COLOSAR-DENK 50/12.5

Indications

• Hypertension
• Chronic heart failure when ACE inhibitors are unsuitable
• Diabetic nephropathy in type 2 diabetes mellitus

Dosage

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

Adults: Initially 50 mg once daily for adults aged 18–75 years, and 25 mg once daily for adults aged 76 years and over. Doses may be increased to 100 mg once daily if necessary.

Mechanism of action

Losartan selectively blocks the binding of angiotensin II to the AT1 receptor, leading to vasodilation, decreased secretion of aldosterone, and reduced blood pressure. This mechanism also contributes to renal protection in diabetic patients by reducing glomerular pressure.

Pharmacodynamics

Losartan exhibits dose-dependent antihypertensive effects, with initial doses often resulting in a reduction of blood pressure within 6 hours. The peak effect is typically reached within 4 to 6 weeks of treatment. Additionally, losartan has a protective effect on renal function in patients with diabetic nephropathy.

Pharmacokinetics

Losartan is well absorbed after oral administration, with a bioavailability of approximately 33%. It is extensively metabolized in the liver to its active metabolite, E3174, which has a longer half-life than losartan itself. The elimination half-life of losartan is around 2 hours, while that of E3174 is approximately 6 to 9 hours. Both losartan and E3174 are primarily excreted in the urine, and renal impairment may affect their clearance.

Contra-indications

• Hypersensitivity to losartan or any of the excipients
• Severe hepatic impairment
• Pregnancy
• Bilateral renal artery stenosis or unilateral renal artery stenosis in a solitary kidney
• History of angioedema

Adverse effects

• Dizziness
• Hypotension
• Hyperkalaemia
• Fatigue
• Postural hypotension
• Abdominal pain
• Nausea
• Diarrhoea
• Headache
• Musculoskeletal pain
• Renal impairment

Interactions

• Other antihypertensive agents may enhance the hypotensive effect
• Potassium supplements or potassium-sparing diuretics may increase the risk of hyperkalaemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Lithium levels may be increased when taken with losartan

Precautions

• Monitor renal function and electrolytes in patients with renal impairment
• Use with caution in patients with a history of angioedema
• Caution in patients with volume depletion
• Not recommended for use in patients with severe heart failure

Pregnancy

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

Breast-feeding

It is not known whether losartan is excreted in human milk; caution is advised when administering to breastfeeding women.

Storage

Store at room temperature (15 to 30 degrees Celsius), protected from light and moisture.

Formulations

• Losartan potassium 12.5 mg tablets
• Losartan potassium 25 mg tablets
• Losartan potassium 50 mg tablets
• Losartan potassium 100 mg tablets
• Losartan with hydrochlorothiazide 50 mg/12.5 mg tablets
• Losartan with hydrochlorothiazide 100 mg/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
• Diabetic nephropathy
• Reduction of stroke risk in certain populations

Dosage

Children: For paediatric patients aged 6 years and older, the starting dose is usually 0.7 mg/kg once daily, with a maximum of 50 mg daily. Dosing should be adjusted based on blood pressure response and tolerance.

Adults: The typical adult dose for hypertension is 50 mg once daily, which may be increased to a maximum of 100 mg once daily, depending on response.

Mechanism of action

Losartan reversibly and competitively prevents angiotensin II from binding to the AT1 receptor in various tissues, including vascular smooth muscle and the adrenal gland. By doing so, it causes relaxation of vascular smooth muscle, leading to decreased blood pressure. Losartan's active metabolite is significantly more potent as an AT1 receptor inhibitor and further enhances the drug's efficacy in blocking the vasoconstrictor and aldosterone-secreting effects of angiotensin II.

Pharmacodynamics

Losartan is classified as an angiotensin II receptor blocker that effectively lowers blood pressure and is indicated for diabetic nephropathy. It has a long duration of action, which supports its once-daily administration. Regular monitoring of patients is recommended to assess for hypotension, renal function, and potassium levels, as the drug can affect these parameters.

Pharmacokinetics

Losartan is well absorbed and undergoes extensive first-pass metabolism, resulting in an active metabolite that contributes to its therapeutic effects. The drug is primarily eliminated through the urine and feces. The half-life of losartan and its active metabolite allows for stable plasma concentrations with once-daily dosing, but renal impairment may affect its clearance.

Contra-indications

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

Adverse effects

• Dizziness
• Hypotension
• Hyperkalemia
• Renal impairment
• Fatigue
• Headache
• Diarrhea

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect of losartan
• Lithium levels may increase when used concurrently with losartan

Precautions

• Monitor blood pressure regularly
• Assess renal function before and during treatment
• Caution in patients with a history of angioedema
• Use with caution in patients with renal artery stenosis

Pregnancy

Losartan is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Losartan is excreted in breast milk, caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place at room temperature, away from direct sunlight.

Formulations

• Tablets: 25 mg, 50 mg, 100 mg

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

Losartan reversibly and competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with 1000 times more affinity than they bind to the AT₂ receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT₁ and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT₁ receptor and induce vasoconstriction, raising blood pressure. Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist. /Salt not specified/ IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro-athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiot

Pharmacodynamics

Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels.