Pharmacotherapy of hypertension

Pharmacotherapy of
Hypertension
Dr. Shahid A. Saache,
Dept of Pharmacology,
BJGMC, Pune.

Grades of hypertension
ESH/ESC 2013 :
Category Systolic Diastolic
Optimal <120 and <80
Normal 120–129 and/or 80–84
High normal 130–139 and/or 85–89
Grade 1 hypertension 140–159 and/or 90–99
Grade 2 hypertension 160–179 and/or 100–109
Grade 3 hypertension ≥180 and/or ≥110
Isolated systolic
hypertension
≥140 and <90

Regulation of blood pressure
• BP= CARDIAC OUTPUTₓ PERIPHERAL VASCULAR
RESISTANCE
• In both normal & hypertensive individuals, BP is
maintained by moment-to-moment regulation of
cardiac output & peripheral vascular resistance

Anatomic sites of B.P. control
• Arterioles (resistance)
• Venules (capacitance)
• Heart (pump output)
• Kidneys (volume)
• Baroreflexes that are controlled by autonomic nervous
system & humoral mechanisms including renin-angiotensin
aldosterone system coordinate these
anatomic sites
• Difference between normal & hypertensive patients is
that baroreceptors are set to higher levels in latter

Types & Causes
Primary HTN:
• Definite cause for rise in BP not known
Secondary HTN:
• Renal→ chronic diffuse glomerulonephritis,
pyelonephritis, polycystic kidneys
• Endocrine→ Cushing's syndrome,
pheochromocytoma, primary hyperaldosteronism
• Vascular→ renal artery disease, coarctation of
aorta
• Drugs

Drug treatment of hypertension – factors
to consider:
• Primary vs. Secondary
- Diagnosis (based on 3 separate office visits) and
severity of hypertension.
• Individualization (age, gender, ethnicity) and patient
compliance.
• Pre-existing risk factors and co-morbid medical
conditions
- Smoking, hyperlipidemia, diabetes, congestive heart
failure, asthma, current medication ………
• Monotherapy vs. Polypharmacy

Currently Used Anti-HTN Agents:
• Diuretics
1.Thiazide & related
agents
2.Loop diuretics
3.K+sparing diuretics
• Sympatholytics drugs
1.β receptor antagonists
2.α receptor antagonists
3.Mixed α-β antagonists
4.Centrally acting
• Calcium channel blockers
• ACE inhibitors
• Angiotensin II receptor
antagonists
• Direct renin inhibitors
• Vasodilators
1.Arteriolar
2.Arterial & venous

DIURETICS
THIAZIDES
Drugs (mg/day) Comments
Chlorthalidone (12.5-25) • Dose in morning
• More effective than
loop
• Chlorthalidone twice
as potent as
hydrochlorothiazide
• Monitoring in patients
with h/o gout or
hyponatremia
Hydrochlorothiazide
(25-100)
Indapamide (1.25-2.5)
Metolazone (1.25-2.5)

LOOP DIURETICS
Drug (mg/day) Comments
Bumetanide (0.5-4) • Dose in morning
K+ SPARING DIURETICS
Amiloride (5-10) • Weak diuretics, used in
combination with thiazides to
minimize hypoK+
• Reserved for diuretic induced
hypoK+
• Avoid in CKD
Triamterene (50-
100)
• Higher doses in severely
decreased GFR or heart
failure
Furosemide (20-80)
Torsemide (5)

ALDOSTERONE ANTAGONISTS
Eplerenone (50-100) • Eplerenone C/I when
creatinine clearance <50
ml/min &↑ Sr Creatinine &
Type2 DM with
microalbuminuria
• Avoid spironolactone in
CKD→hyperK+
Spironolactone (25-50)

ACE INHIBITORS
Captopril (50-200) • Risk of hypotension
• Cause hyperK+ in CKD
patients & those receiving
K+ sparing diuretics,
aldosterone antagonists
or ARBs
• Cause acute kidney
failure in B/L renal artery
stenosis patients
• Brassy cough is common
• C/I in pregnancy or h/o
angioedema
Enalapril (5-20)
Lisinopril (10-40)
Perindopril (4-16)
Ramipril (2.5-10)

ANGIOTENSIN RECEPTOR BLOCKERS
Eprosartan (400-800) • Cause hyperK+ in CKD
patientsor in those with
K+sparing diuretics,
aldosterone antagonists or
ACEI
• No cough
• C/I in pregnancy
Candesartan (4-32)
Losartan (50-100)
Valsartan (40-320)
Irbesartan (75-300)
Telmisartan (20-80)

CALCIUM CHANNEL BLOCKERS
DIHYDROPYRIDINES
Amlodipine (2.5-10) • Short acting DHP should be
avoided
• More potent peripheral
vasodilators than NDHP
• Cause reflex sympathetic
discharge (tachycardia),
dizziness, headache, flushing,
peripheral edema
Felopdipine (5-20)
Isradipine (5-10)
Nicardipine (60-120)
Nifedipine (30-90)

NON DIHYDROPYRIDINES
Diltiazem SR (180-360) • ER preferred
• Blocks slow channels in
heart & ↓HR
Diltiazem ER (120-540)
Verapamil SR (180-480)

Βeta blockers
CARDIOSELECTIVE
Atenolol (25-100) • Abrupt discontinuation →
rebound HTN
• Inhibit β1 at low to moderate
doses, higher doses
stimulate β2, may
exacerbate asthma when
selectivity is lost
Betaxolol (5-20)
Bisoprolol (2.5-10)
Metoprolol (50-200)

NON SELECTIVE
Nadolol (40-120) • Abrupt discontinuation →
rebound HTN
• Exacerbate asthma
• Additional benefits in
essential tremors,
migraine, thyrotoxicosis
Propranolol (160-480)
WITH INTRINSIC SYMPATHAMIMOTIC ACTIVITY
Acebutalol (200-800) • Partially stimulate β
receptors
• Additional benefits in
bradycardiac pts
• C/I in post MI pts
Carteolol (2.5-10)
Penbutalol (10-40)
Pindolol (10-60)

ALPHA BLOCKERS
Doxazosin (1-8) • Additional benefits in men BPH
Prazosin (2-20)
Terazosin (1-20)

Therapy of hypertension
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

Pre-treatment evaluation
• Multiple BP readings in supine & standing positions
after sufficient rest
• Assessment of target organ damage
a) Detailed history & physical examination: dyspnoea,
polyuria, nocturia, edema, cardiomegaly
b) Kidney: urine examination, serum creatinine, serum
electrolytes
c) Heart: ECG, X ray chest
d) fundoscopy

Assessment of other CV risk factors
• Salt intake, Alcohol consumption, smoking, obesity,
diabetes, hyperlipidaemia, premature CV death in
close relatives
Special investigations to identify cause of HTN
• USG urinary tract/renal blood vessels, renal
angiography, test for pheochromocytoma,
aldosteronoma (These are done if indications exist &
HTN is drug resistant)

• Reassurance by physicians & lifestyle modifications
are necessary in all hypertensive patients include
normotensives with risk factors
• Clinically HTN is divided into mild, moderate, severe &
very severe grades

Non pharmacological treatment
Recommendations to reduce BP and/or CV risk factors
Salt intake Restrict 5-6 g/day
Moderate alcohol intake Limit to 20-30 g/day men,
10-20 g/day women
Increase vegetable, fruit, low-fat dairy intake
DASH diet
BMI goal 25 kg/m2
Waist circumference goal Men: <102 cm (40 in.)*
Women: <88 cm (34 in.)*
Exercise goals ≥30 min/day, 5-7 days/week
(moderate, dynamic exercise)
Quit smoking

A young patient with mild hypertension (140-159/90-99)
Non pharmacological treatment/ lifestyle modifications –
trial of 2-3 months
If diastolic BP is still >90 mmHg or its <90 mmHg but risk
factors are present
Pharmacologic therapy

Start a thiazide diuretic like hydrochlorothiazide (25-
50mg) or chlorthalidone (12.5-25mg) OD (unless a
specific C/I exists)
Do not increase dose of hydrochlorothiazide >50mg
cause it produce no any further benefit
Antihypertensive effect established in 2-3 wks,
subsequently smaller doses (12.5mg OD) for
maintenance

• Monitor B.P, BUN/ Sr. creatinine, Sr. electrolytes, uric
acid while using a thiazide diuretic
• if BP is not adequetly controlled by thiazide→ add a
CCBs or beta blocker
• In patients with repeated BP >160/100 → start a 2 drug
therapy (including a thiazide)

A young patient with moderate HTN (160-179/100-109)
• A long acting CCB or ACE inhibitor may be use for
monotherapy or added to a thiazide
• CCBs like amlodipine (5mg OD) initially → ↑ to (10mg
OD) if necessary is effective initial drug
• Peripheral edema is common ADR (8%) other include
fatigue, dizziness, palpitations, headache, dyspepsia
• Monitor for heart rate & BP regularly

• ACE inhibitor like enalapril may also be used in doses
of 5-20 mg, is usually well tolerated & have few ADRs
mainly brassy cough due to raised bradykinin,
hypotension, dizziness, headache, fatigue
• ACE inhibitors are C/I in severe B/L renal artery
stenosis as they reduce the glomerular filtration
causing progressive renal failure, also C/I in pregnancy
• Also regularly monitor for B.P, BUN/ Sr. creatinine, Sr.
potassium while on ACEIs
• If BP is still not controlling then can add thiazide to one
of CCB or ACEI
• ACEI reduce thiazide induced hypokalemia

A patient of severe HTN (180-209/110-119)
Need combination with additional drugs like alpha
blockers, a centrally acting drug or a direct acting
peripheral vasodilator
α methyldopa is used along with thiazide, initial dose is
250 mg 2-4 times a day & it is increased by 250mg at
interval of 2-7 days to a maintenance level

• Hydralazine started in small dose (10mg BD) gradually
increased to 50-100mg BD.
• It is particularly useful in presence of kidney damage
as it dilates renal vessels
• C/I in arteriosclerotic HTN, angina, MI, peptic ulcer

Monotherapy vs. Drug combination strategies to
achieve target BP
Choose between
Single agent Two–drug combination
Previous agent
at full dose
Switch
to different agent
Previous combination
at full dose
Add a third drug
Two drug
combination
at full doses
Mild BP elevation
Low/moderate CV risk
Marked BP elevation
High/very high CV risk
Three drug
combination
at full doses
Switch
to different two–drug
combination
Full dose
monotherapy

Recommendations
Masked hypertension
Consider both lifestyle measures and antihypertensive
drug treatment
White-coat hypertension
No additional risk factors: lifestyle changes only with
close follow-up
High CV risk*: consider drug treatment in addition to
lifestyle changes

Hypertension treatment in the elderly
Clinical scenario Recommendations
Elderly patients with SBP ≥160
mmHg
• Reduce SBP to 140-150
mmHg
Fit elderly patients aged <80
years with initial SBP ≥140
mmHg
• Consider antihypertensive
treatment
• Target SBP: <140 mmHg
Elderly >80 years with initial SBP
≥160 mmHg
• Reduce SBP to 140-150
mmHg
providing in good physical and
mental condition
Frail elderly • Hypertension treatment
decision at discretion of
treating clinician, based on
monitoring of treatment clinical
effects
Continuation of well- tolerated
hypertension treatment
• Consider when patients
become octogenarians

Hypertension treatment in pregnant women
Clinical scenario Recommendations
Drug treatment of severe
hypertension in pregnangy
(SBP >160 mmHg or DBP
>110 mmHg)
• Recommended
Pregnant women with
persistent BP elevations
≥150/95 mmHg
BP ≥140/90 mmHg in
presence of gestational
hypertension, subclinical
OD, or symptoms
• Consider drug treatment

High risk of pre-eclampsia • Consider treating with
low-dose aspirin from 12
weeks until delivery
• Providing low risk of GI
hemorrhage
Women with child-bearing
potential
• RAS blockers not
recommended
Methyldopa (1-2g)
Labetolol (100mg BD)
Nifedipine (30-60mg)
• Consider as preferential
drugs in pregnancy
• For pre-eclampsia:
intravenous labetolol or
infusion of nitroprusside

Hypertension treatment for people with diabetes
Recommendations Additonal considerations
Mandatory: initiate drug
treatment in patients with
SBP ≥160 mmHg
• Strongly recommended:
start drug treatment when
SBP ≥140 mmHg
SBP goals for patients with diabetes: <140 mmHg
DBP goals for patients with diabetes: <85 mmHg
All hypertension treatment
agents are recommended
and may be used in
patients with diabetes
• RAS blockers may be
preferred
• Especially in presence of
preoteinuria or
microalbuminuria
Choice of hypertension treatment must take
comorbidities into account

Hypertension treatment for people with metabolic
syndrome
Lifestyle changes for all • Especially weight loss and
physical activity
• Improve BP and components
of metabolic syndrome, delay
diabetes onset
Antihypertensive agents that
potentially improve – or not
worsen – insulin sensitivity are
recommended
• RAS blockers
• CCBs
BBs and diuretics only as
additional drugs
• Preferably in combination with
a potassium-sparing agent
Prescribe antihypertensive drugs
with particular care in patients
with metabolic disturbances
when…
• BP ≥140/90 mmHg after
lifestyle changes to mantain BP
<140/90 mmHg

Hypertension treatment for people with nephropathy
Consider lowering SBP to <140 mmHg
Consider SBP <130 mmHg with
overt proteinuria
• Monitor changes in eGFR
RAS blockers more effective to
reduce albuminuria than other
agents
• Indicated in presence of
microalbuminuria or overt
proteinuria
Combination therapy usually
required to reach BP goals
• Combine RAS blockers with
other agents
Aldosterone antagonist not
recommended in CKD
• Especially in combination with
a RAS blocker
• Risk of excessive reduction in
renal function, hyperkalemia

Hypertension treatment for people with cerebrovascular
disease
Do not introduce
antihypertensive treatment
during first week after acute
stroke
• Irrispective of BP level
• Use clinical judgment with
very high SBP
Introduce antihypertensive
treatment in patients with
history of stroke or TIA
• Even when initial SBP is 140-
159 mmHg
SBP goals for hypertensive patients with history of stroke or
TIA: <140 mmHg
Consider higher SBP goal in elderly with previous stroke or TIA
All drug regimens
• Provided BP is effectively
recommended for stroke
reduced
prevention

Hypertension treatment for people with heart disease
SBP goals for hypertensive patients with CHD: <140 mmHg
BBs for hypertensive patients
with recent MI
• Other CHD: other
antihypertensive agents can be
used; BBs, CCBs preferred
Diuretics, BBs, ACE-I, ARBs,
and/or mineralcorticoid receptor
antagonist for patients with heart
failure or severe LV dysfunction
• Reduce mortality and
hospitalization
No evidence that any
hypertension drug beneficial for
patients with heart failure and
preserved EF
• However, in these patients and
patients with hypertension and
systolic dysfunction: consider
lowering SBP to ∼ 140 mmHg
• Guide treatment by symptom
relief
Consider ACE-I and ARBs (and BBs and mineralcorticoid receptor
antagonist in coexisting heart failure) in patients at risk of new or

Hypertension treatment for people with atherosclerosis,
arteriosclerosis, and PAD
Consider CCBs and ACE-I in
presence of carotid
atherosclerosis
• Greater efficay in delayng
atherosclerosis than diuretics,
BBs
Drug therapy in hypertensive
patients with PAD to BP target:
<140 mmHg
• Patients with PAD have high
risk of MI, stroke, heart failure,
CV death
Consider BBs for treating arterial
hypertension in patients with
PAD
• Careful follow-up necessary
• Use of BBs not associated with
exacerbation of PAD symptoms

Hypertension treatment for people with resistant
hypertension
Withdraw any drugs in antihypetensive treatment regimen that have
absent or minimal effect
Consider mineralocorticoid
receptor antagonists, amiloride,
and the alpha-1-blocker
doxazosin should be considered
(if no contraindication exists)
• If no contraindications exist
Invasive approaches: renal
denervation and baroreceptor
stimulation may be considered
• If drug treatment ineffective
No long-term efficay, safety data for renal denervation, baroreceptor
stimulation – only experienced clinicians should use
Diagnosis and follow-up should be restricted to hypertension
Centres
Invasive approaches only for • Clinic values: SBP ≥160 mmHg

Hypertensive urgency & emergency
• Hypertensive urgencies – sudden or severe elevation
of BP usually with DBP>120mmHg or higher with an
impending complication
• Include: severe epistaxis, severe perioperative HTN,
unstable angina, diabetic retinopathy, pre eclampsia
etc.
• Need immediate treatment in ICU, DBP needs to be
reduced to 100-110mmHg within 24-48hrs without use
of loading dose

• Hypertensive emergencies defined as severe elevation
of BP to 210/120-130mmHg with evidence of target
organ damage or dysfunction
• These include: hypertensive encephalopathy, ICH,
acute MI, acute LVF with pulmonary edema, eclampsia
• Also require admission to ICU & rapid lowering of BP to
150-160/100-110 within 1 hr

Highlights of JNC8 Guidelines
• In patients 60 years of age or older who do not have
diabetes or chronic kidney disease, the goal blood
pressure level is now <150/90 mmHg
• In patients 18 to 59 years of age without major
comorbidities, and in patients 60 years of age or older
who have diabetes, chronic kidney disease, or both
conditions, the new goal blood pressure level is
<140/90 mmHg
• First-line and later-line treatments should now be
limited to 4 classes of medications: thiazide-type
diuretics, calcium channel blockers (CCBs), ACEIs,
and ARBs
• Second- and third-line alternatives included higher
doses or combinations of ACEIs, ARBs, thiazide-type
diuretics, and CCBs

• Several medications are now designated as later-line
alternatives
• When initiating therapy, patients of African descent
without chronic kidney disease should use CCBs and
thiazides instead of ACEIs
• Use of ACEIs and ARBs is recommended in all patients
with chronic kidney disease regardless of ethnic
background, either as first-line therapy or in addition to
first-line therapy
• ACEIs and ARBs should not be used in the same
patient simultaneously
• CCBs and thiazide-type diuretics should be used
instead of ACEIs and ARBs in patients over the age of
75 with impaired kidney function due to the risk of
hyperkalemia, increased creatinine, and further renal
impairment

Conclusion
• Hypertension is a leading cause of mortality &
morbidity
• Overall goal of treating hypertension is to reduce HTN
associated complications
• A goal B.P of 140/90 mm Hg is appropriate for most of
patients
• Lifestyle modifications are very important & should be
prescribed to all hypertensive patients & those at risk
• If B.P is not controlled by monotherapy then increase
dose or add another drugs to achieve target B.P

• Among the array of antihypertensive drugs available,
thiazide diuretics, ACE inhibitors, ARBs & CCBs are
preferred 1st line agents
• Other classes of drugs may be required for some
special conditions
• Resistant hypertension poses problems in treatment,
though various non pharmacologic procedures are
available for this
• Hypertensive emergencies & urgencies should be
diagnosed accurately & treated

REFERENCES
1.Laurence L. Bruton., Bruce A. Chabner., Bjorn C. Knollmann.: Goodman &
Gilman’s The Pharmacological Basis of Therapeutics; Chapter 27, 12th
edition.,2012, Mc Graw Hill
2.Joseph T. Dipiro., Robert L. Talbert., Gary C. Yee., Gary R. Matzke.,
Barbara G. Wells., L. Michael Posey.: Pharmacotherapy A Pathophysiologic
Approach; Chapter ,6th edition., 2005 Mc Graw Hill
3.Paul A. James, MD; Suzanne Oparil, MD; Barry L. Carter, PharmD;
William C. Cushman, MD; 2014 Evidence-Based Guideline for the
Management of High Blood Pressure in Adults Report From the Panel
Members Appointed to the Eighth Joint National Committee; JAMA. 2014;
311(5):507-520.
4.Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the
management of arterial hypertension: the Task Force for the Management
of Arterial Hypertension of the European Society of Hypertension (ESH)
and of the European Society of Cardiology (ESC). Eur Heart J. 2013;
34(28):2159- 2219.
5.Eckel RH, Jakicic JM, Ard JD, et al. AHA/ACC guideline on lifestyle
management to reduce cardiovascular risk: a report of the American
College of Cardiology/American Heart Association task force on practice
guidelines. Circulation. 2013

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