Hypertension is a progressive cardiovascular disorder defined as a chronic elevation of systemic arterial pressure above 140/90 mmHg. The document discusses the etiopathogenesis and pharmacotherapy of hypertension. Regarding etiology, it discusses arterial stiffness, water-sodium retention, the renin-angiotensin-aldosterone system, sympathetic dysregulation, and genetics as contributing factors. Treatment involves lifestyle modifications and pharmacotherapy including diuretics, ACE inhibitors, ARBs, calcium channel blockers, and beta-blockers. Recent advances discussed include endothelin receptor antagonists, neprilysin inhibition combined with RAAS inhibition, angiotensin II receptor agonists, SGLT2 inhibitors, and renal denervation

1. ETIOPATHOGENESIS AND
PHARMACOTHERAPY OF DISEASE
ASSOCIATED WITH HYPERTENSION
PRESENTED BY
ARBEENA SHAKIR

2. 01 DEFINITION AND ITS
CLASSIFICATION
ETIOPATHOGENESIS
OF HYPERTENSION
TREATMENT OF
HYPERTENSION
RECENT CLINICAL
ADVANCES
COMPELLING
INDICATION
04
02 05
03
Table of contents

3. Definition and its
classification
01

4. DEFINITION OF HYPERTENSION
Hypertension is progressive CV disorder arising from a complex and interrelated etiologies
Hypertension is defined by presence of a chronic elevation of systemic arterial presssure
above a certain threshold value of above 140/90 mmHg .
Progression of hypertension is strongly associated with functional and structural cardiac
and vascular abnormalities that damage the heart,kidneys,brain,vasculature,and other
organs and leads to premature morbidity and death.

5. Stages of hypertension according to AHA

6. 02
_____
Etiopathogenesis of
hypertension

7. Etiopathogenesis of hypertension
—--Diagram representing the renin-angiotensin-aldostrerone system—----

8. 1. Arterial stiffness
Arterial stiffness refers to a reduction in elasticity and distensibility of arteries, and pulse wave velocity
(PWV) is often used to represent the degree of stiffness in large arteries. An increase in PWV indicates
severe arterial stiffness and impaired in arterial dilatation capacity. systolic BP is also associated with a
clinically significant progression of arterial stiffness . It is still a “chicken and egg question” that elevated
blood pressure and arterial stiffness which come first.
Water-sodium retention is a key cause of abnormal increases in intravascular fluid volume. Diuretics
(especially thiazide diuretics) are important in the control of hypertension caused by water-sodium retention.
Except secondary hypertension resulted from renal dysfunction, there is also a group of hypertensive patients
related to water-sodium retention in essential hypertension, namely salt-sensitive hypertension.
Reducing sodium intake has been considered as an important way to reduce the incidence of hypertension.
However, the benefits of using salt with low doses of sodium remain controversial, since low sodium intake is
also associated with an increased risk of cardiovascular disease.
2. Water-sodium retention and salt sensitive

9. Renin-angiotensin-aldosterone system is a consecutive peptidergic system that functions in the
control of the renal, adrenal, and cardiovascular systems. RAAS regulates BP mainly by affecting
arterial constriction and water-sodium retention in the body. Both circulating RAAS and tissue
RAAS (cardiac RAAS, vascular RAAS, intra-renal RAAS, brain RAAS and adipose tissue RAAS)
have been involved in the pathogenesis of essential hypertension and related target organ
damage.
3. Renin-angiotensin-aldosterone system
Several components of axis cascade have been identified in the RAAS, including angiotensinogen,
renin, angiotensin-converting enzyme, angiotensins with various subtypes (Ang I, Ang II, Ang III,
Ang IV, Ang 1-7), aldosterone and aldosterone receptors. Among these, angiotensinogen, produced
by the liver, is the starting point of the system.
4.Sympathetic dysregulation
Sympathetic dysregulation is also an important cause of essential hypertension. The sympathetic overdrive
leads to increased cardiac output, increased systemic vascular tone, and elevated plasma catecholamine
levels. Patients with hypertension can manifest as greater muscle sympathetic nerve activity (MSNA) and lower
baroreflex response .

10. 5. Genetics
Hypertension is closely associated with genes, and our understanding of the relationship between genetics and
BP has been well improved in recent years. More than 500 loci involved in the regulation of BP have been
revealed by genome-wide association studies, taking the total number of BP genetic loci to over 1,000.
Genetics alone is not sufficient to explain the variability in BP, suggesting that other risk factors are involved,
such as epigenetic modifications. Emerge evidence demonstrated potential contribution of epigenetic
mechanisms in essential hypertension.
INTERACTION BETWEEN THE PATHOGENESIS OF HYPERTENSION :

11. 03
Treatment of
hypertension

12. Goal of treatment :
The overall goal is to reduce morbidity and mortality by the least intrusive means possible. JNC7 guidelines
recommend goal BP less than 140/90 mmHg for most patients, less than 140/80 mm Hg for patients with
diabetes mellitus, and less than 130/80 mm Hg for patients with CKD who have persistent albuminuria (>30
mg urine albumin excretion per 24 hours).
Non-pharmacological therapy
Lifestyle modifications: (1) weight loss if overweight, (2) adoption of the Dietary Approaches to Stop
Hypertension (DASH) eating plan, (3) dietary sodium restriction ideally to 1.5 g/day (3.8 g/day sodium
chloride), (4) regular aerobic physical activity, (5) moderate alcohol consumption (two or fewer drinks per
day), and (6)smoking cessation.
• Lifestyle modification alone is sufficient for most patients with prehypertension but inadequate for
patients with hypertension and additional CV risk factors or hypertension-associated target-organ
damage.

13. Pharmacological therapy
Initial drug selection depends on the degree of BP elevation and presence of compelling indications for
selected drugs.
• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium
channel blockers (CCBs), and thiazide diuretics are acceptable first-line options.
•β-Blockers are used to either treat a specific compelling indication or as combination therapy with a
first-line antihypertensive agent for patients without a compelling Indication.
• Most patients with stage 1 hypertension should be treated initially with a first-line
antihypertensive drug or a two-drug combination.
Combination therapy is recommended for patients with stage 2 hypertension, preferably with two
first-line agents.
• There are six compelling indications where specific antihypertensive drug classes
provide unique benefits.
• Other antihypertensive drug classes (α1-blockers, direct renin inhibitors, central α2 agonists, peripheral
adrenergic antagonists, and direct arterial vasodilators) are alternatives that may be used for select
patients after first-line agents .

14. First line and other common antihypertensive drug :

15. Algorithm for treatment of hypertension :

16. Compelling indication for individual drug class

17. 04
Recent clinical
advances

18. The European Society of Cardiology and the European Society of Hypertension (ESC/ESH) define
hypertension by office BP levels ≥140 mmHg systolic or 90 mmHg diastolic, the American Heart Association
(AHA), the American College of Cardiology (ACC) and other scientific societies have endorsed a more
‘aggressive’ definition based on office BP values ≥130 mmHg systolic or 80 mmHg diastolic. In addition, the
International Society of Hypertension (ISH) adopted the 140/90 mmHg definition.
Of note, the more aggressive diagnostic targets endorsed by the US guidelines do no imply that all subjects
with office BP in the range of 130–139/80–89 mmHg require drug treatment. Instead, the AHA/ACC
guidelines suggest to apply more appropriate life-style measures (weight control, smoking cessation,
low-sodium diet, etc.) for these subjects, and to reserve drug treatment for cases of inefficacy of
non-pharmacologic measures.

19. 1.endothelin receptor antagonists
Endothelin regulates vascular tone and BP, producing a powerful vasoconstrictor effect and
contributing to the pathogenesis of hypertension. It causes neurohormonal and sympathetic
activation, hypertensive end-organ damage, fibrosis, endothelial dysfunction, and increased
aldosterone synthesis and secretion.
Furthermore, endothelin-1 (ET-1, the biologically predominant member of the endothelin
peptide family) is an endothelial cell-derived peptide with a wide variety of developmental and
physiological functions, which include embryogenesis and nociception.. More specifically, the
endothelin system plays a role in regulating the development of the specific neural crest cell
population and its derivatives

20. Aprocinentan, a blocker of both endothelin-A and endothelin-B receptors with a very long pharmacological
half-life (about 44 h), proved more effective than placebo and lisinopril. Interestingly, this antihypertensive
agent seems to exert additional mechanisms beyond the expected beneficial effects of sustained BP-lowering
action (including a decrease in renal vascular resistance and left ventricular hypertrophy) supporting the
hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension. Indeed,
aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III
trial.
2. Neprilysin Combined with Renin-Angiotensin System Inhibition
Neprilysin, a zinc endopeptidase, inactivates, not only the cardiac natriuretic peptides, but also
bradykinin,thereby inducing vasodilatation and natriuresis resulting from a more prolonged action by
these agents]. Neprilysin was not developed as monotherapy for clinical use, but combined with drugs
that inhibit the renin-angiotensin-aldosterone system.

21. 3. Angiotensin II Receptor Agonists
Angiotensin II induces vasoconstriction by stimulating the angiotensin 1 receptors, and vasodilatation by
stimulating the angiotensin 2 receptors. In experimental and clinical settings, stimulation of angiotensin 2
receptors inhibits fibrosis and induces vasodilatation, natriuresis, and blood pressure reduction.
Consequently, angiotensin II receptor agonists display an interesting antihypertensive potential and are
currently investigated for efficacy and safety.
4. Sodium-Glucose Cotrasporter-2 Inhibitors
In pivotal phase III clinical trials, selective SGLT2 receptor inhibitors empagliflozin, canagliflozin,
dapagliflozin and ertugliflozin modestly reduced systolic and diastolic BP through various mechanisms
which may include natriuresis, osmotic diuresis and reduction of the sympathetic tone. These drugs
induced a marked reduction in the risk of heart failure . In patients with heart failure and reduced
ejection fraction (HFrEF), both with and without diabetes, empagliflozin and dapagliflozin reduced
cardiovascular mortality and the need of re-hospitalizations for heart failure. In patients with heart failure
with preserved ejection fraction (HFpEF), empagliflozin significantly reduced the risk of cardiovascular
death or hospitalization for heart failure by 21%

22. In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg reduced 24-h ambulatory BP by
3.44/4.16 mmHg more than placebo and the degree of antihypertensive effect was comparable in
the presence of none, one or more than one antihypertensive drug
5. Renal Denervation
Renal sympathetic overactivity contributes to the development and progression of hypertension. Renal
denervation in experimental models of hypertension has been shown to reduce BP and improve renal
function, which laid the foundation for its introduction to clinical practice.
Some clinical trials published over the past 15 years generated many expectations on the clinical utility
of renal denervation.. Unfortunately, the SIMPLICITY HTN-3 trials failed to demonstrate the superiority
of renal denervation over sham control in terms of BP lowering effect. However, the SIMPLICITY HTN-3
trials had several methodological shortcomings. Just to mention some of these limitations, the study
erroneously included patients with secondary hypertension (hyperaldosteronism, etc.), 34% of
operators had executed only one denervation procedure in the past, drug treatment was much more
intense in the ‘sham’ control group than in the denervation group, denervation was not ‘complete’ (not
all quadrants of renal artery were ablated) in 75% of cases. Thus, the entire issue was reconsidered,
with planning and execution of newer better-designed clinical trials, which provided positive results

23. The main effects of inhibition of afferent and efferent sympathetic activity induced by renal denervation.

24. COMPELLING INDICATIONS :
Hypertension may exist in association with other conditions in which there are compelling indications for
use of a particular treatment based on clinical trial data demonstrating benefits of such therapy on the
natural history of the associated condition.

25. 1. Ischemic Heart Disease
pharmacologic therapy should be initiated with a BB.142,156 BBs will lower BP; reduce symptoms of angina;
improve mortality; and reduce cardiac output, heart rate, and AV conduction.
If angina and BP are not controlled by BB therapy alone, or if BBs are contraindicated, as in the presence of
severe reactive airways disease, severe peripheral arterial disease, high-degree AV block, or the sick sinus
syndrome, either long-acting dihydropyridine or nondihydropyridine type CCBs may be used.
2. Heart failure
The inexorable progression to more severe stages of left ventricular dysfunction can be significantly
reduced by effective therapy with ACEIs, BBs, and diuretics. Hypertension precedes the development
of HF in approximately 90 percent of patients and increases risk for HF by two- to threefold.
Hypertension is especially important in HF affecting African American and elderly persons.
HF is a “compelling indication” for the use of ACEI. Abundant evidence exists to justify their use with
all stages of HF (table 12). In patients intolerant of ACEIs, ARBs may be used. BBs are also
recommended in HF because of clinical studies demonstrating decreased morbidity and mortality,
and improvement in HF symptoms

26. 3. Diabetes and hypertension
The concordance of hypertension and diabetes is increased in the population; hypertension is
disproportionately higher in diabetics, while persons with elevated BP are two and a half times more likely
to develop diabetes within 5 years.
Regarding the selection of medications, clinical trials with diuretics, ACEIs, BBs, ARBs, and calcium
antagonists have a demonstrated benefit in the treatment of hypertension in both type 1 and type 2
diabetics.
4. Chronic kidney disease
The joint recommendations of the American Society of Nephrology and the National Kidney Foundation
provide useful guidelines for management of hypertensive patients with CKD. They recommend a goal BP for
all CKD patients of <130/80 mmHg and the need for more than one antihypertensive drug to achieve this
goal. The guidelines indicate that most patients with CKD should receive an ACEI or an ARB in combination
with a diuretic, and many will require a loop diuretic rather than a thiazide.

27. 5. Patients With Cerebrovascular Disease
With respect to the prevention of recurrent stroke, PROGRESS demonstrated that addition of the diuretic,
indapamide, to the ACEI, perindopril, caused a 43 percent reduction in stroke occurence.The reduced
incidence of stroke appeared related to the BP reduction obtained by the combination therapy even though
many patients on entry into the study were not hypertensive.No significant reduction was present in those
on perindopril alone whose BP was only 5/3 mmHg lower than in the control group.

28. REFERENCES :
● Joseph T. Dipiro, pharmacotherapy : a pathophysiological approach, 11th edition chapter 30
pg-273-308
● Joseph T. Dipiro, pharmacotherapy handbook ,9th edition chapter 10 pg-87-90
● https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949859/#sec4-jcdd-09-00072title
● https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616110/
● Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure (JNC7) (nih.gov)