Nebivolol And Valsartan

Uses

Nebivolol is used for the treatment of essential hypertension and adjunct in stable mild to moderate heart failure in patients over 70 years.

Valsartan is used for:

• For hypertension
• To reduce hospitalizations in patients with congestive heart failure
• To reduce death in patients who developed congestive heart failure after myocardial infarction

Nebivolol And Valsartan is also used to associated treatment for these conditions: High Blood Pressure (Hypertension)Cardiovascular Mortality, Diabetic Nephropathy, High Blood Pressure (Hypertension), Left Ventricular Dysfunction, Moderate Essential Hypertension, Chronic heart failure with reduced ejection fraction (NYHA Class II), Chronic heart failure with reduced ejection fraction (NYHA Class III), Chronic heart failure with reduced ejection fraction (NYHA Class IV), Hospitalization due to cardiac failure

How Nebivolol And Valsartan works

Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2 adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol leads to decreased resting heart rate, exercise heart rate, myocardial contracility, systolic blood pressure, and diastolic blood pressure. The selectivity of d-nebivolol limits the magnitude of beta blocker adverse effects in the airways or relating to insulin sensitivity. Nebivolol also inhibits aldosterone, and beta-1 antagonism in the juxtaglomerular apparatus also inhibits the release of renin. Decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. l-nebivolol is responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, increasing nitric oxide levels; leading to vasodilation, decreased peripheral vascular resistance, increased stroke volume, ejection fraction, and cardiac output. The vasodilation, reduced oxidative stress, and reduced platelet volume and aggregation of nebivolol may lead to benefits in heart failure patients.

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy.

The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized.

Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease.

Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor.

Dosage

Nebivolol And Valsartan dosage

Adults: 5 mg daily, maximum recommended dose 40 mg once daily.

Renal Impairment: In patients with severe renal impairment the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.

Hepatic Impairment: In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.

Geriatric Patients: It is not necessary to adjust the dose in the elderly.

Pediatric Use: Safety and effectiveness of Nebivolol in pediatric patients have not been established.

Hypertension: The usual dose of Valsartan is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks.

Heart failure:The usual dose is 40 mg twice daily and may be increased to 80-160 mg twice daily.

Post-Myocardial Infarction:The initial dose after myocardial infarction is 20 mg twice daily. The dose should be increased with a target of 160 mg daily if tolerated without side effects.

Administration of Valsartan with food decreases the absorption of Valsartan by about 40%, so it should be taken on an empty stomach. No initial dosage adjustment is required for elderly patients with mild to moderate renal and hepatic insufficiency.

Side Effects

The most common side effects are headache, nausea and bradycardia.

Valsartan is generally well tolerated and side effects are rare. The most common side effects include headache, dizziness, fatigue, abdominal pain, cough, diarrhea and nausea. Patient may also experience hyperkalemia, impotency, reduced renal function, allergic reactions, dyspnea, constipation, back pain, muscle cramps, rash, anxiety, insomnia and vertigo. Hypotension may also occur if patient have been taking diuretics along with Valsartan.

Toxicity

Patients experiencing an overdose may present with bradycardia, hypotension, cardiac failure, dizziness, hypoglycemia, fatigue, vomiting, bronchospasm and heart block. Treat overdose with general supportive measures including intravenous atropine for bradycardia, vasopressors and intravenous fluids for hypotension, isoproterenol infusion for heart block, digitalis glycosides and diuretics for congestive heart failure, bronchodilators for bronchospasm, and intravenous glucose for hypoglycemia.

Approximate LD50 >2000 mg/kg (Gavage, rat) [F3139]

Reproductive Toxicology Studies

No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation.[F4607]

Pregnancy

When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible.[F4607]

Precaution

Patients with inadequate cardiac function, well-compensated heart failure, myasthenia gravis. Patients undergoing major surgery involving general anaesth. May mask signs and symptoms of hypoglycaemia and hyperthyroidism. Abrupt withdrawal may exacerbate angina symptoms and/or precipitate MI and ventricular arrhythmias in patients with coronary artery disease. Pregnancy and lactation.

Impaired Hepatic Function: As the majority of Valsartan is eliminated in the bile, care should be exercised in patients with mild to moderate hepatic impairment including biliary obstructive disorder.

Impaired Renal Function: Dosage reduction or discontinuation may be required with patients having pre-existing renal impairment.

Heart Failure and Myocardial Infarction: Caution should be exercised when initiating therapy in patients with heart failure and post-myocardial infarction patients.

Interaction

Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.), Do not use Nebivolol with other β-blockers, both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia, Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (verapamil and diltiazem), or antiarrhythmic agents, such as disopyramide.

No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include Cimetidine, Warfarin, Furosemide, Digoxin, Atenolol, Indomethacin, Hydrochlorothiazide, Amlodipine and GlibenclamideAs Valsartan is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with Valsartan. Although valsartan is highly bound to plasma proteins, in vitrostudies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as Diclofenac, Furosemide, and Warfarin. Concomitant use of potassium sparing diuretics (e.g., Spironolactone, Triamterene, Amiloride) potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium. If co medication is considered necessary, caution is advisable

Volume of Distribution

For a 20mg dose, d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72L, l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50L, and both enantiomers together have a volume of distribution of 10,423.42±6796.50L.

The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.[F3139,F3607]

Elimination Route

The absorption of nebivolol is not affected by food. Nebivolol has a T_max of 1.5-4 hours. Bioavailability can range from 12-96% for extensive to poor CYP2D6 metabolizers. For a 20mg dose, d-nebivolol has a C_max of 2.75±1.55ng/mL, l-nebivolol has a C_max of 5.29±2.06ng/mL, both enantiomers have a C_max of 8.02±3.47ng/mL, and nebivolol glucuronides have a C_max of 68.34±44.68ng/mL. For a 20mg dose, d-nebivolol has an AUC of 13.78±15.27ng*h/mL, l-nebivolol has an AUC of 27.72±15.32ng*h/mL, both enantiomers have an AUC of 41.50±29.76ng*h/mL, and nebivolol glucuronides have an AUC of 396.78±297.94ng*h/mL.

After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients.[F3139] Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan genereally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.[F4607]

Half Life

d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers.

After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.[F4607]

Clearance

For a 20mg dose, the clearance of d-nebivolol is 1241.63±749.77L/h, l-nebivolol is 435.53±180.93L/h, and both enantiomers is 635.31±300.25L/h.

Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).[F4607]

Elimination Route

In extensive CYP2D6 metabolizers, 38% is eliminated in the urine and 44% in the feces. In poor CYP2D6 metabolizers, 67% is eliminated in the urine and 13% in the feces. 5

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.[F4607]

Pregnancy & Breastfeeding use

Pregnancy category C and not recommended during nursing.

Pregnancy: Valsartan should not be used in pregnancy, as in 2nd and 3rd trimester it can cause injury and even death to fetus. When pregnancy is detected, Valsartan should be stopped as soon as possible.

Nursing mothers: It is not known whether Valsartan is excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Nebivolol is contraindicated in the following conditions: severe bradycardia, heart block greater than first degree, patients with cardiogenic shock, decompensated cardiac failure, sick sinus syndrome, patients with severe hepatic impairment, patients who are hypersensitive to any component of this product.

Valsartan is contraindicated in patients who are hypersensitive to any component of this product.

Special Warning

Pediatric use: Safety and effectiveness in paediatric patients have not been established.Geriatric use: No overall difference in the efficacy or safety of Valsartan was observed in this patient population, but greater sensitivity of some elderly persons cannot be ruled out.Hepatic Impairment:

• Mild to moderate: Max: 80 mg once daily.
• Severe: Contraindicated.

Acute Overdose

Symptoms: Bradycardia, hypotension, cardiac failure, dizziness, fatigue, hypoglycaemia, vomiting, bronchospasm, heart block.

Management: Symptomatic and supportive treatment. IV atropine may be given for bradycardia, if it persists, admin IV isoproterenol cautiously. For hypotension, admin IV fluids and vasopressors. IV glucagon may also be useful. A β2-agonist and/or aminophylline for bronchospasm. Admin IV glucose for hypoglycaemia and an IV cardiac glycoside and diuretic may be used for CHF.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia, bradycardia could occur from parasympathetic (vagal) stimulation. If excessive hypotension occurs, the patient should be placed in the supine position and if necessary, has to be given an intravenous infusion of normal saline.

Storage Condition

Store between 20-25° C. Protect from light. Keep out of the reach of children.

Store between 15-30° C. Protect from moisture and heat.

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