PHARMACOTHERAPY OF HYPERTENSION

Boban Devasy, K. Nisar

National College of Pharmacy, Manassery, Calicut

Cite this: Boban Devasy, K. Nisar "Pharmacotherapy of hypertension", B. Pharm Projects and Review Articles, Vol. 1, pp. 209-234, 2006. (http://farmacists.blogspot.in/)

 

INTRODUCTION

    High blood pressure, termed "hypertension," is a condition that afflicts more than 50 million Americans and is a leading cause of morbidity and mortality. Hypertension is much more than a "cardiovascular disease" because it affects other organ systems of the body such as kidney, brain, and eye. Tens of millions of Americans are not even aware of being hypertensive because it is usually asymptomatic until the damaging effects of hypertension (such as stroke, myocardial infarction, renal dysfunction, etc.) are observed.

    Hypertension is an intermittent or persistent elevation of the blood pressure (systolic blood pressure above 140 mm Hg or diastolic blood pressure above 90 mm

Hg) or (a systolic and diastolic pressure of 20 mm Hg above the normal baseline pressure). Hypertension has recently increased in incidence throughout the world. It is thought that the stresses of everyday life with a change in the dietary habits and lack of exercise has led to the increasing incidence of hypertension. Previously hypertension was predominant only in industrialized and developed countries. However, of late there has been a sudden increase in the number of cases in developing countries.

    It is often asymptomatic, but even so, the detection rate has increased over the past three decades. Untreated, hypertension can lead to devastating end organ damage. Therefore, clinicians have the important responsibilities of first detection and then adequate treatment.

    Women, the elderly, and minorities have traditionally been underrepresented in clinical trials dealing with hypertension. Recently, detection and treatment of hypertension in women and the elderly have received special emphasis.In the first symposium article, Drs Eileen Reynolds and Robert Baron summarize findings to date in studies including these two populations, and they discuss the implications for treatment choices.

    Lifestyle modification is a key initial intervention for hypertension, and continuation of changes should be encouraged even if drug therapy becomes necessary. In the second article in this symposium, Drs Christian Zellner and Krishnankutty Sudhir describe the benefits patients can gain from exercise, weight loss, cessation of smoking, reduced sodium and alcohol intake, and increased potassium and calcium intake. These modifications can improve overall health in addition to lowering blood pressure.

    Many patients require drug therapy to control their hypertension, and various classes of agents are available (including the new angiotensin II-receptor antagonists). There has been considerable controversy over which class or agent is best for initial therapy. As Dr. Hal Barron and I explain in the third article in this symposium, what is most important is for clinicians to work closely with patients to find a treatment regimen that is tolerable and effective.

    Many patients' hypertension, especiallyin the past, has proved tobe refractory to antihypertensive therapy. A few patients have a secondary cause of hypertension that must be identified and treated, but most, we now understand, have primary hypertension that is being inadequately treated. In the fourth symposium article, Drs Daumil Gandhi and Hector Santiesteban discuss patient and physician-related variables that interfere with treatment and describe how their identification often allows successful control of hypertension.

DEFINITION

    Hypertension is high blood pressure. Blood pressure is the force of blood pushing against the walls of arteries as it flows through them. Arteries are the blood vessels that carry oxygenated blood from the heart to the body's tissues.

DESCRIPTION

    Blood flows through arteries it pushes against the inside of the artery walls. The more pressure the blood exerts on the artery walls, the higher the blood pressure will be. The size of small arteries also affects the blood pressure. When the muscular walls of arteries are relaxed, or dilated, the pressure of the blood flowing through them is lower than when the artery walls narrow, or constrict.

    Blood pressure is highest when the heart beats to push blood out into the arteries. When the heart relaxes to fill with blood again, the pressure is at its lowest point. Blood pressure when the heart beats is called systolic pressure. Blood pressure when the heart is at rest is called diastolic pressure.When blood pressure is measured, the systolic, pressure is stated first and the diastolic pressure second. Blood pressure is measured in millimeters of mercury (mm Hg). For example, if a person's systolic pressure is 120 and diastolic pressure is 80, it is written as 120/80 mm Hg. The American Heart Association considers blood pressure less than 140 over 90 normal for adults.

    Hypertension is a major health problem, especially because it has no symptoms. Many people have hypertension without knowing it, in the United states, about 50 million people age six and older have high blood pressure. Hypertension is more common in men than women and in people over the age of 65 than in younger persons. More than half of all Americans over the age of 65 have hypertension. It is also more common in African-Americans than in white Americans.

    Hypertension is serious because people with the condition have a higher risk for heart disease and other medical problems than people with normal blood pressure. Serious complications can be avoided by getting regular blood pressure checks and treating hypertension as soon as it is diagnosed.

    If left untreated, hypertension can lead to the following medical conditions;

• Arteriosclerosis, also called atherosclerosis
• Heart attack
• Stroke
• Enlarged heart
• Kidney damage

Arteriosclerosis is hardening of the arteries. The walls of arteries have a layer of muscle and elastic tissue that makes them flexible and able to dilate and constrict as blood flows through them. High blood pressure can make the artery walls thicken and harden. When artery walls thicken, the inside of the blood vessel narrows. Cholesterol and fats are more likely to build up on the walls of damaged arteries, making them even narrower. Blood clots can also get trapped in narrowed arteries, blocking the flow of blood.

    Arteries narrowed by arteriosclerosis may not deliver enough blood to organs and other tissues. Reduced or blocked blood flow to the heart can cause a heart attack. If an artery to the brain is blocked, a stroke can result.

    Hypertension makes the heart work harder to pump blood through the body. The extra workload can make the heart muscle thicken and stretch. When the heart becomes too enlarged it cannot pump enough blood. If the hypertension is not treated, the heart may fail.

    The kidneys remove the body's wastes from the blood. If hypertension thickens the arteries to the kidneys, less waste can be filtered from the blood. As the condition worsens, the kidneys fail and wastes build up in the blood. Dialysis or a kidney transplant are needed when the kidneys fail. About 25% of people who receive kidney dialysis have kidney failure caused by hypertension.

 

CLASSIFICATION

Table 1 : Classification of Hypertension

Category	Systolic BPa (mm Hg)		Diastolic BPa (mm Hg)
Normal	<120	and	<80
Pre-hypertension	120-139	or	80-89
Stage 1 hypertension	140-159	or	90-99
Stage 2 hypertension	> 160	or	> 100

^aBP = Blood pressure

 

 

 

 

Table 2: Classification of Hypertension

According to WHO/ISH*

 

Category	Systolic BPa (mm Hg)	Diastolic BPa (mm Hg)
Optimal	< 120	< 80
Normal	< 130	< 85
High Normal	130-139	85-89
Grade I (mild hypertension)	140-159	90-99
Sub group: borderline	140-149	90-94
Grade 2 (moderate hypertension)	160-179	100-109
Grade 3 (severe hypertension)	> 180	> 110
Isolated Systolic Hypertension (ISH)	> 140	< 90
Subgroup (borderline)	140-149	< 90

ISH = International Society of Hypertension.

 

CLASSIFICTION

Secondary Hypertension

A) Systolic hypertension with wide pulse pressure:

• Aortic regurgitation
• Thyrotoxicosis
• Patent ductus arteriosus

B) Systolic and diastolic hypertension with increased PVR

1. Renal

• Glomerulonephritis (acute or chronic)
• Pyelonephritis
• Polycystic kidneys
• Renal artery stenosis

2. Endocrine

• Cushing's syndrome (excessive glucocorticoids)
• Congential adrenal hyperplasia
• Conn's syndrome (primary hyperaldosteronism)
• Phaeochromocytoma
• Hypothyroidism
• Acromegaly

3. Neurogenic

• Raised intracranial pressure
• Psychological ("white coat hypertension")
• Acute porphyria
• Lead poisoning

 

4. Miscellaneous

• Coarctation of the aorta
• Polyarteritis Nodosa
• Hypercalcaemia
• Increased intravascular volume (PRV)

EPIDEMIOLOGY

    Cardiovascular diseases caused 2.3 million deaths in India in the year 1990; this is projected to double by the year 2020. Hypertension is directly responsible for 57% of all stroke deaths and 24% of all coronary heart disease deaths in India. Indian urban population studies in the mid 1950s used older WHO guidelines for diagnosis (BP > or + 160 and/or 95 mmHG) and reported hypertension prevalence of 1.2-4.0%. Subsequent studies report steadily increasing prevalence from 5% in 1960s to 12-15% in 1990s. Hypertension prevalence is lower in the rural Indian population, although there has been a steady increase over time here as well. Recent studies using revised criteria (BP > or = 140 and /or 90 mmHg) have shown a high prevalence of hypertension among urban adults: men 30% women 44% in Jaipur (1995), men 44% in Mumbai (1999), men 31%, women 36% in Thiruvananthapuram (2000).Among the rural populations, hypertension prevalence is men 24%, women 17% in Rajasthan (1994). Hypertension diagnosed by multiple examinations has been reported in 27% male and 28% female executives in Mumbai (2000) and 4.5% rural subjects in Haryana (1999). There is a strong correlation between changing lifestyle factors and increase in hypertension in India. The nature of genetic contribution and gene environment interaction in accelerating the hypertension epidemic in India needs more studies. Pooling of epidemiological studies shows that hypertension is present in 25% urban and 10% rural subjects in India. At an underestimate, there are 31.5 million hypertensives in rural and 34 million in urban populations. A total of 70% of these would be Stage I hypertension (systolic BP 140-159 and/or diastolic BP 90-99mmHg). Recent reports show that borderline hypertension *systolic BP 130-139 and/or diastolic BP 85-89 mmHg) and Stage I hypertension carry a significant cardiovascular risk and there is a need to reduce this blood pressure. Population-based cost-effective hypertension control strategies should be developed.

    The epidemiology of hypertension, in terms both of its importance as a risk factor for cardiovascular and other diseases and of its own etiology, continues to be a major field of investigation with an enormous peer reviewed literature each year. As stated by Paul Elliot in the opening sentence of this book, "Raised blood pressure is one of the most important underlying risk factors for morbidity and mortality in the world today, ranking alongside tobacco in estimates of the worldwide attributable burden of mortality."

    Interest in the pressure level in the circulation dates from 1733, when Hales placed a glass tube in a horse's artery, about 100 years after Harvey demonstrated the circulation of blood. Such direct measurements of arterial pressure were clearly impractical in clinical practice, and efforts to develop devices for indirect measurement persisted throughout the 19^th century, culminating in Riva-Rocci's description in 1896 of a cuff inflated by a pump to occlude the palpated pulse. The occlusion pressure was recorded by a mercury manometer. By 1901, it was appreciated that Riva-Cocci's cuff, which was 5 cm wide, gave erroneously high occlusion pressures, and larger cuffs were introduced. In 1905, Korotkiff published his paper reporting the use of a stethoscope to auscultate the diastolic and systolic blood pressures. This technique became widely accepted within a few years and, along with relatively inexpensive sphygmomanometers, opened the way for routine collection of blood pressure data in large numbers of people. Sources of measurement artifact other than cuff size and the need to standardize measurement methods to reduce these artifacts were well appreciated prior to World War I. Acturial studies soon showed increased risk of mortality among those at the higher end of the blood pressure distribution. The emergence after World War II of chronic disease epidemiology, and particularly of cardiovascular epidemiology, was followed by the development of effective pharmacologic treatments in the 1950s, and their testing in randomized trials starting in the 1960s. The fields of hypertension epidemiology, treatment, and control in populations began to take their modern forms.

    The Handbook of Hypertension is a multi volume series that encompasses these fields as well as experimental, pathophysiologic, and genetic aspects. The present volume is an updated version of the 1985 edition of the Epidemiology of Hypertension and includes 41 chapters by different authors on various aspects of the epidemiology of hypertension. The uniformity very high quality of these chapters is evidence of a strong editorial hand, both in the selection of authors and oversight of the work. There are sections on hypertension in populations; blood pressure measurement; blood pressure and the environment; blood pressure and nutrition; secondary forms of hypertension; genetics and clustering of risk factors; blood pressure, hormone replacement, and oral contraceptives; community control of hypertension; community control of hypertension in different countries and problems in community control. This last section has two chapters, both exemplary, the first issues of clinical labeling (effects of telling people they are hypertensive), and the second on the pervasive role of the pharmaceutical industry in influencing prescribing decisions. A strength throughout this book is the directness of the authors in articulating the limitations of data, the controversies that remain unresolved, and the conflicting views of experts in the field. Another strength, for a US reader, is the largely European author list and the consistent citation of European publications. The literature cited is highly international and is generally very up to date through 1998. Some of the chapters that I thought were particularly excellent included Safar and Smulyan's chapter on systolic versus diastolic blood pressure, Prineas' chapter on blood pressure in children and adolescents, Sever and Poulter's chapter on blood pressure and migration, Simpson's chapter on sodium intake, Robertsons's comprehensive review of the rennin-angiotensin system, and Alderman's chapter on work site hypertension treatment programs. A number of others could be included in this list.

ETIOLOGY OF ESSENTIAL HYPERTENSION

Environment

    A number of environmental factors have been implicated in the development of hypertension, including salt intake, obesity, occupation, alcohol intake, family size, excessive noise exposure and crowding.

Salt Sensitivity

    Sodium is the environmental factor that has received the greatest attention. It is to be noted that approximately 60% of the essential hypertension population is responsive to sodium intake.

Role of Renin

    Renin is an enzyme secreted by the juxtaglomerular cells of the kidney and linked with aldosterone in a negative feedback loop. The range of plasma rennin activities observed in hypertensive subjects in broader than in normotensive individuals. In consequences, some hypertensive patients have been defined as having low rennin and others as having high rennin essential hypertension.

Insulin Resistance

    Insulin is a polypeptide hormone secreted by the pancreas. Its main purpose is to regulate the levels of glucose in the body, it also has some other effects. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. The feature is now widely recognized as part of syndrome X, or the metabolic syndrome.

Sleep Apnea

    Sleep apnea is a common, under recognized cause of hypertension. It is best treated with weight loss and nocturnal nasal positive airway pressure.

Genetics

    Hypertension is one of the most common complex genetic disorders, with genetic heritability averaging 30%.Data supporting this view emerge from animal studies as well as in population studies in humans. Most of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.

    More than 50 genes have been examined in association studies with hypertension, and the number is constantly growing.

Other Etiologies

    There are some anecdotal or transient causes of high blood pressure. These are not to be confused with the disease called hypertension in which there is an intrinsic physiopathological mechanism as described above.

Etiology of Secondary Hypertension

    Only in a small minority of patients with elevated arterial pressure can a specific cause be identified. These individuals will probably have an endocrine or renal defect that if corrected would bring blood pressure back to normal values.

Renal Hypertension

    Hypertension produced by diseases of the kidney. A simple explanation for renal vascular hypertension is that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the rennin angiotensin system.

Adrenal Hypertension

    Hypertension is a feature of a variety of adrenal cortical abnormalities. In primary aldosteronism there is a clear relationship between the aldosterone induced sodium retention and the hypertension.

    In patients with pheochromocytoma increased secretion of catecholamines such as epinephrine and norepinephrine by a tumor (most often located in the adrenal medulla) causes excessive stimulation of (adrenergic receptors), which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).

Coarctation of the Aorta

Diet

    Certain medications, especially NSAIDS (Motrin/ibupofen) and steroids can cause hypertension. Ingestion of imported licorice (Glycyrrhiza glabra) can cause secondary hypoaldosteronism, which itself is a cause of hypertension.

• Age: Over time, the number of collagen fibres in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross sectional area in systole, and so a raised mean arterial blood pressure.

PATHOPHYSIOLOGY

1. Abrupt increases in systemic vascular resistance likely related to humoral vasoconstrictors.
2. Endothelial injury
3. Fibrinoid recrosis of the arterioles
4. Deposition of platelets and fibrin
5. Breakdown of the normal autoregulatory function
6. The resulting ischemia prompts further release of vasoactive substances completing a vicious cycle.

There is still much uncertainty about the pathophysiology of hypertension. A small number of patients (between2% and 5) have anunderlying renal or adrenal disease as the cause for their raised blood pressure. In the remainder, however, no clear single identifiable cause is found and their condition is labeled "essential hypertension". A number of physiological mechanisms are involved in the maintenance of normal blood pressure, and their derangement may play a part in the development of essential hypertension.

    It is probable that a great many interrelated factors contribute to the raised blood pressure in hypertensive patients, and their relative roles may differ between individuals. Among the factors that have been intensively studied are salt intake, obesity and insulin resistance, the rennin-angiotensin system, and the sympathetic nervous system. In the past few years, other factors have been evaluated, including genetics, endothelial dysfunction (as manifested by changes in endothelin and nitric oxide), low birth weight and intrauterine nutrition, and neurovascular anomalies.

SIGNS AND SYMPTOMS

    Most people with high blood pressure have no signs of symptoms, even if blood pressure readings reach dangerously high levels.

    Although a few people with early stage high blood pressure may have dull headaches dizzy spells or a few more nosebleeds than normal, these signs and symptoms typically don't occur until high blood pressure has reached an advanced – possibly life-threatening--stage.

What are the Signs and Symptoms of Pulmonary Arterial Hypertension?

    Difficulty breathing or shortness of breath (dyspnea) is the main symptom of pulmonary arterial hypertension (PAH). If you have PAH, you may feel that it is difficult to get enough air.

Other Common Signs and Symptoms

• Fatique
• Dizziness
• Fainting spells (syncope)
• Swelling in the ankles or legs (edema)
• Bluish lips and skin (cyanosis)
• Chest pain
• Racing pulse
• Palpitations (a strong feeling of a fast heartbeat)
  

As the disease advances

• The pumping action of your heart grows weaker.
  
• Your energy decreases
  

In the more advanced stages, you:

• Are able to perform very little activity
• Have symptoms even when resting
• May become completely bedridden.

RISK FACTORS

High Blood pressure has many risk factors. Some you can't control.

• Age: The risk of high blood pressure increase as you get older.Through early middle age, high blood pressure is more common in men.Women are more likely to develop high blood pressure after menopause.
• Race: High blood pressure is particularly common among blacks, often developing at an earlier age than it does in whites. Serious complications, such as stroke and heart attack, also are more common in blacks.
• Family history: High blood pressure tends to run in families.
• Excess weight: The greater your body mass, the more blood you need to supply oxygen and nutrients to your tissues. As the volume of blood circulated through your blood vessels increases, so does the pressure on your artery walls.
• Inactivity: People who are inactive tend to have higher heart rates. The higher your heart rate, the harder your heart must work with each contraction – and the stronger the force on your arteries. Lack of physical activity also increases the risk of being overweight.
• Tobacco use: The chemicals in tobacco can damage the lining of your artery walls, which promotes narrowing of the arteries.
• Sodium intake: Too much sodium in your diet – especially if you have sodium sensitivity – can lead to fluid retention and increased blood pressure.
• Low potassium intake: Potassium helps balance the amount of sodium in your cells. If you don't consume or retain enough potassium, you may accumulate too much sodium in your blood.
• Excessive alcohol: Over time, heavy drinking can damage your heart.
• Stress: High levels of stress can lead to a temporary but dramatic increase in blood pressure. If you try to relax by eating more, using tobacco or drinking alcohol, you may only fuel problems with high blood pressure.

Certain chronic conditions also may increase your risk of high blood pressure, including high cholesterol, diabetes, kidney disease and sleep apnea. Sometimes pregnancy contributes to high blood pressure.

In a 2006 study, adults who worked more than 40 to 50 hours a week – particularly clerical and unskilled workers – were more likely to have high blood pressure than were those who worked 40 hours or less a week. Researchers tied the higher risk for workers with longer hours to unhealthy eating, less exercise, more stress and less sleep.

    Although high blood pressure is most common in adults, children may be at risk, too. For some children, high blood pressure is caused by problems with the kidneys or heart. But for a growing number of kids, poor lifestyle habits – such as an unhealthy diet and lack of exercise – contribute to high blood pressure.

Method of Measuring Hypertension

Palpatory Method

Ausculatory Method (Instrument : Sphigmomanometre)

CLINICAL MANIFESTATIONS

    The manifestations of hypertensive crises are those of end-organ dysfunction:

1. Hypertensive encephalopathy
2. Acute aortic dissection
3. Acute myocardial infarction
4. Acute cerebral vascular accident
5. Acute hypertensive renal injury
6. Acute congestive heart failure.

It is important to recognize that the absolute level of BP may not be as important as the rate of increase. Patients with longstanding hypertension may tolerate systolic BPs of 200 mm Hg or diastolic BPs of up to 150 mm Hg without developing hypertensive encephalopathy, while children or pregnant women may develop encephalopathy with diastolic BPs 100 mm Hg.

DRUG USED IN THE TREATMENT OF HYPERTENSION

VASODILATORS

e.g.p.o. HYDRALAZINE and MINOXDIL or i.v. SODIUM NITROPRUSSIDE

Mechanisms of Action     

    Hydralazine acts predominantly on arterioles by a still unknown mechanism (independent of Nitric Oxide). Minoxidil (or rather its sulphate metabolite) causes relaxation of vascular smooth muscle by opening ATP-dependent K channels. Sodium nitroprusside is a nitro-dilator directly activating guanylate cyclase.

Uses

    Special indications are pregnancy-induced hypertension )Hydralazine) and severe refractory hypertension (Minoxidil).

    Both hydralazine and minoxidil cause: (1) a reflex tachycardia – that is often profound requiring beta-blockade (2) rebound Na retention – that antagonizes their hypotensive action and especially in the case of minoxidil requires aggressive use of a loop diuretic.

Centrally Acting Anti-Hypertensive Agents

    These agents have historically enjoyed greater usage outside the UK (especially in the USA). They cannot be considered first-line/alternative first/line agents due to:

1. Poor side effect profile
2. Conspicuous lack of outcome data.

NB: a-Methyl-DOPA is still widely prescribed for pregnancy-induced hypertension.

Mechanism

    Act centrally to reduce sympathetic outflow. Target receptors (probably a₂ and not 1₁) are in the hind brain vasomotor nuclei that project to spinal sympathetic efferent cell bodies. They all cause a degree of sedation and many worsen or precipitate depression.

Adverse Reactions

• Rebound hypertension – following missed doses
• Rebound hypertension – Risk greatest with CLONIDINE and least with MOXONIDINE
• Dry mouth –CLONIDINE >>MOXONIDINE
• Haemolytic anaemia 20% of patients on a Methyl DOPA develop a positive Coomb's Test only 1% haemolyse.

Alpha-Blockers

e.g. doxazosin, prazosin (largely obselete)

Mechanism of Action

    Competitive a ₁-receptor antagonists resulting in arteriolar vasodilatation.

Adverse Effects

• Postural hypotension
• Nasal stuffiness – similar side effect to a –methyl-DOPA.
• Ejaculatory failure
• Detrusor relaxation – may alleviate outflow obstruction in men (with BPH) or precipitate urinary incontinence in women.

NB: Phenoxybenzamine differs from other alpha blockers in acting as an irreversible (and relatively non-selective) receptor antagonist. It is only used in patients with PHAEOCHROMOCYTOMA where a competitive blockade can be overcome by the very high circulating catecholamine levels.

Beta-Blockers

Vary with respect to:

• Relative selectivity for b₁ compared to b₂ receptors (cardioselectivity)
• Lipid solubility
• Intrinsic sympathiomimetic activity
• Membrane stabilizing activity

These properties are not important with the exception of the following:

• 
  ₁ selective agents are less likely to worsen peripheral vascular disease or impair awareness of hypoglycaemia in diabetic.
• Lipid soluble beta-blockers penetrate the CNS and are more commonly associated with sleep disturbance/nightmares.
• Agents lacking ISA may be more effective in preventing angina and are effective in preventing migraine attacks.

Mechanism of Action (Chronic dosing)

1. Inhibition of beta-receptor mediated rennin release
2. Increased baroreceptor sensitivity
3. Reduction of noradrenaline release by blockade of presynaptic b–receptors

Adverse Effects

• Worsening bronchoconstriction – even with b₁ selective agents
• Worsening of heart failure
• Cardiac conduction defects
• Worsening peripheral vascular disease
• Loss of awareness of hypoglycaemia
• Exercise related fatigue

Thiazide Diuretics

    Thiazides are the cheapest agents and have the best long-term mortality data for cardiovascular and cerebrovascular disease prevention. Recommended as first line therapy by JNC-VII guidelines after ALLHAT trial success.

Mechanism of Action

1. Natriuretic but weakly compared to loop diuretics. On chronic dosing most patients show little or no reduction in circulating volume.
2. Reduce responsiveness of resistance vessels to endogeneous vasconstrictors
   Eg. Noradrenaline. This may be related to intracellular Na (and hence Ca) or due to an effect on unidentified membrane ion channel.

Adverse Effects

• Impairment of glucose tolerance
• Adverse effect on lipid profile
• Raised blood urate and risk of gout
• Tendency to hypokalaemia
• Impotence
• Photosensitive rashes.

 

Angiotensin Converting Enzyme Inhibitors (ACEI)

e.g. LISINOPRIL and CAPTOPRIL with respectively long & short duration of action.

Mechanism of Action

1. Inhibit the enzyme responsible for conversion of biologically inert angiotensin I to active angiotensin II (ATII)
2. ACEI also block degradation of kinnis (kininase II = ACE). Bradykinin a potent vasodilator.

NB: The effects of ATII on BP (vasconstriction and aldosterone release) are mediated by the type 1 ATII receptors (confusingly referred to as AT1 receptors). The type 2 receptor (even more cvonfusingly dubbed AT@!!) may be important for regulating the matrix response to elevated BP ie. ventricular hypertrophy and resistance vessel remodeling.

 

Adverse Effects

• Dry cough – affects upto 20% of patients; commoner in females and reflects elevated BK levels in the vicinity of airway C fibres.
• Angioneurotic oedema – rare but can be fatal when larynx involved (commoner in Afro Caribbeans).
• Altered taste – only with older agents containing – SH groups eg CAPTOPRIL.
• Risk of hyperkalaemia.
• Deterioration in renal function in patients with renal artery stenosis – glomerular perfusion dependent on ATII.
• First-dose hypotension – only if plasma rennin elevated (eg following DS loop diuretic) hence usually a problem of CCF not hypertension.

NB: Angiotensin receptor antagonists (eg. LOSARTAN, IRBESARTAN) also act on the rennin-angiotensin axis but block AT1 receptors. They may eventually replace ACEI in both hypertension and heart failure BUT.

• There exists no outcome data with AT 1 receptor antagonists for either indication.
• They are licensed currently only for use in hypertension NOT heart failure.
• They are better tolerated than ACEI – they do not cause cough.
• They may be superior to ACEIs in causing regression of LVH due to stimulation of antiproliferative AT2 receptors.

Calcium Channel Blockers

Classification

• Dihydropyridines (DHPs) – Nifedipine, Amlodipine
• Non-dihydropyridines (non-DHPs) – Diltiazem, Verapamil.

Mechanism of Action

    Inhibit passage of calcium through the voltage gated L-type (for large/long-lasting current) calcium channel on vascular smooth muscle cells and cardiac myocytes, reducing calcium availability for muscle contraction. Note that an inhibitor of the T-type (Transient current) cardiac calcium channel, MIBEFRADIL, has recently been terminated due to unacceptable drug interactions. Ion channel blockade explains the observed.

• Peripheral vasodilatation
• Negative inotropic and negative chronotropic effects.

Adverse Effects

• Flushing*
• Headache*
• Palpitations* - reflecting the reflex tachycardia in response to vasodilatation.
• Pedal oedema – dilatation of the precapillary 'sphincters' NOT generally a reflection of worsening heart failure!.
• May worsen heart failure due to their negative inotropic effect**.

* These effects are most commonly reported when absorption is rapid causing a prompt vasomotor response; particularly with early 'instantaneous' release formulations of nifedipine. Agents with a slow onset of action (eg. AMLODIPINE) or reformulation as a 'sustained' release preparation markedly reduces these problems.

** Most agents are negatively inotropic – non-DHP CCBs more so than DHPs. AMLODIPINE is exceptional in having a 'neutral' inotropic effect and is well tolerated in heart failure (PRAISE study).

NB: Non-DHPs also have AV nodal blocking properties (verapami>diltiazem) that preent any reflex tachycardia. They may also interact with other agents affecting conduction: beta-blockers should be combined with verapamil cautiously.

 

WHY SHOULD PHARMACISTS BE INVOLVED IN HYPERTENSION MANAGEMENT?

Advantages

    More than 200 million people visit a pharmacy every day in Europe. A community pharmacist is a highly trained professional who can be seen without appointment, in an informal setting which is often considered to be part of an every day shopping experience. Pharmacists are therefore the most highly accessible members of the primary health care team. Community pharmacies are visited by both people who are sick and people who are in good health. Therefore community pharmacies have a potential for health promotion and disease prevention. Regular visits of a person with hypertension for prescribed drug therapy puts the patient in a regular contact with the pharmacist and provides opportunities for intervention. The pharmacist can complement the GP in hypertension management in various ways (7-10). The following are examples of such opportunities where pharmacists participate with other health care professionals in community based health promotion and disease prevention and management programmes.

• Pharmacists have an extensive knowledge about the principles of drug therapy, use of medicines and prevention.
• Pharmacy can verify and improve the patients' knowledge about necessary lifestyle modifications and the use of medicines and improve compliance with therapy.
• Pharmacists can identify drug therapy related problems and recommend possible solutions including referrals to the GP.
• Pharmacists can monitor therapeutic outcomes of hypertension management.

Adherence to long-term therapies

    Pharmaceutical care is an effective approach in improving adherence to long-term therapies.

    Advice, information and referral by community pharmacists have been demonstrated to significantly improve adherence to antihypertensive therapy and improve blood pressure control.

Pharmacists are also involved in giving information and service to patients with hypertension. It has been shown that after having provided appropriate health education and monitoring services to patients with hypertension, primary care pharmacists managed to get patients to use less expensive antihypertensive medication. Parents with hypertension received pharmaceutical care from community pharmacies comprehending education, assistance to reach compliance and recommendations to their GPs regarding drug therapy. In several studies the intervention group showed a significant decrease in mean blood pressure.

The involvement of pharmacists in hypertension management falls in line with the Good Pharmacy Practice document developed and adopted in 1994 by the Pharmaceutical Group of the European Union (PGEU). It represents the first set of standards for pharmacy practice developed by the Profession and with the international standard for Good Pharmacy Practice (GPP) in Community and Hospital Pharmacy Setting developed by WHO. The first element of Good Pharmacy Practice is Health Promotion and Ill-health Prevention and according to the document a number of national standards have to be elaborated within this area. Currently, new programmes involving community pharmacies in Good Pharmacy Practice programmes or pharmaceutical care programmes are being developed and introduced. Some midterm results from Portugal, Spain and United Kingdom show that community pharmacists are capable of providing pharmaceutical care leading to good results with regards to optimizing the drug therapy and achieving more cost effective outputs.

 

    Many patients with diabetes mellitus and hypertension were not treated according to guidelines, with 47% of the patients meeting the 2003 guidelines definitions of hypertension not being treated with antihypertensive medications. By reducing the cut points for defining hypertension, the proportion of people affected increased substantially. Specific risk factors determined may aid in identifying patients at high risk for inadequate treatment. Patient and provider education, public health approaches, and health system changes are needed to address these issues. Further work is needed to determine the reasons for lack of control, approaches to improve control and long term patients outcomes, and the budget impact and cost effectiveness of using the 2003 guidelines.

    Hypertension is an additional risk factor in those with diabetes mellitus for macrovascular and microvascular complications. The health and budgetary impacts of addressing the treatment gap need to be further explored.

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Cite this: Boban Devasy, K. Nisar "Pharmacotherapy of hypertension", B. Pharm Projects and Review Articles, Vol. 1, pp. 209-234, 2006. (http://farmacists.blogspot.in/)