future of htn
TRANSCRIPT
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
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