1. TREATMENT OF HYPERTENSION

2. Prof. Azza El-Medany Department of Pharmacology

3. OBJECTIVES At the end of lectures, the students should : Identify factors that control blood pressure Identify the pharmacologic classes of drugs used in treatment of hypertension Know examples of each class.

4. OBJECTIVES ( continue) Describe the mechanism of action, therapeutic uses & common adverse effects of each class of drugs including : Adrenoceptor blocking drugs ( β & α blocking drugs ) Diuretics Calcium channel blocking drugs Vasodilators

5. OBJECTIVES ( cont.) Converting enzyme inhibitors Angiotensin receptor blockers. Describe the advantages of ARBs over ACEI

6. Hypertension Blood pressure is determined by : 1- Blood volume 2- Cardiac output ( rate & contractility ) 3- Peripheral resistance

7. FACTORS IN BLOOD PRESSURE CONTROL

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9. Hypertension Is a major risk factor for cerebrovascular disease, heart failure, renal insufficiency and myocardial infarction. It is often asymptomatic until organ damages reaches a critical point.

10. Antihypertensive therapy Initially consists of lifestyle changes, such as weight reduction, smoking cessation, reduction of salt, saturated fat,, excessive alcohol intake, and increased exercise before drug therapy.

11. Indications for Drug Therapy  Sustained blood pressure elevations > 150/ 90 mmHg.  when minimally elevated blood pressure is associated with other cardiovascular risk factors (smoking, diabetes, obesity, hyperlipidemia, genetic predisposition ).  When end organs are affected by hypertension (heart, kidney, brain ).

12. Drug Management of Hypertension  Diuretics  Cardio inhibitory drugs Beta- blockers Calcium –channel blockers  α adrenoceptor blockers  Centrally acting sympatholytic  Vasodilators  Drugs acting on renin-angiotensin aldosterone system

14. Diuretics -A: thiazides ( hydrochlorothiazide) B: Loop diuretics ( furosemide ) ► cause sodium and water loss decrease volume of blood decrease cardiac output lower blood pressure. ►Thiazide may be adequate in mild hypertension Loop agents used in moderate & severe hypertension

15. C.Potassium-sparing diuretics Amiloride as well as spironolactone reduce potassium loss in the urine. Spironolactone has the additional benefit of diminishing the cardiac remodeling that occurs in heart failure.

16. Cardio inhibitory Drugs

17. β - Adrenoceptor –Blocking DRUGS Are used as monotherapy in mild to moderate hypertension. In severe cases used in combination with other drugs. e.g. Nadolol, Propranolol ( non cardio selective) Bisoprolol, Atenolol, metoprolol ( cardio selective) Labetalol, carvidalol ( α – and β adrenergic blockers )

18. Beta Adrenoceptor –Blocking DRUGS Non cardioselective ( β 1 & β 2 ) drugs as propranolol ( contraindicated in patients with asthmatic patients).

19. Antihypertensive effects of Beta – adrenergic receptor blocking drugs Decreases sympathetic tone → ↓ HR & CO Myocardial contractility Decrease renin release

20. CALCIUM CHANNEL BLOCKERS

21. Classification  Dihydropyridine group (nifedipine, nicardipine, amlodipine ) more selective as vasodilator than a cardiac depressant. This group is used for treatment of hypertension

22. Classification ( continue)  Verapamil is more effective as cardiac depressant, therefore it is not used as antihypertensive agent, used as antiarrhythmic.  Diltiazem.Used mainly for treatment of angina

23. Mechanism of action ❏ Block the influx of calcium through L-type calcium channels resulting in: 1- Peripheral vasodilatation 2- Decrease cardiac contractility & heart rate Both effects lower blood pressure

24. Pharmacokinetics: ❏ given orally and intravenous injection ❏ well absorbed from G.I.T ❏ verapamil and nifedipine are highly bound to plasma protiens ( more than 90%) while diltiazem is less ( 70-80%)

25. (Cont’d): ❏ onset of action --- within 1-3 min --- after i.v. 30 min – 2 h --- after oral dose ❏ verapamil & diltiazem have active metabolites, nifedipine does not ❏ sustained-release preparations can permit once-daily dosing

26. Clinical uses Treatment of chronic hypertension with oral preparation Nicardipine can be given by I.V. route & used in hypertensive emergency

27. ADVERSE EFFECTS VerapamilDiltiazemNifedipine Headache, Flushing, Hypotension Peripheral edema (ankle edema) Cardiac depression, A-V block, bradycardia Tachycardia Constipation

28. α-adrenoceptor blockers Prazocin, terazocin Selectively block postsynaptic α 1 adrenergic receptors. They dilate arterioles → lowering BP Added to β- blockers for treatment of hypertension of pheochromocytoma

29. Centrally acting sympatholytic drugs e.g. Clonidine α 2 -agonist Reduce sympathetic outflow to the heart thereby decreasing cardiac output ( by decreasing heart rate & contractility ). Reduced sympathetic output to the vasculature, decreases sympathetic vascular tone, which causes vasodilation & reduced systemic vascular resistance, which decreases arterial pressure.

30. α methyl dopa α 2 agonist is converted to methyl norepinephrine centrally to diminish the adrenergic outflow from the C.N.S. This lead to reduced total peripheral resistance, and a decreased blood pressure. Safely used in hypertensive pregnant women

31. Side effects of centrally acting sympatholyics Depression Dry mouth & nasal mucosa Bradycardia Impotence

32. Side effects ( continue) Fluid retention & edema with chronic use Abrupt cessation of clonidine may cause a serious rebound hypertension Hemolytic anemia ( methyldopa is the only antihypertensive drug associated with hemolytic anemia usually preceded by a positive Coombs, test.

33. VASODILATORS

34. Compensatory Response to Vasodilators

35. Vasodilators Na nitroprussid e MinoxidilHdralazine Arterio & venodilator Arteriodilator Site of action Release of nitric oxide ( NO) Opening of potassium channels in smooth muscle membranes by minoxidil sulfate ( active metabolite ) DirectMechanism of action Intravenous infusion Oral Route of admin.

36. Na nitropruside MinoxidilHdralazine Continue Vasodilators 1.Hpertensive emergency 1.Moderate – severe hypertension 1.Moderate - severe hypertension. CHF Therapeutic uses 2.correction of baldness 2.Hypertensive pregnant woman

37. Na nitroprussideMinoxidilHdralazineContinue Vasodilators Severe hypotension Hypotension, reflex tachycardia, palpitation, angina, salt and water retention ( edema) Adverse effects 1.Methemoglobin during infusion 2. Cyanide toxicity 3. Thiocyanate toxicity Hypertrichosis. Contraindicated in females lupus erythematosus like syndrome Specific adverse effects

38. Give reason : β-blockers & diuretics are added to vasodilators for treatment of hypertension?

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40. angiotensin- converting enzyme Angiotensin I (inactive) Angiotensin II (active vasoconstrictor) Bradykinin (active vasodilator) Inactive metabolites ACE inhibitors Mechanism of action of Angiotensin-converting enzyme inhibitors (ACEI)

41. Mechanism of action: Converting enzyme inhibitors lower blood pressure by reducing angiotensin II, and also by increasing vasodilator peptides such as bradykinin. Reduction of sympathetic activity Inhibition of aldosterone secretion Reduce the arteriolar and left ventricular remodelling that are believed to be important in the pathogenesis of human essential hypertension and post-infarction state Dilatation of arteriol  reduction of peripheral vascular resistance ( ↓ afterload ) Increase of Na + & water excretion in kidney( ↓preload) Decrease of K + excretion in kidney

42. Pharmacokinetics Captopril, enalapril and ramipril. All are rapidly absorbed from GIT after oral administration. Food reduce their bioavailability. Enalapril, ramipril are prodrugs, converted to the active metabolite in the liver Have a long half-life & given once daily Enalaprilat is the active metabolite of enalapril given by i.v. route in hypertensive emergency.

43. Phrmacokinetics Captopril is not a prodrug Has a short half-life & given twice /day All ACEI are distributed to all tissues except CNS.

44. Clinical uses  Treatment of hypertension  Treatment of heart failure  Diabetic nephropathy.

45. ADVERSE EFFECTS:  Acute renal failure, especially in patients with bilateral renal artery stenosis  Hyperkalemia  Persistent cough  Angioneurotic edema

46. (Cont ’ d): ( cough & angioneurotic edema due to increase in bradykinins)  severe hypotension in hypovolemic patients (due to diuretics, salt restriction or gastrointestinal fluid loss)

47. (Cont ’ d):  Taste loss ( due to SH group in captopril molecule)  Skin rash, fever

48. Contraindications Is absolutely contraindicated pregnancy due to the risk of : fetal hypotension,anuria,renal failure & malformations. Bilateral renal artery stenosis or stenosis of a renal artery with solitary kidney causing acute renal failure.

49. Drug interactions With potassium-sparing diuretics NSAIDs impair their hypotensive effects by blocking bradykinin-mediated vasodilatation. N.B. Less effective in African American Patients as monotherapy

50. BLOCKERS OF AT 1 RECEPTOR losartan, valsartan, irbesartan - competitively inhibit angiotensin II at its AT 1 receptor site  most of the effects of angiotensin II - including vasoconstriction and aldosterone release - are mediated by the AT 1 receptor  they influence RAS more effective because of selective blockade (angiotensin II synthesis in tissue is not completely dependent only on renin release, but could be promote by serin- protease -

51. angiotensinogen angiotensin I angiotensin II renin ACE nonrenin proteases cathepsin t-PA chymase CAGE

52. Continue They have no effect on bradykinin system causing neither: cough, wheezing nor angioedema

53. Adverse effects As ACEI except cough,wheezing, and angioedema. Same contraindications as ACEI.

54. Drugs used for management of hypertensive emergencies BP > 180/120 mmHg associated with end- organ damage Sodium nitroprusside Hydralazine Nicardipine Enalaprilat Labetalol

55. Precaution in management of hypertensive emergencies Avoid using short-acting nifedipine because of the risk of rapid, unpredictable hypotension & the possibility of precipitating ischemic events

56. Drugs used for management of hypertension in pregnancy Methyldopa ( the preferred first line ) Labetalol Hydralazine Diuretics

57. THANK YOU