CILNIDONE VT (5+160+12.5)

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

Indications

• Hypertension
• Edema associated with heart failure
• Edema due to liver cirrhosis
• Edema related to renal dysfunction

Dosage

Adults: The usual initial dose for adults is 12.5 mg once daily, which may be increased to 25 mg if necessary. For hypertension management, doses may vary based on individual patient

Mechanism of action

Chlorthalidone prevents reabsorption of sodium and chloride by inhibiting the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. This inhibition leads to an osmotic diuresis, reducing extracellular fluid and plasma volume. The increased sodium delivery to the distal renal tubule causes enhanced potassium excretion through the sodium-potassium exchange mechanism. The antihypertensive effect is attributed to decreased plasma volume, which lowers cardiac output and ultimately reduces blood pressure. Additionally, chlorthalidone may decrease platelet aggregation and vascular permeability, contributing to cardiovascular risk reduction.

Pharmacodynamics

Chlorthalidone exhibits dose-dependent diuretic effects, leading to increased urine output and a reduction in plasma volume. This results in lower cardiac output initially, followed by a decrease in total peripheral resistance, which helps in lowering blood pressure. The drug's ability to affect renal tubular transport of ions also plays a significant role in its therapeutic effects.

Pharmacokinetics

Chlorthalidone is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 2 to 6 hours after oral administration. It has a long half-life, allowing for once-daily dosing. Chlorthalidone is primarily eliminated via the kidneys, with about 60-70% of the dose excreted unchanged in the urine. Its pharmacokinetics can be affected by renal function, necessitating dose adjustments in patients with impaired renal clearance.

Contra-indications

• Hypersensitivity to chlorthalidone or any of its components
• Anuria
• Severe renal impairment
• Electrolyte imbalances, particularly hypokalemia
• Pregnancy (in certain cases)

Adverse effects

• Hypokalemia
• Hyponatremia
• Hyperuricemia
• Gastrointestinal disturbances
• Dizziness
• Headache
• Fatigue
• Rash
• Photosensitivity
• Increased blood sugar levels

Interactions

• Other antihypertensive agents (may enhance hypotensive effects)
• Non-steroidal anti-inflammatory drugs (NSAIDs) (may reduce diuretic effect)
• Lithium (may increase lithium levels)
• Digoxin (enhanced risk of toxicity due to hypokalemia)
• Corticosteroids (may exacerbate hypokalemia)

Precautions

• Monitor electrolyte levels, particularly potassium and sodium
• Use with caution in patients with renal impairment
• Assess volume status in patients at risk of dehydration
• Caution in patients with diabetes mellitus due to possible effects on glucose metabolism
• Consider potential for photosensitivity

Pregnancy

Chlorthalidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is generally advised to avoid use in the first trimester.

Breast-feeding

Chlorthalidone is excreted in breast milk, caution is advised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 25 mg, 50 mg

Indications

• Hypertension
• Essential hypertension

Dosage

Children: Refer to BNF for Children for specific dosing guidance.

Adults: Refer to BNF for specific dosing guidance.

Mechanism of action

Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. It also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure.

Pharmacodynamics

Administration of cilnidipine has been shown to present an antisympathetic profile in vitro and in vivo. It decreases blood pressure safely and effectively without excessive blood pressure reduction or tachycardia.

Contra-indications

• Hypersensitivity to cilnidipine or any of its components
• Severe hypotension
• Aortic stenosis
• Cardiogenic shock

Adverse effects

• Headache
• Dizziness
• Flushing
• Peripheral edema
• Palpitations
• Constipation
• Nausea

Interactions

• May enhance the effect of other antihypertensive agents
• Caution when used with calcium channel blockers
• May interact with drugs that affect cytochrome P450 enzymes

Precautions

• Use with caution in patients with hepatic or renal impairment
• Monitor blood pressure regularly during therapy
• Caution in elderly patients and those with a history of heart failure

Pregnancy

Cilnidipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines.

Breast-feeding

It is not known whether cilnidipine is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 20 mg

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.

Mechanism of action

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects. ...ACT BY INHIBITING RENAL TUBULAR TRANSPORT OF VARIOUS IONS. Decreased plasma volume and decreased extracellular fluid volume; decreased cardiac output initially, followed by decreased total peripheral resistance with normalization of cardiac output ... /from table/ ...ANTIHYPERTENSIVE EFFECT OF CHLORTHALIDONE IS THOUGHT TO BE DUE TO DECR CARDIAC OUTPUT. The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. Initially the drugs decrease extracellular volume and cardiac output. However, the hypotensive effect is maintained during long-term therapy because of reduced vascular resistance ... /Diuretics/ For more Mechanism of Action (Complete) data for CHLORTHALIDONE (8 total), please visit the HSDB record page.

Mechanism of action

Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. Cilnidipine also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure.

Pharmacodynamics

Administration of cilnidipine has been shown to present an antisympathetic profile in vitro and in vivo. It decreases blood pressure safely and effectively without excessive blood pressure reduction or tachycardia.