2. Drug Class 2: Angiotensin II Receptor Blockers (ARBs)

1.1 Types of ARBs

Losartan

Olmesartan

Valsartan

Eprosartan

Irbesartan

Candesartan

Telmisartan

Acronym: Love I can Tell

1.2 Mechanism of Action

  • Competitively (but often this inhibition is insurmountable) blocks binding of angiotensin II to type I angiotensin II receptors (ATII Type 1 receptors). Max response cannot be restored.
  • Inhibits most biological effects of AngII (e.g. Prevent contraction of vascular smooth muscle, rapid+slow pressor response, thirst, ADH release, Aldosterone secretion, Release of Adrenal catecholamines, Enhancement of NAdr transmission, increases in sympathetic tone, changes in renal function and cellular hypertrophy/hyperplasia).
  • Reduce angiotensin-induced vasoconstriction, sodium reabsorption and aldosterone release
  • ARBs are renoprotective in Type 2 Diabetes mellitus-How?

(RAAS causes systemic and glomerular capillary hypertension as well as injury to vascular endothelium and glomerulus.

-Direct profibrotic and pro-inflammatory actions of Ang II and aldosterone may promote kidney damage.

-AngII–>Increases reactive oxygen species and renal damage. Thus, both ARBs and ACE-inhibitors lower proteinuria and serum creatinine. This improves response of renal vasculature to Nitric Oxide (an indicator of endothelial and renal endothelial health).

1.3 Indications

  • Hypertension
  • Heart Failure in patients unable to tolerate ACE-inhibitors (i.e. start with ACE-inhibitors first for CHF)
  • Reduction of Renal Disease Associated with Type 2 diabetes.

*Note all ARBs are indicated for hypertension. However, only some are used in heart failure and reduction of renal disease associated with Type 2 diabetes.

1.4 Precautions

1. Peripheral vascular disease

-In these patients, they are likely to have arterial renal stenosis (Decreased renal perfusion)

2. Volume or sodium depletion

-May activate the renin-angiotensin system leading to excessive hypotension when an ARB is started; correct the dosage accordingly and/or monitor carefully

3. Aortic stenosis

-ARBs may theoretically cause coronary hypoperfusion, systemic hypotension and reduced renal function (However apart from ARBs, ACE-inhibitors have limited therapeutic use patients with aortic stenosis, thus ARBs are preferred.)

4. Primary hyperaldosteronism

-Spironolactone is the drug of choice, ARBs may be ineffective, seek specialist advice

5. Black African, Carribean descent

-Anti-hypertensive effect of monotherapy with ARB or ACE-inhibitor may be reduced (Generally, Calcium channel blocker or thiazide diuretic is more effective)

6. Treatment with drugs that can increase potassium concentration

-K+ sparing diuretics e.g. spironolactone, cyclosporin (ARBs increase risk of hyperkalemia; avoid combination or monitor potassium concentration regularly)

1.4 Use of ARBs in Special Conditions

Renal

-Renal impairment may worsen, increased risk of hyperkalemia. Use lower initial doses and monitor potassium.

-ARBs increase risk of renal failure in bilateral renal artery stenosis.

Women

-Avoid in women planning to conceive or who are using inadequate contraception.

Pregnancy

Contraindicated. use in first trimester may cause congenital malformations, second trimester and third trimester may cause fetal renal dysfunction and oligohydroaminos (lack of aminotic fluid), subsequently fetal death (CAT D-AUS)

Breastfeeding

-Avoid breastfeeding while on ARBs.

1.5 Adverse effects/Side effects

*1. Dizziness, Headache

*2. Hyperkalemia

*3. Fetotoxicity

*4.  Caution when used in Patients highly dependent on renin-angiotensin system

-In such patients, ARBs can cause hypotension, oliguria (low urine output), progressive azotaemia (Increase in urea and Nitrogen levels in blood due to low renal excretion) or acute renal failure.

*Denotes common adverse effects found in Joe’s notes

  • Other infrequent adverse effects found in AMH 2012: First dose hypertension, rash, diarrhea, dyspepsia (indigestion, is a condition of impaired digestion), abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin, renal impairment, pharyngitis, nasal congestion
  • Rare side effects found in AMH 2012: Cough, Uticaria, Angioedema, Henoch-Schonlein purpura, hepatitis, taste disturbance, migraine

*Note: ARBs are far less likely to induce cough (rare), angioedema far less common than ACE-inhibitors

1.6 Comparative information for ARBs

Hypertension

-Effect of ARBs is similar to that of other major anti-hypertensive drug classes

-Both losartan and irbesartan are marketed to reduce progression of renal disease in patients who have type 2 diabetes, hypertension and proteinuria (+microalbuminuria for irbesartan)

ALL except Losartan are available in combination products with hydrochlorothiazide. Olmesartan, telmisartan and valsartan also available combined with amlodipine (CCBs)

High cardiovascular risk, heart failure, post MI

*Currently, recommendations are to use ACE-inhibitors as first line agents for treatment of CHF (cheaper)

-ARBs have not been shown to be superior to ACE-inhibitors for CHF, vascular disease, high-risk diabetes or left ventricular failure/dysfunction post MI. 

-However, they improve prognosis and are an alternative in patients unable to tolerate or unresponsive to ACE-inhibitors.

Candesartan and Valsartan marketed for CHF and valssartan for left ventricular failure/dysfunction after MI.

Should we combine ARBs and ACE-inhibitors?

-At present, there is conflicting evidence regarding the benefit of combining an ARB with an ACE-inhibitor in CHF (combinations may worsen renal function, increase side effects such as hypotension and hyperkalemia-AMH 2012).

– Combination did not provide additional benefit in patients at high risk of vascular disease nor improve survival in patients with left-ventricular failure/dysfunction or post MI.

-Despite conflicting trial results, it may be an option for non-responsive patients or CHF. However, seek specialist advice.

-ARBs are superior to B1 blockers in reducing stroke in hypertensive patients with left ventricular hypertrophy.

Important differences between ARBs and ACE-inhibitors

1) ARBs reduce activation of ATII Type 1 Receptors more effectively than ACE-inhibitors. ACE-inhibitors inhibit production of Angiotensin II but there are alternative pathways where Ang II is generated.

2. ARBs permit activation of ATII Type 2 Receptors.

3) Both ACE-inhibitors and ARBs enhances renin-release. ARBs increase renin release resulting in increased levels of circulating Angiotensin II thus allowing Angiotensin II Type 2 receptors to be activated. ACE-inhibitors increase renin release but since they block the conversion of AngI to AngII, there will be decreased levels of Angiotensin II.

4) ACE-inhibitors may decrease Ang (1-7) levels more than do ARBs (side effects?)

5) ACE-inhibitors result in the accumulation of ACE-substrates, namely bradykinin whereas ARBs do not.

1. 7 Counselling points

-Patient may feel dizzy when started on ARBs. Get up gradually from sitting or lying down to minimise this. Sit down or lie down if patient becomes light headed or dizzy.

DO NOT TAKE POTASSIUM SUPPLEMENTS while on this medicine unless told by doctor to do so.

1.8 Practice Points

-Before starting an ARB, stop potassium supplements and potassium-sparing diuretics

Check Renal function and electrolytes level regularly.

-Unlike ACE-inhibitors, ARBs do not inhibit breakdown of bradykinin. Thus if ACE-inhibitor is not well-tolerated (i.e. cough occurs or angioedema history), ARBs are a better alternative.

-Maximum anti-hypertensive effects occurs about 4-6 weeks after starting treatment (Effects not immediate)

-If initial response to monotherapy with a low maintenance dose of ARBs is insuffficent, consider adding second anti-hypertensive (e.g. thiazide) instead of increasing ARB dose.

1.9 Comparison between ARBs (When and what to use for which patients)

1. Losartan (14% of dose losartan converted to metabolite EXP3174 which is more potent than losartan as a ARB)

Indications: (a) Hypertension (Not used in combination with hydrochlorothiazides), (b) Reduction of renal disease progression in patients with type 2 diabetes, hypertension and proteinuria (urinary albumin to creatinine ratio greater than or equal to 300mg/g or proteinuria >500mg per 24 hours)

-Precautions in hepatic patients (lower dose required), Children (may be used under specialist supervision for children unable to tolerate ACE-inhibitor induced cough).

*Drug interactions specific for Losartan-Rifampicin

-Rifampicin (antibiotic) (CYPC29 inducer) increases metabolism of losartan (uses CYP2C9 and CYP3A4) to EXP3174. Thus, rifampicin potentiates Losartan’s effects (Monitor clinical effect and adjust losartan dose accordingly).

2. Olmesartan (Given as olmesartan medoxomil, inactive ester prodrug, active absorbed in gut)

-Indications: Hypertension (In combination with hydrochlorothiazide or amlodipine)

-Precaution: Renal Impaired (Contraindicated if Creatine Clearance is <30ml/min), hepatic (contraindicated if biliary obstruction, partially eliminated in bile), severe hepatic impairment (Child-Pugh Score 10-15). Concentration increases in moderate impairment (Child-Pugh Score 7-9)

*Child-Pugh Score: Assessment of chronic liver disease especially cirrhosis. Scoring system which depends on serum albumin levels, PT/INR, Ascites, Hepatic Encephalopathy

3. Valsartan

-Indications: (a) Hypertension (In combination with hydrochlorothiazide and/or amlodipine) (b) Heart Failure (NYHA class II-IV) if unable to tolerate an ACE-inhibitor (c) Left ventricular failure/dysfunction after MI, when clinically stable

*NYHA class: New York Heart Association functional classification for the extent of heart failure.

-Precaution: Renal impaired (Manufacturer recommends a lower maximum dosage if CrCl<30ml/min). Hepatic impaired (Mostly excreted unchanged in bile. Contraindicated in cholestasis (bile cannot flow from liver to duodenum), biliary cirrhosis and severe hepatic impairment.

-Valsartan concentrations are increased in mild-to-moderate impairment, manufacturer recommends a lower max dose.

4. Eprosartan (In combination with hydrochlorothiazide)

-Precautions: Hepatic impaired (Lower dosage required)

5. Irbesartan

-Indications: (a) Hypertension (In combination with hydrochlorothiazide) (b) Reduction of renal disease progression in patients with Type 2 diabetes, hypertension and microalbuminuria (>30mg/24 hours) or proteinuria (>900 mg/24 hours)

6. Candesartan (Candesartan cilexetil-Inactive prodrug, absorption in gut)

-Indications: (a) Hypertension (In combination with hydrochlorothiazide) (b) Heart failure in patients unable to tolerate ACE inhibitors or with ACE-inhibitor in patients with low ventricular ejection fraction (May require combination with ACE-inhibitor)

-Precautions: Renal (Lower doses required if Creatine Clearance <30ml/min)

7. Telmisartan

-Indications: (a) Hypertension (In combination with amlodipine or hydrochlorothiazide) (b) Prevention of cardiovascular morbidity and mortality in patients with coronary artery disease, peripheral artery disease, high-risk diabetes, previous stroke or TIA (transient ischemic attack)

-Longest half life of all ARBs.

Acronym: LOVE I can tell.

***All these drugs have >90% protein binding. All have oral bioavailability of <50%. Candesartan and Olmesartan both renal and biliary excreted. Telmisartan is only bile excreted (hepatic affected but not renal insufficiency). Irbesartan excreted as a glucorinide conjugate, parent compound is excreted in urine (20%) and 80% in bile. Losartan is metabolised to EXP3174 by CYP2C9 and CYP3A4 (clearance affected only by hepatic insufficiency). Valsartan is converted into inactive metabolite by CYP2C9, excreted in feces via bile route.

1.10 Drug Interactions for ARBs

1. Lithium

-ARBs may reduce excretion of lithium and increase risk of toxicity (onset may be insidious)

*Monitoring of lithium concentrations, renal function is necessary. Reduce lithium dose if necessary (consider using alternative classes)

2. Loop Diuretics

-Increases risk of excessive hypotension first dose of ARB due to volume depletion. Withhold loop diuretic (or reduce dosage) for at least 24 hours before starting ARBs. *Begin with low dose of ARBs (or give the first dose in evening under supervision)

3. NSAIDs

-May Reduce antihypertensive effect and increase risk of hyperkalemia or acute renal failure. *Avoid combination if not monitor BP, weight, serum creatinine and potassium regularly. Limit daily dose of aspirin to 100-150mg daily.

4. Thiazide Diuretics

-If High dose of thiazides used in combination with ARBs, risk of excessive hypotension after the first dose of ARBs may occur due to volume depletion. Withhold thiazide diuretic for at least 24 hours before starting ARBs. *Begin with low dose of ARB (or give first dose in the evening under supervision). 

*Drug interactions specific for Losartan-Rifampicin

-Rifampicin (antibiotic) (CYPC29 inducer) increases metabolism of losartan (uses CYP2C9 and CYP3A4) to EXP3174. Thus, rifampicin potentiates Losartan’s effects (Monitor clinical effect and adjust losartan dose accordingly).

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