Essential hypertension is a serious concern amongst

cardiovascular diseases because of its widespread prevalence

and association with other co-morbidities and mortality.

In emerging nations like India, essential hypertension has

taken shape of a sinister entity threatening to affect large
populations.

Link with hypertension

In humans, plasma norepinephrine levels in hypertensive patients
are significantly higher than in normotensive controls (p<0.05)3

Sympathetic activation is seen in early phases of hypertension and

may precede blood pressure elevation in some
patients4Sympathetic activity can be high in young subjects with
borderline hypertension

This suggests that increased sympathetic activity is the cause,

rather than the consequence, of blood pressure elevation1

2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 3. Goldstein DS. Hypertension 1981;3:48-52.,
4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13

Sympathetic overactivity
Sympathetic
overactivity may
be a central
feature linking
hypertension
with other
components of
the metabolic
syndrome

Link with obesity

Raised BMI is associated

with an increased rate of
sympathetic nerve
discharge in skeletal
muscle5

There is a correlation
between BMI, body fat
distribution and urinary
norepinephrine excretion6

5. Scherrer U et al. Circulation 1994;89:2634-2640., 6. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158

Link with insulin resistance and diabetes

Sympathetic activation is a major component of

insulin resistance in clinical experiments7 and in
humans with type 2 diabetes8

Cardiac autonomic dysfunction occurs in:

- 30-50% of patients with diabetes
- 40% of obese patients without diabetes9

7. Jamerson KA et al. Hypertension 1993;21:618-623., 8. Huggett RJ et al. Circulation 2003;108:3097-3101.,

9. Valensi P et al. ESC 2004 (www.solvaycardio.com)

Link with other risk factors

Sympathetic overactivity is also

implicated in:

- renal disease10
- left ventricular hypertrophy11

- congestive heart failure12

10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65.,
12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45

Drugs/therapeutic agents acting on

sympathetic nervous system: Sympatholytics:

The classic centrally acting antihypertensive drugs (clonidine,

methyldopa, guanfacine) stimulate pre- or postsynaptic alpha2adrenoceptors, mainly in the NTS, reduce sympathetic efferentation,
decrease TPR and heart rate, and thereby systolic (SBP) and diastolic
(DBP) blood pressure.

Unfavourable effects of these drugs (dry mouth, decreased alertness,

sleepiness, sedation, impotence, constipation) limited their use, so these
agents are not considered as first-line antihypertensive drugs.

Sympatholytics continue

-Adrenoreceptor antagonists are effective antihypertensive agents,

but there are concerns about their safety profile. In the ALLHAT trial,
the -blocker (doxazosin) arm was stopped prematurely because of an
increased risk of cardiovascular events, particularly heart failure.

Similarly, -blockers are effective in obesity-associated hypertension

but do result in reduced energy expenditure leading to a small weight
gain.

In a recent large-scale trial (POISE study group) of over 8,000 patients

undergoing noncardiac surgery, the use of the perioperative -blocker
metoprolol was found to reduce the incidence of MI, but increased the
risk of strokes and death in the 30 days after the operation.

Rationale for moxonidine

Sympathetic tone is regulated centrally in the

rostral ventrolateral medulla (RVLM)15

This region contains imidazoline I1-receptors and

a2-adrenoceptors which regulate sympathetic
activity

Moxonidine binds selectively and with high affinity to I1receptors in the RVLM16
thus reducing peripheral sympathetic activity

15. Hamilton CA. In: van Zwieten PA et al (eds). The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Ed,
London: Roy Soc Med,1996:7-30., 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

Moxonidine versus active comparators

Moxonidine has been found to be similarly
effective to other first-line antihypertensive
agents in reducing blood pressure including:

Diuretics (hydrochlorothiazide - HCTZ)

Beta-blockers (atenolol)

ACE inhibitors (captopril and enalapril)

Calcium-channel blockers (nifedipine)

Highlights
Effective when used as monotherapy
An effective adjunct to other first-line
therapies such as diuretics and ACE-inhibitors

Linear dose-response effect allows dose titration

Improves glucose metabolism / insulin resistance
Neutral effect on the lipid profile
Renal protective effect
Lowers peripheral arterial resistance without significant effects on cardiac output
Relatively little affinity for a2-receptors in the brainstem (adverse events such as
sedation and dry mouth are infrequently reported during prolonged therapy)

Low potential for drug interactions

Thank you
Managing Hypertension at the Source