Lo E

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.

Losartan is an angiotensin II receptor blocker (ARB) used for:

• Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
• Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients.
• Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension.

Lo E is also used to associated treatment for these conditions: Diabetic Nephropathy, High Blood Pressure (Hypertension), Symptomatic Congestive Heart Failure, Asymptomatic Left ventricular dysfunctionDiabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, Stroke

How Lo E 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.

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.

Dosage

Lo E 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

Hypertension:

• Usual adult dose: 50 mg once daily.
• Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg).

Hypertensive Patients with Left Ventricular Hypertrophy:

• Usual starting dose: 50 mg once daily.
• Add hydrochlorothiazide 12.5 mg and/or increase Losartan to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed.

Nephropathy in Type 2 Diabetic Patients:

• Usual dose: 50 mg once daily.
• Increase dose to 100 mg once daily if further blood pressure response is needed.

Use in elderly:

• Patients up to 75 years: No initial dosage adjustment is necessary for this group of patients.
• Patients over 75 years: A lower starting dose of 25 mg once daily is recommended.

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

In controlled clinical trials in patients with essential hypertension, dizziness was the only side effect reported that occurred with an incidence greater than placebo in 1% or more of patients treated with Losartan. Rarely, rash was reported although the incidence in controlled clinical trials was less than placebo. Angioedema, involving swelling of the face, lips and/or tongue has been reported rarely in patients treated with Losartan. Serious hypotension (particularly on initiating treatment in salt-depleted patients) or renal failure (mainly in patients with renal artery stenosis) may be encountered during Losartan treatment.

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 TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D.

Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding.

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.

A lower dose should be considered for patients with a history of hepatic and renal impairment. Losartan should not be used with potassium-sparing diuretic

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.

No drug interaction of clinical significance has been identified. Compounds which have been studied in clinical pharmacokinetic trials include hydrochlorothiazide, digoxin, warfarin, cimetidine, ketoconazole and phenobarbital.

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 of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174).

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.

Losartan is approximately 33% orally bioavailable. Losartan has a T_max of 1 hour and the active metabolite has a T_max of 3-4 hours. Taking losartan with food decreases the C_max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C_max of 200-250ng/mL.

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 terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.

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.

Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/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.

A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.

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.

Although there is no experience with the use of Losartan in pregnant women, animal studies with Losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin angiotensinaldosterone system. Losartan should not be used in pregnancy and if pregnancy is detected Losartan should be discontinued as soon as possible.

It is not known whether Losartan is excreted in human breast milk. However, significant level of Losartan found in rat milk which suggests that the drug should not be used in lactating mother.

Contraindication

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

It is also contraindicated to patients who are hypersensitive to any component of this product. In patients who are intravenously volume depleted (e.g. those treated with high dose diuretics), symptomatic hypotension may occur. These conditions Losartan potassium should be corrected prior to administer Losartan or a lower starting dose (usually 25 mg) should be used.

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.

No initial dosage adjustment is necessary in patients with mild renal impairment (CrCl 20-50 ml/min). For patients with moderate to severe renal impairment (CrCl <20 ml/min) or patients on dialysis, a lower starting dose of 25 mg is recommended.

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.

Limited data are available regarding overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Supportive treatment should include repletion of the intravascular volume. Neither Losartan nor the active metabolite can be removed by hemodialysis.

Storage Condition

Store between 15-30°C

Innovators Monograph

You find simplified version here Lo E