"Enalapril"
Pharmacological properties
Enalapril is a potent ACE inhibitor in vivo, and orally administered enalapril effectively
inhibits serum ACE activity in patients with congestive heart failure. As a consequence
of this ACE inhibition circulating levels of Angiotensin I are increased, and levels of
renin and angiotensin I are increased by the negative feed back, the most evident
point is the inhibition of Angiotensin II in circulation.
Some studies showed that 6 weeks treatment with enalapril 20 mg daily in 14
patients with CHF reduced myocardial noradrenaline release by 88% during maximal
exercise and 55% at rest, compared with placebo.
It has been hypothesised that enalapril may have some effect on Kallikrein-Kinin
prostaglandin systems, since ACE is identical to kinin-prostaglandin system , since
ACE is identical to kininase II, one of the enzyme responsible .for the degradation of
bradykinin.
Kallikrein-Kinin prostaglandin systems
Kallikreins catalyze the formation of plasma Kinins bradykinin, alpha 2 globulin is the
precursor of kininogens which produce plasma Kinins.
Kinin are powerful algesic agents; by the stimulation of nerve ending. Kinins have
many potent biological activities, including dilatation of blood vessels, contraction of
smooth muscles, and enhancement of capillary permeability, constrict airway smooth
muscles, and have many similar actions like histamine.
ACE inhibitors stimulate kinin in the blood by the inhibition of the degradation factors
in the body.
Some of the adverse effects of ACE inhibitors like cough, rash, angioedema may
caused due to the inhibition of endogenous breakdown.
Uses and Administration
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor. It is used in the
treatment of hypertension and heart failure and may be given prophylactically to
patients with asymptomatic left ventricular dysfunction to delay the onset of
symptomatic heart failure; it may also be given prophylactically to those with left
ventricular dysfunction to reduce the incidence of coronary ischaemic events, including
myocardial infarction.
Enalapril owes its activity to enalaprilat to which it is converted after oral
administration. The haemodynamic effects are seen within 1 hour of a single oral dose
and the maximum effect occurs after about 4 to 6 hours, although the full effect may
not develop for several weeks during chronic dosing.
The haemodynamic action lasts for about 24 hours, allowing once-daily dosing.
Enalapril is given by mouth as the maleate. Enalaprilat is not absorbed by mouth but
is given by intravenous injection; its haemodynamic effects develop within 15 minutes
of injection and reach a peak in 1 to 4 hours. The action lasts for about 6 hours at
recommended doses. Enalaprilat is given as the dihydrate, but doses are expressed in
terms of the anhydrous substance.
In the treatment of hypertension, an initial dose of 5 mg of enalapril maleate daily may
be given by mouth. Since there may be a precipitous fall in blood pressure in some
patients when starting therapy with an ACE inhibitor, the first dose should preferably
be given at bedtime.
An initial dose of 2.5 mg daily should be given to patients with renal impairment or to
those who are receiving a diuretic; if possible, the diuretic should be withdrawn 2 or 3
days before enalapril is started and resumed later if necessary. An initial dose of 2.5
mg is also recommended in elderly patients.
The usual maintenance dose is 10 to 20 mg given once daily, although doses of up to
40 mg daily may be required in severe hypertension. It may be given in 2 divided
doses if control is inadequate with a single dose.
When oral therapy of hypertension is impractical enalaprilat may be given in a dose of
1.25 mg by slow intravenous injection over 5 minutes, repeated every 6 hours if
necessary; the dose should be halved in patients with renal impairment (creatinine
clearance less than 30 mL per minute) or those who are receiving a diuretic.
In the management of heart failure, severe first-dose hypotension on introduction of
an ACE inhibitor is common in patients on loop diuretics, but their temporary
withdrawal may cause rebound pulmonary oedema. Thus treatment should be initiated
with a low dose under close medical supervision.
In patients with heart failure or asymptomatic left ventricular dysfunction enalapril
maleate is given by mouth in an initial dose of 2.5 mg daily. Usual maintenance doses
range from 5 to 20 mg per day, usually in 2 divided doses, although it may be given
as a single daily dose.
Heamodynamic effect of enalapril
The short term heamodynamic effect of enalapril induce balance on preload-afterload
with a gradual decrease in blood pressure without an increase in heart rate.
The onset of effects with enalapril occurred after about 2 hours, peaked at about 8
to 12 hours, and lasted longer than 12 hours. As a comparison, with captopril the
time to peak effect is about 1 to 1.5 hours and the duration is about 4 to 8 hours.
By a study enalapril 10 mg daily in 20 patients with congestive heart failure,
enalapril increases LDH5 (Pyruvate reductase), an enzyme present mainly in the liver
and skeletal muscles and indicate the presence of liver damage, enalapril decreases
LDH1(Lactate dehydrogenase), as enzyme in the heart which indicate the presence of
myocardial infarction.
Pharmacokinetic Properties:
Enalapril acts as a pro-drug of the enalaprilat, its active form, which is poorly
absorbed by mouth. Following oral administration about 60% of a dose of enalapril is
absorbed from the gastro-intestinal tract and peak plasma concentrations are
achieved within about 1 hour.
Enalapril is extensively hydrolyzed in the liver to enalaprilat; peak plasma
concentrations of enalaprilat are achieved 3 to 4 hours after an oral dose of enalapril.
About 60% of an oral dose is excreted in urine, as enalaprilat and unchanged drug,
the rest in the faeces.
Enalaprilat is 50 to 60% bound to plasma proteins; its effective half-life for
accumulation following multiple doses of enalapril is reported to be about 11 hours in
patients with normal renal function.
The absolute bioavailability of enalapril as enalaprilat is about 40%. Enalaprilat is about
50% protein bound.
Effect of renal dysfunction and Age on Pharmacokinetics:
Plasma concentration of enalaprilat is marginally increased in elderly subjects, and is
related to a decrease in clearance. Impaired renal function is associated with increased
and delayed peak plasma concentrations of enalaprilat, and a decrease in the
excretion rate and urinary recovery of enalapril and enalaprilat. Thus, drug
accumulation may occur in patients with moderate to severe renal impairment, and
lower doses can be expected to be clinically effective in such patients.
Effect of Hepatic Dysfunction and Congestive Heart Failure on
Pharmacokinetics:
Studies showed that the appearance of enalaprilat in plasma was delayed in 2
patients with hepatic dysfunction, but still no exact relation between hepatic
dysfunction and the concentration of enalaprilat in the blood. The elimination half-life
were increased in patients with CHF compared with hypertensive patients after
enalapril administration; also there is a decrease in clearance of enalapril and increase
in enalaprilat plasma concentration.
Treatment of Congestive Heart Failure
The haemodynamic effect of enalapril put it in the right position in the treatment of
CHF and many other cardiovascular diseases.
In several studies involving small numbers of patients, usually with severe CHF
showed that enalapril was effective when administered for 1 to 3 months.
When we compare enalapril with captopril in patients with severe CHF we conclude
that both treatments produced similar haemodynamic and clinical improvement. The
difference only in captopril a significant haemodynamic response during long term
therapy, but in case of enalapril which showed a sustained effect, so enalapril
produced more prolonged and persistent hypotensive effects than captopril
Effect on mortality
Several studies show that enalapril improve life expectancy in patients with congestive
heart failure, many survival studies (consensus (بالإجماع)) conclude that there was a
high percentage reduction in mortality comparing enalapril with placebo.
There was no difference between the groups in rate of sudden cardiac death, but
there was 50% reduction in mortality caused by the progression of heart failure in the
enalapril treated group. In the coming figure we show a study on mortality rate in
comparison with placebo:
Administration in Renal Failure
Comparison of the pharmacokinetics of enalapril in 6 diabetics with persistent
proteinuria and glomerular filtration rates (GFR) of 44.1 to 58.4 mL per minute with
those in 8 age-matched controls showed that in the diabetic group the peak serum
concentration of enalaprilat was higher, the time to peak concentration longer, renal
clearance lower, Renal clearance of enalaprilat in the diabetics ranged from 56 to 66
mL per minute compared with 105 to 133 mL per minute in controls; clearance
correlated with GFR
Distribution in Breast Milk
Following administration of a single dose of enalapril 20 mg to 5 lactating women
enalaprilat was detected in breast milk in concentrations of 1 to 2.3 ng per mL;
enalapril was also present. This compared with peak serum values of 39 to 112 ng per
mL for enalaprilat and 92 to 151 ng per mL for enalapril. Although enalapril and its
metabolite are thus present in small amounts in breast milk it was calculated that the
average total daily dose to the neonate would only be about 2 mcg of enalaprilat.
Pregnancy
ACE inhibitors have caused low blood pressure, kidney failure, slow skull formation,
and death in developing fetuses when taken during the last 6 months of pregnancy.
Pregnant women should not take ACE inhibitors.
Sexually active women of childbearing age who must take enalapril must use an
effective contraceptive method to prevent pregnancy or use different medicine
Half Life
The terminal half-life for enalaprilat following a single oral dose of enalapril maleate was
found to be approximately 35 hours. This prolonged terminal phase could represent
binding of enalaprilat to angiotensin-converting enzyme and would be unlikely to
contribute to pharmacokinetic parameters during multiple dosing.
An effective half-life of accumulation of 11.1 hours was estimated during multiple
dosing studies, which approximated to the half-life of the phase immediately
preceding the terminal phase. This figure more closely predicted the observed kinetics
for multiple dosing than the terminal elimination half-life.
Administration to Children
Enalapril has been given to infants with severe heart failure in doses of 0.1 to 0.5 mg
per kg body-weight daily as an oral suspension produced by suspending a crushed
tablet in water.
In this study one infant, with severe myocarditis, developed hypotension and the
drug had to be withdrawn; the remaining 7 showed clinical improvement on a mean
enalapril dose of 0.26 mg per kg daily and were able markedly to reduce the dose of
concomitant diuretic required. Another study in 10 infants found that enalapril was
less bioavailable and probably had a shorter duration of action in infants than in
adults, and that doses of 0.08 mg per kg daily were inadequate in the treatment of
infant heart failure.
A larger study in 63 infants and children (median age 5.4 months) with heart failure
found enalapril 0.36 mg per kg daily to be of benefit, whereas there was no
improvement with a lower dose of 0.24 mg per kg daily.
Pharmacological properties
Enalapril is a potent ACE inhibitor in vivo, and orally administered enalapril effectively
inhibits serum ACE activity in patients with congestive heart failure. As a consequence
of this ACE inhibition circulating levels of Angiotensin I are increased, and levels of
renin and angiotensin I are increased by the negative feed back, the most evident
point is the inhibition of Angiotensin II in circulation.
Some studies showed that 6 weeks treatment with enalapril 20 mg daily in 14
patients with CHF reduced myocardial noradrenaline release by 88% during maximal
exercise and 55% at rest, compared with placebo.
It has been hypothesised that enalapril may have some effect on Kallikrein-Kinin
prostaglandin systems, since ACE is identical to kinin-prostaglandin system , since
ACE is identical to kininase II, one of the enzyme responsible .for the degradation of
bradykinin.
Kallikrein-Kinin prostaglandin systems
Kallikreins catalyze the formation of plasma Kinins bradykinin, alpha 2 globulin is the
precursor of kininogens which produce plasma Kinins.
Kinin are powerful algesic agents; by the stimulation of nerve ending. Kinins have
many potent biological activities, including dilatation of blood vessels, contraction of
smooth muscles, and enhancement of capillary permeability, constrict airway smooth
muscles, and have many similar actions like histamine.
ACE inhibitors stimulate kinin in the blood by the inhibition of the degradation factors
in the body.
Some of the adverse effects of ACE inhibitors like cough, rash, angioedema may
caused due to the inhibition of endogenous breakdown.
Uses and Administration
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor. It is used in the
treatment of hypertension and heart failure and may be given prophylactically to
patients with asymptomatic left ventricular dysfunction to delay the onset of
symptomatic heart failure; it may also be given prophylactically to those with left
ventricular dysfunction to reduce the incidence of coronary ischaemic events, including
myocardial infarction.
Enalapril owes its activity to enalaprilat to which it is converted after oral
administration. The haemodynamic effects are seen within 1 hour of a single oral dose
and the maximum effect occurs after about 4 to 6 hours, although the full effect may
not develop for several weeks during chronic dosing.
The haemodynamic action lasts for about 24 hours, allowing once-daily dosing.
Enalapril is given by mouth as the maleate. Enalaprilat is not absorbed by mouth but
is given by intravenous injection; its haemodynamic effects develop within 15 minutes
of injection and reach a peak in 1 to 4 hours. The action lasts for about 6 hours at
recommended doses. Enalaprilat is given as the dihydrate, but doses are expressed in
terms of the anhydrous substance.
In the treatment of hypertension, an initial dose of 5 mg of enalapril maleate daily may
be given by mouth. Since there may be a precipitous fall in blood pressure in some
patients when starting therapy with an ACE inhibitor, the first dose should preferably
be given at bedtime.
An initial dose of 2.5 mg daily should be given to patients with renal impairment or to
those who are receiving a diuretic; if possible, the diuretic should be withdrawn 2 or 3
days before enalapril is started and resumed later if necessary. An initial dose of 2.5
mg is also recommended in elderly patients.
The usual maintenance dose is 10 to 20 mg given once daily, although doses of up to
40 mg daily may be required in severe hypertension. It may be given in 2 divided
doses if control is inadequate with a single dose.
When oral therapy of hypertension is impractical enalaprilat may be given in a dose of
1.25 mg by slow intravenous injection over 5 minutes, repeated every 6 hours if
necessary; the dose should be halved in patients with renal impairment (creatinine
clearance less than 30 mL per minute) or those who are receiving a diuretic.
In the management of heart failure, severe first-dose hypotension on introduction of
an ACE inhibitor is common in patients on loop diuretics, but their temporary
withdrawal may cause rebound pulmonary oedema. Thus treatment should be initiated
with a low dose under close medical supervision.
In patients with heart failure or asymptomatic left ventricular dysfunction enalapril
maleate is given by mouth in an initial dose of 2.5 mg daily. Usual maintenance doses
range from 5 to 20 mg per day, usually in 2 divided doses, although it may be given
as a single daily dose.
Heamodynamic effect of enalapril
The short term heamodynamic effect of enalapril induce balance on preload-afterload
with a gradual decrease in blood pressure without an increase in heart rate.
The onset of effects with enalapril occurred after about 2 hours, peaked at about 8
to 12 hours, and lasted longer than 12 hours. As a comparison, with captopril the
time to peak effect is about 1 to 1.5 hours and the duration is about 4 to 8 hours.
By a study enalapril 10 mg daily in 20 patients with congestive heart failure,
enalapril increases LDH5 (Pyruvate reductase), an enzyme present mainly in the liver
and skeletal muscles and indicate the presence of liver damage, enalapril decreases
LDH1(Lactate dehydrogenase), as enzyme in the heart which indicate the presence of
myocardial infarction.
Pharmacokinetic Properties:
Enalapril acts as a pro-drug of the enalaprilat, its active form, which is poorly
absorbed by mouth. Following oral administration about 60% of a dose of enalapril is
absorbed from the gastro-intestinal tract and peak plasma concentrations are
achieved within about 1 hour.
Enalapril is extensively hydrolyzed in the liver to enalaprilat; peak plasma
concentrations of enalaprilat are achieved 3 to 4 hours after an oral dose of enalapril.
About 60% of an oral dose is excreted in urine, as enalaprilat and unchanged drug,
the rest in the faeces.
Enalaprilat is 50 to 60% bound to plasma proteins; its effective half-life for
accumulation following multiple doses of enalapril is reported to be about 11 hours in
patients with normal renal function.
The absolute bioavailability of enalapril as enalaprilat is about 40%. Enalaprilat is about
50% protein bound.
Effect of renal dysfunction and Age on Pharmacokinetics:
Plasma concentration of enalaprilat is marginally increased in elderly subjects, and is
related to a decrease in clearance. Impaired renal function is associated with increased
and delayed peak plasma concentrations of enalaprilat, and a decrease in the
excretion rate and urinary recovery of enalapril and enalaprilat. Thus, drug
accumulation may occur in patients with moderate to severe renal impairment, and
lower doses can be expected to be clinically effective in such patients.
Effect of Hepatic Dysfunction and Congestive Heart Failure on
Pharmacokinetics:
Studies showed that the appearance of enalaprilat in plasma was delayed in 2
patients with hepatic dysfunction, but still no exact relation between hepatic
dysfunction and the concentration of enalaprilat in the blood. The elimination half-life
were increased in patients with CHF compared with hypertensive patients after
enalapril administration; also there is a decrease in clearance of enalapril and increase
in enalaprilat plasma concentration.
Treatment of Congestive Heart Failure
The haemodynamic effect of enalapril put it in the right position in the treatment of
CHF and many other cardiovascular diseases.
In several studies involving small numbers of patients, usually with severe CHF
showed that enalapril was effective when administered for 1 to 3 months.
When we compare enalapril with captopril in patients with severe CHF we conclude
that both treatments produced similar haemodynamic and clinical improvement. The
difference only in captopril a significant haemodynamic response during long term
therapy, but in case of enalapril which showed a sustained effect, so enalapril
produced more prolonged and persistent hypotensive effects than captopril
Effect on mortality
Several studies show that enalapril improve life expectancy in patients with congestive
heart failure, many survival studies (consensus (بالإجماع)) conclude that there was a
high percentage reduction in mortality comparing enalapril with placebo.
There was no difference between the groups in rate of sudden cardiac death, but
there was 50% reduction in mortality caused by the progression of heart failure in the
enalapril treated group. In the coming figure we show a study on mortality rate in
comparison with placebo:
Administration in Renal Failure
Comparison of the pharmacokinetics of enalapril in 6 diabetics with persistent
proteinuria and glomerular filtration rates (GFR) of 44.1 to 58.4 mL per minute with
those in 8 age-matched controls showed that in the diabetic group the peak serum
concentration of enalaprilat was higher, the time to peak concentration longer, renal
clearance lower, Renal clearance of enalaprilat in the diabetics ranged from 56 to 66
mL per minute compared with 105 to 133 mL per minute in controls; clearance
correlated with GFR
Distribution in Breast Milk
Following administration of a single dose of enalapril 20 mg to 5 lactating women
enalaprilat was detected in breast milk in concentrations of 1 to 2.3 ng per mL;
enalapril was also present. This compared with peak serum values of 39 to 112 ng per
mL for enalaprilat and 92 to 151 ng per mL for enalapril. Although enalapril and its
metabolite are thus present in small amounts in breast milk it was calculated that the
average total daily dose to the neonate would only be about 2 mcg of enalaprilat.
Pregnancy
ACE inhibitors have caused low blood pressure, kidney failure, slow skull formation,
and death in developing fetuses when taken during the last 6 months of pregnancy.
Pregnant women should not take ACE inhibitors.
Sexually active women of childbearing age who must take enalapril must use an
effective contraceptive method to prevent pregnancy or use different medicine
Half Life
The terminal half-life for enalaprilat following a single oral dose of enalapril maleate was
found to be approximately 35 hours. This prolonged terminal phase could represent
binding of enalaprilat to angiotensin-converting enzyme and would be unlikely to
contribute to pharmacokinetic parameters during multiple dosing.
An effective half-life of accumulation of 11.1 hours was estimated during multiple
dosing studies, which approximated to the half-life of the phase immediately
preceding the terminal phase. This figure more closely predicted the observed kinetics
for multiple dosing than the terminal elimination half-life.
Administration to Children
Enalapril has been given to infants with severe heart failure in doses of 0.1 to 0.5 mg
per kg body-weight daily as an oral suspension produced by suspending a crushed
tablet in water.
In this study one infant, with severe myocarditis, developed hypotension and the
drug had to be withdrawn; the remaining 7 showed clinical improvement on a mean
enalapril dose of 0.26 mg per kg daily and were able markedly to reduce the dose of
concomitant diuretic required. Another study in 10 infants found that enalapril was
less bioavailable and probably had a shorter duration of action in infants than in
adults, and that doses of 0.08 mg per kg daily were inadequate in the treatment of
infant heart failure.
A larger study in 63 infants and children (median age 5.4 months) with heart failure
found enalapril 0.36 mg per kg daily to be of benefit, whereas there was no
improvement with a lower dose of 0.24 mg per kg daily.
Cardiovascular Diseases
 |  |
ACEIs