Pharmacologic Interven"On in Hypertension: 2015

4/25/15

Pharmacologic Intervenon in Hypertension: 2015

Larry Warmoth, M.D. Nephrologist Chief of Staﬀ, Covenant Medical Center Associate Professor of Nephrology, Texas Tech School of Medicine

Lifeme Risk of Developing Hypertension Beginning at Age 65

100 Men Women 80

Risk of hypertension Riskof (%) 0 2 4 6 8 10 12 14 16 18 20

Years Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg

1 4/25/15

Frequency Distribuon of Untreated HTN by Age Hypertension – Why a Nephrologist????

Isolated Systolic HTN

Systolic Diastolic HTN

Isolated Diastolic HTN

Accurate BP measurement History

• Who checks your paents BP? • Angina/MI Stroke: Complicaons of HTN, Angina may improve with • You or Staff b-blockers • IF Staff – Do they know what to listen for or do they use automated equipment • Seated properly and quietly for 5 minutes • Asthma, COPD: Preclude the use of b-blockers • Appropriate size cuff • Inflate 20-30 mmHg above loss of radial pulse • Heart failure: ACE inhibitors indicaon • Deflate at 2mmHg per second • DM: ACE preferred • 1st sound SBP ; Disappearance of Korotkoff sound (phase 5) is DBP • Confirm Elevated blood pressure within 2 weeks • Polyuria and nocturia: Suggest renal impairment • Caffeine, exercise, and smoking should be avoided for at least 30 minutes before BP measurement. • The auscultatory method should be used. • 24 hour ambulatory BP monitoring

History-contd. Idenﬁable Causes of HTN

• Claudicaon: May be aggravated by b-blockers, atheromatous RAS • Sleep apnea may be present • Drug-induced or related causes • Gout: May be aggravated by diurecs • Chronic kidney disease • Use of NSAIDs: May cause or aggravate HTN • Primary aldosteronism • Family history of HTN: Important risk factor • Renovascular disease • Family history of premature death: May have been due to HTN • Chronic steroid therapy and Cushing’s syndrome • Pheochromocytoma • Coarctaon of the aorta • Thyroid or parathyroid disease

2 4/25/15

Cardiovascular Risk factors History-contd.

• Hypertension • Family history of DM : Paent may also be Diabec • Cigaree smoking • Cigaree smoker: Aggravate HTN, independently a risk factor for CAD • Obesity (body mass index ≥30 kg/m2) and stroke • Physical inacvity • High alcohol: A cause of HTN • Dyslipidemia • High salt intake: Advice low salt intake • Diabetes mellitus • Albuminuria or esmated GFR <60 mL/min • Age (older than 55 for men, 65 for women) • Family history of premature cardiovascular disease (men under age 55 or women under age 65)

Examinaon Examinaon-contd.

• Appropriate measurement of BP in both arms • Thorough examinaon of the heart and lungs • Opc fundi • Abdomen for enlarged kidneys, masses, and abnormal aorc • Calculaon of BMI ( waist circumference also may be useful) pulsaon • Auscultaon for carod, abdominal, and femoral bruits • Lower extremies for edema and pulses • Palpaon of the thyroid gland. • Neurological assessment

Development of JNC-8 Roune Labs • Commissioned by the NHLBI in 2008 • Panel members appointed • EKG. • Developed focused critical questions relevant to practice • Urinalysis W/ albumin/creanine and protein/creanine raos. • Conducted a systematic search of pertinent literature • Limited to randomized controlled trials (RCTs) published between • Blood glucose and hematocrit; serum potassium, BUN, creanine 1966 and 2009 (eGFR), and calcium. • Included patients age 18 or older with hypertension • HDL cholesterol, LDL cholesterol, and triglycerides. • Sample size of 100 patients or more • Results must have included “hard” outcomes • Subsequent search of studies from 2009 to 2013 required samples of 2000 or more patients

James PA et al. JAMA 2014;311:507-20.

3 4/25/15

Development of JNC-8 Development of JNC-8 • 3 critical questions for adults with hypertension • Does initiating antihypertensive pharmacologic therapy at • In 2013, the NHLBI decides that it will no specific blood pressure thresholds improve health outcomes? longer publish clinical guidelines [When to start therapy?] • Proposes to work collaboratively with other organizations • Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in • The appointed panel members for JNC-8 decided to health outcomes? [How low should I go?] publish their findings independently • Do various antihypertensive drugs or drug classes differ in • Published online in JAMA in December 2013 comparative benefits and harms on specific health outcomes? • Received no endorsements from other organizations [What drug do I use?]

James PA et al. JAMA 2014;311:507-20. James PA et al. JAMA 2014;311:507-20.

But Wait…There’s More JNC-8 Recommendations • A multitude of other hypertension guidelines were also • In patients >60 years of age, start medications at blood published in 2013: pressure of >150/90mm Hg and treat to goal of • AHA/ACC/CDC advisory algorithm <150/90mm Hg • American Society of Hypertension/International Society of Hypertension (ASH/ISH) • European Society of Hypertension and European Society of • In patients >60 years of age, treatment does not need to Cardiology (ESH/ESC) be adjusted if achieved blood pressure is lower than • Canadian Hypertension Education Program (CHEP) goal and well-tolerated

James PA et al. JAMA 2014;311:507-20.

JNC-8 Recommendations JNC-8 Recommendations • In patients <60 years of age, start medications at blood • For the non-black population (including diabetes), pressure of >140/90mm Hg and treat to goal of initial antihypertensive treatment may include a <140/90mm Hg thiazide, ACEI, ARB, or CCB • For the black population (including diabetes), initial • In all adult patients with diabetes or chronic kidney antihypertensive treatment should include a thiazide or disease, start medications at blood pressure of CCB >140/90mm Hg and treat to goal of <140/90mm Hg • For all patients with CKD, initial (or add-on) therapy for hypertension should include an ACEI or ARB

James PA et al. JAMA 2014;311:507-20. James PA et al. JAMA 2014;311:507-20.

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Initial Drug Selection for HTN JNC-8 Recommendations • What happened to the beta-blockers (BB)? • Initiate therapy according to recommendations • Most evidence for BB is from atenolol • If BP is not at goal in one month, increase dose or add a • Does not meet current FDA criteria for a once-daily drug • Losartan Intervention for Endpoint reduction (LIFE) study second agent from recommended classes • Compared losartan vs. atenolol in pts. with HTN & LVH • If patient is still not at goal, add a third drug from • Primary outcome of CV death, MI, or stroke recommended classes • Overall 13% RRR with losartan vs. atenolol (p=0.021) • Do not use an ACEI and ARB together • Driven mainly by 25% reduction in risk of stroke (p=0.001) • Drugs from other classes may be used if additional BP • BB still recommended for many patients with comorbid lowering is needed or if contraindications exist conditions (CHF, CAD, etc.) • Refer to HTN specialist whenever necessary

James PA et al. JAMA 2014;311:507-20. Dahloﬀ B et al. Lancet 2002;359:995-1003.

Comparisons to Other Guidelines

BP Goal JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP

Age < 60 <140/90 <140/90 <140/90 <140/90 <140/90

Age 60-79 <140/90 <150/90 <140/90 <140/90 <140/90

Age 80+ <140/90 <150/90 <150/90 <150/90 <150/90

Diabetes <130/80 <140/90 <140/90 <140/85 <130/80

CKD <130/80 <140/90 <140/90 <130/90 <140/90

Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8.

Comparisons to Other Guidelines JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP

Non-black Thiazide Thiazide, <60:ACEI, Thiazide, Thiazide, (no DM or ACEI, ARB, ARB ACEI, ARB, ACEI, ARB CKD) CCB >60:CCB, CCB, BB (BB if <60) thiazide Black (no Thiazide Thiazide, Thiazide, Thiazide, Thiazide, DM or CCB CCB ACEI, ARB, ARB (BB if CKD) CCB, BB <60) Diabetes ACEI, ARB, CCB, ACEI, ARB, ACEI, ARB ACEI, ARB, CCB, BB, thiazide CCB, CCB, thiazide thiazide thiazide CKD ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB

Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8.

5 4/25/15

Hypertension: Pharmacologic Treatment Pharmacologic Treatment of Hypertension • Selecon of Inial Therapy Treatment Opons • Demographics • Diurecs • Concomitant Diseases and Therapies • ACE inhibitors • Quality of Life • Angiotensin II receptor blockers • Cost • Calcium channel blockers • Drug Interacons • Beta blockers • Alpha blockers • Centrally acng alpha agonists • Direct vasodilators • Peripheral adrenergic blockers

Arch Inter Med 1997

Hypertension Hypertension

Carbonic anhydrase inhibitors • Therapeuc Opons: Diurecs • Promote sodium and water excreon at various sites of the nephron • Loop diurecs Thiazide diuretics • Thiazide/Thiazide-like diurecs diurecs • Potassium-sparing diurecs • Carbonic Anhydrase Inhibitors Potassium-sparing diuretics

Loop diuretics

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Hypertension Hypertension

• Diurecs: Pharmacodynamics • Diurecs: Compelling Indicaons* • Decreased intravascular (blood) fluid volume • Isolated Systolic Hypertension • Decreased extravascular (edema) fluid volume • Congesve Heart Failure • Decreased blood pressure • Diurecs: Possible Favorable Effects • Osteoporosis (thiazides) • Diurecs: Possible Unfavorable Effects • Diabetes • Gout • Renal Insufficiency

Hypertension Hypertension

• Diurecs: Potenal Adverse Effects • Diurecs: Consideraons • Electrolyte disturbances • Useful for paents with ISH, African Americans, CHF • potassium, magnesium, sodium, calcium • Different diurec classes can be combined for addive, or possible • Hyperglycemia synergisc effects • Hypotension, orthostasis • Work well in combinaon with other anhypertensives • Lipid abnormalies • Efficacy drops when renal funcon becomes seriously impaired • Photosensivity • Ototoxicity • Hyperuricemia, gout flare

Hypertension

• Therapeuc Opons: ACE Inhibitors • ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor • Therapeuc Opons: Angiotensin II Receptor Blockers (ARB’s) • ARB’s block the eﬀects of angiotensin II by compeng for binding sites at the receptor

7 4/25/15

Hypertension Hypertension Renin • ACE inhibitors and ARB’s: Pharmacodynamics Angiotensinogen • Vasodilaon • Reduced peripheral resistance Angiotensin I ACE Non-ACE alternate • Increased diuresis pathways (eg, chymase) Angiotensin II • Reduced BP • No change in HR Aldosterone ARB secretionX VasoconstrictionX • No reducon in cardiac output Renal tubular reabsorption of AT1 receptors Catecholamine sodiumX and water secretionX Antidiuretic hormone Stimulation of thirst center (vasoprressin) X secretionX ↓ BP

Hypertension Hypertension

• ACE Inhibitors/ARB’s: Potenal Adverse Eﬀects • ACE inhibitors and ARB’s: Potenal • ACE inhibitors Drug Interacons • Hyperkalemia • Medicaons which promote hyperkalemia • Cough • Medicaons that have acvity which is sensive to changes in serum K+ • Hypotension, dizziness • Medicaons that may cause addive anhypertensive eﬀects • Headache • NSAIDs • Angioedema • ARB’s • Same as ACE inhibitors but cough is uncommon

Hypertension Hypertension

• Therapeuc Opons: ACE inhibitors • ACE inhibitors/ARB’s should be carefully considered: • Compelling Indicaons • Pre-exisng kidney dysfuncon (degree of impairment, response to therapy) • Diabetes Mellitus (Type 1) with proteinuria • Renal artery stenosis (degree of stenosis) • Heart Failure • ACE inhibitors/ARB’s are contraindicated: • Post MI with systolic dysfuncon • Pregnancy • Possible Favorable Eﬀects • History of angioedema • Diabetes Mellitus (Type 1 or 2) with proteinuria • Hyperkalemia • Renal Insuﬃciency

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Escape of Angiotensin II Hypertension Despite ACE Inhibion 100 80 • Therapeuc Opons: Calcium Channel Blockers (CCB’s) Plasma ACE 60 (nmoL/mL/min) 40 • Calcium channel blockers work by blocking calcium channels through which 20 * * * * * * * * calcium ions enter muscle ﬁbers, controlling hypertension. 0 • Calcium Channel Blockers 30 • Dihydropyridine 20 • Plasma Ang II Non-dihydropyridine (pg/mL) 10 *

Placebo 4 h 24 h 1 2 3 4 5 6 Hospital Months *P <.001 vs placebo

Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972. www.hypertensiononline.org

Calcium Channel Blockers (CCB) Classification: Hypertension • Calcium Channel Blockers: Pharmacodynamics • The acvaon of calcium channels can increase: • blood pressure by increasing heart rate • stroke volume • cardiac output • total peripheral resistance • Calcium channel blocking reduces these parameters

Hypertension Hypertension

• CCB’s: Potenal Side Effects • Calcium Channel Blockers: Specific Indicaons • Dihydropyridines • CCB’s: Compelling Indicaons • Peripheral edema • Isolated Systolic Hypertension (long-acng) • reflex tachycardia • flushing/headache • CCB’s: Possible Favorable Effects • hypotension • angina • Nondihydropyridines • atrial tachyarhythmias • conspaon • Cyclosporine-induced HTN • conducon abnormalies • Diabetes Mellitus Type 1 and 2 with proteinuria

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Hypertension Hypertension

• Therapeuc Opons: Beta Blockers • Beta Blockers: CV Pharmacodynamics • Inhibit sympathec smulaon • Reduced heart rate • Beta-1 receptors → heart • Reduced force of heart contracon • Beta-2 receptors → blood vessels, lungs • Reduced cardiac output • Cardioselecve vs. Nonselecve • Reduced blood pressure • Intrinsic sympathomimec acvity (ISA) • Decreased renin

Hypertension Hypertension

• Beta Blockers: Potenal Adverse Eﬀects • Beta Blockers: Precauons • Glucose intolerance, masked hypoglycemia • Bronchospasc disease • Bradycardia, dizziness • Heart Block • Bronchospasm • Sick sinus syndrome • Increased triglycerides and decreased HDL • Diabetes • CNS: Depression, fague, sleep disturbances • Dyslipidemia • Reduced C.O., exacerbaon of heart failure • Depression • Impotence • Exercise intolerance

Hypertension Hypertension

• Beta Blockers: Speciﬁc Indicaons • Therapeuc Opons: Alpha-Beta Blockers • Myocardial Infarcon* • Work by binding to both alpha-1 and beta-1 and/or beta-2 adrenergic • Congesve Heart Failure* receptors consequently prevenng their acvaon by sympathec • Essenal Tremors neurotransmiers. • Carvedilol: alpha-1 + beta-1+ beta-2 blockade • Hyperthyroidism • Labetalol: alpha-1 + beta-1 + beta-2 blockade • Angina • Supraventricular tachycardias • Perioperave Hypertension • Migraine Headaches

*Compelling indications

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α1-sympatholycs α2-sympathomimecs • beside BP reducon they reduce benign prostac hyperplasia

→ indicaon mainly older man with simultaneous BPH • central effect – smulaon of central α2 receptors • in combinaon at severe resistant hypertension through negative feedback inhibit release of • posively influence lipidogram norepinephrine on periphery → reflex BP reducon • strong 1st dose phenomenon! → postural hypotension, syncopes

• prazosin (prototype; Deprazolin), doxazosin (Cardura), • α-metyldopa (Dopegyt), clonidine terazosin • ADR: central depression – sleepiness, bad dreams

• clonidine has significant rebound phenomenon α1-lyc only for the treatment of BPH, without vasodilang effects → tamsulosin • α-metyldopa is advantageous during pregnancy – doesn´t influence negavely blood circulaon of fetus

Direct vasodilators Kallium channel openers • opening of K+ channels on the top of myocytes → hyperpolarisaon → inducon of relaxaon hydralazines

• specific mechanism of acon is unknown; probably directly minoxidil influence contracle system of vessel wall myocytes • vazodilation in the area of arterioles • retenon of Na+, hirsusm, hypertrichosis → used in the • ADR: tachycardia, palpitaons, fluid retenon → treatment of alopecia necessary combinaons • minoxidil is inexpensive

dihydralazine, hydralazine diazoxide • suitable in pregnancy • only short-term use – at hypertension crisis • hydralazine – genet. polymorphism of biotransformaon → at slow acetylators can develop as syndrome similar to • induces hyperglycemia – at short-term use not maers

lupus erythematodes

Direct renin inhibitors (PRI) Aliskiren

• absolutely new group • ﬁrst available peroral PRI

• ↓ plasmac renin acvity • in many ssues is present own renin system with individual receptors → (pro)renin is bind to cell surfaces; • indicaon in 2-combinaon aliskiren + ACEI or aliskirén + ARB system acts pressorically and proliferavely → dual inhibion of RAAS system • it is acvated when smulaon of AT1 receptors decreases → negave feedback • product Rasilez

• this signal way apparently decreases beneﬁt of ACEI! ? - clinical results below expectaons → inhibion of the level of renin → ... beer control

of the whole RAAS → ... possible beer prevenon of organ damage

11 4/25/15

Hypertension in the Elderly HYVET • HYpertension in the Very Elderly Trial • Fastest growing segment of the population • Randomized, double-blind trial • Prevalence of hypertension is very high • Included patients aged 80 or older with SBP>160mmHg • Several issues make managing HTN unique: • Randomized to indapamide +/- perindopril or placebo • Often present with isolated systolic HTN • Target BP of 150/80mmHg • More likely to present with comorbidities • Primary outcome of fatal or nonfatal stroke • Many clinical trials in HTN have excluded these patients (particularly for those 80 years and older) • Elderly are more susceptible to certain adverse effects (orthostatic hypotension)

Becke NS et al. N Engl J Med 2008;358:1887-98.

HYVET Hypertension in the Elderly • Results • HYVET demonstrated that treatment of HTN to goal • Mean BP at the end of the trial • Indapamide +/- perindopril - 143/78 mm Hg BP less than 150/80 mm Hg in patients >80 years old • Placebo – 158/84 mm Hg was safe and effective • 48.0% of indapamide patients achieved goal BP vs. 19.9% of placebo patients (p<0.001) • But…what about a lower BP goal? • Outcomes with indapamide +/- perindopril • 30% reduction in stroke (p=0.06) • 64% reduction in heart failure (p<0.001) • And…what about the patients age 60-80? • 21% reduction in all-cause mortality (p=0.02)

Becke NS et al. N Engl J Med 2008;358:1887-98.

Hypertension in the Elderly Hypertension in the Elderly • Two “treat-to-target” trials in this age group • Japanese Trial to Assess Optimal SBP (JATOS) • 4416 patients aged 65-85 (average age of 74) • Dissension among the ranks! • Randomized to SBP<140 vs. SBP 140-160 • Achieved BP of 136/75 vs. 146/78 • No difference in CV events or renal failure (p=0.99) • VALISH trial • 3079 patients aged 70-84 (average age of 76) • Randomized to SBP<140 or SBP 140-149 • No significant reductions in stroke, CV events, or renal failure • Overall event rates were lower than anticipated in both of these studies

JATOS Study Group. Hypertens Res 2008;31:2115-27. Wright JT Jr et al. Ann Intern Med 2014;160:499-504. Ogihara T et al. Hypertension 2010;56:196-202.

12 4/25/15

Hypertension in the Elderly Pearls • The opposing arguments: • The Japanese trials had low event rates and may not represent the risks in other populations • For resistant HTN – sit down and take a good history • Data from other studies suggests a goal SBP closer to 140mm • How much water, pop, coﬀee, milk, juice, tea, ice – anything liquid do you Hg may be more appropriate for ages 60-80 drink daily. • Methodology may have prevented JNC-8 panel from considering the • Food preferences and salt intake results in their analysis • Drugs/Alcohol • The “Speed Limit” effect • Compliance

Wright JT Jr et al. Ann Intern Med 2014;160:499-504.

Pearls cont.

• The only thiazide that will work with an elevated creanine is metolazone(zaroxolyn) • If elevated creanine. Then will need to use a loop diurec (or with zaroxolyn) • If potassium is elevated – evaluate current meds and add a diurec • If potassium is low – ask why • Check for edema – and ask why • Elderly paents benefit from blood pressure management • Black paents benefit from ACE/ARB – may need to use larger doses to obtain BP lowering effect

“I treat people not numbers”

13 4/25/15

Hypertensive Crises Hypertensive Urgencies

• Hypertensive Urgencies: No progressive target-organ dysfuncon. • Severe elevated BP in the upper range of stage II hypertension. (Accelerated Hypertension) • Without progressive end-organ dysfuncon. • Examples: Highly elevated BP without severe headache, shortness of • Hypertensive Emergencies: Progressive end-organ dysfuncon. breath or chest pain. (Malignant Hypertension) • Usually due to under-controlled HTN.

Barriers to Adherence Hypertensive Emergencies

• Severely elevated BP (>180/120mmHg). • With progressive target organ dysfuncon. • Require emergent lowering of BP.

• Examples: Severely elevated BP with: Hypertensive encephalopathy Acute le ventricular failure with pulmonary edema Acute MI or unstable angina pectoris Dissecng aorc aneurysm Osterberg, L. et al. N Engl J Med 2005;353:487-497

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Paent Evaluaon Objecves Pearls Cont.

• (1) To assess lifestyle and idenfy other cardiovascular risk factors or • Metabolic acidosis and hyperkalemia? – use diurec – loop if concomitant disorders that may affect prognosis and guide treatment creanine is elevated • (2) To reveal idenfiable causes of high BP • Take blood pressure periodically lying and standing so as not to miss • (3) To assess the presence or absence of target organ damage and supine hypertension associated with autonomic insufficiency – this is CVD treated differently

(3) Target Organ Damage Goals of Treatment

• Heart • Treang SBP and DBP to targets that are <140/90 mmHg Le ventricular hypertrophy • Paents with diabetes or renal disease, the BP goal is <130/80 mmHg Angina or prior myocardial infarcon • The primary focus should be on aaining the SBP goal. Prior coronary revascularizaon Heart failure • To reduce cardiovascular and renal morbidity and mortality • Brain Stroke or transient ischemic aack • Chronic kidney disease • Peripheral arterial disease • Renopathy

Lifestyle modiﬁcaons Secondary HTN-Clues in Medical History

• Onset: at age < 30 yrs ( Fibromuscular dysplasi) or > 55 (atheloscleroc renal artery stenosis), sudden onset (thrombus or cholesterol embolism). • Severity: Grade II, unresponsive to treatment. • Episodic, headache and chest pain/palpitaon (pheochromocytoma, thyroid dysfuncon). • Morbid obesity with history of snoring and dayme sleepiness (sleep disorders)

www.nhlbi.nih.gov

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Secondary HTN-clues on Exam Secondary HTN-Clues on Roune Labs

• Pallor, edema, other signs of renal disease. • Increased creanine, abnormal urinalysis ( renovascular and • Abdominal bruit especially with a diastolic component (renovascular) renal parenchymal disease) • Truncal obesity, purple striae, buﬀalo hump (hypercorsolism) • Unexplained hypokalemia (hyperaldosteronism) • Impaired blood glucose ( hypercorsolism) • Impaired TFT (Hypo-/hyperthyroidism)

Diuretics Secondary HTN-Screening Tests

www.nhlbi.nih.gov

Selecvity of CCB Advantages of thiazide diurecs Blood vessels Heart: decrease of vasodilation of arterial Heart AV Strenght of vasculature rate conduction contraction • according to more studies thiazide diurecs are considered the most eﬀecve • they increase anhypertensive eﬀecvity of combined treatment • they proved to reach BP normalisaon • are less expensive than other anhypertensives

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Reaching BP improvement at speciﬁc Other factors inﬂuencing selecon of paents anhypertensives

• Among most paents is necessary combinaon of 2 Potenally prosperous effects: and more anhypertensives. • Thiazide diurecs slower the process of bone • Adminastraon of other drug should start when demineralisaon at osteoporosis monotherapy in required dose doesn´t reduce BP to • βB can have posive influence at ventricular intended value. tachyarrhythmias and fibrilaons, at migraine, short- • If the BP is by 20/10 mm Hg higher than intended termly at thyreotoxicosis, at essenal value, therapy should be started with combinaon of tremor, perioperaonal hypertension 2 anhypertensives. • Ca2+B can be applied at Raynaud syndrome and some arrhythmias

Other factors inﬂuencing selecon of anhypertensives Hypertension

• Therapeuc Treatment Opons • Diurecs Potenally negave eﬀects: • ACE inhibitors • thiazide diurecs at paents with gout and hyponatremia • Angiotensin II receptor blockers in anamnesis • Calcium channel blockers • βB at paents with asthma, allergic diseases of airways and • Beta blockers with A-V blocks of 2nd and 3rd stage • Alpha blockers • ACEI and ARB should not be given if considering pregnancy, • Centrally acng alpha agonists are contraindicated in pregnancy, ACEI at angioneuroc • Direct vasodilators edema • Peripheral adrenergic blockers • aldosterone antagonists and K-sparing diurecs can cause hyperkalemia

Hypertension Hypertension • Selecon of Inial Therapy • Therapeuc Opons: Beta Blockers • Demographics • Inhibit sympathec smulaon • Concomitant Diseases and Therapies • Beta-1 receptors → heart • Quality of Life • Beta-2 receptors → blood vessels, lungs • Cost • Cardioselecve vs. Nonselecve • Drug Interacons • Intrinsic sympathomimec acvity (ISA)

Arch Inter Med 1997

17 4/25/15

Hypertension Hypertension

• Beta Blockers: CV Pharmacodynamics • Beta Blockers: Potenal Adverse Eﬀects • Reduced heart rate • Glucose intolerance, masked hypoglycemia • Reduced force of heart contracon • Bradycardia, dizziness • Reduced cardiac output • Bronchospasm • Reduced blood pressure • Increased triglycerides and decreased HDL • Decreased renin • CNS: Depression, fague, sleep disturbances • Reduced C.O., exacerbaon of heart failure • Impotence • Exercise intolerance

Hypertension Hypertension

• Beta Blockers: Precauons • Beta Blockers: Speciﬁc Indicaons • Bronchospasc disease • Myocardial Infarcon* • Heart Block • Congesve Heart Failure* • Sick sinus syndrome • Essenal Tremors • Diabetes • Hyperthyroidism • Dyslipidemia • Angina • Depression • Supraventricular tachycardias • Perioperave Hypertension • Migraine Headaches Beta blockers are underused!!!

*Compelling indications

Hypertension Hypertension

• Therapeuc Opons: Alpha-Beta Blockers • Therapeuc Opons: Diurecs • Work by binding to both alpha-1 and beta-1 and/or beta-2 adrenergic • Promote sodium and water excreon at various sites of the nephron receptors consequently prevenng their acvaon by sympathec • Loop diurecs neurotransmiers. • Thiazide/Thiazide-like diurecs diurecs • Carvedilol: alpha-1 + beta-1+ beta-2 blockade • Potassium-sparing diurecs • Labetalol: alpha-1 + beta-1 + beta-2 blockade • Carbonic Anhydrase Inhibitors

18 4/25/15

Hypertension Hypertension

Carbonic anhydrase inhibitors • Diurecs: Pharmacodynamics • Decreased intravascular (blood) ﬂuid volume Thiazide diuretics • Decreased extravascular (edema) ﬂuid volume • Decreased blood pressure

Potassium-sparing diuretics

Loop diuretics

Hypertension Hypertension

• Diurecs: Potenal Adverse Effects • Diurecs: Compelling Indicaons* • Electrolyte disturbances • Isolated Systolic Hypertension • potassium, magnesium, sodium, calcium • Congesve Heart Failure • Hyperglycemia • Diurecs: Possible Favorable Effects • Hypotension, orthostasis • Osteoporosis (thiazides) • Lipid abnormalies • Photosensivity • Diurecs: Possible Unfavorable Effects • Ototoxicity • Diabetes • Hyperuricemia, gout flare • Gout • Renal Insufficiency

* Unless contraindicated

Hypertension Hypertension

• Diurecs: Consideraons • Therapeuc Opons: ACE Inhibitors • Useful for paents with ISH, African Americans, CHF • ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a • Different diurec classes can be combined for addive, or possible potent vasoconstrictor synergisc effects • Therapeuc Opons: Angiotensin II Receptor Blockers (ARB’s) • Work well in combinaon with other anhypertensives • ARB’s block the effects of angiotensin II by compeng for binding sites at the • Efficacy drops when renal funcon becomes seriously impaired receptor

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Hypertension Hypertension

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Hypertension in Diabetics • Action to Control CV Risk in Diabetes (ACCORD) • Randomized, double-blind trial • Included patients with T2DM and high CV risk • Randomized to SBP<120 or SBP<140 • Primary outcome of CV death, MI, or stroke • Results • Mean SBP of 119 mm Hg vs. 133 mm Hg • No significant difference in primary outcome (HR=0.88, p=0.2) • Incidence of stroke was lower with intensive treatment (HR 0.59, p=0.01) • Significant increase in serious adverse events

The ACCORD Study Group. N Engl J Med 2010;362:1575-85.

Initial Drug Selection for HTN Initial Drug Selection for HTN • ALLHAT • African-American patients • Randomized, double-blind trial • High risk for CV events • Enrolled 33,357 patients age 55 or older • Less responsive to drugs that act on the renin-angiotensin- • Chlorthalidone aldosterone system • Amlodipine • ACEI, ARB, BB • Lisinopril • Subgroup analysis of black patients in ALLHAT • Doxazosin (this arm stopped early 2° worse outcomes) • Less BP reduction with lisinopril than amlodipine • Primary outcome of CHD death or nonfatal MI • Risk of stroke was significantly higher with lisinopril than with • No significant difference in primary outcome among the amlopdipine (RR 1.51, 95% CI 1.22-1.86) thiazide, ACEI, or CCB • Lisinopril less effective than chlorthalidone in preventing heart failure, stroke, and combined CHD

The ALLHAT Collaborave Research Group. JAMA 2002;288:2981-97. The ALLHAT Collaborave Research Group. JAMA 2002;288:2981-97.