Long-term use and tolerability of Irbesartan for control of Hypertension

Valentina Forni, Gregoire Wuerzner, Menno Pruijm, Michel Burnier Service of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Reported by: DR. MARVIN JINO S. BUGNA

OBJECTIVE To determine the pharmacokinetic and pharmacodynamics characteristic of ARBs and Irbesartan when used as an oral monotherapy or combination therapy in essential hypertension, diabetic nephropathy and cardiac disease.

Hypertension Hypertension is sustained elevation of BP Systolic blood pressure  140 mm Hg Diastolic blood pressure  90 mm Hg

Hypertension Types 1. PRIMARY (Essential) 2. SECONDARY Chronic high blood pressure without a source or associated with any other disease. Most common form of hypertension 2. SECONDARY Elevation of blood pressure associated with another disease such as kidney disease Primary (Essential) Hypertension Elevated BP with unknown cause 90% to 95% of all cases Secondary Hypertension Elevated BP with a specific cause 5% to 10% in adults

BP Classification SBP mmHg DBP mmHg Normal < 120 and < 80 Pre-hypertension* 120-139 or 80-89 Stage 1 Hypertension 140-159 or 90-99 Stage 2 Hypertension > 160 or > 100 *newly recognized, requiring lifestyle modifications

Risk Factors for Primary Hypertension Genetic or Family History Age (>55 for men; >65 for women) Alcohol Cigarette smoking Diabetes mellitus Elevate serum lipids Excess dietary sodium Obesity Ethnicity Sedentary lifestyle Socioeconomic status Stress

Clinical Manifestations Frequently asymptomatic until severe and target organ disease has ocurred. Fatigue, reduced activity tolerance Dizziness Palpitations, angina Dyspnea

Complications Thickening of heart muscle Increase workload of the heart May lead to other conditions such as: Heart attack Stroke Renal failure Nephrosclerosis Retinal damage

HYPERTENSION Left Ventricular Hypertrophy Heart Failure Gangrene of the Lower Extremities Myocardial Infarction Coronary Heart Disease Aortic Aneurym HYPERTENSION Hypertensive encephalopathy Blindness Cerebral Hemorrhage Chronic Kidney Failure Stroke Preeclampsia/Eclampsia Adapted from Dustan HP et al. Arch Intern Med. 1996; 156: 1926-1935

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM one of the most complex and important systems in controlling the blood pressure and fluid balance in the body.

Angiotensin Receptor Blockers Drugs that block the action of angiotensin II, permitting the blood vessels to relax and dilate lowering the blood pressure. ARBS Are medications that block the action of angiotensin II, permitting the blood vessels to relax and dilate lowering the blood pressure. They have effects similar to an ACE inhibitor which is why they are often used when an ACE inhibitor cannot be tolerated by patients.

Mechanism of Action The final active messenger of the renin-angiotensin pathway is Angiotensin II. Angiotensin II binds to AT1 receptors to cause vasoconstriction and fluid retention, both of which lead to an increase in blood pressure.  The angiotensin II receptor blockers lower blood pressure by blocking the AT1 receptors. 

Essential Hypertension Heart Failure Cardiovascular prevention Nephropathy Losartan x Symptomatic NYHA II-III X Decrease stroke risk in LVH Hypertensive, Type II diabetics (Increase creatinine and/or albuminuria >300 mg/day) Valsartan Asymptomatic if recent MI and LVEF < 40% Candesartan If LVEF < 40% Losartan Losartan (Cozaar) can be used alone or as part of combination therapy for hypertension, as well as for treatment of diabetic neuropathy with an elevated serum creatinine and proteinuria in patients with hypertension and type 2 diabetes. 2. Valsartan Valsartan (Diovan) can be used alone or as part of combination therapy for hypertension and for the treatment of heart failure in patients who are intolerant to ACE inhibitors. Usual Dosage: 80-320 mg/d PO 3. Candesartan Candesartan (Atacand) is used alone or as part of combination therapy to treat hypertension. Usual Dosage: 16-32 mg/d PO

IRBESARTAN Essential Hypertension Heart Failure Cardiovascular prevention Nephropathy IRBESARTAN x X Hypertensive, type II diabetics (Increase in creatinine and/or albuminuria >30mg/day) Olmesartan Telmisartan Decrease MI and stroke risk in high CV risk and/or diabetic patients with target organ damage Eprosartan 4. Eprosartan (Teveten) is used alone or as part of combination therapy to treat hypertension in adults. Usual Dosage: 400-800 mg/d PO

IRBESARTAN Used on monotherapy in the treatment of HYPERTENSION but can be combined with other antihypertensive if needed. It is also used to slow the progression of kidney disease in patients with Hypertension and Type 2 Diabetes. The usual starting dosage is 150 mg once daily and can be uptitrated to 300 mg once daily (maintenance dose) A well established angiotensin receptor blocker, approved worldwide for the treatment of hypertension. It lowers blood pressure over 24 hours. The usual starting dosage is 150 mg once daily and can be uptitrated to 300 mg once daily. It is also approved for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. 300 mg once daily is the recommended maintenance dosage.

IRBESARTAN Pharmacology an imidazole derivate with a bipentyl-tetrazole side chain. Does not require biotransformation Has a high affinity for the AT1 receptor in human vascular smooth muscles. Absolute average bioavailability (60-80%), the highest in its class, and is not affected by food intake. an imidazole derivate with a bipentyl-tetrazole side chain. Does not require biotransformation to exert its pharmacological action Has a high affinity for the AT1 receptor in human vascular smooth mucles. Absolute average bioavailability (60-80%), the highest in its class, and is not affected by food intake.

Drug Interactions Pharmacokinetic profile is not affected by Nifedipine, warfarin, simvastatin, tolbutamide, hydrochlorothiazide, or magnesium-aluminum hydroxide. It does not alter the steady-state pharmacokinetics of digoxin. When combined with COX-2 inhibitor with normal renal function, it does not affect renal hemodynamics and renal salt handling.

Therapeutic efficacy Randomized active controlled or placebo-controlled trials up to 3 months duration. Irbesartan in monotherapy is found to be very effective in lowering both systolic and diastolic blood pressure. It is effective in producing a sustained 24 hour blood pressure control. Irbesartan was at least effective as losartan, more effective than valsartan, but less effective than olmesartan at reducing diastolic blood pressure.

Efficacy in hypertension when combined with other drugs Two placebo controlled studies in patients with mild-to-moderate hypertension showed that Irbesartan 150mg + hydrochlorothiazide 12.5mg reduced blood pressure more effectively than placebo or either drug alone. Two placebo controlled studies in patients with mild-to-moderate hypertension showed that Irbesartan 150mg + hydrochlorothiazide 12.5mg reduced blood pressure more effectively than placebo or either drug alone in bother seated blood pressure and 24 hour ambulatory blood pressure. 4x4 placebo-controlled study in 683 patients with mild-to-moderate hypertension: Randomized: Irbesartan (0-300mg once daily) + Hydrochlorothiazide (0-25mg once daily) Mean changes from baseline in blood pressure and total responder rates increased in a dose-dependent manner in both the single and combination therapy. Combination therapy was more effective than either drug alone.

Efficacy in hypertension when combined with other drugs Progressive uptitration to high dose Irbesartan-hydrochlorothiazide 300/25mg once daily lead to substantial reductions in systolic blood pressure (-23.0 + 13.3 mmHg, P< 0.001), between baseline and week 18. It allowed systolic blood pressure goals to be attained in 75% of patients.

Efficacy in diabetic nephropathy and cardiac disease Irbesartan improved microalbuminuria in normotensive subgroup of diabetic patients with early stage microalbuminuric nephropathy. It significantly reduced QT and corrected QT interval dispersion with a reduction in the risk of arrhythmias in cardiac disease. A dosage of 150-300 mg once daily was found to induce greater left ventricular mass index regression. The effect of Irbesartan on microalbuminuria was partly independent of its blood pressure lowering effect. The relative risk of reaching the composite primary endpoint (doubling baseline serum creatinine level, onset of end-stage renal disease, or death from any cause) was significantly lower with irbesartan 300 mg once daily than with placebo (unadjusted relative risk 0.80, 95% CI 0.66 0.97; P = 0.02) or with amlodipine 10 mg once daily (unadjusted relative risk 0.77, 95% CI 0.63–0.93; P = 0.006).

Persistence with a drug can be regarded as a good general indicator of the satisfaction of both patients and physicians with the efficacy and tolerability of the treatment.

CONCLUSION Irbesartan is an effective antihypertensive drug in variety of mild – to – moderate hypertensive population. It is found to be effective on patients with diabetes, obesity, renal insufficiency and cardiovascular disease. Its slows the progression of early stage and late stage renal disease in hypertensive patients with type 2 diabetes and reduces the risks of heart failure episodes Used as monotherapy or in association with hydrochlorothiazide, Irbesartan is an effective antihypertensive drug in variety of mild – to – moderate hypertensive population. It is found to be effective on patients with diabetes, obesity, renal insufficiency and cardiovascular disease. Its action slows the progression of early stage and late stage renal disease in hypertensive patients with type 2 diabetes and reduces the risks of heart failure episodes.

CONCLUSION Promotes regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. Prevents recurrence of arrhythmia in patients with persistent atrial fibrillation when added to classical antiarrhythmic therapy. Treatment with Irbesartan in hypertensive patients with type 2 diabetes and nephropathy resulted in improved life expectancy and appeared to be cost-saving and scores well for patient acceptation and adherence rates. Promotes regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. Prevents recurrence of arrhythmia in patients with persistent atrial fibrillation when added to classical antiarrhythmic therapy. Treatment with Irbesartan in hypertensive patients with type 2 diabetes and nephropathy resulted in improved life expectancy and appeared to be cost-saving and scores well for patient acceptation and adherence rates.