1. Drug Class 1:ACE inhibitors

1) ACE inhibitors/Angiotensin converting enzyme inhibitors

(a) Quinapril

(b) Perindopril

(c) Ramipril

(d) Fosinopril

(e) Moexipril

(f) Lisinopril

(g) Benazapril

(h) Enalapril

(i) Trandolapril

(k) Captopril

Acronym: QPR FML BET CAP

1.1 Mechanism of action

  • All of them block conversion of angiotensin I to angiotensin II.
  • They also inhibit the breakdown of bradykinin
  • Reduce the effects of angiotensin II-induced vasoconstriction, sodium retention and aldosterone release.
  • Reduce the effect of angiotensin II on sympathetic nervous activity and as a growth factor.

1.2 Clinical Indications

-Hypertension

-Heart Failure

-Diabetic Nephropathy (Type 1 Diabetes)

-Prevention of progressive renal failure in patients with persistant proteinuria >1g/day

-Asymptomatic left ventricular dysfunction

-Post Myocardial infarction (acute treatment or in patients with left ventricular dysfunction or heart failure)

Reduction of risk of cardiovascular events in specific patients.

1.3 Side Effects/Adverse effects

*1. Angioedema (can be Heriditary, idiopathic or ACE-induced)

-ACE inhibitors increase risk of further episodes (use alternative class if possible or seek specialist advice)

-Isn’t dose related but may occur within first week of therapy

-Airway obstruction/respiratory distress may lead to death.

-Involves the accumulation of bradykinin (Angiotensin I resemblance) or inhibition of complement 1-esterase inhibitor (Complement cascade inhibitor)

-Once angioedema is gone, use anti-histamines and/or glucocorticoid to protect airways.

2. Fetotoxicity

-Angiotensin II Type 2 receptors expressed in placenta (Refer to precautions for more detail)

3. Skin Rashes (especially captopril), Itching

-Maculopapular rash (Conincally raised skin, coloured rash, may be pruritic)

-Occurs due to sulfhydryl group in captopril but occurs with other ACE inhibitors (less frequent)

*4. Acute Renal Failure

-Can induce acute renal insufficiency in patients with bilateral renal artery sternosis, stenosis of the artery to a single remaining kidney (Decreased perfusion to kidneys), heart failure, or volume depletion due to diarrhea or diuretics

-Care in elderly patients with CHF or particularly susceptible to ACE-induced acute renal failure.

*5. Cough (Induced by bradykinin)

-Occurs more frequently in women than men

-Once ACE-inhibitors stopped, cough disappears within 4 days

*6. Headache, dizziness, nausea, fatigue (Associated with Hypotension)

-Steep fall in blood pressure may occur following first dose of an ACE inhibitor in patients with elevated plasma renin.

*7. Hyperkalemia

-Retains K+, especially in patients with renal insufficiency or patients taking K+ sparing diuretics, K+ supplements, B-blockers or NSAIDs

8. Hypovolemia, dehydration

-Use of ACE-inhibitor increases risk of dehydration and first dose hypotension.

Others Not listed in Joe’s notes: Anaphylactoid reactions, palpitations, chest pain, flushing, fever, taste disturbances, vomitting, anorexia, diarrhea, constipation, stomatitis, dry mouth, sore throat, hoarseness, muscle cramps, elevated hepatic aminotransferases (AST/ALT) and bilirubin, abnormal dreams

*-Means common or infrequent side effects that occur

Rare side effects: Hepatitis (Cholestatic/bile cannot flow from the liver to the duodenum or hepatocellular), Pancreatitis, Proteinuria, Hyponatremia, Thrombocyptopenia, Neutropenia, Aplastic anemia, Agranulocytosis, Hemolytic anemia, Eosinophilia, Myalgia, arthralgia, neuropathy, paraesthesia, photosensitivity, psoriasis, pemphigus, toxic epidermal necrolysis, gynaecomastia, visceral angioedema

1.3 Precautions

(a) Angioedema (Could be hereditary, idiopathic or ACE-inhibitor induced)

-ACE inhibitors increase risk of future occurances (use alternative class if possible or seek specialist advice)

(b) Hypovolemia, Dehydration (e.g. taking a diuretic)

-Increases risk of first dose hypertension

(c) Primary Hyperaldosteronism

-ACE inhibitor is ineffective, use Spironolactone instead (drug of choice)

(d) Black, African or Caribbean descent

Anti-hypertensive effect of monotherapy with an ACE inhibitor or sartan may be reduced (generally a calcium channel blocker or thiazide diuretic is more effective)

(e) Treatment with drugs that can increase potassium concentrations (e.g. potassium-sparing diuretics, spironolactone, cyclosporin)

-increases risk of hyperkalemia; avoid combination if there is no choice monitor potassium blood levels.

1.4 Use of ACE-inhibitors in Special cases or conditions 

Cardiovascular condition

-Limited data to suggest that ACE inhibitors are beneficial in selected patients with aortic stenosis (theoratically they might cause coronary hypoperfusion, systemic hypotension, and reduced renal function)

Caution must be taken to avoid hypotension

-Patients with peripheral vascular disease or artherosclerosis (increased risk of renal failure)–>Avoid use of ACE-inhibitors

Renal impairment/failure

-Renal impairment increases risk of hyperkalemia and may affect the excretion of most ACE inhibitors, dosage may need to be adjusted

-Pre-existing renal impairment may worsen especially if the person is hypovolemic. Also concurrent use with NSAIDs will worsen renal function.

-ACE inhibitors increase risk of renal failure in bilateral renal artery stenosis.

-They may have a myelosuppressive effect  (causing bone marrow suppression) in end-stage renal failure, may require increased epoetin (Epoetin is a type of erythropoietin stimulator used to increase red blood cells count)

Relevance? -Hemodialysis with high flux polyacrylonitrile membranes may result in anaphylactoid reactions (a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation), similar reactions may occur in patients on low density lipoprotein apheresis with dextran sulfate (blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation)

Surgery

-Excessive hypotension may occur during anesthesia or surgery.

Elderly

-May be more predisposed to first dose hypotension, hyperkalemia and renovascular disease than younger patients. Start treatment with lower doses, monitor renal function closely.

Women

-Avoid in women who plan to conceive or who are using inadquate contraception.

Pregnancy (NOT ALLOWED IN PREGNANCY) and Breastfeeding

-Contraindicated. Use in first trimester may cause congenital malformations, use in second and third trimester MAY cause renal dysfunction and oligohydraminos (condition in pregnancy characterized by a deficiency of amniotic fluid. It is the opposite of polyhydramnios)

-Subsequent fetal death (CAT D)

-Breastfeeding: No adverse effects reported with captopril or enalapril. Not sure about others.

1.5 Counselling points/Comparative information/Practice points

-Most ACE-inhibitors except captopril can maintain an anti-hypertensive effect up to 24 hours and can be given once daily.

-Many are available as combination products with a diuretic (hydrochlorothiazides, indapamide), or a Calcium channel blocker

-Reserve for patients stabilised on similar doses of single ingredient products.

Therapeutic points:

-Might feel dizzy when you start taking this medicine. Get up gradually from sitting or lying down to minimise this effect, sit or lie down if patient becomes dizzy or light headed.

DO NOT TAKE POTASSIUM SUPPLEMENTS WHILE TAKING THIS MEDICATION UNLESS DOCTOR INSTRUCTS OTHERWISE.

  • When starting ACE inhibitors, stop potassium supplements and potassium-sparing diuretics, stop other diuretics for 24 hours
  • Always start with low doses
  • Check renal function and electrolytes before starting ACE-inhibitor and review after 1-2 weeks.
  • Onset of ACE inhibitor associated angioedema may not occur for several years

Treatment with ACE inhibitors and ARBs 

-In trials, the combination worsened renal function and increased risk of hypotension and hyperkalemia

-Combination DID NOT PROVIDE ADDITIONAL  benefit for post MI/left ventricular failure patients

-May be an option despite contradicting trial evidence. For patients chronic heart failure or non-responsive BP, seek specialist advice

1.6 Comparison between ACE-inhibitors (When and what to use for which patients)

1. Quinapril (Prodrug)

Indications: Hypertension (Combination with hydrochlorothiazide), Heart Failure

-Hepatic esterases transform prodrug quinapril into quinaprilat

-60% absorption

2. Perindopril (Prodrug)

Indications: Hypertension, Heart Failure, Reduction of risk of MI or cardiac arrest in people with established coronary heart disease without heart failure

  • Can be combined with amlodipine (Calcium channel blocker) for hypertension or stable coronary heart disease.

-Perindopril erbutamine is a prodrug (30% to 50% transformed to perindoprilat by hepatic esterases)

-Biphasic elimination, slow dissocation from tissue

-Not affected by food, bioavailability 75%

3. Ramipril

Indications: Hypertension (Ramipril in combination with felodipine) , Post MI in patients with heart failure, Prevention of MI, stroke, cardiovascular death,

Need for revascularisation procedures in patients >55 years with:

Coronary artery disease, stroke or periphearl vascular disease, diabetes and 1 or more risk factors (Low HDL cholesterol, Previous vascular disease, smoking, microalbuminuria, high total cholesterol, smoking, hypertension)

4. Fosinopril

Indications: Hypertension (in combination with hydrochlorothiazide), heart failure

-Absorbed incompletely (36%), not reduced by food

5, Moexipril

-Not listed in AMH 2012

6. Lisinopril

Indications: Hypertension, Heart failure, Post MI acute treatment

Lys analogue of enalaprilat, lisinopril itself is active.

-Absorbed incompletely 30%, not affected by food

7. Captopril

Indications: Hypertension, Heart Failure, Post MI in patients with left ventricular dysfunction, Diabetic nephropathy (Type 1 Diabetes)

Precautions: Collagen vascular disorders (e.g. scleroderma, systemic lupus erthymetosus/SLE), severe renal impairment-may be predisposed to neutropenia or agranulocytosis.

-Bioavailability 75%, reduced by food to 30%

8. Enalapril

Indications: Hypertension (in combination with hydrochlorothiazide or lercanidipine), Heart failure, Asymptomatic left ventricular dysfunction

-Enalapril maleate is the prodrug hydrolysed by esterases to active enalaprilat

-Bioavailability 60%, not reduced by food

9. Benazepril

-Nost listed in AMH 2012

10. Trandolapril

Indications: Hypertension (in combination with verpamail), Post MI in patients with left ventricular dysfunction

*Precautions: Hepatic impaired patients (Use a lower starting dose in those with hepatic impairment)

Trandolapril metabolised into trandolaprilat

-10% bioavailable as trandolapril and 70% as trandolaprilat

***Biphasic elimination kinetics (slow dissociation from tissue)

****Excretion mostly by kidneys except fosinopril (excreted in urine and bile), quinapril (urine 61% and feces 37%), trandolapril (33% in urine, 66% in feces) 

Drug interactions:

1. NSAIDs-Reduce anti-hypertensive effects of anti-hypertensives (PGI2, PGE2 inhibited, no more compensatory vasodilation)

Increased risk of renal impairment and hyperkalemia.

-Avoid combination in elderly or if renal hypoperfusion/impairment occurs.

2. Loop Diuretics

-Increased risk of hypotension. Withhold loop diuretic for at least 24 hours before starting ACE-inhibitor.

-Begin with low doses of ACE-inhibitor in the evening (under supervision)

*Combination avoided due to the increased risk of renal impairment

3. Thiazides

-increased risk of severe hypotension

*Begin with a low dose in the evening

* Use with caution in the elderly, renal impaired (combination with other anti-hypertensives should be avoided)

4. Lithium

-Lithium excretion decreases when ACE-inhibitors used (Insidious toxicity may occur)

*5. Digoxin

-Increased levels of digoxin, reduces excretion, reduced GFR

6. K+ supplements, K+ sparing diuretics-Result in hyperkalemia

*7. Antacids (Reduce oral bioavailability of ACE-inhibitors)

8. Capsaicin (Worsen bradykinin-induced cough)

*9. Allupurinol

-Increased hypersensitivity reactions to allupurinol

*-Not listed in AMH 2012

NOTE: Monitor Li+/K+ concentration, renal function every 1-2 weeks. Reduce Li+ by adjusting dose if necessary. Alternatively, use other classes of anti-hypertensives.

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