Treatment of hypertension Treatment of hypertension in patients in patients

with peptic ulcer with peptic ulcer and liver pathologyand liver pathology

DM Leonid LazebnikDM Leonid LazebnikDM Olga MikheevaDM Olga Mikheeva

The Central Research institute of gastroenterologyThe Central Research institute of gastroenterology Russian Federation, MoscowRussian Federation, Moscow 2010 2010

Urgency of the problemUrgency of the problem

Statistics show that the increase in blood Statistics show that the increase in blood pressure is observed in 40% of the population, pressure is observed in 40% of the population, of which 30% of patients with hypertension of which 30% of patients with hypertension combined with the pathology of the livercombined with the pathology of the liver

For correction of BP are used antihypertensive For correction of BP are used antihypertensive drugs of various groups, among which most drugs of various groups, among which most often appointed are ACE inhibitorsoften appointed are ACE inhibitors

Pharmacokinetic classification Pharmacokinetic classification of ACE inhibitorsof ACE inhibitors

Pharmacologically active drugs (captopril), which Pharmacologically active drugs (captopril), which are metabolized and converted into active disulfidesare metabolized and converted into active disulfides

Inactive prodrugs converted in the liver to active Inactive prodrugs converted in the liver to active metabolites (enalapril to enalaprilat), which are then metabolites (enalapril to enalaprilat), which are then metabolized into inactive compoundsmetabolized into inactive compounds

Water-soluble drugs (lisinopril), which are not Water-soluble drugs (lisinopril), which are not subjected to metabolism and eliminated through the subjected to metabolism and eliminated through the kidneys unchangedkidneys unchanged

Purpose of the studyPurpose of the study

To investigate the pharmacokinetic and To investigate the pharmacokinetic and pharmacodynamic characteristics of lisinopril in pharmacodynamic characteristics of lisinopril in the treatment of patients with arterial the treatment of patients with arterial hypertension, occurring on the background hypertension, occurring on the background pathology of the digestive systempathology of the digestive system

SStudy designtudy design

The control group consisted of patients with peptic The control group consisted of patients with peptic ulcer disease without dysfunction of the liverulcer disease without dysfunction of the liver

Indicators of ABPM in the treatment Indicators of ABPM in the treatment lisinopril 10 mg hypertensive patients lisinopril 10 mg hypertensive patients with pathology of the digestivewith pathology of the digestive

According to the ABPM all examined patients According to the ABPM all examined patients initially had increased BPinitially had increased BP

No significant differences among indicators ABPM No significant differences among indicators ABPM hypertensive patients with different pathologies of hypertensive patients with different pathologies of the digestive system have been identifiedthe digestive system have been identified

Indicators of ABPM in hypertensive patients Indicators of ABPM in hypertensive patients with pathology of the digestive system during with pathology of the digestive system during treatment with lisinopril 10 mgtreatment with lisinopril 10 mg

average daily SBPaverage daily SBP average daily average daily DDBPBP

average dailyaverage daily ITIT SBPSBPaverage dailyaverage daily ITIT DDBPBP

мм мм HgHg мм мм HgHg

%% %%

Treatment with lisinopril 10 mg leads to significantly Treatment with lisinopril 10 mg leads to significantly decreased mean BP values, temporary indexdecreased mean BP values, temporary index ( (IT)IT) BPBP in in most patients, regardless of the severity of liver changes most patients, regardless of the severity of liver changes in patients with hypertensionin patients with hypertension

The effectiveness The effectiveness ((ITIT BPBP << 30 %) 30 %) of of monotherapy with lisinopril in monotherapy with lisinopril in hypertensive patients with pathology of hypertensive patients with pathology of the digestive systemthe digestive system

The effectiveness The effectiveness of therapyof therapy

lisinopril

10 mg

lisinopril

20 mg

AH patients with steatosis of the liverAH patients with steatosis of the liver

effectiveness effectiveness 50 %50 % 36,7 %36,7 %

AH patients with cirrhosisAH patients with cirrhosis

effectiveness effectiveness 53,3%53,3% 33,3 %33,3 %

CControl groupontrol group

effectiveness effectiveness 53,3%53,3% 30 %30 %

The effectiveness of monotherapy with The effectiveness of monotherapy with lisinopril in hypertensive patients with lisinopril in hypertensive patients with pathology of the liverpathology of the liver

We got a good hypotensive effect in the treatment We got a good hypotensive effect in the treatment with lisinopril 10 mg in 53.3% of the patients with with lisinopril 10 mg in 53.3% of the patients with cirrhosis. cirrhosis.

Increasing the dose in half, gave a good effect even Increasing the dose in half, gave a good effect even in 33,3% of patientsin 33,3% of patients

In 53,3% of patients with hypertension of the control In 53,3% of patients with hypertension of the control group a good hypotensive effect was achieved when group a good hypotensive effect was achieved when taking 10 mg, 30% of patients - 20 mg of lisinopril per taking 10 mg, 30% of patients - 20 mg of lisinopril per dayday

Pharmacokinetic studyPharmacokinetic study

We studied the pharmacokinetics after a single dose We studied the pharmacokinetics after a single dose of lisinopril 10 mg in patients with hypertension and of lisinopril 10 mg in patients with hypertension and gastrointestinal disordersgastrointestinal disorders

We determined the concentration of lisinopril in We determined the concentration of lisinopril in serum of patients by high performance liquid serum of patients by high performance liquid chromatographychromatography

The main pharmacokinetic parametersThe main pharmacokinetic parameters

The area under the curve "concentration - time" The area under the curve "concentration - time" (AUC) - an area the figure bounded pharmacokinetic (AUC) - an area the figure bounded pharmacokinetic curve and the coordinate axescurve and the coordinate axes

C max - maximum concentration of drug in serum C max - maximum concentration of drug in serum (ng/ml)(ng/ml)

T max - time of maximum concentration of drugs (t)T max - time of maximum concentration of drugs (t)

MRT - mean residence time of drugsMRT - mean residence time of drugs (t)(t)

Pharmacokinetic parameters of lisinopril 10 mg in Pharmacokinetic parameters of lisinopril 10 mg in hypertensive patients with digestive diseaseshypertensive patients with digestive diseases

0

2

4

6

8

T max

liver steatosiscirrhosiscontrol group

ngng t/mlt/ml ngng t/mlt/ml

tt

tt

We found that in patients in both groups were We found that in patients in both groups were observed no differences in pharmacokinetic observed no differences in pharmacokinetic parameters after taken of 10 mg of lisinoprilparameters after taken of 10 mg of lisinopril

Pharmacokinetic and pharmacodynamic curves for Pharmacokinetic and pharmacodynamic curves for hypertensive patients with pathology of the digestive hypertensive patients with pathology of the digestive system while taking 10 mg of lisinoprilsystem while taking 10 mg of lisinopril

0

10

20

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

control group

cirrhosis

concentration of lisinoprilconcentration of lisinoprilNg/ml

t

0

20

40

60

80

100

120

140

160

180

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

control croup (MBP)

cirrhosis (MBP)

control croup (MDP)

cirrhosis (MDP)

mean BPmean BP, , mmmm HgHg

tPharmacokinetic parameters did not differ in Pharmacokinetic parameters did not differ in hypertensive patients depending on the hypertensive patients depending on the pathology of the gastrointestinal tractpathology of the gastrointestinal tract

Water-soluble lisinopril is not subjected to Water-soluble lisinopril is not subjected to metabolism of the patient, therefore, its metabolism of the patient, therefore, its concentration in plasma is determined the dose concentration in plasma is determined the dose taken insidetaken inside

Differences of each pharmacokinetic parameter (C Differences of each pharmacokinetic parameter (C max, T max, MRT, AUC) in groups of BP patients max, T max, MRT, AUC) in groups of BP patients with various pathologies of the digestive sistem with various pathologies of the digestive sistem were statistically insignificantwere statistically insignificant

Pharmacokinetic parameters of lisinopril Pharmacokinetic parameters of lisinopril 10 mg in hypertensive patients with 10 mg in hypertensive patients with hepatic pathologyhepatic pathology

ConclusionConclusion

Water-soluble lisinopril initially pharmacologically Water-soluble lisinopril initially pharmacologically active form, therefore has an advantage over ACE active form, therefore has an advantage over ACE inhibitors, which are metabolized in the liverinhibitors, which are metabolized in the liver

We observed no differences in pharmacokinetic We observed no differences in pharmacokinetic parameters in patients with BP, both normal and parameters in patients with BP, both normal and with impaired liver function after taking lisinopril with impaired liver function after taking lisinopril 10 mg10 mg

This is expressed in reaching target BP levels in This is expressed in reaching target BP levels in 53,3% of patients in both groups53,3% of patients in both groups