Pharmacotherapy of Hypertension

Abera J. (BPharm., MSc in Clinical Pharmacy),

School of Pharmacy, CHMS, HU.

07/08/2022 By; Abera J 1

 Outline
– Introduction and Epidemiology
– Etiology

– Pathophysiology
– Clinical presentation and Diagnostic consideration
– Hypertension-Associated Complications
– Treatment
• Non-pharmacologic Therapy
• Pharmacologic Therapy

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 Introduction
HTN is a common disease that is defined as persistently elevated
arterial BP;
SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg.
HTN is one of the most significant risk factors for CV related
morbidity & mortality

Change in the definition of HTN with the 2017 ACC/AHA

guideline (from a BP of ≥140/90 mm Hg to ≥130/80 mm Hg);
has increased the prevalence of HTN.

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 Epidemiology
Around 46% of American adults age 20 years and older have HTN
In Africa, prevalence of HTN ranged from 22.3% to 90%.
In Ethiopia, prevalence of HTN ranged from 7–37%.

The overall incidence of HTN is similar between men and

women…………but varies depending on age.
– The prevalence of high BP is higher in men than women before the age of
65 years
– Similar between the ages 65 and 74 years.
– However, after the age of 74, more women have high BP than men.

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 Etiology
Essential or primary HTN…...occur in over 90% individuals
– Results from unknown pathophysiologic etiology and cannot be cured
– Genetic factors may play a role in the dev’t of essential HTN by affecting
sodium balance or other BP regulating pathways
– There are monogenic and polygenic forms of BP dysregulation that may be
responsible for essential HTN.
• Genetic traits that affect sodium balance, urinary kallikrein excretion, NO
release, and excretion of aldosterone,
• Other adrenal steroids and angiotensinogen are also documented.

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 Etiology…
Secondary HTN….. is much less common than primary HTN (up to 10%)

– Results from either a comorbid disease or a drug (or other product)

– In most cases, renal dysfunction resulting from severe CKD or

renovascular disease is the most common secondary cause of HTN.

– Other comorbid disease which may cause HTN include:

• Cushing syndrome, coarctation of the aorta, parathyroid disease,

pheochromocytoma, primary aldosteronism, thyroid disease.

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 Etiology…
Certain drugs or other products, either directly or indirectly, can cause HTN or
exacerbate HTN by increasing BP.
Amphetamines, Corticosteroids
Decongestants (pseudoephedrine, phenylephrine)
Erythropoiesis stimulating agents (erythropoetin, darbopoetin)
Estrogen-containing OCs
NSAIDs
Cocaine & nicotine
Abrupt discontinuation of BBs or centrally acting alpha agonists
MAOIs with tryamine containing foods

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 Pathophysiology of HTN
Factors contributing to dev’t of primary HTN include:
Humoral abnormalities involving the RAAS

Abnormalities in renal or tissue autoregulatory processes for sodium

excretion, plasma volume, and arteriolar constriction;
Deficiency in synthesis of vasodilating substances in vascular
endothelium (prostacyclin, bradykinin, and NO) or excess
vasoconstricting substances (Ang-II, endothelin-I)

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 Diagram representing the renin–angiotensin–aldosterone system

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 Pathophysiology of HTN…
Arterial BP……..is the pressure in the arterial wall
The two arterial BP values are SBP and DBP.
SBP represents the peak value, which is achieved during cardiac contraction.
DBP is achieved after contraction when the cardiac chambers are filling, and
represents the nadir value.
The absolute difference between SBP and DBP is called the pulse pressure and is
a measure of arterial wall tension.
Mean arterial pressure (MAP) is the average pressure throughout the cardiac
contraction cycle.

It can be used clinically to represent overall arterial BP, especially in

hypertensive emergency.
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 Pathophysiology of HTN…
During a cardiac cycle, two-thirds of the time is spent in diastole and one-
third in systole.
Therefore, the MAP is calculated by using the following equation:
MAP = (SBP x 1/3) + (DBP x 2/3)

Arterial BP is hemodynamically generated by the interplay between

blood flow and the resistance to blood flow. It is mathematically defined as:
BP = CO X TPR
CO is the major determinant of SBP, whereas TPR largely determines DBP.

In turn, CO is a function of stroke volume, HR, and venous capacitance.

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 Pathophysiology of HTN…

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 Classification of BP and HTN
The classification of BP in adults is based on the average of two or more
properly measured BP values from two or more clinical encounters

Elevated……. not a disease category

Associated with an increased CV risks compared to Pts with normal BP
It identifies Pts whose BP is likely to progress to HTN in the future.

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 Classification of BP and HTN…
Hypertensive crises are clinical situations where Pts have extreme BP
elevations, typically >180/120 mm Hg.
They are categorized as either hypertensive emergency or hypertensive
urgency.
Hypertensive emergencies are extreme BP elevations that are accompanied
by acute or progressing end-organ damage.
Hypertensive urgencies are extreme BP elevations without acute or
progressing end-organ injury.
Isolated systolic HTN
When SBP values are elevated ( ≥140 mm Hg) and DBP values are not
(<90 mm Hg, but commonly less than 80 mm Hg)

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 Risk Factors

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 Clinical Presentations
HTN is asymptomatic……silent killer

The Pt may appear healthy or may have the presence of additional CV

risk factors

The Pt may complain of;

Headache
Dizziness

Nervousness
Flushed face
Lack of sleep

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 Diagnostic Considerations
The only sign of essential HTN is elevated BP.
The rest of the physical examination may be completely normal.

Complete medical evaluation (including a comprehensive medical history,

physical examination, and laboratory and/or diagnostic tests) is recommended after
diagnosis to;
Identify secondary causes,
Identify other CV risk factors or comorbid conditions
Assess for the presence or absence of hypertension-associated
complications.
The average of two or more BP measurements taken during two or
more clinical encounters is required to diagnose HTN.

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 HTN Associated Complications
Several complications can result as a consequence of high BP in Pts with
HTN.
CV events (eg, MI, cerebrovascular events, kidney failure) are the primary causes
of CV morbidity and mortality in Pts with HTN.
The probability of CV events and CV morbidity and mortality in Pts with HTN is
directly correlated with the severity of BP elevation.
HTN accelerates the dev’t of atherosclerosis and stimulates left ventricular and
vascular dysfunction.
Retinopathies can occur in HTN and may manifest as a variety of different findings.

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 Treatment
Goal of Treatment
To reduce morbidity and mortality from CV events (eg, coronary events,
cerebrovascular events, HF) and kidney disease.
Therefore, the specific selection of antihypertensive drug therapy should
be based on evidence demonstrating a reduction in morbidity and
mortality, not merely a reduction in BP.
Blood Pressure Goals
The ACC/AHA guideline recommends a goal BP of <130/80 mmHg for the
management of HTN in most Pts

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 General Approach to Treatment
All Pts with elevated BP, stage-I HTN, and stage-2 HTN should be
engaged in lifestyle modifications.

For Pts with elevated BP and those with stage 1 HTN who are at low risk
of ASCVD, lifestyle modification alone is an appropriate initial treatment.
The threshold when drug therapy should be started for these low-risk Pts is
when the BP is ≥140/90 mm Hg with a goal BP of <130/80 mm Hg.

For Pts with stage 1 or 2 HTN who already have ASCVD or who have an
elevated 10-year ASCVD risk ≥10%, the threshold for starting drug therapy
is ≥130/80 mmHg with a goal BP of <130/80 mmHg

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Algorithm for treatment of elevated BP and HTN based on BP
category at initial diagnosis.
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 Non-pharmacologic Therapy

All Pts with elevated blood pressure and HTN should be prescribed lifestyle
modifications.
However, they should never be used as a replacement for antihypertensive drug therapy
for Pts with HTN who are not at goal BP
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 Pharmacotherapy
The choice of initial drug therapy depends on;

The degree of BP elevation and

Presence of compelling indications

Pts with stage-I HTN

initial treatment with a first-line antihypertensive drug or the
combination of two agents

Pts with stage-II HTN

Combination drug therapy with two first-line antihypertensive drugs

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 Pharmacotherapy…
JNC-8 Hypertension Guideline Algorithm

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 Pharmacotherapy…
First-line antihypertensive drugs for Pts without a compelling indication for
a specific drug class
ACEIs
These agents should be used to treat the
ARBs majority of Pts with HTN because of evidence
CCBs demonstrating CV event reduction.
Thiazide diuretics
Alternative antihypertensive drugs
BBs
Central Alpha-2 agonists
Direct vasodilators & alpha-1 antagonists
Renin Inhibitors

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 Drug therapy based on compelling indication

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 ACEIs
Ang-II is a potent vasoconstrictor that stimulates aldosterone secretion,
causing an increase in sodium and water reabsorption with
accompanying potassium loss.
ACEIs inhibit the conversion of angiotensin I to angiotensin
II…..causes vasodilation and a decrease in aldosterone occur.
An ACEIs also blocks degradation of bradykinin and stimulates the
synthesis of other vasodilating substances (PGE2 and prostacyclin).
Increased bradykinin enhances the BP-lowering effects of an ACEIs,
but also is responsible for the side effect of a dry cough.

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 ACEIs…
An ACEIs may effectively prevent or regress LVH by reducing direct
stimulation of Ang-II on myocardial cells.
Preferred antihypertensive agent in Pts with DM and CKD

A regimen including an ACEIs with a thiazide is first-line in recurrent

stroke prevention
ACEIs further reduces CV risk in Pts with stable IHD, especially in Pts
post-MI

These benefits of an ACEIs occur in Pts with ASCVD even in the

absence of LV dysfunction

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 ACEIs…
Doses of ACEIs:

Benazepril, 10-40 mg, QD or BID

Captopril 12.5-150 mg, BID or TID

Enalapril, 5-40 mg, QD or BID

Fosinopril, 10-40 mg, QD

Lisinopril 10-40 mg, QD

Quinapril 10-80 mg, QD or BID
Ramipril 2.5-10 mg, QD or BID

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 ACEIs…
AEs of ACEIs………generally well tolerated.
Hyperkalemia..…..monitoring of serum K+ and Cr values within 4 weeks of
starting or increasing the dose of an ACEIs is recommended
AKI….. Uncommon and occur in less than 1% of Pts and minimized with slow
titration of the ACEIs dose
Preexisting kidney disease increases the risk of this SE.
Elevation in SCr........if absolute increase > 1 mg/dl from baseline reduce dose or
stop therapy
Angioedema…….is a serious potential complication of ACEI therapy.

Occurs in <1% of the population, and is more likely in African Americans

and smokers.
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 ACEIs…
Dry cough…..20% of Pts treated with an ACEIs.
Secondary to inhibition of bradykinin breakdown
Avoid the use of ACEIs in bilateral renal artery stenosis or unilateral renal artery
stenosis in Pts with one functioning kidney
ACEIs are absolutely contraindicated in pregnancy.
Female Pts of childbearing age should be counseled regarding effective forms
of birth control
May induce hypotension in sodium or volume depleted Pts, in HF exacerbation,
very elderly, or on concurrent vasodilators or diuretics

Start at half the normal starting dose and titrate over time

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 ARBs
Ang-II generated by two enzymatic pathways:
The RAAS……which involves ACE
An alternative pathway……….uses other enzymes such as chymase (aka
“tissue ACE”)
ARBs directly block the AT1 receptor that mediates the known effects of
Ang-II:
Vasoconstriction
Aldosterone release
Sympathetic activation
Antidiuretic hormone release and
Constriction of the efferent arterioles of the glomerulus

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 ARBs…
They do not block the AT2 receptor.
Therefore, beneficial effects of AT2 receptor stimulation
(vasodilation, tissue repair, and inhibition of cell growth) remain
intact with ARB use.

Do not block the breakdown of bradykinin

beneficial effects of bradykinin, such as;

vasodilation, regression of myocyte hypertrophy and fibrosis,

and increased levels of tissue plasminogen activator not present
with ARB therapy

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 ARBs…
ARBs are beneficial in diabetic nephropathy / albuminuria & can reduce renal

complications in these Pts

AEs….. ARB therapy has the lowest incidence of SEs

ARBs do not affect bradykinin and do not elicit a dry cough

ARB may cause renal insufficiency, hyperkalemia, and orthostatic hypotension

Monitor for renal insufficiency and hyperkalemia

An ARB should never be used in pregnancy.

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 ARBs…
Doses of ARBs:

Candesartan : 8-32 mg QD or BID

Irbesartan: 150-300 mg QD

Losartan: 50-100 mg QD or BID

Valsartan: 80-320 mg QD
Eprosartan: 600-800 mg QD or BID
Olmesartan: 20-40 mg QD

Telmisartan: 20-80 mg QD

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 CCBs
Both DHCCBs and NDHCCBs are first-line therapies for HTN.
CCBs also have compelling indications in stable IHD.
MOA: work by inhibiting the influx of calcium across the cell
membrane which results in relaxation and dilation

DHCCBs are potent vasodilators of peripheral and coronary

arteries
NDHCCBs directly reduce arteriovenous nodal conduction
resulting in negative chronotropic and inotropic actions

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 CCBs..
DHCCBs are very effective in older Pts with isolated systolic HTN
NDHCCBs (verapamil and diltiazem) decrease HR and slow atrioventricular
nodal conduction.
Similar to a BBs, these drugs may also treat supraventricular tachyarrhythmias
(eg, AF).

Verapamil (and diltiazem to a lesser extent) produces negative inotropic and

chronotropic effects that are responsible for its propensity to precipitate or
cause systolic HF in high-risk Pts.
Should be used in caution with HF Pts
Do not use NDHCCBs with BBs

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 CCBs…
SEs of CCBs include:

Hypotension
Dizziness and headache

Peripheral edema…….common class side effect

Reflex tachycardia…….common with nifedipine and low with
amlodipine

Bradycardia or heart block, and

Constipation…………..common with verapamil

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 CCBs…
Doses of CCBs
Dihydropyridine CCBs
Amlodipine: 2.5- 10 mg, QD
Nifedipine: 30 -90 mg, QD
Felodipine: 5-20mg, QD
Isradipine: 5-10 mg, BID
Non-Dihydropyridine CCBs
Diltiazem (SR): 180-360 mg BID
Verapamil (SR): 180-480 mg QD or BID

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 Thiazide Diuretics
Increase Na/water excretion……..decrease extracellular volume, CO and BP
Thiazides most useful in the elderly
Thiazides not effective in Pts with renal failure (GFR of <30 mL/min/1.73 m2),
use loop diuretics instead
Thiazides preferred in Pts with osteoporosis since they decrease calcium
excretion
Caution in gout Pts, since they may increase uric acid conc.
Caution in hyperlipidemia and DM Pts, since they may increase blood glucose
and cholesterol levels.

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 Thiazide Diuretics…
SEs include;
Hypokalemia and hypomagnesemia,…….may cause muscle fatigue
or cramps
Hyperuricemia, hypercalcemia, sexual dysfunction,
Increases cholesterol & glucose levels
Caution should be taken with sulfur allergic Pts
May cause volume depletion

Monitor K, SCr, lipids, glucose and uric acid levels

Dose in the morning to avoid nocturnal diuresis

Chlorothalidone: 6.25–25 mg, QD

Hydrochlorothiazide: 12.5–25 mg, QD
Metolazone 2.5-10 mg QD
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 Reading Assignment
Alternative Antihypertensive Drugs
Potassium-sparing diuretics and MRAs

Loop diuretics
Beta blockers

Central Alpha Agonists

Alpha Adrenergic Blockers
Direct Arterial Vasodilators

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 Combination Therapy
Using low-dose combinations provides greater reductions in BP compared
with high doses of single agents, with fewer drug-related SEs.
If monotherapy fails,
Increase the dosage of the first agent (can increase S/E)

Replace the first agent (may be suboptimal if the 1st agent is working but
BP is not controlled)
Or add other agents
If a diuretic is not used initially, it should be added to the regimen

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 Recommendations for Combination Therapy

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 Special Population Groups…Pregnancy
Reasonable alternatives
– β-Blockers (other than atenolol)
– Labetalol
– CCBs
ACEIs and ARBs…….known teratogens……absolutely contraindicated
When DBP >105 mm Hg
IV hydralazine or IV labetalol
Women with HTN who become pregnant, or are planning to become pregnant,
should be;

Transitioned to methyldopa, nifedipine, and/or labetalol during

pregnancy

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 Special Population Groups…Pregnancy…

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 Special Population Groups…Elderly
– Presents as isolated systolic HTN
– CV morbidity and mortality……directly correlated to SBP than to DBP
for Pts aged 50 and older
– Elderly Pts are at high risk for HTN related target-organ damage

Preferred agents……..thiazide diuretics, ACEIs and ARBs

– Use smaller-than-usual initial doses
– Centrally acting agents and α1-blockers should generally be avoided
or used with caution
• Associated with dizziness and orthostatic hypotension

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 Resistant HTN
Defined as failure to achieve goal BP of <130/80 mmHg with the use of three or

more drugs on maximum dose that includes a diuretic

Includes Pts who are controlled but require the use of four or more medications
Caused by;
Volume overload….excess sodium intake, kidney disease and inadequate
diuretic therapy
Drug induced
Non-adherence
Obesity
Excess alcohol intake

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 Resistant HTN…
Treatment
Improving medication adherence

Improving detection and correction of secondary cause

Assuring adequate diuretic therapy
Adding an aldosterone antagonist

Appropriate use of combination therapies

Using alternative antihypertensive agents when needed

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 Hypertensive Crisis
Characterized by the presence of very elevated BP………..>180/120 mm
Hg
Hypertensive Urgencies…….not associated with acute or immediately
progressing target organ injury

Hypertensive Emergencies…….associated with acute or immediately

progressing target organ injury
Acute target-organ injury includes: encephalopathy, ICH, acute left
ventricular failure with pulmonary edema, dissecting aortic aneurysm,
unstable angina, and eclampsia or severe HTN during pregnancy

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 Hypertensive Urgency…Treatment
Gradual reduction in BP preferred
– Rapid reductions in BP results in cerebrovascular accidents, MI,
and AKI.
Managed by adjusting maintenance therapy
By adding a new antihypertensive, and/or by increasing the dose of a
present medication
BP reductions with oral antihypertensive agents to stage 1 values
over a period of several hours to several days

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 Hypertensive Emergency…Treatment
Require immediate BP reduction
To limit new or progressing target-organ damage
Require parenteral therapy
Initial target is a reduction in MAP of up to 25% within minutes to hours
If the Pt is stable, DBP can be reduced to 100–110 mm Hg within the next 2
to 6 hours
Gradual reductions toward goal BP values can be attempted after 24 to 48
hours
Except in acute ischemic stroke where maintaining an elevated BP is needed
for a longer period of time

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 Intravenous Antihypertensive Drugs for Treatment
of Hypertensive Emergencies

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 Intravenous Antihypertensive Drugs for
Treatment of Hypertensive Emergencies…

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 Evaluation of Therapeutic Outcomes
Assess disease progression (target organ damage)
BP response should be evaluated 2 to 4 weeks after initiating or
making changes in therapy

Once goal BP values are attained……….BP monitoring every 3 to 6

months
Laboratory monitoring should typically occur 2 to 4 weeks after
starting a new agent or dose increase
Every 6 to 12 months in stable Pts
Adherence with each office visit
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 Monitoring

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THANK YOU.

07/08/2022 By; Abera J 57