FUTURE OF HYPERTENSION

- Anirudhya J

Introduction• Arterial hypertension is a controllable disease that

affects as much as 30-45 % of general population.

• The prevalence of treatment resistant hypertension has been reported to be from 10-15 %

• Uncontrolled hypertension was found in 35.9 % of patients of which 2.2 % were resistant.

Goal BP : JNC 8• Patients < 60 yrs of age : < 140/90 mm Hg• Patients with DM : < 140/90 mm Hg• Patients with CKD : < 140/90 mm Hg• Patients >/= 60 yrs of age : < 150/90 mm Hg

Higher goals for elderly, DM, CAD and CKD vs. JNC 7.

Azilsartan Medoxomil (2011) :

- Prodrug

- Hydrolyzed into azilsartan in both the GIT and plasma.

- Selective AT1 receptor antagonist.

- Causes vasodilatation and attenuated aldosterone effects.

- Has very high affinity and slow dissociation from AT1 receptor.

- Only ARB approved for use in a fixed dose combination with chlorthalidone.

Azilsartan - PharmacokineticsParameters Values Clinical relevance

Bioavailability 60% 24 hrs (Round the clock) action

Tmax 3 hours Faster Onset of BP lowering effect

Plasma half life 11 hoursSteady-state concentration 5 days

Longer Duration of action

Plasma protein binding > 99% Longer duration of action

Metabolism Hepatic cytochrome P450M-I and M-II

No drug drug interactions

Elimination Renal:42%Fecal: 55%

Safe to be given in CKD pts without dose modification

Pharmacol Rev 65:809–848, April 2013

Future paradigm in management Telemonitoring of BP

Mobile health technology (mHealth) offers opportunities to support self-management behaviour, thereby actively engaging patients in their care and reduce the number of office visits.

Interventional therapies• May be considered in patients with resistant

hypertension.

1) Baroreceptor activation therapy: - Carotid baroreceptors play a key role in BP regulation and impairment in their function has been associated with development and maintenance of hypertension.

Continued…- Chronic electrical stimulation of carotid sinus nerves via implantable devices has shown significant reduction in BP.

- The Rheos Baroreflex activation therapy system was used earlier.

- A modified version of this – Barostim neo system is a second generation device for baroreflex activation therapy.

- 26/13 mm Hg fall in BP after 3-6 months.

- Rheos pivotal trial : LV mass index fell by 13% after 1 year.

- Adverse effects : Infection, Nerve damage (Tongue paresis), Pain in the glossopharyngeal nerve area, Shifting of the implanted generator that required further surgery.

• Barostim neo system :

• Pulse generator in pectoral region and single lead that delivers impulses to the carotid sinus.

• Restores sympatho-vagal balance and homeostasis by increasing parasympathetic tone and decreasing sympathetic tone.

2 ) Renal denervation :

- Renal sympathetic nerves contribute to both development and maintenance of hypertension.

- Catheter based RDN has emerged as a potential treatment modality for resistant hypertension.

- The procedure involves catheter based ablation of both afferent and efferent nerves in the renal arteries.

Continued…

• The Symplicity HTN-1 and HTN-2 trials have shown substantial BP reduction of 30/15 mm Hg.

• But after Symplicity HTN-3 trial in 2014, development of these devices were halted as the results failed to meet its primary end point.

• New trials using modified RDN catheters was initiated in 2015.

The Paradise ultrasound RDN system

• The most futuristic of the RDN systems -Delivers externally focused ultrasound energy to the renal nerves using Doppler-based ultrasound image guidance to track and correct for renal artery motion during treatment.

3) ROX coupler :

- Another device based intervention for resistant hypertension.

- The Coupler is surgically implanted between a vein and an artery in the upper thigh.

- It acts on arterial compliance and vascular resistance to reduce BP.

Chronotherapy• A 69 % prevalence of nocturnal non-dipping has

been observed in patients with resistant hypertension.

• Non-dipping is partly related to the absence of homogeneous 24 hour therapeutic coverage in patients treated with single morning doses.

• A novel therapeutic strategy based on chronotherapy can be adopted which involves a unique time of the

day for conventional drug administration.

Endothelin a receptor antagonists• Endothelin (ET) is an endogenous peptide

secreted predominantly by endothelial cells that mediates its effects via vasoconstriction and hypertrophy of vascular smooth muscle. 

• Selective ET receptor blockade has been shown to have therapeutic potential in HTN, atherosclerosis, HF, pulmonary disease and renal end organ damage.

• Sitaxentan, Ambrisentan, Atrasentan, Zibosentan are selective Endothelin a receptor antagonists.

Melatonin• Melatonin is a naturally occurring hormone and

neurotransmitter that influences the suprachiasmic nucleus which regulates HR and autonomic tone.

• SCN function may be suppressed in hypertensives.

• A nocturnal surge in melatonin excretion has been reported in non dipping hypertensives.

• It has been demonstrated that 3-4 weeks of melatonin 2-3mg supplementation 1 hr before sleep caused reduction in BP by 6/4 mm Hg.

Dopamine receptors• Renal dopamine activates specific cell surface

dopamine D1-like receptor on the proximal tubules, thereby inhibiting tubular sodium reabsorption and maintaining sodium homeostasis and subsequently BP.

• At low doses, dopamine lowers diastolic BP and increases renal perfusion. At intermediate doses, it increases HR and cardiac contractility. At higher doses, it causes vasoconstriction and hypertension.

• The vasodilator and renal effects of dopamine were mediated by activation of the D1 receptor.

• Fenoldopam – First selective dopamine-1 receptor agonist.

Pharmacogenomics • Personalized or individualized medicine

• Recommendations on drug treatment can be made based on an individual’s genetic background.

• The ultimate goal is to correlate specific genetic features with the differential risk of diseases or the efficacy of certain therapeutic interventions.

Individually tailored therapy• Guidelines still somewhat represent a one-for-all

approach.

• Studies should be aimed at identifying patient groups that could benefit from a particular treatment option. (High renin, high ACE, low ACE2 activity)

• A large prevalence of aldosteronism among resistant hypertensives has been found and thus these patients should be identified before being labeled resistant and initiating non-pharmacological treatment as they could benefit from aldosterone antagonists.

Vaccines for hypertension• Immunization against components of the renin

angiotensin system offers the prospect of improved long-term control of hypertension.

• Renin immunization demonstrated effective blood pressure reduction in animal models of hypertension but was accompanied by autoimmune disease of the kidney.

• There are theoretical arguments that angiotensin immunization may have limited effectiveness and clinical studies confirmed these limitations.

• Vaccination against the angiotensin II type 1 receptor is another possible approach but has yet to undergo clinical evaluation.

• Thus, the role of vaccination in hypertension management remains to be established.

References:

• API updates 2016• Pubmed• Vascular health and risk management

Thank you