生命科学与技术学院

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教研室：药理学  教师姓名：欧和生

Part 1  Renin-Aangiotensin-System

Introduction

1.Element of RAS (renin, angiotensinogen,angiotensin, ACE, ATR)

Renin is an enzyme that acts on angiotensinogen to catalyze the formation of the decapeptide angiotensin I.

Angiotensin I is then cleaved by ACE to yield the octapeptide angiotensin II.

ATR: AT1R, AT2R

2.The regulation effect of RAS on blood pressure

The renin-angiotensinsystem is an important participant in both the short-and long-term regulationof arterial blood pressure.

Angiotensin II acts in several ways to increase totalperipheral resistance and thereby contributes to the short-term regulation ofarterial blood pressure. Perhaps the more important is the ability of angiotensin II to inhibit excretion of Na+ and water by thekidneys.

Angiotensin II – induced changes in renal functionplay an important role in long-term stabilization of arterial blood pressure.

Part 2  Angiotensinconverting enzyme inhibitors (ACEI)

1.Pharmacological effects

(1) Inhibit the formation of Ang II.

 (2) Maintain the activity of brandykinin (BK).

 (3) Protection of endothelium andanti-atherosclerosis

 (4) Anti-iscamiaand protection of myocardial cell

 (5) Increase the sensitivity of insulin

(6) Inhibit the pathological cardiovascular remodeling

2. Clinical uses

(1) Hypertension

(2) CHF and myocardial infarction

(3) DMEM and nephropathy

3. Untoward effects

(1) Hypotension: occurring in the first use.

(2) Cough: of 6 ~ 12%

(3) Hyperkalemia

(4) Low blood sugar

(5) Renal function trauma

(6) Affection of the development of fetus and newborn.

(7) Neuro Oedema.

(8) Malfunction of taste, tetter (thedrugs with –SH).

4.The drugs of ACEI.

. Captopril

Pharmacological Action :

 i  Directly inhibited ACE. (IC50:23 ~ 35 nmol /L), The depressor effect associated with the activitystate of RAS.

ii   The protection of heart is relatedto abolishing of ROS, such as iscamia.

Pharmacokinetics

o  Absorption : Po, F=75%. T_action :30 min. T_max=1h.

o  Distribution: extensivelydistributed in body , Pb=30%.

o  Metabolism: oxygen in –SH.

o  Excretion: from kidney: 40-50%in parent drug and the others in metabolites.

Clinical uses

o  Hypertension: single or combination.

o  CHF

o  Cardiac infarct.

o  DMEM-nephropathy (only captopril).

Untoward effects

Apart fromthe common side effect, cough is usually complaint.

Enalapril

o  Action : the action of inhibition of ACE is 10 times stronger than captopril.

o  The absorption is not affectedby food. Po. TP=4-6h.  Tmaintain=24h,q.d.

o  Metabolism: enalaprilat(MK22)

o  Distribution extensively inbody. T1/2: 11h.

o  Excretion from kidney.

o  Uses: hypertensionwww.med126.com/sanji/ and CHF.

o  Aside effect: cough ,hypotension, hyperkalemiaetc.

Fosinopril

o  Prodrug (poo-): fosinoprilacid is the activity chemical.

o  Tp=3-6 h

o  Pb=95%

o&www.med126.com/kuaiji/nbsp; T1/2=12h

o  Distribution : heart and brain(much)

o  Excretion: from liver and kidney,  no toxicityaccumulation for light malfunction of kidney.

o  No use：lactation

Lisinopril

benazepril

Part 3  The blockade of angiotension II receptor

losartan、valsartan、erbesartan、candesartan、tasosartan、eprosartan、telmisartan

1. Pharmacological effects and mechanism

 (1) Block the AT1R   vasodilatation 

     Aldostrone  Hypotension

(2) Block theAT1R Renin  AngII AT2RBK-NO 

Vasodilatation, regression of remodeling Hypotension.

Losartan

1.Pharmacological effects

（1)AT1R: Losartan block AT1R>AT2R (2-3万倍).   EXP3174 >losartanin  blocking  AT1R  (10- 40 times)

（2)Vasodilate renalartery, decrease reabsorption of water and Na⁺in renal tube.

（3)Protect kidney：Hypertension，DM and failure of kidney.

（4)Inhibit vascular remodeling.

2. Clinical uses

 (1) Hypertension

 (2)CHF

3. Untoward effects: less than ACEI, avoid use with low efficacy diuretics.

Part 4 Howabout combination of AT1Ranta and ACEI

  1. Increase effects(cure in hypertension, CHF), decrease disadvantage of the two class drugs.

  2. Have not found anyadverse effects

Questions:

1. Describe the advantages anddisadvantages of AT1R and ACEI in therapeutics of hypertension.

2. what is thecommon side effect of Captopril?