Drug in htn(2) (1)

Mastaneh Moghtaderi
Pediatric Nephrologist
Children´s Hospital Medical Center
Tehran University of Medical Science

Pharmacologic Treatment of HTN

 By definition, 3.5-5% of children have HTN
(2004); 10%–11% have elevated blood
pressure (BP)(2017)
 Increase in prevalence High BP due to obesity
in childhood increases the risk for adult HTN
and cardiovascular disease.

 Iran J Kidney Dis. 2013 Jul;7(4):282-9.
 Prevalence of childhood obesity and hypertension in south of Iran.
 Basiratnia M1, Derakhshan D, Ajdari S, Saki F.
 Abstract
 INTRODUCTION:
 Obesity is a growing problem worldwide and is likely a major cause of the increased
prevalence of high blood pressure in children. The aim of this study was to investigate
the frequency of pediatric obesity and its association with hypertension in a sample of
children and adolescents in Fars province (south of Iran).
 MATERIALS AND METHODS:
 This cross-sectional study was carried out in Shiraz during a period from 2010 to 2011.
A total of 2000 healthy students aged 11 to 17 years were included. Data on weight,
height, systolic and diastolic blood pressure (measured 3 times with 5-minute
intervals), and parental history of hypertension and educational level were obtained.
The 95th percentile body mass index for age and sex was considered obesity.
 RESULTS:
 Overall, 7% and 11.8% of the students were obese and hypertensive, respectively.
Blood pressure was associated with body mass index. Maternal education level was not
associated with hypertension in the child.
 CONCLUSIONS:
 In this study, obesity was an important risk factor for hypertension. Our data showed
that prevalence of obesity has not been changed in the recent 5 years in Iran, but that
of hypertension has risen significantly. The high prevalence of hypertension in
overweight and obese children emphasizes the need for prevention and control of
childhood obesity and hypertension in early stages.

 High prevalence of hypertension among Iranian children and adolescents
a systematic review and meta-analysis
 Akbari, Maryama; Moosazadeh, Mahmoodb; Ghahramani, Sulmazc; Tabrizi, Rezac; Kolahdooz,
Faribad; Asemi, Zatollahe; Lankarani, Kamran B.f
 Journal of Hypertension: June 2017 - Volume 35 - Issue 6 - p 1155–1163
 Background: High blood pressure in children is a public health problem and the most important
risk factor for cardiovascular disease at an older age. Several preliminary studies have been
published regarding the prevalence of high blood pressure in which there was significant disparity.
 Objective: This study aimed to estimate the prevalence of hypertension in Iranian children using
the meta-analysis approach.
 Methods: A systematic search of national and international databases was conducted through
September 30, 2015, for population studies providing estimates on the prevalence of
hypertension in Iranian children and adolescents. From the extracted prevalence rates, the
heterogenic index of the studies was determined using Cochran's (Q) and Chi-squared (I2) tests,
and on the basis of the heterogenetic results, a fixed or random effects model was employed to
estimate the pooled prevalence rate of hypertension. Meta-regression was performed to
determine those factors suspected of generating heterogeneity.
 Results: Of 2360 articles initially identified, 17 were considered eligible. The meta-analyses
included 79 231 children and adolescents aged between 3 and 18 years. The pooled prevalence of
hypertension among children and adolescents was estimated to be 8.9% [95% confidence interval
(95% CI): 7.5–10.3] in overall, 10.3% (95% CI: 7.5–12.6) in males and 9.1% (95% CI: 7.4–10.7) in
females. The prevalence rates of high DBP and SBP were estimated at 6.6% (95% CI: 3.9–9.2) and
6.9% (95% CI: 5.6–8.2), respectively.
 Conclusion: There is a high prevalence of hypertension among Iranian children and adolescents.
Although it is slightly higher among boys than girls, the difference was not statistically significant.

 Hypertension and associated factors in the Islamic Republic of Iran: a population-based study
 Marzieh Katibeh,1, 2 Ali Sanjari Moghaddam,3 Mehdi Yaseri,4 Dinesh Neupane,2 Per Kallestrup,2 and Hamid
Ahmadieh 3
 1Ophthalmic Epidemiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Islamic
Republic of Iran. 2Center for Global Health, Department of Public Health, Aarhus University, Aarhus, Denmark.
3Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Islmic Republic of Iran.
4Tehran, Islamic Republic of Iran. (Correspondence to: Ali Sanjari Moghaddam:
 Abstract
 Background: Hypertension (HTN) is a major risk factor of cardiovascular diseases and has a high prevalence in the
Eastern Mediterranean Region.
 Aims: The aim of this study was to estimate the prevalence and awareness of hypertension and its associated
factors in the central district of the Islamic Republic of Iran.
 Methods: This cross-sectional study was conducted among 2320 adults aged 40–80 years in Yazd, Islamic Republic
of Iran, in 2010–2011. Multivariable logistic regression analysis was performed to calculate the odds ratios (OR) for
exploring the association between hypertension and associated risk factors. Of eligible subjects, 2098 participated
in clinical exams (response rate: 90.4%).
 Results: The sex- and age-standardized prevalence of HTN was 52.8% (95% CI: 49.6; 56.1%). Of participants with
HTN (n=1170), 421 cases were diagnosed for the first time in this survey; therefore, unawareness proportion was
36.0% (95% CI: 33.2%-38.8%). Among known cases (749 out of 1170 participants with HTN), 68.5% (95% CI: 65.0;
71.8) had uncontrolled blood pressure. Age [OR age group 70–80 vs. age group 40–50 =7.01 (95% CI: 4.01; 12.24)],
obesity [OR=2.78 (95% CI: 2.06; 3.75)], diabetes [OR=1.46 (95% CI: 1.12; 1.89)], hyperlipidemia [OR=1.60 (95% CI:
1.26; 2.03)] and living in rural area [OR=1.57 (95% CI: 1.00; 2.45)] were significantly associated factors with HTN.
 Conclusions: Although age is the inevitable risk factor of HTN, a high proportion of unawareness and uncontrolled
HTN and modifiable associated risk factors such as obesity, hyperlipidemia and diabetes demand effective
preventive and curative strategies.
 Keywords: Hypertension, high blood pressure, prevalence, risk factor, Iran

 Goals of HTN Therapy
 In asymptomatic children, the NHBPEP recommends
achieving the target BP of:
 • <95th percentile for children with persistent HTN after
instituting lifestyle measures.
 • <90th percentile in children with evidence of coexisting
cardiovascular risk factors, diabetes, symptomatic PH, or
in those with associated end-organ damage.
 Overt proteinuria or progressive chronic kidney disease is
also an indication for lowering BP <90th percentile

1. Stage I HTN who are unresponsive to changes in
lifestyle and in those with Stage II HTN.
2. Symptomatic HTN including headaches, changes in
mental process or consciousness, or irritability.
3. Secondary HTN.
4. Evidence that the high BP is causing end-organ
damage. This may be evident by LVH

5. Coexisting diabetes. All children with HTN
and diabetes should be considered for
pharmacologic therapy, independent of
albuminuria status.
6. The presence of additional cardiovascular
risks including elevated serum cholesterol,
known heart disorders, severe obesity, etc.

 LVH on echocardiography is perhaps the most
sensitive means for detecting end-organ injury in
children with well-established HTN.
 Microalbuminuria, as a marker of microvascular
disease, is another early clinical indicator of end-
organ damage in adults with HTN, but its
importance has only been investigated in children
with type 1 diabetes

 The overall benefit of BP lowering with
lifestyle measures is conservatively
estimated to be equivalent to drug
monotherapy for HTN .
 These include diet, exercise, and social
habits.

 In general, the use of fewer medications with
fewer adverse effects leads to better compliance.
 Single medications with extended-release or long
action or combination drugs may also enhance
compliance, particularly in adolescents.
 It should be noted, however, that even among the
best conceived studies, target BP may be achieved in
only 45–63 % of the children

 As a rule, one should start with one medication at a
time using the lower dosage range.
 BP should be closely monitored at home, school, or
at the primary care physician’s office.
 If the child is asymptomatic and BP fails to improve
within2–3 days after using the agent at the mid-range
dosage, there are three general guidelines:

 1. Further increase the dosage gradually to the
maximum tolerable dose (“stepped” or “stepup”
care).
 2. Replace the initial agent with that of another class
(“sequential monotherapy”) on the assumption that
it is not possible to predict how all children with a
given disorder will respond to any individual agent.
 3. Add another agent (“add-on” care).

 Based on a meta-analysis showing a greater efficacy
of antihypertensive monotherapy administration at
night rather than in the morning, there has been a
trend toward evening dosing of such agents

 Because renal disease comprises 60–70 % of the
etiology of HTN in preadolescent children, the use of
angiotensin-converting enzyme inhibitor (ACEI) and
angiotensin receptor blocker (ARB) is more prevalent
in children than in adults, while other classes of
medications may also be equally effective.
 Pediatric nephrologists utilize ACEI as first-line drugs
in 84 % of children with HTN associated with renal
disorders. PH is much more prevalent in adolescents.

 In this population the initial medication choice may
be much wider Because children and adolescents in
general participate in more vigorous activities than
adults, antihypertensive agents which tend to limit
reflex tachycardia and interfere with cardiovascular
performance (β-blockers) or those which adversely
impact intravascular volume and stroke volume
(diuretics) and produce orthostatic symptoms, the
use of such agents is generally limited to
“Management of Specific Disorders”

 In choosing antihypertensive agents for any
indication, one must always consider the presence of
other medical conditions.
 For instance, thiazide diuretics should be avoided in
individuals with gout, diabetes, or hyperlipidemia; β-
blockers are relatively contraindicated in individuals
with bronchospasm, asthma, or peripheral vascular
disease; CCB should be avoided in individuals with
certain cardiovascular disorders; and ACEI and ARB
must be avoided throughout pregnancy.

 The ability of several diuretics to block tubular
reabsorption of sodium and thereby induce diuresis
may be useful in managing HTN.
 These clinical properties are particularly beneficial in
HTN associated with edema- or salt-retaining
disorders.
 Children with low birth weight and blacks tend to
have impaired BP natriuresis, or salt sensitive HTN,
and respond well to diuretics.

 Unlike the widespread use of diuretics for initial
treatment in many adults with PH, such agents are
utilized much less frequently in children in whom
they are often used as secondary or add-on drugs or
in fixed-drug combinations with the goal of obtaining
an additive or synergistic action.

 The two most common classes are loop diuretics
which are particularly used to manage HTN
associated with acute glomerulonephritis and
overflow rather than underfill edema, and thiazide
diuretics for more chronic forms of HTN.
 Osmotic diuretics, such as mannitol, expand the
extracellular fluid compartment and should not be
utilized in the management of HTN

 Resistance to diuretics used in the setting of HTN may
be caused by several factors including a high salt
intake, progressive renal insufficiency, and use of
nonsteroidal anti-inflammatory agents which inhibit
renal synthesis of vasodilatory and natriuretic
prostaglandins

 These include furosemide, ethacrynic acid, and
bumetanide. By blocking the Na+/K+/2 Cl (NKCC2)
electroneutral cotransporter in the luminal
membrane of the medullary and the cortical
segments of the ascending limb of the loop of Henle,
these agents may increase the fractional excretion of
sodium (FENa) by inhibiting the reabsorption of as
much as 20 % of the filtered sodium and thereby lead
to dramatic diuresis.

 Potassium, calcium, and magnesium depletion is also
enhanced by these rapidly acting agents.
 These agents are contraindicated in children with
hypercalciuria or nephrocalcinosis.
 Metabolic alkalosis and volume contraction may
result, especially if hypokalemia is not corrected.

 Hydrochlorothiazide (HCTZ), chlorothiazide, and
metolazone directly inhibit the Na+/Cl cotransporter
in the cortical thick ascending limb and in the early
distal tubule.
 HCTZ is by far the most popular thiazide diuretic
 These agents are contraindicated in individuals with
high bilirubin concentrations, particularly newborns
with hyperbilirubinemia.

 Because thiazides often cause volume contraction,
more reabsorption of solutes such as glucose,
calcium, and uric acid, as well as fluid, can take place
in the proximal tubule.
 Thus, hyperglycemia, hypercalcemia, and
hyperuricemia (gout) may occur, while serum
potassium and magnesium concentrations may fall.

 Metolazone is the most powerful thiazide diuretic
and can be used in individuals with renal insufficiency
where other thiazide diuretics are ineffective.
 Metolazone is especially effective when combined
with loop diuretics. It can be given orally or enterally
and has a longer duration of action than other agents
in this class.

 Spironolactone, canrenone, and eplerenone are
aldosterone receptor antagonists and inhibit
potassium excretion by the principal cells located at
the cortical collecting duct and to a lesser degree at
the connecting tubule.
 Spironolactone is mainly used as a potassium-sparing
diuretic and has a slow onset of action (about 2 days)
and a relatively long half-life (20 h).

 All potassium-sparing diuretics are relatively
contraindicated in hyperkalemic disorders unless
combined with another diuretic such as
spironolactone/thiazide (Aldactazide).
 Both spironolactone and canrenone cause
gynecomastia and amenorrhea, and prolonged use of
these agents is not recommended in children.
 Eplerenone is relatively devoid of such side effects
and is gaining wider use in the pediatric population

 Triamterene and amiloride
 These agents are often combined with loop
or thiazide diuretics and may also cause
hyperkalemia particularly when used in
individuals with renal impairment who also
receive ACE inhibitors, angiotensin receptor
blockers, or direct renin inhibitors

 Agents in this class (clonidine, methyldopa,
guanabenz, guanfacine)
 This results in the inhibition of central sympathetic
outflow to peripheral vessels and hence lowers
peripheral vascular resistance
 cardiac output and renal blood flow, as well as
glomerular filtration rate (GFR), are not affected by
these agents

 Hence, agents such as clonidine are often utilized as
second- or third-line medications in the management
of sustained HTN, particularly in children with renal
disorders.
 Lastly, such agents are useful in managing disorders in
which sympathetic overactivity may be playing a role,
such as pheochromocytoma, diabetes, or the
metabolic syndrome.

 Clonidine is the most commonly utilized centrally
acting agent in children.
 It is well-absorbed when given enterally, or via the
transdermal route and requires no adjustment in
dosage in renal failure.
 It is also minimally removed by dialysis.
 Clonidine is especially effective in lowering BP when
used adjunctively with vasodilators that cause reflex
tachycardia including hydralazine and minoxidil.

 Clonidine has a rapid onset of action (30–60
min), and may be suitable in managing
hypertensive urgencies, particularly if anxiety
is contributing to HTN.
 However, transdermal delivery is not useful
in this setting because the peak action occurs
after 1–2 days, although effectiveness lasts
for up to 7 days

 Like other agents in this class, sedation and dry
mouth are the most common adverse effects of
clonidine.
 Postural hypotension, muscular weakness, and
gastrointestinal symptoms are less frequent side
effects.
 These adverse effects may particularly affect the
lifestyle of children participating in competitive
sports

 Also, sudden withdrawal of clonidine may result in
rebound HTN particularly when high dosages are
utilized.
 With prolonged use, and particularly with high
dosages of clonidine, vasodilation may occur and
result in salt and water retention. This may be offset
by the addition of a diuretic.

 Because Alpha-methyldopa can cause Coombs-
positive hemolytic anemia and greater somnolence
and depression compared to clonidine, this agent has
limited use in the pediatric population
 It should not be used in children with hepatitis or
other active liver disorders.
 However, α-methyldopa may be useful in agitated
children with HTN following brain injury and may also
be utilized to manage pregnancy associated HTN
because it does not interfere with placental blood
flow and it is not teratogenic.

 These are fourth- or fifth-line drugs in
children with chronic HTN.
 Among the drugs in this only prazosin has
had any notable use in children.
 However, phenoxybenzamine has specific
utility in the management of
pheochromocytoma

 Metoprolol is widely utilized in children.
 It is a cardioselective β-blocker, metoprolol,
and has shown safety and efficacy in both
regular form and its extended-release form
(Toprol-XL) in children.
 Bisoprolol in combination with
hydrochlorothiazide (Ziac) is also effective in
managing pediatric HTN

 In addition to having heterogeneous hemodynamic
effects, β-blockers have very diverse effects on lipid
and glucose metabolism and other adverse effects
that may promote weight gain, insulin sensitivity, and
new-onset diabetes, thereby undermining their
cardiovascular benefit.
 Such unfavorable adverse effects reported with
atenolol have led to an increasing trend toward use of
β-adrenergic blockers which also possess α-blocking
effects an therefore are also capable of vasodilation

 These agents include the non-cardioselective
α/β-blockers carvedilol and its once per day
dosing controlled release formulation
(carvedilol CR)
 Labetalol combines β- and α-adrenergic
blockade and is available in oral and
intravenous forms and is particularly useful
in managing postoperative HTN in children.

 Pediatric use of β-blockers is largely limited
to children with compelling indications or as
add-on second- or third-line agents.
 Beta-blockers do have a special role in
managing hypertensive disorders such as
pheochromocytoma and post-coarctectomy
HTN

 Intravenous esmolol is also useful in managing
hypertensive crisis
 Beta-blockers are also indicated for the management
of myocardial infarction and heart failure in adults.
However, these disorders are uncommon in
hypertensive children, further limiting the use of β-
blockers in the pediatric population, particularly as
monotherapy.

 Classic adverse effects of β-blockers include fatigue,
nightmares, anxiety, dizziness, and bronchospasm, as
well as hyperlipidemia and hyperglycemia.
 Thus, they are relatively contraindicated in children
with asthma or diabetes, although α/β-blockers may
be used in diabetics.

 The use of β-blockers, including metoprolol,
is discouraged in competitive athletes or
runners with HTN because they prevent the
compensatory rise in pulse rate which is
necessary to maintain a higher BP during
strenuous activity

 This class includes hydralazine, minoxidil, and
diazoxide.
 Among drugs in this class, hydralazine is widely
utilized intravenously to manage severe HTN in the
emergency department setting particularly if the
specific etiology of the HTN is not known.
 Common side effects include skin flushing and
tachycardia which limit maintenance use of oral
hydralazine to manage chronic HTN.

 Minoxidil is a very effective vasodilator and is utilized
to manage HTN which is refractory to other agents;
hirsutism is a common and prominent drawback that
prevents its use as a maintenance agent in children.
 Diazoxide can cause a precipitous fall in BP, and its
use has been supplanted by newer safer medications
and may be unavailable in many countries.
 Sodium nitroprusside is a potent direct vasodilator
which is very useful in managing hypertensive
emergencies

 Most of the CCB utilized in children belong to the more
cardioselective dihydropyridine class which includes
amlodipine, nifedipine, nicardipine, isradipine, and
felodipine.
 Generally, there is less reflex tachycardia with isradipine,
sustained release nifedipine, and amlodipine.
 The negative effect on atrioventricular conduction and
slowing of the heart rate of CCB belonging to the
phenylalkylamine (verapamil) and benzothiazepine
(diltiazem) classes limits their use in pediatric HTN
Calcium Channel Blockers (CCB)

 It should be noted that the dihydropyridine CCB
should not be taken together with meals that have a
high fat content or with grapefruit or grapefruit juice.
Such foods inhibit the enterocyte CYP3A4 system
which degrades CCB and may increase their
bioavailability by as much as a factor of two- to
fourfold
 CCB should not be given to children with heart failure or
actual damage of the myocardium.

 CCB are perhaps only second to ACEI and ARB in
frequency of use in pediatric HTN.
 Most CCB are typically given twice daily.
 Preparations which combine CCB with a diuretic (e.g.,
Nifedical) may aid compliance in children requiring
the use of both of these agents.

 Amlodipine is very widely utilized in hypertensive
children.
 It is inherently long acting and probably has the least
negative inotropic cardiac effects .
 Pharmacokinetic studies suggest that once-daily
administration may suffice in older children. Children
under 13 years of age may require double the daily
dosage used in older children (0.30 +/ 0.16
mg/kg/day versus 0.16 +/ 0.12 mg/kg/day) and often
need twice daily dosing for optimal BP .

 Compared with nifedipine, amlodipine use is
associated with less gingival hyperplasia
which occurs frequently in children with
transplants managed with cyclosporine-
based immunosuppressive regimens

 Short-acting nifedipine is used primarily in the
management of acute HTN, or in children with
impaired gastrointestinal absorption, or in those who
are unable to swallow medications. It lowers BP
within 20 min of oral or sublingual administration.
 The use of short-acting nifedipine has declined over
the past decade in large part because of safety
concerns including rapid hypotension, syncope, and
other cardiovascular risks mainly reported in adults
and because of the availability of newer agents
thought to be safer.

 Nicardipine also has relatively few adverse effects on
the myocardium.
 It is especially useful in managing children with renal
insufficiency who develop hypertensive emergency
 Among CCB, nicardipine inhibits the metabolism of
tacrolimus and cyclosporine more effectively and
can lead to toxic blood levels of these drugs.
 Thus, close monitoring of such levels is needed if
nicardipine is used to manage posttransplant HTN.

 Isradipine is a useful agent particularly in younger
children with HTN associated with renal disorders in
general and is often used in hypertensive urgency
situations
 Common adverse effects of all CCB (about 10 %
each) include headache, dizziness, skin flushing,
and fatigue associated with vasodilation.
 Lower extremity edema is also linked to
vasodilation and is unresponsive to diuretics.

 Such edema and tachycardia which occurs
more frequently in infants and younger
children receiving isradipine are leading
causes for discontinuing CCB.
 Nifedipine, as well as diltiazem, is associated
with a higher incidence of gingival
hyperplasia, particularly when used
concurrently with cyclosporine.

 The main use of these agents is in managing
children with PH and to slow down the
progression of renal injury in hypertensive
individuals with diabetes, proteinuric
disorders, and chronic renal disorders with or
without hyperreninemia
Renin-Angiotensin-Aldosterone
System (RAAS) Inhibitors

 Common class adverse effects of angiotensin
converting enzyme inhibitors (ACEI) include
hyperkalemia and persistent nonproductive cough,
while angioedema, neutropenia, and anemia are
other less common adverse effects.
 In order to offset hyperkalemia or salt and water
retention associated with excessive aldosterone
secretion in many renal disorders, several fixed
combinations of ACEI or ARB with
hydrochlorothiazide are now available

 They can also cause renal functional impairment
particularly in individuals with initial GFR below 60
mL/min/1.73 m2 or in those with severe renal
artery stenosis.
 Periodic monitoring of serum creatinine,
potassium, and sodium concentrations is needed to
identify important metabolic disturbances that may
require modification in drug dosage

 Also, a complete blood count may be done
every 4–6 months to detect neutropenia or
anemia with chronic use of these agents.
Many adverse effects typically resolve after
lowering of dosage or discontinuing these
agents.
 All RAAS inhibitors are teratogenic and
should not be used at any time during
pregnancy

Direct Renin Inhibitors
• Although ACEI are effective in lowering BP in
several hyperreninemic disorders leading to
increased circulating angiotensin II concentrations,
such agents stimulate renin release by interfering
with angiotensin II type 1 receptor induced
inhibition of renin release

• Ultimately, this leads to reduced sustained
antihypertensive effectiveness.
• This effect may be obviated by using one of
several novel renin inhibitors which have
demonstrated efficacy in binding to the catalytic
site of the enzyme renin and directly antagonize
its effect.
• However, except for the prototype aliskiren, most
of these agents have poor oral bioavailability.

 Several randomized human trials showed that orally
administered aliskiren at 75 or 150 mg once daily was
not only, safe but also very effective in lowering BP in
adults with mild-to moderate HTN .
 Its antihypertensive action was additive when
combined with amlodipine or HCTZ .
 However, the combined use of aliskiren and another
RAAS blocker should be avoided because it can result
in serious adverse effects including marked
hypotension, rapid decline in renal function, and
hyperkalemia

Angiotensin-Converting Enzyme
Inhibitors (ACEI)
• ACEI block kininase thereby decreasing the
degradation of bradykinin; the latter enhances the
antihypertensive action of ACEI.
• In addition, ACEI exert a beneficial effect on HTN
by direct effects on atrial natriuretic peptide,
vasopressin, and prostaglandins and by
downregulation of adrenergic sympathetic activity

• In addition to their effects on all arterial vessels,
both ACEI and ARB lower intra glomerular
pressure by their preferential dilation of the
efferent arteriole and by reducing the
vasoconstrictive effect of angiotensin II (AT-II)

• This may limit the adverse effects of ACEI related
to higher bradykinin and lower plasma
aldosterone concentrations, including
hyperkalemia, chronic dry cough, and
angioedema.
• Thus, ARB use is often preferred in managing HTN
caused by diverse renal disorders

• The addition of anti-aldosterone agents, such as
spironolactone, to augment the antihypertensive
action of ACEI and ARB in disorders associated
with RAAS activation offers theoretical
advantages.
• This drug combination may afford synergism and
may be more nephroprotective than when either
agent used alone.

• However, aldosterone blockade often
potentiates the hyperkalemic, and possibly,
the hyponatremic effects of ACEI.
• Thus, the combined use of spironolactone
and ACEI should be avoided especially in
children with reduced GFR

• Among widely employed ACEI, the longest and
more informative experience has been gained
with captopril, enalapril, and lisinopril.
• Captopril is the only ACEI containing a disulfhydryl
moiety that has been credited with antioxidant
and anti inflammatory action.

• Thus, captopril may be value of special in
hypertensive children with lupus or other renal
disorders.
• It has a short duration of action, and it usually
requires three daily dosages.
• Titration should take place slowly over several
days, particularly if it is utilized in hypertensive
neonates.

• This is because neonates have physiologically higher
renin activity which helps to maintain constant renal
blood flow and GFR at a relatively low prevailing
mean arterial BP in neonates.
• Enalapril and lisinopril have a more prolonged action
enabling single or as twice-daily dosing .
• Lisinopril is also available in combination with
hydrochlorothiazide (Zestoretic).
• Enalapril is the only ACEI that can be administered
intravenously, but it should be carefully titrated in
neonates in order to lower the risk of acute renal
injury.

Angiotensin Receptor Blockers
(ARB)
• All are highly protein bound and therefore not
easily removed by dialysis
• Losartan (Cozaar) has the widest experience of
pediatric use
• The drug is excreted by the kidneys and in the bile
and is not dialyzed.
• Valsartan is also relatively short acting and is
excreted by the kidneys (30 %) and bile (70 %);
absorption is decreased by 40 % when taken with
food.

Combination Drugs
Combination therapy for HTN in the pediatric age
group has its greatest application in older children
or adolescents and may be especially useful in
those with renal-related etiologies and more
severe or stage II HTN requiring more than one
agent for optimal control

• Combining drugs with complementary
mechanisms of action, such as a RAAS
inhibitor with a thiazide diuretic, can result
in synergistic lowering of blood pressure,
even at lower and potentially more safe
dosages of each drug , and better
compliance

• Moreover, the RAAS inhibitor in such combination
agents counteracts several unintended effects of
diuretics such as hypovolemia and secondary
activation of RAAS, hypokalemia, and glucose
intolerance often resulting from diuretic use .
• Also, combining drugs that inhibit the RAAS (ACEI,
ARB, or renin inhibitors) with a CCB such as
amlodipine may have an additive effect on BP
lowering

• For example, ACEI-CCB combination proved
superior to an ACEI-diuretic combination
• Another advantage of such combination is
the decreased incidence of peripheral
edema which is a common cause of drug
discontinuation in individuals receiving CCB

• A notable example of unacceptable drug
combination is dual inhibition of RAAS which can
result in syncope, hypotension, renal dysfunction,
and hyperkalemia .
• Note that triple combination drugs are also
available and are comprised of HCTZ, amlodipine,
and either aliskiren or an angiotensin receptor
blocker

Combining Antihypertensive and
Lipid-Lowering Drugs
• Pfizer Corp. introduced a combination drug,
Caduet, consisting of amlodipine (Norvasc) and
atorvastatin (Lipitor) to manage HTN together
with hypercholesterolemia.
• This is an example of combining drugs that can
reduce cardiovascular events by diverse but
interrelated mechanisms.
• In theory, such combinations will lead to
improved drug adherence and reduced cost

Drug in htn(2) (1)

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