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25. Drugs acting on RASTHE RENIN-ANGIOTENSIN SYSTEMThe renin-angiotensin system cooperates with the sympathetic nervous system, forexampleby increasing the release of noradrenaline from sympathetic nerve terminals. It

stimulatesaldosterone secretion and plays a central role in the control of Na+ excretion and fluidvolume,as well as of vascular tone.

The two main groups of indirectly acting vasodilator drugs are inhibitors of:1. sympathetic vasoconstriction2. the renin-angiotensin-aldosterone system.

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Clinical uses of angiotensin-converting enzyme inhibitorsHypertension.Cardiac failure.Following myocardial infarction (especially when there isventricular dysfunction).In people at high risk of ischaemic heart disease.Diabetic nephropathy.Progressive renal insufficiency.

Angiotensin-converting enzyme inhibitorsThe first ACEI to be marketed was captopril

Angiotensin II receptor antagonists

Losartan, candesartan, valsartan and irbesartan (sartans) are non-peptide, orally

activeAT1 receptor antagonists. ARBs differ pharmacologically from ACEIs but behavesimilarly to ACEIs in clinical practice.

Inhibit the renin-angiotensin-aldosterone systemThe renin-angiotensin-aldosterone system is inappropriately activated in patients withcardiacfailure, especially when they are treated with diuretics. This provided a rationale forstudying the effect of combiningspironolactone (an aldosterone antagonist) with ACEI treatment, and this furtherreduces

mortality. Eplerenone is an aldosterone antagonist.

Block adrenoceptorsHeart failure is accompanied by potentially harmful activation of the sympatheticnervoussystem as well as of the renin-angiotensin system, providing a rationale for using -adrenoceptor antagonists. Metoprolol, carvedilol and bisoprolol, patients with chronicheart failure.

26. Vasodilators as Antihypertensive Agents

Vasodilator drugs play a major role in the treatment of common conditions including

hypertension, cardiac failure and angina pectoris, as well as several less common but severe

diseases including pulmonary hypertension and Raynaud's disease (A circulatory disorder caused

by insufficient blood supply to the hands and feet and resulting in cyanosis, numbness, pain, and,

in extreme cases, gangrene).

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Vasoconstrictor substances

The main groups are sympathomimetic amines (direct and indirect),certain eicosanoids (especially thromboxane A2, peptides (angiotensin

II, antidiuretic hormone [ADH] and endothelin; and a group of

miscellaneous drugs (e.g. ergot alkaloids.

Clinical uses include local applications (e.g. nasal decongestion,co-administration with local anaesthetics). Sympathomimetic amines

and ADH are used in circulatory shock. Adrenaline is life-saving in

anaphylactic shock and in cardiac arrest. ADH may be used to stop

bleeding from oesophageal varices in patients with portal

hypertension caused by liver disease.

DIRECTLY ACTING VASODILATORS, Fig 4.10

Targets on which drugs act to relax vascular smooth muscle include plasma membrane

voltage-dependent calcium channels, sarcoplasmic reticulum channels (Ca2+

release or reuptake)

and enzymes that determine Ca2+

sensitivity of the contractile proteins

Calcium antagonists, nifedipine, diltiazem,verapamil.

Drugs that activate potassium channels, drugs (e.g. minoxidil, diazoxide) relax smooth muscleby opening KATP channels.

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Drugs that act via cyclic nucleotides, epoprostenol, glyceryl trinitrate,nitroprusside,sildenafil.

Indirectly acting vasodilators

Table 22-4. Summary of drugs that inhibit the renin-angiotensin-aldosterone system, ingar i

indirekt

The two main groups of indirectly acting vasodilator drugs are inhibitors of:

sympathetic vasoconstriction och the renin-angiotensin-aldosterone system

Renin inhibitors

Angiotensin-converting enzyme inhibitors

Angiotensin II receptor antagonists

Drugs that block the renin-angiotensin system:

- renin inhibitors (e.g. aliskiren)

- angiotensin-converting enzyme inhibitors (e.g. ramipril); dry cough may betroublesome

- AT1 receptor antagonists (e.g. losartan).

Vasodilators whose mechanism is uncertain, Miscellaneous drugs including alcohol, propofol

and hydralazine.

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Drugs used in chronic heart failure:

Loop diuretics, for example furosemide(Ch. 28). Angiotensin-converting enzyme inhibitors

(e.g. ramipril).

Angiotensin II subtype 1 receptor antagonists (e.g. valsartan, candesartan).

-adrenoceptor antagonists (e.g. metoprolol, bisoprolol, carvedilol), introduced in low dose instable patients.

Aldosterone receptor antagonists (e.g. spironolactone,Ch. 28; and eplerenone).

Digoxin (seeCh. 21), especially for heart failure associated with established rapid atrial

fibrillation. It is also indicated in patients who remain symptomatic despite optimal treatment.

Organic nitrates (e.g. isosorbide mononitrate) reduce preload, and hydralazine reduces

afterload. Used in combination, these prolong life in African-Americans.

Diagram showing the main mechanisms involved in arterial blood pressure regulation(black lines), and the sites of action of antihypertensive drugs (hatched boxes + orange lines).

ACE, angiotensin-converting enzyme; AI, angiotensin I; AII, angiotensin II; ET-1, endothelin-1;

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NA, noradrenaline; NO, nitric oxide.