This document discusses hypertension and its treatment. It begins by defining hypertension and describing its various classifications and categories based on systolic and diastolic blood pressure readings. It then discusses the effects of hypertension on the body and the mechanisms involved, including the renin-angiotensin system. Causes of resistant hypertension and classifications of oral antihypertensive agents are provided. The document concludes by outlining investigations into new therapies for hypertension, such as guanylate cyclase stimulators, prostacyclin receptor agonists, endothelin receptor blockers, and endothelial nitric oxide synthase couplers.
New Therapies and Investigations in Hypertension Management
1. BY : JYOTI B. SHARMA
GUIDE : Mr. IMTIYAZ ANSARI
ORIENTAL COLLEGE OF PHARMACY
2. Sr. No.
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CONTENTS
Introduction
Effect of hypertension on our body
Mechanism of hypertension
Causes of resistant hypertension
Classification of Oral Anti-hypertensive Agents
Investigations and New therapies in hypertension
Invasion therapy
Cow urine therapy
Reference
5. • 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.
6. • ADOLESCENT
• CHILDHOOD
• INFANT
100 / 75 mmHg
85 / 55 mmHg
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:
7. Categories of hypertension
Categories
Systolic
Diastolic
High Normal
130-139
85-89
Stage 1
140-159
90-99
Stage 2
160-179
100-109
Stage 3
> 180
>110
ISH
> 140
< 90
PPH
(pulse pressure > 65 mmHg)
Normal ration is
3:2:1
(systolic/diastolic/pulse pressure)
HYPERTENSION
10. Classification of Hypertensive crises.
Hypertensive Urgency
Introduction:
• 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 Emergency
Introduction:
•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
11. 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.
13. Renal mechanism
The renin-angiotensin system (RAS) or the renin-angiotensinaldosterone 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 pathways
1. Macula densa pathways
2. Intrarenal baroreceptor or pathways
3. B-adrenergic receptor pathways
14. INHIBITION OF RENIN-ANGIOTENSIN SYSTEM:
1.
2.
3.
4.
5.
Sympathetic blockers
(B-blockers, adrenergic neuron
blockers, central sympatholytics )-decrease renin release.
Renin inhibitory peptides and renin specific antibodies
block renin action-interfere with generation of A-1 from
angiotensinogen (rate limiting step)
Angiotensin
converting
enzyme
inhibitors-prevent
generation of active principle A-2.
Angiotensin receptor (AT1) antagonists-block the action of
A-2 on target cells.
Aldosterone antagonists- block mineralocorticoid receptor.
15.
16. Nitric oxide
synthase and
Nitric oxide
Serotonin
transporter and
Serotonin uptake
Dysfunctional
Kv channels
Environmental
factor
Genetic
Mutation
Pulmonary
vascular
remodeling and
vasoconstriction
PAH
Modifier
Genes
Endothelin
Prostacyclin
synthase and
Prostacyclin
ACE
Angiotensin 2
20. 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
21. •
•
•
•
•
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
22. 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
bumetanide
furosemide
torsemide
Potassium-sparing
diuretics
amiloride
triamterene
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
With all, a high potassium level
and digestive upset and menstrual
irregularities in women
23. Aldosterone receptor
blockers
eplerenone
spironolactone
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 dysfunction
With some beta-blockers, an increased
triglyceride level
Combined alpha- and carvedilol
BBs
labetalol., etc
Low blood pressure when the person
stands and spasm of the airways
Angitensinogin
Converting Enzyme
Inhibitor(ACEIs)
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
Benazepril, captopril
Enalapril, fosinopril
Lisinopril, moexipril
perindopril., quinapril
Ramipril, Trandolapril
24. Angiotensin II
antagonists
Candesartan, eprosartan
Irbesartan, losartan
Olmesartan, telmisartan
Valsartan.
Calcium Channel
Diltiazem , diltiazem
Blockers (CCBs)—
Verapamil.
non-Dihydropyridines
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, felodipine
Isradipine, 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.
26. Sr. no.
1.
Potential classes of new medications
Novel approaches for treatment of hypertension
a.
b.
Prostacyclin receptor agonists
c.
Endothelin Receptor Blockers
d.
Rho-kinase inhibitors
e.
Serotonin inhibitors
f.
Vasoactive intestinal peptide
g.
Adrenomedullin
h.
2.
Guanylate cyclase stimulators
Endothelial nitric oxide synthase couplers
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
27. Guanylate cyclase stimulators:
• Riociguat has a dual mechanism
of action:
a) To stimulate sGC in an NOdependent
and-independent
mode of action and thereby to
enhance
cGMP
synthesis,
producing vasodilatation.
b) Riociguat improved pulmonary
hemodynamics and prevented
adverse structural remodeling.
28. 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.
29. Prostacyclin receptor
agonists:
• 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.
30. • 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.
31. Endothelin Receptor
Blockers:
• 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
32. 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.
33. Serotonin inhibitors
• 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
34. 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.
35. 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.
36. 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
37. • 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.
38. 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 longterm beneficial effect against pulmonary hypertension.
• Inhibitors are imatinib, sorafenib, and nilotinib.
39. • 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.
40. 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.
41. 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.
42. 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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43. 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.
44. Goal of gene therapy in hypertension
• Gene therapy aimed at
nullifying the renninAngiotensin 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.
45. 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.
46. 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.
47.
48. 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.
49. 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 nanovectorsused for gene transfer
51. 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 cells
b) Adult stem cells
c) Pluripotent stem cells
52.
53.
54. 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
55. • 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
56. • 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.
57. 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 stress
Cardioprotective: Protects heart
Suppresses fast rhythms of the heart.
Anti hypertensive: Helps reduce hypertension
Diuretic: Helps elevate the rate of urination.
58. • 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.
59. 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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