1. Clinical Pharmacology of Drugs for Controlling Vascular Tone. ANTIHYPERTENSIVE DRUGS

2. ANTIHYPERTENSIVE DRUGS I. DIURETICS Bumetanide, furosemide, hydrochlorthiazide, spironolactone, triamterene II.  -BLOCKERS Atenolol, labetalol, metoprolol, propranolol, timolol III. ACE INHIBITORS Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril IV. ANGIOTENSIN II ANTAGONIST Losartan V. Ca++CHANNEL BLOCKERS Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil VI.  -BLOCKERS Doxazosin, prazosin, terazosin VII. OTHER Clonidine, diazoxide, hydralazine,  -methyldopa, minoxidil, sodium nitroprusside

3. TREATMENT STRATEGIES Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a  -blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A  -blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a  -blocker. A vasodilator can be added as a third step for those patients who still fail to respond.

5. Treatment of arterial hypertension Drugs of first row -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotesine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second row : -α-adrenoblockers (prasosine, terasosine) -agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker) Treatment of arterial hypertension Drugs of first row -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotesine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second row : -α-adrenoblockers (prasosine, terasosine) -agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker)

7. Hydrochlorothiazide+Losartan

8. Thiazide diuretics. Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be monitored closely on patients who are predisposed to cardiac arrhythmias (with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) (to prevent development of fatigue, cramps, and arrhythmias) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia

9. Loop diuretics The loop diuretics act promptly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics.

11.  -blockers. Therapeutic uses The  -blockers are more effective for treating hypertension in white young patients. They are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, glaucoma, and migraine headache.

12. β-adrenoblockers Used for mostly mild to moderate cases of AH (frequently in combinations with other drugs) Stable hypotensive response develops over 1-3 weeks Titration the effective dose. The  -blockers may take several weeks to develop their full effects Antihypertensive action is maintained over 24 hr after single daily dose Contraindications: bronchial asthma, peripheral vascular disease, diabetes

13. ACE-INHIBITORS The angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril, perindopril) are recommended when the preferred first-line agents (diuretics or  - blockers) are contraindicated or ineffective.

14. MECHANISM OF ACTION OF IACE Decrease of arterial pressure sympathetic tone peripheral vessels tone retention of Na+ and H 2 O bradicinine ANGIOTENSINOGEN ANGIOTENSIN (inactive) IACE Decrease angiotensine II production Decrease aldosterone production - ACE Renin (kidneys)

16. Therapeutic uses Like  -blockers, ACE inhibitors are most effective in hypertensive patients who are white and young. However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black hypertensive patients. ACE inhibitors are effective in the management of patients with chronic congestive heart failure. ACE inhibitors are now a standard in the care of a patient following a myocardial infarction. Therapy is started 24 hours after the end of the infarction.

17. ACE inhibitors adverse effects Common side effects include dry cough, rashes, fever, altered taste, hypotension, and hyperkalemia. Potassium levels must be monitored, and potassium supplements or spironolactone are contraindicated. Because of the risk of angioedema and first dose syncope, ACE inhibitors are first administered in the physician’s office with close observation. Reversible renal failure can occur in patients with severe renal artery stenosis. ACE inhibitors are fetotoxic and should not be used in pregnant women.

18. ANGIOTENSIN II ANTAGONISTS Losartan (Cozaar®), Valsartan (Diovan®), Irbesartan (Avapro®), Candesartan (Atacand®). The nanopeptide losartan, a highly selective angiotensin II receptor blocker, has recently been approved for antihypertensive therapy. Its pharmacologic effects are similar to ACE inhibitors in that it produces vasodilation and blocks aldosterone secretion. Its adverse effects is improved over the ACE inhibitors, although it is fetotoxic.

19. ANGIOTENSIN II ANTAGONISTS

20. CALCIUM CHANNEL BLOCKERS –Calcium channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective. –Calcium channel antagonists block the inward movement of calcium by binding to L-tipe calcium channels in the heart and in the smooth-muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles. –Calcium channel blockers have an intrinsic natriuretic effect ; therefore, they do not usually require the addition of a diuretic.

22.  -ADRENERGIC BLOCKING AGENTS Prazosin, doxazosin and terazosin produce a competitive block of  1 adrenoreceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects

24. CENTRALLY-ACTING ADRENERGIC DRUGS Clonidine –  2-agonist – diminishes central adrenergic outflow. Clonidine does not decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension complicated by renal disease. Because it causes sodium and water retention, clonidine is usually administered in combination with diuretic.

25. CENTRALLY-ACTING ADRENERGIC DRUGS Adverse effects are generally mild, but the drug can produce sedation and drying of nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine. The dug therefore should be withdrawal slowly if the clinician wishes to change agents.

26. CENTRALLY-ACTING ADRENERGIC DRUGS  -Methyldopa. This  2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. Because blood flow to the kidney is not diminished by its use,  - methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of  -methyldopa are sedation and drowsiness.

27. VASODILATORS The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as primary drugs to treat hypertension. They act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure. These agents produce reflex stimulation of the heart. They may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.

28. VASODILATORS

29. PRINCIPLES OF THERAPY Therapeutic Regimens Once the diagnosis of hypertension is established, a therapeutic regimen must be designed and implemented. The goal of management for most clients is to achieve and maintain normal blood pressure range (below 140/90 mm Hg). If this goal cannot be achieved, lowering blood pressure to any extent is still considered beneficial in decreasing the incidence of coronary artery disease and stroke.

30. PRINCIPLES OF THERAPY (cont’d) If the initial drug (and dose) does not produce the desired blood pressure, options for further management include increasing the drug dose, substituting another drug, or adding a second drug from a different group. If the response is still inadequate, a second or third drug may be added, including a diuretic if not previously prescribed. When current management is ineffective, reassess the client’s compliance with lifestyle modifications and drug therapy. In addition, review other factors that may decrease the therapeutic response,such as over-the-counter appetite suppressants, dietary or herbal supplements, or nasal decongestants, which raise blood pressure.

31. HYPERTENSIVE EMERGENCY – is a life-threatening situation in which the diastolic blood pressure is either over 150 mm Hg (with systolic blood pressure greater than 210 mm Hg) in an otherwise healthy person, or 130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly reduce blood pressure.

32. MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously) DrugDoseOnset Side effects Sodiumnitroprussid 0,5-10 mcg/kg/min (dropply) 0,5-10 mcg/kg/min (dropply)immediately nausea, vomiting, fibrillation of muscles, sweating Nitroglyceri- num 5-10 mcg/kg (dropply) 2-5 min tachicardia, flushing, headache, vomiting, Diazoxidum 50-100 mg (quickly) 300 mg (during 10 min) 2-4 min nausea, vomiting,, hypotension, tachicardia, flushing, redness of skin, chest pain Apressinum 10-20 mg 10 min flushing, redness of skin, headache, vomiting Furosemidum 20-60-100 mg during 10-15 sec 2-3 min hypotension, fatigue Clophelinum 0,5-1 ml 0,01 % solution (in 15-20 ml 0,9 % solution NaCI slowly) 15-20 min somnolence Anaprilinum 5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly) 20-30 min bradicardia Magnesiumsulfas 5-10-20 ml 25 % solution (i. v. very slowly or dropply) 15-20 min redness of skin Labetololum 20-80 mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – 50-300 mg 5-10 min nausea, vomiting,, hypotension, dizzeness

33. REFERENCES http://www.escardio.org http://www.cardiosmart.org http://www.medscape.com/cardiology