ZESTORETIC 20/12.5 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

• Essential hypertension
• Heart failure (adjunctive treatment)
• Myocardial infarction (post-myocardial infarction management)
• Diabetic nephropathy (under expert supervision)

Dosage

Children: For children aged 12-17 years: Initially 5 mg once daily; usual maintenance 10-20 mg once daily, with a maximum of 80 mg per day. For children aged 12-17 years: Initially 2.5 mg once daily, increased in steps of up to 10 mg

Adults: Initially 10 mg once daily; usual maintenance 20 mg daily, with a maximum of 40 mg daily as needed.

Mechanism of action

Lisinopril inhibits angiotensin converting enzyme (ACE), thereby preventing the conversion of angiotensin I to angiotensin II. This inhibition results in decreased levels of angiotensin II, leading to reduced vasoconstriction and decreased aldosterone secretion, which together lower blood pressure. Additionally, increased bradykinin levels due to ACE inhibition contribute to vasodilation.

Pharmacodynamics

As an ACE inhibitor, lisinopril primarily lowers blood pressure through inhibition of the renin-angiotensin-aldosterone system. This results in reduced vasopressor activity and helps in maintaining cardiac output in heart failure. The drug has a wide therapeutic index and is effective in a range of doses from 10 to 80 mg daily, allowing for individualized treatment plans.

Pharmacokinetics

Lisinopril is well absorbed following oral administration, with peak plasma concentrations occurring within 6-8 hours. It has a long half-life, allowing for once-daily dosing. The drug is primarily excreted unchanged in the urine, and its pharmacokinetics may be altered in patients with renal impairment, necessitating dose adjustment.

Contra-indications

• History of angioedema related to previous treatment with an ACE inhibitor
• Hereditary or idiopathic angioedema
• Concomitant use with aliskiren in patients with diabetes
• Severe renal impairment (creatinine clearance less than 30 mL/min)

Adverse effects

• Cough
• Hyperkalemia
• Hypotension
• Dizziness
• Fatigue
• Headache
• Renal impairment
• Angioedema
• Rash
• Gastrointestinal disturbances

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Diuretics may potentiate the hypotensive effect
• Lithium levels may increase when used concurrently
• Other antihypertensive agents may enhance the hypotensive effect

Precautions

• Monitor renal function and serum potassium levels
• Use with caution in patients with a history of heart failure
• May cause hypotension, especially after the first dose
• Consider alternative treatments in patients with a history of angioedema
• Adjust dosage in cases of hepatic impairment

Pregnancy

Not recommended during pregnancy. Use in pregnancy may cause fetal harm, especially in the second and third trimesters.

Breast-feeding

Not recommended; alternative treatment options with better established safety during breastfeeding are available.

Storage

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

Formulations

• Tablets: 2.5 mg, 5 mg, 10 mg, 20 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

Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Lisinopril is an angiotensin converting enzyme inhibitor (ACEI), preventing the conversion of angiotensin I to angiotensin II. This action prevents myocyte hypertrophy and vascular smooth muscle cell proliferation seen in untreated patients. Increased levels of bradykinin also exhibit vasodilating effects for patients taking ACEIs. Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I. Orally active angiotensin-converting enzyme inhibitor. Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. The action of the angiotensin-converting enzyme (ACE) inhibitor lisinopril on the consequences of myocardial reoxygenation and oxidative damage was assessed in cultured chick embryonic ventricular cardiomyocytes. Lisinopril, 10(-8) M to 10(-6) M, produced a significant (P < 0.05) dose-dependent enhancement of the restoration of contractile frequency occurring during myocardial reoxygenation but did not alter the depression in contractile frequency during hypoxia. Lisinopril significantly (P < 0.05) shifted the dose-response relationship of ammonium persulfate-induced reduction in cardiac contractile frequency. Lisinopril significantly (P < 0.05) reduced the effect of another oxidative agent, tertbutylhydroperoxide which produced a time-dependent reduction in cardiac contractile frequency. Lisinopril did not alter cardiac contractile frequency in the absence of hypoxia or ammonium persulfate or tertbutylhydroperoxide. The viability of cardiomyocytes, assessed by trypan blue exclusion, paralleled the changes in cardiac contractile frequency. Lisinopril significantly (P < 0.05) improved viability of cardiomyocytes exposed to either ammonium persulfate or tertbutylhydroperoxide. Lisinopril did not display any antioxidant properties against the free radical alpha,alpha-diphenyl-beta-picrylhydrazyl. These data suggest that lisinopril accelerates the recovery of cardiomyocytes during reoxygenation and blunts the effects of oxidative agents through mechanisms involving the endogenous renin angiotensin system and/or a direct cellular action.

Pharmacodynamics

Lisinopril is an angiotensin converting enzyme inhibitor used to treat hypertension, heart failure, and myocardial infarction. Lisinopril is not a prodrug, and functions by inhibition of angiotensin converting enzyme as well as the renin angiotensin aldosterone system. It has a wide therapeutic index and a long duration of action as patients are generally given 10-80mg daily.