Actions of Spec Perindopril in details
Pharmacology: Pharmacodynamics: Mechanism of Action: Spec Perindopril is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. Angiotensin-converting enzyme is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis, and may be associated with a small increase of serum potassium.
Angiotensin-converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor, ACE play a role in the therapeutic effects of Spec Perindopril tablets remains to be elucidated.
While the principal mechanism of Spec Perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Spec Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to Spec Perindopril was about half the response seen in non-blacks, a finding consistent with previous experience of other ACE inhibitors.
After administration of Spec Perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80-90% attained by 8 mg persisting for 10-12 hrs. Twenty-four (24) hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by Spec Perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hrs after a 12-mg dose.
Pharmacokinetics: Absorption:
Oral administration of Spec Perindopril results in its rapid absorption with peak plasma concentrations (Cmax) occurring at approximately 1 hr. The absolute oral bioavailability of Spec Perindopril is about 75%. Following absorption, approximately 30-50% of systemically available Spec Perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3-7 hrs after Spec Perindopril administration.
The presence of food in the gastrointestinal tract does not affect the rate or extent of absorption of Spec Perindopril but reduces bioavailability of perindoprilat by about 35%.
With 4-, 8- and 16-mg doses of Spec Perindopril, Cmax and area under the concentration-time curve (AUC) of Spec Perindopril and perindoprilat increase in a linear and dose-proportional manner following both single oral dosing and at steady-state during a once-a-day multiple dosing regimen.
Distribution: Approximately, 60% of circulating Spec Perindopril is bound to plasma proteins and only 10-20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
At usual antihypertensive dosages, little radioactivity (<5% of the dose) was distributed to the brain after administration of 14C-Spec Perindopril to rats. Radioactivity was detectable in fetuses and in milk after administration of 14C-Spec Perindopril to pregnant and lactating rats.
Metabolism: Spec Perindopril is extensively metabolized following oral administration, with only 4-12% of the dose recovered unchanged in the urine. Six (6) metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed Spec Perindopril), Spec Perindopril and perindoprilat glucuronides, dehydrated Spec Perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of Spec Perindopril.
The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of Spec Perindopril. Formation of perindoprilat is gradual with Cmax occurring between 3 and 7 hrs. The subsequent decline in plasma concentration shows an apparent mean half-life (t½) of 3-10 hrs for the majority of the elimination, with a prolonged terminal elimination t½ of 30-120 hrs resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with Spec Perindopril, perindoprilat accumulates about 1.5-2-fold and attains steady-state plasma levels in 3-6 days.
Excretion: The clearance of perindoprilat and its metabolites is almost exclusively renal. Spec Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean t½ of Spec Perindopril associated with most of its elimination is approximately 0.8-1 hr. At very low plasma concentrations of Spec Perindopril (<3 ng/mL), there is a prolonged terminal elimination t½, similar to that seen with other ACE inhibitors, that results from slow dissociation of Spec Perindopril from plasma/tissue ACE binding sites. Spec Perindopril does not accumulate with a once-a-day multiple dosing regimen. Mean total body clearance of Spec Perindopril is 219-362 mL/min and its mean renal clearance is 23.3-28.6 mL/min.
Pharmacokinetics in Special Populations: Elderly Patients: Plasma concentrations of both Spec Perindopril and perindoprilat in elderly patients (>70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of Spec Perindopril to perindoprilat and decreased renal excretion of perindoprilat.
Heart Failure Patients: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
Patients with Renal Insufficiency: With Spec Perindopril doses of 2-4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances (CrCl) of 30-80 mL/min, AUC is about double that of 100 mL/min. When CrCl drops <30 mL/min, AUC increases more markedly.
In a limited number of patients studied, Spec Perindopril dialysis clearance ranged from 41.7-76.7 mL/min (mean 52 mL/min). Perindoprilat dialysis clearance ranged from 37.4-91 mL/min (mean 67.2 mL/min).
Patients with Hepatic Insufficiency: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
How should I take Spec Perindopril?
Take Spec Perindopril exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Take each dose with a full glass of water. Drink plenty of liquids while you are taking Spec Perindopril.
Spec Perindopril can be taken with or without food.
Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.
Your blood pressure will need to be checked often. Your kidney or liver function may also need to be checked.
If you need surgery, tell the surgeon ahead of time that you are using Spec Perindopril. You may need to stop using the medicine for a short time.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat.
Spec Perindopril administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results.
Take each dose with a full glass of water. Drink plenty of liquids while you are taking Spec Perindopril.
Spec Perindopril can be taken with or without food.
Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.
Your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.
If you need surgery, tell the surgeon ahead of time that you are using Spec Perindopril. You may need to stop using the medicine for a short time.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat.
Spec Perindopril pharmacology
Mechanism of Action
Spec Perindopril® (Spec Perindopril erbumine) is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Spec Perindopril remains to be elucidated.
While the principal mechanism of Spec Perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Spec Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to Spec Perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.
Pharmacodynamics
After administration of Spec Perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by Spec Perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.
Pharmacokinetics
Absorption:
Oral administration of Spec Perindopril results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of Spec Perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available Spec Perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after Spec Perindopril administration.
Oral administration of Spec Perindopril with food does not significantly lower the rate or extent of Spec Perindopril absorption relative to the fasted state. However, the extent of biotransformation of Spec Perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, Spec Perindopril was generally administered in a non-fasting state.
With 4 mg, 8 mg and 16 mg doses of Spec Perindopril, Cmax and AUC of Spec Perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.
Distribution: Approximately 60% of circulating Spec Perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
Metabolism and Elimination: Following oral administration Spec Perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of Spec Perindopril associated with most of its elimination is approximately 0.8 to 1 hours.
Spec Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed Spec Perindopril), Spec Perindopril and perindoprilat glucuronides, dehydrated Spec Perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of Spec Perindopril.
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of Spec Perindopril. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with Spec Perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.
Elderly: Plasma concentrations of both Spec Perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of Spec Perindopril to perindoprilat and decreased renal excretion of perindoprilat.
Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
Renal Impairment: With Spec Perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.
In a limited number of patients studied, Spec Perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min.
Hepatic Impairment: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
References
- NCIt. "Perindopril: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Perindopril: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
