Drugs used to treat hypertension

1. Drugs used to treat hypertension prof. Ján Mojžiš Department of Pharmacology, Medical Faculty, P.J. Šafarik University Košice

2. Target-Organ Damage Brain: stroke, transient ischemic attack, dementia Eyes: retinopathy Heart: left ventricular hypertrophy, angina Kidney: chronic kidney disease Peripheral Vasculature: peripheral arterial disease 2

3. Adult Classification Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252. 3

4. Treatment Goals Reduce morbidity & mortality Select drug therapy based on evidence demonstrating risk reduction 4

5. Hypertension • Essential (primary) • - most (90-95 %) patients with persistent arterial hypertension • genesis of hypertension unknown • predisposing factors: • Secondary • is secondary to some • distinct diseases: • Renal + renovascular desease • (artery stenosis) • Hormonal defects • (Cushing´s syndrome, • pheochromocytoma) • Mechanical defect • (coarctation of aorta) • Hypertension in pregnancy • Drug-induced hypertension • (sympatomimetics, • glucocorticoids) • Neurologic disease susceptive (obesity, stress, salt intake, lack of Mg2+, K+, Ca2+, ethanol  dose, smoking) non-susceptive (positive family history, insulin resistance, age, sex, defect of local vasomotoric regualtion)

6. Treatment of hyperternsion A: Non-pharmacological Changes of lifestyl

7. Lifestyle Modifications 7 DASH, Dietary Approaches to Stop Hypertension.

8. Standard drink A standard drink is about 142 ml or 5 oz of wine (12% alcohol). 341 mL or 12 oz of beer (5% alcohol) 43 mL or 1.5 oz of spirits (40% alcohol).

10. B. Pharmacological • Diuretics • -blockers • ACE-I, blockers of AT1 receptor • 4. Calcium channel blockers • 5. Other

11. Diuretics • Thiazide • chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metipamid, clopamid • Loop • bumetanide, furosemide, torsemide • Potassium-sparing • spironolactone, amiloride 11

12. DIURETICS – cont. - preferable (to loop diuretics) for the treatment of uncomplicated hypertension- given by mouth as a single morning dose (to avoid nocturnal diuresis)- begin to act within 1-2 hours and work for 12-24 hours- treatment should be started using a low dose • drugs of first choice for treating patients with mild hypertension often combined with another drug in treatment of more severe hypertension THIAZIDES

13. Lumen – urine Distal convoluted tubule Interstitium - blood Thiazides

14. Mechanism of action: • lower blood pressure by reduction of blood volume and by direct vascular effect • inhibition of sodium chloride transport in the early segment of the distal convoluted tubule  natriuresis, decrease in preload and cardiacoutput -renal effect • slow decrease of total peripheral resistance(raised initially) during chronic treatment, suggesting an action on resistance vessels -extrarenal effects

15. Adverse effects • -metabolic and electrolyte changes • hyponatremia • hypokalemia (combine with potassium-sparing diuretics) • hypomagnesemia • hyperuricemia (most diuretics reduce urate clearance) • hyperglycemia • hypercalcemia(thiazides reduce urinary calcium ion clearance) • idiosyncratic reactions(rashes - may be photosensitiv, purpura) • lithium toxicity with concurrent administration

16. LOOP DIURETICS - useful in hypertensive patients with moderate or severe renalimpairment, or in patients with hypertensive heart failure - relatively short-acting (diuresis occurs over the 4 hours following a dose)  used in hypertension if response to thiazides is inadequate Mechanism of action: - they inhibit the co-transport of Na+, K+and 2Cl- - of Ca2+ and Mg2+ excretion - they have useful pulmonary vasodilating effects (unknown mechanism)

17. Lumen – urine Thick ascending limb Interstitium - blood Furosemide

18. Adverse effects - hypokalemic metabolic alkalosis ( excretion of K+) - ototoxicity (dose dependent, reversible) - hypomagnesemia - hyperuricemia (block of uric acid tubular secretion) - sulfonamide allergy - risk of dehydration (> 4 L urine/ 24 h) Important drug interaction may occurs if loop diuretic is given with Li+ (antimanic drug). Decrease of Na+ reabsorption can lead to increase of Li+ reabsorption  toxicity.

19. Potassium-sparing diuretics act in the distal tubule and the collecting tubule to inhibit Na+ reabsorption, K+ secretion, H+ secretion they are often used with a thiazide diuretic to spare potassium Spironolactone -  it is an aldosterone antagonist - is useful in patients with high level of aldosterone - it has low diuretic efficacy  its advantage is sparing of potassium - it is often used with loop or thiazide diuretics

20. Potassium-sparing diuretics– cont. Amiloride - it has similar potassium-spring action to that of spironolactone - its efect is independent on aldosterone concentration - it si also frequently used with other diuretics • Adverse effects: • may cause hyperkalemia especially in combination with ACE inhibitor, angiotensin-receptor blocker or potassium supplements

21. -adrenoreceptor antagonists

22. β-Receptors • Distributed throughout the body • concentrate differently in certain organs & tissues • β1 receptors: • heart, kidney • stimulation increases HR, contractility, renin release • β2 receptors: • lungs, liver, pancreas, arteriolar smooth muscle • stimulation causes bronchodilation & vasodilation • mediate insulin secretion & glycogenolysis • β3 receptors: • adipose tissue, skeletal muscle • stimulation causes lipolysis in adiposetissue •  thermogenesis in skeletal muscle

23. Mechanism of action • Negative chronotropic & inotropic cardiac effects • Inhibit renin release (weak association with antihypertensive effect) • Membrane-stabilizing action on cardiac cells at high enough doses (?) • Possible mechanisms include: • b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by b-receptor antagonists

24. -adrenoreceptor antagonists– cont. cardio-selective: 1 blockersatenolol, metoprolol 1 blockers with ISA acebutol cardio non-selective: 1 + 2 blockersmetiprolol, propranolol, nadolol 1 + 2 blockers with ISApindolol, bopindolol 1+2+ 1 blockerslabetalol, carvedilol

25. Cardioselective β-Blockers • Greater affinity for β1 than β2 receptors • inhibit β1 receptors at low to moderate dose • higher doses block β2 receptors • Safer in patients with bronchospastic disease, peripheral arterial disease, diabetes • may exacerbate bronchospastic disease when selectivity lost at high doses • dose where selectivity lost varies from patient to patient • Generally preferred β-blockers 25

26. Nonselective β-Blockers • Inhibit β1 & β2 receptors at all doses • Can exacerbate bronchospastic disease • Additional benefits in: • essential tremor • migraine headache • thyrotoxicosis 26

27. -adrenoreceptor antagonists– cont. Adverse effects - bradycardia - AV blockade - CHF - asthmatic attack(in patients with airway disease) - hypoglycemia in patients with DM - cold extremities - CNS adverse effects - sedation, fatigue, and sleep alterations.

28. Angiotensin-converting enzyme inhibitors (ACE-I)

29. Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril Indications - hypertension where thiazide diuretics and -blockers are contraindicated - useful in hypertensive patients with heart failure (beneficial effect) -diabetic nephropathy

30. Angiotensin I (inactive) Bradykinine (vasodilator) ACE ACE-I Angiotensin II (vasoconstrictor) Inactive metabolites

31. Effect of ACE-I RENIN ACE Inhibitors Angiotensin IANGIOTENSIN II Angiotensinogen  ACE  RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

32. ACE-I – cont. Dilatation of arteriol  reduction of peripheral vascular resistance, blood pressure and afterload Increase of Na+ and decrease of K+ excretion in kidney Decreasenoradrenaline release  reduction of sympatheticactivity (use is not associated with reflex tachycardia) Inhibition of aldosteronesecretion contributes to the antihypertensive effects of ACE-I Influence on the arteriolar and left ventricularremodellingthat are believed to be important in the pathogenesis of human essential hypertension and post-infarction state

33. Summary of the three major effects of angiotensin II and the mechanisms that mediate them.

34. ACE-I – cont. • Pharmacokinetics • active when administered orally • most of ACE-Is are highly polar, eliminated in the urine, without CNS penetration • captopril, lisinopril - active per se • enalapril, quinapril - prodrugs  require metabolic activation • enalapril, quinapril and lisinopril - given once daily • captopril - administered twice daily

35. ACE-I – cont.

36. ACE-I – cont. • Adverse effects • well tolerated • First dose hypotension- particularly in those receiving diuretic therapy; the first dose should preferably be given at bedtime. • Dry cough- the most frequent (5-30%) symptom; • Urticaria and angioneurotic edema-  kinin concentrations  urticarial reactions and angioneurotic edema • Functional renal failure- mainly in patients with bilateral renalartery stenosis • Fetal injury- results in oligohydramnios, craniofacial malformations

37. ACE-I – cont. Hyperkalemia – monitor !! - ACE-Is cause a modest increase in plasma potassium as aresult of reduced aldosterone secretion. - potassium accumulation may be marked, especially if thepatient is consuming high-potassium diet and/or potasssium-sparing diuretics.

38. BLOCKERS OF AT1 RECEPTOR

39. losartan, valosartan, irbesartan • itcompetitively inhibit angiotensin IIat its AT1 receptor site • Mechanisms responsible for antihypertensive effect: • inhibition of direct vasoconstrictive effect of A-II • decrease of sympathetic nerve activity • decrease of A-II-mediated aldosterone release • decrease of RAS activity in CNS • decrease of smooth muscle and cardiac hypertrophy and hyperplasia

40. Inhibition of the effects of angiotensin II RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other paths AT1 Receptor Antagonists AT II AT II  RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

41. Other paths for A-II synthesis angiotensinogen renin non-renin proteases cathepsin t-PA angiotensin I ACE angiotensin II

42. Blockers of AT1 receptor– cont. losartan - prodrug (metabolite is 10-40x potent than losartan) - rapid absorption, food has minor effect on the absorption, bound to albumin valsartan - active drug (40, 000 x greater affinity to AT-1 than AT-2) rapid absorption, food has minor effect on the absorption, bound to albumin

43. Blockers of AT1 receptor– cont. Clinical use in hypertension losartan -    aditive effect to hydrochlorthiazide (HCTZ) -    fixed dose combination: losartan 50 mg + 12.5 mg HCTZ valsartan -   in placebo-controlled trials  80 mg decrease syst. and diastol. pressure aproximately about 7-10 mm Hg -   equivalent to 20 mg of enalapril or 10 mg of lisinopril

44. BLOCKERS OF AT1 RECEPTOR– cont. -these drugs lower blood pressure as the ACE inhibitors and have the advantage of much lower incidence of adverse effects resulting from accumulation of bradykinin (cough, angioneurotic oedema) - they cause fetal renal toxicity (like that of the ACE inhibitors) - these drugs reduce aldosterone levels and cause potassium accumulation (attainment of toxic levels - hazardous in patientswith renal impairment)

45. Renin Inhibitor • 1st agent FDA approved in 2007: aliskiren • Inhibits angiotensinogen to angiotensin I conversion • FDA approved as monotherapy & combination therapy with other antihypertensives • combination with other antihypertensives including amlodipine, HCTZ, ACEIs/ARBs • Does not block bradykinin breakdown • less cough than ACE Inhibitors • Adverse effects: orthostatic hypotension, hyperkalemia

46. Calcium channelblockers (CCBs)

47. 1. dihydropyridines(nifedipine, nicardipine, amlodipine) 2. benzothiazepines (diltiazem) 3. phenylalkylamines (verapamil) 4. tetralol (mibefradil) • they block voltage-dependent „L-type“ calcium channels  relaxation of smooth muscle vasodilation  reduce peripheral vascular resistance reduction of BP • negatively inotropic drugs • they differ in selectivity for calcium channels in vascular smooth muscles and cardiac tissues

48. Dihydropyridine CCBs • Dihydropyridines more potent peripheral vasodilators than non-dihydropyridines • may cause more reflex sympathetic discharge: tachycardia, dizziness, headaches, flushing, peripheral edema • Additional benefits in Raynaud’s syndrome • Effective in older patients with isolated systolic hypertension 48

49. Indication: all grades of essential hypertension • alone (nifedipine, amlodipine) in patients with mild hypertensionfor patients in whom thiazide diuretics and b-blockers are contraindicated • combinations • angina (with -blockers)

50. Non-dihydropyridine CCBs extended release products preferred for hypertension Block cardiac SA (diltiazem)or AV (verapamil) nodes: reduce HR May produce heart block Additional benefits in patients with atrial tachyarrhythmia 50