Memoire Online - An assessment of adherence to antihypertensive treatment and associated factors in patients at the Yaounde general hospital

· Adherence (to a medication regimen): The World Health Organization (WHO) defines adherence as ``the extent to which a person's behaviour taking medication, following a diet, and/or executing life style changes corresponds with agreed recommendations from a health care provider''[23].

· Disability-Adjusted Life Year (DALY):Measure of years of life lost from deaths which occur before some theoretically achievable age (e.g., international reports use 80 years for men and 82.5 years for women) and attributing this loss to death rates. DALYs for a disease or health condition are calculated as the sum of the Years of Life Lost due to premature mortality in the population and the Years Lost due to Disability for people living with the health condition or its consequences[24].

· Compliance: Term suggesting that a patient is passively following the doctor's orders and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the physician[10].

· Hypertension:Systolic blood pressure equal to or above 140 mm Hg and/or diastolic blood pressure equal to or above 90 mm Hg[1].

In 2010, the three leading risk factors for global disease burden were high bloodpressure (7.0% of global DALYs), tobacco smoking includingsecond-hand smoke (6.3%), and alcohol use (5.5%)[2]. Hypertension alone accounts for 9.4 million deaths worldwide[1].Dietaryrisk factors and physical inactivity collectively accounted for 10.0% of globalDALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high insodium[2].Hypertension is responsible for at least 45% of deaths due toheart disease, and 51% of deaths due tostroke[1].Figure 1 shows the total stroke mortality rate in the world.Globally, the overall prevalence of raised blood pressure in adults aged 25 and over was around 40% in 2008[4].Figure 2 shows the global age-standardized prevalence of raised blood pressure in adults aged 25+ years.The proportion of the world's population with high blood pressure, or uncontrolled hypertension, fell modestly between 1980 and 2008. However, because of population growth and ageing, the number of people with hypertension rose from 600 million in 1980 to nearly 1 billion in 2008[4]. Still in 2008, the prevalence of raised blood pressure was highest in the African continent, where it was 46% for both sexes combined[4].

Figure 2: Age-standardized prevalence of raised blood pressure in adults aged 25+ years[4]

The lowest prevalence of raised blood pressure was in the WHO Region of theAmericas, with 35% for both sexes[4]. In all WHO regions, men have slightly higher prevalence of raised blood pressure than women, but this difference was only statistically significant in the American and European continents[4].Across the income groups of countries, the prevalence of raised blood pressure was consistently high in low and lower-middle income countries while upper-middle-income countries all had rates of around 40%for both sexes. The prevalence in high-income countries was lower, at 35% for both sexes[4].Not only is hypertension more prevalent in low- and middle-income countries, there are also more people affected because more people live in those countries than in high-income countries[1,5].Further, because of weak health systems, the number of people with hypertension who are undiagnosed, untreated and uncontrolled are also higher in low- and middle-income countries compared to high-income countries. The increasing prevalence of hypertension is attributed to population growth, ageing and behavioural risk factors[1,11].Figure 3 shows the 2015 distribution of the world's population by age and sex.

The adverse health consequences of hypertensionare compounded because many peopleaffected also have other health risk factorsthat increase the odds of heart attack,stroke and kidney failure. These risk factorsinclude tobacco use, obesity, high cholesteroland diabetesmellitus[1].In 2008, 1 billion people weresmokers and the global prevalence of obesity has nearly doubled since 1980[1]. The global prevalenceof high cholesterol was 39% and prevalenceof diabetes was 10% in adults over 25years[4]. Tobacco use, unhealthy diet, harmfuluse of alcohol and physical inactivity are alsothe main behavioural risk factors of all majornoncommunicable diseases, i.e. cardiovasculardisease, diabetes, chronic respiratory disease and cancer.If appropriate action[1] is not taken, deaths dueto cardiovascular disease are projected to rise further [25].Figure 4 shows the projected global deaths for selected causes for the 2004-2030 timeframe.

Between 1994 and 2003, blood pressure levels havedeteriorated over time in rural and urban Cameroonian menand women with the prevalence of hypertension increasing by twofold to fivefold[26].This has beenattributed to the rapid urbanization associated with thehigh rates of obesity, physical inactivity, diabetes,increased salt consumption, and tobacco use[27].In 2011, Dzudie A et al. reported a prevalence rate for hypertension of up to 47.5% in self-selectedurban dwellers in Cameroon[28].In a more recent nationwide study, Kingue et al. found a prevalence rate of 29.7% in urban areas of Cameroon;indicating asteadyrise in the trend of hypertension toward a super epidemic in 20 years to come[8].

In the majority of cases, high BP is termedprimary or essentialhypertensionand isprobably multifactorial in origin, with genotype, as well asexternal factors such as diet and body-weight, playing arole. Hypertension may also be associated with surgery[29]or pregnancy[30] and is prevalent in diabetics[31]. In a limitednumber of cases hypertension is secondaryto some othercondition, such as renal disease, Cushing's syndrome,phaeochromocytoma, or to the adverse effects of drugs suchas oestrogens, and such causes may be suspected particularlyin resistant or malignant hypertension[32].

Although it has frequently been indicated that the causes ofessential hypertension are unknown, this is only partially true because little information is available on genetic variationsor genes that are over-expressed or under-expressed as well asthe intermediary phenotypes that they regulate to cause hypertension.Variation in BP that is genetically determined is called «inherited BP,»although the genes which cause BP to vary are not known; it is known from familystudies that inherited BP can range from low normal BP tosevere hypertension. Factors that increase BP, (such as obesity, insulin resistance, high alcohol intake, high salt intake (in salt-sensitive patients), ageing and perhapssedentary lifestyle, stress, low potassium intake, and low calcium intake) are called «hypertensinogenic factors.» Some of these factors have inherited,behavioural, and environmental components. Inherited BPcould be considered core BP, whereas hypertensinogenicfactors cause BP to increase above the range of inherited BPs. Figure 5 illustrates the additive effect of hypertensinogenic factors on hereditary systolic and diastolic BP. It shows that patients with normalor high normal inherited BP become hypertensive stage 1 whenBP is increased by a hypertensinogenic factor. In patients withinherited hypertension in stages 1 to 3, their hypertensionbecomes more severe when hypertensinogenic factors areadded.

Figure 5: Additive effect of hypertensinogenic factors (hatched areas) on hereditary systolic (white areas) and diastolic blood pressure (black areas)[33]

Hypertension related to a specific aetiology is termed secondaryhypertension,markedly differing from essential hypertension, ofwhich the aetiology cannot be clearly identified. Secondary hypertension is often resistant hypertension,for which a target blood pressure is difficult to achieve bystandard treatment. However, BP can be effectivelyreduced by identifying its aetiology and treating the condition.

Frequent etiological factors for secondary hypertension includerenal parenchymal hypertension, primary aldosteronism (PA), renovascularhypertension and sleep apnea syndrome. As other etiological factors for secondary hypertension, the following conditions have been reported in endocrine hypertension: pheochromocytomaand Cushing's syndrome which are related to an excessiveproduction of catecholamines and cortisol, respectively. Hypo-/hyperthyroidism, hyperparathyroidism and acromegaly are alsoetiologically involved in hypertension. In vascular hypertension, angiitissyndrome, such as aortitis syndrome, polyarteritis nodosa (PN)and systemic scleroderma, aortic coarctation and aortic insufficiencyhave been reported. Compression of the rostral ventrolateral medullaby brainstem blood vessels causes hypertension through hyperactivityof the sympathetic nerves. Furthermore, hypertension is also observedin patients with brain tumours or cerebrovascular disease. In addition,drug-induced hypertension has been reported (by drugs such as NSAIDs, oral contraceptive, liquorice, sympathomimetics, glucocorticoids, cyclosporine, tacrolimus, erythropoietin, tricyclic/tetracyclic antidepressants, monoamine oxygenase inhibitors, Anti-VEGF antibody preparations).

It has been recognized that secondary hypertension accounts for about 10% of hypertensive patients. According to several studies, PA accounts for approximately 5-10% of hypertensive patients, and it is the most frequent in endocrine hypertension.

Generally, the presence of severe or resistant hypertension, juvenile hypertension and the rapid onset of hypertension suggest the possibility of secondary hypertension. In such hypertensive patients, a close inquiry on medical history, medical examination and adequate examinations must be performed, considering the possibility of secondary hypertension. The possibility of secondary hypertension should be considered in the diagnosis and treatment of all hypertensive patients. It is important to conduct appropriate examinations without overlooking findings of secondary hypertension.

There is a common misconceptionthat people with hypertensionalwaysexperience symptoms, but the reality isthat mosthypertensive people have nosymptoms at all. The condition is a silent killer. Therefore it is important for everybody to know their blood pressure reading.

Sometimes hypertensioncauses symptoms such as headache, shortnessof breath, dizziness, chest pain, palpitationsof the heart and nose bleeds. It canbe dangerous to ignore such symptoms,but neither can they be relied upon to signifyhypertension.

Left untreated, high BP can have damaging effects. Theprimary way it causes harm is by increasing the workload of the heart and arteries,which causes damage to the circulatory system over time. Also, high BP can cause the heart to enlarge because it has to work harderto supply the blood the body needs. It is also a contributing factor toatherosclerosis, in which the walls of the arteries become stiff and brittle as fattydeposits build up inside them. Other conditions caused by hypertension include coronary heart disease, heart failure, heartattack, stroke, kidney damage, angina (chest pain related to heart disease), peripheralartery disease, and other serious conditions (aneurysms, cognitive changes, eye damage). In fact, people with BP over 140/90 are far more likely to havethese dangerous conditions thus hypertension is a serious warning sign that significant lifestyle changes have to be adopted.

Current options for BP measuring devices include mercury sphygmomanometers, aneroid manometers, semiautomatic devices and fully automatic electronic devices. Validated and affordable electronic BP measuring devices, that have the option to select manual readings, appear to be the preferred option for lowresource settings according to WHO[39].Semi-automatic devices enable manual readingsto be taken when batteries run down,a common problem in resource-constrainedsettings. Given that mercury is toxic,it is recommended that mercury devices bephased out in favour of electronic devices[39].Aneroid devices should be considered only if calibrated at regular intervals (every 6 months for example) and users should be trained and assessed in measuring BP using such devices[1,39].

Diagnostic procedures aim at: 1) establishing blood pressurelevels; 2) identifying secondary causes of hypertension;3) evaluating the overall cardiovascular risk bysearching for other risk factors, target organ damageand concomitant diseases or accompanying clinicalconditions.The diagnostic procedures comprise[40]:

Some ofthese should be considered part of the routine approachin all subjects with high BP; some arerecommended and may be used extensively in thedeveloped health systems; some are indicatedonly when suggested by the basic examination or theclinical course of the patient[40].

Blood pressure is characterized by large spontaneousvariations both during the day and between days, monthsand seasons.Therefore the diagnosis of hypertension should be based on multiple BP measurements, taken on separate occasions over a period of time. If BP is only slightly elevated, repeated measurements should be obtained over a period of several months to define the patients ``usual'' BP as accurately as possible. On the other hand, if the patient has a more marked BP elevation, evidence of hypertension-related organ damage or a high or very high cardiovascular risk profile, repeated measurements should be obtained over shorter periods of time (weeks or days). In general, the diagnosis of hypertension should be based on at least 2 blood pressure measurements per visit and at least 2 to 3 visits, although in particularly severe cases the diagnosis can be based on measurements taken at a single visit. Blood pressures can be measured by the doctor or the nurse in the office or in the clinic (office or clinic blood pressure), by the patient or a relative at home, or automatically over 24 h. Based on specific recommendations of the European Society of Hypertension[40], these procedures can be summarized as follows:

BP can be measured by a mercury sphygmomanometer the various parts of which (rubber tubes, valves, quantity of mercury, etc.) should be kept in proper working order. Other non-invasive devices (auscultatory or oscillometric semiautomatic devices) can also be used and will indeed become increasingly important because of the progressive banning of the medical use of mercury[39]. However, these devices should be validated according to standardized protocols[43], and their accuracy shouldbe checked periodically by comparison with mercurysphygmomanometric values. Table I shows the instructions for correctoffice BP measurements.

Several devices (mostly oscillometric) are available forautomatic BP measurements in patients allowed to conduct a near normal life. They provide information on 24-hour average BP as well as on mean values over more restricted periods such as the day, night or morning. This information should not be regarded as a substitute for information derived from conventional BP measurements. Studies have shown that ambulatory BP : 1) correlates with hypertension-related organ damage and it changes by treatment more closely than does office blood pressure, 2) has a relationship with cardiovascular events that is steeper than that observed for clinic BP, with a prediction of cardiovascular risk greater than the prediction provided by office BP values in populations of untreated and treated hypertensives[44-46] and 3) measures more accurately than clinic BP the extent of BP reduction induced by treatment, because of a higher reproducibility over time and an absent or negligible ``white coat''[47] and placebo effect[48].

When measuring BP, care should be taken to:
1	Allow the patients to sit for several minutes in aquiet room before beginning BP measurements
2	Take at least two measurements spaced by1-2 minutes, and additional measurements if thefirst two are quite different
3	Use a standard bladder (12-13 cm long and 35 cmwide) but have a larger and a smaller bladderavailable for fat and thin arms, respectively. Usethe smaller bladder in children
4	Have the cuff at the heart level, whatever theposition of the patient
5	Use phase I and V (disappearance) Korotkoffsounds to identify systolic and diastolic BP,respectively
6	Measure BP in both arms at first visit to detectpossible differences due to peripheral vasculardisease. In this instance, take the higher valueas the reference one
7	Measure BP 1 and 5min after assumption ofthe standing position in elderly subjects, diabeticpatients, and in other conditions in which posturalhypotension may be frequent or suspected
8	Measure heart rate by pulse palpation (at least30 sec) after the second measurement in the sittingposition

Although some of the aboveadvantages can be obtained by increasing the number ofoffice BP measurements, 24-hourambulatory BP monitoring may be useful atthe time of diagnosis and at varying intervals duringtreatment[40]. Efforts should be made to extend ambulatory BP monitoring to 24 hours in order to obtaininformation on both daytimeand night-timeBP profiles, day-night BP difference, morning BP rise and BP variability.Daytimeand night-time blood pressure values and changes bytreatment are related to each other, but the prognosticvalue of night-time blood pressure has been found tobe superior to that of daytime blood pressure[45,49]. Evidence is also available thatcardiac and cerebrovascular events have a peak prevalencein the morning,possibly in relation to thesharp blood pressure rise occurring at awaking fromsleep, as well as to an increased plateletaggregability, a reduced fibrinolytic activity and a sympatheticactivation[40,41].

· Use cuffs of appropriate size and compare the initial values with those from a sphygmomanometer to checkthat the differences are not greater than #177; 5mmHg

· Set the automatic readings at no more than 30 min intervals to obtain an adequate number of values and have most hours represented if some readings arerejected because of artefact.

· Automatic deflation of the equipment should be at arate of no more than 2mmHg/s.

· Instruct the patients to engage in normal activities but to refrain from strenuous exercise, and to keep the armextended 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 nightsleep.

· Obtain another ambulatory BP if the first examination has less than 70% of the expected number of valid values because of frequent artefacts. Ensure that the proportion of valid values is similar for the dayand night periods.

· Remember that ambulatory BP is usually several mmHg lower than office BP. Different population studies indicate that office values of 140/90mmHg correspond to average 24-h values of either 125-130mmHg systolic and 80mmHg diastolic, the corresponding average daytime and night-time values being 130-135/85 and 120/70mmHg. These values may be regarded as approximate threshold values for diagnosinghypertension by ambulatory BP. Table II indicates blood pressure thresholds for the definition of hypertension with different types of measurement

· Clinical judgement should be mainly based on average 24-hour, day and/or night values. Other information derived from ambulatory blood pressure (e.g. morning blood pressure surge and blood pressure standard deviations) is clinically promising, but the field shouldstill be regarded as in the research phase.

Table II: Blood pressure thresholds (mmHg) for definition of hypertension with different types of measurement[40]

	SBP	DBP
Office or clinic	140	90
24-hour	125-130	80
Day	130-135	85
Night	120	70
Home	130-135	85

A comprehensive family history should be obtained withparticular attention to hypertension, diabetes, dyslipidaemia,premature coronary heart disease, stroke, peripheralartery or renal disease.The clinical history should include: a) duration andprevious levels of high blood pressure; b) symptomssuggestive of secondary causes of hypertension andintake of drugs or substances that can raise blood pressure,such as liquorice, nasal drops, cocaine, amphetamines,oral contraceptives, steroids, nonsteroidal anti-inflammatory drugs, erythropoietin, and cyclosporin;c) lifestyle factors, such as dietary intake of fat (animalfat in particular), salt and alcohol, quantification of smokingand physical activity, weight gain since early adultlife; d) past history or current symptoms of coronarydisease, heart failure, cerebrovascular or peripheralvascular disease, renal disease, diabetes mellitus, gout,dyslipidaemia, asthma or any other significant illnesses,and drugs used to treat those conditions; e) previousantihypertensive therapy, its results and adverse effects;and f) personal, family and environmental factors thatmay influence blood pressure, cardiovascular risk, as wellas the course and outcome of therapy. Also, physiciansshould enquire after the patient and/or partner aboutsnoring which may be a sign of sleep apnoea syndromeand increased cardiovascular risk.

In addition to BP, heart rate should be carefullymeasured (pulse counting over at least 30s or longer ifarrhythmias are reported) because the repeated findingof values above normal may be an indication of greaterrisk, increased sympathetic or decreased parasympatheticactivity[51], or of heart failure. Physical examinationshould search for evidence of additional risk factors, forsigns suggesting secondary hypertension, and for evidenceof organdamage. Table III highlights the physical examination for secondary hypertension, organ damage and visceral obesity.Waist circumference should be measuredwith the patient standing and body weight and heightshould be obtained to calculate the body mass index.

Laboratory tests are directed at providing evidencefor additional risk factors, searching for secondaryhypertension and looking for the absence or presenceof organ damage. Investigations should progress from themost simple to the more complicated. The youngerthe patient, the higher the BP and the fasterthe development of hypertension, the more detailed thediagnostic work-up should be. However, the minimum laboratory investigations needed remain a matter ofdebate.

Table III: Physical examination for secondary hypertension, organ damage and visceral obesity[40]

Signs suggesting secondary hypertension and

organ damage

-Features of Cushing syndrome

-Skin stigmata of neurofibromatosis(phaeochromocytoma)

-Palpation of enlarged kidneys (polycystic kidney)

-Auscultation of abdominal murmurs (renovascular

hypertension)

-Auscultation of precordial or chest murmurs (aortic

coarctation or aortic disease)

-Diminished and delayed femoral pulses and

reduced femoral BP (aortic coarctation, aortic

disease)

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 oedema

-Peripheral arteries: absence, reduction, or asymmetryof pulses, cold extremities, ischaemic skinlesions

-Carotid arteries: systolic murmurs

Evidence of visceral obesity

-Body weight

-Increased waist circumference (standing position)

M: > 102 cm; F: > 88 cm

-Increased body mass index [body weight (kg)/

height (m)²]

-Overweight =25 kg/m²; Obesity =30 kg/m²

Where cardiovasculardiseases are the primary cause of morbidityand mortality, routine laboratory investigations shouldinclude: blood chemistry for fasting glucose, total cholesterol,LDL-cholesterol, HDL-cholesterol, triglycerides(fasting), urate, creatinine, potassium, haemoglobin andhaematocrit; urinalysis by a dipstick test that permits thedetection of microalbuminuria; urine microscopic examinationand an electrocardiogram[40].

Serum creatinine values should be used to estimatecreatinine clearance via the Cockroft Gault formula[52], easy procedures allowing identificationof patients with reduced glomerular filtration andincreased cardiovascular risk but in whom serum creatininevalues are still in the normal range. When fasting plasma glucose is =5.6 mmol/L(100 mg/dL), a post-load plasma glucose (glucose tolerancetest) is recommended[53]. The repeated findingof a fasting plasma glucose =7.0 mmol/L (126 mg/dL),and an abnormal glucose tolerance test are consideredindicative of diabetes mellitus[53].

Although highsensitivity C reactive protein (hsCRP)has been reportedto predict the incidence of cardiovascular events inseveral clinical settings[54], its added value in determiningtotal cardiovascular risk is uncertain,except in patients with metabolic syndrome in whomhsCRP values have been reported to be associatedwith a further marked increase in risk[55].Table IV gives a summary of the possible laboratory investigations.

Routine tests

_ Fasting plasma glucose

_ Serum total cholesterol

_ Serum LDL-cholesterol

_ Serum HDL-cholesterol

_ Fasting serum triglycerides

_ Serum potassium

_ Serum uric acid

_ Serum creatinine

_ Estimated creatinine clearance (Cockroft-Gaultformula) or glomerular filtration rate (MDRDformula)

_ Haemoglobin and haematocrit

_ Urinalysis (complemented by microalbuminuriavia dipstick test and microscopic examination)

_ Electrocardiogram

Recommended tests

_ Echocardiogram

_ Carotid ultrasound

_ Quantitative proteinuria (if dipstick test positive)

_ Ankle-brachial BP Index

_ Fundoscopy

_ Glucose tolerance test (if fasting plasma glucose>5.6 mmol/L (100 mg/dL)

_ Home and 24 h ambulatory BP monitoring

_ Pulse wave velocity measurement (where available)

Most of what follows is linked to primary or essential hypertension in adults.Hypertension may be discovered because of adverse vascularevents, especially in the eyes, brain, kidneys, orheart, but is more often asymptomatic and only discoveredon routine measurement of blood pressure[1,38]. Once diagnosed,decisions have to be made about the need for treatment.It is well-established that hypertension is a risk factorfor the development of stroke, heart failure, and renaldamage, and to a lesser extent ischaemic heart disease, anda reduction in blood pressure is generally beneficial, althoughmortality remains higher than in non-hypertensives[56].

Treatment of hypertensionmay involve both non-pharmacological and pharmacologicalinterventions to reduce blood pressure, as well asassessment and treatment of any other cardiovascular riskfactors; anyco-existing diseases should also be treated[3]. Differences inthe detail of guidelines on the management of hypertensionreflect varying judgements on the justification for interventionand the relative risks and benefits of differenttreatments.

Adopting a healthylifestyle is beneficial for all individuals, and any patientwith raised blood pressure should be encouraged to makelifestyle changes that will reduce their cardiovascular risk.Some of these changes may also reduce blood pressure,and in those who are at low overall risk no other treatment may be needed[57,58]. A trial of non-pharmacologicaltreatment is recommended in most patients beforestarting drug therapy, but should not unnecessarily delaytreatment, especially if the patient is at high risk[40,59-61]. Interventionsthat have been shown to reduce blood pressureinclude[1,3]:

Other interventions that have been tried, but with less evidenceof benefit, include[3]:

These lifestyle changes may also be promoted in the populationas a whole, or in individuals most likely to develophypertension, in strategies for the primary preventionofhigh blood pressure[1,62].

The main decisions in drugtreatment relate to the blood pressure at which therapyshould be begun, the target blood pressure, and the mostappropriate drug regimen to use[3]. Controversies exist in allthese areas.When to intervenewith antihypertensive drugs dependson factors including both the measured blood pressure andthe overall cardiovascular risk. Several guidelines have been published on the measures which entail pharmacological treatment[40,59,60]:

· Patients with grade 3 hypertension (180/110 mmHg or higher) should receive prompt drug treatment.

· In grade 2 hypertension, drug therapy is indicated if blood pressure remains at 160/100 mmHg or higher after a period of lifestyle modification, which varies depending on the overall level of risk; prompt drug therapy is advised for those at high or very high risk.

· For patients with grade 1 hypertension, the need for treatment is less well established; those with associated risk factors should be given drug therapy if lifestyle modification is inadequate, but some guidelines suggest that antihypertensives are not indicated in those at lower risk, or state that priority should be given to those at highest risk.

· Lower thresholds may apply in patients with renal disease or diabetes, but whether there is any benefit in treating uncomplicated patients with prehypertension is controversial.

Guidelines therefore generallyrecommend that treatment decisions should not be basedon age, although slower titration of drugs has beensuggested[40] in older patients since they may be more susceptibleto adverse effects. In the very old (those over 80years) the benefit of starting therapy is less clear[63,64], althougha study[65] in patients aged 80 years and over found a reduction in mortality. Those already being treated shouldcontinue[40,60].

Target blood pressuresare also controversial. The HOT study found that effective control to maintain the diastolic pressure at about 85 mmHg reduced therate of cardiovascular events, but lower pressures (ofaround 70 mmHg) did not provide any further benefit[66]. Target blood pressures of below140/90 mmHg[40,61], or below 140/85 mmHg[60] are now recommended;lower targets may be considered if toleratedby the patient, particularly in patients at high risk[40]. A lowertarget of below 130/80 mmHg has also been suggested for patients with established ischaemic heart disease[67], andlower targets may also be appropriate in diabetics and patients with renal disease.

Antihypertensive drugs comprise several classes of active pharmaceutical ingredients (APIs) with the therapeutic objective of controlling hypertension. Table V shows the different classes and subclasses of antihypertensives.

Table V: Classes and subclasses of antihypertensive medications with common examples[68]

CLASS	EXAMPLES
Targeting renin-angiotensin system
Angiotensin-converting enzyme inhibitors	Captopril, lisinopril, ramipril
Angiotensin receptor antagonists	Candesartan, losartan, valsartan
Direct renin antagonists	Aliskiren
Adrenoceptor antagonists
â-Blockers	Atenolol, metoprolol, propranolol
á-Blockers	Doxazosin, labetalol (also a â-blocker), phentolamine, phenoxybenzamine
Calcium channel blockers
Phenylalkylamine	Verapamil
Dihydropyridines	Amlodipine, nifedipine, nimodipine
Benzothiazepines	Diltiazem
Diuretics
Thiazides	Bendroflumethiazide, hydrochlorothiazide
Loop	Furosemide, bumetanide
Potassium sparing/ aldosterone antagonist	Amiloride, spironolactone
Vasodilators	Hydralazine, minoxidil
Centrally acting agents	Clonidine, methyldopa
Ganglion block	Trimetaphan

The classes of antihypertensive drugs differ in their chemical structures thence their varying functions. Antihypertensive drugs are frequently used in other unrelated conditions, for
example, â-blockers in thyrotoxicosis[69]and anxiety[70], or angiotensin-converting enzyme inhibitors (ACEIs) in heart failure.

The following subsections will focus on the applied pharmacology of agents used in the management of hypertension, some of their side-effects, as well as some drug interactions.

Three drug classes directly target points of the RAS pathway. They act to reduce production of the peptide hormone angiotensin II, or reduce its receptor binding. Figure 6 shows the different sites of action of drugs affecting the renin-angiotensin system.

Figure 6: Sites of action of drugs affecting the renin-angiotensin system.[68]

Angiotensin II has high affinity for AT1 G-protein-coupled receptors, activation of which causes increased arteriolar tone and systemic vascular resistance (SVR). It also causes sympathetic nervous system activation, increased pituitary secretion of antidiuretic and adrenocortocotrophic hormones, and increased adrenocortical secretion of aldosterone[71].By antagonizing the RAS pathway, SVR and arterial pressure are reduced. This effect is potentiated by a reduction in aldosterone secretion with resultant reduction in renal sodium and water retention. Negative feedback results in increased renin release by the juxtaglomerular apparatus.

The discovery that the venom of the Brazilian pit viper, which causes a massive decrease in arterial pressure, works by inhibition of angiotensin-converting enzyme (ACE) led to the development of synthetic, orally administered ACEIs. ACEIs are among the first-line treatment in non-black patients under 55 years of age with primary hypertension.They are also indicated in heart failure, post-myocardial infarction, diabetic nephropathy, and chronic kidney disease (although not acute kidney injury). The renaland cardiac protective effects of ACEIs are greater than those expected by arterial pressure control alone.

ACE is a metallopeptidase enzyme which occurs mainly within the pulmonary vasculature. The inhibition of ACE reduces the cleavage of the decapeptide hormone angiotensin I to the octapeptide angiotensin IIand reduces metabolism of the peptide bradykinin to inactivesubstances. The reduction in angiotensin II is responsible formost of the therapeutic effects.

Perindopril is available as oral tablets and when taken as the erbumine salt should be taken before food. Perindopril is also available as the arginine salt; 5 mg ofperindopril arginine is equivalent to about 4 mg ofperindopril erbumine.In the treatment of hypertension perindopril is givenin an initial dose of 4 mg of the erbumine or 5 mg of thearginine salt once daily.

Perindopril acts as a prodrug of the diacid perindoprilat, its active form. After oral doses perindopril is rapidly absorbed with a bioavailability of about 65 to 75%. It is extensively metabolised, mainly in the liver,to perindoprilat and inactive metabolites including glucuronides. The presence of food is reported to reducethe conversion of perindopril to perindoprilat. Peakplasma concentrations of perindoprilat are achieved 3to 4 hours after an oral dose of perindopril. Perindoprilat is about 10 to 20% bound to plasma proteins. Perindopril is excreted predominantly in the urine, asunchanged drug, as perindoprilat, and as other metabolites. The elimination ofperindoprilat is biphasic witha distribution half-life of about 5 hours and an elimination half-life of 25 to 30 hours or longer, the latter half-life probably representing strong binding to angiotensin-converting enzyme. The excretion of perindoprilat is decreased in renal impairment.

Perindopril, as well as other ACE inhibitors, inhibit ACE, which isinvolved in the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates the synthesis andsecretion of aldosterone and raises blood pressure via apotent direct vasoconstrictor effect.The pharmacological actions of ACEinhibitors are thought to be primarily due to the inhibition of the renin-angiotensin-aldosterone system, butsince they also effectively reduce blood pressure in patients with low renin concentrations other mechanismsare probably also involved.

The accumulation of bradykininhas some therapeutic advantage through vasodilatation, but isalso responsible for a dry cough in susceptible individuals.
ACEIs can also precipitate renal dysfunction by decreasing renal efferent arteriolar tone, thereby decreasing effective renal perfusion pressure, a particular risk in renal artery stenosis. Otherside-effects include hyperkalaemia due to reduced aldosterone secretion, agranulocytosis, skin rashes, and taste disturbance. A rare idiosyncratic reaction to ACEIs can cause angioedema with potential upper airway obstruction; this can occur several years after initiation of ACEI therapy. ACEIs are contraindicatedin pregnancy as they are associated with birth defects. ACEIs may interactwith drugs used perioperatively. For example, non-steroidal anti-inflammatory drugs can precipitaterenal dysfunction in combination with ACEIs. They can also reduce the efficacy of ACEIs by decreasing prostaglandin synthesis.Interactions with diuretics may cause hypovolaemia and hyponatraemia, while concurrent use of potassium supplements orpotassium-sparing diuretics may result in hyperkalaemia.Drugs which are renally excreted (e.g. digoxin and lithium) may accumulatein patients taking ACEIs.

ARAs are commonly used in patients who are intolerant to ACEIsas they are less likely to cause a dry cough.

Losartan is given orally as the potassium salt in tablet and sachet forms.In hypertension the usual dose of losartan potassiumis 50 mg once daily. The dose may be increased, if necessary, to 100 mg daily as a single dose or in two divided doses. An initial dose of 25 mg once daily should begiven to patients with intravascular fluid depletion, and is recommended in the UK in patients over 75 years ofage. Similar reductions may be appropriate in patients with hepatic or renal impairment

Losartan is readily absorbed from the gastrointestinal tract after oral doses, but undergoes substantial firstpass metabolism resulting in a systemic bioavailability of about 33%. It is metabolized to an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan; some inactive metabolites are also formed. Metabolism is primarilyby cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan andE-3174 occur about 1 hour and 3 to 4 hours, respectively, after an oral dose. Both losartan and E-3174 aremore than 98% bound to plasma proteins. Losartan isexcreted in the urine, and in the faeces via bile, asunchanged drug and metabolites. About 4% of an oraldose is excreted unchanged in urine and about 6% is excreted in urine as the active metabolite. The terminal elimination half-lives of losartan and E-3174 are about1.5 to 2.5 hours and 3 to 9 hours, respectively.

Losartan is a competitive angiotensin II receptor antagonist with antihypertensive activity due mainly to selectiveblockade of AT1 receptors and the consequent reducedpressor effect of angiotensin II.

The therapeutic andside-effects are broadly similar to those of ACEIs, with evidenceof reduced risk of new onset diabetes, stroke, progression of cardiac failure, and all-cause mortality in patients with chronic kidney disease.Direct targeting of angiotensin II receptors has theoretical advantages over ACE inhibition. Angiotensin II may be producedthrough non-ACE pathways, for example, by the enzyme chymase in kidney tissue, which is not affected by ACEIs. ARAs do not inhibit bradykinin metabolism, and therefore, the incidence of cough is much less than with ACEIs. The risk of angiooedema is greatly reduced with ARAs compared with ACEIs. Losartan is contra-indicated in pregnancy.It should be used with caution in patients with renal artery stenosis. Losartan is excreted in urine and in bileand reduced doses may therefore be required in patients with renal impairment and should be consideredin patients with hepatic impairment. Patients with volume depletion (for example those who have receivedhigh-dose diuretic therapy) may experience hypotension; volume depletion should be corrected beforestarting therapy, or a low initial dose should be used.Since hyperkalaemia may occur, serum-potassium concentrations should be monitored, especially in theelderly and patients with renal impairment, and potassium-sparing diuretics should generally be avoided.

Aliskiren, a piperidine derivative, is the only available drug in this
class and is used by specialists in patients who are unresponsive to, or intolerant of, other antihypertensives.

Aliskiren is given as the fumarate. Doses are expressed in terms of the base; 165.8 mg of aliskiren fumarate is equivalent to about150 mg of aliskiren. The usual initial oral dose of aliskiren is 150 mg once daily, increased to 300 mg oncedaily if necessary. Doses may be taken before or afterfood, but patients should establish a routine patternwith regard to meals.

Aliskiren is poorly absorbed from the gastrointestinal tract with a bioavailability of about 2.5%. Peak plasma concentrations are reached about 1 to 3 hours after anoral dose. Absorption is reduced when aliskiren is taken with a high-fat meal. Aliskiren is about 50% boundto plasma proteins. It is excreted mainly in the faeces,possibly via the bile; about 25% of the absorbed doseis excreted in the urine as unchanged drug. Aliskiren is a substrate for the cytochrome P450 isoenzymeCYP3A4 but metabolism appears to be minimal. The elimination half-life is about 24 to 40 hours, and steady-state concentrations are reached in about 7 to 8days.

Aliskiren directly inhibits the enzyme renin, which is secreted by granular cells of the juxtaglomerular apparatus. Renin inhibition reduces theconversion of the hepatically secreted polypeptide angiotensinogen to angiotensin I.Its effect on the RAS is therefore `upstream' of ACEIs and ARAs and it does not cause bradykinin accumulation.

DRIs have the same potential to cause renal dysfunction and electrolyte disturbances as ACEIs and ARAs. It should therefore be used with caution in patients with renal impairment or renovascular hypertension. Patients withsodium or volume depletion (for example those receiving high-dose diuretics) may experience symptomatic hypotension on starting aliskiren and treatment shouldbegin under close medical supervision.Diarrhea is aspecific side-effect to higher doses of DRIs. Aliskiren may have a larger role in the management ofhypertension in future, possibly in combination with other drugs. Aliskiren should be avoided in pregnancy since drugsacting on the renin-angiotensin system have been associated with fetal and neonatal morbidity and mortality.

Use of aliskiren with other antihypertensives or drugsthat cause hypotension may have an additive effect.Renal function and electrolytes should be monitored indiabetic patients taking aliskiren and ACE inhibitorssince there is an increased risk of hyperkalaemia andrenal impairment.Aliskiren is metabolised to a small extent by the cytochrome P450 isoenzyme CYP3A4 but few significant interactions have been reported. Plasma-aliskiren concentrations may be reduced by irbesartan and increasedby atorvastatin and ketoconazole but the clinical relevance is not clear. Aliskiren has caused significant decreases in furosemide concentrations.

â-Blockers are not used as first-line antihypertensives unless there are otherindications, for example, after myocardial infarction, or in tachyarrhythmias such as atrial fibrillation. Theirdiverse indications include stable heart failure, thyrotoxicosis, oesophageal varices, anxiety, and glaucoma.

â-Blockers antagonize catecholamines at â-adrenoceptors.
These Gs type G-protein-coupled receptors are classified as â1, present mainly within the heart and kidneys; and â2, present throughout the body in lungs, blood vessels, and muscle. The reduction in arterial pressure achieved by â-blockers is attributable
to their effects upon multiple pathways. Block of â1 receptors in
the sinoatrial node reduces heart rate and block of myocardial receptors reduces contractility (reduced chronotropy and inotropy, respectively). They also reduce sympathetic nervous system activity, while block of receptors in the juxtaglomerular apparatus reduces renin secretion.

Propranolol hydrochloride is usually given orally. Inhypertension it is given in initial doses of 40 to 80 mgtwice daily increased as required to a usual range of 160 to 320 mg daily; some patients may require up to640 mg daily.

Propranolol is almost completely absorbed from thegastrointestinal tract, but is subject to considerablehepatic-tissue binding and first-pass metabolism. Peakplasma concentrations occur about 1 to 2 hours after anoral dose. Plasma concentrations vary greatly between individuals. Propranolol has high lipid solubility. Itcrosses the blood-brain barrier and the placenta, and is distributed into breast milk. Propranolol is about 90% bound to plasma proteins. It is metabolised in the liverand at least one of its metabolites (4-hydroxypropranolol) is considered to be active, but the contribution of metabolites to its overall activity is uncertain.The metabolites and small amounts of unchanged drug are excreted in the urine. The plasma half-life of propranolol is about 3 to 6 hours.

Propranolol is a non-cardioselective â-blocker. Propranolol also blocks sodium channels andhave membrane stabilizing activity and is thus classed as Vaughan-Williams class 2 antiarrhythmic with other â-blockers. In addition to their antihypertensive effect, propranolol improves the myocardial oxygen supply:demand ratio and help reduce myocardial ischemiaby prolonging the period of diastole.

While â-blockers are used instable heart failure, they have the potential to worsen symptomsin some patients by reducing cardiac output. Poor peripheralcirculation and Raynaud's phenomenon may be precipitatedboth by reduced cardiac output and block of peripheral â2 receptors. Bronchospasm caused by â2 block may be a significantrespiratory side-effect in susceptible individuals, for example,asthmatics. Central nervous system effects include malaise,tiredness, and vivid dreams, particularly with lipid-solubledrugs. Ininsulin-dependent diabetic patients, the symptoms ofhypoglycaemia may be suppressed by sympathetic block.

á-Blockers are used to treat hypertension in patients resistantto, or intolerant of, other treatments. Specific indications fortheir use in secondary hypertension include labetalol for preeclampsia and phentolamine in the perioperative management of phaeochromocytoma. á-blockers are also commonly used to improve urinary flow in benign prostatic hyperplasia, for
example, tamsulosin.

Prazosin is given orally as the hydrochloride, but dosesare usually expressed in terms of the base. Prazosin hydrochloride 1.1 mg is equivalent to about 1 mg of prazosin.In hypertension, the usual initial dose is500 micrograms two or three times daily for 3 to 7days; if tolerated the dose may then be increased to1 mg two or three times daily for a further 3 to 7 days,and thereafter gradually increased, according to the patient's response, to a usual maximum of 20 mg daily individed doses.

Prazosin is readily absorbed from the gastrointestinaltract with peak plasma concentrations occurring 1 to 3hours after an oral dose. The bioavailability is variableand a range of 43 to 85% has been reported. Prazosinis highly bound to plasma proteins. It is extensivelymetabolised in the liver and some of the metabolites are reported to have hypotensive activity. It is excretedas the metabolites and 5 to 11% as unchanged prazosinmainly in the faeces via the bile. Less than 10% is excreted in the urine. Small amounts are distributed intobreast milk. Its duration of action is longer than wouldbe predicted from its relatively short plasma half-life ofabout 2 to 4 hours. Half-life is reported to be increasedto about 7 hours in patients with heart failure.

Prazosin is an alpha blocker that acts by selective blockade of alpha1-adrenoceptors.Prazosin produces peripheral dilatation of both arterioles and veins and reduction of peripheral resistance,usually without reflex tachycardia. It reduces bothstanding and supine blood pressure with a greater effect on the diastolic pressure.

Treatment with prazosin should be introduced cautiously because of the risk of sudden collapse following the initial dose. Extra caution is necessary in patients with hepatic or renal impairment and in theelderly.Prazosin is not recommended for the treatment of heart failure caused by mechanical obstruction, for exampleaortic or mitral valve stenosis, pulmonary embolism,and restrictive pericardial disease. It should be used with caution in patients with angina pectoris. Prazosinmay cause drowsiness or dizziness; patients so affected should not drive or operate machinery.The hypotensive effects of prazosin may be enhancedby use with diuretics and other antihypertensives, andby alcohol and other drugs that cause hypotension. Therisk of first-dose hypotension may be particularly increased in patients receiving beta blockers or calcium-channel blockers.

CCBs are first-line treatment for primary hypertension in patients over the age of 55 and black patients of African orCaribbean family origin. Rate-controlling CCBs (diltiazem, verapamil) are also used to manage tachyarrhythmias and angina,where their negative inotropic and chronotropic effects improvethe myocardial oxygen supply. Some CCBs havespecific non-cardiac indications, for example, nimodipine inneurosurgery to reduce cerebralvasospasm in patients afterspontaneous subarachnoid hemorrhage, and verapamil inneurology to treat cluster headache.

Amlodipine is given orally as the besilate, but doses are usually expressed in terms of the base; amlodipine besilate 6.9 mg is equivalent to about 5 mg of amlodipine. The camsilate, maleate, and mesilate are alsoused.In hypertension the usual initial dose is 5 mg once daily, increased, if necessary, to 10 mg once daily.

Amlodipine is well absorbed after oral doses with peakblood concentrations occurring after 6 to 12 hours. Thebioavailability varies but is usually about 60 to 65%.Amlodipine is reported to be about 97.5% bound toplasma proteins. It has a prolonged terminal elimination half-life of 35 to 50 hours and steady-state plasmaconcentrations are not achieved until after 7 to 8 daysof use. Amlodipine is extensively metabolized in theliver; metabolites are mostly excreted in urine togetherwith less than 10% of a dose as unchanged drug.

Amlodipine as well as other dihydropyridines act on L-type calcium channels present in vascularsmooth muscle and in myocardial and nodal tissues. The variable affinity of the different CCBs to these different tissues determines their effects.

Cardiovascular side-effects include reflex tachycardia which may potentiate myocardial ischemia, disturbance of the peripheral microcirculation leading to swelling of the hands and feet, flushing, and headache. Rate-limiting agents prolongatrioventricular conduction and cause bradycardia; the negativeinotropic and chronotropic effects may worsen heart failure. Amlodipine may enhance the antihypertensive effects ofother antihypertensive drugs such as beta blockers although the combination is generally well tolerated. Enhanced antihypertensive effects may also be seen ifused with drugs such as aldesleukin and antipsychotics that cause hypotension. Amlodipine may modify insulinand glucose responses and therefore diabetic patientsmay need to adjust their antidiabetic treatment when receiving amlodipine. Amlodipine is extensively metabolized in the liver by the cytochrome P450 isoenzymeCYP3A4, and interactions may occur with other drugs,such as quinidine, sharing the same metabolic pathway, and with enzyme inducers, such as carbamazepine, phenytoin, and rifampicin, and enzymeinhibitors, such as cimetidine, erythromycin, and HIVprotease inhibitors.

Thiazide (bendroflumethiazide, hydrochlorothiazide) and thiazide-like (chlortalidone, indapamide) diuretics are the most commonly prescribed diuretic agents used to treat hypertension.They are used in patients intolerant of CCBs and in patients with heart failure, or at risk of heart failure. They are also usedas `add on' drugs in patients who have not responded to firstand second-line antihypertensive treatments.

Thiazides are usuallygiven in the morning so that sleep is not interrupted by diuresis.Hydrochlorothiazide is given orally.In the treatment of hypertension an initial dose of12.5 mg may be sufficient, increasing to 25 to 50 mgdaily if necessary, either alone or with other antihypertensives. Doses of up to 100 mg have been suggestedbut are rarely necessary.

Hydrochlorothiazide is fairly rapidly absorbed fromthe gastrointestinal tract. It is reported to have a bioavailability of about 65 to 70%. It has been estimated tohave a plasma half-life of between about 5 and 15hours and appears to be preferentially bound to redblood cells. It is excreted mainly unchanged in theurine. Hydrochlorothiazide crosses the placental barrier and is distributed into breast milk.

Thiazides are moderately potent diuretics and exerttheir diuretic effect by reducing the reabsorption ofelectrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. They act mainly at the beginning ofthe distal tubules. The excretion of other electrolytes,notably potassium and magnesium, is also increased.The excretion of calcium is reduced. They also reduce carbonic-anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small compared with the effect on chloride excretion and does notappreciably alter the pH of the urine. They may also reduce the glomerular filtration rate.Their hypotensive effect is probably partly due to a reduction in peripheral resistance; they also enhance theeffects of other antihypertensives. Paradoxically, thiazides have an antidiuretic effect in patients with diabetes insipidus.

Thiazide diuretics have many clinically relevant biochemicalside-effects including hypokalaemia, hypercalcaemia, hyponatraemia, hypomagnesaemia, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, and hypochloraemic alkalosis. Plasma volume loss may precipitate dehydration and acute kidney injury. Less common side-effects include skin rashes, photosensitivity reactions, and blood dyscrasias including thrombocytopaenia.
Many of the interactions of hydrochlorothiazide andother thiazides are due to their effects on fluid and electrolyte balance. Diuretic-induced hypokalaemia mayenhance the toxicity of digitalis glycosides and mayalso increase the risk of arrhythmias with drugs that prolong the QT interval, such as astemizole, terfenadine, halofantrine, pimozide, and sotalol. Thiazidesmay enhance the neuromuscular blocking action of competitive neuromuscular blockers, such as atracurium, probably by their hypokalaemic effect. The potassium-depleting effect of diuretics may be enhanced bycorticosteroids, corticotropin, beta2 agonists such as salbutamol, carbenoxolone, amphotericin B, or reboxetine.

Diuretics may enhance the effect of other antihypertensives, particularly the first-dose hypotension that occurs with alpha blockers or ACE inhibitors. Orthostatichypotension associated with diuretics may be enhanced by alcohol, barbiturates, or opioids. The antihypertensive effects of diuretics may be antagonised bydrugs that cause fluid retention, such as corticosteroids,NSAIDs, or carbenoxolone; diuretics may enhance the nephrotoxicity of NSAIDs. Thiazides have been reported to diminish the response to pressor amines, suchas noradrenaline, but the clinical significance of this effect is uncertain.Thiazides should not usually be used with lithium sincethe association may lead to toxic blood concentrations of lithium. Other drugs for which increased toxicity hasbeen reported when given with thiazides include allopurinol and tetracyclines. Thiazides may alter the requirements for hypoglycaemics in diabetic patients.

Other diuretics include aldosterone antagonists, for example, spironolactone, are recommended as fourth-line treatment of primary hypertension. The use of these drugs carries a risk of hyperkalaemia, particularly in patients with impaired renal function or who are taking other potassium-sparing agents. Loop diuretics are indicated for resistant hypertension in patients with heart failure, chronic kidney disease, and in those at risk of hyperkalaemia.

Directly acting vasodilators, for example, hydralazine andminoxidil, are seldom used due to their side-effect profiles.Hydralazine is used in hypertension secondary to pre-eclampsia. In addition to its antihypertensive effects, minoxidil is used topically as a treatment for male pattern baldness.

In the treatment of hypertension minoxidil is givenwith a beta blocker, or with methyldopa, to diminishthe cardiac-accelerating effects, and with a diuretic,usually a loop diuretic, to control oedema.An initial dose of 5 mg of minoxidil daily(or 2.5 mg daily in the elderly) is gradually increased atintervals of not less than 3 days to 40 or 50 mg dailyaccording to response; in exceptional circumstances up to 100 mg daily has been given.

In the treatment ofalopecia androgenetica (male-pattern baldness) 1 ml of a 2% or 5% solution of minoxidil is applied twice daily to the scalp. The 5% solutionis not recommended for women.

About 90% of an oral dose of minoxidil is absorbedfrom the gastrointestinal tract. The plasma half-life isabout 4.2 hours although the haemodynamic effectmay persist for up to 75 hours, presumably due to accumulation at its site ofaction. Minoxidil is not boundto plasma proteins. It is distributed into breast milk.Minoxidil is extensively metabolised by the liver. It requires sulfation to become active, but the major metabolite is a glucuronide conjugate. Minoxidil is excretedpredominantly in the urine mainly in the form ofmetabolites. Minoxidil and its metabolites are dialysable, although the pharmacological effect is not reversed. About 0.3 to 4.5% of a topical dose of minoxidil is absorbed from intact scalp.

Vasodilators cause relaxation of vascular smooth muscle in resistance (arteriolar) vessels. Minoxidil achieves this via adenosine triphosphate-dependent potassium channels on smoothmuscle cell membranes.Vasodilatation provokes reflex cardiac stimulation (which may precipitate cardiac ischemia) and RAS activation. These compensatory responses may be offset by â-blockersor diuretics.

Vasodilator drugs are poorly tolerated. Side-effects includeheadache, fluid retention, and edema. Other specific side effects include left ventricular hypertrophy, pericardial and
pleural effusions, hypertrichosis and coarsening of featureswith minoxidil, while peripheral neuropathy, blood dyscrasias,and a lupus-like reaction can occur with hydralazine.The antihypertensive effect of minoxidil may be enhanced by use of other hypotensive drugs. Severeorthostatic hypotension may occur if minoxidil andsympathetic blocking drugs such as guanethidine aregiven concurrently.Topical minoxidil should not be used with other topicalagents known to enhance absorption, such as corticosteroids, retinoids, or occlusive ointment bases.

Centrally acting agents include clonidine (á2 adrenoceptor agonist), methyldopa (precursor of an á2 adrenoceptor agonist), and moxonidine (agonist at imidazoline binding sites). Their use inprimary hypertension is limited to difficult to treat cases, while methyldopa is used to treat hypertension in pregnancy. The evidence base for the use of centrally acting drugs in hypertension is limited and adverse effects are common. Clonidine is an analgesic and sedative drug which reduces the minimumalveolarconcentration of inhalation anestheticagents. Both of these drugs cause side-effects including drymouth and sedation. Methyldopa has immunological side effects, including pyrexia, hemolytic anemia, and hepatitis.Cessation of treatment with clonidine can cause reboundhypertension.

Methyldopa is given orally as the sesquihydrate, butdoses are usually expressed in terms of anhydrousmethyldopa. Methyldopa sesquihydrate 1.13 g isequivalent to about 1 g of anhydrous methyldopa. Forhypertensive crises, methyldopa has been given intravenously as methyldopate hydrochloride.In hypertension, the usual initial adult oral dose is250 mg of methyldopa two or three times daily for 2days; this is then adjusted, not more frequently than every 2 days according to response, up to a usual maximum dose of 3 g daily. The usual maintenance dosage is 0.5 to 2 g of methyldopa daily. In the elderly an initial dose of 125 mg twice daily has been used; this dosemay be increased gradually if necessary, but should not exceed 2 g daily

After oral use methyldopa is variably and incompletelyabsorbed, apparently by an amino-acid active transportsystem. The mean bioavailability has been reported to be about 50%. It is extensively metabolised and is excreted in urine mainly as unchanged drug and the Osulfate conjugate. It crosses the blood-brain barrier andis decarboxylated in the CNS to active alpha-methylnoradrenaline.The elimination is biphasic with a half-life of about 1.7 hours in the initial phase; the second phase is more prolonged. Clearance is decreased and half-life prolongedin renal impairment. Plasma protein binding is reported to be minimal. Methyldopa crosses the placenta; smallamounts are distributed into breast milk.

Methyldopa is an antihypertensive that is thought tohave a mainly central action. It is decarboxylated in theCNS to alpha-methylnoradrenaline, which is thoughtto stimulate alpha2 adrenoceptors resulting in a reduction in sympathetic tone and a fall in blood pressure. Itmay also act as a false neurotransmitter, and have some inhibitory actions on plasma renin activity. Methyldopa reduces the tissue concentrations of dopamine,noradrenaline, adrenaline, and serotonin.

Methyldopa should be used with caution in the elderly,and in patients with hepatic or renal impairment or witha history of haemolytic anaemia, liver disease, or depression. Care is also advisable in patients with Parkinsonism. It should not be given to patients with active liver disease or depression and it is not recommendedfor phaeochromocytoma.It is advisable to make periodic blood counts and toperform liver function tests at intervals during the first6 to 12 weeks of treatment or if the patient develops anunexplained fever. Patients taking methyldopa mayproduce a positive response to a direct Coombs' test; if blood transfusion is required, prior knowledge of apositive direct Coombs' test reaction will aid crossmatching. Methyldopa may cause sedation; if affected, patients should not drive or operate machinery. The hypotensive effects ofmethyldopa are potentiatedby diuretics, other antihypertensives, and drugs withhypotensive effects. However, there have been reportsof paradoxical antagonism of the hypotensive effectsby tricyclic antidepressants, antipsychotics, and betablockers. Sympathomimetics may also antagonise the hypotensive effects.There may be an interaction between methyldopa andMAOIs and care is required if they are given together.Caution is also needed with catechol-O-methyltransferase inhibitors, such as entacapone, since they might reduce the metabolism of methyldopa.

Ganglion blockers, such as trimetaphan, antagonize acetylcholine at nicotinic receptors, including those at the adrenal cortex. Trimetaphan causes vasodilatation with a consequent rapid reduction in arterial pressure. Although ganglion blockers may be
used to manage hypertensive crises or to provide hypotensive anesthesia, their use is increasingly rare.

The drug regimenmay include drugs with differing pharmacological actions; the antihypertensive mechanism is not fully understood in all cases. Historically, thiazide diuretics and beta blockers have been the mainstay of drug therapy for hypertension, but CCBs, ACEI, ARAs, and alpha blockers are now also widely used[3].

Studies such as the TOMHS[75] (comparing chlortalidone, acebutolol, amlodipine, enalapril, and doxazosin), and a similar study[76] (comparing hydrochlorothiazide, atenolol, diltiazem, captopril, prazosin, and clonidine), have shown that the main types of antihypertensive drug reduce blood pressure to a similar extent and in a similar proportion of patients, although the response may also depend on individual factors such as age[77] and race[78,79]. ARAs also effectively reduceblood pressure. However, it is now generally acknowledgedthat a single drug is unlikely to control blood pressureadequately and most patients will require more thanone drug to reach their treatment target. Tolerance of thedrug groups is also similar, although there has been concernabout the metabolic effects of thiazides and betablockers. Alpha blockers (specifically doxazosin[80]) havebeen associated with an increased risk of heart failure,which may limit their use. The safety of short-acting dihydropyridine CCBs has also been questioned,and they are no longer generally recommended forhypertension[3]; long-acting dihydropyridines,however, are of established benefit[81]. Diuretics(particularly thiazides) and beta blockers were the firstdrugs to demonstrate an effect on mortality in long-termoutcome studies and have therefore been preferred for initialtherapy[3]. However, long-term studies with other druggroups have now been performed, and have generallyshown comparable effects on mortality and morbidity. Ameta-analysis concluded that there was little differencein overall cardiovascular outcomes for regimens based on ACEIs, ARAs, CCBs, beta blockers, or diuretics, suggestingthe major benefit of treatment related to reduction of blood pressure rather than to specific properties of the individualdrugs[82]. In general, guidelines acknowledge that lowering bloodpressure appears to be more important than which drug ischosen for initial therapy, and that most patients will requirea combination of drugs, making the initial choice lessimportant[3]. Thiazide diuretics, ACEIs, ARAs, or CCBs mayall be used, and choice should take into account individualpatient characteristics, including age, ethnicity, contra-indicationsor compelling indications for specific drugs, adverseeffects, and relative cost-effectiveness[40,59-61]. Strictguidance is therefore not generally given, although foruncomplicated patients WHO guidelines[59]recommend thiazide diureticsas first-line, whereas in theUK[81] diuretics or CCBsare recommendedfor older patients (55 years or over) and black patients,while in younger, non-black patients ACEIs or ARAsare preferred. Compellingindications in all the guidelines include the use of ACEIs or ARAs in patientswith nephropathy, diuretics or CCBs in elderly patients, and beta blockers in patientswho have had a myocardial infarction.

Having decided what drug to use, treatment is started at thelowest recommended dose. If this is ineffective or onlypartially effective the dose may be increased (except in thecase of thiazide diuretics where there is generally no additionalbenefit, but more adverse effects); alternativelyanother first-line drug may either be substituted (sequential therapy) or added (combination therapy). Two-drugcombinations will control blood pressure in a higher proportionof patients and may be necessary in most patientsto achieve optimal levels, although the effects of the twodrugs may not be fully additive. Combination therapy alsoallows lower doses of the individual drugs to be used witha consequent reduction in adverse effects. Initial treatmentwith a low-dose combination may be considered in somepatients[40,61].

The most effective combinations involve drugsthat act on different physiological systems. Appropriatecombinations therefore include[3]:

Alpha blockersmay be used with any of the other classesbut are usually reserved for third-line therapy unless specificallyindicated for another reason. A 3-drug combinationis often required, especially in severe hypertension. Inpatients who maintain an elevated diastolic blood pressuredespite triple therapy the possibility of secondary hypertensionshould be considered, although factors such as non-compliance, NSAID use, or alcohol abuse may contributeto resistance[83,84].

Other classesof antihypertensive drugs that are sometimesused include: centrally acting drugs such as clonidine,methyldopa, and the less sedating moxonidine; direct-actingvasodilators such as hydralazine and minoxidil; the aldosteroneantagonist, eplerenone; and the DRI,aliskiren[3]. Endopeptidase inhibitors and endothelinantagonists are among various drug groups thatare under investigation.

It has been standard teachingthat drug treatment for hypertension is continued indefinitely,but there have been some reports of successfulwithdrawal in selected patients[85,86]. If this is attempted,blood pressure must be closely monitored and lifestylemeasures should be continued indefinitely[40,81].

The mainobjective of hypertension management is to achieve BP control through changes in lifestyle andappropriate therapeutic measures[1,3]. In the recent years,a growing number of patients seem to present resistanceto the antihypertensive treatment[87]. Non-adherence has important economic implications: itdecreases the cost-effectiveness of interventions, leading topoor clinical results with increased costs for public health[88].

Different methods to measure therapeutic adherence areavailable; all have favourable and unfavourable aspects andthere currently is no gold standard[10]. These methods canbe classified as direct or indirect: interviews and questionnairesadministered to patients (one of the most used isMorisky's scale), diaries, pill count, electronic monitoringof orally administered drugs, rates of prescriptions' refillingthrough pharmacies' databases and direct dosage ofdrug levels in biological fluids[10].At the present time therapeutic drug monitoring (TDM)is available for most antihypertensive drugs and severalstudies have demonstrated its efficacy in the evaluation ofadherence[89,90].

Therapeutic adherence describes the extent to which patients actively take medications as prescribed by their health care providers based on a therapeutic alliance or contract established between them; it differs from the term compliance, withwhich it is often confused[10]. The term compliance suggests apassive attitude when the patient follows the physician'sinstructions and treatment plan, without a real therapeuticalliance[10].In any case, these two terms do not allow to differentiatepatients who systematically fail to follow the recommendationsfrom those who occasionally forget a pill or reducethe dose of the drug[91].

Several conditions could affect therapeutic adherence:type of prescribed therapy, patient socio-cultural level,frequency of clinical controls[92]. The WHO hasidentified five different conditions[23] correlated with pooradherence: social and economic factors, condition-relatedfactors, therapy-related factors, patient-related factors andhealth care system/health care team-related factors. Moreover,frequently patients start the prescribed therapy, butadherence is progressively reduced because they do notpersist[23].

Different methods to measure therapeutic adherence areavailable. Indirect methods are less invasive andless expensive. Indirect methods for evaluating drug adherence include: patient interview, diaries, questionnaires,pill count, review of prescriptions, electronic monitoring[15,21].Conversely, direct methods are more invasive, expensiveand include the direct observation of the patient duringthe administration of therapy and the measurement of thedrug or of its metabolites in blood or urine[93]. Nonetheless, only a limited number of drugs can be monitored in this way because the bioavailability and completenessof absorption of various drugs, as well as the rate of metabolismand excretion, are factors that make it difficult tocorrelate drug concentrations in blood or urine with adherence[15].

In clinical practice, each method has advantages anddisadvantages and not all can be easily used in all settings;it is often not possible to accurately determine the realdegree of adherence.

The patient interview is one of the simplest and lessexpensive methods, but its efficacy is strongly influenced bythe ability of the interviewer and by the way in which thequestions are asked; it also heavily relies on a strongdoctor-patient relationship. Interviews may allow a pharmacist to show concern for the patient andprovide immediate feedback. Typical questions include askingthe patient to report the name, the dosage and the timeof drug intake. Alternatively, the doctor may ask the patienthow often they forget to take the pills during a week or amonth; according to the answers the physician can theninfer the degree of adherence.The patient interview can also be targeted to encouragebehavioural changes and to improve therapeutic adherence.

A drawback of this method isthat it can overestimate adherence, and its accuracy dependson the patient's cognitive abilities and the honesty of replies,as well as the interviewer's correct interpretation of responses.

The questionnaires are simple and economical methods toevaluate adherence. They are usually composed of a limitednumber of questions that the patient is asked to answer.A potential disadvantage is represented by the difficultysome subjects may have understanding the questions incase of low level of education.One of the most frequently used questionnaire is theMorisky 8 items MMAS-8 (Eight-Item Morisky MedicationAdherence Scale), which has a higher specificity(93%) compared to the original 4-item questionnaire.The MMAS-8 consists of seven binary questions (YES/NO) and one last multiple choice question. A clearlimitation of this instrument is represented by patients whomight answer the questions untruthfully. Similarly to thepatient interview, questionnaires are useful to evaluateunintentional poor adherence.

Counting pills is a simple and cost-effectiveness method toevaluate therapeutic adherence, but it is characterized byseveral limitations[94]. Among these, the most relevantlimitation is represented by the fact that patients canmislead the doctor, throwing away the pills before the visit.Furthermore, this method does not provide accurateinformation on daily adherence[10].The accuracy of the pill count method is adequate when compliance is excellent because there is nothing to return; however, in cases of low compliance, the pill count is not accurate.

An effective but at the same time more complex andexpensive method is electronic monitoring, in which thepill count is performed automatically and continuously by adevice at the patients' home[96].

There are different electronic monitoring systems, usuallyvery expensive and invasive. However, in view of theirhigh efficacy they can be considered as the gold standardfor assessing drug adherence.One of the less invasive options is the medication events monitoring system (MEMS), which uses a device to recordthe time and the date in which medications are taken fromthe box. In the last years, a more invasive system was validated: the ingestible sensor technology. In thiscase the sensor is inside the pill, so it becomes possible toaccurately document each time a pill is ingested.

The most accurate direct method for evaluating therapeuticadherence is the measurement of the drug concentration (orthe concentration of its metabolites) in body fluids (bloodor urine)[94]. For this purpose, liquid chromatography-massspectrometry analysis can be used[93].In the recent years, several studies used TDM to evaluatetherapeutic adherence, especially in patients withsuspected resistant hypertension[89,90]. Chung et al.[98]have recently demonstrated that TDM is a cost-effectivemethod to assess adherence in the workup of resistanthypertension, independently by sex and age. TDM wouldallow a substantial economic advantage when comparedwith previous cost-effectiveness analyses of invasive proceduresfor the treatment of resistant hypertension[99,100].

TDM, however, has some limitations: it provides resultswithout giving information about the causes of non-adherence;it is very intrusive for the patient; it can induce thephenomenon of white-coat adherence; antihypertensivedrugs can present an altered metabolism when taken withother drugs. An ethical problem should also be considered:such measurements need to be done with the informedconsent of patients and thus tend to induce white-coatadherence[94]. Despite these limitations, TDM, used inselected cases, may provide a way to decrease health costs, by reducing the number of visits in patients who intentionallydo not take drugs and by identifying those patientswho would undergo unnecessary and sometimes invasiveprocedures.

Properly identify patients who do not take prescribedtherapy has important consequences, such as execution ofunnecessary medical visits or diagnostic tests, as well asscreening evaluation for secondary forms of hypertension.For this reason it is important to improve therapeuticadherence in all patients with hypertension, mostly in thosewith difficult to treat or resistant hypertension. Although itis a difficult task, physician should help individual patientto get better therapeutic compliance.

There are different strategies for improving long termtherapeutic adherence: simplifying medical regime withfixed associations of drugs when available, giving patientsinstructional material, counselling about therapy, remindingfor medications and appointments, cuing medications todaily events and explicitly acknowledging patient's effortto adhere.Therefore, treating physician should establish a goodrelationship with each individual patient to address andresolve poor therapeutic adherence.

In a cross-sectional study carried out by Lin et al. in 1995 in Tainan City, the medication adherence rate found was 57.6%. Subjects taking 80% or more of their prescribed medicines were considered adherent[102]. The factors associated significantly with poor adherence included: more than once daily dose frequency, no health check-up in the previous year, disbelief in the efficacy of antihypertensives, and presence of adverse drug reactions in the past 6 months.

In a cross-sectional study by Hashmi et al. in 2005 in Pakistan, 77% of their cases were adherent. Univariate analyses showed that decreasing age, poor awareness and decreasing number of pills prescribed significantly promoted poor adherence[103].

In Bangladesh, Hussain et al. found in 2006 that 85% of the study population were non-adherent to treatment. The reasons pointed out were low levels of education, low family income, duration of diagnosis, insufficient knowledge of the disease, lack of accompanying person to go to the physician/hospital, and deficiencies in information from the service provider[104].

In a cohort study carried out in Italy involving 18,806 newly diagnosed hypertensive patients =35 years of age, Mazzaglia et al. in 2009 found varying adherence rates. 6 months after index diagnosis, the authors found rates of 8.1%, 40.5%, and 51.4% corresponding to high, intermediate, and low adherence levels, respectively. The authors also found thatthe risk of being a poor adherer increased in the absence of concurrent treatment[105].

In a descriptive exploratory study conducted by Demoner et al. in 2011 in Brazil, 64% of patients in the study were nonadherent to antihypertensive therapy. Adherence level was assessed using the Morisky-Green Test. Poor adherence was significantly associated with participants who were: in the youngest age group, working, lack of understanding of the health team recommendations and presenting with overweight or obesity[106].The younger patients (18-40 years) presented lowerlevels of adherence compared to those in older agegroups. This may be related to the fact that HTN is asilent disease and, thus, leads to a certain nonchalance inyounger individuals regarding the control of the disease,who only give importance to adequate treatment whenthere is a worsening of symptoms, increasing risks ofserious complications and mortality for stroke and MI.

In a cross-sectional study carried out in 2014 in Iran, Behnood-Rod et al. found that about half of the sample population (49.6%) showed low adherence (8-item Morisky Medication Adherence Scale <6). In addition the authors also found that overweight/obesity, previous history of admission to emergency services due to hypertensive crisis, and getting medication directly from drugstore without refill prescription in hand were factors recognized to have statistically significant association with the 8-item Morisky Medication Adherence Scale score[107].

In a retrospective cohort study including 5025 Swedish adult patients in 2015, Hedna et al. found that non-adherence to any antihypertensive medication was higher among persons < 65 years (17.5%) and with the lowest income (12.8%). Also the authors found that, non-adherence to the full AHT regimen was higher among new users (44.2%), persons using specialized healthcare (38.3%) and having multiple antihypertensive medications (54.3%). Finally, the authors noted that non-adherence to any antihypertensive medication a month prior to healthcare visit wasassociated with elevated BP[108].

In cross-sectional correlational study by Lo et al. in Hong Kong in 2016, more than half of the respondents (55.9%) acknowledged some degree of medication nonadherence. Older age, living alone, and perception related to treatment control were independently associated with increased odds of medication non-adherence[109].

In a cross sectional study carried out in Northwest Ethiopia in 2011, Ambaw et al. found that more than half (64.6%) of the study participants were found to be adherent to their treatment. Male gender, insufficient knowledge about hypertension and its treatment, distance from the hospital and presence of comorbidity were found to be significantly associated with poor treatment adherence[7].

In 2013, Okwuonu et al. found in a cross-sectional study carried out in Nigeria that BP control was optimal in 33%, good knowledge of hypertension was found in 52% and only 31.8% were adherent to prescribed medications. The authors also added that the duration ofhypertension from time of diagnosis, systolic and diastolic blood pressures andtotal number of pills swallowed per time were found to independently correlatewith medication adherence, albeit negatively[110].

In a multicenter cross-sectional study conducted in 2013 by Boima et al., medication non-adherence was found in 66.7% of the study population. Medication non-adherence showed correlation with depression, concern about medications, and knowledge of hypertension. Adherence was associated with formal education and use of herbal preparation. Poor BP control was observed in 69.7% and there was significant association between medication non-adherence and poor BP control[111].

Tufon et al. found in a cross-sectional study carried out at the Mankon Sub-Divisional Health Center in 2014 that level of adherence was found to be low (80.0%) with smoking (85%) and alcohol intake (55%) identified as associated factors. Moderate level of knowledge (77.5%) was found as opposed to a high level of adherence (80.0%) and the authors found no significant relationship between the level of knowledge and level of adherence[18].

Essomba et al. reported in 2015 in a cross-sectional and analytical study, that 26.2% of their study population had good adherence to antihypertensive treatment. At the same time, 25.7% were bad adherers. Reasons for non-adherence included: forgetfulness, medication cost and poor knowledge of the disease[19].

Akoko et al. in 2015 reported that antihypertensive compliance rate was 43.9% in their cross-sectional study. Independent predictors of noncompliance were forgetfulness, lack of motivation due to the incurable nature of the disease, and lack of symptoms of the disease[20].

Mbouemboue et al. reported in 2016 that, 12.9% of patients enrolled in the study in the Medico-Social Centre of the National Social Insurance Fund in Garouafollowed up their treatment correctly, 52.9% had minor observance problems, and 34.3% had a poor therapeutic adherence to antihypertensive drugs. Therapeutic adherence was evaluated on the basis of the Girerd X observance test. The determining factors of poor adherence were the presence of complications of high BP, the presence of a handicap, and a low level of education[16].

An assessment of adherence to antihypertensive treatment and associated factors in patients at the Yaounde general hospital

CHAPTER II: LITERATURE REVIEW