Hypertension - CSA322 Therapeutics in Practice 3A

2/11/24, 9:38 AM CSA322 Therapeutics in Practice 3A
Hypertension
Intended learning outcomes

On completion of these activities, you should be able to:
Describe the pathophysiology, epidemiology, typical presenting features and

consequences of hypertension.
Demonstrate an understanding of evidence-based pharmacotherapy for

hypertension, including potential adverse effects, precautions and appropriate
monitoring.
Demonstrate the ability to advise on appropriate strategies for management of

individual patients with hypertension
This content has been updated in 2023 to reflect therapeutic developments.
Please note this module contains definitions important to all therapeutic

topics.
Recommended reading
Therapeutic Guidelines (eTG): Blood pressure reduction 
 Guideline for the diagnosis and management of hypertension in adults (Heart

Foundation 2016)
NPS: What is hypertension (2020). Article and podcast  available.
Hypertension
Hypertension (HTN) is one of the most common medical conditions in the world. It is defined as persistently
elevated arterial blood pressure.
https://mylo.utas.edu.au/d2l/le/content/561556/viewContent/4790095/View 1/33
Not surprisingly, drugs to treat hypertension are amongst the most widely used of all medications, both here in
Australia and overseas.
Based on measured data from the 2017–18 Australian Bureau of Statistics National Health Survey 
, about 1 in 3 people aged 18 and over (34%) have high blood pressure.
Blood pressure values increase with age and the lifetime risk of developing hypertension in those 55
years and older who are normotensive is 90%.
Importance of blood pressure

The presence of ‘blood pressure’ is essential for functioning organs.
Without adequate pressure, vital organs (eg. kidneys, liver) can reduce function, fail and lead to mortality
(due to reduced oxygen supply).
It is also necessary for the body to moderate blood pressure to the level required for the body at a
particular time. For example, when the sympathetic nervous system is activated (‘flight or fight’), blood
pressure is increased.
Blood pressure is a medical concern when it is sustained at a high level for an unknown reason. This is
unnecessary and undesirable.
There are multiple body systems involved in maintaining an appropriate blood pressure.
Your learnings through therapeutics, over multiple body systems, will assist in your understanding of blood pressure
maintenance. For instance, kidneys (renal system) are a major contributing system to blood pressure control.
Pathophysiology of hypertension
Blood pressure is a product of:

Cardiac output
Peripheral resistance
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Although many factors are involved in BP control, two systems are particularly important:
Renin-Angiotensin-Aldosterone System (RAAS)
Sympathetic Nervous System (SNS)
Reproduced from US guidelines 
Signs and Symptoms

Going forward with pharmacotherapeutics study, we will commonly be discussing ‘signs and symptoms’ of
conditions. To distinguish signs and symptoms, please note the following definitions:
 Signs
Are things we can see or measure
General examples include internal bleeding, a rash, etc.
In hypertension a sign would be elevated BP
Signs are objective
 Symptoms
Are things that a person feels
General examples include nausea, dizziness
In hypertension, a symptom could be a headache
Symptoms are subjective
Signs and symptoms of Hypertension

There are often none! Hypertension is a largely asymptomatic disease and it is sometimes referred to as
the silent killer.
This is particularly the case when the BP is only modestly elevated.
As hypertension is an asymptomatic, or ‘silent’ disease, it is difficult to identify, diagnose and manage.
That is why it is important (where possible) for measurement of blood pressure to occur at health care
encounters.
Patients with hypertension, and other asymptomatic conditions, may struggle with compliance to
medications and lifestyle changes as they cannot experience changes in their wellbeing (rather prevent
undesirable outcomes such as stroke or heart attack).
If symptoms do occur, they are largely vague and non-descript to form a diagnosis:
Pressure S&S Vascular S&S
• Dizziness • Bleeding e.g. epistaxis
• Palpitations • Blurred vision
• Fatigue • Manifestations of cerebral ischaemia (e.g.

weakness/dizziness) or myocardial ischaemia
• Headache (occipital)
(e.g. chest pain)
• Heart failure e.g. oedema
• Renal impairment
Signs and symptoms of Hypertension
Risk factors of Hypertension
The main risk factors for hypertension are largely lifestyle based and align with risk factors for CVD:
Age
Family history
Diet including high salt intake
Alcohol intake
Smoking
Obesity and weight gain
Physical inactivity
Patients with dyslipidaemia and type 2 diabetes (T2DM) are also at risk of having hypertension.
These conditions are largely affected by the above lifestyle risk factors and are too, often
asymptomatic (initially for T2DM).
Another risk factor for hypertension is the administration of medicines that may increase blood
pressure.
Substances and medications that may influence blood pressure.

Source: Guideline for the diagnosis and management of hypertension in adults, Heart Foundation 2016.
 Sodium content in medications
As dietary sodium can be an issue, there are medicines that contain a considerable amount of sodium that
may increase blood pressure.
For instance, soluble tablets (such as paracetamol) and some IV antibiotics (such as piperacillin with
tazobactam).
Whilst there is little risk when these medications are used short term, the use of soluble tablets
over time may be associated with an increased risk of cardiovascular events (George J et al,
BMJ 2013; 347: f6954).
Further, recent cohort studies  found that sodium-containing (effervescent or soluble)

paracetamol (acetaminophen) use was associated with a statistically significant higher risk of
incident cardiovascular disease and all-cause mortality compared with non-sodium-containing
paracetamol in individuals with or without hypertension.
Source: Zeng, C. et al. Sodium-containing acetaminophen and cardiovascular outcomes in individuals

with and without hypertension. European Heart Journal, 2022; ehac059,
https://doi.org/10.1093/eurheartj/ehac059 
Importance of blood pressure control

As discussed in your Cardiovascular risk module, hypertension is a major risk factor for CVD.
The major issue is that consistent elevated blood pressure increases the risk of major CVD
events (such as myocardial infarction and stroke).
Whilst management of these events has improved over decades, patients who experience
significant events still experience morbidity and mortality, either immediately during the
event or for years post-event (for instance, heart failure after myocardial infarction).
Therefore, blood pressure management aims to reduce the risk of these CV events occurring -
rather than focusing on the blood pressure results (and reducing them) for the sake of it.
Sometimes, hypertension is referred to as a disease, however, it is more appropriate to

consider it a risk factor for other diseases.
Morbidity and mortality
Morbidity: Ill health in an individual, and levels of ill health in a population or group (i.e. affect on quality of life)
Mortality: Death
Reference: https://www.aihw.gov.au/reports-data/health-conditions-disability-deaths/burden-of-disease/glossary 
There are many adverse consequences of hypertension on the CV system. Other systems are also affected:
Source: Saler, et al. NEJM 2018 
There is a direct relationship between hypertension and stroke, and hypertension and coronary heart disease.
This has been known for decades:
Lancet 1990
Categories of hypertension
Hypertension may be:
 Primary ('essential')
No specific underlying cause (condition or medication) is identifiable as numerous factors are known
to contribute to the pathogenesis of hypertension
Accounts for >90% of cases
 Secondary
Where something causes BP to be elevated
Many possible causes (eg. conditions or medications)
Some patients initially thought to have primary hypertension are later found to have secondary
hypertension
Secondary Causes of Hypertension
Source: "Hypertension." DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12e Eds. Joseph T. DiPiro, et
al. McGraw Hill, 2023
Blood pressure measurement
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As hypertension is largely asymptomatic, the ongoing review of blood pressure is essential. Blood pressure
measurements report both:
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
Conventionally we report BP as SBP/DBP and in units of mmHg
e.g. 160/95 mmHg
The gap between the SBP and DBP is known as the ‘pulse pressure’ and this tends to increase with age.
Both SBP and DBP impact on clinical outcomes, but the impact of SBP elevation is greater*
*Reference: Flint A et al, NEJM 2019 
 Measurement of BP
Appropriate measurement of BP is an essential starting point and requires:
Validated equipment
Competent operator
Correct technique
Prior rest
Position of cuff
Cuff size
The arm position and whether sitting or standing also affects blood pressure result.
Diagnosis of hypertension should not be based on just one BP measurement. Several BP measurements are
needed, typically:
Over several clinic appointments (days/weeks apart)
Within each clinic appointment
Factors affecting BP levels include:
Time of day
Recent smoking/caffeine, anxiety, acute pain etc.
Record results and communicate to patients
Blood pressure monitoring methods
Traditionally, blood pressure monitoring occurred in a GPs office

(clinic blood pressure). There are now alternatives!
There is an opportunity for pharmacists with access to blood

pressure monitoring to provide BP monitoring. Pharmacists can
be involved in the ongoing monitoring and recording of blood
pressure results.
The purchase of a blood pressure machine allows for home blood

pressure monitoring (HBPM). This may encourage patients to
have more active interest in their disease, make changes to
lifestyle and reinforce need for medication adherence.
Ambulatory blood pressure monitoring is also available (ABPM). Source: Guideline for diagnosis and
ABPM measures blood pressure every 15-30 minutes over a 24- management of hypertension in adults (2016)
hour period to determine if hypertension is sustained.
White coat hypertension

'White coat' hypertension is common. A patient's contact with healthcare professionals
(including GP and pharmacists), or the clinical environment, may lead to a rise in BP. This may
cause a false diagnosis of hypertension or a false impression of poor control in those with
hypertension (leading to over treatment). Conversely, some people may have 'masked
hypertension' - blood pressure is normal during measurements but elevated at other times.
Dippers, Non-Dippers and Reverse Dippers?!

The circadian pattern of BP usually follows a person's sleep/ wake cycle where we see a 'dip' in BP when
a person is asleep in comparison to when they are awake.
However, over a number of decades of research we now know that not all people are 'dippers'. There are
also significant cohorts of people who are 'non-dippers' (their BP does not dip at night) and 'reverse
dippers' (where their BP increases at night). Without detection and management, these cohorts have
poorer cardiovascular outcomes.
Because of these fluctuations in BP and other factors that affect BP mentioned above, ABPM is
considered the gold standard for identifying hypertension.
24Hr Ambulatory Blood Pressure Monitor
View in new window 
Additional reading:
Measuring blood pressure - NPS MedicineWise 
Hypertension diagnosis and definitions
The diagnostic threshold for hypertension depends on the method of measurement.
With in-clinic measurements, the diagnostic threshold is ≥ 140/90mmHg

However, there is a strong recommendation for patients to be offered ambulatory/home monitoring
to confirm blood pressure level
But results with different techniques not equivalent, therefore these must be taken into account. For
example: A daytime ambulatory or home blood pressure of 135/85 mmHg is approximately equivalent
to a clinic blood pressure of 140/90 mmHg
Therefore when diagnosing hypertension, important to know what technique used
Research also suggests patients with more variable BP may be at higher risk of CVD
Optional additional reading: Clark D et al, JAMA 2019. 
Commencing antihypertensive therapy
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"Lifestyle modification is indicated for all patients with hypertension, regardless of drug therapy, because it may
reduce or even abolish the need for antihypertensive drugs."
Guideline for the diagnosis and management of hypertension in adults 2016
Please refer to the relevant section in the Lifestyle Interventions module
Consider existing medication

Before commencing another medicine, remember that a patient's
currently prescribed medications can cause (or contribute to) another
medical condition!
As a pharmacist, it is important to review a patient's list of medications

to identify if hypertension is caused by an offending drug (and if so, to
 avoid a prescribing cascade).
If there is an offending drug:
it may be reduced, stopped or replaced with an alternative that carries no risk

of a lower risk of aggravating hypertension
if considered essential, the offending drug may be continued, and hypertension

then treated
Several factors influence the decision to initiate drug treatment:
Absolute CVD risk - See relevant section in Cardiovascular risk module
Degree of elevation of blood pressure- See relevant section in Cardiovascular risk module
Presence of target organ damage
Family history of premature CVD
Aboriginal and Torres Strait Islander status
Another important factor is the patient’s willingness to commence treatment. It may be influenced by their
understanding of HTN and the potential adverse consequences, beliefs about medicines etc.
Pharmacological treatment of hypertension
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Recommended Other options
There are currently four main classes of However, for some patients, with certain medical
anti-hypertensive medicines conditions, or uncontrolled hypertension, the
recommended for use in Australia: following medication classes may be of benefit:
Angiotensin converting enzyme Beta-blockers

inhibitors (ACEIs)
Alpha-blockers
Angiotensin receptor blockers
(ARBs) Centrally-acting agents
Calcium channel blockers (CCBs) Vasodilators
Thiazide and ‘thiazide-like’ Aldosterone antagonists

diuretics
Pharmacological management of hypertension
Choice of anti-hypertensive should be influenced by:

Patient factors e.g. co-morbidities and age
Effectiveness
 Adverse effects
Cost
Availability
Most anti-hypertensive drugs are effective at lowering blood pressure to a similar degree (at
equivalent doses).
However, effectiveness of anti-hypertensive medications is more meaningful when the medicine is effective at
reducing the risk of CVD (e.g. stroke and MI).
The recommended medications provide an improvement in 'clinical outcomes' rather than simply an improvement
in blood pressure management. This is illustrated by findings of the ALLHAT study.
Important to remember that when new antihypertensive drugs are launched there is rarely evidence regarding
impact on clinical outcomes. Studies tend to rely on showing BP reduction as a surrogate (or ‘proxy’) for
effectiveness.
 The ALLHAT study
ALLHAT compared four classes of drug:
ACEI: Lisinopril
CCB: Amlodipine
Diuretic: Chlortalidone
α-blocker: Doxazosin
The results of the study showed:
Effect to lower BP was similar, but treatment with doxazosin was associated with worse outcomes
Study: The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in
High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel
Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. 2002;288(23):2981–2997. doi:10.1001/jama.288.23.2981
Starting pharmacological therapy

Guidelines recommend starting with one medicine.
If target BP is not reached within three months:
Check compliance to ensure patient is taking medicine appropriately
If compliance is adequate, continue 1st medicine and commence 2nd medicine

If there are significant adverse effects with a medicine, stop medicine and replace with an
alternative (from a different class).
There is specific dosing advice for adding medicines. See figure below.
A single anti-hypertensive medication will rarely achieve blood pressure target for patients. It is
common a patient will require more than one anti-hypertensive medication.
Source: Guideline for the diagnosis and management of hypertension in adults (2016)
The approach of utilising two medications, rather than increasing dose of single medicine, is recommended as the
synergistic effect of two medicines with differing mechanisms of actions will control BP better than a higher dose
of one drug.
However, increasing the dose of one drug before adding a second may be appropriate in some cases:
Financial and/or compliance barriers
If there is a comorbidity where up-titrating the dose of one medicine may have specific benefits
As always, treat each patient individually and modify the recommended approach accordingly.
Also, while starting with one drug usually recommended, some research supports starting with combinations:
ACCELERATE trial showed starting with a combination of two drugs leads to better initial and sustained
BP control
Research has also found that a ‘Triple pill’ or ‘Quad pill’ approach (containing 3 or 4 antihypertensives at
low doses) delivered good BP control with few side-effects
Another study found using combination therapy initially may even reduce CV events
Nonetheless, a Cochrane review found the current evidence not strong enough to draw firm conclusions
about relative efficacy of initial monotherapy and combinations
Refs: Brown et al Lancet 2011, Chow et al, Lancet 2017, Rea et al Eur Heart J 2018, Wang N et al JAMA Cardiology 2020
and Garjon J Cochrane Database of Systematic Reviews 2020
Persistence, adherence and BP control

Poor persistence and adherence to antihypertensive therapy are major barriers to good BP control.
 Contributory factors:
Lack of symptoms in hypertension
No (short term) incentive to take medication
Concerns about adverse effects
Medication burden
Remember many people with hypertension will be on additional drugs to manage other CV risk
factors, and other non-CV conditions.
Around 20% of people who stop anti-hypertensive treatment do so after a single prescription (Ref: Am J Hyp Feb
2012;25(2):195-203).
Addressing the challenge of poor adherence and persistence with anti-hypertensives is essential.
 Options to encourage persistence in hypertension:
Communication and support with education, shared decision making and considering home BP
monitoring (if appropriate)
Simplifying regimens to support adherence/persistence with once daily doses (where possible),
combination products (if appropriate) and dose administration aids (DAA) and reminder charts
Timing of anti-hypertensives
Recent evidence suggested taking >1 antihypertensive at bedtime may be helpful for:
Improved BP control
Reduction in CV events
Reduction in symptomatic adverse effects such as dizziness
However, the 2022 TIME study (a prospective, randomised, open label, blind endpoint clinical trial) found no
difference between two groups of people taking their antihypertensive medications either in the morning or in
the evening in terms of major CVD outcomes at five years.
Many people express a preference for taking once-daily medication in the morning. So, if this assists with good
adherence and thus improves BP control it makes good sense.
Again this highlights the need to take an individualised approach to management and engage in shared decision
making.
Pharmacological management
Angiotensin Converting Enzyme (ACE) inhibitors (ACEI)

Evidence for ACE inhibitors in hypertension is excellent
Supporting trials: ALLHAT, PROGRESS, ASCOT-BPLA
The most widely used ACE inhibitors in Australia are:

Ramipril: 1.25-10mg/day (usually once daily dose)
Perindopril: 2/2.5-8/10mg/day (always once daily dose) *two salts arginine and erbumine
Both ramipril and perindopril are included in the Top 20 PBS drugs (by highest total prescription volume)
(2021-22)
There are several other ACE-inhibitors used in Australia and overseas: captopril, enalapril, fosinopril,
lisinopril, quinapril, trandolapril, benzepril and cilazapril (very popular in NZ).
There are also several combination products containing an ACE inhibitor (e.g. in combination with diuretic
or CCB)
 ACE-inhibitors: other indications
ACE inhibitors are also approved for use in several other indications:
Heart failure with reduced ejection fracture (HFrEF)
Post-MI
Prevention of MI, stroke and CVD death (high-risk patients)
Diabetic nephropathy
Prevention of progressive renal failure (if proteinuria)
If patients have hypertension, as well as an above condition, ACE inhibitors are an excellent choice!
 ACE inhibitors: selected adverse effects
Hypotension (may present as dizziness/light-headedness)
Persistent dry cough
Hyperkalaemia
Initial increased serum creatinine (reduced renal function)
Angioedema (uncommon)
Therefore, monitoring required for ACE inhibitors includes potassium and serum creatinine.
 ACE inhibitors: key practice points
Baseline/periodic laboratory monitoring of potassium and creatinine
Initiate at low/medium dose
More caution in the elderly or if fluid depleted
Generally avoid combining with other potassium sparing medicines (unless compelling reasons to do
so - risk of hyperkalaemia)
Angiotensin Receptor Blockers (ARBs)

Evidence for ARBs in hypertension is good
Supporting trials: LIFE, VALUE
Most widely used in Australia are:

Candesartan: 2-32mg/day, as once daily dose
Irbesartan: 75-300mg/day, as once daily dose
Telmisartan: 20-80mg/day, as once daily dose
These medicines are very common.

All three are included in the Top 20 PBS drugs (by highest total prescription volume) (2021-22).
Other ARBs include: eprosartan, losartan, olmesartan, valsartan and others are available overseas
(e.g. azilsartan, fimasartan)
Traditionally used second line for patients intolerant to an ACE-inhibitor (e.g. due to cough) but are
increasingly being used first line
Initial studies did not show ARBs favourable for reducing mortality
Optional additional reading: RACGP AFP 2013: ACEIs for cardiovascular risk reduction. Have we taken our
eye off the ball? 
There are also several fixed dose combinations available e.g. ARB + (diuretic +/- CCB)
ARBs and ACE-inhibitors should NOT be combined. The combination increases adverse effects (especially
renal dysfunction) without improving benefit
Optional additional reading: ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in
patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-1559 .
ARBs are also known as AIIRAs, Angiotensin Receptor Antagonists (ARAs) or simple 'sartans'.
 ARBs: other indications
Heart failure with reduced ejection fraction
Post-MI if LVD
Prevention of CV morbidity and mortality (high risk patients)
If patients have hypertension, and one or more of these other conditions, an ARB is a good choice!
 ARBs: selected adverse effects
Hypotension, which may present as dizziness/light-headedness
Hyperkalaemia
Increased serum creatinine/decreased renal function
 ARBs: key practice points (same as ACE-inhibitor)
Baseline/periodic laboratory monitoring of potassium and creatinine
More caution in the elderly or if fluid depleted
Generally avoid combining with other potassium sparing medicines (unless compelling reasons to do
so)
Calcium Channel Blockers (CCBs)

In the treatment of hypertension, the dihydropyridine (DHP) sub-class of CCBs are usually most
appropriate. Other CCBs (non-dihydropyridines, diltiazem and verapamil) are generally only used in
hypertension if indicated for a co-existing condition (i.e. hypertension in a patient with a tachyarrhythmia).
Evidence for DHP CCBs in hypertension is good

Supporting trials : HOT, ALLHAT, VALUE, ASCOT-BPLA
The most common DHP CCBs in Australia are:

Amlodipine: 2.5-10 mg/day, as once daily dose
Lercanidipine: 5-20mg/day, as once daily dose
These are the inherently long-acting agents
Other DHP CCBs available in Australia include:

Felodipine (available in MR)
Nifedipine (available in MR)
Nimodipine (only used for SAH)
Clevidipine (IV - only short term use)
Other available overseas include isradipine, nicardipine and nisoldipine.
The available non-DHP CCB in Australia are:

Verapamil MR: 160-480 mg/day
Diltiazem MR: 180-360 mg/day
There are a few fixed dose combinations available e.g. CCB + (ACEI/ARB +/- thiazide)
 CCBs: other indications
Angina (diltiazem/verapamil preferred)
Tachyarrhythmias (only verapamil or diltiazem)
Raynaud's phenomena (DHPs)
Cluster headaches (only verapamil)
 CCBs: selected adverse effects
Flushing, headache, ankle oedema resistant to diuretics (worse with DHPs)
Bradycardia (with diltiazem/verapamil)
Gum hyperplasia (rare)
 CCBs: key practice points
No routine laboratory monitoring is required
Monitor heart rate for diltiazem or verapamil
Some potential drug interactions:

CYP3A4: esp. verapamil and diltiazem, but also amlodipine
P-glycoprotein: verapamil
Thiazide and thiazide-like diuretics

For the indication of hypertension, thiazide or thiazide-like diuretics are invariably the most appropriate
Good evidence for thiazide or thiazide-like agents in hypertension:

Supporting trials: ALLHAT, SHEP, HYVET
Three available in Australia:
Thiazide diuretics:
Hydrochlorothiazide: 12.5-25 mg/day, as once daily dose
‘Thiazide-like’ diuretics:
Indapamide (inc. MR): 0.625-2.5 mg/day, as once daily dose
Chlorthalidone: 6.25-25 mg/day, as once daily dose
There are others available overseas (bendroflumethiazide [bendrofluazide] and trichlormethiazide)
Dose-dependent BP lowering effect is seen with hydrochlorothiazide (but not for thiazide-like
medicines)
Whilst these medicines are referred to as diuretics; the hypotensive effect is actually a 'sub-diuretic' dose
Low-dose thiazides work to lower BP via vasodilation
Most patients will not notice much, or any, diuretic effect
Nonetheless, remains appropriate to administer these medicines in the morning
In renal impairment, the antihypertensive effect of thiazides and related drugs is maintained
This contrasts with their diuretic effect, which is usually only seen with higher doses and
which diminishes in renal impairment (CrCl < 25mL/min)
There are also several fixed dose combinations available e.g. thiazide/thiazide-like + (ACEI/ARB)
 Thiazide-diuretics: other indications
Thiazide/thiazide-like diuretics are invariably used for hypertension, but occasionally for other conditions:
Heart failure (to treat fluid overload) - at higher doses

However, the more potent loop diuretics (furosemide) have a superior effect and are much
more widely used
Non-CV indications (e.g. rare use in Meniere's disease)
 Thiazide-diuretics: selected adverse effects
Hyponatraemia
Hypokalaemia
Other adverse metabolic effects e.g. increase SUA (increase risk of gout), BGL (increase risk of
diabetes diagnosis; caution with beta-blockers [similar risk]) - these are likely dose-dependent
ALLHAT trial showed that despite the increase in DM, none of the other classes of drug studied (e.g.
ACEI or CCB) were superior in preventing adverse CV outcomes. There have been multiple reviews
demonstrating that thiazide or thiazide-like diuretics are efficacious in reducing morbidity and
mortality (compared with ACEI or CCB).
Photo-sensitivity with hydrochlorothiazide may slightly increase risk of non-melanoma cancer in long
term use
 Thiazide-diuretics: key practice points
Baseline and periodic monitoring of potassium and sodium is appropriate
Evidence of improved outcomes is stronger in older patients and impact on BGLs makes thiazide,
thiazide-like diuretics less suitable for younger patients
Beta-blockers
Beta-blockers were once routinely used for hypertension, however, in recent years clinical evidence has
shown little morbidity and mortality benefits where beta-blockers are used solely for hypertension. A
Cochrane review  has nicely summarised this:
"Current evidence suggests that initiating treatment of hypertension with beta-blockers leads to modest CVD reductions
and little or no effects on mortality. These beta-blocker effects are inferior to those of other antihypertensive drugs.”
Where there is another indication for a beta-blocker (e.g. IHD, HFrEF), and this co-exists with
hypertension, use of a beta-blocker is strongly justified.
The two most commonly used ß-blockers in Australia are:

Atenolol: 25-100 mg/day (usually OD dose)
This is despite a distinct lack of good outcome evidence
Avoid taking with fruit juice due to OAT-P interactions
Metoprolol: 50-200 mg/day (usually BD dose)
Other ß-blockers are generally less commonly used, but there are significant exceptions:
If co-existing HFrEF, agents such as bisoprolol, carvedilol or nebivolol are favoured, as they are
proven to improve outcomes
In portal hypertension, propranolol remains commonly used as non-selective effects (i.e. ß1 and ß2-
blockade) are needed
Agents that are both ß and α-blockers e.g. labetalol or carvedilol are sometimes used specifically to
provide this dual effect
 Beta-blockers: other indications
Angina prevention
Post-MI
Heart failure with reduced ejection fraction (HFrEF)
Tachy-arrhythmias e.g. atrial fibrillation (AF)
Non-CV indication: migraine prevention and tremor
In some conditions, the BP lowering effect of beta-blockers may be desirable, but in other cases it can be
problematic.
 Beta-blockers: selected adverse effects
Hypotension > dizziness
Bradycardia
Bronchospasm
Cold extremities
Vivid dreams
Increase onset of T2DM (especially when combined with thiazide diuretic)
 Beta-blockers: key practice points
Baseline and periodic monitoring of heart rate
Caution if using other drugs prone to cause bradycardia
Risk/benefit unfavourable for people with airways disease (asthma in particular)
Avoid use with thiazide where possible (to avoid increased T2DM onset)
Avoid stopping abruptly
Cochrane Review
A recent systematic Cochrane review (2022) concluded the following for the treatment
of hypertension:
Diuretics reduce major cardiovascular events and congestive heart failure more than CCBs
(moderate certainty evidence).
CCBs probably reduce major cardiovascular events more than beta-blockers (low to moderate
certainty evidence)
CCBs reduced stroke when compared to ACEI and reduced myocardial infarction when compared
to ARBs (low to moderate certainty evidence)
CCBs increased congestive heart failure when compared to ACE inhibitors and ARBs.
Other anti-hypertensive options

Other classes of anti-hypertensives tend to have niche roles for specific patients.
For example:
Patient's BP target still not met despite maximal standard therapy
Special circumstances or co-morbidites (e.g. severe renal impairment)
Stable, long term prescribing with hesitation to change
These medicines are effective at lowering blood pressure but are relegated to having a more minor role due to:
Less favourable adverse effect profile
Less (or no) evidence regarding impact on clinical outcomes (i.e. reducing rate of CVD)
Some require more than 2 doses per day which is an issue for compliance
Lack of indication for use in common CV co-morbidities and in some cases contraindicated for use in these
 Mineralocorticoid receptor antagonists (MRAs)
Also known as potassium-sparing diuretics and aldosterone antagonists
PATHWAY-2 trial studied mineralocorticoid receptor (aldosterone) antagonist (MRA) spironolactone

in resistant hypertension:
Compared it with ß-blocker and alpha-blocker
Found spironolactone 25-50mg once daily was more effective
Researchers concluded that salt-retention is commonly the cause of resistant hypertension
Depending on concurrent drugs, the K+ sparing effect of spironolactone can be:

Helpful if on a thiazide diuretic as it may offset K+ loss
Hazardous if on an ACEI or ARB as it may potentiate K+ retention, so caution and follow-up
monitoring is needed
Spironolactone is reserved for patients with resistant hypertension (with aforementioned therapy) or
hypertension with other medical conditions where spironolactone is of benefit (heart failure +/-
refractory oedema [at high dose])
Adverse effects include dizziness and hyperkalaemia
Eplerenone (alternative to spironolactone with fewer adverse effects), amiloride and triamterene are
additional MRAs.
 Alpha-blockers
Prazosin
Use in hypertension limited to patients not controlled with standard therapies or men who (also)
have benign prostatic hyperplasia (BPH).
Can cause profound postural hypotension, especially with first dose
Essential to start with low dose and titrate slowly
Dose range 1-20mg/day, usually in 2 to 3 divided doses
Profound BP lowering effect sometimes utilised in hypertensive urgency/emergency
Tamsulosin is another 'uro-selective' alpha-blocker with no significant effect on BP. However, it provides
relief in the management of benign prostatic hyperplasia (BPH) - discussed in fourth year.
Doxazosin is available overseas as a single daily dose. This dosing has resulted in preferential use over
prazosin.
 Centrally-acting agents
Moxonidine
Limited to 4th or 5th line (e.g. in resistant hypertension, intolerance to more mainstream medicines
or renal impairment)
Effective at lowering blood pressure, however, no evidence of improved clinical outcomes
Once daily dose is beneficial
AEs limit usefulness:

Dry mouth
Sedation
Headache
Contraindicated in heart failure, bradycardia, renal impairment and may worse coronary heart
disease
Methyldopa
A long-established centrally acting agent (alpha 2 adrenoreceptor agonist)
Other than in pregnancy, largely replaced by moxonidine

In pregnancy continues to be widely used as it is one of the few drugs where safety
established in this setting
Requires ≥ 2 doses/day to provide sustained BP control
AEs: sedation, dry mouth, depression
Clonidine
Rarely used in hypertension
AEs: sedation, dry mouth, depression
Sudden cessation may precipitate a withdrawal syndrome which includes increased BP and HR. Slow
weaning required for cessation (including in short-term hospital setting).
 Loop diuretics
Loop diuretics are not generally used for hypertension (unless co-morbidity exists)
BP lowering effect is not as effective as other medicines
Significant diuresis is not welcomed by most patients and increases risk of problematic
dehydration
Electrolyte loss can be problematic
Lack of outcome evidence (ie. may not affect morbidity or mortality)
Furosemide is the most common loop diuretic in Australia
Other examples are ethacrynic acid and bumetanide
 Direct-acting vasodilators
Hydralazine and minoxidil
Now mainly used only for hypertensive emergencies (IV) or in hypertension resistant to
combinations of other drugs
Tends to cause dizziness, tachycardia (beta-blocker may be required in combination), flushing and
oedema (diuretics may be required in combination)
For these reasons it is invariably given in combination with a ß-blocker and a diuretic
May rarely cause a ‘lupus-like’ syndrome (monitor bloods)
Selecting the most-appropriate medicine

Within Therapeutic Guidelines, ACEI, ARB, CCB or thiazide/thiazide-like diuretics are all recommended as first
line options. Therefore, for the selection of specific anti-hypertensive medication, patient and medication factors
require consideration.
There is no single 'best' option for all patients with hypertension.
Anti-hypertensive selection
When selecting a medication you need to think about the evidence based medicine, blood test results
(eg. electrolytes), co-morbidities (contraindicated and potentially, beneficial), allergies and age (avoid
thiazide in younger patients).
The Heart Foundation Hypertension Guidelines highlight situations where certain drugs should be avoided
(contraindications).
Age is an important consideration:
For those ≥ 65 years of age, any of the four first line classes of antihypertensive may be used
For those < 65 years of age, a thiazide/thiazide-like agent is not usually considered appropriate as initial
treatment (due to early onset of diabetes)
Reminder!
It is very unlikely a patient will only require one anti-hypertensive to achieve their target BP
Antihypertensive combinations
The Australian guidelines recommend specific combinations to prescribe, or avoid, for particular patient
comorbidities.
The common need to use a combination of two or more drugs has led to the development of many fixed dose
combination (FDC) products.
 Advantages of FDC products
Reduced tablet burden for the patient (and improved compliance)
Reduced cost to the patient
Reduced cost to the government / insurer (e.g. PBS)
 Disadvantages of FDC products
Confusion over constituents (may lead to duplication)
In some cases, reduced flexibility when titrating dose up/down
A recent multi-centre Australian study demonstrated a combination pill of low dose anti-hypertensives
(irbesartan 37·5 mg, amlodipine 1·25 mg, indapamide 0·625 mg, and bisoprolol 2·5 mg) achieved greater blood
pressure control compared with initial monotherapy with irbesartan 150mg. However, the study did not include
an analysis of clinical outcomes (i.e. prevalence of CV events).
Specific BP Issues
Severe hypertension
Markedly elevated BPs are not to be ignored:
BP ≥ 180/110mmHg = ‘Hypertensive Urgency’ or Grade 3 HTN
BP ≥ 220/140mmHg = ‘Hypertensive Emergency’ or Grade 4 HTN
At very high BP levels, the risk of an adverse outcome (e.g. stroke, organ damage and death) is significantly
increased. Therefore, aggressive management is required to reduce blood pressure, without causing a significant
fall in blood pressure (ensuring adequate perfusion to organs).
 If BP > 220/140 mmHg (emergency)
Hospitalisation and IV anti-hypertensives is required
Retinal haemorrhages indicate ‘accelerated hypertension’ which carries a particularly poor prognosis
Aim to reduce BP over 2-6 hours
Medications utilised: hydrazaline, metoprolol, GTN infusion, sodium nitroprusside, labetalol (all
intravenously)
This is important in the community setting - if a patient presents with a severely elevated blood pressure, urgent
attention is required.
 If BP is between 180/110mmHg and 220/140 mmHg (urgency)
If signs of organ damage (ie. patient has symptoms), manage as emergency as above (occasionally,
oral medicines, such as nifedipine or clonidine, may be used in hospital if BP between this range)
If asymptomatic, community treatment with oral anti-hypertensives and follow-up within 24 - 72

hours usually appropriate
Aim for blood pressure to return to below 180/110mmHg
This is important in the community setting - if a patient presents with an elevated blood pressure, referral is required
Pulmonary Arterial Hypertension (PAH)
PAH is a complex condition managed by specialists
People with PAH often present with symptoms e.g. fatigue, breathlessness, exercise intolerance
Several forms of PAH, for example: idiopathic, heart disease-related, lung disease-related, thromboembolic
cause.
Additional classification exists dependent on level of symptoms (e.g. Class I with minimal symptoms up to
Class IV with inability to carry out physical activity)
Diagnosis by catheterisation of right side of heart
Poor prognosis, if untreated many patients die < 3 years
Depending on the form of PAH anticoagulation or a specific type of surgery (pulmonary endarterectomy)
may be required
In some cases PAH co-exists with normal hypertension

In these cases patients may be on the below PAH-specific agents as well as standard
anti-hypertensives e.g. ACEI, CCB etc
 PAH-specific medications
Endothelin antagonists e.g. ambrisentan, bosentan, macicentan
PDE-5 inhibitors e.g., tadalafil, sildenafil
Guanylate cyclase stimulator: riociguat
Prostacyclin receptor agonist: selexipag
Prostanoid analogues: epoprostenol and iloprost
Orthostatic hypotension
Sudden drop in BP on standing from sitting or lying down
Can occur when autonomic reflexes are impaired or intravascular volume is depleted
Commonly referred to as 'postural hypotension' or having 'postural drops'
Defined as a fall in SBP > 20mmHg and/or DBP > 10mmHg within 3 minutes of standing
Can occur in people with or without hypertension
BP should be measured standing and sitting where:

Orthostatic hypotension is known to be a problem
Significant risk factors for orthostatic hypotension are present
Where orthostatic hypotension occurs it can lead to dizziness, fainting, injury (including fractures) and can
impact QOL
 Risk factors
Increasing age
Isolated systolic hypertension
Diabetes mellitus
Parkinson’s disease
Dehydration
Medications that lower blood pressure

Any prescribed antihypertensive can aggravate orthostatic hypotension
Vasodilatory drugs can be particularly problematic (e.g. nitrates)
Some non-CV drugs such as:

Tricyclic antidepressants e.g. amitriptyline
Antipsychotics e.g. risperidone
 Management
Management is individualised, but two steps are routinely undertaken prior to commencing medication:
Step 1 - Assess hydration
Assessing whether dehydration is present is important
Low circulating blood volume invariably worsens hypotension
If hypovolaemia confirmed, then this needs to be corrected
However, for patients with heart failure or severe renal impairment, need care to avoiding
overloading with fluid
Step 2 - Assess medications
Other is to assess whether any medications may be aggravating the problem:
Is there an indication to continue them?
Does this indication outweigh the risks?
Could the problem be eased by dose reduction?
For patients on antihypertensives, problematic orthostatic hypotension may require de-escalation of therapy.
Lowering BP may reduce risk of stroke etc, but if the patient is having falls this may be a bigger worry, especially for
the elderly who are at increased risk of bone fractures etc.
In some cases, orthostatic hypotension remains problematic (despite above management approaches) and may
require specific treatment:
Increased fluid intake
Increased salt intake
Use of compression stockings and/ or abdominal binders
Vasoconstrictors e.g. midodrine 
Mineralocorticoids e.g. fludrocortisone
Summary
Hypertension is one of the most common diseases in the world
Hypertension left untreated is associated with an increased risk of cardiovascular disease and
kidney damage
Hypertension management involves a combination of lifestyle changes, medication and regular

monitoring by health professionals
Medications used to treat primary hypertension predominantly include ACEi, ARBs, CCBs and/or
thiazides/thiazide like diuretics
Choice of antihypertensive agents depends on a number of factors including severity, age, co-
morbidities, patient preference, cost.
Hypertension is largely an asymptomatic disease, however if symptoms do occur they are

largely vague and non-descript. Which of the following are the correct combination of signs and
symptoms to monitor for
 Weakness, dizziness, constipation, fatigue
 Bleeding, blurred vision, dizziness, hunger
 Headache, depression, liver dysfunction, fatigue
 Dizziness, blurred vision, headache, fatigue
 Check   Submit
This online module has been developed by Chanelle Brodie. With acknowledgement to Angus
Thompson and Caitlan O'Keefe from whose materials this content has been developed.

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2/11/24, 9:38 AM CSA322 Therapeutics in Practice 3A

Intended learning outcomes

Describe the pathophysiology, epidemiology, typical presenting features and

Demonstrate an understanding of evidence-based pharmacotherapy for

Demonstrate the ability to advise on appropriate strategies for management of

This content has been updated in 2023 to reflect therapeutic developments.

Please note this module contains definitions important to all therapeutic

 Guideline for the diagnosis and management of hypertension in adults (Heart

NPS: What is hypertension (2020). Article and podcast  available.

Importance of blood pressure

Blood pressure is a product of:

Renin-Angiotensin-Aldosterone System (RAAS)

Sympathetic Nervous System (SNS)

Reproduced from US guidelines 

Signs and Symptoms

Are things we can see or measure

General examples include internal bleeding, a rash, etc.

In hypertension a sign would be elevated BP

Signs are objective

Are things that a person feels

General examples include nausea, dizziness

In hypertension, a symptom could be a headache

Symptoms are subjective

Signs and symptoms of Hypertension

This is particularly the case when the BP is only modestly elevated.

As hypertension is an asymptomatic, or ‘silent’ disease, it is difficult to identify, diagnose and manage.

Pressure S&S Vascular S&S

• Dizziness • Bleeding e.g. epistaxis

• Palpitations • Blurred vision

• Fatigue • Manifestations of cerebral ischaemia (e.g.

• Heart failure e.g. oedema

Signs and symptoms of Hypertension

Risk factors of Hypertension

Diet including high salt intake

Obesity and weight gain

Substances and medications that may influence blood pressure.

 Sodium content in medications

Further, recent cohort studies  found that sodium-containing (effervescent or soluble)

Source: Zeng, C. et al. Sodium-containing acetaminophen and cardiovascular outcomes in individuals

Importance of blood pressure control

Sometimes, hypertension is referred to as a disease, however, it is more appropriate to

Morbidity and mortality

Source: Saler, et al. NEJM 2018 

This has been known for decades:

Hypertension may be:

Accounts for >90% of cases

Where something causes BP to be elevated

Many possible causes (eg. conditions or medications)

Secondary Causes of Hypertension

Blood pressure measurement

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Conventionally we report BP as SBP/DBP and in units of mmHg

e.g. 160/95 mmHg

*Reference: Flint A et al, NEJM 2019 

Appropriate measurement of BP is an essential starting point and requires:

Over several clinic appointments (days/weeks apart)

Within each clinic appointment

Factors affecting BP levels include:

Recent smoking/caffeine, anxiety, acute pain etc.