Clinical guideline on Arterial hypertension in adults

ARTERIAL HYPERTENSION IN ADULTS
Clinical guideline

Ulaanbaatar, 2010
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Clinical guideline on Arterial hypertension in adults CONTENT
Abbreviations ......................................................................................................4 PREFACE...............................................................................................................5 Summary points ......................................................................................................................5 A. INTRODUCTION..................................................................................................6 A.4. The aims of the guideline .................................................................................................6 A.7. List and contact information of authors and persons that participated in the guideline’s development ...........................................................................................................................6 A.8. Definitions and terminology used in guideline: ................................................................7 A9. Epidemiologic information: ...............................................................................................7 B. MANAGEMENT ALGORITHM.................................................................................9 C. EVALUATION AND MANAGEMENT......................................................................10 C.1. Classification of hypertension ........................................................................................10 C.2. Blood pressure measurement.........................................................................................10 C.3. Primary prevention.........................................................................................................12 C.3.1. Lifestyle changes ....................................................................................................12 C.3.1.1. Salt reduction....................................................................................................13 C.3.1.2. Other dietary recommendations........................................................................13 C.3.1.3. Alcohol consumption.........................................................................................13 C.3.1.4. Weight reduction ..............................................................................................14 C.3.1.5. Physical exercise...............................................................................................14 C.3.1.6. Smoking cessation............................................................................................14 C.3.1.7. Environmental support for lifestyle changes.....................................................15 C.4. Screening of hypertension .............................................................................................16 C.5. Evaluation of a patient with hypertension.......................................................................16 C.5.1. Family and clinical history........................................................................................16 C.5.2. Physical examination...............................................................................................17 C.5.3. Laboratory and other investigations .......................................................................17 C.5.4. Indications for specialist referral .............................................................................18 C.5.5. Searching for subclinical TOD..................................................................................18 C.5.6. Estimation of the CVD risk.......................................................................................19 C.6. Antihypertensive Treatment ..........................................................................................21 C.6.1. Lifestyle modification...............................................................................................21 C.6.2. Antihypertensive drug therapy ...............................................................................21 C.6.3. Treatment of associated risk factors .......................................................................26 C.7. Management of HTA in special conditions......................................................................26 C.7.1. Essential hypertension without complications..........................................................26 C.7.2. Elderly......................................................................................................................27 C.7.3. Diabetes mellitus.....................................................................................................27 C.7.4. Renal diseases.........................................................................................................28 C.7.5. Cerebrovascular diseases .......................................................................................28 C.7.6. Cognitive dysfunction and dementia........................................................................28 C.7.7. Coronary heart disease ..........................................................................................28 C.7.8. Heart failure.............................................................................................................28 C.7.9. Artial fibrillation ......................................................................................................29 C.7.10. Metabolic syndrome ..............................................................................................29 C.7.11. Hypertension in women ........................................................................................29 C.7.12. Hypertension in pregnancy ...................................................................................29 C.7.13. Secondary hypertension........................................................................................30 C.7.14. Resistant hypertension .........................................................................................31 C.7.15. Hypertensive Crisis................................................................................................32 C.8. Follow up of patients with hypertension unless hypertensive emergencies or urgencies ..............................................................................................................................................33

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Clinical guideline on Arterial hypertension in adults
REFERENCES........................................................................................................34 ANNEXES.............................................................................................................35 Annex 1. Instrumental signs of target organ damage............................................................35 Annex 2. Outline curriculum for schools of patients with hypertension .................................36 Annex 3. Pharmacotherapy of Hypertension..........................................................................38 Annex 4. Pharmacotherapy of Hypertensive emergency.......................................................48 Annex 5. Pharmacotherapy of Hypertensive urgency............................................................52

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Clinical guideline on Arterial hypertension in adults

ABBREVIATIONS
ARB ACE inhibitor AV blockade BP BMI CVD CHD DBP ESRD E-GFR ESH ESC ECG HSUM HDL IMT ISH LDL LVH MCA-Mongolia MHA MOH MDRD NCD SBP TOD WHO Angiotensin Receptor Blocker Angiotensin Converting Enzyme inhibitor Atria-Ventricular blockade Blood Pressure Body Mass Index Cardiovascular Disease Coronary Heart Disease Diastolic Blood Pressure End Stage Renal Disease Estimated Glomerular Filtration Rate European Society of Hypertension European Society of Cardiology Electrocardiogram Health Sciences University of Mongolia High Density Lipoprotein Intimae Media Thickness International Society of Hypertension Low Density Lipoprotein Left Ventricular Hypertrophy Millennium Challenge Account-Mongolia Mongolian Heart Association Ministry of Health Modification of Diet in Renal Disease Non-Communicable Diseases Systolic Blood Pressure Target Organ Damage World Health Organization

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Clinical guideline on Arterial hypertension in adults 1.3 PREFACE • • If no hypertensive emergency or urgency is present, antihypertensive drug treatment should be initiated gradually. The goal for BP treatment is: SBP < 140 mm Hg and DBP < 85 mm Hg. In hypertensive people with proteinuria and renal disease the goal is SBP < 130 mm Hg and DBP < 80 mm Hg and in the very elderly SBP<150 mmHg. In patients using diuretics, ACEinhibitors or ATR blockers, regular monitoring of serum potassium, sodium and creatinine level is mandatory Most people with high BP will require at least two BP lowering drugs to achieve the recommended goals. When no disadvantages of cost exist, fixed drug combinations are recommended Low dose aspirin (75 mg/day) is recommended for secondary prevention in subjects with previous CVD or present renal failure. Statins are recommended for hypertensive at high CVD risk to lower total cholesterol to the level less than 4.5 mmol/L with an option of, 4 mmol/L if feasible, and LDL cholesterol, 2.5 mmol/L with an option of 2 mmol/L if feasible. Treatment of hypertension and monitoring BP level and lifestyle changes should be continued for life because in correctly diagnosed patients cessation of treatment is usually followed by return to the hypertensive state.

This guideline was developed by the working group of the Ministry of Health (MOH) of Mongolia, in co-operation with Millennium Challenge Account-Mongolia (MCA-M) Health Project. The MOH working group included representatives from the Mongolian Heart Association (MHA), Health Sciences University of Mongolia, Mongolian Cardiologist’s Association, Mongolian EchoCardiographist’s Association, Mongolian Family Doctor’s Association, a representative of private hospitals (Humuun hospital), Pharmacy school and School of Nursing, Health Science University Mongolia, and the National Institute for Health and Welfare (THL) and EPOS Health Management. The clinical guidelines have been developed based on most recent international (WHO, European and Finnish national) guidelines on the management of hypertension. Summary points The objective of hypertension prevention and treatment is a reduction of the hypertension associated overall CVD morbidity and mortality. • • • • All people with high BP, borderline or high normal BP should be advised on lifestyle modifications. Diagnosis of hypertension is based on at least four (six) BP measurements made during at least two (three) separate visits. Initiate antihypertensive drug therapy if sustained SBP 160 mmHg or sustained DBP 100 mm Hg, If sustained SBP is 140-159 mmHg or sustained DBP 90-99 mmHg, consider initiating treatment if CVD or other target organ damages or diabetes are present or if estimated 10 year risk of CVD is high. The antihypertensive drug should be carried out according to the BP level, the presence of subclinical and clinical TOD and other compelling conditions.

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Clinical guideline on Arterial hypertension in adults A. INTRODUCTION A.7. List and contact information of authors and persons that participated in the guideline’s development
Name Position Dr. Riitta Antikainen Dr. D. Narantuya Dr. Ghenadie Curocichin Dr. А. Olziikhutag Dr. D. Serjee Dr. G.Dejeekhuu Dr. D.Zulgerel Dr. P.Batkhuyag Dr. Ts. Burmaa Dr. D. Myagmartseren Dr. Ch. Enkhtuul Dr. B. Tsogzolmaa Dr. Pekka Jousilahti Dr. Elena Maximenco Dr. Sh. Oyunbileg Dr. N. Oyunbileg International Medical Expert, The National Institute of Health and Welfare, Finland (THL) General Secretary, Mongolian Heart Foundation International Medical Expert, EPOS Health Management President, Mongolian Heart Foundation Head of the Society of Echocardiographists Director, “Khumuun” private hospital,Mongolian Heart Foundation Head of the Cardiology Department, Health Sciences University of Mongolia Member of the Professional Council on Pharmacology, Ministry of Health Specialist, Standardization and Measurement Center Lecturer, Department of General Medicine, Health Sciences University of Mongolia Lecturer, School of Nursing, Health Sciences University of Mongolia NCD Specialist, WHO Mongolia International Public Health Expert, Research Professor, The National Institute for Health and Welfare, Finland (THL) EPOS Health Management, Team leader/Senior public health expert EPOS Health Management, Public Health Expert Team leader, MCA-Mongolia Health Project, CVD specialist MCA-Mongolia Health Project,

A.1. Clinical diagnosis of hypertension
According to the international guidelines, the person is considered as hypertensive if her/his average systolic blood pressure (SBP) is at least 140mmHg or the average diastolic blood pressure (DBP) is at least 90mmHg, based on several measurements (4 to 6). If the patient is on antihypertensive drug treatment and the measured average SBP or DBP levels are not hypertensive, the diagnosis should base on the blood pressure (BP) levels preceding the treatment.

A.2. Disease code (ICD 10): I 10- I 13 A.3. Users:
• General practitioners/Family doctors • Internal medicine doctors • Cardiologists • Other specialists and members of committees and government and NGO working on this field. A.4. The aims of the guideline • To intensify the identification of hypertension and to improve the awareness, treatment and control of hypertension • To improve the population based prevention of hypertension, reduction of hypertension associated global cardiovascular disease (CVD) risk and finally, reduction of the overall CVD disease morbidity and mortality. Both the individual approach strategy focusing on the screening and treatment of high-risk patients with hypertension and the population approach strategy focusing on lowering BP levels in the entire population are needed to prevent the premature deaths and disability related to high BP.

Dr. J. Enkhsaikhan

A.5. Date of guideline development:
2010

A.6. Date of next revision: 2014
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Clinical guideline on Arterial hypertension in adults Isolated office (or clinic) or white-coat hypertension is diagnosed when the office BP is constantly elevated, while the 24-hour ambulatory BP monitoring results or home BP are within their normal values. Masked ambulatory or masked hypertension is diagnosed when individuals with the normal office BP (<140/90mmHg) have ambulatory or home BP values consistent with diagnostic criteria of hypertension. Metabolic syndrome (MS) means the presence of any of 3 out of 5 risk factors: presence of the abdominal obesity, elevated fasting plasma glucose or triglyceride level or the treatment for these conditions, a decreased HDL-cholesterol level or hypertension. Office or clinic BP is measured at the office. Pulse pressure = SBP-DBP (mmHg). Secondary hypertension is BP elevation with a specific cause. Total CVD risk means the likelihood of a person developing a CVD event over a defined period of time. In this paper refers to the 10-year risk for developing a first fatal or nonfatal major CVD event (myocardial infarction or stroke). A9. Epidemiologic information: Hypertension is one of the most common modifiable risk factors for CVD. SBP increases with age until the age of 80 years, DBP until the age of 55 years in Western Population. Increase in SBP/DBP by 20/10 mmHg doubles the risk of stroke and myocardial infarction. In hypertensive patients, other CVD risk factors as well as clinical and subclinical target organ damages (TOD) are common. The presence of other risk factor multiplies the risks associated with hypertension. The risk of CVD can vary among hypertensive individuals with same BP level depending on the level of other associated risk factors. According to these guidelines, decision about the management of hypertension should not be based only on the 7

Guideline was discussed, approved and countersigned by:
Organization MOH Sub-working group meetings of clinical guideline development for Arterial hypertension Consensus meeting of MOH Sub-working group of clinical guideline development for Arterial hypertension Meeting of MOH Coordination committee of clinical guidelines development Meeting of HSUM Medical Terminology Committee Meeting of MOH Internal Medicine Professional subCommittee Responsible persons Dr. D. Narantuya, MOH Sub-working group on clinical guideline for Arterial hypertension Dr. D. Baigalmaa Deputy Director, Department of Public Health Policy Implementation and Coordination, MOH Dr. S. Tugsdelger Director, Department of Public Health Policy Implementation and Coordination, MOH Prof. G. Tsagaankhuu Chairman, HSUM Medical Terminology Committee Prof. B. Tserendash, Chairman, MOH Professional sub-Committee

A.8. Definitions and terminology used in guideline: Ambulatory BP is a 24-hour average BP as well as mean values of day, night or morning BP measurements. Arterial hypertension is defined as sustained SBP is at least 140mmHg or sustained DBP is at least 90mmHg, based on several measurements Essential hypertension is a highly heterogeneous disorder, which points to a multi-factorial aetiology and polygenic abnormalities. Home BP is measured by the patients themselves at home. Hypertension emergency is severe elevation of arterial BP (DBP usually but not always >130 mm Hg) with an acute damage to target organs. Hypertension urgency is severe elevation on blood pressure without organ damages

Clinical guideline on Arterial hypertension in adults measured BP level, but it should also take into the account the presence of other CVD risk factors, signs of TOD and associated clinical conditions. Thus, the management of hypertension should be related to quantification of the global (total) CVD risk. Epidemiology of hypertension in Mongolia Diseases of the circulatory system are among the leading causes of morbidity and mortality in Mongolia. According to the National Health Indicators 2009, the rate of circulatory system diseases has increased from 502 per 10,000 persons in 2008 to 679 per 10,000 persons in 2009, ranking 4th among leading causes of morbidity. In 2009, 34% of hospitalized patients had hypertension. Disease of circulatory system accounts for 38% of overall mortality with rate of 24 per 10,000 males and 19 per 10,000 females. The highest mortality rate is among people aged 65 years or older. Territorial differences exist, i.e. highest mortality rates are observed in Khangai and Western regions and lowest rate in eastern provinces. According to the results of STEPS 2009 Survey on the Prevalence of Noncommunicable Disease (NCD) Risk Factors, prevalence of hypertension also increases with age in Mongolian population. In 2009, it was 55 % in men aged 45-54 years and 71% in men aged 55-64, in women the prevalences of hypertension was 52% and 66 %, respectively. Results of the STEPS 2009 Survey showed that almost half of patient with a newly diagnosed hypertension had never had their BP measured before. Self-monitoring of BP in the population is not sufficient. Only 13% of treated hypertensive people successfully control their BP with medication. Nonpharmacological treatment options are underutilized and medical practitioners do not provide sufficient counselling on weight loss and smoking cessation.

Table 1. Age-adjusted prevalence of common frisk factors (STEPS 2009 Survey on the Prevalence of Noncommunicable Disease Risk Factors) among people aged 15-64 years
2005 (N=3411) % (95% CI) Male Femal e 43.4 4.5 (40.1(3.246.7) 5.8) 1.1 0.2 (0.6(0.01.6) 0.4) 92.3 90.0 (90.7- (88.394.0) 91.5) 7.0 (5.38.8) 25.6 (23.427.9) 30.1 (27.432.8) 66.2 (59.872.6) 13.3 (9.517.0) 23.5 (18.128.8) 7.7 (5.99.4) 38.8 (35.941.6) 27.0 (23.530.5) 34.0 (27.840.2) 7.0 (4.99.0) 24.4 (19.229.7) 2009 (N=5438) % (95% CI) Male Female 44.3 (41.547.1) 1.2 (0.52.0) 93.8 (91.096.7) 7.4 (5.09.8) 37.0 (34.040.1) 31.6 (28.934.4) 74.4 (69.679.3) 8.8 (6.011.7) 29.4 (22.536.3) 5.3 (3.86.8) 0.4 (0.00.7) 92.7 (89.895.5) 7.6 (4.910.3) 44.2 (41.846.5) 24.2 (21.926.4) 48.1 (43.452.7) 4.5 (2.76.2) 23.2 (17.828.6)

Current smokers Excessive alcohol consumption Low consumption of fruit and/or vegetables daily Low levels of physical activity Overweight people (BMI≥25 kg/m2) Hypertensive people Hypertensive people who are not currently on antihypertensive drug treatment Hyperglycaemia Hypercholestero lemia

Notes: Hypertensive people are those with SBP≥140 and/or DBP≥90 mmHg or currently on antihypertensive drug treatment. Hyperglycaemia is estimated that impaired fasting glycaemia as defined below whole blood value ≥5.6mmol/l (100 mgdl) and ≤6.1 mmol/l (110 mg/dl) Hypercholesterolemia was estimated as raised total cholesterol ( ≥5.0 mmol/l or ≥190 mg/dl), or currently on medication for raised cholesterol Excessive alcohol consumption: drank on 5 or more days per week in the past 12 months.

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Clinical guideline on Arterial hypertension in adults

B. MANAGEMENT ALGORITHM

Adopted from 2004-BHS, modified by authors

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Clinical guideline on Arterial hypertension in adults

C. EVALUATION AND MANAGEMENT
C.1. Classification of hypertension Table 2. Classification of hypertension based on multiple blood pressure measurements (Category).Blood pressure thresholds for intervention in by initial blood pressure level of a new patient Category Optimal Normal High normal Grade 1 hypertension* Grade 2 hypertension* Grade 3 hypertension* SBP (mmHg) <120 120-129 130-139 140-159 160-179 ≥ 180 and and and/ or and/ or and/ or and/ or DBP (mmHg) <80 80-84 85-89 90-99 100-109 ≥ 110 Intervention
(procedures for a patient in whom BP level was identified for the first time)

repeat measurements in 5 years repeat measurements in 2 years lifestyle advice, repeat measurements in 1 year lifestyle advice, repeat measurements in 8 weeks lifestyle advice, repeat measurements in 3-4 weeks lifestyle advice, repeat measurements in 1-2 weeks, however, if hypertensive emergency, treat immediately or if urgency, treat urgently** ***

Isolated systolic hypertension ≥ 140 <90

Note: When patient’s SBP and DBP fall in different categories, the higher category should apply for the classification *. Classification is based on at least two measurements per visit and on at least two to three separate visits **Classification is based on repeated measures during single visit ***Isolated systolic hypertension should be graded and treated according to SBP level

The diagnosis and classification of hypertension should be based on multiple BP measurements using validated devices, in general, on at least two measurements per visit and at least two to three separate visits, in severe cases of hypertension over shorter period. BP can be measured by the doctor or the nurse in the office or in the clinic (office or clinic BP), by the patient or a relative at home (home BP), or automatically over 24 h (ambulatory BP)

C.2. Blood pressure measurement Use accurate and according to standardized protocols validated BP measurement devices (a mercury sphygmomanometer or other noninvasive devices for office and home measurements, devices validated by international standardized protocols for ambulatory BP measurements). Normal values are different for office, ambulatory and home BP.

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Clinical guideline on Arterial hypertension in adults When measuring office and home BP, following care should be taken: • Allow the patients to sit for several minutes in a quiet room before beginning BP measurements. • Take at least two measurements with interval of 1–2 minutes and additional measurements if the first two are quite different. • Use a standard bladder (12–13 cm long and 35 cm wide); have a larger and a smaller bladder available for fat and thin arms, respectively; Table 3 Blood pressure cuff size for mercury sphygmomanometer, semiautomatic and ambulatory monitors (British Hypertension Society 2004-BHS IV) • Measure BP 1 and 5 min after assumption of the standing position in elderly subjects, diabetic patients, and in other conditions in which postural hypotension may be frequent or suspected. Measure heart rate by pulse palpation (at least 30 sec) after the second measurement in the sitting position.

Home measured BP Self-measurement of BP at home is of clinical value and its prognostic significance is now demonstrated. Instruct the patient to make the measurement prior to drug intake preferably twice in the morning and in the evening. The average of the readings during following seven (four) days is taken as the home BP level. Home BP measurements should be considered for following reasons: • Provide more information on the BP lowering effect of treatment at trough, and thus on therapeutic coverage throughout the dose-to-dose time interval • Improve patient’s adherence to treatment regimens • There are doubts on technical reliability/environmental conditions of ambulatory BP data Self-measurement of BP at home should be discouraged whenever: • It causes anxiety to the patient • It induces self-modification of the treatment regimen Ambulatory BP measurements Although office BP should be used as reference, ambulatory BP may improve prediction of CVD risk in untreated and treated patients. 24-h ambulatory BP monitoring should be considered, particularly in the following cases • Considerable variability of office BP is found over the same or different visits • High office BP is measured in subjects otherwise at low total CVD risk • There is a marked discrepancy between BP values measured in the office and at home 11

• •

• • • •

Have the cuff fixed around an arm at the heart level, whatever the position of the patient is. If measuring BP using auscultation method, rise the pressure of the bladder 30mmHg over SBP palpated in radial artery. The bladder is slowly deflated at a rate of no more than 2mmHg/s. Use phase IV and V (disappearance) Korotkoff sounds to identify SBP and DBP. Read blood pressure to the nearest 2 mmHg. Measure BP in both arms at first visit to detect possible differences due to peripheral vascular disease. In case if difference is found, the higher value should be taken as the reference. Take the mean of at least two readings; more recordings are needed if marked differences between initial measurements are found.

Clinical guideline on Arterial hypertension in adults • • • Resistance to drug treatment is suspected Hypotensive episodes are suspected, particularly in elderly and diabetic patients Office BP is elevated in pregnant women and pre- eclampsia is suspected represented if some readings are rejected because of artifact. To adjust the automatic deflation of the equipment to be at a rate of no more than 2mmHg/s. Instruct the patients to engage in normal activities but to refrain from strenuous exercise, and to keep the arm extended and still at the time of cuff inflations. Ask the patient to provide information in a diary on unusual events and on duration and quality of night sleep. Obtain another ambulatory BP if the first examination has less than 70% of the expected number of valid values because of frequent artifacts. Ensure that the proportion of valid values is similar for the day and night periods.

• •

When doing 24 hour ambulatory BP monitoring, following care should be taken: • Use bladder of appropriate size and compare the initial values with those from a sphygmomanometer to check that the differences are not greater than ≥ 5mmHg. • Set the automatic readings at no more than 30 min intervals to obtain an adequate number of values and have most hours

• •

Table 4. Blood pressure thresholds (mmHg) for definition of hypertension with different types of measurements SBP (mmHg) DBP (mmHg) Office clinic 140 90 Home 130–135 85 24-hour 125–130 80 Day 130–135 85 Night 120 70 C.3. Primary prevention Isolated office (or clinic) or white coat hypertension should be diagnosed whenever the mean of office BP measurements are equal or higher than 140/90mmHg on at least three occasions, while daytime or 24-hour mean BP or home mean BP measurements are within their normal range. Identification of isolated office hypertension should be followed by a search for metabolic risk factors, signs of TODs, lifestyle changes and close follow-up. Isolated ambulatory or masked hypertension should be diagnosed in individuals with normal office BP (<140/90mmHg) having elevated ambulatory or home BP values. Masked hypertension identifies individuals with a higher risk profile and increased CVD risk. C.3.1. Lifestyle changes • The goal of lifestyle changes is to reduce BP, to control other risk factors and thereby to reduce the total CVD risk. Additionally, the goal of life-style changes is to reduce the number of antihypertensive drugs in treated patients. • Lifestyle measures should be instituted, whenever appropriate, in all patients, including subjects with high-normal BP and patients who require drug treatment. • Lifestyle recommendations should be instituted with adequate behavioral and expert support, and reinforced at every visit to the physician. Patients under nonpharmacological treatment should be followed-up closely to start drug treatment when needed and in a timely fashion. • The lifestyle measures that are widely 12

Clinical guideline on Arterial hypertension in adults recognized to lower BP or CVD risk, and that should be considered are: o reduction of salt intake o increase in fruit and vegetable intake, decrease in saturated (animal) and total fat intake o reduction of excessive alcohol drinking o weight reduction in the overweight and obese people and maintenance of an optimal body weight o daily physical exercise o smoking cessation C.3.1.1. Salt reduction • Dietary salt (sodium chloride) intake is a major contributor to BP elevation and a cause of hypertension. • Salt restriction may have a greater antihypertensive effect if combined with other dietary modifications. Salt restriction improves the effect of antihypertensive drugs and may allow reduction of doses and number of antihypertensive drugs employed to control BP. • In a restricted salt diet, patients should be advised to avoid added salt, and obviously over salted food - particularly processed food with hidden salt - and to eat more meals cooked directly from natural ingredients, fruits and berries containing more potassium. • An achievable recommendation for daily salt intake is less than 6 grams1 (corresponding with 2400 mg sodium). • It is important to make Mongolian people accustomed to drinking salt free tea. That will do a favor to reduce salt intake. C.3.1.2. Other dietary recommendations • A diet rich in fruits, vegetables, and lowfat dairy products, with a reduced content of saturated and total fat as well as an increase in a potassium intake have BP lowering effects. • Increased intake of dietary fibre may reduce BP in patients with hypertension. An intervention period of at least 8 weeks may be necessary to achieve the maximum reduction in BP.

Additionally • Use low fat or skim milk products • Reduce animal fat intake • Eat fish at least twice a week, if possible • Use vegetable oil (ripe, olive) and vegetable oil based margarine recommended for cooking and bread spread, instead of butter As a general measure, hypertensive patients should be advised to eat more fruits and vegetables (at least 5 servings per day1, corresponding with 300-400 grams), reduce animal fat consumption by using low and skimmed milk products, replacing butter by vegetable oil and vegetable oil-based margarine in cooking and bread spread, and reducing the use of fatty meats, and to eat more fish. Counselling by trained dieticians may be useful. C.3.1.3. Alcohol consumption • The relationship between alcohol consumption, BP levels and the prevalence of hypertension is linear in populations. • In people whose weekly intake of alcohol correspondents of at least 240 g ethanol, BP is 3-4mmHg/2-3 mmHg higher than in those with lowers consumption. • High levels of alcohol consumption (particularly binge drinking) are associated with high risk of stroke. • Alcohol attenuates the effects of antihypertensive drug therapy. • Heavy drinkers (five or more standard drinks per day) may experience a rise in BP after acute alcohol withdrawal. • Trials of alcohol reduction have shown a significant reduction in SBP and DBP.

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Clinical guideline on Arterial hypertension in adults • Hypertensive men who drink alcohol should be advised to limit their consumption to no more than 20–30 g ethanol (two standard drinks) per day, and hypertensive women to no more than 10– 20 g ethanol (one standard drink) per day. C.3.1.5. Physical exercise Lack of physical fitness is associated with an increased risk high BP and of CVD mortality. Physical exercise (aerobic endurance training) reduces SBP and DBP by 7/5mmHg in hypertensive subjects. Moderate levels of exercise lowers BP, reduces body weight, body fat and waist circumference, increases insulin sensitivity and HDL-cholesterol levels. • Sedentary patients should be advised to take up exercise of moderate intensity on a regular basis, e.g. 30–45 min daily. • The type of exercise should be primarily endurance physical activity (a rapid walking, jogging, swimming) supplemented by resistance exercise. • The extent of pre-training evaluation of the CVD status will depend on the extent of the envisaged exercise and on the patient’s symptoms and signs, total CVD risk and associated clinical conditions. • If hypertension is poorly controlled, heavy physical exercise must be postponed until appropriate drug treatment has been instituted and BP lowered. C.3.1.6. Smoking cessation Smoking is a powerful CVD risk factor and smoking cessation is probably the single most effective lifestyle measure for the prevention of a large number of CVD. Passive smoking has now been shown to produce an increase in the risk of coronary and other smokingrelated diseases. • Everyone shall be advise do not start smoking. • Hypertensive smokers should be counselled regarding smoking cessation. • It is desirable that regulations to decline exposure to passive smoking should be introduced.

C.3.1.4. Weight reduction Body weight is directly associated with BP and excess body fat predisposes to increased BP and hypertension. Body fat can be assessed by BMI (weight divided by height squared) and by measuring waist circumference. The optimal BMI is equal or over 18.5kg/m2 and less than 25 kg/m2. People with BMI 25-30 are considered and overweight and 30 or over as obese. The recommended waist circumference in less than 90 cm in men and less than 80 cm in women. • Weight reduction lowers BP in obese patients and has beneficial effects on associated risk factors such as insulin resistance, diabetes, hyperlipidemia, left ventricular hypertrophy (LVH), and obstructive sleep apnoea. • The mean BP reductions associated with an average weight loss of 5 kg were 4 mmHg for SBP and 2 mmHg for DBP. Greater weight loss leads to a greater BP reduction. • Modest weight loss can prevent hypertension in overweight individuals with high normal BP and can facilitate medication step-down and drug withdrawal. Weight stabilization in patients without overweight is also a useful goal.

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Clinical guideline on Arterial hypertension in adults

Table 5. Recommendations for life-style changes Risk factor Salt intake Other dietary recommendations - fruit and vegetables1 Recommendation Less than 6 grams salt/day =2400 mg sodium. Remember also hidden salt in processed food.

Increase to 5 servings per day Decrease; (1) replace butter by vegetable oil or vegetable oil-based, margarine, (2) use low fat or - saturated (animal) fat skimmed milk products, (3) reduce the use of fatty meat products, (4) eat fish 1-2 times weekly, if possible Increase the use of whole grain products, fruits and - fibers vegetables Do not drink alcohol. If not possible decrease the amount of consumed alcohol to: Alcohol drinking Less than 2 standard drinks* daily for men and less than one standard drink daily for women, avoid binge drinking Weight reduction in overweight and obese people. The recommended BMI is 18.5-25 kg/m2. The Overweight and obesity (excess body fat) recommended waist circumference is <90 cm in men and <80 cm in women. Physical activity At least 30 min at a time ≥5 occasions in a week Smoking Cessation * one standard drink: small bottle of beer (330 ml), one glass wine (150 ml), 50 ml of vodka.
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WHO recommendation

C.3.1.7. Environmental support for lifestyle changes Even though every person decides him/herself what to eat and whether to have physical activity or to quit smoking, governments can made decisions, which make healthy choices easier for individuals. As the underlying determinants of hypertension and other NCDs often lie outside the health sector, the involvement of both public and private actors in multiple sectors, such as agriculture, finance, trade, transport, urban planning, education and sport are needed. Health effects should be taken into consideration in all political decision making. Different settings may be considered for action, for example schools, workplaces, households, and local communities. Below are examples, how

political decision making and intersectoral collaboration can promote health: • Tobacco smoking: increase tobacco price and taxation and prohibit smuggling, ban tobacco advertising, prohibit tobacco selling to young people, promote smoke-free environment by banning smoking in public and work places and restaurants • Healthy diet (sodium and saturated fat reduction, increase use of fruits and vegetables): food labelling, collaboration with private industries and shops to develop and market lowsalt and low-saturated fat foods, educate people for healthy cooking, healthy meals in schools and work places. 15

Clinical guideline on Arterial hypertension in adults • Physical activity: promote daily physical activity by building the environment, which is safe and friendly for walking and biking (good sidewalks, proper lightening, traffic lights, road safety, restrictions of car use, etc.), provide low-cost and accessible facilities for leisure-time physical activity. Harmful alcohol consumption: increase alcohol price and taxation, restrict availability of alcohol (particularly for young people), restrict or ban alcohol advertising. C.5. Evaluation of a patient with hypertension Diagnostic procedures include clinical history, physical examination, laboratory and other methods. The aim of these procedures is establishing BP levels, evaluating the overall CVD risk by searching for other risk factors, signs of TODs and concomitant diseases or accompanying clinical conditions and identifying secondary causes of secondary hypertension and contraindications for specific drugs. The younger the patient, the higher the BP and the faster the development of hypertension, the more detailed the diagnostic work-up should be. C.5.1. Family and clinical history Duration and previous level of high BP, drug(s) used efficacy and adverse effects of the drugs. Risk factors for CVD: • Family and personal history of hypertension and CVD disease, dyslipidemia, diabetes mellitus • Lifestyle; smoking and alcohol drinking habits, dietary habits (intake of fat, salt), obesity, weight gain since early adult life, amount of physical exercise, alcohol consumption, drugs used • Snoring; sleep apnea (information also from partner) Target organ damage: • Brain and eyes: headache, vertigo, impaired vision, transient ischemic attacks, sensory or motor deficit • Heart: palpitation, chest pain, shortness of breath, swollen ankles • Kidney: thirst, polyuria, nocturia, haematuria • Peripheral arteries: cold extremities, intermittent claudicating Indications of secondary hypertension • Family history of renal disease (polycystic kidney) • Renal disease (especially glomerulonephritis), urinary tract 16

C.4. Screening of hypertension Screening for hypertension in adults is costeffective and every adult should be screened for hypertension. The standard method for detecting hypertension is via manual sphygmomanometer or other standardized non-invasive devices. In people older than 18 years, BP should be measured according to the legislation (eg: while joining the army, entering college and university, maternity health care, being permitted driving licence) or by their own request. Among patients without known hypertension, BP should be investigated also presenting the clinic or other health care professionals from other reasons. Health care professionals can call people for blood pressure measurements by letters, patient education, inserting advertisement in a paper or other media or calling family members of people visiting offices and clinics for measurements. Persons with optimal BP level should be called for routine BP measurements every 5 years. In people older than 40 years with optimal and normal BP level, BP should be measured every year. If repeated measurements are not optimal, the patient must be included for structured follow-up and treatment shown in Table 2 independently of the screening method used.

Clinical guideline on Arterial hypertension in adults infection, haematuria Drug/substance intake: oral contraceptives, sympathomimetics (nasal decongestant drops such as naphozoline, adrenaline and ephedra containing drops, anorectics such as amphetamines), cocaine, adrenal- and corticosteroids, nonsteroidal anti-inflammatory drugs, erythropoietin, cyclosporine, some dietary supplements(e.g. Ephedra containing) Episodes of sweating, headache, anxiety, palpitation (phaeochromocytoma) Episodes of muscle weakness and tetany (aldosteronism) • Diminished and delayed femoral pulses and reduced femoral BP (aortic coarctation, aortic disease)

• •

Evidence of visceral obesity • Body mass index (BMI) equals to body weight (kg)/ height (m)2. Overweight: BMI 25 kg/m2-29 kg/m2 Obesity: BMI≥30 kg/ m2. Increased waist circumference (standing position) M: >90 cm; W: >80 cm C.5.3. Laboratory and other investigations Routine tests • Fasting plasma glucose • Lipid profile ( likely fasted) • Serum potassium, sodium, creatinine, uric acid • Estimated creatinine clearance or glomerular filtration rate • Uri analysis (protein, blood) • Electrocardiogram • Hemoglobin and hematocrit By consideration • Fundoscopy • Home BP monitoring • 24 h ambulatory BP monitoring • Chest X-ray if heart failure suggested by the clinical investigations • A glucose tolerance test is recommended, when fasting plasma glucose is ≥ 5.6 mmol/l. The repeated findings of a fasting plasma glucose ≥ 7.0 mmol/L, or an abnormal glucose tolerance test are considered indicative of diabetes mellitus. • Echocardiogram • 2D duplex Carotid ultrasound • Quantitative proteinuria • Uri analysis for microalbuminuria, potassium, sodium • Ankle/brachial BP index • Pulse wave velocity measurement Extended evaluation when indicated • Further search for cerebral, cardiac, renal and vascular damage. 17

Other compelling diseases to use of antihypertensive drugs • Asthma, renal disease or failure, diabetes, gout C.5.2. Physical examination General appearance of the patient: Signs of organ damage • Brain: murmurs over neck arteries, motor or sensory defects • Retina: fundoscopic abnormalities • Heart: location and characteristics of apical impulse, abnormal cardiac rhythms, ventricular gallop, pulmonary rales, peripheral edema • Peripheral arteries: absence, reduction, or asymmetry of pulses, cold extremities, ischemic skin lesions • Carotid arteries: systolic murmurs Secondary causes of hypertension and organ damage • Features of Cushing syndrome • Skin stigmata of neurofibromatosis (phaeochromocytoma) • Palpation of enlarged kidneys (polycystic kidney) • Auscultation of abdominal (renovascular hypertension) and precordial or chest murmurs (aortic coarctation or aortic disease)

Clinical guideline on Arterial hypertension in adults • Search for secondary hypertension when suggested by history, physical examination or routine tests: measurement of renin, aldosterone, corticosteroids, catecholamine in plasma and/or urine; arteriographies; renal and adrenal ultrasound; computer- assisted tomography; magnetic resonance imaging. C.5.4. Indications for specialist referral Hypertensive crisis (see details C7.15.) 1. Hypertensive emergencies, in the presence of acute end organ damage admit for emergency treatment • DBP is usually ≥130 mmHg (SBP≥200 mmHg) but not always 2. Hypertensive urgencies, in the absence of acute end-organ involvement admit for urgent treatment • particularly severe hypertension (> 220/120 mm Hg) Possible underlying causes see details secondary hypertension 7.14 • Any clue in history or examination of a secondary cause, e.g. such as hypokalemia with increased or high normal plasma sodium (Conn's syndrome) or Cushing habits. • elevated serum creatinine, E-GFR<60 ml/min • proteinuria or hematuria • sudden onset or worsening of hypertension • Resistant to multidrug regimen ( 3 drugs in proper doses) See details resistant hypertension C 7.13. • multiple drug allergen and contraindications, difficult to select drugs due to these • non-compliance • young age (any hypertension in persons under 20 years; need for antihypertensive drug treatment in persons under 30 years)

Special situations • Unusual BP variability • Possible white-coat hypertension • Hypertension in pregnancy. C.5.5. Searching for subclinical TOD Due to the importance of subclinical TOD as a determinant of total CVD risk, signs of organ involvement should be sought carefully: Heart Left ventricular hypertrophy (LVH) is an independent predictor of CVD events; its regression by treatment appears to be valuable at least in patients over 54 years. • Electrocardiography (ECG) should be part of all routine assessment of subjects with high BP in order to detect LVH, patterns of ‘‘strain’’, ischemia, conduction defects and arrhythmias. LVH can be diagnosed using ECG (Annex 1): o Sokolow-Lyon voltage criterion o Cornell product criterion Echocardiography is recommended when a more sensitive detection of LVH is considered useful or if ECG is not accurate (as in the presence of bundle branch block). Thresholds for left ventricular mass index of 125 g/m2 for men, and 110 g/m2 for women are widely used for conservative estimates of LVH. Additionally, echocardiography provides information on systolic left ventricular function and on significant heart valve diseases and on left ventricular mass Kidney • A reduced renal function and/or on an elevated urinary excretion of albumin have shown to increase both CVD and renal disease risk. • Assessment of renal function is needed to search renal failure and also it should be

18

Clinical guideline on Arterial hypertension in adults taken into account while determining the correct dose for the prescribed drugs. o serum creatinine, o Estimated glomerular filtration rate (MDRD formula or creatinine clearance Cockroft-Gault formula) (see Annex 1). Proteinuria: a positive dipstick, if negative, the micro-albuminuria should be determined. Albumin/creatinine random sample in urine Total CVD risk in these guidelines means likelihood of a person to develop a fatal or nonfatal major CVD event in 10-year period of time. In patients with established CVD or renal disease, type-2 diabetes, type-1 diabetes with proteinuria and in individuals with severely elevated single risk factors such as serum cholesterol concentration >8 mmol/l or TOD, the total CVD risk is high (i.e. 10-year risk of a fatal or nonfatal major CVD event is>20%), indicating for the intense CVD risk reducing measures. For hypertensive persons who do not belong to one of the above categories, an identification of those at high risk requires the use of models to estimate total CVD risk to allow adjusting the intensity of the therapeutic approach accordingly. Instructions for using WHO/ISH risk prediction charts The WHO/ISH risk prediction charts indicate 10-year risk of a fatal or nonfatal major CVD event (myocardial infarction or stroke), according to age, sex, SBP, smoking status, total blood cholesterol for WHO Western Pacific epidemiological regions including Mongolia. There are two sets of charts, one is for settings where blood cholesterol can be measured, and the other one is for settings in which it cannot be measured. The charts provide approximate estimates of CVD risk in people who do not have established CVD or renal disease, diabetes, TOD or very high cholesterol level. They are useful as tools to help identify those at high CVD risk, and to motivate patients, particularly to change behaviour and, when appropriate, to take antihypertensive, lipid-lowering drugs and aspirin. How to use the charts to assess cardiovascular risk? If blood cholesterol cannot be measured due to resource limitations, use the charts that do not have total cholesterol. Before applying the chart to estimate the 10year CVD risk of an individual, the following information is necessary 19

• •

Fundoscopy • Hemorrhages, exudates and papilloedema, only present in severe hypertension, are associated with increased CV risk. Milder degrees of retinopathy to be used for prognosis have been questioned. Examination of eye grounds is recommended in patients with severe hypertension (DBP≥120 mmHg) and young patients only Subclinical organ damages in blood vessels can be evaluated using following procedures if available • Carotid intima-media thickness (IMT) at the bifurcation reflecting arteriosclerosis and the common carotid IMT reflecting vascular hypertrophy predict CVD risk. Ultrasound scanning of carotid arteries is recommended when detection of vascular hypertrophy or asymptomatic atherosclerosis is deemed useful. IMT≥0.9 mm or the presence of plaque means existing abnormalities. • Pulse wave velocity can be used to measure artery stiffening (leading to ISH in the elderly and to an increased CVD risk). Additionally, central BP and augmentation index are predictors of CVD events. • A low ankle-brachial BP (<0,9) index signals advanced peripheral artery disease C.5.6. Estimation of the CVD risk

Clinical guideline on Arterial hypertension in adults • • Gender Smoker or non-smoker. o All current smokers and those who quit smoking less than 1 year before the assessment are considered smokers for assessing cardiovascular risk. Age SBP Total blood cholesterol Step 2 Select smoker or non smoker boxes Step 3 Select age group box (if age is 50-59 years select 50, if 60-69 years select 60 etc) Step 4 Within this box find the nearest cell where the individuals SBP (mm Hg) and total blood cholesterol level (mmol/l) cross. The colour of this cell determines the 10 year cardiovascular risk.

• • •

Once the above information is available proceed to estimate the 10-year cardiovascular risk as follows: Step 1 select corresponding table for males or females High risk means the risk of ≥ 20%

This chart can only be used in settings where blood cholesterol can be measured Figure 1a WHO/ISH risk prediction charts

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Clinical guideline on Arterial hypertension in adults

This chart can only be used in settings where blood cholesterol can not be measured Figure 1b WHO/ISH risk prediction charts C.6. Antihypertensive Treatment Please note that CVD risk may be higher than indicated by the charts in the presence of following: • already on antihypertensive therapy • premature menopause • approaching the next age category or SBP category • obesity (including central obesity) • sedentary lifestyle • family history of premature coronary heart disease (CHD) or stroke in first degree relative (male <55 years, female < 65 years) • raised triglyceride level (>2.0 mmol/l or 180 mg/dl) • low HDL cholesterol level (< 1 mmol/l or 40mg/dl in males, < 1.3 mmol/l or 50 mg/dl in females) • raised levels of C-reactive protein, fibrinogen, homocysteine, • apolipoprotein B or Lp(a), or fasting glycaemia, or impaired glucose tolerance • microalbuminuria • raised pulse rate • socioeconomic deprivation The treatment of hypertension should be taken to mean total management to reducing the risk of CVD. This includes detailed lifestyle advice to all patients with high BP. If non-pharmacological treatment has proved unsuccessful, use of antihypertensive drug treatment is should be bases on the level of SBP and DBP and the level of total CVD risk. C.6.1. Lifestyle modification Lifestyle measures should be instituted, whenever appropriate, in all patients, including subjects with high normal BP and patients who require drug treatment, (See more details in C3.1.) C.6.2. Antihypertensive drug therapy Main benefits of antihypertensive therapy are due to the effective lowering of BP per se. Based on data from randomized controlled trial and results from meta-analyses: antihypertensive drug therapy translates into significant reductions of CVD morbidity and mortality while having a less significant effect on all cause mortality, with a major reduction 21

Clinical guideline on Arterial hypertension in adults in the risk of fatal or non-fatal stroke (about 30–40%), to a lesser degree coronary events (20%). Antihypertensive treatment appears to cause a large reduction in the incidence of heart failure. The benefit can also be seen at older ages, including patients with isolated systolic hypertension (ISH). The proportional reduction of CVD risk is similar in men and women. The treatment has a beneficial effect in Caucasian, Asian and black populations, which suggests that it is present across various ethnic groups. Five major classes of antihypertensive agents – diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists and B-blockers – are suitable for the initiation and maintenance of antihypertensive treatment, alone or in combination. The different classes of drugs used standard doses reduce BP about the same extent and the BP reduction itself explains the CVD preventive effect of drugs. The outcome benefit of diuretics has been reported for low doses, not for high doses. Using a single drug, BP decreases on by 9/6 mmHg on an average. The other drugs such as aliskiren, spironolactone, pratsozine clonidine, moxodine and long acting nitrated are effective in the BP lowering, but there is no evidence on their protective effect of CVD events. Antihypertensive drug treatment is recommend for patients whose BP based on repeated BP measurements is • SBP≥160 mmHg and/or DBP≥ 100 mmHg o (SBP≥180 mmHg and/or DBP≥ 110 mmHg , start promptly ) • SBP≥140 mmHg and/or DBP≥ 90 mmHg and the patient at high CVD risk with established o CVD o renal disease o type 2 diabetes, type1 diabetes with proteinuria o TOD o Very high level of individual risk factor such as total cholesterol level (>8 mmol/l) o Global CVD risk based on the tables is higher than 20% (See Figures 1a and 1b. WHO risk prediction charts for Western Pacific Region including Mongolia). Goal of treatment • The primary goal of treatment of the hypertensive patient is to achieve the maximum reduction in the long-term total risk of CVD diseases. • This requires treatment of the raised BP as well as of all associated reversible risk factors. Target blood pressure value The goal of BP treatment is lower SBP below 140 mmHg and DBP<85mmHg, if tolerated, in all hypertensive patients. • In patients with renal dysfunction and /or proteinuria, target values are <130/80 mmHg even lower, although the evidence is scanty. • In the elderly ≥60 years o 140 mmHg systolic and 90mmHg diastolic, if tolerated. However, no placebo controlled trials until now achieved ontreatment SBP less than 140mmHg in this age-group. The optimum DBP to be achieved by treatment is not clear. o In patients’ ≥70 years, the goal is 150 mmHg. Drug treatments of isolated office and isolated home hypertension are usually based on the values received using ambulatory or home BP measurements and total CVD risk. Monotherapy and combination therapy • Monotherapy allows achieving BP target in only a limited number of hypertensive patients. 22

Clinical guideline on Arterial hypertension in adults • Combining two agents from any two antihypertensive drug classes decreases BP more than doubling the dose of one agent. The combination of lower doses is more likely to be free of side effects compared to full dose monotherapy. • Antihypertensive drug treatment can be initiated in uncomplicated hypertensives and in the elderly using monotherapy at low dose and subsequently adjust the dose gradually • A combination of two drugs at low doses could be preferred as first step treatment (or to combine early another drug with the initial monotherapy) with a subsequent increase in drug doses or number, when hypertensive patients have a high initial BP or total CVD risk is high/very high, in which early or prompt BP control may be desirable. • The drug needs to be withdrawn if side effects appear or in the absence of any BP-lowering effect. • Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment.

Figure 2. Monotherapy versus combination therapy strategies (ESH/ESC 2007) Preferred drug combinations • Several two-drug combinations are suitable for clinical use. The combinations of ACE inhibitor / diuretic, ATR-antagonist /diuretic, calcium antagonist/diuretic, ACE inhibitor/ calcium antagonist the ß-blocker/diuretic have been documented effective in outcome trials • However, the ßblocker/diuretic combination favors the development of diabetes and should thus be avoided, in predisposed patients, unless required for other reasons. • ACE-inhibitor/calcium antagonist combination may superior be to the combination of ACE-inhibitors/ diuretics or the ß-blocker/diuretic combination in higher risk patients. • Use of an ACE-inhibitor/ATRantagonist combination presents with a consistent increase of serious side-effects without decrease in CVD events, the combination should not be used for treatment of hypertension. • If BP control is not achieved by two drugs, and a combination of three of more drugs is required. The most rational combination appears to be ACE 23

Clinical guideline on Arterial hypertension in adults inhibitor or ATR-blocker, a calcium antagonist and a diuretic.

Diuretic

β-B

ARB

α-B

CCB

A CEI
Rec ommended combinations Possible combinations Not recommended for treatment of hypertension

Figure 3 Possible combinations between different classes of antihypertensive agents (ESH/ESC Guidelines 2007, modified by authors)
Combination of diltiazem or verapamil with beta blocker should be avoided The framed drugs represent those of confirmed benefits in randomized controlled trials

Choice of a specific drug or a drug combination The choice of a specific drug or a drug combination, and the avoidance of others, should take into account the following: • The previous favorable or unfavorable experience of the individual patient with a given class of compounds. • The effect of drugs on CVD risk factors in relation to the CVD risk profile of the individual patient. • The presence of subclinical TOD, clinical CVD, renal disease or diabetes which may be more favorably treated by some drugs than others. • The presence of other disorders that may

• •

limit the use of particular classes of antihypertensive drugs. The possibilities of interactions with drugs used for other conditions. The cost of drugs, either to the individual patient or to the health provider, but cost considerations should never predominate over efficacy, tolerability, and protection of the individual patient. Continuing attention should be given to side effects of drugs, because they are the most important cause of noncompliance. Drugs are not equal in terms of adverse effects, particularly in individual patients. 24

Clinical guideline on Arterial hypertension in adults • The BP lowering effect should last 24 hours. This can be checked by office or home BP measurements at trough or by ambulatory BP monitoring. Choice of antihypertensive drugs Table 6. Antihypertensive treatment: preferred drugs Essential hypertension without complications Subclinical organ damage LVH Asymptomatic atherosclerosis Microalbuminuria Renal dysfunction Clinical events Previous stroke Previous MI Angina pectoris Heart failure Atrial fibrillation • Recurrent • Permanent ESRD/proteinuria Peripheral artery disease Associated condition ISH (elderly) Metabolic syndrome Diabetes mellitus Pregnancy diuretics, CA ACEI, ARB, CA ACEI, ARB Labetalol, CA, methyldopa, BB Any BP lowering agent BB, ACEI, ARB BB, CA diuretics, BB, ACEI, antialdosterone agents ARB, ACEI BB, non-dyhidropiridine CA ACEI, ARB, loop diuretics CA ACEI, ARB, CA CA, ACEI ACEI, ARB ACEI, ARB ACEI, ARB, CA , diuretics, ß-blocker • Drugs which exert their antihypertensive effect over 24 hours with a once-a-day administration should be preferred because a simple treatment schedule favors compliance.

ARB,

Abbreviations: LVH: left ventricular hypertrophy; ESRD: renal failure; ACEI: ACE inhibitors; ARB: angiotensin receptor antagonists; CA: calcium antagonists, BB: ß-blockers

Table 7. Compelling and possible contraindications to use of antihypertensive drugs Compelling Possible Thiazide diuretics Gout (hyperuricemia) Metabolic syndrome Glucose intolerance Pregnancy Erectile dysfunction Beta-blockers Asthma A-V block (grade 2 or 3) pregnancy (not first line) Metabolic syndrome Glucose intolerance Athletes and physically active patients 25

Clinical guideline on Arterial hypertension in adults Chronic obstructive Pulmonary disease Erectile dysfunction Calcium antagonists (dihydropyridines) Calcium antagonists (verapamil, diltiazem) ACE inhibitors Post-myocardial infarction A-V block (grade 2 or 3) Heart failure Pregnancy Angioneurotic oedema Hyperkalaemia Bilateral renal artery stenosis Pregnancy Hyperkalaemia Bilateral renal artery stenosis Renal failure Hyperkalaemia Tachyarrthytmias Heart failure

Angiotensin receptor antagonists Diuretics (antialdosterone)

C.6.3. Treatment of associated risk factors The goal is to reduce the total CVD risk in hypertensive patients. Lipid lowering agents The Cholesterol target • In general, total plasma cholesterol should be below 5 mmol/L, and LDL cholesterol should be below 3 mmol/L. • For patients at high risk o Total cholesterol< 4.5 mmol/L with an option of <4 mmol/L if feasible, and LDL cholesterol <2.5 mmol/L with an option of <2 mol/L if feasible. Antiplatelet therapy Low-dose aspirin should be prescribed to hypertensive patients in the absence of other contraindications for antiplatelet therapy, if there is no excessive risk of bleeding and the BP level is <150mmg/90mmHg • With previous CVD events.

With a moderate renal failure (eGFR<45ml/min). Attention should be given to the increased possibility of bleeding. The benefits of antiplatelet therapy in diabetic patients remain to be established. In patients with low and high risk without previous CVD or renal failure, the benefit-torisk ratio of this intervention (reduction in myocardial infarction greater than the risk of bleeding) has been proven been so tiny, that treatment has not been recommended. Glycemic control Effective glycemic control is of great importance in patients with hypertension and diabetes. Please see guidelines for Diabetes Mellitus. C.7. Management of HTA in special conditions C.7.1. Essential hypertension without complications • Five major classes of antihypertensive agents – diuretics, ACE inhibitors, 26

Clinical guideline on Arterial hypertension in adults calcium antagonists, angiotensin receptor antagonists and b-blockers – are suitable for the initiation and maintenance of antihypertensive treatment, alone or in combination. Calcium channel blocker has possible an additional positive effect in preventing stroke (and possibly less effect in preventing heart failure). ß-blockers given shortly after myocardial infarction may have extra protective effect. The ß-blocker/diuretic combination favors the development of diabetes and should thus be avoided, in predisposed patients, unless required for other reasons. • Drug treatment should be tailored to the risk factors, TOD, decreased renal function and associated CVD and nonCVD conditions that are frequent in the elderly. Before drug treatment and during followup, the renal function should be determined as elderly people are at the risk of deterioration of the renal function Because of the increased risk of postural hypotension, BP should always be measured also in the erect posture. No trials on the treatment of elderly hypertensive patients with BP 140-149 is available

• •

• •

C.7.2. Elderly • Older patients (≥ 60 years) benefit from antihypertensive drug treatment in terms of reduced CVD morbidity and mortality, irrespective of whether they have systolic/diastolic hypertension. Antihypertensive treatment has shown to be beneficial in preventing dying from stroke and all causes and reduction the rate of heart failure also in persons 80 years of age or older who are in good physical and mental conditions and without major CVD at baseline Antihypertensive drug treatment should be initiated o Generally with thiazide diuretics, calcium antagonists, ACE inhibitors, ATR antagonists, and ß-blockers, in line with general guidelines o In patients with ISH, thiazides and calcium antagonists have been shown to be beneficial in the treatment o In patients ≥80 years, the use of diuretics and ACE inhibitor has been beneficial • Initial doses and subsequent dose titration should be more gradual because of a greater chance of undesirable effects.

C.7.3. Diabetes mellitus The co-existence of hypertension and diabetes mellitus increases the risk of stroke, coronary heart disease, congestive heart failure, peripheral artery disease and CVD and renal diseases. The presence of microalbuminuria in diabetic patients is an early marker of renal disease and an indicator of increased CVD. • All major five antihypertensive drug classes protect against CVD complications by lowering BP per se. Antihypertensive treatment additionally exerts a major protective effect against renal complications, whereas evidence of a similar effect on eye and neural complications is less consistent. ACE-inhibitors or ATR-blocker should be a regular component of combination treatment and the one preferred when monotherapy is sufficient, because it’s superior protective effect against initiation or progression of nephropathy. ACE inhibitor in association with calcium blocker has been reported to be superior when compared with ACE inhibitor and diuretic in high risk diabetic patients with hypertension. Treatment strategies should consider an intervention against all CVD risk factors, including tight blood glucose control (see Clinical guidelines for type 2 diabetes). 27

Clinical guideline on Arterial hypertension in adults C.7.4. Renal diseases • Improving renal outcomes with diabetic nephropathy may require additionally to targeting BP also targeting on proteinuria. • To achieve the BP goal, combination of therapy of several antihypertensive agents, in the first line with calcium blockers is required including loop diuretic. • To target reduction of microalbuminuria and proteinuria mostly through ACE inhibitor or ATR blocker, in order to reduce of end-stage renal disease and CVD. Careful monitoring of serum creatinine and potassium level is mandatory. • Treatment strategies should consider an intervention against all CVD risk factors because renal dysfunction and failure are associated with a very high risk of CVD. C.7.5. Cerebrovascular diseases • In patients with a history of stroke or transient ischemic attacks, antihypertensive treatment markedly reduces the incidence of stroke recurrence and lowers the associated high risk of cardiac events. • Because evidence from trials suggests that the benefit largely depends on BP lowering per se, all available drugs and rational combinations can be used. Trial data have been mostly obtained with ACE inhibitors and ATR antagonists, in association with or on the top of diuretic and conventional treatment, but more evidence is needed before their specific cerebrovascular protective properties are established. • There is at present many uncertainties whether BP lowering in acute stroke has a beneficial effect. Until now, beneficial impact on administrating of lisinopril or atenolol in patients with acute stroke and SBP >160 mmHg has been suggested. C.7.6. Cognitive dysfunction and dementia • In observational studies, cognitive decline and incidence of dementia have a positive relationship with BP values. There is some evidence that both can be somewhat delayed by antihypertensive treatment. • Lowering of BP improve performance of screening tests for dementia and memory. • The incidence of dementia was lower in older (≥60 years) subjects with ISH treated with nifedipine compared with placebo. • Antihypertensive treatment in the elderly patients aged 80 or more did not reduce incidence of dementia. C.7.7. Coronary heart disease • Hypertension is an important risk factor for CHD and hypertensive patients surviving a myocardial infarction are in an increased risk of recurrent myocardial infarction. • In patients surviving a myocardial infarction, early administration of ßblockers, ACE inhibitors or ATR blockers reduces the incidence of recurrent myocardial infarction and death. These beneficial effects can be ascribed to the specific protective properties of these drugs but possibly also to the associated small BP reduction. • Antihypertensive treatment is also beneficial in hypertensive patients with chronic CHD. The benefit can be obtained with different drugs such ß-blockers, calcium antagonists (dihydropyridines should be combined with ß-blockers), ACE-inhibitors, ATR-blockers and drug combinations.ACE –inhibitor should be prescribed for all hypertensive subjects with CHD, if tolerated (if not tolerated, can be replaced with ARB). • There is contradictory evidence on the presence or absence of benefit of lowering SBP below 130 mmHg. C.7.8. Heart failure • In the patients with symptoms associated with heart failure, treatment 28

Clinical guideline on Arterial hypertension in adults can be started with thiazide or loop diuretics following by ACE inhibitors or ATR antagonists if ACE-inhibitors were not tolerated and antialdosterone drugs on top of diuretics. ß-blockers can be gradually administrated after the overt heart failure has been treated. • Diastolic heart failure is common in patients with a history of hypertension and has an adverse prognosis. The same drug groups will be used, as there no evidence on the superiority of specific antihypertensive drugs. C.7.9. Artial fibrillation Hypertension is the most important risk factor for atrial fibrillation on a population basis. Atrial fibrillation increases the risk of CVD morbidity and mortality. Increased left ventricular mass and enlargement of the left atrium have been identified as independent determinants of new onset atrial fibrillation. Hypertensive people with these alterations appear to require intensive antihypertensive therapy • BP control appears to be strictly required when anticoagulant treatment is given because stroke and bleeding episodes are more frequent when SBP is ≥140 mmHg. • ß-blockers and non-dihydropyridine calcium antagonists (verapamil or diltiazem) remain important classes of drugs in order to control ventricular rate. • ß-blockers, ACE inhibitors and ATR antagonists have reduced the incidence of episodes of atrial fibrillation in patients with heart failure and hypertension. • ACE inhibitors and ATR antagonists may also reduce the recurrent episodes of atrial fibrillation. C.7.10. Metabolic syndrome • The metabolic syndrome is characterized by the variable combination of visceral obesity and alterations in glucose metabolism, lipid metabolism and BP. It has a high prevalence in the middle age and elderly population. • In all individuals with metabolic syndrome, intense lifestyle measures should be adopted. A possible hypertension drug treatment should be chosen on the way that is unlikely to facilitate onset to diabetes.

C.7.11. Hypertension in women Compared with men, middle-aged women typically have lower SBP levels, but it rises more steeply with age in women than in men. Thus, beyond 60 years of age prevalence of hypertension is higher in women than in men. • Both BP lowering and reduction in outcomes have shown to have been similar in both men and women and no sex related differences in response to various classes of antihypertensive agents could be detected. • ACE inhibitors and ATR antagonists should be avoided in fertile women, in pregnant and pregnancy planning women because of potential teratogenic effects during pregnancy. • Oral contraceptives: Even low estrogen oral contraceptives are associated with increased risk of hypertension, stroke and myocardial infarction. The progestogenonly pill is a contraceptive option for women with high BP, but influence on CVD outcomes has been insufficiently investigated. C.7.12. Hypertension in pregnancy Particularly pre-eclampsia, may adversely affect neo- natal and maternal outcomes. For both diagnostic and treatment purposes ambulatory BP monitoring may be useful (better predicting proteinuria, risk of pre-term delivery, infant weight at birth and in general outcome of pregnancy) particularly • in high-risk pregnant women with hypertension • Pregnant women with diabetic or renal damage. Oedema occurs in up to 60% of normal pregnancies, and is no longer used in the diagnosis of pre-eclampsia. 29

Clinical guideline on Arterial hypertension in adults C.7.13. Secondary hypertension A specific cause of BP elevation can be identified in a small proportion of adult patients with hypertension. Screening for secondary forms of hypertension can be obtained from clinical history, physical examination and routine laboratory investigations. Furthermore, a secondary form of hypertension is suggested by a severe BP elevation, sudden onset or worsening of hypertension and BP responding poorly to drug therapy. In these cases, specific diagnostic clues and signs may be present although not in all patients, as outlined below. Renal parenchymal disease, the most common cause of secondary hypertension. • Bilateral upper abdominal masses (polycystic kidney disease). • The presence of protein, erythrocytes or leucocytes at microscopic examination of the urine. An increase in serum creatinine concentration (renal parenchymal disease) Renovascular hypertension, the second most common cause of secondary hypertension (fibromuscular dysplasia in younger, arterial stenosis in the elderly people • Hypertension of abrupt onset or worsening as well as high BPs difficult to treat • Abdominal bruit with lateralization, hypokalaemia and progressive decline in renal function. • Of note, in the presence of bilateral renal artery stenosis, the treatment with antihypertensive drugs can lower perfusion pressure beyond the stenotic site associating with an acute deterioration of renal function and an increase in serum creatinine concentration. Because of the high risk of progression of atherosclerotic lesions, their treatment consists of intense lifestyle modifications, low dose aspirin, statin and multiple antihypertensive drug administration. Use should be made of a thiazide diuretic at appropriate doses and a calcium antagonist with the possible addition of a reninangiotensin blocker, except in the presence of bilateral renal artery stenosis. Close 30

Treatment • Non-pharmacological management (normal diet without salt restriction is advised close supervision and restriction of activities) should be considered for pregnant women with SBP 140 – 149 mmHg or DBP 90 – 95 mmHg. • Drug treatment is indicated at BP levels ≥150mmHg systolic or 95 mmHg diastolic. • BP level ≥140 systolic or≥ 90 mmHg diastolic, treatment is indicated in women with subclinical organ damage or symptoms such as headache, blurred vision, proteinuria or ankle swelling at any time during pregnancy • SBP levels 170 or DBP 110 mmHg should be considered an emergency requiring hospitalization. o In non-severe hypertension, oral methyldopa, labetalol, longactingcalcium antagonists and (less frequently) ß-blockers are drugs of choice. o In pre-eclampsia with pulmonary edema, nitroglycerine is the drug of choice. o ACE inhibitors and ATR antagonists are contraindicated. o Diuretic therapy is inappropriate because plasma volume is reduced. o As emergency, intravenous labetalol, oral methyldopa and oral nifedipine are indicated. Intravenous infusion of sodium nitroprusside is useful in hypertensive crises, but prolonged administration should be avoided. In-pre-eclampsia, nitroglycerin is the drug of choice. o Calcium supplementation, fish oil and low dose aspirin are not recommended. However, low dose aspirin may be used prophylactically in women with a history of early onset (28 weeks) pre-eclampsia. The goal pressure is <140/90 mmHg, although an excessive BP lowering can be harmful for fetal development.

Clinical guideline on Arterial hypertension in adults monitoring of serum creatinine and potassium level is mandatory. Phaeochromocytoma, a very rare secondary hypertensive state • Stable or paroxysmal hypertension • Headache, sweating, palpitations and pallor Definite treatment requires excision of the tumor. In advance of this the patient must be adequately prepared. This requires the introduction of an? Adrenoreceptor blocker and, after adequate treatment with this blocker, ß-blockers can be introduced. Primary aldosteronism • Hypokalemia (early stage in their disease rare) together with resistant hypertension • Intake of even small amounts of liquorices can be associated with resistant hypertension together with hypokalemia Cushing’s syndrome, rare • suggested by the typical body habits Obstructive sleep apnea • Recurrent episodes of cessation of respiratory airflow caused by upper airway inspiratory collapse during sleep • Daytime somnolence, impaired, concentration, unrefreshing and restless sleep, and choking episodes during sleep, witnessed apnoeas, nocturia, irritability and personality changes, decreased libido and increased motor vehicles accidents. • In obese patients often, non-dippers in 24h ambulatory BP measurement Coarctation of the aorta, rare • Hypertension in children and young adults. • A midsystolic murmur, which may become continuous with time, is heard over the anterior part of the chest and also over the back. • The femoral pulse is absent or delayed relative to the radial pulse. Drug-induced hypertension Substances or drugs that can raise BP include: liquorices, oral contraceptives, steroids, nonsteroidal anti-inflammatory drugs, cocaine and amphetamines, sympathmimetic, erythropoietin, cyclosporine, tacrolimus. C.7.14. Resistant hypertension Resistant or refractory to treatment, when a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower SBP and DBP to goal. Causes of resistant hypertension • Poor adherence to therapeutic plan • Inadequate medication or inappropriate drug combination, interactions • Failure to modify lifestyle including weight gain or heavy alcohol intake (NB: binge drinking) • Continued intake of drugs that raise BP(liquorice, cocaine, glucocorticoids, non-steroid anti-inflammatory drugs, etc) • Obstructive sleep apnoea • Unsuspected secondary cause (e.g. renal artery stenosis) • Irreversible or scarcely reversible organ damage • Volume overload due to: o Inadequate diuretic therapy o Progressive renal insufficiency o High sodium intake o Hyperaldosteronism • Causes of spurious resistant hypertension o Isolated office (white-coat) hypertension o Failure to use large cuff on large arm o Pseudohypertension in the elderly Examination and management: • A careful elicitation of the history and examination of the patient to exclude secondary causes of hypertension. • Ambulatory BP monitoring to characterize the degree of BP elevation compliance. 31

Clinical guideline on Arterial hypertension in adults • • Ultimately, many patients will need administration of more than three drugs. At present, the optimal choice of the 3rd, 4th and 5th line antihypertensive agents has not been addressed by proper randomized trials. Spironolactone, however, was found to cause a good additional antihypertensive response when given at a relatively small dose (25mg/day). A good response to amiloride has also been reported. Whether the good response to antialdosterone agents to some resistant hypertensive is due to undiscovered primary aldosteronism or to secondary aldosteronism induced by multiple therapies is at present unknown. Using small doses of spironolactone makes its adverse effects less likely to occur, but attention to serum potassium and creatinine concentrations is necessary because many of these patients may have poor renal function and are likely to concomitantly take renin-angiotensin system blockers. disturbascies hypertensive left ventricular failure hypertension with myocardial infarction hypertension with unstable angina hypertension and dissection of the aorta severe hypertension associated with subarachnoid haemorrhage cerebro-vascular accident Crisis associated with phaeochromocytoma Acute progressing renal failure Retinal hemorrage, exudates or papillaödema Hypertension perioperatively Severe pre-eclampsia or eclampsia Haemolysis, disseminated intravascular coagulation

• • • • • • • • • • •

Prevention of hypertensive emergencies: • Good BP control and good identification of secondary causes and their treatment. Patients with hypertensive emergencies require the immediate reduction of the elevated BP. Specialist referral is warranted, treatment demands usually intravenous drugs. Possible drugs are labetalole, natriumnitroprusside, glycerylnitrate, clonidine. Oral medication (long-acting or medium-long acting calcium blockers-not for chewing) can be used if BP is responsive. Goal of DBP is 100-110 over 24 hours. 2) Hypertension urgencies Severe elevation on blood pressure without organ damages Use oral medications to lower BP gradually (see C 6). Follow-up should be during 1 to 3 day. Too rapid reduction may result in marked reduction in perfusion.

C.7.15. Hypertensive Crisis Conditions leading to hypertension emergencies are usually severe or poorly treated essential hypertension or the presence of secondary hypertension. Severe form of hypertension classified based on seriousness of the situation 1) 2) 1) Hypertensive Emergencies (=malignant hypertension) Hypertensive Urgencies Hypertension emergencies severe elevation of arterial BP (DBP usually but not always >130 mm Hg) with an acute damage to target organs. If untreated, prognosis is extremely poor, with 50% of individuals dying within 12 months. The most important emergencies: • hypertensive encephalopathy (headache, mental changes, vision

32

Clinical guideline on Arterial hypertension in adults C.8. Follow up of patients with hypertension unless hypertensive emergencies or urgencies Follow-up of hypertensive patients should be carried out according to the BP level, the presence of subclinical and clinical TOD and other compelling conditions. Follow-up should carry out lifestyle changes, drug treatment, side-effects of drugs and how to reach the goal. • During the drug titration phase after initial visit, patients should be see for the first time in 2 weeks for safety. o Appearance of side effects, dose reduction or drug withdrawal o Ipatients with diuretic, ACEinhibitor or ATR blocker, serum creatinine, sodium and potassium level should be measured, e-GFR additionally if needed. Monitoring should also be considered if the dose of these drugs has been changed During following titration phase, patients should be seen every 1-2 months or if drugs have been adjusted. o Increase in drug dose, addition of other drugs, dose reduction or drug withdrawal in accordance to the achieved BP or the adverse effects. o Frequency of visits every 6 months • Low CVD risk and mild degrees of BP elevation o More frequent visits • A high or very high CVD risk and with a higher initial BP level • Patients on nonpharmacological treatment • Compliance to this intervention is low • The BP response is variable • This treatment requires reinforcement • • Home measurement of BP may allow to extend the periods between visits in patients with diuretic, ACE-inhibitor or ATR blocker, serum creatinine, sodium and potassium level should be measured annually, e-GFR additionally if needed. If BP goals are not achieved within 6 months, the BP level is very high (180/110 mmHg) or a previously good control is lost, referral to a hypertension specialist or clinic should be considered. Subclinical organ damage should be assessed during treatment periodically because a number of treatment-induced regressions or lack of progression has favorable prognostic implications. Because treatment induced changes in left ventricular mass and carotid artery wall thickness are slow, there is no reason to perform these examinations at less than 1 year intervals.

After the goal of therapy has been reached, achievement of target BP (<140/85 mmHg, elderly SBP<150 mmHg) and control of all correctable risk factor Treatment of hypertension should be continued for life because in correctly diagnosed patient cessation of treatment is usually followed by return to the hypertensive state. Cautious downward titration of the existing treatment may be attempted in low risk patients after longterm BP control, particularly if non-pharmacological treatment can be successfully implemented.

33

REFERENCES
1. Mongolian STEPS Survey on the Prevalence of Noncommunicable Disease and Injury Risk factors-2009. World Health Organization, Ulaanbaatar. Mongolia, 2010. 2. Alberti KGMM, Eckel RH, Grundy SM et al. Harmonizing the Metabolic Syndrome: Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; Natioanal Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120;1640-1645. 3. Blood Pressure Lowering Treatment Trialists' Collaboration, Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.BMJ. 2008 May 17;336:1121-1123. 4. Drug Information Handbook 11th Edition. Lexi-Comp’s 2003.

5. Graham I, Atar D, Borch-Johnsen K et al, European guidelines on CVD disease
prevention in clinical practice: executive summary.Fourth Joint Task Force of the European Society of Cardiology and Other Societies on CVD Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts), Eur Heart J. 2007 Oct;28(19):2375-414.

6. Law MR, Morris K, Wald NJ. Use of blood pressure lowering drugs in the
prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338;b1665 doi: 10.1136/BMJ.b1665.

7. Mancia G, De Backer G, Dominiczak A et al 2007 ESH-ESC Practice
Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension.J Hypertens. 2007 Sep;25(9):1105-87.

8. Mancia G, Laurent S, Agabiti-Rosei E et al. Reappraisal of European guidelines
on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158 9. Suomalainen Lääkäriseura Duodecimin ja Suomen Verenapineyhdistys ry:n asettama työryhmä. Kohonnut verenpaine. Käypähoito-suositus. Päivitetty 23.11.2009. 10. Williams B, Poulter NR, Brown MJ et al. British Hypertension Society guidelines. Guidelines for management of hypertension: report ot the fourth working party on the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004; 18: 139-185 34

11. World Health Organization, Mongolian step survey on the prevalence of noncommunicable disease and injury Risk 2009. Ulaanbaatar, Mongolia 2010 12. World Health Organization. Prevention of CVD diseases. WHO/ISH CVD Risk Prediction Charts for WHO epidemiological sub regions WPR A, WPR B) 2007.

ANNEXES
Annex 1. Instrumental signs of target organ damage Electrocardiographic diagnosis of LVH (ECG LVH) - Sokolow-Lyon voltage criterion i.e. when the amplitude of SV1+ (max RV5 or RV6) was equal to or above 3.8mV. - Cornell product criterion i.e. when QRS duration times (RavL+SV3) >244mVms for men and QRS duration times (RavL+SV3+0.8mV) >244mVms for women Renal function: - estimated glomerular filtration rate (MDRD formula)1 - creatinine clearance (Cockroft-Gault formula). for men: 1,23x*(140-age (years))* weight (kg)/P-crea (mmol/l for women: 1,23x*(140-age (years))* weight (kg)*o,85/P-crea (mmol/l

1

http://www.nkdep.nih.gov/professionals/gfr_calculators/orig_si.htm 35

Annex 2. Outline curriculum for schools of patients with hypertension 1. Basic notions of blood pressure Mechanisms of generating systolic blood pressure Mechanisms of generating diastolic blood pressure Mechanisms of regulation of blood pressure 2. Causes and classification of hypertension Classification of blood pressure levels Risk factors for hypertension Types of hypertension Taking blood pressure in office and at home

• • •

• • • •

3. Diagnosis of hypertension • • • Risks of hypertension Additional laboratory analyses and instrumental examinations Estimation of global CVD risk using risk charts

4. Recommendations regarding life style modification for hypertension patient Lifestyle modifications salt and fat reduction quitting smoking weight control physical activity coping with stress

• • • • • •

5. Treatment of hypertension Pharmacological treatment of hypertension Pharmacological treatment of concomitant conditions Main classes of antihypertensive medications Main mechanisms of action for main classes of antihypertensive drugs Safety, frequency of adverse effects What is the best pill? 36

• • •

6. Monitoring of hypertension Target blood pressure values Varying doses of medications Importance of appropriate control of blood pressure 7. Signs to approach the doctor Signs of pure blood pressure control Signs of over dosage Signs of typical adverse effects Signs of imminent complications

• • • •

37

Annex 3. Pharmacotherapy of Hypertension2 ACE inhibitors Captopril, Cilazapril, Enalapril, Lisinopril, Perindopril, Ramipril ACE inhibitors are suitable for initiation and maintenance of therapy. Have been shown to reduce mortality and morbidity in patients with CHF and post MI patients with reduced LV ejection fraction; also effective in reducing LV hypertrophy and preserving kidney function Action: Block the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE) Effects: Lower BP by vasodilation and reduction of peripheral resistance - Produce reduction in preload and afterload in patients with HF and they reduce LV remodeling which is a process that often follows MI - Generally well-tolerated and do not effect lipid or glucose metabolism Angiotensin II Antagonists Losartan, Valsartan Angiotensin II antagonists are suitable for initiation and maintenance of therapy Beneficial effect in early and advanced type 2 DM nephropathy and HF Reduce major CV events in patients with hypertensive LV hypertrophy and diastolic HF • Should be considered in HF patients intolerant of ACE inhibitors Action: Block angiotensin II receptors Effects: Cause vasodilation and fall in BP - Due to receptor selectivity and lack of potentiation of bradikinin and other vasoactive peptides, cough and angioedema are less likely to occur compared with ACE inhibitors - Generally well-tolerated and do not effect lipid or glucose metabolism CalciumAntagonists • Ñà antagonists are suitable for initiation (1st line of therapy for ≥55 yr) and maintenance of therapy Action: Inhibit the cellular influx of Ca which is responsible for maintenance of the plateau phase of the action potential - The cells they affect are typically the vascular smooth muscle, myocardial cells and cells with the SA and AV nodes - They dilate coronary and peripheral arteries with little or no effect on venous tone Dihydropyridine Ca Antagonists Amlodipine, Felodipine, Nicardipine, Nifedipine • Usually used for their antihypertensive and anti-anginal effects • Have greater selectivity for vascular smooth muscle than for myocardium and their main effect is vascular relaxation
2

• •

• • •

* Please see: contraindications of the drugs on the page 28 of the guideline, monotherapy and combination therapy, preferred drugs on the pages 26-29 of the guideline, other indications of some antihypertensive drugs on the table 8.

38

They have little or no effect at the SA or AV nodes and inotropic activity is not typical at therapeutic doses Non-dihydropyridine Ca Antagonists) Diltiazem (benzothiazepine),Verapamil (phenylalkylamine) • Typically used for their antiarrhythmio (more effective superventricular tachyarrhythmia), anti-anginal and antihypertensive properties • Tend to have less selective vasodilatory activity than dihydropyridine Ca antagonists - They have direct effect on myocardium causing depression of SA and AV conduction • Preferred in patients with proteinuria due to the additional antiproteinuric effect in diltiazem and verapamil Diuretics • Use of diuretics has been well established in the treatment of hypertension - When used in combination, diuretics may enhance the efficacy of concurrently used antihypertensive drug - Reduce the risk of fatal and nonfatal stroke and have been shown to reduce CV morbidity and mortality and all-cause mortality - Drug choice in the elderly with no comorbid conditions Loop diuretics Furosemide,Torasemide • Loop diuretics are preferred over thiazide diuretics in patients with renal insufficiency Thiazed diuretics Chlorothiazide,Chlorthalidone, Hydrochlorothiazide Action: Blocks renal tubular reabsorption of Na leading to urinary Na loss • Inexpensive and are the most widely used of the antihypertensive agents • Used in combination with potassium sparing diuretic to prevent thiazideinduced hypokalemia • In patients with normal renal function and essential hypertension, thiazide diuretics are more potent than loop diuretics - Not recommended in patients with metabolic syndrome or at high risk of diabetes, especially when used in combination with beta-blockers Aldosterone Antagonist Spironolactone Action: Antagonize the action of aldosterone at mineralocorticoid receptors that inhibit sodium resorption in the collecting duct of the nephron in the kidneys. • • Use of this group drug as adjunctive therapy, in combination with other drugs, for the management of chronic HF The first member of the glass management of hyperaldosteronism

-

Potassium-Sparing Diuretics Amiloride 39

Usually used in conjunction with loop or thiazide diuretics prevents to develop hypokalemia.

Beta-Blockers Atenalol, Bisoprolol, Labetalol, Metoprolol, Proponalol Action: Competitive antagonists of the effects of catecholamines at beta-adrenergic receptor sites. Pharmacodynamic differences exist because of selectivity for β1, β2 or α1 adrenoreceptor blockade among the beta blockers. - Beta2- blockade can increase bronchial resistance and inhibition of catecholamine-induced glucose metabolism - Beta-blockers have different affinities for beta1- or beta2-blockade but as doses are increased, activity of beta2 receptors can become apparent in beta1 selective inhibitors • Combination with thiazide diuretic is shown to have dysmetabolic effect and increased incidence of new onset diabetes among patients Alpha-blockers Doxazine, Prazosin Usually preferred antihypertensive in patients with benign prostatic hyperplasia (BPH) • There is limited evidence favoring use of alpha-blockers compared to the evidence for other antihypertensive agents Actions: Lower BP by reducing peripheral resistance - They also reduce prostatic and urethral smooth muscle tone - Provides symptomatic relief for patients with early BPH - Favorable effect on lipid metabolism Other Agents Centrally-Acting Agents Clonidine, Methyldopa • Safer and more effective agents are now available and the use of these agents is generally not recommended Methyldopa may be considered in resistant hypertension in combination with other antihypertensive agents. Safe to use in pregnancy •

Direct Vasodilators hydralazine Hydralazine, Minoxidil Usefulness of these antihypertensives is usually limited by their side effects

Table 8. Conditions favouring use of some antihypertensive drugs versus others
Thiazide diuretics • Isolated systolic hypertension (elderly) Heart failure • Hypertension in black Beta-blockers Angina pectoris • Post-myocardial infarction Heart failure Calcium antagonists (dihydropyridines) • Isolated systolic hypertension (elderly) Angina pectoris Calcium antagonists (verapamil/diltiazem) Angina pectoris • Carotid/ coronary atherosclerosis

40

Tachyarrhythmia Glaucoma Pregnancy

ACE inhibitors Angiotensin receptor antagonists • Heart failure • Heart failure • LV dysfunction • Post-myocardial • Post-myocardial infarction infarction Diabetic nephropathy Diabetic nephropathy • Proteinuria/ micro• Non-diabetic albuminuria nephropathy • LV hypertrophy • LV hypertrophy • Carotid atherosclerosis • Atrial fibrillation • Metabolic syndrome • Proteinuria/ microalbuminuria • ACEI- induced cough • Atrial fibrilllation • Metabolic syndrome ACEI: ACE inhibitors; LV: left ventricle

LV hypertrophy • Carotid/ coronary atherosclerosis Pregnancy Hypertension in black Diuretics (antialdosterone) • Heart failure • Post-myocardial infarction

• Supraventricular tachycardia

Loop diuretics End stage of real disease Heart failure

Table 9. Wide using some antihypertensive drugs: dosage, adverse reactions, Precautions
Drug Captopril ACE inhibitors** Dosage Remarks Initial dose: 12.5 mg PO bid-tid. Adverse Reactions (1-10%): May increase gradually at 2-4 wk CV effects (hypotension, angioedema); CNS intervals effects (fatigue, headache); GI effects (test Maintenance: 25-50 mg PO bid disturbances); Resp effect (persistent dry Max dose: 150 mg/day cough; upper resp tract symptoms); Dermatologic effects (skin rashes, erythema Initial dose: 1-1.25 mg PO once multiforme, toxic epidermalnecrolysis); daily x 2 days Hypersensitivity reactions; Renal effects Maintenance: 2.5-5 mg PO once (renal impairment); electrolyte disturbances daily (hyperkalemia, hyponatremia); Blood Initial dose (patient taking disorders diuretics): 2.5 mg PO once daily. Precautions: Initial dose (patient not on Patient with HF and those who may be salt or diuretics): 2.5 mg PO once daily. water depleted (taking diuretic or on dialysis or from other reasons) may experience Maintenance: 15-30 mg PO bid hypotension during initial stages of ACE Max dose: 120 mg/day inhibitor therapy Initial dose (patient taking - Start treatment only under close diuretics): 5 mg PO once daily. medical supervision; in these patients Initial dose (patient not on use a low dose and have the patient in diuretics): 5-10 mg PO once daily. a supine position. Maintenance dose: 20 mg PO once daily Avoid in patients with aortic stenosis or outflow Max dose: 80 mg/day tract obstruction and should generally be Initial dose: 4-5 mg PO once daily avoided in suspected or actual bilateral May increase to 8-10 mg PO once renovascular disease daily Max dose: 8-10 mg/day Use with caution in patients with history of Initial dose: 1.25-2.5 mg PO once hereditary or idiopathic angioedema daily Maintenance: 2.5-5 mg PO once Renal function and serum electrolyte (sodium daily potassium) levels should be assessed prior to Max dose: 10 mg/day

Cilazapril

Enalapril

Lisinopril

Perindopril

Ramipril

41

administration of ACE inhibitors and should be monitored during therapy **if possible, discontinue diuretics 2-3 wk before initiating therapy with ACE inhibitors. Otherwise, monitor patients closely during therapy Angiotensin II antagonist Drug Dosage Remarks Losartan Initial dose: 50 mg PO once Adverse Reactions (1-10%): daily. Usually mild and transient: CNS effects Maintenance: 50-100 mg/day PO (dizzines);CV effects (dose-related orthostatic once daily or 100 mg PO bid hypotension which may be occur particularly in Max dose: 150 mg/day patients with volume depletion); Renal impairment Rare misc effects: rash, angioedema, elevated Valsartan Initial dose: 80 or 160 mg PO LFTs; myalgia once daily Precautions: May increase to 320 mg PO once Patient with volume depletion (eg high-dose daily diuretic therapy) may experience hypotension and should be started on low dose Use with caution in patients with renal artery stenosis, renal impairment or hepatic impairment Serum K should be monitored patients with renal impairment and K-sparing diuretics should be avoided. Calcium antagonists Dosage Remarks Initial dose: 5 mg PO once daily Max dose: 10 mg/day Initial dose: 2.5-5 mg PO once daily. Maintenance dose: 2.5-10 mg/day PO once daily Max dose: 20 mg/day Regular release: Initial dose: 10-20 mg PO tid. May be increased to 20-40 mg PO tid Extended release: 40 mg PO bid. May be increased to 80-120 mg PO bid Regular release: Initial dose: 5-10 mg PO tid. May stepwise to 20 mg tid Max dose: 60-180 mg/day Extended release (once daily): Initial dose: 20-90 mg PO once daily. Maintenance dose: 30-60 mg/day PO Max dose: 120-180 mg/day Extended release (twice-daily): Initial dose: 10-20 mg PO bid. Maintenance dose: 20 mg PO bid May increase stepwise to 40 mg bid Max dose: 120-180 mg/day Regular release: 40-80 mg PO tid-qid or 80-160 mg PO bid-tid. Max dose: 480 mg/day Extended release: 120-240 mg PO once daily. May increase to 240 mg PO bid Max dose: 480 mg/day Regular release: Adverse Reactions: CV effects (depression of cardiac function, hypotension doserelated 2.5-5%, worsening HF 2%, edema dose-related 7-10%, flushing 10-25%, bradycardia); GI effects (constipation, nifedipine ≤2%, verapamil 1242%); CNS effects (headache 1023%, dizziness 10-27%); HR modulating Ca antagonists (eg. Dilitiazem, Verapamil): AV dissociation <1%, AV block 1.2%, bradicardia 1.2-1.4%, sinus node dysfunction <1; Short-acting dihydropyridine (nifedipine) agents should be avoided because they have the potential to enhance risk of adverse cardiac events Precautions: Contraindicated in patients with overt decompensated HF, though vasoselective dihydropyridines (eg amlodipine, felodipine) are tolerated in patients with decreased LV ejection fraction. HR modulating Ca antagonist are contraindicated in patients with bradicardia, sinus node dysfunction and AV nodal block.

Drug Dihydropyridines Amlodipine Felodipine Nicardipine

Nifedipine

Phenylalkylamine Verapamil

Benzothiazepine Diltiazem

42

Initial dose: 30-60 mg PO tid or 60-120 mg PO bid May increase to 180-360 mg/day PO divided tid Extended release (once daily): Initial dose: 90-180 mg PO once daily. May increase dose at 14-day intervals to 240-360 mg PO once daily Max dose: 540 mg/day Extended release (twice-daily): 90-180 mg PO bid. Max dose: 360 mg/day Diuretics Drug Dosage Remarks Aldosterone Antagonist Spironolactone 25-50 mg/day Adverse Reactions: May increase up to 100 CNS effects 23% (headache, drowsiness, ataxia, mg/day mental confusion); GI effects (cramps, diarrhea); Endocrine and metabolic effects (gynecomastia 9%, hirutism, menstrual irregularities, impotence, mild acidosis, hyponatremia, hyperkalemia 1-2%) Precautions: Avoid in patients with hyperkalemia or renal impairment; Use with caution in patients at increased risk of developing hyperkalemia (eg DM, elderly, patients with renal or hepatic impairment); Serum electrolytes and BUN should be measured periodically Loop diuretics Furosemide 20-80 mg/day once daily usually in the morning May increase up to 100 mg/day Initial dose: 2.5-5 mg PO once daily. Max dose: 5 mg/day Extended release (twicedaily): 90-180 mg PO bid. Max dose: 360 mg/day Adverse Reactions***: Endocrine and metabolic effects (hyponatremia, hypokalemia and hypochloremic alkalosis esp after large doses or prolonged administration, hyperglycemia, glycosuria, hyperuricemia and may precipitate gout); Signs of electrolyte imbalances: headache, muscle cramps, dry mouth, hypotension, thirst, weakness, drowsiness, etc; Less common misc effects (blurred vision, dizziness, orthostatic hypotension, skin rashes, hypersensitivity reactions) Precautions: Avoid in patients with anuria or in renal insufficiency caused by nephrotoxic or hepatotoxic drugs or caused by hepatic coma; Use with caution in patients with existing or in those at risk of fluid and electrolyte imbalances, in patients with prostatic hyperplasia or impairment of micturition, patients with hepatic cirrhosis are more likely to develop hypokalemia and patients with severe HF are more likely to suffer hyponatremia, use with caution patients susceptible to gout;

Torasemide

43

Monitor patients for signs of fluid or electrolyte balance Thiazides and Related Diuretics Chlorthiazide 250-500 mg/day PO once daily or divided bid Max dose: 1 g/day Chlorthalidone 12.5-25 mg PO once daily May increase to 50 mg/day PO Hydrochlorthiazide 12.5-50 mg PO once daily Indapamide Regular release: 1.25-2.5 mg PO once daily Extended release: 1.5 mg PO once daily. Adverse Reactions (1-10%): Endocrine and metabolic effects (hyperuricemia and may precipitate gout in some patients, hypochloremic alkalosis, hyponatremia, hypokalemia, hyponatremia, hypomagnesemia, hyperglycemia and glucosuria in DM or other suspectible patients); GL effects (GI irritation, N/V, constipation, anorexia, diarrhea); CNS effects (headache, dizziness); misc effects (photosensitivity reactions, postural hypotension, impotence, hypersensitivity reactions); Signs of electrolyte imbalances: headache, muscle cramps, dry mouth, hypotension, thirst, weakness, drowsiness, etc Precautions:: Avoid in patients with severe hepatic inpairement since encephalopathy may be precipitated; in patients with severe impairment, anuria or preexisting hypercalcemia; Use with caution in patients with existing or in those at risk of fluid and electrolyte imbalances (eg elderly), patients with hepatic cirrhosis are more likely to develop hypokalemia and patients with severe HF are more likely to suffer hyponatremia, use with caution with renal impairment, in patients susceptible to gout and in DM patients; Monitor patients for signs of fluid or electrolyte imbalance Beta-blockers Dosage Remarks 50-100 mg PO once daily Adverse Reactions (1-10%): Max dose: 100 mg/day CNS effects (fatigue, depression, dizziness, confusion, sleep disturbances); CV effects (HF, Initial dose: 5 mg PO once heart block, coldness of extremities, male daily. Maintenance dose: 5-10 mg PO impotence); Resp effect (bronchspasm in susceptible patients and drug with beta1 selectie once daily should be used with caution in these patients); Max dose: 20 mg/day GI effects (N/V, diarrhea, constipation); 100 mg PO bid Metabolic effects (can produce hyper-or May increase dose after 2 wk to hypoglycemia, changes in serum cholesterol and 200-400 mg/day PO Max dose: triglycerides) 2400 mg/day Precautions: Regular release: Initial dose: 50-100 mg PO once Contraindicated in severe bradycardia, preexisting high degree of AV block, sick sinus syndrome and daily-bid. May increase to 100severe, unstable LV failure; 400 mg/day Max dose: 400 mg/day Use with caution in patients with bronchospasm, Extended release: astma or obstructive airway diseases. Use with 25-100 mg PO once daily caution in 1st degree block, depression, patients with Regular release: PD, and patients on insulin; Initial dose: 40-80 mg PO bid. May increase to 160-320 mg/day Beta blockers may mask the symptoms of PO divided bid-qid hyperthyroidism and hypoglycemia and may Max dose: 640 mg/day aggravate psoriasis; Extended release:

Drug Atenolol Bisoprolol

Labetolol

Metoprolol

Propranolol

44

Drug Doxazosin

Prazosin

Initial dose: 80 mg PO once Patients on long-term treatment should not daily. May increase to 120-160 discontinue abruptly; discontinue gradually over 1-2 mg PO once daily week Max dose: 640 mg/day Alpha-Blockers Dosage Remarks Initial dose: 1 mg PO once Adverse Reactions (1-10%): daily. May increase dose at 1- Postural hypotension which may be seere after 1st dose 2 wk intervals to 2 mg/day PO and can produse syncope which may be preceded by and then to 4 mg PO once tachycardia; daily Max dose: 8-16 mg/day Effects which may diminish after continued therapy: CNS effects (dizziness, headache, lack of energy); GI Initial dose: 0.5 mg PO bidtid. Increase dose gradually effects (nausea); CV effects (palpitations); every 3-7 days to: Maintenance dose: 3-15 Other CV effects (edema, chest pain, dyspnea); GI mg/day PO in divided doses effects (constipation, diarrhea, omitting, dry mouth); Max dose: 20 mg/day CNS effects (depression, nervousness, sleep disturbances, vertigo, hallucinations, paresthesia); urinary effects (urinary frequency, incontinence); Ophtalmic effect (blurred vision); Hepatic effects (abnormal LFTs, pancreatitis); Misc effects (arthralgia, skin rashes, impotence, priapism) Precautions:: Start treatment with low dose, preferably at night to avoid postural hypotension; Not recommended for HF treatment in patients with mechanical obstruction; Use with caution in the elderly, in patients with renal or hepatic failure or in patients with angina Others Remarks Adverse Reactions: CNS effects (drowsiness 35%, dizziness 16%, headache, depression 1%, anxiety 3%, fatigue 10%, sleep disturbances, impotence 3%); GI effects (dry mouth 40%, constipation 10%, nausea 5%, anorexia 1%); GU effects 1% (urinary retention, incontinence); CV effects (orthostatic hypotension 3%, fluid retention); Less common misc effects: Bradycardia, ECG disturbances, HF, hallucinations, etc Precautions: Use with caution in patients with cerebrovascular disease, renal impairment, ischemic heart disease, MI, occlusive peripheral vascular disorders or in those with history of depression; Patients on long-term treatment should not discontinue abruptly Adverse Reactions***: Most adverse effects are transient or reversible CNS effects (drowsiness, dizziness, lightheadedness, headache, weakness, fatigue, impotence, disturbed sleep, paraesthesia, depression etg); CV effects (orthostatic hypotension, fluid retention, edema, and

Drug Dosage Centrally-Acting Agents Clonidine Initial dose: 50-100 mg PO tid or 75-150 mcg PO bid. Maintenance dose: 300-1200 mcg/day PO in divided doses Max dose: 2.4 mg/day

Methyldopa

Initial dose: 250 mg PO bidtid. May increase or decrease dose not more frequently than 2 day intervals until desired effect is achieved Max dose: 3 g/day

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may aggravate angina); GI effects (N/V, diarrhea, constipation, rare pancreatitis, colitis or sore tongue); Hematologic effects (thrombocytopenia, leucopenia, hemolytic anemia and granulocytopenia hae occurred); hypersensitivity reactions Precautions: Avoid in patients with liver disease or depression; Use with caution in patients with impaired renal or hepatic function, history of hemolytic anemia, liver disease or depression and patients with parkinsonism; CBC should be measured periodically during the 1 st 612 week of therapy or if patient develops unexplained fever Direct Vasodilators Hydralazine Initial dose: 40-50 mg/day PO in divided into doses. May increase by 10-25 mg/dose every 2-5 days Max dose: 200 mg/day Adverse Reactions***: Typically subside with continued therapy: CNS effects (tachycardia, palpitations, angina, flushing); GI effects (anorexia, N/V, diarrhea); Misc effects (dizziness, nasal congestion); Other C effects (postural hypotension, fluid retention, edema); other misc effects (wt gain, tremor, conjunctivits, muscle cramps, lachrymation); Less common: Pyridoxine depletion resulting in peripheral neuropathy; hematologic effects (blood dyscrasia, hemolytic anemia); Hepatic effects (hepatotoxicity); Genitourinary effects (difficulty in urinating, glomerulonephritis); CNS effects (depression, anxiety); GI effects (paralytic ileus, constipation); hypersensitivity reactions; can also cause a condition resembling SLE when prolonged high doses are used and is more common in women and in patients with renal impairment Precautions: Avoid in patients with severe tachycardia, HF with high cardiac output, dissecting aortic aneurysm, cor pulmonale or myocardial insufficiency due to mechanical obstruction, idiopathic SLE and related disorders; Use with caution in patients with ischemic heart disease, recent MI, HF, impaired renal or hepatic function; CBC, antinuclear antibody determinations and urinalysis should be done periodically during long-term therapy Indicated only for severe HTN that has not responded to other antihypertensive therapy; Minoxidil is usually given in combination with a betablocker to diminish cardiac-accelerating effects and with diuretics to control edema. Adverse Reactions (1-10%): CV effects (reflex tachycardia, fluid retention, edema, deterioration of existing HF, ECG changes, pericarditis with effusion, pericarditis, angina); hypertrichosis Less common: CNS effects (headache); endocrine and metabolic effects (gynecomastia, polymenorrhea); skin

Minoxidil

Initial dose: 2.5-5 mg/day PO once daily or in divided doses. May increase dose gradually at 3-day intervals to 40-50 mg/day PO once daily or in divided doses Max dose: 100 mg/day

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rashes, Stevens-Johnson syndrome, thrombocytopenia); Precautions: Avoid in patients with pheochromocytoma Use with caution in patients with recent MI, pulmonary HTN, angina, CHF and significant renal impairment *** Frequency not defined

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Annex 4. Pharmacotherapy of Hypertensive emergency Treatment goal Depending on the clinical situation (see details C7.15): • Reduction of mean arterial BP by 25% or reduction of DBP to around 100-110 mmHg over 3-12 hr but not lower than 160/90 mmHg Preferred antihypertensive Agents for select some Hypertensive Emergencies Acute Aortic Dissection • Preferred treatments: Labetalol, Nicardipin, Nitroprusside (with beta-blocker) or Esmolol • IV antihypertensive treatment should be started as soon as acute aortic dissection is suspected • Avoid beta-blockers in the presence of aortic valvular regurgitation or suspected cardiac tamponade • SBP should be reduced to <120 mmHg within 20 min Acute Coronary Syndrome • Preferred treatments: Labetalol, Esmolol • Give treatment if SBP>160 mmHg and/or DBP>100 mmHg • Thrombolytics should not be given if BP is >185/100 mmHg Acute Heart Failure • Preferred treatments: GTN, Enalaprilat • Use vasodilators+diuretics for SBP≥140 mmHg; GTN, given IV or sublingually, is preferred Acute renal Failure • Preferred treatments: Nicardipine Acute Ischemic Stroke • Preferred treatments: Labetolol or Nicardipine • Do not give antihypertensive agents unless SBP>220 mmHg or DBP>120 mmHg; however, if patient is receiving fibrinolytic therapy, the goal BP is <185/110 mmHg • After fibrinolytic therapy, BP should be maintained <180/105 mmHg Subarachnoid Hemorrhage • Preferred treatments: Labetolol, Nicardipine, or Esmolol • SBP should be maintained <160 mmHg until aneurism is treated or cerebral vasospasm occurs Pheochromocytoma • Preferred treatments: Nitroprusside • Alpha-blockers are preferred agents - Avoid selective beta-blockers which can worsen HTN Severe Preeclampsia or Eclampsia

• • • •

Preferred treatments: Nifedipine, Labetalol, Hydralazine Avoid Nitroprusside, ACE inhibitors and Esmolol BP should be <160/110 mmHg in prepartum and intrapartum periods; <150/100 mmHg if platelet count falls to below 100 000 cells/mm3 Magnesium sulfate should be given to prevent seizures

Perioperative HTN • Preferred treatments: Nitroprusside, or Esmolol • Perioperative beta-blockers are first choice in patients who will undergo vascular procedures or in those with cardiac complications Table 10. Some antihypertensive drugs in hypertensive emergency: dosage, adverse reactions, precautions
Drug Beta-blockers Esmolol ADRENERGIC INHIBITORS Dosage Intra-op tachycardia and HTN (immediate control) Loading dose: 80 mg IV over 15-30 sec, followed by 150 mcg/kg/min IV infusion, may increase to 300 mcg/kg/min, if needed SVT and post-op tachycardia and HTN (gradual control) Loading dose: 500 mcg/kg IV over 1 min Followed by: Maintenance infusion: 50 mcg/kg/min IV over 4 min, if necessary, repeat the loading dose and may increase maintenance infusion rate by 50 mcg /kg/min Max dose: 300 mcg/kg/min Remarks

Adverse reactions: CV effects (hypotension that usually resolves within 30 min after decrease in dose or infusion is stopped, peripheral ischemia); CNS effects (dizziness, somnolence, confusion, headache); GI effects (N/V); Local effects (pain on injection); Misc effect (diaphoresis) Less common misc effects: HF, bronchospasm, severe bradycardia/asystole, skin necrosis from extravasation Precautions: Monitor BP during therapy Avoid in patients with sinus bradycardia, heart block>1st degree, cardiogenic shock, bronchial asthma, uncompensated cardiac failure, hypotension Use with caution in compensated HF and monitor for worsening of the condition, also use with caution in patients with peripheral vascular disease (PVD) or DM, Esmolol can mask signs of thyrotoxicosis Adverse reactions: CV effects (orthostatic hypotension, moderate hypotension, may cause or exacerbate CHF, arrhythmias have occurred; rarely heart block); CNS effects (drowsiness, dizziness, mild paresthesia); GI effects (N/V); Rare hepatic effects (elevated LFT, jaundice, hepatitis); Precautions: Monitor BP during therapy Avoid in patients with heart block>1st degree, cardiogenic shock, bronchial asthma, severe bradycardia, hypotension, overt cardiac failure

Labetolol

Loading dose: 50 mg IV for at least 1 min. May repeat at 5 min intervals until satisfactory response occurs Max dose: 200 mg/day or IV infusion: Starting at 2 mg/min IV titrated to desired response Max dose: 200 mg/day

Drug Dosage Anti-Anginal drug Nitroglycerin Initial dose: 5-25 mcg/min IV infusion Increase by 5 mcg/min every 3-5 min until some response is noted If there is still no response at 20 mcg/min: May increase at increments of 10 mcg /min and later if required, 20 mcg/min increments can be used Usual dose: 10-200 mcg/min IV infusion Once a partial BP response is obtained, increases in dose increments should be decreased and time between dose increases should be longer Max dose: 200 mcg/min

Use with caution in compensated HF and monitor for worsening of the condition, in patients with PVD or DM, use with caution in patients with pheochromocytoma and in patients with impaired hepatic function. VASODILATORS Remarks Adverse reactions: IV administration (esp if given too rapidly); May cause CV effects (sevete hypotension, retrosternal discomfort, palpitations); CNS effects (apprehension, restlessness, muscle twitching, syncope); GI effects (N/V); Local effects (pain on injection); Misc effect (diaphoresis); prolonged administration has been associated with methemoglobinemia; Nitrate tolerance usually develops with long-term use and dosing with adequate nitrate nitrate-free interval is recommended. Precautions: Avoid in patients with severe hypotension, hypovolemia, marked anemia, HF due to obstruction or raised intracranial pressure due to head trauma or hemorrhage; Use with caution in patients with severe renal or hepatic dysfunction, hypothyroidism, malnutrition or hypothermia; Close monitoring of HR and BP is necessary during IV infusion; Do not administer to patients who have taken phosphodiesterase inhibitors within the past 24 hr; The plastic used for administration may adsorb GTN and dosing may need to be adjusted for this.

Calcium antagonist Nicardipine Initial IV infusion (diluted to 0.1 mg/ml): 5 mg/hr IV titrated to desired effect by 2.5 mg/hr IV every 5 min Max dose: 15 mg/hr and reduced to 3 mg/hr

Adverse reactions: CV effects (hypotension, depression of cardiac function, worsening HF, edema, flushing, tachycardia); GI effects (N/V, constipation); CNS effects (headache, dizziness) Precautions: Contraindicated in patients with overt decompensated HF; Use with caution in patients with HF, hepatic impairment or reduced hepatic blood flow, patients with portal hypertension, patients with impaired renal function

Direct Vasodilators Hydralazine 5-10 mg slow IV May repeat after 20-30 min, if needed or Initial dose: 200-300 mcg/min continuous IV infusion Maintenance dose: 50-150 mcg/min

Adverse reactions: CV effects (tachycardia, palpitations, angina, flushing, postural hypotension, fluid retention, edema); GI effects (anorexia, N/V, diarrhea); Misc effect (dizziness, nasal congestion, tremor, muscle cramps, lacrimation);

Less common: Pyridoxine depletion with resulting peripheral neuropathy; hematologic effects (blood dyscrasia, hemolytic anemia); Hepatic effects (hepatotoxicity); Genitourinary effects (difficulty in urinating, glomerulonephritis); CNS effects (depression, anxiety); GI effects (paralytic ileus, constipation); hypersensitivity reactions Special instructions: Avoid in patients with severe tachycardia, HF with high cardiac output, dissecting aortic aneurysm, cor pulmonale or myocardial insufficiency due to mechanical obstruction, idiopathic SLE and related disorders; Use with caution in patients with ischemic heart disease, recent MI, HF, impaired renal or hepatic function Adverse reactions: Adverse effects are typically either due to hypotensive effects or from excessive cyanide accumulation; These effects may be reduced with a decrease in infusion rate: GI effects (N/V, abdominal pain); CNS effects (apprehension, headache, dizziness, restlessness); CV effects (retrosternal discomfort, palpitations); Misc effect (perspiration, muscle twitching); Excessive cyanide may result in: Tachycardia, sweating, hyperventilation, arrhythmias and metabolic acidosis; methemoglobinemia may also occur; Thiocyanate may cause: Tinnitus, miosis, hyperreflexia, confusion, hallucination and convulsions have been reported Precautions: BP and acid base balance should be monitored closely; Avoid extravasation; Avoid in compensatory hypertension; Use with caution or not at all in hepatic impairment and in patients with low plasma cobalamin conc or Leber’s optic atrophy; Use with caution in patients with impaired cerebrovascular circulation, patients with hypothyroidism; If continued for >72 hr, plasma concentrations of cyanide should be monitored; When discontinuing, reduce dose slowly

Na nitroprusside

Initial dose: 0.3 mcg/kg/min IV infusion. Gradually titrate up every few min until BP control is achieved Usual dose range: 0.5-6 mcg/kg/min IV Max dose: 8-10 mcg/kg/min

Annex 5. Pharmacotherapy of Hypertensive urgency • • Reduced by 25% within 24 hr but not lower than 160/90 mmHg Reduction of BP in these patients may be achieved with oral medications and without intensive monitoring

Preferred medications for Hypertensive Urgency Please see annex 3 on Pharmacotreatment for full dosage guideline of the following oral agents: Captopril: • Oncet of action is within 15-30 min; sublingually, effective in 10-20 min • Co-administration of a loop diuretic enhances the effect of this drug • Avoid in patients with high-grade bilateral renal artery stenosis Clonidine • Oncet of action is within 30-60 min • Avoid in patients requiring mental status monitoring Labetalol • Oncet of action is within 1-2 hr • Avoid in patients with asthma as this may worsen bronchospasm • Use with caution in patients with symptomatic bradycardia, congestive HF and heart block Nifedepine (expended-release) • Oncet of action is within 20-50 min • Avoid in patients with severe ventricular dysfunction Prazosin • Oncet of action is within 2-4 hr • May provide added benefit in patients with benign prostatic hyperplasia • May cause postural hypotension and syncope with first dose Note: Annex 3 and 3.1.1, 3.1.2 were written according to “Pharmacotherapy Guide to Cardiovascular and Metabolic Disorders” MIMS special edition for Word Congress of Cardiology Scientific Sessions 2010, which was adjusted by authors. The frequency of adverse effects (%) were written by “drug information handbook 11th edition” 2003.

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