good diastolic and systolic BP reductions

G. Reducing Hyperkalemia Risk with ACE-I or ARB [69]

  1. Increasingly common use of ACE-I or ARB with other drugs that cause hyperkalemia
  2. Estimate Renal Function to assess specific Hyperkalemia Risk
    1. Glomerular filtration rate (mL/min/1.73m2) = 186 x serum creatinine (mg/dL) x age (yr)
    2. For women, multiply GFR above by 0.742; for blacks, multiply by 1.210
    3. Creatinine clearance (mL/min) = (140-age)xweight (kg) / (creatinine x 72)
    4. For women, multiply CrCl above by 0.85
    5. Persons with reduced GFR or CrCl (especially <30mL/min) have increased hyperkalemia risk
  3. If possible, discontinue other drugs which interfere with potassium excretion
    1. Reduce or eliminate use of NSAIDs and COX-2 selective inhibitors
    2. Inquire about use of herbal preparations
  4. Low potassium diet and elimination of potassium containing salt substitutes
  5. Initiation of low dose ACE-I or ARB with at least weekly monitoring K+, creatinine
  6. Increase in K+ with Drugs
    1. If K+ levels increase >5.4mmol/L, reduce dose of ACE-I or ARB and/or other drugs
    2. If K+ levels do not drop <5.5mmol/L with appropriate measures, discontinue ACE-I or ARB
  7. Addition of Aldosterone Blocker [69,70]
    1. Do not use combination ACE-I/ARB with aldosterone blocker if GFR<30mL/min
    2. Dose of spironolactone should not exceed 25mg qd in combination with ACE-I or ARB

H. Vasopeptidase Inhibitors [35]

  1. Simultaneously inhibits both neutral endopeptidase and ACE
    1. Increase availability of peptides with vasodilatory and other effects
    2. Inhibit production of AT2
  2. Neutral Endopeptidase (NEP)
    1. Metalloprotease enzyme
    2. Mainly found in brush border membrane of renal tubules
    3. Also in lungs, intestine, adrenal, brain, heart, peripheral blood vessels
    4. Catalyzes breakdown of A-, B-, C- type natriuretic peptides
    5. Also degrades adrenomedullin, urodilatin, and bradykinin
    6. Sodium ingestion increases NEP activity
  3. Vasopeptidase inhibitors reduce BP independent of age or race (unlike ACE-I)
  4. May have beneficial effects in CHF beyond ACE inhibition
  5. Incidence of cough and angioedema appear similar to ACE I
  6. Vasopeptidase Ihhibitors in Development
    1. None are FDA approved to date
    2. Omapatrilat is being evaluated in several large Phase III trials
    3. MDL-100240
    4. Sampatrilat
    5. Fasidotril (Alatriopril)
    6. Gemopatrilat
  7. Omapatrilat is as at least as good as, and may be superior to, lisinopril in CHF [36]

I. Renin Inhibitors [9,78]

  1. Inhibition in first step in production of angiotensin
  2. Aliskiren (Tekturna®) is orally available, non-peptide selective renin inhibitor now approved
  3. Blood pressure reduction similar to ACE-I and ARB
  4. Do not affect degradation of BK
  5. Appear to be particularly useful in combination with drugs that lead to reactive increase in renin including ACE-I, ARB, diuretics
  6. Alikiren combined with losartan (Cozaar®, an ARB), reduces urinary albumin- to-creatinine ratio by 20% in type 2 DM with nephropathy versus losartan alone [29]
  7. Do not cause angioedema
  8. Aliskiren dose is 150mg qd initially, then up to 300mg po qd

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