ADVANCE THERAPY IN

HYPERTENSIONBY : JYOTI B. SHARMA

GUIDE : Mr. IMTIYAZ ANSARIORIENTAL COLLEGE OF PHARMACY

Sr. No.CONTENTS

1 Introduction

2 Effect of hypertension on our body

3 Mechanism of hypertension

4 Causes of resistant hypertension

5 Classification of Oral Anti-hypertensive Agents

6 Investigations and New therapies in hypertension

7 Invasion therapy

8 Cow urine therapy

9Reference

How to remain without tension ?

WHAT IS HYPERTENSION ?

It also called as “SILENT KILLER”

• Hypertension is generally defined as mild when the diastolic pressure is between 90 to 104 mmHg, moderate when it is 105 to 114 mmHg and severe when it is above 115 mmHg.

•Hypertension can be divided into two major divisions:

a) Primary or essential hypertension: where definite cause for the rise in BP is unknown but sympathetic and renin-angiotensin system may overactive and do contribute to the tone of blood vessels and cardiac output in hypertension.

b) Secondary hypertension: secondary to renal (chronic diffuse glomerulonephritis, pyelonephrities, polycystic kidneys); endocrine (Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism); and vascular (renal artery disease, pulmonary artery disease, coarctation of aorta) lesion.

• ADOLESCENT 100 / 75 mmHg• CHILDHOOD 85 / 55 mmHg• INFANT 70 / 45 mmHg

• Systolic Hypertension is marker of Macro-Vascular Disease large Arterial stiffening. (atherosclerosis )

• Diastolic Hypertension is consequence of Micro-Vascular Disease involving arterioles of < 1mm size (arteriosclerosis )

• As per Joint National Committee for Detection, Evaluation and Treatment of high BP has defined ‘Normal BP’ as that below 120/80 mmHg and following:

Categories of hypertensionCategories Systolic Diastolic

High Normal 130-139 85-89

HYPERTENSION

Stage 1 140-159 90-99

Stage 2 160-179 100-109

Stage 3 > 180 >110

I S H > 140 < 90

P P H (pulse pressure > 65 mmHg)

Normal ration is 3:2:1

(systolic/diastolic/pulse pressure)

Effect of hypertension

effect of hypertension in our body.xspf

Classification of Hypertensive crises.

Hypertensive UrgencyIntroduction:• a rapid and severe elevation in BP in the absence of organ injury• Those experiencing hypertensive urgency may or may not experience one or more of these symptoms:• Severe headache• Shortness of breath• Nosebleeds• Severe anxiety• urgencies may be treated on an outpatient basis, by gradually reducing BP using oral antihypertensives

Hypertensive EmergencyIntroduction:•a rapid and severe elevation in BP in the presence of target organ damage•The clinical presentation will depend on the particular organ that is undergoing injury, addition to other symptoms like Swelling or edema (fluid buildup in the tissues), severe chest pain, Severe headache, accompanied by confusion and blurred vision, nausea and vomiting, severe anxiety, shortness of breath, seizures & unresponsiveness• requires more immediate treatment with IV antihypertensives in an inpatient setting

Mechanism of hypertension

• The kidney plays a crucial role in blood pressure regulation. It controls the excretion of salt and water from the body, which affects blood volume and blood pressure. The organ also communicates with the brain, which helps regulate blood pressure by narrowing blood vessels or increasing the pumping action of the heart

• There are 3 main mechanism responsible for hypertension:

1. Renal mechanism,

2. Vascular mechanism and

3. Central mechanism.

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End- stage renal

disease

Congestive heart failure

StrokeMyocardia

l infarction

Ventricular tachycardia

orVentricular fibrillation

Systolic/diastolic

dysfunction

DementiaTransientischemic

attack

AtrialfibrillationVentricula

rarrhythmi

as

Chronic Renal failure

Left-ventricularhypertrophy

RetinopathyBinswanger

lesions

ProteinuriaNephrosclerosis

Prehypertension

Established hypertension

KIDNEY HEART BRAIN

Mechanism of hypertension

Renal mechanism The renin-angiotensin system (RAS) or the renin-angiotensin-

aldosterone system (RAAS) is a hormone system that regulate blood pressure and water (fluid) balance.

This system is synergistic with sympathetic nervous system, for e.g. by increasing the release of noradrenalin from sympathetic nerve terminals.

It stimulates aldosterone secretion and control Na+ excretion and also control vascular tone.

Renin : It is a proteolytic enzyme that is secreted by the juxtaglomerular

apparatus, which is a part of nephrone in kidneys. The secretion of renin is controlled by three pathways1. Macula densa pathways2. Intrarenal baroreceptor or pathways3. B-adrenergic receptor pathways

INHIBITION OF RENIN-ANGIOTENSIN SYSTEM:

1. Sympathetic blockers (B-blockers, adrenergic neuron blockers, central sympatholytics )-decrease renin release.

2. Renin inhibitory peptides and renin specific antibodies block renin action-interfere with generation of A-1 from angiotensinogen (rate limiting step)

3. Angiotensin converting enzyme inhibitors-prevent generation of active principle A-2.

4. Angiotensin receptor (AT1) antagonists-block the action of A-2 on target cells.

5. Aldosterone antagonists- block mineralocorticoid receptor.

PAH

Environmental factor

Pulmonary vascular

remodeling and vasoconstriction

Modifier Genes

Serotonin transporter and Serotonin uptake

Nitric oxide synthase and Nitric oxide

Dysfunctional Kv channels

Endothelin

Prostacyclin synthase and Prostacyclin

ACEAngiotensin 2

Genetic Mutation

Vascular diseases

Role of cholesterol in hypertension

Causes of resistant hypertension

1. Improper BP Measurement

2. Volume Overload and Pseudo-tolerance• Excess sodium intake• Volume retention from kidney disease

3. Drug-Induced cause hypertension• Non-adherence• Inadequate doses• Inappropriate combinations• Non-steroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors• Cocaine, amphetamines, other illicit drugs• Sympathomimetics (decongestants, anorectics)• Oral contraceptives

• Adrenal steroids• Cyclosporine and tacrolimus• Erythropoietin• Liquorice (including some chewing tobacco)• Selected over-the-counter dietary supplements and medicines(e.g.,

ephedra, ma hang, bitter orange)

4. Associated Conditions• Obesity• Excess alcohol intake

5. Identifiable Causes of Hypertension.• Chronic kidney disease• Primary aldosteronism• Renovascular disease• Chronic steroid therapy and Cushing’s syndrome• Pheochromocytoma• Coarctation of the aorta• Thyroid or parathyroid disease

Classification of Oral Anti-hypertensive Agents

Class Drug Some Side Effects

Thiazide diuretics Chlorothiazide , chlorthalidone, hydrochlorothiazide, polythiazide, indapamide, metolazone , metolazone.

Decreased levels of potassium and magnesium, increased levels of calcium and uric acid, sexual dysfunction in men, and digestive upset

Loop diuretics bumetanidefurosemidetorsemide

Decreased levels of potassium and magnesium, temporarily increased levels of blood sugar and cholesterol, an increased level of uric acid, sexual dysfunction in men, and digestive upset

Potassium-sparing diuretics

amiloridetriamterene

With all, a high potassium level and digestive upset and menstrual irregularities in women

Aldosterone receptor blockers

eplerenonespironolactone

Dizziness, an increased potassium level, angioedema (rare), and, in pregnant women, serious injury to the fetus, With spironolactone, breast enlargement in men (gynecomastia)

B-blockers (BBs) Atenolol, betaxolol, bisoprolol, metoprolol , metoprolol, nadolol , propranolol , propranolol,timolol .

Spasm of the airways (bronchospasm), an abnormally slow heart rate (bradycardia), heart failure, possible masking of low blood sugar levels after insulin, injections impaired peripheral circulation, insomnia, fatigue, shortness of breath, depression, Raynaud syndrome, vivid dreams, hallucinations, and sexual dysfunctionWith some beta-blockers, an increased triglyceride level

Combined alpha- and BBs

carvedilollabetalol., etc

Low blood pressure when the person stands and spasm of the airways

Angitensinogin Converting Enzyme Inhibitor(ACEIs)

Benazepril, captoprilEnalapril, fosinoprilLisinopril, moexiprilperindopril., quinaprilRamipril, Trandolapril

Cough (in up to 20% of people), low blood pressure, an increased potassium level, rash, angioedema (allergic swelling that affects the face, lips, and windpipe and may interfere with breathing), and, in pregnant women, serious injury to the fetus

Angiotensin II antagonists

Candesartan, eprosartan Irbesartan, losartan Olmesartan, telmisartanValsartan.

Calcium Channel Blockers (CCBs)—non-Dihydropyridines

Diltiazem , diltiazemVerapamil.

Headache, dizziness, flushing, fluid retention, problems in the heart's electrical conduction system (including heart block), an abnormally slow heart rate (bradycardia), heart failure, and enlarged gums. With verapamil, constipation

CCBs—Dihydropyridines

Amlodipine, felodipineIsradipine, Nicardipine

Dizziness, fluid retention in the ankles, flushing, headache, heartburn, enlarged gums, and an abnormally fast heart rate (tachycardia).

Vasodilators Hydralazine, Minoxidil, Diazoxide, Sodium nitroprusside.

Investigations and New therapies in hypertension

Sr. no. Potential classes of new medications1. Novel approaches for treatment of hypertension

a. Guanylate cyclase stimulators

b. Prostacyclin receptor agonists

c. Endothelin Receptor Blockers

d. Rho-kinase inhibitors

e. Serotonin inhibitors

f. Vasoactive intestinal peptide

g. Adrenomedullin

h. Endothelial nitric oxide synthase couplers

2. Agents that target proliferation and apoptosis in the treatment of hypertension

a. Tyrosine kinase inhibitor

b. EGF receptor blockers

3. Drugs targeting the BMP/TGFβ pathway

4. Gene therapy for hypertension

5 Stem cells therapy for hypertension

• Riociguat has a dual mechanism of action:

a) To stimulate sGC in an NO-dependent and-independent mode of action and thereby to enhance cGMP synthesis, producing vasodilatation.

b) Riociguat improved pulmonary hemodynamics and prevented adverse structural remodeling.

Guanylate cyclase stimulators:

Phosphodiesterase-5 Inhibitors:

a. Sildenafil:• PDE type 5 inhibitor• Reduce metabolism of cGMP• Metabolized by CYP3A4 and 2C9 substrate• Concentration increased by concurrent bosentan

b. Tadalafil:• It is a longer acting PDE-5 inhibitor which is currently

undergoing clinical trials and remains investigational as a therapeutic agent for patients with PAH.

• Epoprostenol:Administered Intravenously.It was first prostacyclin analog

approved by the US FDA to treat hypertension.

It has rapid onset of action with very short half life.

• Treprostinil:Administered Subcutaneously. It is a prostacyclin analog with a

longer half life.

Prostacyclin receptor agonists:

• Iloprost: It is a synthetic prostanoid Administered by inhalation through an adaptive aerosol device.• Beraprost: Orally active prostanoids, not FDA approved, but currently used

in Japan. It has been shown to improve symptoms of hypertension.• Selexipag: It is a first-in-class orally active prodrug. It’s metabolized to the highly selective prostacyclin receptor

agonist, which has a half-life of over six hours. Selexipag exerts vasodilatory activity on both large and small

pulmonary arterial branches. These properties show greater vasodilatory activity than with

beraprost and iloprost.

• Endothelin-1 which is the most potent vasoconstrictor ever isolated.

• Various endothelin receptor blockers are available for therapy.

a. Bosentan: It is a non-selective endothelin

antagonist blocking both ETA and ETB and was the first oral drug which was FDA approved for the treatment of PAH

b. Sitaxsentan: It is an ETA receptor selective

antagonist which is administered as a once daily oral dose.

It is not FDA approved, but is currently in use in Europe and Canada.

It is not as hepatotoxic as bosentan

Endothelin Receptor Blockers:

Rho-kinase inhibitors

• Rho-kinase inactivates MLC phosphatase, leading to increased levels of phosphorylated MLC which causes vascular smooth muscle contraction.

• Agents that inhibits phosphorylation of the myosin light chain (MLC)

•  Its activity is switched on when Rho-GTP binds to the kinase coiled-coil domain

• Rho-kinase inhibitor are as follow:

a) Azaindole-1:• Precursor for fasudil.

b) Fasudil:• Administred by inhalation, to avoid systemic vasodilation.

• Serotonin promotes PASMC proliferation, PA vasoconstriction and local microthrombosis.

• Inhibition of serotonin receptors or the serotonin transporter (SERT) has been shown to inhibit PAH.

• There are currently six SSRIs prescribed are:• Citalopram• Escitalopram• Fluoxetine• Fluvoxamine• Paroxetine• Sertraline

Serotonin inhibitors

Vasoactive intestinal peptide (VIP):

• The lack of gene for VIP spontaneously developed features of moderately severe iPAH.

• Administration of VIP to these animals had a beneficial therapeutic effect in PAH.

• Administered by inhalation of peptide.• The patients having deficiency in the production of the

peptide (for a variety of reasons), in those patient substitution of the hormone results in substantial improvement of hemodynamic parameters.

• Systemic dosing may be limited by reduced systemic vascular resistance.

Adrenomedullin (ADM)

• ADM is a potent vasodilator peptide.• Its effects are mediated through cAMP and nitric oxide

(NO) dependent mechanisms.• ADM gene-modified endothelial progenitor cells (EPCs)

have been shown to incorporate into the lung tissue and attenuate PH.

• Aerosolized ADM appears not to cause systemic vasodilatation.

• Administration of ADM, either by intravenous or intratracheal routes, significantly decreases PA pressure and pulmonary vascular resistance in patients with PH.

eNOS couplers:

• Endothelial dysfunction.• impaired production/bioavailability and

downstream activity of NO.• eNOS is critical to maintain normal tone in

the vasculature.• Two potential eNOS couplers are:a) Pteridine cofactor tetrahydrobiopterin

(BH4)b) Cicletanine hydrochloride

• Pteridine cofactor tetrahydrobiopterin (BH4): Function: eNOS activity and maintain endothelial function. The pharmaceutical formulation of BH4 is sapropterin

dihydrochloride, was studied as add-on to treatment with sildenafil and/or ERAs.

• Cicletanine hydrochloride: An antihypertensive with thiazide-like diuretic properties for the

treatment of systemic hypertension. The treatment of disorders associated with endothelial dysfunction. Co-administered with any two-drug combination to improve in

exercise tolerance, symptoms, or cardiopulmonary hemodynamics . Used to decreases the production of peroxynitrite or decreases

superoxide in treated patients.

Tyrosine kinases (TKs) inhibitors:

• Tyrosine kinase inhibitors are therapeutic effects due to inhibition of cell growth-related kinases and attenuate vascular remodeling.

• Concentration-dependently and completely reversed the contraction of hypertensive pulmonary arterial due to inhibition of nitric oxide synthase.

• Tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension.

• Inhibitors are imatinib, sorafenib, and nilotinib.

• Imatinib: Imatinib reversed serotonin-induced contractions. Imatinib inhibited activation of myosin phosphatase which is produced

by phosphorylation of myosin light chain phosphatase (Ca2+ desensitization).

Acute intravenous administration of imatinib reduced high right ventricular systolic pressure, with little effect on left ventricular systolic pressure and cardiac output.

• Sorafenib Sorafenib is a multi-kinase inhibitor It relaxed the induced contraction with a wider spectrum of TK activity

than imatinib and shown to attenuate pulmonary vascular remodeling and hemodynamic changes.

Sorafenib conferred increases in ejection fraction.• Nilotinib

The second-generation RTK inhibitor. Nilotinib showed efficacy on hemodynamics and pulmonary vascular

remodeling.

EGF receptor blockers

• Activated serine elastases within the PA wall can directly activate EGF receptors, this lead to the auto-phosphorylation of the EGF receptor.

• EGF receptor blockers inhibit EGF signaling might mimic inhibition of serine elastases which was shown to both, inhibit and reverse remodeling.

• This is important because at the moment elastase inhibitors, it inhibits phosphorylation and activation of the EGF receptor, results in decrease PA pressure, reverse vascular remodeling, and improve survival in PH.

• Similarly, the EGF receptor antagonist’s are : Gefitinib, Erlotinib and Lapatinib.

Drugs targeting the BMP/TGFβ pathway:• BMPR2 is a receptor for the transforming growth factor-beta (TGF-

β) superfamily • Mutations have been identified beneficial in increasing BMPR2

expression (by adenovirus)• Mutations in BMPR2 has been identified in activin-like receptor

kinase-1 (ALK-1) in PAH patients, as well as mutations in genes encoding the canonical downstream BMP signaling intermediaries, Smad 1 and 8.

• The lung endothelial targeting of BMPR2 expression • specific mutations in the ligand-binding domain of BMPR2 are

retained within the endoplasmic reticulum due to protein misfolding. • Correction of misfolding offers the opportunity for intervention in

these cases.

the cells in the central core of plexiform lesions lack the expression of TGF-β receptor 2, TGF-β receptor 1 and their signaling Smad(s) 2,1, 3 and 4, including the phosphorylated Smad 1/5/8 and 2.

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Gene Therapy

Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although the technology is still in its infancy, it has been used with some success.

Goal of gene therapy in hypertension• Gene therapy aimed at

nullifying the rennin-Angiotensin system is a speculation, through not in conceivable, approach to the semi-permanent or permanent treatment of hypertension.

• In this regard, two approaches have been suggested:

a) A mutant angiotensinogen gene strategy and

b) An antisense strategy.

Genetic Studies:• Establish an international blood and tissue bank for PAH that will have wide

access for genomic, proteomic, biomarker and histological studies.

• Support sequencing of the complete BMPR2 gene in patients without known predisposing mutations and the search for other major genes causing heritable PPH.

• Screen BMPR2 mutation :- positive families for genes that modify the penetrance of disease using genome; wide searches and new techniques of statistical genetics.

• Support functional studies of likely candidate modifier genes (e.g., serotonin transporter, NOS synthase, VIP, many others).

• Transgenic mice and transfected cells are important models for testing biological effects of altered genes and for therapies, and need further implementation.

Adenovirus

• A recombinant adenovirus vector has been used to incorporate the p21 gene, which regulates cell cycle progression of pulmonary hypertension.

• The p21 adenovirus vector was successfully transfected into the tissue, and the overexpression of p21 inhibited the development of PAH.

Adeno-Associated Viral

• An adeno-associated viral (AAV) vector used to transfect human PGIS to determine the effect on PAH.

• The AAV-PGIS was injected and significant pulmonary hypertension was observed that a smaller increase in RV systolic pressures, upregulation of brain natriuretic peptide levels in the RV

• Decrease in pulmonary arterial wall thickening and prolonged survival.

Nonviral Gene Therapy

• Nonviral approaches have been developed for gene transfer.

• Naked gene-transfer of PGIS • Polyplex nanomicelles-used to

deliver a therapeutic plasmid with the gene for human adrenomedullin, a vasodilator peptide.

• Biocompatible micelle nanovectors- used for gene transfer

Tissue-Specific Gene Therapy

Stem Cell Therapy• Stem Cells are cells that can divide to replace

indefinite cells. They can also give rise to daughter cells, called “progenitor” cells 

• This cell cannot self-renew and have a limited capacity to differentiate, produce mature cells of a single type. 

• Stem cells come from two main sources:a) Embryonic stem cellsb) Adult stem cellsc) Pluripotent stem cells

Invasive therapy:

• Renal denervation:Renal denervation may help to reduce high blood pressure

in patients with so-called treatment-resistant disease.Nerve signals from the brain to the kidney tend to increase

blood pressure, in part by stimulating production of the enzyme renin, which initiates a cascade of hormones that directly and indirectly lead to narrowing of arteries and decreases in excretion of salt and water.

When the kidney can’t “hear” the brain, blood pressure seems to fall. Thus the disruption of signaling to the kidney seems not to cause other problems

• Pulmonary Thrombentarterctomy:It is a highly specialized surgery. It considered as a treatment option in patients with

CTEPH if they have surgically accessible disease.Emboli in the pulmonary arteries can cause several

problems. If enough of these arteries are blocked, the amount of oxygen delivered to the blood is decreased.

These blockages in the arteries in the lungs also make it harder for the right side of the heart to pump properly.

The pressure in the blood vessels in the lungs increases, resulting in pulmonary hypertension.

The purpose of a pulmonary thromboendarterectomy is to remove blood clots that are blocking the pulmonary arteries in order to allow the right side of the heart to work properly

• Atrial septostomy: Creating an interatrial communication allows right to left

shunting decompressing the right ventricle. It has been shown to be of benefit in patients with refractory

right heart failure.

 • Lung and combined heart lung transplant: These have been used as treatment options for 30 years with long

term outcomes being comparable with patients with other primary indications for the same surgery.

Hemodynamic studies, post-surgery, have shown improvement in pulmonary hemodynamics with reduction in pulmonary vascular resistance and improvement in right ventricular function.

Hypertension and Cow Urine Therapy:

Pharmacological Activities:Cardiotonic : A tonic for heart, increases the efficiency of contractions

of the heart muscle.Anti-inflammatory: Reduces inflammation.Antioxidant: Capable of slowing down or preventing the oxidation of

molecules, to protect body cells from the damaging effects of oxidation.

Helps reduce stressCardioprotective: Protects heartSuppresses fast rhythms of the heart.Anti hypertensive: Helps reduce hypertensionDiuretic: Helps elevate the rate of urination.

• Cow urine is considered to have fat-lowering qualities. Apart from this, it is also known to bring down the quantity of glucose and blood lipids in the blood.

• Cow urine is also known for its clot dissolving abilities and it also helps to smoothen the muscles of the blood vessels.

• Cow urine also gives strength to the heart and the brain.• Cow urine has high antioxidant properties besides being

prominently used for building up the immunity system of the body.

• All these qualities of cow urine are found to be quite useful in the treatment and remedy of hypertension symptoms.

• Cow urine therapy is also gaining popularity because it has the ability to cure many different ailments affecting our body and that too without any side effects.

Conclusion:

• Hypertension is one of the most common chronic diseases worldwide. However, many people have hypertension without awareness and treatment of the disease, indicating it is necessary to provide some basic knowledge and essential information of hypertension to our audience, upper primary pupils at early stage of their life's to prepare them early in prevention or management of this disorder in their future life.

• Many risk factors are related with hypertension. Avoiding the factors help to prevent hypertension, reduce symptoms and prolong lives.

• Complications of hypertension are major sources of mortality. Reducing blood pressure with medication or keeping it within normal range will prevent, attenuates or reduce these complications.

• The content (advance therapy) created in this seminar report will be important and useful resources for future education on hypertension.

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