Combipres (ANTIHYPERTENSIVES_DIURETICS)

Uses

Enalapril is used for-

• All grades of essential hypertension and renovascular hypertension either alone or in combination with other antihypertensive agents especially thiazide diuretics.
• Prevention of symptomatic heart failure.
• Treatment of congestive heart failure (adjunct), usually in combination with diuretics and digitalis.
• Prevention of coronary ischaemic events in patients with left ventricular dysfunction.

Enalapril is also used either alone or as an adjunct in the treatment of angina, diabetic nephropathy and Raynaud's disease.

Hydrochlorothiazide is used for-

• Edema associated with congestive heart failure, hepatic cirrohosis, various forms of renal dysfunction and corticosteroid and estrogen therapy
• Management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe form of hypertension
• Management of diabetes insipidus
• Management of proximal renal tubular acidosis
• Idiopathic hypercalciuria and calcium nephrolithiasis, osteoporosis and exercise induced hyperkalemia

Combipres (ANTIHYPERTENSIVES_DIURETICS) is also used to associated treatment for these conditions: Diabetic Nephropathy, High Blood Pressure (Hypertension), Symptomatic Congestive Heart Failure, Asymptomatic Left ventricular dysfunctionAcidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsia

How Combipres (ANTIHYPERTENSIVES_DIURETICS) works

The renin-angiotensin-aldosterone system (RAAS) is a signaling pathway that works in synergism with the sympathetic system to regulate blood pressure and fluid and electrolyte homeostasis. Activation of this system upon stimulation by different factors, such as low blood pressure and nerve impulses, leads to increased release of norepinephrine (NE) from sympathetic nerve terminals and effects on the vascular growth, vasoconstriction, and salt retention in the kidneys. Renin is released from Renin acts on the precursor prottein angiotensinogen, which is a plasma globulin synthesized from the liver, to produce cleaved peptide hormone angiotensin I. Angiotensin I then can be further cleaved by ACE to produce angiotensin II, a vasoconstrictive peptide hormone. Present in different isoforms, angiotensin converting enzyme (ACE) is peptidyl dipeptidase enzyme expressed in various tissues, including the vascular tissues, such as the heart, brain, and kidneys. ACE also plays a role in inactivation of bradykinin, a potent vasodepressor peptide. Angiotensin II mediates various actions on the body by working on its G-protein coupled receptors, AT1 and AT2. It causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of NE thereby increasing available levels, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium ions and water by promoting proximal tubular reabsorption, stimulates synthesis and release of aldosterone from the adrenal cortex, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes.

Enalapril is a pharmacologically inactive prodrug that requires hepatic biotransformation to form enalaprilat, its active metabolite that works on the RAAS to inhibit ACE. Biotransformation is critial for the therapeutic actions of the drug, as enalapril itself is only a weak inhibitor of ACE. ACE inhibition results in reduced production and plasma levels of angiotensin II, increased plasma renin activity due to the loss of feedback inhibition by angiotensin II, and decreased aldosterone secretion. However, plasma aldosterone levels usually return to normal during long-term administration of enalapril. Decreased levels of angiotensin II subsequently leads to the dilatation of peripheral vessles and reduced vascular resistance which in turn lower blood pressure. While inhibition of ACE leading to suppression of RAAS is thought to be the primary mechanism of action of enalapril, the drug was shown to still exert antihypertensive effects on individuals with low-renin hypertension. It is suggested that enalapril may mediate its pharmacological actions via other modes of action that are not fully understood. As ACE is structurally similar to kininase I, which is a carboxypeptidase that degrades bradykinin, whether increased levels of bradykinin play a role in the therapeutic effects of enalapril remains to be elucidated.

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.

Dosage

Combipres (ANTIHYPERTENSIVES_DIURETICS) dosage

Hypertension: Initially 5 mg once daily if used alone or 2.5 mg daily if used in addition to diuretic, in elderly patients or in patients with renal impairment. Usual maintenance dose is 10-20 mg once daily. However, in severe hypertension it may be increased to a maximum of 40 mg once daily.

Heart failure (adjunct) and asymptomatic left ventricular dysfunction: Initially 2.5 mg under close medical supervision. Usual maintenance dose is 20 mg daily in 1-2 divided doses

Adults-

For Edema: The usual adult dosage is 25 to 100 mg daily as a single or divided dose.

For Control of Hypertension: The usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium. In some patients (especially the elderly) an initial dose of 12.5 mg daily may be sufficient.

Infants and children-

For diuresis and for control of hypertension: The usual pediatric dosage is 1 to 2 mg/kg/day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 3 mg/kg/day in two divided doses may be required.

Side Effects

Dizziness and headache are more commonly reported side effects. Fatigue and asthenia were reported in 2-3% of patients. Other side effects occurred in less than 2% of patients and included hypotension, orthostatic hypotension, syncope, nausea, diarrhoea, muscle cramps, rash and cough.

Less frequently renal dysfunction, renal failure and oliguria have been reported. Angioedema, hyperkalemia and hyponatremia have also been reported rarely

Generally, Hydrochlorothiazide is well tolerated. However, a few side effects may occur like weakness, restlessness, dizziness, headache, fever, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia, and hypotension. In rare case hyperglycemia, glycosuria, hyperuricemia and muscle spasm may occur.

Toxicity

LD₅₀ and Overdose

Oral LD₅₀ in rats is 2973 mg/kg. Lethality was observed with single oral doses of enalapril above 1000 mg/kg in mice and greater than or equal to 1775 mg/kg in rats. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively. While there is limited data about enalapril overdose in humans, overdosage may result in marked hypotension and stupor based on the pharmacological properties of the drug. Most common adverse effects of enalapril include cough, hypotension, stupor, headache, dizziness and fatigue. If hypotension is seen, usual treatment of intravenous infusion of normal saline solution is recommended. Enalaprilat may be removed from systemic circulation with the use of hemodialysis. It has been removed from neonatal circulation by peritoneal dialysis.

Nonclinical toxicology

Maternal and fetal toxicity occudred in some rabbits treated with enalapril at doses of 1 mg/kg/day or more. There was no fetotoxicity, expressed as a decrease in average fetal weight, or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day, which is about 333 times the maximum human dose. In mice and rats receiving enalapril at doses ranging from 90 to 180 mg/kg/day, there was no evidence of a tumorigenic effect. Neither enalapril or its active metabolite were shown to be mutagenic or genotoxic in in vitro and in vivo studies. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril.

Use in special populations

Caution is warranted in patients who are concurrently using another ACE inhibitors with enalapril, as there have been incidences of agranulocytosis with the use of captopril, which is another ACE inhibitor. This adverse event may be particularly significant in patients with renal impairment or collagen vascular disease. As enalapril and enalaprilat were shown to be secreted in human milk in trace amounts, the use of enalaprilat in nursing women is not recommended. Significant fetal transfer occurs with enalapril and enalaprilat thus the use of the drug in pregnant women should be strongly avoided. Caution is advised when enalapril is used in patients who are elderly or with renal impairment, as dosage adjustments may be appropriate. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in individuals of African descent, usually a low-renin hypertensive population.

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

Precaution

Assess renal function; regular WBC counts in patient w/ collagen vascular disease eg SLE & scleroderma. Patient receiving immunosuppressive therapy; those prone to salt or water depletion. Pregnancy.

Thiazides should be used with caution in patients with severe renal disease, impaired hepatic function or progressive liver disease and gout.

Interaction

Combination with other antihypertensive agents such as b blockers, Methyldopa, calcium antagonists and diuretics may increase the antihypertensive efficacy. Adrenergic blocking drugs should only be combined with Enalapril under careful supervision. Concomitant Propranolol may reduce the bioavailability of Enalapril, but this does not appear to be of any clinical significance. Concomitant therapy with Lithium may increase the serum Lithium concentration.

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): Thiazides can impair control of diabetes mellitus by diet and antidiabetic Drugs. Antihypertensive Drugs: Additive effect or potentiation.

Volume of Distribution

The volume of distribution of enalapril has not been established. Enalaprilat is shown to penetrate into most tissuesm, in particular the kidneys and vascular tissuem, although penetration of the blood-brain barrier has not been demonstrated after administration at therapeutic doses. In dog studies, enalapril and enalaprilat cross the blood-brain barrier poorly. Minimal penetration occurs into breast milk but significant fetal transfer occurs. The drug crosses the placental barrier in rats and hamsters.

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

Elimination Route

Following oral administration, the peak plasma concentrations (Cmax) of enalapril is achieved within 1 hour post dosing while the Cmax of enalaprilat occurs at three to four hours post dosing. The steady-state is achieved by the fourth daily dose and there is no accumulation with repeated dosing. However, accumulation of enalaprilat may occur in patients with creatinine clearance less than 30 mL/min. Food intake is reported to have a minimal effect on drug absorption. Following oral administration, about 60% of enalapril was absorbed. Bioavailability of enalapril averaged about 40% when intravenous enalaprilat was used as a reference standard.

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

Half Life

The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours. The prolonged terminal half-life is due to the binding of enalaprilat to ACE.

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

Clearance

Following oral administration in healthy male volunteers, the renal clearance was approximately 158 ± 47 mL/min. It is reported that enalapril and enalaprilat are undetectable in the plasma by 4 hours post-dosing.

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

Elimination Route

Enalapril is mainly eliminated through renal excretion, where approximately 94% of the total dose is excreted via urine or feces as either enalaprilat or unchanged parent compound. About 61% and 33% of the total dose can be recovered in the urine and feces, respectively. In the urine, about 40% of the recovered dose is in the form of enalaprilat.

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

Pregnancy & Breastfeeding use

Category D: Contraindicated in pregnancy. The drug is excreted in trace amount in human milk and caution should be exercised if given to nursing mothers.

Pregnancy: Evidence of fetal risk in hydrochlorothiazide therapy is found, but it is indicated if benefits outweigh risks. Thiazides are indicated in pregnancy when edema is due to pathologic causes.\

Lactation: Neonatal side effects have been seen incase of hydrochlorothiazide therapy and therefore it is not recommended.

Contraindication

Aortic stenosis or outflow tract obstruction. Renovascular disease. Severe resistant HTN. Peripheral vascular disease or generalized atherosclerosis.

Hydrochlorothiazide is contraindicated to the patients of anuria and those who are sensitive to hydrochlorothiazide or to other sulfonamide-derived drugs. Therapy is not to be initiated in diabetes mellitus.

Special Warning

Use in the elderly (over 65 years): The starting dose should be 2.5 mg. Enaril is effective in the treatment of hypertension in the elderly. The dose should be titrated according to need for the control of blood pressure.

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

Acute Overdose

symptoms-

• Lightheadedness, dizziness, or fainting
• Decrease in urine output
• Drowsiness, headache, or back pain
• Slow or irregular heartbeat.

Management-

• Fluids through an intravenous line (IV)
• Medications to increase blood pressure
• Other treatments based on complications that occur
• Closely monitoring the heart and lungs.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Rarely, autoimmune hemolytic anemia and other hypersensitivity reactions may complicate the picture.

In the event of over dosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. Hemodialysis can be used successfully to treat severe intoxication.

Storage Condition

Store between 15-30°C. Protect from light, moisture and freezing.

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