25.

Drugs acting on RAS

THE RENIN-ANGIOTENSIN SYSTEM The renin-angiotensin system cooperates with the sympathetic nervous system, for example by increasing the release of noradrenaline from sympathetic nerve terminals. It stimulates aldosterone secretion and plays a central role in the control of Na+ excretion and fluid volume, as well as of vascular tone.

The two main groups of indirectly acting vasodilator drugs are inhibitors of: 1. sympathetic vasoconstriction 2. the renin-angiotensin-aldosterone system.

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

Angiotensin-converting enzyme inhibitors

The first ACEI to be marketed was captopril

Angiotensin II receptor antagonists

Losartan, candesartan, valsartan and irbesartan (sartans) are non-peptide, orally active AT1 receptor antagonists. ARBs differ pharmacologically from ACEIs but behave similarly to ACEIs in clinical practice.

Inhibit the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system is inappropriately activated in patients with cardiac failure, especially when they are treated with diuretics. This provided a rationale for studying the effect of combining spironolactone (an aldosterone antagonist) with ACEI treatment, and this further reduces mortality. Eplerenone is an aldosterone antagonist.

Block adrenoceptors
Heart failure is accompanied by potentially harmful activation of the sympathetic nervous system as well as of the renin-angiotensin system, providing a rationale for using adrenoceptor antagonists. Metoprolol, carvedilol and bisoprolol, patients with chronic heart 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).

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 muscle by opening KATP channels.

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

Vasodilators whose mechanism is uncertain, Miscellaneous drugs including alcohol, propofol and hydralazine.

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 in stable patients. Aldosterone receptor antagonists (e.g. spironolactone, Ch. 28; and eplerenone). Digoxin (see Ch. 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;

NA, noradrenaline; NO, nitric oxide.