pharmacologic intervervention in hypertension · 2018. 4. 14. · 4/25/15 4 development of jnc-8...

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Pharmacologic Interven1on in Hypertension: 2015

Larry Warmoth, M.D. Nephrologist

Chief of Staff, Covenant Medical Center Associate Professor of Nephrology, Texas Tech School of Medicine

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

Years

Life1me Risk of Developing Hypertension Beginning at Age 65

Men Women

Vasan RS, et al. JAMA. 2002; 287:1003-1010. Copyright 2002, American Medical Association.

www.hypertensiononline.org

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Frequency Distribu1on of Untreated HTN by Age

Isolated Systolic HTN

Isolated Diastolic HTN

Systolic Diastolic HTN

Hypertension – Why a Nephrologist????

Accurate BP measurement

• Who checks your paIents BP? •  You or Staff

•  IF Staff – Do they know what to listen for or do they use automated equipment •  Seated properly and quietly for 5 minutes •  Appropriate size cuff •  Inflate 20-‐30 mmHg above loss of radial pulse •  Deflate at 2mmHg per second •  1st sound SBP ; Disappearance of Korotkoff sound (phase 5) is DBP •  Confirm Elevated blood pressure within 2 weeks •  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

• Angina/MI Stroke: ComplicaIons of HTN, Angina may improve with b-‐blockers

• Asthma, COPD: Preclude the use of b-‐blockers • Heart failure: ACE inhibitors indicaIon • DM: ACE preferred • Polyuria and nocturia: Suggest renal impairment

History-‐contd.

• ClaudicaHon: May be aggravated by b-‐blockers, atheromatous RAS may be present

• Gout: May be aggravated by diureIcs • Use of NSAIDs: May cause or aggravate HTN •  Family history of HTN: Important risk factor •  Family history of premature death: May have been due to HTN

Iden1fiable Causes of HTN

•  Sleep apnea • Drug-‐induced or related causes • Chronic kidney disease • Primary aldosteronism • Renovascular disease • Chronic steroid therapy and Cushing’s syndrome • Pheochromocytoma • CoarctaIon of the aorta •  Thyroid or parathyroid disease

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Cardiovascular Risk factors

•  Hypertension •  Cigarece smoking •  Obesity (body mass index ≥30 kg/m2) •  Physical inacIvity •  Dyslipidemia •  Diabetes mellitus •  Albuminuria or esImated 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)

History-‐contd.

•  Family history of DM : PaIent may also be DiabeIc • CigareLe smoker: Aggravate HTN, independently a risk factor for CAD and stroke

• High alcohol: A cause of HTN • High salt intake: Advice low salt intake

Examina1on

• Appropriate measurement of BP in both arms • OpIc fundi • CalculaIon of BMI ( waist circumference also may be useful) • AuscultaIon for caroId, abdominal, and femoral bruits • PalpaIon of the thyroid gland.

Examina1on-‐contd.

•  Thorough examinaIon of the heart and lungs • Abdomen for enlarged kidneys, masses, and abnormal aorIc pulsaIon

•  Lower extremiIes for edema and pulses • Neurological assessment

Rou1ne Labs

•  EKG. •  Urinalysis W/ albumin/creaInine and protein/creaInine raIos. •  Blood glucose and hematocrit; serum potassium, BUN, creaHnine (eGFR), and calcium.

•  HDL cholesterol, LDL cholesterol, and triglycerides.

Development of JNC-8 • Commissioned by the NHLBI in 2008

•  Panel members appointed • Developed focused critical questions relevant to practice • Conducted a systematic search of pertinent literature

•  Limited to randomized controlled trials (RCTs) published between 1966 and 2009

•  Included patients age 18 or older with hypertension •  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.

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Development of JNC-8 •  3 critical questions for adults with hypertension

•  Does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? [When to start therapy?]

•  Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes? [How low should I go?]

•  Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? [What drug do I use?]


Development of JNC-8 • In 2013, the NHLBI decides that it will no longer publish clinical guidelines

•  Proposes to work collaboratively with other organizations • The appointed panel members for JNC-8 decided to

publish their findings independently •  Published online in JAMA in December 2013 •  Received no endorsements from other organizations


But Wait…There’s More • A multitude of other hypertension guidelines were also

published in 2013: •  AHA/ACC/CDC advisory algorithm •  American Society of Hypertension/International Society of

Hypertension (ASH/ISH) •  European Society of Hypertension and European Society of

Cardiology (ESH/ESC) •  Canadian Hypertension Education Program (CHEP)

JNC-8 Recommendations •  In patients >60 years of age, start medications at blood

pressure of >150/90mm Hg and treat to goal of <150/90mm Hg

•  In patients >60 years of age, treatment does not need to be adjusted if achieved blood pressure is lower than goal and well-tolerated


JNC-8 Recommendations •  In patients <60 years of age, start medications at blood

pressure of >140/90mm Hg and treat to goal of <140/90mm Hg

•  In all adult patients with diabetes or chronic kidney disease, start medications at blood pressure of >140/90mm Hg and treat to goal of <140/90mm Hg


JNC-8 Recommendations • For the non-black population (including diabetes),

initial antihypertensive treatment may include a thiazide, ACEI, ARB, or CCB

• For the black population (including diabetes), initial antihypertensive treatment should include a thiazide or CCB

• For all patients with CKD, initial (or add-on) therapy for hypertension should include an ACEI or ARB


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Initial Drug Selection for HTN • What happened to the beta-blockers (BB)?

•  Most evidence for BB is from atenolol •  Does not meet current FDA criteria for a once-daily drug

•  Losartan Intervention for Endpoint reduction (LIFE) study •  Compared losartan vs. atenolol in pts. with HTN & LVH •  Primary outcome of CV death, MI, or stroke •  Overall 13% RRR with losartan vs. atenolol (p=0.021) •  Driven mainly by 25% reduction in risk of stroke (p=0.001)

• BB still recommended for many patients with comorbid conditions (CHF, CAD, etc.)

Dahloff B et al. Lancet 2002;359:995-‐1003.

JNC-8 Recommendations •  Initiate therapy according to recommendations •  If BP is not at goal in one month, increase dose or add a

second agent from recommended classes •  If patient is still not at goal, add a third drug from

recommended classes •  Do not use an ACEI and ARB together

• Drugs from other classes may be used if additional BP lowering is needed or if contraindications exist

• Refer to HTN specialist whenever necessary


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 (no DM or CKD)

Thiazide Thiazide, ACEI, ARB, CCB

<60:ACEI,ARB >60:CCB, thiazide

Thiazide, ACEI, ARB, CCB, BB

Thiazide, ACEI, ARB (BB if <60)

Black (no DM or CKD)

Thiazide Thiazide, CCB

Thiazide, CCB

Thiazide, ACEI, ARB, CCB, BB

Thiazide, ARB (BB if <60)

Diabetes ACEI, ARB, CCB, BB, thiazide

CCB, thiazide

ACEI, ARB, CCB, thiazide

ACEI, ARB ACEI, ARB, CCB, thiazide

CKD ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB

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

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Arch Inter Med 1997

Hypertension: Pharmacologic Treatment •  SelecIon of IniIal Therapy

•  Demographics •  Concomitant Diseases and Therapies •  Quality of Life •  Cost •  Drug InteracIons

Pharmacologic Treatment of Hypertension

Treatment OpIons •  Diure&cs •  ACE inhibitors •  Angiotensin II receptor blockers •  Calcium channel blockers •  Beta blockers •  Alpha blockers •  Centrally acIng alpha agonists •  Direct vasodilators •  Peripheral adrenergic blockers

Hypertension

•  TherapeuIc OpIons: DiureIcs •  Promote sodium and water excreIon at various sites of the nephron

•  Loop diureIcs •  Thiazide/Thiazide-‐like diureIcs diureIcs •  Potassium-‐sparing diureIcs •  Carbonic Anhydrase Inhibitors

Hypertension

Loop diuretics

Thiazide diuretics

Potassium-sparing diuretics

Carbonic anhydrase inhibitors

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Hypertension

• DiureIcs: Pharmacodynamics •  Decreased intravascular (blood) fluid volume •  Decreased extravascular (edema) fluid volume •  Decreased blood pressure

Hypertension

• DiureIcs: Compelling IndicaIons* •  Isolated Systolic Hypertension •  CongesIve Heart Failure

• DiureIcs: Possible Favorable Effects •  Osteoporosis (thiazides)

• DiureIcs: Possible Unfavorable Effects •  Diabetes •  Gout •  Renal Insufficiency

Hypertension

• DiureIcs: PotenIal Adverse Effects •  Electrolyte disturbances

•  potassium, magnesium, sodium, calcium •  Hyperglycemia •  Hypotension, orthostasis •  Lipid abnormaliIes •  PhotosensiIvity •  Ototoxicity •  Hyperuricemia, gout flare

Hypertension

• DiureIcs: ConsideraIons •  Useful for paIents with ISH, African Americans, CHF •  Different diureIc classes can be combined for addiIve, or possible synergisIc effects

• Work well in combinaIon with other anIhypertensives •  Efficacy drops when renal funcIon becomes seriously impaired

Hypertension

•  TherapeuIc OpIons: ACE Inhibitors •  ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor

•  TherapeuIc OpIons: Angiotensin II Receptor Blockers (ARB’s) •  ARB’s block the effects of angiotensin II by compeIng for binding sites at the receptor

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Renin

Angiotensinogen

ACE Angiotensin I

Angiotensin II Non-ACE alternate pathways (eg, chymase)

ARB

AT1 receptors

Vasoconstriction Aldosterone

secretion Renal tubular

reabsorption of sodium and water

Antidiuretic hormone (vasoprressin)

secretion Stimulation of thirst center

Catecholamine secretion

X X

X X

X X ↓ BP

Hypertension Hypertension • ACE inhibitors and ARB’s: Pharmacodynamics

•  VasodilaIon •  Reduced peripheral resistance •  Increased diuresis •  Reduced BP •  No change in HR •  No reducIon in cardiac output

Hypertension

• ACE Inhibitors/ARB’s: PotenIal Adverse Effects • ACE inhibitors

•  Hyperkalemia •  Cough •  Hypotension, dizziness •  Headache •  Angioedema

• ARB’s •  Same as ACE inhibitors but cough is uncommon

Hypertension

• ACE inhibitors and ARB’s: PotenIal Drug InteracIons

•  MedicaIons which promote hyperkalemia •  MedicaIons that have acIvity which is sensiIve to changes in serum K+ •  MedicaIons that may cause addiIve anIhypertensive effects •  NSAIDs

Hypertension

•  TherapeuIc OpIons: ACE inhibitors • Compelling IndicaIons

•  Diabetes Mellitus (Type 1) with proteinuria •  Heart Failure •  Post MI with systolic dysfuncIon

• Possible Favorable Effects •  Diabetes Mellitus (Type 1 or 2) with proteinuria •  Renal Insufficiency

Hypertension

• ACE inhibitors/ARB’s should be carefully considered: •  Pre-‐exisIng kidney dysfuncIon (degree of impairment, response to therapy) •  Renal artery stenosis (degree of stenosis)

• ACE inhibitors/ARB’s are contraindicated: •  Pregnancy •  History of angioedema •  Hyperkalemia

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Escape of Angiotensin II Despite ACE Inhibi1on

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

Plasma Ang II (pg/mL)

Plasma ACE (nmoL/mL/min)

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Placebo 4 h 24 h 1 2 3 4 5 6

Hospital Months

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*P <.001 vs placebo

www.hypertensiononline.org

Hypertension

•  TherapeuIc OpIons: Calcium Channel Blockers (CCB’s) •  Calcium channel blockers work by blocking calcium channels through which calcium ions enter muscle fibers, controlling hypertension.

• Calcium Channel Blockers •  Dihydropyridine •  Non-‐dihydropyridine

Calcium Channel Blockers (CCB) Classification: Hypertension

• Calcium Channel Blockers: Pharmacodynamics •  The acIvaIon 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

• CCB’s: PotenIal Side Effects •  Dihydropyridines

•  Peripheral edema •  reflex tachycardia •  flushing/headache •  hypotension

•  Nondihydropyridines •  consIpaIon •  conducIon abnormaliIes

Hypertension

• Calcium Channel Blockers: Specific IndicaIons • CCB’s: Compelling IndicaIons

•  Isolated Systolic Hypertension (long-‐acIng) • CCB’s: Possible Favorable Effects

•  angina •  atrial tachyarhythmias •  Cyclosporine-‐induced HTN •  Diabetes Mellitus Type 1 and 2 with proteinuria

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Hypertension

•  TherapeuIc OpIons: Beta Blockers •  Inhibit sympatheIc sImulaIon

•  Beta-‐1 receptors → heart •  Beta-‐2 receptors → blood vessels, lungs

•  CardioselecIve vs. NonselecIve •  Intrinsic sympathomimeIc acIvity (ISA)

Hypertension

• Beta Blockers: CV Pharmacodynamics •  Reduced heart rate •  Reduced force of heart contracIon •  Reduced cardiac output •  Reduced blood pressure •  Decreased renin

Hypertension

• Beta Blockers: PotenIal Adverse Effects •  Glucose intolerance, masked hypoglycemia •  Bradycardia, dizziness •  Bronchospasm •  Increased triglycerides and decreased HDL •  CNS: Depression, faIgue, sleep disturbances •  Reduced C.O., exacerbaIon of heart failure •  Impotence •  Exercise intolerance

Hypertension

• Beta Blockers: PrecauIons •  BronchospasIc disease •  Heart Block •  Sick sinus syndrome •  Diabetes •  Dyslipidemia •  Depression

Hypertension

• Beta Blockers: Specific IndicaIons •  Myocardial Infarc6on* •  Conges6ve Heart Failure* •  EssenIal Tremors •  Hyperthyroidism •  Angina •  Supraventricular tachycardias •  PerioperaIve Hypertension •  Migraine Headaches

*Compelling indications

Hypertension

•  TherapeuIc OpIons: Alpha-‐Beta Blockers • Work by binding to both alpha-‐1 and beta-‐1 and/or beta-‐2 adrenergic receptors consequently prevenIng their acIvaIon by sympatheIc neurotransmicers.

•  Carvedilol: alpha-‐1 + beta-‐1+ beta-‐2 blockade •  Labetalol: alpha-‐1 + beta-‐1 + beta-‐2 blockade

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α1-‐sympatholyIcs • beside BP reducIon they reduce benign prostaIc hyperplasia → indicaIon mainly older man with simultaneous BPH • in combinaIon at severe resistant hypertension • posiIvely influence lipidogram • strong 1st dose phenomenon! → postural hypotension, syncopes • prazosin (prototype; Deprazolin), doxazosin (Cardura), terazosin α1-‐lyIc only for the treatment of BPH, without vasodilaIng effects → tamsulosin

α2-‐sympathomimeIcs • central effect – sImulaIon of central α2 receptors through negative feedback inhibit release of norepinephrine on periphery → reflex BP reducIon • α-‐metyldopa (Dopegyt), clonidine • ADR: central depression – sleepiness, bad dreams • clonidine has significant rebound phenomenon • α-‐metyldopa is advantageous during pregnancy – doesn´t influence negaIvely blood circulaIon of fetus

Direct vasodilators hydralazines • specific mechanism of acIon is unknown; probably directly influence contracIle system of vessel wall myocytes • ADR: tachycardia, palpitaIons, fluid retenIon → necessary combinaIons dihydralazine, hydralazine • suitable in pregnancy • hydralazine – genet. polymorphism of biotransformaIon → at slow acetylators can develop as syndrome similar to

lupus erythematodes

Kallium channel openers • opening of K+ channels on the top of myocytes → hyperpolarisaIon → inducIon of relaxaIon

minoxidil • vazodilation in the area of arterioles • retenIon of Na+, hirsuIsm, hypertrichosis → used in the treatment of alopecia

• minoxidil is inexpensive diazoxide • only short-‐term use – at hypertension crisis • induces hyperglycemia – at short-‐term use not macers

Direct renin inhibitors (PRI) • absolutely new group • in many Issues is present own renin system with individual receptors → (pro)renin is bind to cell surfaces; system acts pressorically and proliferaIvely

• it is acIvated when sImulaIon of AT1 receptors decreases → negaIve feedback

• this signal way apparently decreases benefit of ACEI! → inhibiIon of the level of renin → ... becer control

of the whole RAAS → ... possible becer prevenIon of organ damage

Aliskiren • first available peroral PRI • ↓ plasmaIc renin acIvity • indicaIon in 2-‐combinaIon aliskiren + ACEI or aliskirén + ARB → dual inhibiIon of RAAS system • product Rasilez ? -‐ clinical results below expectaIons

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Hypertension in the Elderly • Fastest growing segment of the population • Prevalence of hypertension is very high • Several issues make managing HTN unique:

•  Often present with isolated systolic HTN •  More likely to present with comorbidities •  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)

HYVET • HYpertension in the Very Elderly Trial

•  Randomized, double-blind trial •  Included patients aged 80 or older with SBP>160mmHg •  Randomized to indapamide +/- perindopril or placebo •  Target BP of 150/80mmHg •  Primary outcome of fatal or nonfatal stroke

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

HYVET • Results

•  Mean BP at the end of the trial •  Indapamide +/- perindopril - 143/78 mm Hg •  Placebo – 158/84 mm Hg

•  48.0% of indapamide patients achieved goal BP vs. 19.9% of placebo patients (p<0.001)

•  Outcomes with indapamide +/- perindopril •  30% reduction in stroke (p=0.06) •  64% reduction in heart failure (p<0.001) •  21% reduction in all-cause mortality (p=0.02)

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

Hypertension in the Elderly • HYVET demonstrated that treatment of HTN to goal

BP less than 150/80 mm Hg in patients >80 years old was safe and effective

• But…what about a lower BP goal?

• And…what about the patients age 60-80?

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) •  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. Ogihara T et al. Hypertension 2010;56:196-‐202.

Hypertension in the Elderly

• Dissension among the ranks!

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

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Hypertension in the Elderly • The opposing arguments:

•  The Japanese trials had low event rates and may not represent the risks in other populations

•  Data from other studies suggests a goal SBP closer to 140mm Hg may be more appropriate for ages 60-80

•  Methodology may have prevented JNC-8 panel from considering the results in their analysis

•  The “Speed Limit” effect

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

Pearls

•  For resistant HTN – sit down and take a good history •  How much water, pop, coffee, milk, juice, tea, ice – anything liquid do you drink daily.

•  Food preferences and salt intake •  Drugs/Alcohol •  Compliance

Pearls cont.

•  The only thiazide that will work with an elevated creaInine is metolazone(zaroxolyn)

•  If elevated creaInine. Then will need to use a loop diureIc (or with zaroxolyn)

•  If potassium is elevated – evaluate current meds and add a diureIc •  If potassium is low – ask why •  Check for edema – and ask why •  Elderly paIents benefit from blood pressure management •  Black paIents benefit from ACE/ARB – may need to use larger doses to obtain BP lowering effect

“I treat people not numbers”

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Hypertensive Crises • Hypertensive Urgencies: No progressive target-‐organ dysfuncIon. (Accelerated Hypertension)

• Hypertensive Emergencies: Progressive end-‐organ dysfuncIon. (Malignant Hypertension)

Hypertensive Urgencies

•  Severe elevated BP in the upper range of stage II hypertension. • Without progressive end-‐organ dysfuncIon. •  Examples: Highly elevated BP without severe headache, shortness of breath or chest pain.

• Usually due to under-‐controlled HTN.

Hypertensive Emergencies

•  Severely elevated BP (>180/120mmHg). • With progressive target organ dysfuncIon. • 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 DissecIng aorIc aneurysm

Osterberg, L. et al. N Engl J Med 2005;353:487-497

Barriers to Adherence

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Pa1ent Evalua1on Objec1ves

•  (1) To assess lifestyle and idenIfy other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment

•  (2) To reveal idenIfiable causes of high BP •  (3) To assess the presence or absence of target organ damage and CVD

Pearls Cont.

• Metabolic acidosis and hyperkalemia? – use diureIc – loop if creaInine is elevated

•  Take blood pressure periodically lying and standing so as not to miss supine hypertension associated with autonomic insufficiency – this is treated differently

(3) Target Organ Damage

• Heart Le{ ventricular hypertrophy Angina or prior myocardial infarcIon Prior coronary revascularizaIon Heart failure • Brain Stroke or transient ischemic acack • Chronic kidney disease • Peripheral arterial disease • ReInopathy

Goals of Treatment

•  TreaIng SBP and DBP to targets that are <140/90 mmHg • PaIents with diabetes or renal disease, the BP goal is <130/80 mmHg •  The primary focus should be on acaining the SBP goal. •  To reduce cardiovascular and renal morbidity and mortality

Lifestyle modifica1ons

www.nhlbi.nih.gov

Secondary HTN-‐Clues in Medical History

• Onset: at age < 30 yrs ( Fibromuscular dysplasi) or > 55 (atheloscleroIc renal artery stenosis), sudden onset (thrombus or cholesterol embolism).

•  Severity: Grade II, unresponsive to treatment. •  Episodic, headache and chest pain/palpitaIon (pheochromocytoma, thyroid dysfuncIon).

• Morbid obesity with history of snoring and dayIme sleepiness (sleep disorders)

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Secondary HTN-‐clues on Exam

• Pallor, edema, other signs of renal disease. • Abdominal bruit especially with a diastolic component (renovascular) •  Truncal obesity, purple striae, buffalo hump (hypercorIsolism)

Secondary HTN-‐Clues on Rou1ne Labs

•  Increased creaInine, abnormal urinalysis ( renovascular and renal parenchymal disease)

• Unexplained hypokalemia (hyperaldosteronism) •  Impaired blood glucose ( hypercorIsolism)

•  Impaired TFT (Hypo-‐/hyper-‐ thyroidism)

Secondary HTN-‐Screening Tests

www.nhlbi.nih.gov

Diuretics

Selec1vity of CCB

Blood vessels vasodilation of arterial vasculature

Heart: decrease of

Heart rate

AV conduction

Strenght of contraction

Advantages of thiazide diure1cs

•  according to more studies thiazide diureIcs are considered the most effecIve

•  they increase anIhypertensive effecIvity of combined treatment

•  they proved to reach BP normalisaIon •  are less expensive than other anIhypertensives

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Reaching BP improvement at specific pa1ents

• Among most paIents is necessary combinaHon of 2 and more anIhypertensives.

• AdminastraIon of other drug should start when monotherapy in required dose doesn´t reduce BP to intended value.

•  If the BP is by 20/10 mm Hg higher than intended value, therapy should be started with combinaHon of 2 anHhypertensives.

Other factors influencing selec1on of an1hypertensives

PotenIally prosperous effects: •  Thiazide diureHcs slower the process of bone demineralisaIon at osteoporosis

• βB can have posiIve influence at ventricular tachyarrhythmias and fibrilaIons, at migraine, short-‐termly at thyreotoxicosis, at essenIal tremor, perioperaIonal hypertension

• Ca2+B can be applied at Raynaud syndrome and some arrhythmias

Other factors influencing selec1on of an1hypertensives

PotenIally negaIve effects: •  thiazide diureHcs at paIents with gout and hyponatremia in anamnesis

•  βB at paIents with asthma, allergic diseases of airways and with A-‐V blocks of 2nd and 3rd stage

•  ACEI and ARB should not be given if considering pregnancy, are contraindicated in pregnancy, ACEI at angioneuroIc edema

•  aldosterone antagonists and K-‐sparing diureIcs can cause hyperkalemia

Hypertension

•  TherapeuIc Treatment OpIons •  Diure&cs •  ACE inhibitors •  Angiotensin II receptor blockers •  Calcium channel blockers •  Beta blockers •  Alpha blockers •  Centrally acIng alpha agonists •  Direct vasodilators •  Peripheral adrenergic blockers

Arch Inter Med 1997

Hypertension •  SelecIon of IniIal Therapy

•  Demographics •  Concomitant Diseases and Therapies •  Quality of Life •  Cost •  Drug InteracIons

Hypertension

•  TherapeuIc OpIons: Beta Blockers •  Inhibit sympatheIc sImulaIon

•  Beta-‐1 receptors → heart •  Beta-‐2 receptors → blood vessels, lungs

•  CardioselecIve vs. NonselecIve •  Intrinsic sympathomimeIc acIvity (ISA)

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Hypertension

• Beta Blockers: CV Pharmacodynamics •  Reduced heart rate •  Reduced force of heart contracIon •  Reduced cardiac output •  Reduced blood pressure •  Decreased renin

Hypertension

• Beta Blockers: PotenIal Adverse Effects •  Glucose intolerance, masked hypoglycemia •  Bradycardia, dizziness •  Bronchospasm •  Increased triglycerides and decreased HDL •  CNS: Depression, faIgue, sleep disturbances •  Reduced C.O., exacerbaIon of heart failure •  Impotence •  Exercise intolerance

Hypertension

• Beta Blockers: PrecauIons •  BronchospasIc disease •  Heart Block •  Sick sinus syndrome •  Diabetes •  Dyslipidemia •  Depression

Hypertension

• Beta Blockers: Specific IndicaIons •  Myocardial Infarc6on* •  Conges6ve Heart Failure* •  EssenIal Tremors •  Hyperthyroidism •  Angina •  Supraventricular tachycardias •  PerioperaIve Hypertension •  Migraine Headaches

Beta blockers are underused!!!

*Compelling indications

Hypertension

•  TherapeuIc OpIons: Alpha-‐Beta Blockers • Work by binding to both alpha-‐1 and beta-‐1 and/or beta-‐2 adrenergic receptors consequently prevenIng their acIvaIon by sympatheIc neurotransmicers.

•  Carvedilol: alpha-‐1 + beta-‐1+ beta-‐2 blockade •  Labetalol: alpha-‐1 + beta-‐1 + beta-‐2 blockade

Hypertension

•  TherapeuIc OpIons: DiureIcs •  Promote sodium and water excreIon at various sites of the nephron

•  Loop diureIcs •  Thiazide/Thiazide-‐like diureIcs diureIcs •  Potassium-‐sparing diureIcs •  Carbonic Anhydrase Inhibitors

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Hypertension

Loop diuretics

Thiazide diuretics

Potassium-sparing diuretics

Carbonic anhydrase inhibitors

Hypertension

• DiureIcs: Pharmacodynamics •  Decreased intravascular (blood) fluid volume •  Decreased extravascular (edema) fluid volume •  Decreased blood pressure

Hypertension

• DiureIcs: PotenIal Adverse Effects •  Electrolyte disturbances

•  potassium, magnesium, sodium, calcium •  Hyperglycemia •  Hypotension, orthostasis •  Lipid abnormaliIes •  PhotosensiIvity •  Ototoxicity •  Hyperuricemia, gout flare

* Unless contraindicated

Hypertension

• DiureIcs: Compelling IndicaIons* •  Isolated Systolic Hypertension •  CongesIve Heart Failure

• DiureIcs: Possible Favorable Effects •  Osteoporosis (thiazides)

• DiureIcs: Possible Unfavorable Effects •  Diabetes •  Gout •  Renal Insufficiency

Hypertension

• DiureIcs: ConsideraIons •  Useful for paIents with ISH, African Americans, CHF •  Different diureIc classes can be combined for addiIve, or possible synergisIc effects

• Work well in combinaIon with other anIhypertensives •  Efficacy drops when renal funcIon becomes seriously impaired

Hypertension

•  TherapeuIc OpIons: ACE Inhibitors •  ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor

•  TherapeuIc OpIons: Angiotensin II Receptor Blockers (ARB’s) •  ARB’s block the effects of angiotensin II by compeIng for binding sites at the receptor

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Renin

Angiotensinogen

ACE Angiotensin I

Angiotensin II Non-ACE alternate pathways (eg, chymase)

ARB

AT1 receptors

Vasoconstriction Aldosterone

secretion Renal tubular

reabsorption of sodium and water

Antidiuretic hormone (vasoprressin)

secretion Stimulation of thirst center

Catecholamine secretion

X X

X X

X X ↓ BP

Hypertension Hypertension • ACE inhibitors and ARB’s: Pharmacodynamics

•  VasodilaIon •  Reduced peripheral resistance •  Increased diuresis •  Reduced BP •  No change in HR •  No reducIon in cardiac output

Hypertension

• ACE Inhibitors/ARB’s: PotenIal Adverse Effects • ACE inhibitors

•  Hyperkalemia •  Cough •  Hypotension, dizziness •  Headache •  Angioedema

• ARB’s •  Same as ACE inhibitors but cough is uncommon

Hypertension

• ACE inhibitors and ARB’s: PotenIal Drug InteracIons

•  MedicaIons which promote hyperkalemia •  MedicaIons that have acIvity which is sensiIve to changes in serum K+ •  MedicaIons that may cause addiIve anIhypertensive effects •  NSAIDs

Hypertension

•  TherapeuIc OpIons: ACE inhibitors • Compelling IndicaIons

•  Diabetes Mellitus (Type 1) with proteinuria •  Heart Failure •  Post MI with systolic dysfuncIon

• Possible Favorable Effects •  Diabetes Mellitus (Type 1 or 2) with proteinuria •  Renal Insufficiency

Hypertension

• ACE inhibitors/ARB’s should be carefully considered: •  Pre-‐exisIng kidney dysfuncIon (degree of impairment, response to therapy) •  Renal artery stenosis (degree of stenosis)

• ACE inhibitors/ARB’s are contraindicated: •  Pregnancy •  History of angioedema •  Hyperkalemia

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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 • ALLHAT

•  Randomized, double-blind trial •  Enrolled 33,357 patients age 55 or older

•  Chlorthalidone •  Amlodipine •  Lisinopril •  Doxazosin (this arm stopped early 2° worse outcomes)

•  Primary outcome of CHD death or nonfatal MI •  No significant difference in primary outcome among the

thiazide, ACEI, or CCB

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

Initial Drug Selection for HTN • African-American patients

•  High risk for CV events •  Less responsive to drugs that act on the renin-angiotensin-

aldosterone system •  ACEI, ARB, BB

•  Subgroup analysis of black patients in ALLHAT •  Less BP reduction with lisinopril than amlodipine •  Risk of stroke was significantly higher with lisinopril than with

amlopdipine (RR 1.51, 95% CI 1.22-1.86) •  Lisinopril less effective than chlorthalidone in preventing heart

failure, stroke, and combined CHD

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

pharmacologic intervervention in hypertension · 2018. 4. 14. · 4/25/15 4 development of jnc-8...

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