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

1. Long-term use and tolerability of Irbesartanfor control of Hypertension

2. ValentinaForni, GregoireWuerzner, Menno Pruijm, Michel Burnier Service of Nephrology and Hypertension, Department of Medicine, Centre HospitalierUniversitaireVaudois, Lausanne, Switzerland Reported by: DR. MARVIN JINO S. BUGNA

3. 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.

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

5. Hypertension Types 1. PRIMARY (Essential) • 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

7. 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

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

9. 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

10. 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

11. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

12. Angiotensin Receptor Blockers • Drugs that block the action of angiotensin II, permitting the blood vessels to relax and dilate lowering the blood pressure.

13. 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.

16. IRBESARTAN • Used on monotherapy in the treatment of HYPERTENSIONbut can be combined with other antihypertensive if needed. • It is also used to slow the progression of kidney diseasein 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)

17. IRBESARTANPharmacology • 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. Efficacy in diabetic nephropathy and cardiac disease • Irbesartan improved microalbuminuria in normotensive subgroup of diabetic patients with early stage microalbuminuricnephropathy. • 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.

24. 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

25. 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.