Blood pressure Medications

Annemarie Hennessy
August 2019
• 4 x 10 minute presentations
• Basic Pharmacology/ Mechanisms of action of antihypertensive medications
• A clinical case of refractory hypertension and the medications used
• Common lists; indications, compelling indications and contraindications
• How to start someone on BP medications

• All have a quiz at the end

Learning objectives
• Appreciate the importance of adequate control of hypertension
• Understand the mechanisms of action of commonly used
antihypertensives
• Understand the factors which may limit the usefulness of some
antihypertensives agents in a particular patient
• Understand the notion of compelling indications
Presentation one : Basic Pharmacology/ Mechanisms of action of
antihypertensive medications

• If you remember the mechanisms of hypertension then targeting those mechanisms

should lower BP readings.

• Core Mechanisms:
1) vasoconstriction: large, medium and small artery constriction (aided by long term vascular
smooth muscle (VSM) hypertrophy as a result of continuous arterial stress and mitogenic
responses (growing more VSM)
2) Rarefaction: reduced capillary density
3) Fluid overload

Note: These are contributed to by vascular reactivity, activation of the renin angiotensin system,
other mineralocorticoid hormones; hyperdynamic circulation such as thyroid hyperactivity;
sympathetic nervous system activation (obstructive sleep apnoea).
 Volume

Tone
Renin and angiotensin system

SNS
local tone, and salt retention VSM contraction
Local constrictors
• Systemic hormone effects include those that activate the SNS and fluid
retention
• Renal renin activation is a core mechanism of the hypertension associated with chronic
kidney disease
• Local hormones causing regional arteriolar constriction and local endothelial
reactions include Endothelin, endothelial derived hyperpolarising factor,
calcitonin gene regulating peptide, and nitric oxide deficiency
• These have been less easy to target as treatments for systemic hypertension (have been
more useful in pulmonary hypertension)
• Capillary density has not proved to be an easy target for treatment
• Fluid overload : common in aldosterone overactivity (RAAS related), or
primary, chronic kidney disease
 Classes of Drugs
Diuretics Target volume
Mineralocorticoid receptor antagonists

Vasodilators Tone
Antiadrenergic agents
SNS
Calcium channel antagonists VSM contraction
Local constrictors

Angiotensin converting enzyme inhibitors Hormonal control

Angiotensin receptor antagonists

Renin and angiotensin
System –local tone
and salt retention
Obvious Targets for treatment are
• Target vascular constriction
• Use a vasodilator
• Target local hormone production (endothelial function)
• Diet and reduced fat content in the diet
• Target cardiac hyperdynamic circulation
• block cardiac heart rate
• Target fluid overload
• Target capillary density
• Target adrenal overproduction in specific and rare circumstances
(Phaeochromocytoma)
 It makes sense that
you would target
more than one
mechanism at a time
as a strategy.

+1 +1 +1
What do think might be the immediate term
consequences of delivering a vasodilator?
A transient vasodilation only
B activation of adrenalin
C activation of vagus control of heart rate
D activation of salt and water retention
E postural hypertension
What do think might be the immediate term
consequences of delivering a vasodilator?
• ANS: further activation of the RAAS in the setting of an acute
reduction in blood pressure
• Increasing salt and water retention which mitigates against blood
pressure control
Draw the autoregulation curve as it pertains
to someone with ongoing hypertension?
Draw the autoregulation curve as it pertains
to someone with ongoing hypertension?
Arguments for starting more that One
medication at the same time?
PROS (better treatment)
Data to show better long term BP
control
Reducing the salt retaining impact of
vasodilators
Better impact and therefore long term
compliance
Combinations make compliance and
potential cost easier
Reduced side effects due to reduced
doses
CONS (overtreatment)
Risk of falls and collapse from over-
treating the blood pressure;
Reduced compliance from
hypotensive symptoms
Worse impacts in the elderly
Cost when these are new and on
licence
Increase in predictable side effects
due to more medication exposure
Presentation two : a clinical case of
hypertension and the medications used
• 53 year old women (Kylie) with a history of hypertension in pregnancy
in her 4th and 5th pregnancies (at age 27 and 28 years) which have
resulted in long term hypertension
• At 27 years of age she had a period of headache and right side
weakness when her BP was 210/130 mmHg. This lasted 5 days but
resolved with BP control

• She subsequently had a period of cortical blindness and the following are
indicative scans:
 MRI with Cortical
Blindness

Recovery
Her current list of medications include:
• minoxidil 40mg bd
• prazocin 5 mg qid
• quinapril 20 mg bd
• spironolactone 25 mg tds
• nifedipine 60 mg bd
• frusemide 500 mg mane, 250mg midi
• chlotride 1 mane
• telmisartan 80 mg bd
• clonazepam 500 ug daily
Look up the mechanism of action of each of
these:
 Her current list of medications include:

• minoxidil 40mg bd • Vasodilator

• prazocin 5 mg qid
• quinapril 20 mg bd
• spironolactone 25 mg tds
• nifedipine 60 mg bd
• frusemide 500 mg mane, 250mg midi
• chlotride 1 mane
• telmisartan 80 mg bd
• clonazepam 500 mg daily
• Vasodilator
• ACE inhibitor
• Aldosterone antagonist/ diuretic
• Calcium channel blocker/ vasodilator
• Diuretic (loop)
• Diuretic
• Angiotensin 2 receptor antagonist
• Benzodiazepine (for anxiety/restless legs)
Lets add that up
• Three diuretics working at three different mechanisms of Na+ balance
in the kidney
• Three vasodilators and
• Two blockade steps in the RAAS (Very Dangerous)
• These also work as vasodilators

• What classes of drugs are missing in this list?

• ANS: Beta blockers : she had asthma
• This is an absolute contraindication to betablockers if unstable. They can only
be used with extreme caution so as not to precipitate and asthma attack

• Central acting medications:

She had mood disturbance in the past

• Adrenal blockade : phenoxybenzamine, or phentolamine

• Used only in diagnosed phaeochromocytoma; she didn’t have an adrenal tumour
• Are any of the drugs CONTAINDICATED as a combination?

• YES : ACEI and ATRA together cause unacceptable hyperkalaemia

Definitions of Control or lack thereof
Her BP was mostly 190/110 on these medications
= resistant hypertension

• Had she been controlled on more that three medications including a diuretic,
then she would have Refractory hypertension.

• Can you think of reasons for poor control?

• Undiagnosed secondary causes
• Renal artery stenosis developing as part of vascular progression
• Development of some other secondary cause (highly unlikely)
• Other drug use: cocaine, caffeine, NSAIDS
• Medical non-adherence
• Cost
• Acceptability
• Side effects
• Lack of understanding
• Secondary gain
What happened to her….
• Joined weight watchers with her daughter (Although her initial BMI
was 25kg/m2)
• Stopped drinking 7-10 cans of caffeinated soft drink every day
• Now on irbesartan 300 mg daily with BP of 120/80 mmHg

• Was she ever taking her medications?

• Examined for renal artery stenosis several times 8 year apart
Presentation three:
Common lists; indications, compelling indications and
contraindications

• These are very busy slides

• You will spend a lifetime learning about these and new BP meds which
come on the market
• Some broad principles remain which we expect you to know and
understand:
• They target different physiological mechanisms which you must know
• They can be life saving, but can be dangerous
• They are commonly used in the broader community
• They save lots of lives, strokes, kidney and heart disease
• There is increasing understanding of their purpose, use and side effects in the
broader community
Ending in –olol or -alol
• The beta blockers
• These are complicated and fall into selective and non-selective categories;
• There are some such as carvidolol which are used more commonly in cardiac
conditions such as Congestive cardiac failure (biventricular failure).
• You will only really know these when you start prescribing them…
• They are differentiated by their selectivity, their half life and their use in
clinical trials proving survival benefit vs their ability to control the BP per se

Compelling indications Contraindications

Migraine Asthma
Thyroid disease Diabetes with hypoglycaemia and awareness
Critical peripheral blood flow reduction
Classes of beta blockers
Action Adrenergic selectivity ExamplesHalf life
Non-selective beta1 and beta2 propranolol short sotalol* medium
Selective beta1 > beta2 atenolol long
metoprolol succinate medium
metoprolol tartrate
(sustained release)

bisoprolol long
Non-selective and beta1, beta2 and labetalol short
vasodilating alpha1 carvedilolmedium
Non-selective and beta1 and beta2 nebivolol medium
†vasodilating (nitric oxide pathway)
* used primarily as a class III antiarrhythmic drug
† not currently available in Australia
Ending in –ipine (or not)
Calcium channel blockers
There are two major categories
Dihydropyridine Non- dihydropyridine
These are associated with potential These are not associated with heart block and
reduced heart rate: can cause heart therefore safe to use with beta blockers
block if used in combination with Cause ankle swelling as a common side effect
beta blockers
Long acting and generally well tolerated.

Compelling indications Contraindications

Migraine with the non-dihyropyridines Betablockers with the non-

dihydropyridines
Clinically important pharmacokinetic properties of calcium channel antagonists

Oral bioavailability (%) Elimination half-life (hours)

• Verapamil 20 4
• Diltiazem 40-50 4
• Nifedipine 50 2
• Felodipine 15-20 15-20
• Amlodipine 65 35-45
Diuretics
• Are essential component of any three drug plan
• Are often part of a two drug plan
• Act at different parts of the renal tubule to encourage sodium excretion
• Are cheap and have been proven to save lives
• Have a relatively high side effect profile

Compelling indications Contraindications

Fluid overload/CKD Hyponatraemia esp in the elderly
Impending procedures
Vasodilators
• Act to dilate blood vessels by differ mechanisms
• Potassium channel blockers
• VSM relaxation
• Generally old fashioned

Compelling indications Contraindications

Bladder dysfunction (prazocin)
Central acting agents
• Aldomethyl dopa or clonidine or moxonidine
• Alpha 1 blocker (post synaptic inactivation), alpha 2 activation (presynaptic inhibitory
activation),
• Contraindicated in circumstances of potential depression or other mental illness

Compelling indications Contraindications

Pregnancy Mental illness
Ending in -pril
• Angiotensin converting enzyme inhibitors
• Designed to specifically block conversion of angiotensin I to angiotensin II to
block potent vasoconstriction
• Widely used as a first line agent

Compelling indications Contraindications

Cardiac failure Hyperkalaemia in CKD and Diabetes
Renoprotection in early chronic kidney disease (Renal Tubular acidosis)
Assists with thirst management in late CKD
Ending in -sartan
• Angiotensin two receptor antagonists
• Drugs designed to block the receptor at the end of the RAAS cascade
• Generally less side effects than the ACEI
• Long half lives designed for ease of adherence
• Widely used as a first line agent (sometimes with a diuretic)

Compelling indications Contraindications

Presentation Four: starting someone on a
medication
• Where do I start?
• Ascertain absolute risk;
• This will be different for a young thin person with a single reading of 140/90 compared
to our case in presentation two.
• Work on the life style factors always
• Think about secondary causes and examine for those
• Look at where the evidence is for the “best” treatment (none are perfect)
”best “ = cost effective, targeting that age group, low side effects, simple compliance
regime, has a compelling indication, has no contraindication, has no serious drug
interaction with existing medications, where you have some experience with use and
dosing.
• What are you trying to achieve: primary, secondary or tertiary prevention?
This is where Guidelines come in
• There are lots of them
• They are renewed regularly
• They are specific to different countries to do with the way countries
approve and fund their drugs
• They are based on level one evidence and they examine population
benefits
• They provide some guidance as to the start BP and the target BP to be
achieved
• This needs to be then tailored to the patient in front of you.
Absolute risk Scenario One
Mr Kim is a 69 year old Korean man, who has come in to see you with a
headache.
Using the following figures: calculate the Absolute stroke risk for Mr
Kim
Male/69years/170mm Hg systolic BP/ Total Cholesterol 6.5 mmol/l;
Non smoking
HDL 2.0 mmol/l and Diabetes no/ ECG LVH no

• http://www.cvdcheck.org.au/
Absolute risk Scenario two
• Now change is BP to 120 mmHg systolic

• Think about how powerful it is to send this message to him in terms

of his future cardiovascular health.
An example of the
evidence
Figure 1 - Reduction in major vascular events, by
baseline risk factor level
Combination blood pressure lowering Cholesterol lowering and major
and stroke in PROGRESS vascular events in HPS
Baseline blood Favours Favours Baseline Favours Favours
pressure active placebo cholesterol active placebo

SBP > 160 TC > 6.0

SBP 140 - 160 TC 5.0 – 6.0

SBP < 140 TC < 5.0

DBP > 90 LDL > 3.5

DBP 85 - 94 LDL 3.0–3.5

DBP < 85 LDL < 3.0

43% 21%
Total Total
(29 -51%) (17-25%)

0.50 0.75 1.00 1.25 0.50 0.75 1.00 1.25

Relative Risk Relative Risk
P August 2003 NEJM
• https://www.nejm.org/doi/10.1056/NEJMcp010357
Profile in 2016
• https://www.heartfoundation.org.au/images/uploads/publications/P
RO-167_Hypertension-guideline-2016_WEB.pdf
An Australian Approach
• Australian national blood pressure intervention trials 1 and 2
• ANBP1 and ANBP2

• Compare drug regimes and discusses how they work and also the
progression of effective and affordable medications?

• How would design ANBP WSU 2019?

https://www.tandfonline.com/doi/pdf/10.3109
/10641969709083186?needAccess=true