BY : JYOTI B. SHARMA
GUIDE : Mr. IMTIYAZ ANSARI
ORIENTAL COLLEGE OF PHARMACY
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
Cow urine therapy
• 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.
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:
Categories of hypertension
(pulse pressure > 65 mmHg)
Normal ration is
Classification of Hypertensive crises.
• 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
• Severe anxiety
• urgencies may be treated on an
outpatient basis, by gradually
reducing BP using oral antihypertensives
•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
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.
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.
It is a proteolytic enzyme that is secreted by the
juxtaglomerular apparatus, which is a part of nephrone in
The secretion of renin is controlled by three pathways
1. Macula densa pathways
2. Intrarenal baroreceptor or pathways
3. B-adrenergic receptor pathways
INHIBITION OF RENIN-ANGIOTENSIN SYSTEM:
(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)
generation of active principle A-2.
Angiotensin receptor (AT1) antagonists-block the action of
A-2 on target cells.
Aldosterone antagonists- block mineralocorticoid receptor.
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
• Inadequate doses
• Inappropriate combinations
• Non-steroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors
• Cocaine, amphetamines, other illicit drugs
• Sympathomimetics (decongestants, anorectics)
• Oral contraceptives
Cyclosporine and tacrolimus
Liquorice (including some chewing tobacco)
Selected over-the-counter dietary supplements and medicines(e.g.,
ephedra, ma hang, bitter orange)
4. Associated Conditions
• Excess alcohol intake
5. Identifiable Causes of Hypertension.
• Chronic kidney disease
• Primary aldosteronism
• Renovascular disease
• Chronic steroid therapy and Cushing’s syndrome
• Coarctation of the aorta
• Thyroid or parathyroid disease
Classification of Oral Anti-hypertensive
Some Side Effects
metolazone , metolazone.
Decreased levels of potassium and
magnesium, increased levels of
calcium and uric acid, sexual
dysfunction in men, and digestive
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
Dizziness, an increased potassium
level, angioedema (rare), and, in
pregnant women, serious injury to the
fetus, With spironolactone, breast
enlargement in men (gynecomastia)
, metoprolol, nadolol ,
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
Combined alpha- and carvedilol
Low blood pressure when the person
stands and spasm of the airways
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
Diltiazem , diltiazem
Headache, dizziness, flushing, fluid
retention, problems in the heart's
(including heart block), an abnormally
slow heart rate (bradycardia), heart
With verapamil, constipation
Dizziness, fluid retention in the
ankles, flushing, headache, heartburn,
enlarged gums, and an abnormally fast
heart rate (tachycardia).
Investigations and New therapies in hypertension
Potential classes of new medications
Novel approaches for treatment of hypertension
Prostacyclin receptor agonists
Endothelin Receptor Blockers
Vasoactive intestinal peptide
Guanylate cyclase stimulators
Endothelial nitric oxide synthase couplers
Agents that target proliferation and apoptosis in the treatment of
Tyrosine kinase inhibitor
EGF receptor blockers
Drugs targeting the BMP/TGFβ pathway
Gene therapy for hypertension
Stem cells therapy for hypertension
Guanylate cyclase stimulators:
• Riociguat has a dual mechanism
a) To stimulate sGC in an NOdependent
mode of action and thereby to
b) Riociguat improved pulmonary
hemodynamics and prevented
adverse structural remodeling.
• PDE type 5 inhibitor
• Reduce metabolism of cGMP
• Metabolized by CYP3A4 and 2C9 substrate
• Concentration increased by concurrent bosentan
• It is a longer acting PDE-5 inhibitor which is
currently undergoing clinical trials and remains
investigational as a therapeutic agent for patients
It was first prostacyclin analog
approved by the US FDA to treat
It has rapid onset of action with
very short half life.
It is a prostacyclin analog with a
longer half life.
It is a synthetic prostanoid
Administered by inhalation through an adaptive aerosol
Orally active prostanoids, not FDA approved, but currently
used in Japan.
It has been shown to improve symptoms of hypertension.
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.
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
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
It is not as hepatotoxic as bosentan
• Rho-kinase inactivates MLC phosphatase, leading to increased
levels of phosphorylated MLC which causes vascular smooth
• Agents that inhibits phosphorylation of the myosin light chain
• Its activity is switched on when Rho-GTP binds to the kinase
• Rho-kinase inhibitor are as follow:
• Precursor for 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:
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
Systemic dosing may be limited by reduced systemic vascular
• ADM is a potent vasodilator peptide.
• Its effects are mediated through cAMP and nitric oxide (NO)
• ADM gene-modified endothelial progenitor cells (EPCs) have
been shown to incorporate into the lung tissue and attenuate
• Aerosolized ADM appears not to cause systemic
• Administration of ADM, either by intravenous or intratracheal
routes, significantly decreases PA pressure and pulmonary
vascular resistance in patients with PH.
• Endothelial dysfunction.
• impaired production/bioavailability and downstream
activity of NO.
• eNOS is critical to maintain normal tone in the
• 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
Co-administered with any two-drug combination to improve in
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
• 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.
Imatinib reversed serotonin-induced contractions.
Imatinib inhibited activation of myosin phosphatase which is produced
by phosphorylation of myosin light chain phosphatase (Ca2+
Acute intravenous administration of imatinib reduced high right
ventricular systolic pressure, with little effect on left ventricular systolic
pressure and cardiac output.
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.
The second-generation RTK inhibitor.
Nilotinib showed efficacy on hemodynamics and pulmonary vascular
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 :
Drugs targeting the BMP/TGFβ pathway:
• BMPR2 is a receptor for the transforming growth factor-beta
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
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.
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
Goal of gene therapy in hypertension
• Gene therapy aimed at
nullifying the renninAngiotensin system is a
speculation, through not in
conceivable, approach to the
permanent treatment of
• In this regard, two
approaches have been
a) A mutant angiotensinogen
gene strategy and
b) An antisense strategy.
• 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
• Screen BMPR2 mutation :- positive families for genes that modify the
penetrance of disease using genome; wide searches and new techniques of
• 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
• A recombinant adenovirus vector
has been used to incorporate the
p21 gene, which regulates cell cycle
• The p21 adenovirus vector was
successfully transfected into the
tissue, and the overexpression of
p21 inhibited the development of
• An adeno-associated viral (AAV)
vector used to transfect human
PGIS to determine the effect on
• The AAV-PGIS was injected and
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
Nonviral Gene Therapy
approaches have been
developed for gene transfer.
• Naked gene-transfer of PGIS
deliver a therapeutic plasmid with
• Biocompatible micelle nanovectorsused for gene transfer
Stem Cell Therapy
• Stem Cells are cells that can divide to replace indefinite
cells. They can also give rise to daughter cells, called
• 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
• 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
• 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:
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.
• 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
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.
• 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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