Pharmacotherapy of Hypertension

1. By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
Pharmacotherapy Cardiovascular Disorders
Lesson 2
Hypertension
January, 2019 tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609

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3.  Session Tips
– Classify BP levels and treatment goals
– Recognize underlying causes & contributing factors
– Describe the appropriate measurement of BP
– Recommend appropriate non-pharmacologic &pharmacologic Rx
– Identify those requiring special consideration
– Construct an appropriate monitoring plan
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4.  BP is a surrogate end point. So, why we worry about?
 Say true or false
1. Definition of hypertension is age dependent 
2. Most patients with hypertension have no symptoms
3. Hypertension can easily be treated
 List category of drugs used in treatment of hypertension
1. ACEIs/ARBs
2. CCBs
3. Diuretics
4. B-blockers, etc
4
False
True
True

5. Left ventricle contracts: Systole
Left ventricle relaxes: diastole
MAP: used to represent BP
– Especially in patients with hypertensive emergency.
– Collectively reflects both SBP & DBP
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7.  Hypertension: an elevated SBP, DBP, or both.
– Its clinical diagnosis is based on ≥ 2 properly measured seated BP
measurements taken on two or more occasions.
– On no antihypertensive medications
– Not acutely ill
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8. ~~~80 million Americans have hypertension.
– ~33% of adult [most frequently chronic medical condition]
– One in three adults ≥20 years of age
~77% : on antihypertensive medications
– Only 54% have controlled BP (<140/90 mmHg]
Most significant risk factors for CV morbidity and mortality
– From TOD : heart, brain, kidney, and eyes
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9. Globally, 51% of all strokes and 45% of IHD deaths are
attributable to hypertension
Annual in direct & indirect cost ~$46.4 billion.
Prevalence differs based on age, sex,& ethnicity.
– Older: risk of systolic hypertension increases
– More prevalent in men before age of 45 yrs.
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10.  Hypertension in Ethiopia is under reported because of poor access to
health care
 The prevalence of high blood pressure is estimated to be around 30% in
Addis Ababa
 The overall national prevalence ranges from 10 - 20%.
 It is the most common risk factor associated with stroke and myocardial
infarction in Black Lion Hospital.
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HTNHTN
Essential/Primary
Secondary
– No identifiable cause
– 90-95%
– Have a specific identified cause
– only 5% to 10%
– Some are potentially reversible
If patient presents for the first time with high BP before 30 yrs and > 55

12. CKD
Coarctation of the aorta
Cushing syndrome and other glucocorticoid excess states
Drug induced/related
Pheochromocytoma
Primary aldosteronism and other mineralocorticoid excess states
Renovascular hypertension
Sleep apnea
Thyroid or parathyroid disease
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13. Adrenal steroid hormones, Amphotericin B
Cocaine, amphetamines, and other illicit drugs
Cyclosporine, tacrolimus, Erythropoietin
Fluid retention from kidney disease or potent vasodilators (eg,
minoxidil)
Neurologic and psychiatric agents (eg, venlafaxine, modafinil)
NSAIDS, Oral contraceptive hormones
Recent caffeine or nicotine intake
Sympathomimetics (decongestants, anorectics, and stimulants)
Vascular endothelial growth factor inhibitors (bevacizumab,
sorafenib, sunitinib)
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14. Patients failing to achieve goal BP despite adherence to optimal
doses of 3 antihypertensive agents of different classes (ideally,
one being a diuretic).
– Should be evaluated for secondary causes of hypertension
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15. Apparent Resistance
– Improper blood pressure measurement
– Failure to receive or take antihypertensive medication
appropriately (non-adherence)
– Inadequate doses (sub-therapeutic)
– Improper antihypertensive selection or combination
– White coat hypertension
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16.  True Resistance
– Secondary hypertension
– Drug effects and interactions
– Volume overload
– Excess sodium intake
– Comorbidities
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aFailure of plasma catecholamines to ↓ by 50% within 3 hours of administration of 0.3 mg clonidine highly suggests pheochromocytoma.

19.  Patients who have consistently elevated BP values measured in a clinical
environment;
 Persistently elevated average office BP of >140/90 mm Hg & an
average awake ambulatory reading of <135/85 mm Hg
– Yet, when measured elsewhere or with 24-hour ambulatory
monitoring, BP is not elevated.
– Home BP monitoring or 24-hour ABPM is warranted in patients.
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NB: The label white-coat hypertension applies only to patients without target-organ
disease who are not on antihypertensive therapy

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21.  Obesity
 Excess alcohol
 Excess salt intake
 Lack of exercise
 Environmental stress
 Dyslipidemia
 Diabetes mellitus
 Renal Parenchymal Diseases
 Endocrine disorders
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22.  Heterogeneous but ultimately exerts its effects through the two primary
determinants of BP:
– Cardiac output (CO)
– Peripheral resistance (PR).
 Involves interplay between genetic and environmental factors;
– Interacting with multiple physiological systems including neural, renal,
hormonal, and vascular.
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23.  Smoking and caffeine: transient increases in BP via norepinephrine release
 Alcohol ingestion: increased due to sympathetic nerve activity/oxidative
stress.
 Obesity, physical inactivity, fetal environment (eg, maternal malnutrition,
 Increased fetal exposure to maternal glucocorticoids),
 Premature birth and low birth weight,
 Potassium and magnesium depletion, vitamin D deficiency,
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24.  Over activity of the sympathetic nervous system increased HR, CO,
and peripheral vasoconstriction
– Target for: α- and β-adrenergic blockers
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25.  Excess sodium intake and/or abnormal sodium excretion by the kidneys.
Dietary salt intake
Vascular Mechanisms
– Remodeling/change in vascular tone, may be modulated by various
endothelium derived vasoactive substances, growth factors, & cytokines
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26.  Renin is produced and stored in the juxtaglomerular cells of the kidney,
– Its release is stimulated by impaired renal perfusion, salt depletion,
and β1-adrenergic stimulation.
– Its release is rate-limiting step for Ang II, potent vasoconstrictor
 Role of the renin-angiotensin-aldosterone system (RAAS): Essential
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 Presence of diabetes mellitus (DM), dyslipidemia, obesity, and CKD.
 Many other described under secondary cause of hypertension

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 Most patients are asymptomatic/silent Killer
1. Symptoms related to elevated BP
a. Headache
– Characteristic of only severe hypertension
– Most commonly localized to the occipital region and present when
the patient awakens in the morning, subsiding spontaneously after
several hours.
b. Dizziness
c. Palpitations
d. Easy fatigability
e. Epistaxis

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2. Symptoms related to vascular disease
– Hematuria
– Blurring of vision due to retinal changes
– Episodes of weakness
– Dizziness due to transient cerebral ischemia

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 Known duration of raised BP and previous levels
 Previous antihypertensive therapy, efficacy and adverse effects
 Past history or current symptoms of IHD, HF , cerebrovascular disease or
peripheral arterial disease
 Past history or current symptoms that suggest CKD, e.g. nocturia, dark
urine (suggesting hematuria)
 Secondary hypertension

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 Family history : hypertension, diabetes, dyslipidemia, stroke, CKD or
premature (before age 60 years) coronary heart disease
 Modifiable lifestyle risk factors: obesity, physical inactivity, smoking,
excessive intake of alcohol, salt or saturated fats, recreational drug use
(amphetamines, cocaine)
 Medications that raise BP
– Corticosteroids
– Amphetamines…

33.  Physical Examination
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– Pulse rate, rhythm and character
– Jugular venous pulse and pressure
– Cardiac enlargement (displaced apex, extra heart sounds)
– Waist circumference (cm) and/or body mass index (BMI):

34. 5. ECG
6. CBC (Hct)
7. Plasma glucose
8. Lipid profile
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1. Urinalysis
2. Serum creatinine, BUN
3. serum K+
4. CXR
 All patients with documented HTN should have:

35. Desired Outcomes
 To reduce the risk of CVD & TOD[MI, HF, stroke, & kidney disease]
– Associated morbidity and mortality (also called CV events).
 Targeting a specific BP is a surrogate goal that has been associated
with reductions in CVD and target organ damage.
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37.  Always adjunctive non-pharmacologic strategies
 Chronotherapy, or adjusting administration timing of certain
pharmacotherapy for therapeutic benefit [esp. in comorbidities]
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2ASH/ISH: American/international society of HTN
6ESH/ESC: European society of HTN/Cardiology
3JNC-8

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 Albuminuria >30 mg of albumin at any level of GFR
 GFR < 60 mL/minute

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43.  1st line
– Non-black patients: thiazide-type diuretic, calcium-channel blocker
(CCB), ACEI, or ARB
– Black patients ± diabetes: thiazide-type diuretic or CCB
– CKD: ACEI, or ARB ( initial/add on)
– Regardless of race or diabetes status
– Reductions in CV events with ACEI, ARB, CCB, or thiazide diuretic are
comparable!
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44.  Second line
– β-blocker: no longer 1st line
– Renin Inhibitors: Aliskiren
– α1-blockers: doxazosin, terazosin, and prazosin
– Central α2-Agonists: clonidine, methyldopa, guanfacine, guanabenz
– Direct vasodilators: hydralazine and minoxidil
– Post-ganglionic sympathetic inhibitors: guanethidine, guanadrel
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45.  For uncomplicated HTN
 Types: thiazides, loop diuretics, potassium-sparing agents, aldosterone
antagonists.
 Thiazides: more commonly used
– Hydrochlorothiazide (25-50mg) Chlorthalidone (25 mg)
– Antihypertensive & side effects: dose dependent
– Side effects:
– Metabolic effects (hyperlipidemic and hyperglycemic) and electrolyte-related
effects (hypokalemic, hypomagnesemic, hyperuricemic, and hypercalcemic)
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46.  CrCl < 30 mL/min, thiazide diuretics have limited efficacy   loop
diuretics preferred.
 Loop diuretics
– Furosemide, bumetanide, torsemide, ethacrynic acid
– Site of action in the thick ascending limb of the loop of Henle
– Dosed bid vs Once based for antihypertensive (vs diuretic) effect.
– Except Torsemide (longer half-life)
– Side effects: hyponatremia or hypotension, hypokalemia,
hypomagnesemia, hypocalcemia
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47.  Potassium-sparing diuretics: that do not act through mineralocorticoid
receptors
– Includes: triamterene & amiloride
– Often prescribed with potassium-wasting diuretics to mitigate
potassium losses.
– Have modest diuresis
– Act on the late distal tubule and collecting ducts
– Side effects: hyperkalemia
– Especially with NSAIDS, ACEI/ARB
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48.  Includes: spironolactone & eplerenone
 Modulate vascular tone through a variety of mechanisms besides diuresis
 Have potassium-sparing effects [aldosterone antagonism]
 Rx: for resistant hypertension ± primary aldosteronism
– Low-dose spironolactone (12.5–50 mg/day) ± diuretics/ACE-Is/ARBs
 Side effects:
– Hyperkalemia (esp. in renal disease, with other mediactions)
– Gynecomastia (use eplerenone)
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50.  Not first line
 But, used in patients with specific select comorbidities [HF/recent
MI/angina, ACS]
 MOA: reduction in CO and/or reduction in PR along with their negative
inotropic/chronotropic actions
– Renin modulation
 Cardio selectivity: dose dependent
– Essential: incase of asthma, COPD or PAD(intermittent claudication)
 Side effects: bradycardia, heart block, HF sxs,
– Ischemic syndromes (if abrupt DC), Diabetes (concern)
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53.  Effective anti-hypertensives, particularly in the elderly
 Two class: DHP & Non-DHP
– Nifedipine, amlodipine, nicardipine , nimodipine
– Diltiazem , verapamil
 Side effects: edema (nifedipine, amlodipine), constipation
– Negative inotropic/chronotropic effects (non-DHP)
– Heart block, avoid in HFrEF
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55.  Extensively studied and used in HTN
 Also in used type 1 or 2 DM, HF, prior-MI, CKD, or recurrent stroke
prevention.
 Includes: Benazepril, Captopril, Enalapril Fosinopril, Lisinopril etc
 Side effects: hyperkalemia, dry cough, angioedema, first dose
hypotension , AKI
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56.  Inhibitors of the angiotensin-1 (AT1) receptors
 Same as ACEI in therapeutics
 Used in case of intolerance from ACEI (cough)
 Same side effects as in case of ACEI
 Includes: Irbesartan, Losartan, Valsartan, Candesartan
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57.  Directly blocks renin  reducing PRA   AT1 and AT2 with a
resultant reduction in BP.
 Agent: Aliskiren
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59.  Considered inferior agents and should not be used as monotherapy.
 Associated with an increase in cardiovascular events
 Considered as add-on therapy to other agents (e.g, 4th or 5th line)
 Anti-hypertensive regimen for elderly men with prostatism
 Includes: doxazosin, terazosin, prazosin
 Side effects: syncope, dizziness, or palpitations following the first dose
and orthostatic hypotension with chronic use
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60.  MOA: reduce sympathetic outflow and enhance parasympathetic
activity, thereby reducing HR, CO, & TPR
 Includes: Clonidine, methyldopa, guanfacine, and guanabenz.
 Used for cases of resistant hypertension
 Limited by their tendency to cause orthostasis, sedation, dry mouth, and
vision disturbances.
 The issue of severe rebound hypertension when clonidine is abruptly
discontinued.
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67.  List important behavioural modifications to combat HTN.
a) Weight reduction
b) DASH diet
c) Reduce sodium intake
d) Increase physical activity
e) Limit alcohol consumption
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68.  You are looking to add a second medication to help a patient better
control their blood pressure. The patient has a history of asthma and
benign prostatic hypertrophy. Which of the following would be a poor
choice for this patient?
a) Calcium Channel Blocker
b) Beta blocker
c) Alpha Blocker
d) ACEI
e) None of the above
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

69.  Efficacy & safety
– Clinical signs and symptoms
– Laboratory tests and investigations
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