GEMVALAZ CO

Indications

• Mixed hyperlipidaemia
• Primary hypercholesterolaemia
• Adjunct to diet and other appropriate measures in patients where statins are contraindicated or not tolerated

Dosage

Adults: 600 mg taken twice daily, ideally 30 minutes before morning and evening meals. Maximum dose is 1.2 g daily.

Mechanism of action

Gemfibrozil activates peroxisome proliferator-activated receptor-alpha (PPARα), which modifies lipid metabolism. This activation enhances HDL, apo AI, and apo AII levels, increases lipoprotein lipase (LPL), inhibits apo B synthesis, reduces free fatty acid removal by the liver, and boosts clearance of apoB. The upregulation of LPL lowers plasma triglyceride levels, while decreased hepatic removal of fatty acids diminishes triglyceride production. These effects together reduce very-low-density lipoprotein (VLDL) production, further decreasing plasma triglyceride levels. Gemfibrozil's glucuronide metabolite also acts as an inhibitor of CYP2C8.

Pharmacodynamics

Gemfibrozil effectively alters lipid metabolism, making it beneficial for patients with hyperlipidaemia. It requires twice-daily dosing due to a mean residence time of up to 9.6 hours in patients with chronic renal failure. The drug has a wide therapeutic index, and higher doses have not been associated with severe side effects. However, patients may have an increased risk of gallstone formation and cholecystitis.

Pharmacokinetics

Gemfibrozil is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 4 hours. It undergoes extensive hepatic metabolism, primarily through glucuronidation, and has a plasma half-life of approximately 1.5 hours. The drug is excreted mainly in the urine, with renal impairment necessitating careful monitoring and possible dose adjustments.

Indications

• Hypertension
• Heart failure
• Prevention of cardiovascular events in patients with established atherosclerotic cardiovascular disease

Dosage

Children: For neonates, 250–500 micrograms/kg every 8–12 hours, increased if necessary to 2–3

Adults: Initially 80 mg once daily, increased if necessary up to a maximum of 320 mg daily, based on clinical response.

Mechanism of action

Valsartan selectively binds to angiotensin receptor 1 (AT1), preventing angiotensin II from exerting its hypertensive effects, such as vasoconstriction and aldosterone secretion. This blockade results in reduced blood pressure, lower aldosterone levels, decreased cardiac activity, and increased sodium excretion. Additionally, valsartan modulates the renin-angiotensin-aldosterone system (RAAS), which is critical in cardiovascular and kidney function regulation.

Pharmacodynamics

Valsartan inhibits the hypertensive effects of angiotensin II, with an oral dose of 80 mg achieving approximately 80% inhibition of the pressor effect at peak, and about 30% inhibition persisting for 24 hours. It minimally affects plasma aldosterone levels and does not significantly alter total cholesterol, triglycerides, serum glucose, or uric acid levels. Hypotension is rare, but caution is advised in patients with an activated renin-angiotensin system, such as those on high-dose diuretics or with heart failure.

Pharmacokinetics

Valsartan is well absorbed after oral administration, with peak plasma concentrations occurring within 2 to 4 hours. It has an elimination half-life of approximately 6 hours, with a bioavailability of around 25% due to first-pass metabolism. Valsartan is primarily eliminated via the feces and to a lesser extent through urine, with renal impairment not significantly affecting its pharmacokinetics.

Contra-indications

• Biliary obstructive disorders
• Cholestasis

Adverse effects

• Anaemia
• Arrhythmias
• Chest pain
• Cystitis
• Depression
• Dyspnoea
• Flatulence
• Gastrointestinal disturbances
• Interstitial lung disease
• Liver disorder
• Pain in extremities
• Sepsis
• Taste alteration
• Tendon pain
• Visual impairment

Interactions

• Taxanes (unknown effect on exposure)

Precautions

• Caution in patients with heart failure
• Monitor for symptomatic hypotension in patients with activated renin-angiotensin system
• Adjust dose in hepatic impairment
• Initial lower doses in renal impairment

Pregnancy

Use only if potential benefit justifies potential risk to the fetus. Contraindicated in the second and third trimesters due to potential harm.

Breast-feeding

Not recommended due to potential adverse effects on the infant.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Valsartan 40 mg capsules
• Valsartan 80 mg capsules
• Oral suspension

Mechanism of action

Gemfibrozil activates peroxisome proliferator-activated receptor-α (PPARα), which alters lipid metabolism. This activation leads to increased HDL, apo AI, apo AII, lipoprotein lipase (LPL), inhibition of apo B synthesis, peripheral lipolysis, decreased removal of free fatty acids by the liver, and increased clearance of apoB. Upregulated LPL reduces plasma triglyceride levels. Decreased hepatic removal of fatty acids decreases the production of triglycerides. The effects on apoB synthesis and clearance decrease VLDL production which also reduce plasma triglyceride levels. Gemfibrozil's glucuronide metabolite is also an inhibitor of CYP2C8. The present study underlines the importance of PI3K in mediating the anti-inflammatory effect of gemfibrozil, a prescribed lipid-lowering drug for humans, in mouse microglia. Gemfibrozil inhibited LPS-induced expression of inducible NO synthase (iNOS) and proinflammatory cytokines in mouse BV-2 microglial cells and primary microglia. By overexpressing wild-type and dominant-negative constructs of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in microglial cells and isolating primary microglia from PPAR-alpha-/- mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-alpha. Interestingly, gemfibrozil induced the activation of p85alpha-associated PI3K (p110beta but not p110alpha) and inhibition of that PI3K by either chemical inhibitors or dominant-negative mutants abrogated the inhibitory effect of gemfibrozil. Conversely, overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS-induced expression of proinflammatory molecules. Similarly, gemfibrozil also inhibited fibrillar amyloid beta (Abeta)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP+)-, but not IFN-gamma-, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on Abeta-, PrP-, poly IC-, Tat-, and MPP+-induced microglial expression of iNOS. Involvement of NF-kappaB activation in LPS-, Abeta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of IkappaBalpha expression and inhibition of NF-kappaB activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappaB and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of IkappaBalpha. ... After 2-4 months of gemfibrozil therapy in patients with type IIa, IIb, IV, or V hyperlipoproteinemia, HDL-apoprotein A-I (HDL-apoA-I) may be either unchanged or increased and HDL-apoprotein A-II (HDL-apoA-II) is increased. Unlike niacin, gemfibrozil has not been shown to reduce HDL2 catabolism. Gemfibrozil has been reported to increase the synthetic rates of HDL-apoA-I and HDL-apoA-II in patients with type V hyperlipoproteinemia. The HDL2 subfraction is increased to a greater degree than the HDL3 subfraction during gemfibrozil therapy. Low HDL2 concentrations have been reported to correlate with increased coronary heart disease. Gemfibrozil increases serum reserve cholesterol binding capacity (SRCBC), the capacity of serum to solubilize additional cholesterol, by about 60%. SRCBC exists in a subclass of HDL.31 In patients with types IIa, IIb, or IV hyperlipoproteinemia, serum concentrations of apoprotein B usually decrease during gemfibrozil therapy; decreases in apoprotein B follow changes in LDL-cholesterol. However, in another study in patients with primary hypertriglyceridemia associated with coronary heart disease (CHD), LDL-apoprotein B increased in a few patients. In patients with type V hyperlipoproteinemia, apoprotein B concentration has been reported to increase during gemfibrozil therapy. In humans, gemfibrozil inhibits lipolysis of fat in adipose tissue and decreases the hepatic uptake of plasma free fatty acids (i.e., free fatty acid turnov

Pharmacodynamics

Gemfibrozil alters lipid metabolism to treat patients with hyperlipidemia. The duration of action requires twice daily dosing as the mean residence time of gemfibrozil is up to 9.6h in patients with chronic renal failure. Gemfibrozil has a wide therapeutic index as trials with twice the standard dose were not associated with severe side effects. Patients taking gemfibrozil may be at an increased risk of developing cholelithiasis and cholecystitis, as seen in patients taking [clofibrate].

Mechanism of action

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. Valsartan, a nonpeptide tetrazole derivative, is an angiotensin II type 1 (AT1) receptor antagonist. Valsartan has pharmacologic actions similar to those of losartan; however, unlike losartan, valsartan is not a prodrug and its pharmacologic activity does not depend on hydrolysis in the liver. Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects, by selectively inhibiting access of angiotensin II to AT1 receptors within many tissues, including vascular smooth muscle and the adrenal gland. By comparison, angiotensin-converting enzyme (ACE, kininase II) inhibitors block the conversion of angiotensin I to angiotensin II; however, the blockade of angiotensin II production by ACE inhibitors is not complete since the vasopressor hormone can be formed via other enzymes that are not blocked by ACE inhibitors. Because valsartan, unlike ACE inhibitors, does not inhibit ACE, the drug does not interfere with response to bradykinins and substance P; a beneficial consequence is the absence of certain ACE inhibitor-induced adverse effects (e.g., cough),

Pharmacodynamics

Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. **Hypotension** Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. **Impaired Renal Function** Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. **Hyperkalemia** Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required.