Hypertension

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Usama Talib, BSc, MD [3]

Synonyms and keywords: Blood pressure; hypertension; high blood pressure; systolic blood pressure; essential hypertension

Overview

Hypertension is a major risk factor for cardiovascular disease and a major public health problem. The prevalence of hypertension increased among the united states due to changing The previous cut-off 140/90 mmHg (the previous 2003 threshold from the Joint National Committee (JNC) 7 guideline 3) to a lower threshold of greater than or equal to 130/80 mmHg. Hypertension is a leading cause of mortality worldwide. More than half of hypertensive patients are not aware of the disorder and some diagnosed patients do not take the medication. The new guideline recommends considering the average of reading BP≥ 2 visits office. Home blood pressure monitoring (HBPM) and ambulatory blood pressure monitoring (ABPM) are better than clinic or home blood pressure readings to determine masked hypertension or white coat hypertension out of the office.

Historical Perspective

• Hypertension was first discovered by Scipione Riva-Rocci, an Italian physician, in 1896 following the invention of the cuff-based mercury sphygmomanometer and measurement of the peak systolic blood pressure by noting the cuff pressure at which the radial pulse was no longer palpable.
• In 1905, the sound after cuff deflation of sphygmomanometer was first identified by Russian physician Nikolai.
• Between 1910 and 1914, essential hypertension and malignant hypertension were described.

Classification

Hypertension classified based on presence of underlying disorders into two groups:

• Chronic hypertension, also called primary hypertension or essential hypertension, (90-95%)

• Gradually rising in blood pressure
• History of environmental exposure (weight gain, high-sodium diet, decreased physical activity, job change leading increased travel, excessive consumption of alcohol
• Family history of hypertension

• Secondary hypertension, (5%), due to underlying disorder

• BP lability, suddenly rising BP with pallor and dizziness (pheochromocytoma)
• Snoring, hypersomnolence (obstructive sleep apnea)
• Prostatism (chronic kidney disease due to post-renal urinary tract obstruction)
• Muscle cramps, weakness (hypokalemia from primary aldosteronism or secondary aldosteronism due to renovascular disease)
• Weight loss, palpitations, heat intolerance (hyperthyroidism)
• Edema, fatigue, frequent urination (kidney disease or kidney failure)
• History of coarctation repair (residual hypertension associated with coarctation)
• Central obesity, facial rounding, easy bruisability (Cushing syndrome)
• Medication or substance use (alcohol, NSAIDS, cocaine, amphetamines)
• Absence of family history of hypertension

• Resistant hypertension is defined as a higher level of BP above the goal in spite of concurrent use of three antihypertensive drugs including a long-acting calcium channel blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a diuretic and requires ≥ medications.
• Refractory hypertension is explained as failing to control hypertension with at least five classes of antihypertensive drugs including long-acting thiazide-type diuretic, such as chlorthalidone, and a mineralocorticoid receptor antagonist, such as spironolactone.

Comparison between two guidelines of hypertension

Hypertension Guidline	2017 ACC/AHA	2018 ESC/ESH
Definition of hypertension (mmHg)	≥130/80	≥140/90
Normal blood pressure range (mmHg)	Normal: <120/80 Elevated:120-129/<80	Optimal:<120/80 Normal:120-129/80-84 High normal:130-139/85-89
Hypertension stage (mmHg)	Stage1:130-139/80-89 Stage2: ≥140/90	Grade1:140-159/90-99 Grade2:160-179/100-109 Grade3: ≥180/110
Age specific blood pressure targets(9mmHg)	<65 years:<130/80 ≥65 years:<130/80	<65years:<120-129/70-79 >65 years:<130-139/70-79

2017/ACC/AHA Guideline of hypertension

• Hypertension can be classified based on the guideline into 2 stages:

Blood pressure category	Systolic blood pressure	Diastolic blood pressure
Normal	<120/80 mmHg	<80 mmHg
Elevated	120-129 mmHg	<80 mmHg
Stage 1 hypertension	130–139 mm Hg	80–89 mm Hg
Stage 2 hypertension	≥140 mm Hg	≥90 mm Hg

Pathophysiology

• The pathogenesis of hypertension is characterized by a malfunction in the renin-angiotensin-aldosterone system (RAAS), natriuretic peptides ,endothelium, sympathetic nervous system (SNS),immune system.
• Allelic variants of several genes have been associated with the development of primary hypertension.
• Endothelial dysfunction and increased TGF-B was shown in salt sensitivity patients lead to increased systolic blood pressure 10 mmHg following ingestion of 5 gr salt.

Causes

Common causes of hypertension include:

• Genetic susceptibility

• Hypertension is a Polygenic disorder
• Findings of 25 rare mutations,120 single-nucleotide polymorphisms in hypertensive patients
• Monogenic forms of hypertension in conditions such as: Glucocorticoid-remediable aldosteronism, Liddle syndrome, Gordon’s syndrome
• Association between high blood pressure and older age with increased defects in the gene

Environmental exposure

• Overweight, obesity

• Direct relationship between body mass index and BP
• Strong relationship between waist-to hip ratio, distribution of central fat and BP
• Relation between obesity at a young age with further hypertension

• Sodium intake

• Association between sodium intake and BP in migrants
• Triat of salt sensitivity in blacks, older adults, patients with higher level of BP, CKD, DM, metabolic syndrome

• Potassium

• Inverse relation with BP
• Inverse relation with stroke
• Higher level of potassium may reduce the effect of sodium on BP

• Physical fitness

• Inverse relation between physical fitness and physical activity with BP
• Modest exercise activity reduces the risk of BP

• Alcohol

Pharmacological causes of hypertension	Management:
Alcohol	Limiting alcohol to ≤1 drink daily for women and ≤2 drinks for men
Amphetamines (amphetamine, methylphenidate, dextroamphetamine)	Discontinue or decrease the dose Behavior therapy for ADHD
Antidepressants (MAOI, SNRI, TCA)	Using alternative agents such as SSRI Avoidance of taking tyramine-containing foods with MAOI
Atypical antipsychotics (clozapine, olanzapine)	Discontinue or decrease the dose Using alternative agents such as aripiprazole, ziprasidone with a lower risk of weight gain, diabetes mellitus, dyslipidemia
Caffeine	Limiting caffeine intake to <300 mg/day in uncontrolled hypertension Cause of increased blood pressure in hypertensive patients No relationship between long-term use of caffeine and hypertension or cardiovascular disease
Decongestants (phenylephrine, pseudoephedrine)	Avoidance in severe uncontrolled hypertension Using shortest duration types Using alternative agents such as nasal saline, intranasal corticosteroids, antihistamines
Herbal supplements such as Ma Huang ephedra, St. John’s wort (with MAO inhibitors, yohimbine)	Avoid use
Immunosuppressants (cyclosporine)	Using an alternative agent such as tacrolimus with less effect on blood pressure
Oral contraceptives	Avoidance in uncontrolled hypertension Using progestin-only form Using low dose 20-30 mcg Ethinyl estradiol agents Alternative agents (barrier, abstinence, IUD)
NSAIDs	Using alternative agents such as acetaminophen, tramadol, topical NSAIDs
Recreational drugs (bath salts MDPV, cocaine, methamphetamine	Avoide use
Systemic corticosteroids (dexamethasone, fludrocortisone, methylprednisolone, prednisone, prednisolone)	Using alternative agents (inhaled, topical)

Differentiating hypertension from other Diseases

• Differential diagnosis of hypertension includes:

Differentiating hypertension	Explanation
Isolated systolic hypertension	More common in older patients, SBP ≥130 mmHg, DBP<80 mmHg
Isolated diastolic hypertension	Systolic BP< 130 mm, diastolic BP ≥ 80 mm Hg, more common in younger individuals
Masked hypertension	Out-of-office daytime BP ≥135/85 mmHg, nighttime BP ≥120/70 mmHg, 24 h average BP ≥130/80 mmHg, normal BP in office
White coat hypertension	Office systolic/diastolic blood pressure readings of ≥140/90 mm Hg and a 24-hour blood pressure <130/80 mm Hg
Severe hypertension	Systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥120 mmHg) without evidence of end-organ damage
Malignant hypertension (emergency hypertension)	Extremely high blood pressure with the diastolic blood pressure >130 mmHg with evidence of end-organ damage such as brain, heart, kidneys, and eyes, even in absence of symptoms

Epidemiology and Demographics

• The prevalence of hypertension is approximately 45,600 per 100,000 individuals worldwide.
• Between the years 2000-2002, the incidence of hypertension was estimated to be 5680 for whites, 8490 for African-Americans, 6570 for Hispanics, and 5220 for Chinese cases per 100,000 individuals in United States.

Age

• Hypertension is more commonly observed among elderly patients

Gender

• Males are more commonly affected with hypertension than females.

Race

• Hypertension usually affects individuals of the black race, Asians and Hispanic Americans.

Risk Factors

• Common risk factors in the development of hypertension are:

• Diabetes mellitus
• Family history of hypertension
• Dyslipidemia
• Increased age
• Obesity
• Low socioeconomic state
• Physical inactivity/low fitness
• Male sex
• Unhealthy diet
• Obstructive sleep apnea
• Psychological stress

• Common risk factors associated with resistant hypertension include:

• Older age
• Obesity
• CKD
• Black race
• DM

Modifiable risk factors	Fixed risk factors
Current smoker, secondhand smoking	Chronic kidney disease
Diabetes mellitus	Family history
Dyslipidemia/hypercholesterolemia	Increased age
Obesity	Low socioeconomic/educational status
Physical inactivity/low fitness	Male sex
Unhealthy diet	Obstructive sleep apnea Psychological stress

Natural History, Complications and Prognosis

• The patients with primary hypertension usually remain asymptomatic.

• The clinical features of secondary hypertension dependent on the characteristics of an underlying disorder.

• If hypertension left untreated, 33% of patients with hypertension may progress to developheart attack and stroke.

• Common complications of resistant hypertension include MI, stroke, ESRD, and death that are 2-7 times higher compared with patients without resistant hypertension.
• Prognosis is generally poor without treatment, and the 10­ year mortality rate of patients with hypertension is approximately 11%.

Conditions	Clinical features
Renal parenchymal disease	Urinary tract infection Urinary tract obstruction Hematuria Urinary frequency, nocturia Analgesic abuse Family history of polycystic kidney disease Increased serum creatinine Abnormal urinalysis
Renovascular disease	Resistant hypertension Abrupt onset of hypertension or sustained hypertension worsening or difficult to control Flash pulmonary edema Early-onset hypertension, especially in women (fibromuscular hyperplasia)
Primary aldosteronism	Resistant hypertension Hypertension with hypokalemia (spontaneous or diuretic-induced) Hypertension and muscle cramps or weakness Hypertension and incidentally discovered adrenal mass Hypertension and family history of early-onset hypertension or stroke
Obstructive sleep apnea	Resistant hypertension Snoring Breathing pauses during sleep Daytime sleepiness
Drug or alcohol induced	Sodium-containing antacids Caffeine Nicotine (smoking) Alcohol NSAIDs Oral contraceptives Cyclosporine or tacrolimus Sympathomimetics (decongestants, anorectics) Cocaine Amphetamines Neuropsychiatric agents Erythropoiesis-stimulating agents Clonidine withdrawal Herbal agents (Ma Huang, ephedra)
Pheochromocytoma/paraganglioma	Resistant hypertension Paroxysmal hypertension Hypertension crisis superimposed on sustained hypertension(Spell) Blood pressure lability Headache, sweating, palpitations, pallor Family history of pheochromocytoma/paraganglioma Adrenal incidentaloma
Cushing syndrome	Rapid weight gain, especially with central distribution Proximal muscle weakness Depression Hyperglycemia
Hypothyroidism	Dry skin Cold intolerance Constipation Hoarseness Weight gain
Hyperthyroidism	Warm, moist skin Heat intolerance nervousness Tremulousness Insomnia Weight loss Diarrhea Proximal muscle weakness
Coarctation of aorta	Hypertension before 30 years old
Primary hyperparathyroidism	Hypercalcemia
Congenital adrenal hyperplasia	Hypertension and hypokalemia Virilization (11-beta-hydroxylase deficiency Masculinization in males and Primary amenorrhea in females (17-alpha-hydroxylase deficiency|)
Mineralocorticoid excess syndromes other than primary aldosteronism	Early-onset hypertension Resistant hypertension Hypokalemia or hyperkalemia
Acromegaly	Acral features Enlarging shoe, glove, or hat size Headache Visual disturbances Diabetes mellitus

Diagnosis

Diagnostic Criteria

• The diagnosis of hypertension is made when at least three of the following diagnostic criteria are met:

• Accurate measurement of BP
• Assessment of cardiovascular risk
• Assessment about secondary hypertension

Abbreviations: SBP: Systolic blood pressure; DBP: Diastolic blood pressure; BP: Blood pressure

Blood pressure measurement	Definition
Systolic blood pressure (SBP)	First Korotkoff sound
Diastolic blood pressure(DBP)	Fifth Korotkoff sound
Pulse pressure	SBP minus DBP
Mean arterial pressure	DBP plus one third pulse pressure
Mid- blood pressure	(SBP+DBP) divided by 2

Arm circumference	cuff size
22-26 cm	Small adult
27-34 cm	Adult
35-44 cm	Large adult
45-52 cm	Adult thigh

Key steps for accurate blood pressure measurement	Educations
Properly prepare the patient	Have the patient relax, sitting on a chair, feet on the floor, back supported for more than 5 minutes Avoidance of caffeine, smoking, exercise for at least 30 minutes before measurement Emptying bladder before measurement No talk during measurement Removing all clothing covered the cuff location
Using proper technique	Cuff size 80% of arm
Taking proper measurement	Recording blood pressure in both arms at the first visit Using the arm with higher blood pressure for the latter measurement 1-2 minutes between two measurements Cuff inflation 20-30 mmHg above the palpable radial pulse and deflation with the speed of 2 mmHg/seconds
Documentation of reading blood pressure	Systolic blood pressure is the onset of the first Korotkoff sound and diastolic blood pressure is the disappearance of all Korotkoff sounds
Average the reading	Using ≥2 readings obtained on ≥2 occasions for determination the level of blood pressure
Providing blood pressure reading to patient	Providing patients the SBP/DBP readings both verbally and in writing

New onset or uncontrolled hypertension in adult

* Drug resistance hypertension Abrupt onset of hypertension Onset of hypertension before 30 years old Worsening of previous controlled hypertension Target organ damage Accelerated, malignant hypertension Onset of diastolic hypertension ≥ 65 years old Unprovoked hypokalemia

Yes

No

Screening for secondary hypertension

No need for screening

Abbreviations: ABPM: Ambulatory blood pressure monitoring; HBPM: Home blood pressure monitoring; BP: Blood pressure

Office BP≥130/80 mm Hg, but < 160/100 mmHg after 3 months of life style modification, suspected white coat hypertension

Daytime ABPM or HBPM, BP<130/80 mmHg

YES White coat hypertension Annual ABPM or HBPM for detection of progression (class 2a)

NO Hypertension Life style modification and starting antihypertensive drug therapy (class 2a)

Abbreviations: ABPM: Ambulatory blood pressure monitoring; HBPM: Home blood pressure monitoring; BP: Blood pressure

Office BP: 120-129/<80 mmHg after 3 months of lifestyle modification, suspected masked hypertension

Daytime ABPM or HBPM, BP≥130/80 mm Hg

Yes Masked hypertension Lifestyle modification, antihypertensive therapy (class 2a)

NO Elevated BP Lifestyle modification Annual ABPM or HBPM (class2a)

Abbreviations: ABPM: Ambulatory blood pressure monitoring; HBPM: Home blood pressure monitoring; BP: Blood pressure

Recommendations for masked hypertension and white coat hypertension : (Class IIa, Level of Evidence B)

❑ Screening for white-coat hypertension in patients with systolic blood pressure 130-160 mmHg and diastolic blood pressure 80-110 mmHg by using ABPM or HBPM before the diagnosis of hypertension

(Class IIa, Level of Evidence C)

❑ Periodic monitoring of blood pressure with ABPM or HBPM for detection of transient or sustained hypertension inwhite coat hypertension

(Class IIa, Level of Evidence C)

❑ Finding of white coat hypertension by HBPM and ABPM in high office blood pressure in spite of receiving treatment, is recommended

(Class IIa, Level of Evidence B)

❑ Finding of mask hypertension by HBPM or ABPM in-office blood pressure 120-129 /75-79 mmHg

(Class IIb, Level of Evidence C)

❑ Finding of white coat hypertension by HBPM or ABPM if office blood pressure is 10 mmHg higher than normal in spite of receiving multiple medications ❑ Finding of masked hypertension by HBPM in patients with end-organ damage or high cardiovascular risk but office reading blood pressure is at goal ❑ Finding of masked hypertension by ABPM in patients with high HBPM in spite of receiving medications

2017 ACC/AHA Guideline	Screening for Primary adlostronism:
Class of recommendation:I Level of evidence:C	Resistant hypertension Hypokalemia ( diuretic-induced), Incidentally discovered adrenal mass Family history of early-onset hypertension or stroke at a young age (<40 years)

History and Symptoms

• Primary hypertensive patients are usually asymptomatic.
• Symptoms related to underlying causes of secondary hypertension may include the following:

• Palpitation
• Headache
• Sweeting
• Abdominal pain
• Urinary symptoms
• Muscle cramps
• Abdominal mass
• Skin lesions
• Edema

Physical Examination

• Patients with primary hypertension usually are asymptomatic.
• In secondary hypertension physical examination may be remarkable for :

• Arterial bruit
• Irregular pulses, Tachycardia, Absent femoral pulses
• Fine tremor
• Acute abdominal pain, abdominal mass
• Skin stigmata, Violaceous striae
• Hirsutism
• Warm skin, moist skin, Skin pallor
• Central obesity
• Moon face
• Dorsal and supraclavicular fat pads
• Loss of normal nocturnal blood pressure fall
• Orthostatic hypotension
• Periorbital puffiness,Coarse skin, Cold skin, Slow movement,Goiter
• continuous murmur over back or chest
• Abdominal bruit

Conditions	Physical examination
Renal parenchymal disease	Abdominal mass (polycystic kidney disease) Skin pallor
Renovascular disease	Abdominal systolic or diastolic bruit Femoral or carotid arteried bruits
Primary aldosteronism	Arrhythmias with hypokalemia Atrial fibrillation
Obstructive sleep apnea	Overweight Short, thick neck loss of normal nocturnal blood pressure fall
Drug or alcohol induced	Fine tremor, Tachycardia, Sweating (cocaine, ephedrine, MAO inhibitors) Acute abdominal pain (cocaine)
Pheochromocytoma/paraganglioma	Skin stigmata of neurofibromatosis (cafe-au-lait spots, neurofibromas) Orthostatic hypotension
Cushing syndrome	Central obesity Moon face Dorsal and supraclavicular fat pads, Violaceous striae Hirsutism
Hypothyroidism	Delayed ankle reflex Periorbital puffiness Coarse skin Cold skin Slow movement Goiter
Hyperthyroidism	Lid lag Fine tremor Warm, moist skin
Coarctation of aorta	Blood pressure higher in upper extremities than in lower extremities Absent femoral pulses continuous murmur over patient’s back, chest Abdominal bruit
Congenital adrenal hyperplasia	Signs of virilization (11-beta-OH) or incomplete masculinization (17-alpha-OH)
Acromegaly	Acral features Large hands and feet Frontal bossing

Laboratory Findings

• Basic laboratory test should be taken in patients with the diagnosis of hypertension include:

• Fasting blood sugar
• Complete blood count
• Lipid profile
• Serum creatinine with eGFR
• Serum sodium, potassium, calcium
• Thyroid-stimulating hormone
• Urinalysis

• Optional laboratory test in hypertensive patients include:

• Uric acid
• Urinary albumin to creatinine ratio

Electrocardiogram

• An ECG may be helpful in the diagnosis of left ventricular hypertrophy associated hypertension. Findings on an ECG suggestive of left ventricular hypertrophy include
• Cornell criteria: R wave in aVL + S wave in V3> 28 millimeters in males or greater than 20 mm in females
• Modified Cornell Criteria: R wave in aVL> 12 mm
• Sokolow-Lyon Criteria: S wave in V1 + R wave in V5 or V6> 35mm
• Romhilt-Estes: If the score equals 4, LVH is present with 30% to 54% sensitivity. If the score is greater than 5, LVH is present with 83% to 97% specificity.

• The amplitude of the largest R or S in limb leads ≥ 20 mm = 3 points
• The amplitude of S in V1 or V2 ≥ 30 mm = 3 points
• The amplitude of R in V5 or V6 ≥ 30 mm = 3 points
• ST and T wave changes opposite QRS without digoxin = 3 points
• ST and T wave changes opposite QRS with digoxin = 1 point
• Left Atrial Enlargement = 3 points
• Left Axis Deviation = 2 points
• QRS duration ≥ 90 ms = 1 point
• Intrinsicoid deflection in V5 or V6 > 50 ms = 1 point

Chest X-ray

• Finding on a chest x-ray associated target organ damage in hypertension include widening aortic knob.
• Ascending aorta dilation and increased cardiothoracic ratio may be associated with hypertension.

Echocardiography or Ultrasound

Echocardiography may be helpful in the diagnosis of complications of hypertension, which include left ventricular hypertrophy (LVH), left ventricular (LV) diastolic dysfunction and left atrial dilation.

CT scan

• CT scan may be helpful in the diagnosis of underlying causes of secondary hypertension such as hyperaldosteronism, pheochromocytoma, hyperparathyroidism, aortic coarctation.

• CT scan may also show the complication of hypertension including:

• Cardiovascular system: aortic aneurysm, acute aortic syndrome
• Central nervous system: stroke, subarachnoid hemorrhage, posterior reversible encephalopathy syndrome

MRI

• Cardiac MRI is a reliable tool in the diagnosis of hypertensive heart disease by evaluation of left ventricular hypertrophy, left ventricular mass, biventricular function, valvular disease, inflammation and stress myocardial perfusion-fibrosis.

Other Imaging Findings

• There are no other imaging findings associated with hypertension.

Other Diagnostic Studies

• There are no other diagnostic studies associated with hypertension.

Treatment

Medical Therapy

• The mainstay of treatment for hypertension is: Initiation of treatment with one or more of three classes of first-line BP lowering agents:

• Calcium channel blocker (CCB)
• Renin-angiotensin-convertng enzyme inhibitors (ACEI or ARB)
• Thiazide-like diuretic

• Betablocker is first line therapy in the presence of angina and heart failure.
• Second-line lowering BP agents are used in resistant hypertension or specific conditions.

• The mainstay of therapy for resistant hypertension is:

• Improving medications adherence
• Diagnosis and treatment of the causes of secondary hypertension
• Adding spironolactone or hydralazine or minoxidil to first line therapy (CCBs, inhibitors of RAS, chlorthalidone.

Treatment strategy

Nomal BP (BP<120/80 mmHg)

Elevated BP (BP120-129/<80mmHg)

Stage1 hypertension(BP 130-139/80-89mmHg

Stage 2 hypertension (BP≥ 140/90

Life style modifications

Nonpharmocological therapy (class1)

10 years cardiovascular disease (CVD) risk≥ 10%

Non pharmacological therapy and BPlowering medication

Reevaulation in 1 year (class 2a)

Reevaulation in 3-6 months (class 1)

NO, nonpharmocological therapy (class1)

Yes,non pharmacological therapy and BP lowering medication

Reevaulation in 3-6 months(class 1)

Reevaulation in 1 months(class 1)

BPgoal reached

NO, evaluation and optimization the adherence to medical therapy

Yes,Reevaulation in 3-6 months(class 1)

Intensification of medical therapy

First line of treatment	Drug_ Dosage(mg/day)_ Frequency	Comments
Thiazide or thiazidetype diuretics	Chlorthalidone 12.5–25 1 Hydrochlorothiazide 25–50 1 Indapamide 1.25–2.5 1 Metolazone 2.5–5 1	Chlorthalidone is a prolonged half-life drug and reduces cardiovascular risk Hyponatremia, hypokalemia, uric acid, and calcium levels should be monitored
ACE inhibitors	Benazepril 10–40 1-2 Captopril 12.2-150 2-3 Enalapril 5-40 1-2 Fosinopril 10–40 1 Lisinopril 10-40 1 Moexipril 7.5–30 1-2 Perindopril 4-16 1 Quinapril 10-80 1-2 Ramipril 2.5-20 1-2 Trandolapril 1-4 1	Avoidance of using in combination with ARB and direct renin inhibitor Using with caution in CKD or patients who are on K sparing agents due to the risk of hyperkalemia Avoidance in pregnancy Avoidance in patients with a history of angioedema with ACEI Avoidance in severe bilateral renal artery stenosis
ARB	Azilsartan 40-80 1 Candesartan 8–32 1 Eprosartan 600-800 1-2 Irbesartan 150-300 1 Losartan 50-100 1-2 Olmesartan 20-40 1 Telmisartan 20-80 1 Valsartan 80-320 1	Avoidance of using in combination with ACEI or direct renin inhibitor Using with caution in CKD or in patients who are on K sparing drugs due to the risk of hyperkalemia Avoidance in pregnancy Avoidance in patients with a history of angioedema with ARB It can be used in patients with a history of angioedema with ACEI after 6 weeks of discontinuation of ACEI Avoidance in severe bilateral renal artery stenosis
CCB—dihydropyridines	Amlodipine 2.5–10 1 Felodipine 2.5–10 1 Isradipine 5–10 2 Nicardipine SR 60–120 2 Nifedipine LA 30–90 1 Nisoldipine 17–34 1	Avoidance of using in heart failure reduced EF except for amlodipine, felodipine Pedal edema is dose associated, more common in women
CCB—nondihydropyridines	Diltiazem ER 120–360 1 Verapamil IR 120–360 3 Verapamil SR 120–360 1-2 Verapamil-delayed onset ER 100–300 1 (in the evening)	Avoidance of using in combination with betablocker due to the risk of bradycardia Avoidance of using in heart failure reduced EF Avoidance of using diltiazem with verapamil due to drug interaction via CYP3A4
Second line of treatment	Drug_ Dosage(mg/day)_ Frequency	Comments
Diuretics—loop	Bumetanide 0.5–2 2 Furosemide 20–80 2 Torsemide 5–10 1	Preferred diuretic in symptomatic heart failure Preffered diuretic in moderate to severe CKD (GFR<30 cc/min)
Diuretics—potassium sparing	Amiloride 5–10 1-2 Triamterene 50–100 1-2	Mild antihypertensive effect Useful for treatment of hypokalemia due to thiazide monotherapy Avoidance of using in patients with significant CKD (GFR <45 mL/min).
Diuretics—aldosterone antagonists	Eplerenone 50–100 1-2 Spironolactone 25–100 1	Preferred for primary aldostronism and resistant hypertension Add-on therapy in resistant hypertension Lesser risk of gyncomasty and impotence with eplerenone Avoidance of combination therapy with K sparing agents
Betablocker-cardioselective	Atenolol 25–100 2 Betaxolol 5–20 1 Bisoprolol 2.5–10 1 Metoprolol tartrate 100–200 2 Metoprolol succinate 50–200 1	Beta-blockers are not first-line therapy for hypertension unless in the presence of IHD or heart failure Preferredbeta-blockers in bronchospastic airway disease Preferred bisoprolol, metoprolol succinate in heart failure reduced EF
Betablocker-cardioselective and vasodilatory	Nebivolol 5–40 1	Induction of nitric oxide Vasodilarory effect
Beta blockers—noncardioselective	Nadolol 40–120 1 Propranolol IR 80–160 2 Propranolol LA 80–160 1	Not recommended, especially in IHD or heart failure
Beta blockers—intrinsic sympathomimetic activity	Acebutolol 200–800 2 Penbutolol 10–40 1 Pindolol 10–60 2	Not recommended, especially in IHD or heart failure
Beta blockers—combined alpha-beta receptor	Carvedilol 12.5–50 2 Carvedilol phosphate 20–80 1 Labetalol 200–800 2	Carvedilol is preferred in heart failure reduced EF
Direct renin inhibitor	Aliskiren 150–300 1	Avoidance of using in combination with ARB or ACEI Using with caution in CKD or patients are on potassium-sparing agents due to the risk of hyperkalemia Avoidance in pregnancy Avoidance in severe bilateral renal artery stenosis
Alpha-1 blockers	Doxazosin 1–16 1 Prazosin 2–20 2-3 Terazosin 1–20 1-2	Side-effect is orthostasis hypotension, especially in old patients Seconde line of treatment, preferred in BPH and hypertension
Central alpha2-agonist and other centrally acting drugs	Clonidine oral 0.1–0.8 2 Clonidine patch 0.1–0.3 1 weekly Methyldopa 250–1000 2 Guanfacine 0.5–2 1	Last line of treatment due to CNS adverse effect on elderly patients Avoidance of abrupt discontinuation of clonidine because of rebound hypertension
Direct vasodilators	Hydralazine 100–200 2-3 Minoxidil 5–100 1-3	Recommended to use with beta-blocker and diuretic due to sodium and water retention and reflex tachycardia Side effect of hydralazine is drug-induced lupus-like syndrome at higher doses The side effect of Minoxidil: Hirsutism, pericardial effusion

Class I, Level of evidence:A

In patients with atherosclerotic renal artery stenosis, medical therapy is recommended

Class IIb, Level of evidence:C

Revascularization (percutaneous renal artery angioplasty and/ or stent placement) indicates in patients with refractory hypertension, worsening renal function, intractable heart failure, nonatherosclerotic disease (fibromuscular dysplasia)

Class IIb, Level of evidence:B

The effectiveness of continuous positive airway pressure (CPAP) to decrease blood pressure in patients with obstructive sleep apnea and hypertension is not verified

Surgery

• Surgical procedure may be performed for patients with secondary hypertension such as coarctation of aorta, primary aldosteronism.

Prevention

• Effective measures for the primary prevention of hypertension include:

• Weight loss: Reduction 1 mmHg in blood pressure for every one kilogram weight reduction
• Healthy diet: A diet rich in fruits, vegetables, whole grains, low-fat dairy products, reduced content of saturated and total fat
• Reduced intake of dietary sodium: Less than 1000-15000 mg/day
• Enhanced intake of dietarypotassium:3500–5000 mg/d by intaking rich diet with potassium
• Physical activity: Aerobic ( 90–150 min/week), dynamic resistance (90–150 min/week), Isometric resistance (4 × 2 min handgrip, 1 min rest between exercises, 3 sessions per week)
• Reduced alcohol intake: Men ≤2 drinks daily, Women ≤1 drink daily

• Once diagnosed and treated, patients with hypertension are followed-up every month for evaluation of medication adherence and response to treatment.