UNITEL H-80

Indications

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

Dosage

Children: For children, the dosage should be individualized and is generally based on the child's weight and condition

Adults: Typically, the initial adult dose is 12.5 mg to 25 mg once daily, which may be adjusted based on response, up to a maximum of 100 mg per day.

Mechanism of action

Hydrochlorothiazide is transported into epithelial cells of the distal convoluted tubule through organic anion transporters OAT1, OAT3, and OAT4. It inhibits the sodium-chloride symporter (SLC12A3) in the proximal region of the distal convoluted tubule, which reduces sodium and water reabsorption. This inhibition leads to increased sodium and water excretion in urine, thereby reducing blood volume and blood pressure.

Pharmacodynamics

The primary pharmacodynamic effect of hydrochlorothiazide is its ability to prevent the reabsorption of sodium and water from the distal convoluted tubule. This results in increased urine output and decreased blood pressure. The drug is noted for its wide therapeutic window, allowing for individualized dosing, typically ranging from 25 to 100 mg. Caution is advised in patients with impaired renal or hepatic function.

Pharmacokinetics

Hydrochlorothiazide is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. The drug has a half-life of approximately 6 to 15 hours, allowing for once-daily dosing in most cases. It is primarily excreted unchanged in the urine, with a small portion undergoing hepatic metabolism. The diuretic effect typically begins within 2 hours, peaking at about 4 to 6 hours and lasting for up to 12 hours.

Contra-indications

• Hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs
• Anuria
• Severe renal impairment

Adverse effects

• Electrolyte imbalances (hyponatremia, hypokalemia)
• Hypotension
• Dizziness
• Headache
• Gastrointestinal disturbances (nausea, vomiting)
• Skin rashes
• Hyperuricemia
• Increased blood glucose levels

Interactions

• NSAIDs may reduce the antihypertensive effect
• Corticosteroids may increase the risk of hypokalemia
• Lithium levels may increase leading to toxicity
• Antidiabetic medications may require dosage adjustment due to altered glycemic control

Precautions

• Use with caution in patients with liver disease, diabetes mellitus, or gout
• Monitor electrolyte levels regularly
• Assess renal function prior to initiation and periodically during treatment
• May cause sensitivity to sunlight

Pregnancy

Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution is advised.

Breast-feeding

Hydrochlorothiazide 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 (12.5 mg, 25 mg, 50 mg)
• Oral solution (available in some regions)

Indications

• Hypertension
• Heart failure
• Chronic kidney disease
• Diabetic nephropathy

Dosage

Children: For paediatric patients, refer to the BNF for Children for appropriate dosing guidelines.

Adults: The usual starting dose is 40 mg once daily, which may be adjusted based on blood pressure response. The maximum recommended dose is 80 mg per day.

Mechanism of action

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT1 receptor by selectively binding to these receptors in vascular smooth muscle and the adrenal gland. This blockage leads to reduced systemic vascular resistance and lower blood pressure. Telmisartan is not an ACE inhibitor and does not affect other hormone receptors or ion channels. It may also enhance carbohydrate and lipid metabolism via its PPARγ activity.

Pharmacodynamics

Telmisartan exhibits high affinity for the AT1 receptor subtype, making it an effective angiotensin II antagonist. It plays a significant role in lowering blood pressure by preventing vasoconstriction and aldosterone release. The potential PPARγ agonistic properties suggest additional metabolic advantages, including improved glucose and lipid metabolism.

Pharmacokinetics

Telmisartan is administered orally and has a high bioavailability. It is extensively bound to plasma proteins and undergoes hepatic metabolism, primarily via glucuronidation. The drug has a long half-life, allowing for once-daily dosing. Excretion occurs mainly through the feces, with minimal renal elimination.

Contra-indications

• Hypersensitivity to telmisartan or any of the excipients
• Severe hepatic impairment
• Severe renal impairment or patients on dialysis

Adverse effects

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

Interactions

• Other antihypertensives
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Lithium
• Potassium-sparing diuretics
• Renin-angiotensin-aldosterone system (RAAS) inhibitors

Precautions

• Monitor renal function, particularly in patients with renal artery stenosis
• Caution in patients with a history of angioedema
• Use with caution in patients with diabetes
• Monitor potassium levels in patients at risk for hyperkalemia

Pregnancy

Telmisartan is not recommended during pregnancy, particularly in the second and third trimesters, due to potential harm to the fetus.

Breast-feeding

The effects of telmisartan on breastfed infants are unknown; caution should be exercised.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 20 mg, 40 mg
• Combination tablets with hydrochlorothiazide: 20 mg/12.5 mg, 40 mg/12.5 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

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT₁-receptor by binding reversibly and selectively to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Telmisartan does not inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Studies also suggest that telmisartan is a partial agonist of PPAR&gamma;, which is an established target for antidiabetic drugs. This suggests that telmisartan can improve carbohydrate and lipid metabolism, as well as control insulin resistance without causing the side effects that are associated with full PPAR&gamma; activators. Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-gamma-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARgamma in this context. CD4-positive lymphocytes express both the AT1R and PPARgamma. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1+/-3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6+/-0.7-fold induction at 10 mumol/L of telmisartan (P<0.01 compared with SDF-1-treated cells; n=22). Three different PPARgamma activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPARgamma-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPARgamma small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARgamma. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPARgamma-activating properties. 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. Telmisartan 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. Telmisartan has much greater affinity (>3,000 fold) for the AT1 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 telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Block

Pharmacodynamics

Telmisartan is an orally active nonpeptide angiotensin II antagonist that acts on the AT₁ receptor subtype. It has the highest affinity for the AT₁ receptor among commercially available ARBs and has minimal affinity for the AT₂ receptor. New studies suggest that telmisartan may also have PPAR&gamma; agonistic properties that could potentially confer beneficial metabolic effects, as PPAR&gamma; is a nuclear receptor that regulates specific gene transcription, and whose target genes are involved in the regulation of glucose and lipid metabolism, as well as anti-inflammatory responses. This observation is currently being explored in clinical trials. 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. Telmisartan works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II.