GARDIA® PLUS (16/12.5)MG TABLETS

Indications

• Hypertension
• Edema associated with congestive heart failure
• Edema due to renal dysfunction

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: 2.5 mg daily, taken in the morning for hypertension; higher doses may be used for other indications.

Mechanism of action

Hydrochlorothiazide is transported into epithelial cells of the distal convoluted tubule via organic anion transporters OAT1, OAT3, and OAT4. It inhibits the sodium-chloride symporter (SLC12A3), preventing sodium reabsorption. This action reduces the concentration gradient that promotes water reabsorption, leading to increased urine production.

Pharmacodynamics

Hydrochlorothiazide increases the excretion of sodium and water, thereby promoting diuresis. It is effective in lowering blood pressure and has a wide therapeutic range, with doses typically ranging from 25 to 100 mg. The drug exhibits a greater antihypertensive effect at lower doses due to enhanced vasodilation, while higher doses primarily exert their effects through diuresis. Caution is advised in patients with renal or hepatic impairment.

Pharmacokinetics

Hydrochlorothiazide is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours post-administration. It has a half-life of about 6-15 hours, depending on individual patient factors. The drug is primarily excreted unchanged in the urine. Dosage adjustments may be necessary in patients with renal impairment due to the risk of accumulation.

Contra-indications

• History of hypersensitivity to sulfonamides
• Acute porphyrias
• Severe renal impairment

Adverse effects

• Angina pectoris
• Arrhythmias
• Arthralgia
• Asthenia
• Chest pain
• Confusion
• Dry mouth
• Haemolytic anaemia
• Hepatic disorders
• Hyperkalaemia
• Hypokalemia
• Nausea
• Rhabdomyolysis
• Syncope
• Vertigo

Interactions

• Potassium-sparing diuretics
• Other antihypertensives
• Lithium
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids

Precautions

• Diabetes mellitus
• Elderly patients
• Basal cell carcinoma
• Cutaneous lupus erythematosus
• Patients with hepatic impairment
• Monitoring of electrolytes

Pregnancy

Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is advisable to avoid use, especially during the first trimester.

Breast-feeding

Hydrochlorothiazide is present in breast milk; however, the amount is probably too small to be harmful. Caution is advised as large doses may suppress lactation.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets: 12.5 mg, 25 mg
• Oral solution
• Combination products with amiloride

Indications

• Hypertension
• Heart failure
• Left ventricular dysfunction post-myocardial infarction

Dosage

Children: For children aged 1 to 17 years, the dose is based on body weight. The recommended starting dose is 0.05 to 0.1 mg/kg once daily, with a maximum dose of 0.4 mg/kg or 32 mg, whichever is lower.

Adults: The typical adult starting dose for hypertension is 8 mg once daily, which may be increased to a maximum of 32 mg once daily based on blood pressure response.

Mechanism of action

Candesartan selectively antagonizes the type I angiotensin II receptor (AT1), preventing angiotensin II from exerting its vasoconstrictive and aldosterone-secreting effects. This inhibition allows for vasodilation and decreased aldosterone release, promoting sodium excretion and lowering blood pressure. Candesartan does not affect the degradation of bradykinin, thus minimizing the common side effects associated with ACE inhibitors, such as cough and angioedema.

Pharmacodynamics

Candesartan effectively reduces systemic vascular resistance and lowers blood pressure, which can lead to a decrease in myocardial oxygen demand. Its long duration of action allows for once-daily dosing, and it has shown efficacy in both monotherapy and in combination with other antihypertensive agents. It also demonstrates cardioprotective effects, making it beneficial in the management of heart failure.

Pharmacokinetics

Candesartan is well-absorbed following oral administration, with peak plasma concentrations occurring approximately 1 to 3 hours after dosing. It has a bioavailability of around 15% due to extensive first-pass metabolism. Candesartan is primarily excreted via the kidneys, with a half-life of about 9 hours. The presence of food does not significantly affect its absorption.

Contra-indications

• Hypersensitivity to candesartan or any of its excipients
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Dizziness
• Fatigue
• Hypotension
• Hyperkalemia
• Renal impairment
• Angioedema

Interactions

• Other antihypertensive agents may increase the hypotensive effect
• Potassium-sparing diuretics or potassium supplements may increase the risk of hyperkalemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect and increase the risk of renal impairment

Precautions

• Caution in patients with renal artery stenosis
• Monitor renal function, especially in patients with pre-existing renal impairment
• Caution in patients with aortic stenosis or hypertrophic cardiomyopathy
• Use with caution in patients with a history of angioedema

Pregnancy

Candesartan is contraindicated in pregnancy due to potential harm to the fetus, particularly in the second and third trimesters.

Breast-feeding

Candesartan is excreted in breast milk, and caution should be exercised when administering to breastfeeding women.

Storage

Store below 25°C in a dry place, protect from light.

Formulations

• Tablets: 4 mg, 8 mg, 16 mg, 32 mg

Indications

• Hypertension
• Heart failure
• Certain cardiovascular conditions

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Refer to the BNF for specific dosing information.

Mechanism of action

Cilexetil is converted to its active form, which blocks the action of angiotensin II, a potent vasoconstrictor involved in blood pressure regulation. By inhibiting the angiotensin II receptor, cilexetil promotes vasodilation and decreases peripheral vascular resistance, leading to a reduction in blood pressure.

Pharmacodynamics

Cilexetil's antihypertensive effects are realized through its antagonistic action on the angiotensin II receptors, which results in decreased levels of aldosterone, inhibition of vasoconstriction, and reduced secretion of antidiuretic hormone. The overall pharmacodynamic profile contributes to improved cardiac output and reduced workload on the heart.

Pharmacokinetics

Cilexetil is well-absorbed following oral administration and undergoes extensive first-pass metabolism to its active metabolite. The pharmacokinetic profile indicates a moderate half-life, allowing for once-daily dosing. The distribution of cilexetil is extensive, with high protein binding rates, primarily to serum albumin. Metabolism occurs mainly in the liver, and renal excretion is the primary route for elimination of the drug and its metabolites.

Pregnancy

There is limited data on the use of cilexetil in pregnancy. Caution is advised.

Breast-feeding

It is not known whether cilexetil is excreted in human milk. Caution is recommended.

Storage

Store in a cool, dry place away from direct sunlight and moisture.

Mechanism of action

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Pharmacodynamics

Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function.

Mechanism of action

Although these agents /angiotensin II receptor antagonists/ are similar to ACE inhibitors in that they decrease the effects of angiotensin II, rather than decreasing the formation of angiotensin II, drugs antagonize angiotensin II at the type I angiotensin receptor. This allows the drugs to inhibit the vasoconstrictive and aldosterone promoting effects of angiotensin II without interfering with bradykinin degradation, significantly reducing the adverse effects of cough and angioedema seen with ACE inhibitor therapy. ... /Angiotensin II receptor antagonists/ Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the ATI receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.