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102 Chapter 5 Hypertension
DH:
1) Bendroflumethiazide
Note: In some parts of the world bendroflumethiazide is called bendrofluazide.
Poor control of hypertension by drugs may be due to poor compliance (i.e. patient not taking drugs
as prescribed). Andreas openly admits to not taking the medication prescribed.
O/E:
1) Blood pressure (systolic/diastolic) = 210/135 mmHg (ideal <140/90 mmHg)
The recommended values are less than 140/90 mmHg. Andreas’s blood pressure (BP) is extremely
elevated. Blood pressure this high represents a medical emergency because of the high risk of renal
damage, retinopathy, stroke, encephalopathy, or myocardial infarction (heart attack).
2) Pulse = 60/min (normal)
Biochemistry:
1) Sodium = 142 mmol/l (normal 135–145 mmol/l)
2) Potassium = 4.2 mmol/l (normal 3.5–5.5 mmol/l)
These are both within recommended range.
Diagnosis: Hypertensive crisis
Plan:
Scenario 1: Start sodium nitroprusside infusion
Scenario 2: Start oral labetalol
LucyexplainstoAndreasthathisheadacheanddizzinesswerebroughtaboutbyhisveryhigh
BP.ShesaysBPof210/135mmHgisamedicalemergency,andcouldleadtopermanentorgan
damage or even death.
PART 1: EXPLORING ANDREAS’S CONDITION
Andreas’s BP was extremely elevated at 210/135 mmHg.
1a) What is the meaning of the two readings? Use the terms ‘systolic’ and ‘diastolic’ in your answer.
1b) What are considered normal blood pressures? How do you assess urgency of treatment on the
basis of blood pressure readings?
2a) What are diastole and systole?
2b) Explain the meaning of the following statement: ‘When left ventricular systole starts, pressure inside
the ventricles rises immediately, but there is a short delay before blood is ejected into the aorta (ejection
phase).’
Refer to Figure 5.5.
WORKBOOK 2 Hypertension 103
2c) Andreas’s diastolic BP is very high. Will this increase or decrease the delay between onset of
left ventricular systole and the beginning of the ejection phase? What effect does this have on stroke
volume?
See Section 5.1.3.
3) Do you think the activity of the sinoatrial (SA) node is a problem in Andreas’s case? Is his pacemaker
slope appropriate? Should we think in his case of using drugs intended to target the SA node pacemaker
slope?
Clue: Consider his pulse. Also refer to Section 5.1.2 and Figure 5.2.
4) Considering that blood pressure = heart rate × stroke volume × total peripheral resistance (Section
5.1.1), which of these three determinants of BP should be the target of drug therapy for Andreas?
5) If we wish to target total peripheral resistance (TPR) using a vasodilatory drug, suggest two types of
drug, one type acting directly as a vasodilator and one type acting at a defined receptor subtype. Give
examples.
6) If we wish to directly target stroke volume (SV) with drugs acting at heart muscle cells, suggest a
receptor target and indicate how drugs acting here may influence SV.
Immediate treatments for Andreas’s hypertension
For this imaginary patient suffering a hypertensive crisis we provide two alternative approaches to
immediate drug treatment once he has been admitted to hospital. In the first, the patient is treated
with an intravenous antihypertensive drug to rapidly reduce BP. It is, however, recognized that a very
rapid drop in BP may lead to inadequate perfusion of critical organs, and so may promote the very
conditions which the treatment is intended to avoid, i.e. heart, brain, retina, and kidney
pathologies. Because of this, the intravenous vasodilator approach (Scenario 1) has fallen out of
favour. If the condition is not deemed life/organ-threatening, clinical judgement may favour an
approach whereby BP is reduced gradually over 24 hours. This could involve the use of oral labetalol,
or a -blocker, and optimizing hypertensive medication according to local recommendations (ACE
inhibitor/calcium channel blocker).
Either approach would then be followed by a long-term strategy optimizing oral medication with the
aim of reducing BP beyond the 140/90 mmHg systolic/diastolic target.
These two alternative approaches for Andreas, once he arrives at hospital, are explored below.
Scenario 1: Intravenous vasodilator
Lucy explains that sodium nitroprusside will be administered to bring down Andreas’s BP
quickly. If his BP is not reduced immediately, it could lead to damage to the retina, heart attack,
stroke, or kidney failure. The drug has a very short half-life so must be given by intravenous
infusion, which also contributes to a rapid onset of action.
Once introduced into the bloodstream, sodium nitroprusside rapidly distributes around the body. It
diffuses into vascular smooth muscle cells (arterial and venous), where it interacts with sulphydryl
groups and generates nitric oxide (NO) within the cells, causing widespread vasodilatation. For more
on NO, see Box 5.2.
104 Chapter 5 Hypertension
7) In normal vascular physiology endothelial cells regulate local vasodilatation by synthesis and release of
NO, which then acts on the adjacent vascular smooth muscle cells. Draw a simple diagram showing how
this works, and indicate where sodium nitroprusside interacts with this system.
(Refer to Box 5.2)
Note the widespread vasodilator action of the drug, and use the knowledge you have gained about
the cardiovascular system to work out the consequences for heart function.
8a) What effect will sodium nitroprusside have on peripheral resistance?
8b) How does this affect:
• afterload?
• blood pressure?
8c) What effect will sodium nitroprusside have on central venous pressure and how will this lead to
changes in:
• preload?
• end-diastolic volume?
• force of contraction of the ventricles?
Andreas’s BP is checked every 5 min after commencing the sodium nitroprusside infusion. After
15 min, it has dropped to an acceptable level. The infusion is then tapered off, and stopped
over a period of time.
Investigations 15 min after infusion: BP = 170/95 mmHg (target <145/95 mmHg).
This is still elevated, but Andreas can be considered as being over the ‘crisis’. His current BP can
now be reduced slowly, using oral medication.
Moniqueisamazedathowquicklythisdrughasworked.
Sodium nitroprusside is mainly used for a fast effect, although it may be given intravenously over a
large number of hours if necessary. The drug is, however, broken down in the body to produce a
toxic thiocyanate product. For longer-term administration (e.g. 48 hours), the patient must be
monitored for cyanide toxicity. If this occurs, intravenous labetalol administered with close
monitoring, might be an alternative (see below).
Scenario 2: Oral labetalol
Lucy explains that a regime for bringing down Andreas’s BP over 24 hours will be used. This is
considered the safest option, and Andreas will be kept in hospital during this time.
Andreas is started on oral labetalol with regular BP checks.
After 24 hours his BP is down to 175/100 mmHg.
Labetalol can also be administered intravenously as a continuous infusion for a rapid response.
WORKBOOK 2 Hypertension 105
9) What is the mechanism of action of labetalol? What makes it different from other widely used
-adrenoceptor antagonists?
Note: What receptor subtype(s) does it act on?
Long-term treatment for Andreas’ hypertension
By the next day Andreas is feeling well, and talks with Lucy about his condition and its
treatment. He is embarrassed at having failed to take his earlier medication for hypertension—
afterallheisapharmacist!—andherecognizesthatthismeanshewaspartlyresponsiblefor
his crisis the day before. He wants to discuss his treatment.
10) List three illnesses which Andreas’ hypertension could cause if left untreated.
The doctor explains to Andreas that the choice of antihypertensive is based on the following:
• cost
• tolerabilityinindividualpatients
• concomitantdisordersandcontraindications(e.g.patientswithheartfailureshoulduseACE
inhibitors; patients with gout should not be given diuretics)
• raceandage.
Itisdecidednottoprescribebendroumethiazide.
11) Why has Andreas not been prescribed bendroflumethiazide? Consider the treatment algorithm for
newly diagnosed hypertensives (Figure 5.10 and Section 5.3). How do you think this should be applied
to Andreas, who is a young white male?
12a) To which class of drugs does bendroflumethiazide belong?
12b) Where is the site of action of these drugs?
12c) How do drugs from this class act to reduce BP (Section 5.2.2)?
12d) Is there any reason to consider that the antihypertensive effect of these drugs may not be solely
due to their diuretic action (Figure 5.9)?
Lucy explains that Andreas’s BP had probably risen gradually over a long period.
Andreassheepishlyadmitsthathehadoftenexperiencedstrangeheadachesanddizzyspells,
but had dismissed them as minor.
He admits that he had intentionally not complied with treatment for his hypertension. This was
becauseaftertakingthebendroumethiazideforaweek,hehadrealizedthatheneededto
urinate more often, particularly at night. The hypertension had only been diagnosed during a
physical examination requested by his insurance company, and as he had no symptoms, he
had quite quickly stopped taking the medication.
106 Chapter 5 Hypertension
13) To minimize non-compliance, Andreas should have been advised to take bendroflumethiazide in the
morning. Explain why.
14) What first-line treatment should be considered for Andreas once his hypertensive crisis is over?
Jo, the pharmacist, discusses Andreas’s case with the doctor; they decide that an angiotensin-
convertingenzyme(ACE)inhibitoristhebesttreatmentforAndreas.Heisprescribedlisinopril.
Andreas agrees that from now on he will take his medication every day without fail.
15) Which octapeptide’s formation will be blocked by the ACE inhibitor when Andreas starts taking it to
reduce his BP? What is the whole system called?
16) Do you think that the ACE inhibitor alone is likely to be sufficient to control Andreas’s BP in the long
run? Explain.
17) Referring back to question 4, which of the three determinants of BP (stroke volume, heart rate, and
peripheral resistance) will be most directly modified by the ACE inhibitor?
18) The ACE inhibitor will be expected to have an indirect effect on kidney function through aldosterone.
Explain this effect.
When Andreas was training he was taught that -adrenoceptor antagonists (-blockers) were
commonly prescribed for the long-term treatment of hypertension. He mentions this to Lucy,
and asks why they have not considered -blockers in his case. Lucy asks the pharmacist to join
them, and they discuss the situation regarding -blockers.
19) Why were -blockers not prescribed for Andreas?
In the UK, prescribing of -blockers (more formally -adrenoceptor antagonists) has changed over the
last few years. These drugs have a long history as major antihypertensive drugs, and are still used for
hypertension and other indications. However, in many countries, including the UK, they are no longer
recommended as first-line antihypertensive therapy for newly diagnosed patients, where alternative
antihypertensives are believed to produce a better outcome with less associated adverse effects.
20) When might it be appropriate for a patient to be taking -blockers to control hypertension?
21a) What is the mechanism by which -blockers influence BP? Which receptors are influenced and
where are they found (see Section 5.2.5)?
21b) How does activity at these receptors change cardiac function?
Clue: Draw a ventricular myocyte action potential, and illustrate the effect on the calcium plateau of
(i) stimulating -adrenoceptors and (ii) a -adrenoceptor antagonist. Describe what the effect will
be on cardiac function (i.e. force of contraction, stroke volume, cardiac output).
21c) Are effects of -blockers also expected at sinoatrial node action potentials?
Jo, the pharmacist, and the registrar talk in detail about -blockers. They use words like
cardioselective and non-selective.
WORKBOOK 2 Hypertension 107
22) List some of the possible unwanted effects of -blockers.
23a) Why might a drug that is selective for 1 receptors over 2 receptors be of clinical interest? How
would this relate to the notion of a cardioselective drug?
23b) Are there -blockers that can be freely prescribed to asthmatics?
Jo and Lucy point out to Andreas that the current guidelines do not recommend -blockers for
a young white patient, and that some of their side effects mean that they may not be the most
suitable drugs for him. The side effects she mentions include impotence, and there are risks
associated with sudden discontinuation, of particular concern considering Andreas’s
compliance history.
Andreas is determined to try and remember his cardiovascular pharmacology from his college
days, and asks why he has not been prescribed calcium channel blockers. He also mentions
that his line manager at work was recently diagnosed as hypertensive, and was given
amlodipine. Lucy asks about his ethnicity, and it turns out that he is of African origin.
Jo points out that initial prescribing for hypertension is related to race and age, and that
patients aged over 55 years, and patients of any age who are of African or Caribbean origin, are
expected to have a less satisfactory response to ACE inhibitors as a first-line drug; they are
therefore likely to be prescribed a calcium channel blocker.
24) Why are patients over 55 years, and those of any age who are of African Caribbean origin, not
prescribed ACE inhibitors first-line?
25a) What is the effect of a calcium channel blocker? What type of calcium channels are blocked by
therapeutically significant calcium channel blockers?
25b) What effect do calcium channel blockers have on blood vessels?
Andreas knows the dihydropyridine calcium channel blockers but cannot remember the names
of the non-dihydropyridines. Lucy tells him.
26) List the two non-dihydropyridine calcium channel blockers.
Which one is cardioselective?
• Thedihydropyridinenifedipinepreferentiallyaffectscalciumchannelsinthevasculature,withlittle
effect on the heart.
• WhentheBPisrapidlyloweredbynifedipinetheheartcompensatesbybeatingfaster;thisiscalled
reflex tachycardia.
• Acardioselectivenon-dihydropyridinereducesBPbydirectlyactingonthehearttoslowthecardiac
pacemaker, and therefore does not cause reflex tachycardia.
Andreas is discharged from hospital and takes his lisinopril regularly. He attends the local
hypertension clinic frequently to check his BP. Although the ACE inhibitor successfully lowers
Andreas’ blood pressure, he quickly develops a horrible dry cough which he can’t stand.
108 Chapter 5 Hypertension
The enzyme ACE is responsible not only for the synthesis of angiotensin II, but also for the
breakdown of bradykinin. ACE inhibitors allow this peptide to accumulate in the upper respiratory
tract, which is believed to be the reason for the cough.
To replace the ACE inhibitor, Andreas is prescribed losartan, an angiotensin II receptor
antagonist (or angiotensin receptor blocker (ARB), also known as ‘sartans’).
27a) What is the mechanism of action of angiotensin II receptor antagonists? At which receptor type are
they antagonists? How does this lead to reduced blood pressure?
See Section 5.2.1 and Box 5.1.
27b) List two physiological functions controlled by angiotensin II acting on this receptor.
28) Why are angiotensin II receptor antagonists less likely to cause a cough?
Andreas takes the losartan as instructed and the cough soon disappears. This treatment is,
however, also unsatisfactory since on repeated measurements in the hypertension clinic his BP
is found to be around 170/105 mmHg, a long way from the target of <140/90 mmHg; this
substantially increases (more than doubles) his chances of having a major cardiovascular event.
Thedoctormentionsthateventuallyathiazide-relateddiureticcouldbeprescribed,butthathe
also wants to consider other drugs.
29a) Multiple drug prescribing is commonly required to reach target BP. What are the three main drug
types used in hypertension, one or more of which is likely to be added to Andreas’s treatment?
29b) Which of these would you prescribe as a second drug for Andreas to take with his losartan?
Explain your answer, not just in terms of the guidelines indicated in Figure 5.10, but also in terms of the
complementary mechanisms of action of the drugs.
30) Other drugs are available if targets are not reached with two drugs. Set out a long-term strategy for
treating Andreas, making the assumption that first three and then four drugs are prescribed in an attempt
to reach the target.
Chapter 6
Atherosclerosis and ischaemic
heart disease
Useful terms for this topic
Angina: Symptom of chest pain resulting from
reduced oxygen supply to the heart.
Atherogenesis: Development of an atherosclerotic
plaque/atheroma.
Atherosclerosis: Growth of plaque (atheroma) on
inner face of artery, leading to narrowing of blood
vessel.
Chylomicrons: Lipoproteins that carry dietary lipids
away from the intestines.
Coronary arteries: Blood vessels supplying the heart
muscle.
Dyslipidaemia: Alterations in the levels of circulating
lipoproteins, or of their composition.
Ischaemia: Inadequate blood supply to an organ/part
of the body, starving cells of oxygen.
Ischaemic heart disease: Reduced supply of oxygen
to the heart muscle.
Lipoproteins: Macromolecular complexes of lipids
and proteins, which enable lipids to be carried in the
bloodstream.
Myopathy/myositis: Disease/inammation of skeletal
muscle.
Necrosis: Death of tissue which can result from
prolonged ischaemia.
Myocardial infarction: Death of heart muscle tissue,
heart attack.
Myocardium: Heart muscle.
If a man of 20 develops acute and uncomfortable chest
pains, he is likely to put it down to indigestion and wait for
it to go away. If, however, this happens to a 60-year-old
man, the response may be quite dierent, and the
individual may fear that the pain is caused by heart
disease and that it could lead to a heart attack. e fear is
not without foundation, and so these symptoms require
prompt clinical investigation. Such a situation is explored
in the case of our imaginary patient Brian in Workbook 3
at the end of this chapter. Of course, chest pain can be
unrelated to heart disease, but it can also, as in Brian’s
case, result from partial blockage of coronary arteries.
ese blood vessels serve the heart; their blockage
reduces the supply of oxygenated blood to areas of the
heart muscle, and so causes myocardial ischaemia, or
ischaemic heart disease (also referred to as coronary
heart disease/coronary artery disease). is can result in
angina pectoris, the symptom of chest pain often
radiating to the neck, jaw, and arms (particularly the left),
which occurs without permanent damage to the heart.
However, when ischaemia is prolonged or extensive it can
lead to the death (necrosis) of heart tissue (a heart attack,
also called a myocardial infarction; MI). ere is
commonly, but not always, underlying disease of the
coronary arteries caused by atherosclerosis which has
developed over preceding years. Angina can be taken as a
warning that ischaemic heart disease exists, enabling
interventions to reduce the risk of a later MI. (More rarely,
myocardial ischaemia can occur in the absence of chest
pain.) e development of atherosclerotic disease can be
inuenced by changes to lifestyle and by medication. e
course of angina or a heart attack can also be modied by
a variety of drugs which can profoundly increase the
patient’s chances of survival. In this chapter we will study
the process of atherosclerosis, and the events associated
with angina and heart attack, in order to understand how
these drugs work, and how they may be best employed in
the treatment of individual patients.
Ischaemic heart disease is the most common cause of
death worldwide. In the UK it is estimated that around two
110 Chapter 6 Atherosclerosis and ischaemic heart disease
Increased cardiac work
million people suer from its most common symptom,
angina, and ischaemic heart disease causes approximately
100,000 deaths each year. In the majority of these fatal
cases there is no long-term record of heart disease. Such
observations highlight an obvious need for improved
prevention and treatment. Lifestyle changes, including
regular exercise, reduction in alcohol intake and cessation
of smoking, healthy eating, and stress reduction, oer
great benet in the prevention of ischaemic heart disease.
ere is also room for improved use of the drugs which are
already available. Finally, as our understanding of the
cellular and molecular events underlying ischaemic heart
disease improves, it will no doubt lead to the development
of better pharmacological tools.
6.1 Coronary arteries, heart muscle, and oxygen supply
and demand
e heart is mainly muscle, which contracts about once
per second throughout a person’s life. e frequency and
force of contraction varies according to the activities of
the individual, changing the amount of work done by the
heart and therefore its demand for oxygen. Oxygenated
blood is supplied to the heart by the coronary arteries.
ese course along the surface of the heart (Figure 6.1),
sending arterioles deep into the muscle tissue.
In a healthy person, an increased demand for oxygen by
the heart is met by an increased supply. is is achieved
by dilatation of the coronary arterioles, resulting in
enhanced blood ow and hence increased oxygen supply
to the heart muscle. In ischaemic heart disease, the
internal surface of the artery wall becomes thickened and
lined with an atherosclerotic plaque, which reduces the
maximum lumen of the blood vessel and can restrict the
vessel’s ability to dilate when required to do so. is
partial occlusion of the coronary arteries may mean that
the ow of blood cannot be increased suciently for the
oxygen supply to meet its demand, for instance when the
heart works harder. is can then lead to ischaemia and
angina (Figure 6.2).
Right coronary
artery
Left coronary
artery
Left anterior
descending
coronary artery
Figure 6.1 The major vessels that are blocked in
ischaemic heart disease are found on the surface of
the heart.
Arterioles of diminishing size then descend into the muscle walls
of the ventricles. When the major coronary arteries are partially
blocked, there is a reduction in the maximum flow of blood that
fully dilated arterioles can deliver to the heart muscle tissue. In
addition to those shown here, the left circumflex coronary artery
is often affected in ischaemic heart disease.
Oxygen demand increases
Healthy heart
Increased
blood supply
Oxygen demand
= oxygen supply
Figure 6.2 Cardiac ischaemia occurs when the coronary
blood vessels cannot deliver enough blood for the oxygen
supply to meet the demand of the heart muscle cells.
Unhealthy heart with partly
occluded coronary arteries
Cannot sufciently
increase blood supply
Oxygen demand
> oxygen supply
= ISCHAEMIA
e partial occlusion of the coronary arteries can come
about in three ways.
1) Growth of an atherosclerotic plaque on the blood
vessel wall, producing a stable partial block.
6.2 Atherosclerosis 111
2) Blockage by thrombus/embolus, which can develop
rapidly and be unstable, and may occur as a
consequence of long-term atherosclerosis.
3) Contraction (spasm) of coronary arterial smooth muscle.
ese dierent causes of ischaemia underlie the
clinical categories of angina discussed in Section 6.4.2
6.2 Atherosclerosis
Atherosclerosis is a disease in which the growth of
plaques on the inner face of arterial blood vessels results
in them becoming narrowed and unable to dilate; clearly,
if this happens in a blood vessel serving the heart (a
coronary artery) it gives rise to a serious situation—this is
ischaemic heart disease.
Essentially, atherosclerosis is a focal disease of the arterial
tree that aects the tunica intima (i.e. the inner lining) of
large and medium-sized arteries. e formation of a
brous plaque, or atheroma, results in a decrease in the
size of the lumen of the aected blood vessel, reducing
blood ow through it. ere is, in addition, a risk that the
plaque itself may rupture, and can then act as a focus for
the generation of a thrombus (see Chapter 4).
e essential features of atheroma formation are:
1) a compromised or dysfunctional endothelial layer
2) accumulation within the intima of cholesterol/lipids,
vascular smooth muscle cells, and cellular debris,
occurring together with local inammation
3) the formation of a brous plaque, which develops a
calcied surface as it matures.
e process is intimately aected by the levels and forms
of circulating cholesterol, a subject we must review before
looking at the initiation and maturation of an atheroma in
more detail.
and depicted in Figure 6.8. Atherogenesis (the
generation of an atheroma or atherosclerotic plaque) is
the principal long-term pathological process contributing
to ischaemic heart disease. We shall now consider this
process and the way in which it can be modied
by drugs.
hormones, vitamin D, and bile salts. e major site of
cholesterol synthesis is the liver, although the intestine
also forms signicant amounts. Cholesterol is transported
around the body in the blood, both towards and away
from tissues, in the form of lipoproteins.
Triglycerides are obtained from the diet as well as being
produced in the liver from the metabolism of fats,
carbohydrates, alcohol, and cholesterol. ey are stored
as fat in adipose tissue, and represent a form of
transportable energy, supplying fatty acids as fuel for
muscle and other tissues. Triglycerides, like
cholesterol, are mobilized in the blood in the form
of lipoproteins.
Lipoprotein particles are complexes consisting of a core
of hydrophobic lipids, which include triglyceride and
cholesterol esters, surrounded by a shell of more polar
lipids and proteins (apolipoproteins). e protein
component serves two roles: to solubilize the
hydrophobic lipids, and to act as targeting molecules
which interact with specic receptors on the destination
cells. e complement of apolipoproteins therefore varies
between the types of lipoproteins according to their role.
In this way, the various lipoproteins transport their lipid
cargoes in well-dened directions between specic
tissues. To understand the role of lipoproteins and the
clinical use of drugs aimed at modifying them, we must
rst consider their dierent types.
6.2.1 Cholesterol and triglycerides
circulate in the form of lipoproteins
in the blood
Cholesterol is an essential lipid component of the cell
membrane of all cells within our bodies, and it modulates
membrane uidity. Its supply from the blood is a
necessity for cell growth and viability. In addition, it has
more specialized roles as the precursor for steroid
Types of lipoprotein: good or bad?
e movement of cholesterol around our bodies utilizes a
complex system, involving a number of wellcharacterized forms of lipoprotein which transport this
essential lipid in a controlled manner to ensure that all
cells receive the necessary supply to maintain cell
integrity. e lipoproteins have well-dened and distinct
compositions, each varying in the relative proportions of