Irbesartan (IRB) : it is a drug used orally for the dealing with hypertension , is a nonpeptide, special competitive antagonist of the Angiotensin II receptor (AT1 subtype). 75 The medicine is lipophilic and practically insoluble in water.
Irbesartan (IBS) figure 1. is used for treatment of hypertension. it part of class II drug according to biopharmaceutical classification system (BCS)76 . i.e. low solubility and high permeability. According to BCS drug substance is measured to be highly soluble when highest dose of drug dissolve in less than 250 ml of water. It is measured to be highly permeable when the extent of absorption in human is more than 90% of an administered dose.
It is a potent and selective angiotensin II subtype receptor antagonist indicated for the use in patients with type 2diabetes and nephropathy.
And it is effective in reducing hypertension Hypertension is the most prevalent modifiable risk factor for cardiovascular disease.77
Figure 1 : The chemical structure of irbesartan.
Mechanism of Action :
Angiotensin II is a potent vasoconstrictor made from angiotensin I in a reaction catalyzed by angiotensin – converting enzyme (ACE, kininase III). Angiontensin II is the principal presser agent of the renin – angiontensin system (RAS) and also inspires aldosterone synthesis and secretion by adrenal rotex, cardiac contraction , renal resorption of sodium, action of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan block the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively binding of the AT1 angiotensin II receptor.
There is also an AT2 receptor in many tissues, but not involved in cardiovascular homeostasis. Irbesartan is a specific competitive.
antagonist of AT1 receptors with a much greater affinity for the AT1receptor than for the AT2 receptor and no agonist activity Blockade of the AT1 receptor removes the negative feedback of angiotensin Il on renin secretion, but the subsequent increased plasma remin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure Irbesartan doesn’t inhibit ACE or renin or affect other hormone receptors or ion channels identified to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin, whether this has clinical relevance is not known. 78
PHARMACOKINETICPROFILE OF IRBESARTAN
Irbesartan has an excellent pharmacokinetic profile that is unique among AIIRA (Table 1). It has the highest oral bioavailability in its class, is well absorbed in the presence or absence of food, has a prolonged elimination half-life (T1/2)has the highest plasma free fraction of the AIIRA, and does not rely on biotransformation for its pharmacologic effect In addition, the pharmacokinetics of irbesartan are not altered in patientswith renal or hepatic impairment or based on differences in gender or age.
Absorption The oral absorption of irbesartan is rapid and complete, with an average absolute bioavailability of 60% to 80%.2 Its oral bioavailability is higher than that of other AIRA, including losartan (33%)3 and valsartan (10% to 35%) (Table 1).4 Peak plasma concentrations of irbesartan are attained within 1.5 to 2 h after oral administration (Figure 2.5 Food does not affect the bioavailability of
irbesartan,6,7 whereas food decreases the area under the concentration-time curve (AUC) of valsartan by 40% and reduces the maximum concentration (Cmax) by 50%.4 The absorption of losartan is ?slightly delayed by food.3 The results of two double blind, placebo controlled studies involving 88 healthy subjects demonstrate that irbesartan displays linear, dose-related pharmacokinetics (Figure 3) and. with the exception of tasosartan’s active metabolite, has the longest T1/2 (11 to 15 h) of the AIRA (Table 1) 5 (data file Bristol-Myers Squibb/sanofi). Steady state concentrations of irbesartanare achieved within 3 days of once daily oral dosingand limited accumulation of irbesartan is observed in plasma with repeated administration.5
Protein Binding: Another distinguishing feature of irbesartan is that it has the highest plasma free fraction(10%) in its class (data on file, Bristol Myers Squibb/Sanofi) limiting the potential for interaction with drugs highly bound to proteins losartan,3 EXP 3174,3 valsartan,4 and candesartan8 are more highly bound to plasma proteins (Table 1).
Metabolism and Excretion: Irbesartan does not require biotransformation for its pharmacologic activity.9 In contrast, much of the All inhibiting effect of losartan, candesartan, and tasosartan can be attributed to their active metabolites EXP 3174,10 CV-11974,8 and enoltasosartan,11 respectively, The results of in vitro studies indicate that glucuronidation and oxidation are the major routes of metabolism of irbesartan and that the cytochrome P450 isoform 209 is the primary pathway for oxidation12 (data on file, Bristole Myers Squibb/Sanofi). Metabolism by the cytochrome P450 isoform 3A4 is negligible.
Irbesartan metabolites have been identified in human plasma ,urine, and
feces. following oral or intravenous administarion of 14c-laberea irbesartan, more than 80% of the circulating plasma radioactivity is atributable to unchanged irbesartan. The primary circulating metabolite is the irbesartan glucuronide (%6%). Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of radioactivity is recovered in the urine and the remainder in the feces (data on file, BristolMyers Squibb/Sanofi).
Patients with Renal or Hepatic Impairment An open label, parallel study compared the single dose and steady state pharmacokinetics of irbesartan in 39 patients with vanying degrees of renal function, as assessed by 24 h creatinine clearance (CrCI).13 Patients had either normal (24-h crCI. 74 m//min/1.73 m2), mild-to-moderate (24 hCrC 30 to 74 mumin/1.73 m2), or severe (24 h CrCI , 30 ml/min/1.73 m2) renal impairment, or required hemodialysis Irbesartan was administered at a once daily dosage of 100 mg for 8 days. Patients on hemodialysis received a higher dose of irbesartan (300 mg) for g days to provide better blood pressure control. There were no statistically significant differences among the four groups in the dose normalized AUc for irbesartan (Figure 4) and no indication of drug accumulation. Irbesartan was not cleared by hemodialysis, as the concentrations of irbesartan in the venous and arterial blood of patients during hemodialysis were similar Another open label, parallel study compared the single dose and steady state pharmacokinetics of irbesartan in 10 patients with hepatic cirrhosis and a matched group of 10 subjects with normal hepatic function.14 Irbesartan was administered at a once daily dosage of 300 mg for 7 days. There were no statistically significant differences between the two groups in AUC or C max of irbesartan Figure s) and no indication
of drug accumulation. The time of maximum concentration (Tmax) and T1/2 or irbesartan also remained constant. Thus, the pharmacokinetics of irbesartan is not altered in patients with renal or hepatic impairment and, therefore, no adjustment of irbesartan dosage is necessary in these patient populations. These findings are likely due to irbesratan’s dual excretion character- istic. in contrast , plasma concentrations of losartan and its active metabolite are reported to be 5 times and 1.7 times higher, respectively , in patients with mildto- moderate hepatic cirrhosis compared with normal subject.3 A lower starting dosage of losartan may therefore be required in patients with a history of hepatic impairment. 3
Age or Gender Differences
The Single does pharmacokinetics of irbesartan were assessed in an open label, paralled study involving 48 healthy subjects. 15 subjects were classified as young men (mean age, 30 years) , young women (mean age, 31 years), elderly men (mean age, 72 years) , and elderly women (mean age, 69 years). irbesartan was administered as a 50 mg dose after an overnight fast. No statistically significant gender related effects were observed in AUC to infinity (AUCO-‘) , Cmax, Tmax, or T1/2. The geometric mean AUCO-‘ and Cmax of irbesartan were statistically significantly increased in elderly subjects compared with those of young subjects; however , the T1/2 of irbesartan and the total cumulative amount of irbesartan excreted unchanged in the urine were comparable in these patient subgroups. Because the previous study was conducted with a 50 mg oral dose , which is not within the rapeutically effective dose range of irbesartan (150 t0 300 mg) , another open label, parallel
Study was performed to assess the effect of age on the pharmacokinetics of higher dose of irbesartan. 16 in this study, 12 healthy young subjects (mean age, 29 years) and 12 healthy elderly subject (mean age, 69 years) received a single, oral dose of irbesartan 150 mg after an overnight fast. No statistically significant differences were observed between the two groups in AUCO-‘, Cmax, Tmax, or T1/2; mean AUCO-‘ and Cmax were about 20% higher in elderly subjects. Based on the comparable efficacy and safety profile or irbesratan in young and elderly patients with hypertension (data on file, Bristol – Myers Squibb Sanofi) , the magnitude of the observed pharmacokinetic differences by age do not appear to be clinically significant. Thus , no adjustment of irbesartan dosage is necessary based on gender or age.
Side Effects :
Irbesratan may cause side effects:
• excessive tiredness
Some side effects can be serious :
• Swelling of the face, throat, tongue , lips , eyes, hands , geet, angles, or lower legs.
• difficulty breathing or swallowing.79
Drug – drug interaction :
1. ibuprofen ? irbesartan : Combining these medications may reduse the effects of irbesartan in lowering blood pressure. in addition , these medications may affect the renal function , especially by using together frequently or chronically ; developing impaired kidney function during treatment with these medications if adding to them a diuretic also in elderly patient or having preexisting kidney disease. the signs and symptoms that may suggest kidney damage are nausea, vomiting , loss of appetite, increased or decreased urination , sudden weight gain or weight loss, fluid retention, swelling, shortness of breath, muscle cramps, tiredness, weakness, dizziness, shortness of breath, muscle cramps, tiredness, weakness, dizziness, confusion , and irregular heart.
2. Aspirin ? irbesartan combining these medications may reduce the effects of irbesartan in lowering blood pressure. in addition , these medications may affect renal function , especially when they are used together frequently or chronically. impaired kidney function during treatment with these medications increasing by also using a diuretic with them and in elderly or have preexisting kidney disease.
3. Codeine ? irbesartan have additive effects in lowering your blood pressure. The symptoms are headache, dizziness, lightheadedness , fainting , and/ or changes in pulse or hear rate. Especially at the beginning of treatment.
4. Irbesartan ? pregabalin may cause angioedema, a condition associated with swelling of the face, eyes, lips , tongue , throat, and occasionally also the hands and feet. Each medication alone can
also cause angioedema , but the risk may be increased when they are combined. Angioedema can occur with the first dose of medication or after many doses.
5. Irbesartan ? sildenafil can add to the blood pressure- lowering effect of irbesartan. signs and symptoms of low blood pressure such as dizziness, lightheadedness, fainting, flushing , headache , or a rapid pulse or heart rate. Especially at the beginning of treatment , following a dose increase.