Blood pressure (BP) control. Hypertension

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1

2 Blood pressure (BP) control

3 Normal heart function

4 Blood pressure (BP) control blood pressure (BP) cardiac output (CO) = total peripheral resistance (TPR) heart rate (HR) filling pressure arteriolar volume contractility blood volume venous tone

5 Blood pressure (BP) control 1. Baroreceptors aortic arch and carotid sinus kidneys 2. Autonomic control sympathetic (adrenergic) para-sympathetic (cholinergic) 3. Renin-angiotensin-aldosterone system (RAAS) 4. Chemoreceptors 5. CNS control 6. Vasopressin (anti-diuretic hormone)

6 Blood pressure (BP) control 1. Baroreceptors aortic arch and carotid sinus kidneys 2. Autonomic control sympathetic (adrenergic) para-sympathetic (cholinergic) 3. Renin-angiotensin-aldosterone system (RAAS) 4. Chemoreceptors 5. CNS control 6. Vasopressin (Anti-diuretic hormone)

7 Sympathetic control rapid, momentary regulation affects sympathetic and para-sympathetic systems alters vascular constriction and CO

8 Sympathetic control

9 Sympathetic control

10 RAAS control long-term regulation affects angiotensin-ii and aldosterone secretion potent vasoconstrictor affects vascular constriction controls water balance affects blood volume

11 RAAS control

12 Combined control sympathetic activity BLOOD PRESSURE DECREASED renal blood flow cardiac β 1 -adrenoceptors activated smooth muscle α 1 -adrenoceptors activated Sympathetic mediation renin RAAS mediation angiotensin-ii CO TPR BLOOD PRESSURE INCREASED aldosterone Glomerular filtration rate Na +, water retention blood volume

13 (HTN) Classical definition BP > 140/90 NHLBI previous classification Category Normal High Normal Stage 1 (mild HTN) Stage 2 (moderate HTN) Stage 3 (severe HTN) Stage 4 (very severe HTN) Systolic (mm Hg) < Diastolic (mm Hg) <

14 (HTN) Risk assessment Other Risk Factors & Disease History Grade 1 (mild hypertension) SBP or DBP BLOOD PRESSURE (mmhg) Grade 2 (moderate hypertension) SBP or DBP Grade 3 (severe hypertension) SBP 180 or DBP 110 I. no other risk factors LOW RISK MED RISK HIGH RISK II. 1-2 risk factors MED RISK MED RISK VERY HIGH RISK III. 3 or more risk factors or TOD 1 or diabetes HIGH RISK HIGH RISK VERY HIGH RISK IV. ACC 2 VERY HIGH RISK VERY HIGH RISK VERY HIGH RISK 1 - TOD = Target Organ Damage 2 - ACC = Associated Clinical Conditions, including clinical cardiovascular disease and renal disease.

15 JNC-7 guidelines 2003 HTN prevalence - USA: ~ 50 million people

16 JNC-7 guidelines 2003

17 JNC-7 guidelines 2003 Benefits of Lowering BP average % reduction stroke incidence 35 40% myocardial infarction 20 25% heart failure 50% In stage 1 HTN and additional CVD risk factors, achieving a sustained 12 mmhg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated (NNT=11).

18 JNC-7 guidelines 2003 Benefits of Lowering BP the BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors. each increment of 20/10 mmhg doubles the risk of CVD across the entire BP range starting from 115/75 mmhg.

19 JNC-7 guidelines 2003 Benefits of Lowering BP for persons over age 50, SBP is a more important than DBP as CVD risk factor. those with SBP mmhg or DBP mmhg should be considered pre-hypertensive who require health-promoting lifestyle modifications to prevent CVD.

20 JNC-7 guidelines 2003 Goals of antihypertensive therapy reduce CVD and renal morbidity and mortality. treat to BP <140/90 mmhg or BP <130/80 mmhg in patients with diabetes or chronic kidney disease. achieve SBP goal especially in persons >50yo.

21 JNC-7 guidelines 2003

22 JNC-7 guidelines 2003 Identifiable causes of HTN sleep apnea drug-induced or related causes chronic kidney disease primary aldosteronism reno-vascular disease chronic steroid therapy and Cushing s syndrome pheochromocytoma coarctation of the aorta thyroid or parathyroid disease

23 JNC-7 guidelines 2003

24 JNC-7 guidelines 2003 HTN-related target organ damage heart left ventricular hypertrophy angina or prior myocardial infarction prior coronary revascularization heart failure brain stroke or transient ischemic attack chronic kidney disease peripheral arterial disease retinopathy

25 JNC-7 guidelines 2003 Lifestyle modifications Modification weight reduction DASH eating plan dietary Na + reduction physical activity alcohol consumption Approximate SBP reduction 5-20 mmhg/10 kg weight loss 8-14 mmhg 2-8 mmhg 4-9 mmhg 2-4 mmhg

26 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

27 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

28 Diuretics (thiazides) currently considered 1 st line (elderly) effective in low oral doses (monotherapy/combination) reduce mortality (stroke, MI, CHF) Hydrochlorothiazide (HCTZ) = Disothiazide

29 Thiazide diuretics most effective diuretics in HTN mechanism: peripheral resistance Na +, H 2 O excretion blood volume blood pressure cardiac output

30 Thiazide diuretics - PK good bioavailability (50-80%) not metabolized HCTZ T 1/2-6-12hr renal excretion HCTZ dosing range mg/d ineffective in moderate-severe renal failure (metolazone/indapamide)

31 Thiazide diuretics - PD HCTZ (mg/d)

32 Thiazide diuretics - ADEs hypokalemia (common) - monitor per risk factors hyperuricemia (common) hyperglycemia (10%) hypomagnesemia

33 Thiazide diuretics - DDIs digoxin (hypokalemia may exacerbate digoxin effect) lithium (thazides reduce lithium renal clearance) other diuretic/hypotensive medications (additive effect)

34 Potassium-sparing diuretics spironolactone (Aldospirone ) reduce K + excretion mild hypotensive effect

35 Loop diuretics furosemide (Fusid ) not used as hypotensives: less effective short T 1/2

36 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

37 β-blockers (BBs)- mechanism β-blocker administration 1 2 cardiac β 1 receptor activation renin release cardiac output angiotensin-ii formation peripheral resistance blood pressure aldosterone secretion Na+, H2O excretion blood volume

38 β-blockers selectivity β 1 vs. β 2 non-selective: propranolol = Deralin, Prolol β 1 -selective: atenolol = Normiten, Normalol metoprolol = Lopressor, Neobloc bisoprolol = Concor, Cardiloc

39 β-blockers - ADEs bradycardia hypotension fatigue insomnia sexual dysfunction altered lipid profile

40 β-blockers - DDIs effect of hypoglycemics effect of digoxin, CCBs, α-blockers, other hypotensives β-blockers precautions and contra-indications might mask hypoglycemic effect of hypoglycemics β 2 -blockade in respiratory disease (propranolol - C/I) severe CHF

41 β-blockers - therapeutic considerations more effective in caucasians than in blacks (as monotherapy) additional benefit in concomitant diseases (CHF, IHD, migraine, post-mi, certain arrhythmias)

42 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

43 α 1 -blockers - mechanism α 1 -blocker administration smooth muscle relaxation arterial venous peripheral resistance blood pressure

44 α-blockers - therapeutic considerations α 1 vs. α 2 α 1 -selective: prazosin (Hypotens ) doxazosin (Cardoral, Cadex, Doxaloc ) terazosin (Hytrin )

45 α 1 -blockers - ADEs postural hypotension (1 st -dose syncope) fatigue headache

46 α 1 -blockers - DDIs other hypotensives effect may be decreased by NSAIDs α 1 -blockers - precautions reflex tachycardia upon initiation (short-term β-blocker)

47 α 1 -blockers - therapeutic considerations reflex tachycardia upon initiation (short-term β-blocker) for mild-moderate HTN usually in combination Tx minimal effect on CO, renal function may improve lipid profile may increase mortality risk in HF patients additional benefit in benign prostate hypertrophy (BPH)

48 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

49 CCBs - subclasses Dihydropyridines HTN-Tx nifedipine (Pressolat, (Osmo)Adalat ) amlodipine (Norvasc, Amlow ) lercanidipine (Vasodip ) felodipine (Logimax )

50 CCBs - subclasses Non-dihydropyridines arrhythmia, IHD verapamil (Ikacor /Ikapress, Veracor /Verapress ) (phenylalkylamine - negative inotropic, minimally vasodilating) diltiazem (Dilatam /Dilapress /Adizam ) (benzothiazepine - intermediate inotrpic/vasodilator) relative affinity to nifedipine diltiazem verapamil cardiac Ca ++ channels vascular Ca ++ channels

51 CCBs - mechanism myocardial and smooth muscle cells dihydropyridine CCB administration artery dilation peripheral resistance intracellular calcium blood pressure muscle contraction

52 CCBs - ADEs hypotension constipation fatigue headache peripheral and pulmonary edema

53 CCBs - DDIs nifedipine - with many drugs: - H 2 blockers, omeprazole - antimicrobials (ciprofloxacin, macrolides, azoles) - levodopa - metoprolol - antieplipetic drugs (phenytoin, valproic acid, phenobarbital) - digoxin less with newer dihydropyridines (amlodipine)

54 CCBs - DDIs diltiazem - with many drugs: - amiodarone - β-blockers - azole antifungals, macrolides, ciprofloxacin - metoprolol - statins - digoxin - antieplipetic drugs (phenytoin, valproic acid, phenobarbital) - grapefruit juice

55 CCBs - DDIs verapamil - with many drugs: - amiodarone - β-blockers - azole antifungals, erythromycin - lithium - statins - digoxin - theophylline - grapefruit juice

56 CCBs - therapeutic considerations intrinsic natriuretic effect (no diuretic required) generally safe in asthma, diabetes, IHD may be effective as monotherapy avoid verapamil in CHF additional benefit: certain arrhythmias

57 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

58 RAAS modifiers

59 RAAS modifiers - ACEIs captopril (Aceril ) enalapril (Convertin, Enaladex ) cilazapril (Vascace, Cilaril ) ramipril (Tritace, Ramitens ) lisinopril (Tensopril ) moexipril (Perdix ) benazepril (Cibacen ) 59 fixed combinations with HCTZ

60 RAAS modifiers - ACEIs 60

61 RAAS modifiers - ACEIs angiotensin-converting enzyme angiotensin-i ACEIs other enzymes vasoconstriction angiotensin-ii aldosterone bradykinin 61 water retention sodium retention vasoconstriction

62 RAAS modifiers - ACEIs angiotensin-converting enzyme angiotensin-i ACEIs other enzymes vasoconstriction angiotensin-ii aldosterone bradykinin 62 water retention sodium retention vasoconstriction

63 RAAS modifiers - ACEIs CO increased: bradykinin, aldosterone, epinephrine water and sodium retention BP vascular resistance 63

64 RAAS modifiers - ACEIs PK: adequate oral absorption (empty stomach) most ACEIs are prodrugs (hepatic activation) PK T 1/2-2-12hr; PD - longer for most ACEIs: renal elimination 64

65 RAAS modifiers - ACEIs ADEs: postural hypotn renal impairment angioedema (0.13%) dry cough (20%) bradykinin hyperkalemia 65

66 RAAS modifiers - ACEIs DDIs: potassium-sparing agents, potassium supplements hypoglycemics (improved insulin sensitivity) NSAIDs (vasoconstriction, renal effect) lithium (decreased renal clearance of Li) 66

67 RAAS modifiers - ACEIs additional benefits: HF diabetes post-mi proteinuric chronic renal failure 67

68 RAAS modifiers - ARBs (ATRAs) losartan (Ocsaar, Lotan ) valsartan (Diovan ) candesartan (Atacand ) olmesartan (Olmetec ) fixed combinations with HCTZ 68

69 RAAS modifiers - ARBs (ATRAs) 69

70 RAAS modifiers - ARBs (ATRAs) angiotensin-i angiotensin-converting enzyme other enzymes vasoconstriction angiotensin-ii ARBs aldosterone bradykinin 70 water retention sodium retention vasoconstriction

71 RAAS modifiers - ARBs (ATRAs) advantages over ACEIs: more complete angiotensin-ii blockade no effect on bradykinin 71

72 RAAS modifiers - ARBs (ATRAs) PK: good oral absorption long T 1/2, once-daily administration combined renal-fecal elimination 72

73 RAAS modifiers - ARBs (ATRAs) ADEs: generally similar to those of ACEIs cough ( ) angioedema 73

74 RAAS modifiers - ARBs (ATRAs) DDIs - similar to those of ACEIs: potassium-sparing agents, potassium supplements hypoglycemics (improved insulin sensitivity) NSAIDs (vasoconstriction, renal effect) lithium (decreased renal clearance of Li) 74

75 RAAS modifiers - ARBs (ATRAs) additional benefits similar to those of ACEIs: HF diabetes post-mi proteinuric chronic renal failure 75

76 RAAS modifiers - aldosterone antagonist spironolactone (Aldospirone ) potassium-sparing diuretic not as monotherapy for HTN (excessive fluid retention, reflex tachycardia) hyperkalemia, hyponatremia, gynecomastia might decrease effect of digoxin (hyperkalemia) additional benefit - CHF 76

77 Therapeutic options: Diuretics β-blockers α 1 -blockers Calcium-channel blockers RAAS modifiers Other

78 Centrally-acting adrenergic drugs 1. clonidine (Normopressan ) α 2 -agonist inhibition of adrenergic activity BP devoid of renal effect H 2 O, Na + retention: combine with diuretic sedation, nasal dryness gradual tapering-off (rebound)

79 Centrally-acting adrenergic drugs 2. α-methyl dopa (Aldomin ) methylnorepinephrine prodrug, centrally active inhibition of adrenergic activity TPR, BP CO and organ blood supply unchanged devoid of renal effects sedation, drowsiness, dry mouth, impaired LFTs 1 st choice in pregnancy

80 Direct vasodilators smooth muscle relaxation peripheral resistance BP

81 Direct vasodilators 1. hydralazine most active in arteries, peripheral resistance non-teratogenic ADEs: nausea, sweating, lupus-like syndrome (rare) devoid of renal effect H 2 O, Na + retention: combine with diuretic

82 Direct vasodilators 2. minoxidil mainly active in arteries for Tx of refractory HTN ADEs: severe reflex tachycardia, peripheral edema; hair growth

83 Direct vasodilators β-blocker renin activity smooth muscle relaxation peripheral resistance cardiac activity H 2 O, Na + retention BP BP HR, O 2 demand diuretic

84 JNC-7 guidelines 2003

85 JNC-7 guidelines 2003 Widely accepted 1 st line therapy: low-dose HCTZ change drug? goal unmet? increase dose? add 2 nd drug?

86 JNC-7 guidelines 2003 thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes. certain high-risk conditions are compelling indications for other drug classes. most patients will require two or more antihypertensive drugs to achieve goal BP. if BP is >20/10 mmhg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

87 JNC-7 guidelines 2003 Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmhg) (<130/80 mmhg for those with diabetes or chronic kidney disease) Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 HTN: (SBP or DBP mmhg): Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 HTN (SBP >160 or DBP >100 mmhg): 2-drug combination for most (usually thiazide + ACEI/ARB/BB/CCB) Not at Goal Blood Pressure Bi-functional drugs: (diuretics, ACEI, ARB, BB, CCB) as needed. Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with HTN specialist.

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89 JNC-7 guidelines 2003 Potential favorable effects of HTN-Tx: thiazide-type diuretics useful in slowing demineralization in osteoporosis. BBs useful in the treatment of atrial tachyarrhythmias/fibrillation, migraine, thyrotoxicosis (short-term), essential tremor, or perioperative HTN. CCBs useful in Raynaud s syndrome and certain arrhythmias. α-blockers useful in prostatism.

90 JNC-7 guidelines 2003 Potential unfavorable effects of HTN-Tx: thiazide diuretics should be used cautiously in gout or a history of significant hyponatremia. BBs should be generally avoided in patients with asthma, reactive airways disease, or second- or third-degree heart block. ACEIs and ARBs: C/I in pregnancy ACEIs should not be used with a history of angioedema. aldosterone antagonists and K + -sparing diuretics can cause hyperkalemia.

91 JNC-7 guidelines 2003 (non)adherence issues JNC-8 expected release: 2011

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93 Current trends Outcomes dependent on achieved BP reduction regardless of therapeutic class beta-blockers less preferred, unless additional indication newer CCBs and RAAS modifiers appealing due to effectiveness, convenience and safety

94 Discontinuation of antihypertensive Tx When to D/C? well-controlled, mild HTN lifestyle modifications importance of patient characteristics

95 Discontinuation of antihypertensive Tx How to D/C? gradual withdrawal preferred abrupt cessation of short-acting β-blockers (propranolol) and α 2 -agonists (clonidine) might cause a fatal withdrawal syndrome these should therefore be tapered-off over weeks

96 - hypertension DRUGS FOR EXAM hydrochlorothiazide spironolactone propranolol metoprolol doxazosin amlodipine diltiazem verapamil enalapril losartan clonidine hydralazine α-methyl-dopa 96