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Hypertension

An elevation of systolic and/or diastolic blood pressure to the point where it increases the
risk of CV disease ~140/90

Blood pressure is proportional to the output of the heart (CO) and TPR.
Peak BP occurs during systole as L ventricle contracts

- An elevation of systolic pressure is particularly dangerous


- Prevalence: affects approx 25% of the population
- 50% over 50yrs
- Major risk for: stroke, coronary artery disease and congestive heart failure
- Promotes atherogenesis probably damaging the endothelium
- Higher cardiac workload imposed by the increased pressure causes a thickening
of the left ventricular wall (LVH) and therefore predisposes the myocardium to
arrythmias and ischaemia, and is a major contributor to heart failure, MI and
sudden death.
- ISH (isolated systolic hypertension) that occurs in the elderly is particularly
deleterious.
- Repeated measurements must be made to confirm hypertension on at least two
separate occasions.

Types of hypertension:

1. Primary or ‘essential’: no obvious cause (90% of cases)


- Polygenetic predispostion (genes unknown)
- Environmental influences (e.g. high salt, stress)

2. Secondary: cause can be found (10% of cases)


- Renal (e.g. renal stenosis)- abnormal narrowing of blood vessels causing renin
secretion and therefore hypertension
- Endocrine (e.g. phaeochromocytoma, birth control pill) – small vascular tumour
of the inner region (medulla) of the adrenal gland. Uncontrolled secretion of
hormones adrenaline and NA. these cause attacks of raised BP, increased HR,
palpitations and headache.

The causes of primary hypertension are unknown.


- Often starts early in life with raised CO, later the CO falls to normal but TPR is
raised.
BP controlled by integrated neuronal and hormonal control system, modulating:
1. Blood volume
2. CO
3. Peripheral vascular resistance

Drugs acting directly or indirectly on these 3.


Main theories include:
1. Kidneys cannot excrete Na+ properly: reduced number of nephrons? So blood
volume increases and therefore so does CO
2. Renin-angiotensin-aldosterone system is overactive leading to vasoconstriction
and Na+/water retention
3. SNS is overactive leading to vasoconstriction (possible link with stress)

- Mechanisms that initiate hypertension may change over time.


- E.g insufficient Na+ secretion may then be succeeded and/or amplified by
additional secondary mechanisms e.g. renal damage and vascular structural
remodeling, which are caused by, and maintain the initial rise in pressure.
- Natriuretic factor hypothesis: decreased Na+ excretion causes the release of
natruietic factors which inhibit Na+/K+ATPase pumps and therefore increase Na+
excretion. Due to Na+/Ca2+ antiport in smooth muscle cells, vasoconstriction and
therefore TPR is increased, causing sustained hypertension. (Plasma levels of
hypertensives are found to contain high levels of Na+ pump inhibitors)

Treatment of hypertensives:
- Reduction of BP reduces risk of CHD. However, further improvements in
outcome may be possible
- Treat if blood pressure is over 150/90 for 6 months and overall risk of CV death is
greater than 2% per year
E.g diabetes, obesity, dislipidaemia and a family history of CV disease, or disease of
target organ vulnerable to hypertension (e.g. kidneys and brain)
Benefits:
- Decreased risk of stroke and CHD

Drawbacks:
- Adverse drug side effects
- Cost

The goal: to reduce the BP to below 140/90 (or to below 135/85 in diabetics and those
with renal disease)

First option is non-drug treatment e.g. exercise, weight loss, stop smoking
Poor compliance with drugs as mostly pts are asymptomatic

Thiazide-type diuretics: Bendroflumethiazide

Mechanism:
- Causes an initial increase in Na+ excretion by the kidneys
- Due to this inhibition of the Na+/Cl- symport in the distal nephron
- This reduces blood volume and therefore CO.
- TPR also falls but by an unknown mechanism.
Adverse effects:
- Hypokalaemia : by promoting Na+/K+ exchange in the collecting tubule.
- This can be prevented by giving K+ sparing diuretics e.g. amiloride to reduce
Na+ reabsorption by blocking Na+ in the collecting duct.
- Reduced plasma Na+ -- increased rennin--- increased aldosterone ---
hypokalaemia
- Increased plasma cholesterol

Contraindicated in:
- Gout (promote gout by inhibiting uric acid secretion)

Indicated in:
- Elderly patients

Notes:
- Can be combined with vasodilators (alpha-1 blockers, Ca2+ channel antagonists),
which may elicit volume expansion and oedema due to rennin-angiotensin-
aldosterone system activation.
- ALLHAT study, diuretic chlorthalidone lowered BP as well as amlodipine and
lisinopril and was superior to both in preventing major CV disease.

Beta adrengenic antagonists:


- There are many with diverse properties, but all block beta-1 receptors
- E.g. non-selctive - propanalol
- E.g. B1 selective – atenolol
- Decrease CO and reduced renin secretion
- Partial agonist (intrinsic sympathetic activity) – pinodolol (acting more as
vasodilators than reducing CO)
- Partial agonists: antagonists when normal or high sympathetic drive, agonists
when low sympathetic drive e.g. at night.

Mechanism:
- Antagonise sympathetic stimulation of the cardiac B-receptors (mainly B1),
thereby reducing CO via negative ino and chronotropic effects.
- Also block beta-receptors on juxtaglomerular granular cells in the kidney, thus
inhibiting rennin release and reducing plasma levels of angiotensin II and
aldosterone.
- B blockers which are partial agonists cause some vasodilatation and less reduction
in CO

Adverse effects:
- Bronchospasm
- Cardiac depression (use with care in heart failure)
- Fatigue
- Decrease glucose tolerance
Contraindicated in:
- Asthmatics- due to their potential effects on bronchiolar B2 receptors.
Indicated in:
- Angina
- Post MI
Notes:
- Beta blockers are proven to reduce mortality after MI, and in chronic heart failure
and therefore are the preferred initial treatment.

ACE inhibitors: Captopril, enalapril and lisinopril

Mechanism:
- Block the conversion of angiotensinI -- angiotensin II.
- Reduces TPR
- (angII stimulates the SNS centrally, promoting the release of NA and
vasoconstricts directly)
- The fall in plasma angII and therefore aldosterone also promotes
diuresis/natruiesis, because both hormones cause Na+ and water retention
- Inhibits bradykinin breakdown

Adverse effects:
- Chronic dry cough – due to the increased levels of bradykinin
- (this effect does not occur with AT1 receptor blockers such as losartan and
valsartan)
- Hypotension (especially on first dose)
- Deterioration of renal function

Contraindicated in:
- Pregnancy
- Renal failure
- Bilateral renal stenosis

Indicated in:
- Post MI
- Cardiac failure
- Diabetic patients

Angiotensin receptor antagonists Losartan and Valsartan

Mechanism:
- Block AngII receptors

Adverse effects:
- Similar to ACE inhibitors but NO dry cough
- These are Newer drugs

Side effects: raised plasma K+, bad taste

Calcium-channel blockers (CCBs) nifedipine, verapamil and diltiazem

Mechanism:
- Inhibit constriction of arterioles by agonists (eg NA, AngII) by blocking voltage-
gated calcium channels
- Decrease TPR

Adverse effects:
- Tachycardia
- Headache
- Peripheral Oedema: vasodilator effects
- For the heart: negative inotropy and bradycardia
- Short acting preparations may increase risk of MI therefore their use is
discouraged.

Contraindicated in:
- Heart failure
- Pregnancy

Indicated in:
- angina
- ISH
Notes:
- The dihydropyridine CCB’s which are selective for vascular smooth muscle over
the heart, are used more widely and also have a useful diuretic effect.
(Amlodipine)
- Non selective = verapamil, diltiazem
- Longer acting ones, nitrendipine and felodipine are comparable to B-blockers in
reducing and diuretics in reducing mortality

Alpha-1 adrengenic antagonists: Prazosin, Doxazosin

Mechanism:
- Block sympathetically-mediated constriction of arterioles (NA)
- decrease TPR
-
Adverse effects:
- postural hypotension
- Ankle Oedema
- Drowsiness

Mainly used in combination with other anti-hypertensive drugs


Contraindicated in:
- Mild heart failure
- Orthostatic hypertension

Indicated in:
- Benign prostatic hypertrophy
- Hyperlipidaemia

Notes:
- Used in preference to non-selective alpha antagonists in order to prevent
increased NA release from sympathetic nerves, which would occur if presynaptic
alpha-2 receptors were blocked.

Methyldopa- pregnant hypertensives

Mechanism:
Alpha -methyl NA produced in the brain
activates a2 receptors
reduces sympathetic outflow

Safe for asthmatics, pregnants and heart failure

Clondine

Mechanism:
- Activates a2 receptors in the brainstem, reduces sympathetic outflow
- Also used in opiate withdrawal syndrome as a sedative

K+ channel agonist: e.g. Minoxidil

Mechanism:
- Open K+ channels in vascular smooth muscle cells
- resulting hyperpolarisation
- reverses vasoconstrictor mediated depolaristaion and contraction

- Used only in refractory cases

- Severe vasodilator side-effects, so combined with diuretics and Beta blockers

- Used for growing hair for bald men


Theraputic choices: tailor the drug regiment to the individual patient

1st : CCB or diuretic


2nd: Combine 1 with ACE-I or AII antagonist
3rd: combine CCB, diuretic, ACE-I/AngII
4th: add beta1or alpha 1 antagonist

Co-existing conditions:
- Beta blockers and asthma
- CCB’s and heart failure

Indications:
- Beta blockers and certain arrythmias
- ACE-I and post MI

Patients younger than 55:


1st: ACE-I or Ang II –I
2nd: CCB or diuretic
3rd: use all 3
4th: add Beta1/alpha 1 antagonist

Beta blockers and ACE inhibitors often not useful in afro-caribbeans

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