Angiotensin Converting Enzyme Inhibitor (patient information)

# Overview
A Class of pharmacologic agents that inhibit angiotensin converting enzyme (ACE).
Specific agents in the class include but are not limited to:
Captopril
Enalapril
Lisinopril

# Current Indications
- Hypertension
- Congestive heart failure

# Angiotensin Formation and Inhibition
- Angiotensin is formed both systemically and locally (in autocrine, paracrine 	systems).
- Local systems have been identified in blood vessels, the heart, adrenal glands, kidney and brain.
- The conversion of angiotensinogen to angiotensin I is facilitated by renin, the rate-	limiting enzyme.
- Angiotensin I, a decapeptide requires angiotensin converting enzyme to be converted to angiotensin II, an octapeptide.
- ACE inhibitors act on both systemic and local angiotensin renin systems.
- Besides enhancing the synthesis of the vasoconstrictor angiotensin II, angiotensin converting enzyme also facilitates the degradation of the potent vasodilator bradykinin.
- ACE inhibitors, therefore, increase bradykinin levels, which in turn facilitate the conversion of arachidonic acid to prostaglandins enhancing vasodilation.
- The increased synthesis of bradykinins and prostaglandins may explain the frequent side-effect of cough.

# Use of ACE Inhibitors in the Treatment of Hypertension
- In renal artery stenosis, there is decreased perfusion of the kidney and increased release of renin by the juxtaglomerular apparatus. ACE inhibitors inhibit the synthesis of angiotensin II in this hypereninemic state.
- In patients without renal artery stenosis, ACE inhibitors act via 6 mechanisms:
Inhibition of conversion of circulating angiotensin I to angiotensin II.
Reduce the secretion of aldosterone to induce natriuresis.
They induce renal vasodilation and enhance natriuresis.
The inactivation of vasodilatory bradykinins is reduced.
Inhibition of local formation of angiotensin II in vascular tissue and myocardium.
Indirect adrenergic modulation.
- Inhibition of conversion of circulating angiotensin I to angiotensin II.
- Reduce the secretion of aldosterone to induce natriuresis.
- They induce renal vasodilation and enhance natriuresis.
- The inactivation of vasodilatory bradykinins is reduced.
- Inhibition of local formation of angiotensin II in vascular tissue and myocardium.
- Indirect adrenergic modulation.
- Quality of life. It has been claimed that angiotensin converting enzymes have a favorable side-effect profile and offer an improved quality of life compared with other anti-hypertensives. However, the comparative studies have used medications with central and sexual side-effects, namely methyldopa and Inderal and cough was not included in the analysis.

# Angiotensin Converting Enzyme Inhibitors in the Treatment of Congestive Heart failure
- In congestive heart failure, there is a vicious cycle in which a diminished cardiac output decreases baroreceptor stimulation and increases SVR, further increasing the afterload on the failing myocardium.
- Angiotensin converting enzymes work by reducing the SVR and minimizing afterload.
- Patients with CHF are also at risk for VEA and ACE inhibitors may provide a 	benefit by increasing serum potassium and decreasing circulating norepinephrine levels.  Specific studies, however, remain to be done to document this effect.
- Therapy is usually initiated with a test dose of Captopril 6.25 mg because of its shorter half-life and overdiuresis is avoided to prevent a hypereninemic state prior to initiation of the therapy.
- In patients with liver dysfunction Captopril may be preferable to Enalapril because Enalapril requires activation by the liver.
- Diuretics remain the first line agent. ACE inhibitors do not appear to work well in the absence of diuretics and therefore are primarily second line agents.
- Patients with a low sodium concentration ( i.e. below 130 meq/l ) are likely to be hypereninemic and may experience a precipitous fall in blood pressure.
- Avoid hyperkalemia in patients already treated with potassium sparing diuretics or with potassium supplements especially if renal function is already impaired.

# Angiotensin Converting Enzymes and Post-Infarction Remodeling
- Both experimental and clinical studies support the use of angiotensin converting enzymes inhibitors to decrease LV dilation post MI.

# Angiotensin Converting Enzyme Inhibitors in Patients with Renal Impairment
- Exert a renal vasodilatory effect by dilating efferent arterioles and relieving intraglomerular pressure.
- In diabetic nephropathy, Captopril has been shown to decrease proteinuria without changing creatinine which has been thought to be due to reduced intraglomerular hypertension i.e. reducing the filtered load.
- The role of Captopril in other forms of renal failure is less clear.

# Class Side Effects
- Cough, dry, irritating, non-productive. Most common side effect.  Patients with CHF frequently cough anyway. Cough was ignored in the "quality of life" study. Incidence may be as high as 10-15%. Thought to be secondary to increased formation of bradykinin and prostaglandins. NSAIDs may help, but at the expense of renal vasodilatory effects of ACE inhibitors.
- Hypotension: When initial blood pressure is very low, further afterload reduction can cause hypotension and renal hypoperfusion.
- Renal side effects:  Again, hypotension can lead to renal failure which is usually temporary. 3 situations in which this is a possibility include
severe CHF
unilateral renal artery stenosis
bilateral renal artery stenosis
- severe CHF
- unilateral renal artery stenosis
- bilateral renal artery stenosis
- Occasionally irreversible renal failure has been precipitated in patients with bilateral renal artery stenosis and this is a contraindication.
- To minimize these possibilities a low dose of short acting Captopril 6.25 mg is given to patients with CHF.
- Angioedema rare, 0.1% life-threatening. No known method of prediction.

# Coadministration with Other Drugs
- Avoid hyperkalemia with K+ sparing agents
- Monitor plasma lithium levels
- Combination with thiazide diuretics increases the hypotensive effects of ACE inhibitors.
- Captopril increases digoxin levels.
- ACE inhibitors and  blockers both decrease renin levels, but their is some evidence to suggest that the effect is additive.
- ACE inhibitors and calcium channel blockers are a good combination because both are free of CNS effects.

# Captopril
- The first ACE inhibitor
- t1/2 = 2 to 3 hours
- Dosing:
HTN: 25 to 50 mg bid
CHF: 75 to 150 mg daily in 2 to 3 divided doses. Test dose of 6.25 mg, particularly if recently diuresed
- HTN: 25 to 50 mg bid
- CHF: 75 to 150 mg daily in 2 to 3 divided doses. Test dose of 6.25 mg, particularly if recently diuresed
- Improves proteinuria in diabetic nephropathy
- Contraindications:
Bilateral renal artery stenosis
Unilateral renal artery stenosis in a single kidney
Immune-based renal disease (4/100 incidence of neutropenia in those with collagen vascular disease and renal impairment).
Cr > 1.6 mg/dl
Pre-existing neutropenia
Hypotension
- Bilateral renal artery stenosis
- Unilateral renal artery stenosis in a single kidney
- Immune-based renal disease (4/100 incidence of neutropenia in those with collagen vascular disease and renal impairment).
- Cr > 1.6 mg/dl
- Pre-existing neutropenia
- Hypotension
- Immune-based side-effects peculiar to captopril include taste disturbances (2-7%), skin rashes (4-10%) and neutropenia (1/8600). In patients with renal impairment at the time of initiation of therapy, then WBC counts need to be checked q 2 wks for 3 mos.
- Proteinuria occurs in 1% of patients taking captopril and is due to immune mechanisms and decreased renal perfusion.

# Enalapril (Vasotec)
- Longer half-life (4 to 5 hours in HTN and 7 to 8 hours in CHF)
- Requires hydrolysis of the pro-drug to the active drug, enalaprilat in the liver, thus in liver disease requires higher dosing.
- Does not have the sulfhydryl group and therefore less of a risk of immune-based side effects.
- 95% renal excretion
- Peak antihypertensive effect in 4 to 6 hours after the initial dose.
- Dosing:
HTN: 2.5 to 20 mg daily as 1 or 2 daily doses
CHF: Initial dosing 2.5 mg to avoid the risk of hypotension and renal failure
If GFR < 30 ml/min, then reduce the dose
- HTN: 2.5 to 20 mg daily as 1 or 2 daily doses
- CHF: Initial dosing 2.5 mg to avoid the risk of hypotension and renal failure
- If GFR < 30 ml/min, then reduce the dose
- Side-effects: neutropenia less frequent. Cough still occurs. Can be safe when captopril causes a rash. Regular neutrophil monitoring is not required.

# Lisinopril (Zestril, Prinivil)
- Is not a pro-drug, excreted unchanged by the kidney.
- t1/2 = 12 - 14 hours.
- No sulfhydryl group, therefore few immune-based side effects.
- Dosing similar to enalapril.

# Benazepril
- Studied in 95 american studies.
- The prodrug is benazepril, the esterified form.
- Benazepril is hydrolyzed in the liver to the active unesterified form, benazeprilat.
- Initial dose: 10 mg PO qd. Chronic dosing: 20 mg or 40 mg PO qd. Occasionally a patient will require 40 mg PO bid.
- Five most common side effects in 3,500 patients were headache, dizziness, fatigue, cough (3.4% in treatment group compared with 1.3% in placebo arm), and nausea.
- In patients with a creatinine clearance less than 30 ml/min a reduction in the initial dosage is decreased.
- No need to reduce dose in cirrhosis.
- No dose reduction in the elderly.