The document discusses the pathophysiology and pharmacotherapy of hypertension. It begins by defining hypertension and classifying blood pressure levels. It then examines the humoral mechanisms that regulate blood pressure such as the renin-angiotensin-aldosterone system. The document outlines the etiology of both primary and secondary hypertension. It discusses diagnostic considerations and treatment goals and options, including non-pharmacological therapies and drug treatments. Recent clinical advances in treating hypertension, such as dual-acting RAS-neprilysin inhibitors and angiotensinogen small interfering RNAs, are also summarized.

1. Pathopysiology and
pharmacotherapy of hypertension
-Anukrati Agnihotri
School of P’ceutical education & research
Jamia Hamdard University

2. CONTENT
• Definition
• Classification of BP
• Humoral Mechanism
• Etiology
• Diagnostic considerations
• Treatment
• Compelling indications
• Recent Clinical advances
• References

3. Hypertension
• Defined as long term medical condition in which
the blood pressure in the arteries is persistently
elevated.
• The systolic BP will be equal or more than
140mmHg & diastolic BP will be equal or more
than 90mmHg.

4. • JN7 Guidelines
• Seventh report of the Joint national committee
on the detection, evaluation and treatment of
High blood pressure.
• JN7 is the national clinical guideline that was
develoed to aid clinicians in the management of
hypertension.

6. Arterial Blood Pressure
• It is the pressure in the arterial wall & is
measured in millimeters of mercury(mmHg).
• Two arterial BP values are systolic BP(SBP) and
Diastolic BP(DBP).
• The absolute diff. between SBP and DBP is
called Pulse Pressure.

7. • MAP = (SBP*1/3)+(DBP*2/3)
(Mean Arterial pressure)
Mathematically, Arterial BP is defined as the
product of Cardiac output and total peripheral
resistance.
BP= CO*TPR

8. Classification of BP
• The classification of BP in adults is based on the
average of two or more properly measured BP
values.

9. Humoral Mechanisms
• The Renin-Angiotensin-Aldosterone system
• Natriuretic hormone
• Neuronal regulation
• Vascular endothelial mechanism
• Electrolytes

10. 1. The Renin-Angiotensin-Aldosterone System-

11. 2. Natriuretic Hormone
• It inhibits sodium and potassium ATPase and
thus interferes with sodium transport across cell
membranees.
• A compensatory increase in the concentration of
circulating natriuretic hormone theoretically
could increase urinary excretion of sodium and
water.
• The increased intracellular sodium conc.
ultimately increases vascular tone and BP.

12. 3.Neuronal Regulation
• Central & autonomic nervous systems are
intricately involved in the regulation of arterial BP.
• The purpose of these neuronal mechanisms is to
regulate BP and maintain homeostasis.
• Pathologic disturbances in any of the four major
components (autonomic nerve fibres, adrenergic
receptors,baroreceptors, central nervous system)
could chronically elevate BP.

13. 4.Vascular endothelial Mechanisms
• Regulating functions are mediated by vasoactive
substances that are synthesized by endothelial
cells.
• Deficiency in local synthesis of vasodialating
substances (eg., angiotensinII and endothelin I)
contributes to essential hypertension,
atherosclerosis and other CV diseases.

14. 5.Electrolytes
• Excess sodium intake is associated with
hypertension. Population based studies
demonstrate that high sodium diets are
associated with a high prevalence of stroke and
hypertension.

15. Etiology
• In most patients hypertension results from
unknown pathophysiologic etiology (Primary or
essential hypertension). This form cannot be
cured but it can be controlled.
• A smaller percentage of patients have a specific
cause of their hypertension (secondary
hypertension).

16. • Primary Hypertension – Most individuals with
BP(over 90%) have essential or primary
hypertension. The exact factor which leads to the
development of primary hypertension is still
unknown. Genetic factors may play a role in the
development of this essential hypertension.
• Secondary Hypertension- In this type of
hypertension either a comorbid disease or a drug
is responsible for elevating BP & is much less
common than primary hypertension.

17. Secondary causes of hypertension
• Renal diseases Drugs
• Endocrine disease
• hyperaldosteronism,
• hypercorticoidism
• Growth hormone excess
• Catecholamine excess
• Pre clampsia
• Vascular causes
• Renal artery stenosis
• fibromuscular hyperplasia
• renal artery atheroma
• High salt
• Alcohol intake
• Obesity

18. Diagnostic considerations
• History collection and physical examination
• Medical history of diabetes mellitus
• Complete blood count
• Chest X-ray
• ECG

19. Clinical presentation
• Hypertension is called the silent killer because most patients do not
have symptoms.The diagnosis of hypertension cannot be made based
on one elevated BP measurement. The average of two or more BP
measurements is required to diagnose hypertension.
1. Cuff measurement
2. Ambulatory and home BP monitoring
• Severe cases may present –
1. Headache
2. visual disturbance
3. Evidence of target organ damage ( stroke, ischaemic heart disease
or renal failure)
• Malignant hypertension : accelerated/uncommon/ emergency,
usually >220/120mmHg evidence of Small vessel damage

20. Treatment
Goals of therapy of hypertension
• Immediate goal- To control both systolic &
diastolic B.P. within normal range with minimum
possible drugs & in lowest possible dose without
causing hypotension & thus maintaining quality
of life.
• Long term goal - To prevent complications such
as MI, stroke, damage to other target organs
leading to LVH, angina, arteriosclerotic
peripheral vascular disease, dissecting
aneurysm, retinopathy, nephropathy

21. 1.Non-Pharmacological Therapy
• Patients with mild hypertension in the range of 140-
159/90-100mmHg offered lifestyle advice
• Over weight- weight loss reduces BP about
2.5/1.5mmHg/kg
• DASH (dietary approaches to stop hypertension) found
to lower BP significantly 4.5/2.7mmHg • Subjects should
reduce their salt intake (6g NaCl)
• Significant hidden salt in the processed meat, ready
meals, cheese and even bread
• Control intake of calories and saturated fat
• Regular aerobic exercise (min 30mins)
• Alcohol intake 2 units for females and 3 units for male
• Smoking should be quit, or else reduce the units

22. 2.Pharmacological Therapy

26. Hypertensive emergencies and
urgencies
• Characterized by the presence of very elevated
BP, typically >180/120mmHg.
• Need for emergent anti-hypertensive therapy
must be determined based on the presence of
acute or progressing end organ injury, not
elevated BP alone.

27. Compelling indications

28. Recent Clinical advances
1.Dual-acting RAS–neprilysin inhibitors
Neprilysin (NEP) is a metalloprotease
responsible for the degradation of atrial
natriuretic peptide and brain natriuretic peptide.
Efforts to develop an antihypertensive NEP
inhibitor did not flourish because of concomitant
degenerative effects on vasoconstrictive
peptides such as angiotensin II and endothelin.
Thus, research proceeded on dual pathways,
combining NEP and RAS inhibition together.

29. • 2. Sodium-glucose cotransporter-2 inhibitors
These are novel oral hypoglycemic drugs that
inhibit the renal reabsorption of glucose in the
proximal tubule.
• Besides offering glycemic control and a
favorable cardiorenal impact, SGLT2is
demonstrated a modest but significant decrease
of BP levels in all relevant studies8. However, as
confirmed by recent meta-analyses, the level of
BP reduction is slight. Regarding the potential
side effects, major concerns have been raised
because of the higher incidence of urinary tract
infections, diabetic ketoacidosis, fractures, and
limb amputations noticed in some of the main
trials of SGLT-2is.

30. 2. Angiotensinogen small interfering RNAs.
Small interfering RNAs (siRNAs) are molecules
that silence the translation of selected target
mRNAs. Inclisiran inhibits the translation of
proprotein convertase subtilisin/kexin type 9
mRNA in hepatocytes, offering a long-term
sustained reduction of LDL. Likewise, an
angiotensinogen siRNA developed in an effort to
inhibit the renin angiotensin aldosterone system
(RAAS) at its roots has shown promising results
in an animal study.

31. 3. Microbiota-targeted therapy, vaccines, and
nutraceuticals. Recent experimental data have
associated alterations in gut microbiome caused by high
salt consumption with the activation of Th17
lymphocytes, which in turn are believed to promote
autoimmunity and HTN. Preliminary data have identified
Lactobacillus as a “natural inhibitor” of the high-salt
environment activation of TH17 cells.
• AngQb was a promising vaccine against angiotensin II
that has already completed a phase IIa trial in patients
with primary HTN and demonstrated significant reduction
of ABP without raising major safety issues.
• Many dietary ingredients have been shown to lower BP
levels via different pathways. To date, there are no
available data from RCTs to support the beneficial
effects of such nutraceuticals in HTN treatment.

32. 4. Centrally Acting Aminopeptidase Inhibitors
Activation of the brain RAS plays an important
role in the pathogenesis of hypertension in
animal models. Two membrane-bound zinc
metalloproteases, aminopeptidase A (APA) and
aminopeptidase N, are involved in the
metabolism of brain Ang II and III, respectively.

33. REFERENCES
• Leontsinis, I., Mantzouranis, E., Tsioufis, P.,
Andrikou, I., & Tsioufis, C. (2020). Recent
advances in managing primary hypertension.
Faculty Reviews. https://doi.org/10.12703/b/9-4
• Oparil, S., & Schmieder, R. E. (2015). New
approaches in the treatment of hypertension.
Circulation Research, 116(6), 1074–1095.
https://doi.org/10.1161/circresaha.116.303603
• DiPiro J.T., & Yee G.C., & Posey L, & Haines S.T.,
& Nolin T.D., & Ellingrod V(Eds.), (2020).
Pharmacotherapy: A Pathophysiologic Approach,
11e. McGraw Hill.
https://accesspharmacy.mhmedical.com/content.
aspx?bookid=2577&sectionid=248126979