Transcript HYPERTENSION ABC & Update

HYPERTENSION
ABC & Update
Mahmoud Khattab, Ph.D.
Professor of Pharmacology &
Toxicology
1
Development of Structural and
Functional Alterations in the
Hypertensive Vessel Wall
2
Smooth Muscles & Endothelial
Morphologic Changes In
Hypertension
 The smooth muscle content
of arteries can be
augmented by an increase
in cell number (hyperplasia)
or an increase in cell mass
(hypertrophy)
 The volume of the
endothelial cells increases
and the surface
configuration becomes
more globular, so that the
cells protrude into the
lumen of the vessel
3
Linkage Between Structural
& Functional Changes
Poiseuille’s Law:
Resistance α 1/r4
4
Possible mechanisms of Apparent
Increased Sensitivity to
Vasoconstrictors
Patients with essential hypertension have apparent
increased sensitivity to forearm infusion of norepinephrine
(0.40 μg/min) (increase in resistance)
o True increased sensitivity to vasoconstrictors
o Increased receptor sensitivity
o Increased activation of second messengers or ion
channels
o Apparent increased sensitivity due to effects of
structure or function to increase resistance
o Hypertrophy or hyperplasia
o Decreased endothelial-dependent vasodilator
5
mechanisms
Characteristics of
Hypertension
 Elevated BP at maintained cardiac output
 Interaction of environmental and genetic factors
 Both structural and functional changes in arterioles leading




to increased resistance
Structural changes resulting from growth or remodeling of
the vessel due to the positive influence of growth factors or
the removal of growth inhibitors
Functional abnormalities involving endothelial and
vascular smooth muscle dysfunction
Abnormalities in membrane ionic control mechanisms likely
underlying abnormalities in both contraction and growth
Enhanced vascular responsiveness to vasoconstrictors
6
AHA Classification
Classification
Normal
SBP
DBP
(mm Hg) (mm Hg)
<120
AND <80
Prehypertension
120-139 OR 80-89
Stage 1
Hypertension
140-159 OR 90-99
Stage 2
Hypertension
≥160
OR ≥100
7
Classification and Goal
JAMA 2003;289:2560–2572
 The seventh Report of the Joint National
Committee on Detection, Evaluation, and
Treatment of High BP (JNC 7) classified
hypertension as in the given table
 A clinical HTN is based upon two or more seated
BP measurements on two more occasions
 Ultimate GOALs:
 Decrease BP
 Reduce associated morbidity manifested as
TARGET-ORGAN DAMAGE
 CVS risk factors increase frequency of target
organ damage (HP+LVH: CHF)
8
Hypertension -related Target Organ
Damage
 Brain: stroke/transient ischemic attack
 Eyes: retinopathy
 Heart: LV hypertrophy, HF, angina
 Kidney: chronic kidney disease
 Peripheral vasculature: peripheral arterial
disease
9
Hypertension -related Target Organ
Damage
Heart
 Promoting atherosclerotic
changes (indirectly)
 Pressure-related:
o Enhancement of CVD
o Increase risk for IHD
(angina & MI)
Antihypertensive therapy
reduce such risks
 Enhance the progress of
LVH (LVH+HP;
Framingham Study:
Increased CHF)





BRAIN
HTN frequently leads to
cerebro-vascular disease as:
Transient ischemic attacks
Ischemic strokes
Cerebral infarcts
Antihypertensive therapy
reduce the risk of initial and
recurrent stroke
10
Hypertension -related Target Organ
Damage
Kidney
 HP leads to increased intraglomerular pressure
causing nephrosclerosis
 HTN-Kidney lesion, What comes first?
 Chronic kidney disease can proceed to kidney
failure (dialysis)
 Moderate (Stage 3) Kidney disease (GFR 30-59
mL/min) indicates target organ damage
(Creatinine 1.3-1.5 mg/dL)
 Albuminurea (>300 mg/day or 200 mg albumin/g
creatinine) indicates target organ damage
11
Hypertension -related Target Organ
Damage
Peripheral Arterial
Disease
 An atherosclerotic vascular
disease equivalent in risk to
CAD
 BP reduction, risk factor
modification & antiplatelets
are needed to stop progress
 Complications can attain
infection & necrosis
o
o
o
o
EYE
Hypertension can induce
retinopathy that may
proceed to blindness
G 1: arterial
vasoconstriction
G2: Arteriovenous nicking
(atherosclerosis)
G3: Cotton wool exudates
& hemorrhage (untreated
HP or accelerated
12
Major CVS Risk Factors
 Age: more than 55 years men, 65 years women
 Cigarette smoking
 Diabetes mellitus
 Hypertension
 Dyslipedimia
 Obesity
 Physical inactivity
 Kidney disease: GFR ≤60mL/min
13
CVS Risk versus BP
 Direct correlation between risk of CVD & BP
values (epidemiological studies)
 Above 115/75 mm Hg, with each increment of
20/10 mm Hg, the risk of CVD doubles
 Pre-hypertensive patients are at higher CVD
risk than normal
 Clinically, elevated SBP is a more predictor of
CVD than elevated DBP in patients over 50
years
14
BP Numerical Values Goal
 In most patients, the target BP value is reduce
BP lower than 140/90 mm Hg
 In diabetic patients and chronic kidney
disease patients (estimated GFR ≤60 mL/min
or albumin-urea), Coronary Artery Disease
(CAD): BP goal is less than 130/80 mm Hg
 In LV dysfunction, goal BP is <120/80
 These patients are at high risk for target organ
damage
15
Hypertension Misconceptios
 Stress-related: Apart from white coat HP, most HP
patients have elevated BP independent of their
stress status
 Headache (and other symptoms) have no
correlation with hypertension
 Hypertension though asymptomatic, it has serious
long-term complications; long-term therapy
 Stress management is not that beneficial in
controlling HP
 Clinically evidenced, a better quality of life with
proper medication; drugs are NOT worsening
quality of life
16
Patient Evaluation/Risk
Assessment
I.
II.
III.
Absence or presence of various forms of
hypertension-related target organ damage
Identifiable (secondary) causes of
hypertension
Concomitant major CV risk factors, other
disorders, and assessment of lifestyle
habits
17
HYPERTENSION THERAPY
Lifestyle Modification
 For BP lowering & reduction of CV risk
 In prehypertensives: lifestyle modification leads
to BP lowering + inhibition or minimizing HTN
progress
 Possible reduction of dose and/or No of
antihypertensive drugs used
PATIENT EDUCATION IS NEEDED
18
Lifestyle Modification
Weight Reduction
 5-10% wt reduction
in overweight
persons may lower
CV risk
 For every 1 kg wt
loss, there is
lowering of SBP &
DBP by 2.5 & 1.5
mm Hg respectively
DASH Diet
 Dietary Approaches to
Stop Hypertension
(DASH) diet is rich in
fruits, vegetables &
low-at dairy foods,
combined to less
saturated & total fat
 A 8-14 mm Hg reduction
in SBP can be produced
19
DASH Diet
20
Lifestyle Modification
Dietary Sodium
Restriction

 Epidemiology: positive
correlation between BP
and sodium intake
 Trials: 2-8 mm Hg
reduction in SBP on
restricted sodium diet ≤
2.4 g/day



Physical Activity
There is 4-9 mm Hg
reduction in SBP in most
patients upon regular PA
HTN patients with
compromised CVD
need medical
evaluation before PA
Physical activity: at
least 30 min for 3-5
days/week
Walking, running,
cycling, swimming
21
Lifestyle Modification
Smoking Cessation
 The most important
Unproven Modifications
 High levels of K+, Ca2+, &
modifiable CV risk factor
 Cigarette smoking
increases CV & total

mortality, cessation lowers
CVD incidence
 It interferes with response 
to some drugs (β blockers)
 Patient education
Mg2+ relate to lower BP, no
reduction of CV risk
K+& Mg2+ intake in HP/chronic
renal disease may be harmful
(cardiac toxicity)
Caffeine drinks limitation is
not essential unless for other
medical reason
22
Algorithm for Treatment of
Hypertension
Beta-blockers not
first-line in AHA
guidelines 2007
23
Patient Education About
Treatment
 Assess patient’s understanding and acceptance of the diagnosis of






o
o
o
hypertension
Discuss patient’s concerns and clarify misunderstandings
Tell patient BP reading and provide a written copy
Come to agreement with the patient on goal BP
Ask patient to rate (1 to 10) his or her chance of staying on treatment
Inform patient about recommended treatment and provide specific
written information about the role of lifestyle, including diet, physical
activity, dietary supplements, and alcohol intake; use standard
brochures when available
Emphasize:
Need to continue treatment
Control does not mean cure
One cannot tell if BP is elevated by feeling or symptoms; BP must
be measured
24
Evidence-Based Hypertension
Therapy SELECTION
 JNC7 drug therapy algorithm follows evidence-
based approach linked to clinical trials
interpretation
 Thiazide-type diuretic-based therapy leads to
significant reductions in:
o Stroke (25-47%), Heart attacks (13-27%), Allcause CVD (17-40%), & Survival improvement
 Systolic Hypertension in Elderly Program (SHEP),
 Swedish Trial of Old Patients with Hypertension
(STOP-hypertension)
 Medical Research Council (MRC)
25
Thiazide-Based Therapy versus Newer
Agents (The ALLHAT study)
 Several clinical trials using newer agents (ACE
inhibitors, ARBs, and CCBs) found reduction of
BP and CV risk in a similar to thiazides
 Possibly ACEIs having better effects
 The 2007 AHA HTN guidelines are now the
most recent for treatment (Circulation 2007,
115: 2761)
26
Algorithm for Treatment of
Hypertension
Betablockers
NOT 1st line
in 2007
AHA
guidelines
27
The ALLHAT Study
 The Antihypertensive & Lipid Lowering Treatment
to prevent Heart Attack Trial provides recent
evidence for thiazide efficacy as used by JNC7
 Designed to testify hypothesis of superiority of
newer drugs: amlodipine, doxazosin & lisinopril
over the thiazide diuretic chlorthalidone
 End-point: combined fatal CHD & non-fatal MI
 42,418 patients for a mean of 4.9 years
 Doxazosin arm prematurely terminated because of
increased HF risk
28
The ALLHAT Study
 Outcome: No significant difference between
chlorthalidone and either amlodipine or lisinopril as
regards combined end point
 Secondary endpoints pointed to better efficacy of
thiazide over amlodipine (less HF) and lisinopril
(less combined CVD, HF, & stroke)
 Investigators concluded superiority of thiazide
diuretics or at least unsurpassed activity
 A 2003 network meta-analysis of 42 clinical trials
found that low-dose diuretic were most effective
first-line treatment for prevention CVD & mortality
JAMA;289: 2534 (2003)
29
Hypertension with Compelling
Indications
Compelling
Indication
1ST Line
Diabetes Mellitus
ACEI/ARB
Chronic Kidney
Disease
ACEI/ARB
Acute/Chronic CAD
Prior Ischemic Stroke
Left Ventricular
Dysfunction
β-blockers & ACEI (or
ARB)
Sequential Therapy
thiazide diuretic, CCB or βblockers
thiazide diuretic for BP
control, CCB for ischemia
control
ACEI & thiazide
diuretic, or ARB
ACEI (or ARB) &
thiazide (loop) diuretic
& β-blockers
Aldosterone antagonist in
severe HF,
30
Hydralazine/dinitrate in black
Starting Drug Therapy
 MONOTHERAPY when INITIAL BP IS CLOSE
TO GOAL VALUE, 15-20 mm Hg SBP & 10 mm
Hg DBP (JNC 7 & others)
 STEPPED CARE,
o A single drug is chosen & dose increased till
BP control occurred, max dose reached, or
dose-limiting toxicity
o A second drug from a different class is added
31
Starting Drug Therapy
SEQUENTIAL THERAPY
o If goal BP is not achieved an alternative drug is
chosen, to replace an initial one
o It is more advised when the initial drug is not
well tolerated or achieved poor BP efficacy
Combination Therapy
 Encouraged for patients stage 2 hypertension
or far from BP goal
 Initial combination therapy can be useful for
chronic renal disease/diabetes/other resistant
patients
32
THERAPY MONITORING
 Four aspects are considered upon monitoring:
 BP control evaluated 1-4 weeks after therapy
o
o
o



initiation/modification
Initial BP lowering needs 1-2 weeks, but steady BP up to 4
weeks
Average of 2 measurements is used
Standing BP measurement for orthostatic hypotension
evaluation (whenever dizziness occurs)
Compliance (adherence)
Progression of the disease; target-organ damage points
to therapy modification
33
Toxicity
Diuretics
Thiazides
 Are diuretic of choice achieving goal BP values in
50-80% of patients
 Hydrochlorthiazide (HCTZ) & chlorthalidone
are the most frequently used
 Dose of 12.5-25 mg once daily can lower SBP
by 15-20 mm Hg & DBP 8-15 mm Hg
 Low-dose therapy is equi-effective for both
agents according to huge clinical evidence
34
Diuretics
Loop Diuretics
 HCTZ is more effective than loop diuretics though
less potent
 Furosemide is the most frequently used agent,
but given more than once daily
 They are diuretics of choice in hypertensive
patients with severe kidney disease or failure
(creatinine 2.5-3 mg/dL)
 They are preferred in patients with CHF or severe
edema
35
Diuretics
K+-sparing Diuretics
 Amiloride/triametrene are reserved for patients
developing diuretic-induced hypokalemia
 Fixed-dose products including HCTZ & K+-sparing
diuretic are available, but initial usage to avoid
hypokalemia is not rationalized
 They have modest antihypertensive effect when
used as monotherapy
36
Diuretics
Aldosterone Receptor Antagonists
• Spironolactone & eplerenone cause hyperkalemia,
•
•
•
•
especially in chronic renal disease
Eplerenone is more specific, less gynecomastia but
causes greater hyperkalemia
Eplerenone is contraindicated in patients at high risk of
hyperkalemia including diabetic 2 patients/albuminurea
Spironolactone is beneficial in hypertensive patients
with CHF where it reduces morbidity & mortality
Eplerenone reduces mortality in HF & LV failure in early
post MI patients
37
Diuretics
Side-Effects
Contraindication
Annoying
Harmful
ThiazideDiuretics
Urination (initial),
weakness, muscle
cramps, GIT upset,
hyperuricemia
Hypokalemia, hyponatremia,
hyperglycemia, hypercalcemia,
azotemia, skin rash,
photosensitivity, lithium
toxicity, hyper-TG & cholesterolemia
Persistant
anuria/oliguria,
kidney failure
Loop
Diuretics
Urination (initial),
weakness, muscle
cramps, GIT upset,
hyperuricemia
Hypokalemia, hyponatremia,
hyperglycemia, hypocalcemia,
azotemia, skin rash,
photosensitivity, lithium
toxicity, hyper-TG & cholesterolemia
Hearing loss (large IV doses)
Not
contraindicated
in renal failure
Hyperkalemia, hyponatremia
Kidney failure,
hyperkalemia,
hyponatremia
Aldosterone Hirsutism,
Antagonists menstrual
irregularities,
gynecomastia, GIT
upset
38
β-Adrenoceptor Blockers
 β-Blockers reduce morbidity & mortality in
hypertensive patients with compelling indications;
CHF, post-MI, high-risk CHD, & diabetes
 All β-Blockers have similar activity on BP lowering
 Incidence of side-effects is low in practice and is
dose-dependent, i.e., can be minimized with lowto moderate-doses
39
Pharmacologic Characteristics
of β-Blockers
β1-SELECTIVITY ISA α-BLOCKADE
NODonotaing
Acebutolol
+
+
−
Alprenolol
−
+
−
Atenolol
+
−
−
Betaxolol
+
−
−
Bisoprolol
+
−
−
Bopindolol
−
+
−
Carvedilol
+
−
+
Celiprolol
+
+β2
−
Dilevolol
+
+β2
−
Labetalol
−
−
+
Metoprolol
+
−
−
Nadolol
−
−
−
Nebivolol
+
−
−
Oxprenolol
−
+
−
Pindolol
−
+
−
Propranolol
−
−
−
Sotalol
−
−
−
Timolol
−
−
40
Hemodynamic Response to
β-Adrenoceptor Blockade
 BP decrease after acute
response) is modest, with
continued treatment the BP
decrease becomes much
larger in most patients
 The magnitude of the
decrease in heart rate and
cardiac output and the
reactive increase in PVR
vary with the degree of ISA
 These responses do not
account for the long-term
decrease in BP
41
Adverse Effects of β-Adrenoceptor
Blockers
Annoying
Beta
Bradycardia,
Blockers Weakness,
Lethargy,
GIT
disturbance
Harmful
Contraindication
•Systolic heart failure (carvedilol &
•Asthma
metoprolol approved for systolic
HF)
•Bronchospasm (asthma patients)
•Hypoglycemia (non-selectives can
mask symptoms of /potentiate
hypoglycemia
•Hyperglycemia (non-selectives can
lower insulin secretion in Type 2
diabetes patients)
•Peripheral arterial disease
aggravation
•Nightmares, insomnia,
•Impotence
•Hypertriglceridemia, decreased
HDL
(Severe)
•2nd/3rd degree
heart block
•Systolic HF
exacerbation
•“Brittle”
diabetes
mellitus
42
β-Blockers
 Nonselective β-Blockers are preferred in
patients with non-CV indications like migraine
prophylaxis/tremor
 ISA β-Blockers are indicated for patients
responding with severe bradycardia to nonISA β-blockers
 ISA β-Blockers should be avoided in patients
with MI history where agonistic properties may
worsen the cardiac function
43
β-Blockers
Lipid Solubility
 Lipid solubility is of max clinical relevance in
patients with renal/hepatic impairment
o High lipid sol drugs like propranolol are
hepatically cleared
o Hydrophilic ones (atenolol) have main renal
excretion (require dose adjustment)
o Lipophilic agents are probably associated with
increases CNS side effects like nightmares,
depression
 High lipid soluble drugs are desirable for migraine
prophylaxis due to better CNS access
44
β-Blockers
Compelling Indications
 Heart failure (systolic); metoprolol & carvedilol
are approved with reduced CV morbidity & mortality
• Start with LOW DOSE & gradually increase it
 Post-MI & acute MI patients (including relatively
contraindicated ones) have prolonged survival &
reduced re-infarction
 High-Risk CHD: HTN patients with chronic angina
or acute CHD (non-ST segment elevation MI &
unstable angina) may proceed to fatal MI or others
o Decreased HR, contractility & myocardial O2
demand produced by β-blockers reduce the risk
45
β-Blockers
Compelling Indications
 Diabetes; a cardio-selective agent is preferred
 β-Blockers decrease coronary events, the renal disease





progression, and stroke in diabetics
All agents can mask symptoms of epinephrine-associated
hypoglycemia (tremors, hunger & palpitations) but not
sweating
They cause insulin release inhibition
Non-selective agents can worsen hypoglycemia & prolong
recovery from hypoglycemia
β-Blockers are best avoided in Type 1 diabetes but
hypoglycemic effects are less common in Type 2
Non-selective agents should be avoided in “brittle” diabetics
especially insulin-dependent patients
46
ACE Inhibitors
Effects of Chronic ACE Inhibition on the RAA
System
 Angiotensin II disappears from the circulation at peak ACE block
 Plasma renin activity, active & inactive renin concentrations increase
 The hyperreninemia leads to a rise in plasma angiotensin I levels
 The plasma levels of aldosterone are reduced during ACE inhibition
 There is an induction of ACE synthesis during long-term treatment
Generic Names
Brand Names
Captopril
Capoten,
Benazepril
Lotensin
Enalapril
Innovace
Fosinopril
Staril
Imidapril
Tanatril
Lisinopril
Carace, Zestril
Moexipril
Perdix
Perindopril
Coversyl
Quinapril
Accupro
Ramipril
Tritace
47
ACE Inhibitors
Clinical Pharmacological Profile
 ACEIs lower BP via peripheral vasodilation with no
alteration of CO/HR/or GFR through RAA system
& increased vasodilating bradykinin & PGs
 Beneficial effects include correction of endothelial
dysfunction, LVH regression, insulin sensitivity
improvement & collateral vessel development
 They can raise serum K+ especially in renal
impairment patients
 Acute renal compromise in patients with bilateral
renal stenosis can occur
 Modest creatinine rise, NOT discontinue ACEIs
48
ACE Inhibitors
Risk of Hypotension
 First dose ACEIs can induce dizziness, orthostatic
hypotension, or even syncope in volume depleted,
hyponatremic or exacerbated HF patients
 First-dose response is related to increased
pretreatment activity of RAA system
 Concurrent diuretic therapy may increase the
incidence of first-dose response in sensitive
patients
 Elderly & African American patients mostly have low
renin hypertension & less responsive to ACEIs
 Diuretic-ACEI combination overcome age- & racerelated poor response
49
ACE Inhibitors
Compelling Indications
 Heart Failure: ACEI (+diuretic) is considered
fist-line & standard regimen in HTN+ systolic HF
 Post-MI: ACEI+β-blocker showed reduction of
CV risk independent of LV function & BP
 High-Risk CHD: ACEIs must be early given in nonST elevation MI & Unstable angina (as β-blocker)
o In chronic angina: ACEI can be added after βblocker or non-DHP CCB
 Diabetes ACEIs reduced hypertension-related
CV events & nephropathy in diabetic (mostly type
2) patients (HOPE & UKPDS studies)
50
ACE Inhibitors: Compelling Indications
Diabetes
 ACEIs are comparable or better than diuretics &
better than CCBS in reduction of CV risk
 NO adverse effect on glucose metabolism
Chronic Kidney Disease (CKD)
 CKD: increased intra-glomerular pressure+mesangial
cell proliferation resulting in proteinuria & progressive
renal damage (reduced RBF-increased RAA-efferent
arteriolar vasoconstriction- renal impairment)
• ACEIs dilate efferent arteriole-relieves intraglomerular P
• ACEIs may be of unique renal preserving apart from its
BP lowering properties
• ACEIs are highly efficacious in preserving renal
51
function in diabetes type-1 & -2
ACE Inhibitors: Compelling Indications
Recurrent Stroke Prevention
 ACEI + Thiazide diuretic reduced the incidence of
stroke & total vascular events in hypertensive/nonhypertensive patients with history of stroke/TIA
 The reductions were independent of baseline BP
& BP lowering ( the PROGRESS trial)
 Elderly Patients:
 ACEIs are less effective in lowering BP in elderly
 ACEIs (& CCBs) are equivalent to old agents
(diuretic- β-blockers) in reduction of fatal CV
events (MI, Stroke, ..etc., STOP-2 trial)
52
Angiotensin II Type-1 Receptor
Blockers (ARBs)
Pharmacological Profile
 ARBs are the newest class of
Generic
Trade
antihypertensive agents
Name
Name
 ARBs selectively block the effects
Losartan
Cozaar
of Angiotensin II (ANG II) on type1 receptors
Valsartan
Diovan
 Type-1 receptors mediate
Candesartan Atacand
vasoconstriction, aldosterone
Eprosartan Teveten
secretion (salt & water retention),
myocyte and SM hypertrophy &
Irbesartan Aprovel
sympathetic NS stimulation
Olmesartan Benicar
 Type-2 receptors mediate antiprofilerative actions, tissue repair, Temisartan Micardis
& cell differentiation
53
ARBs
Pharmacological Profile vs ACI
 Unlike ARBs, ACE inhibition suppresses
stimulation of both ANG II type-1 & -2 receptors
o Hence, it is possible that ARBs are superior to
ACEIs in amelioration of HTN-related damage
o However, this is just speculation, & there NO
supportive clinical data
 Vasodilating bradykinin increase with ACEI but
NOT with ARB, but without changing BP lowering
efficacy
 Similar to ACEIs, combinations with a thiazide
diuretic are of high efficacy
54
ARBs
Pharmacological Profile
 Losartan & valsartan have lower blockade potency
of type-1 receptors than others, but NO significant
clinical difference exist agents
 They can be dosed ONCE daily, but twice daily
may be used whenever high doses of losartan,
eprosartan or candesartan are needed
 Initial dose may be lowered in elderly & diuretictreated or volume-depleted patients?
55
ARBs Compelling Indications
Heart Failure
 ARBs are probable
Diabetes
 ARB reduce diabetic
nephropathy progression
alternatives in hypertension
especially in type2 diabetes
+ HF ACEI-intolerant
more than CCBs
patients (ACEI-induced
o ARBs are the only
angioedema; AHA & ACC)
antihypertensive agent showing
o ACEIs & ARBs are
evidence of reduction of renal
equivalent in symptomatic
failure in type 2 diabetes &
HF relief, but ARBs are of
nephropathy
similar or weaker mortality o Benefits are BP loweringrate reduction
independent
o Val-HeFT study: Patients
are recommended to
with systolic HF treated with o ARBs
lower nephropathy in HTN,
valsartan have less
diabetes & proteinuria
combined morbidity/
(American Diabetes Association
mortality vs placebo
56
ARBs Compelling Indications
 Chronic Kidney Disease ARBs, similar to ACEIs,
protect against renal damage in CKD
o Both ACEIs & ARBs dilate the efferent arteriole
o For non-diabetic renal disease, evidence is weaker,
& ARBs are reserved as ACEIs alternatives
 Hypertension with LVH:
 FDA approved losartan for stroke reduction in
hypertensive patients with LVH
 The LIFE trial found reduced CV events (mainly
stroke) with losartan more than atenolol
57
Side Effects of ACEIs & ARBs
Annoying
Harmful
ACE
Inhibitor
Dizziness,
faintness,
lightheadedness, cough,
taste changes
ARBs
As ACEIs
Except cough
Hypotension
(elderly), skin
rash (disappear
or discontinue),
proteinuria,
leukopenia
Same as ACEIs
Contraindication
Bilateral renal
stenosis,
volume
depletion,
hyponatremia,
pregnancy
Same as ACEIs
58
Calcium Channel Blockers
(DHPs) Amlodipine, felodipine, isradipine, lacidipine,
lercanidipine, nicardipine, nitrendipine, nifedipine
 They are effective antihypertensive agents
 Elderly & African American get better BP lowering than
other agents
 They have no metabolic effects
 Addition to a diuretic is additive
Verapamil
Diltiazem
Dihydropyrines
Peripheral Vasodilation
Increase
Increase
marked increase
Heart Rate
Marked
decrease
decrease
increase
Contractility
Marked
decrease
decrease
No change
/decrease
SA/AV conductivity
Decrease
Decrease
NO change
Coronary B Flow
Increase
Increase
Marked increase
59
Immediate-Release (IR)
Nifedipine
 IR CCBs-MI link was first reported in 1995
 Observational analysis showed that IR CCBs are
associated with higher risk of MI compared with
thiazide diuretics & β-lockers
 This risk is present with the three CCBs classes,
being strongest with NIFEDIPINE
 FDA concluded that IR CCBs, especially
nifedipine, are neither SAFE nor EFFICACEOUS
and should be avoided
60
Sustained-Release (SR)
Formulations
 Except for AMLODIPINE, all CCBs are of short
half-lives, requiring frequent doses/day
 SR preparations are preferred when CCBs are
used for hypertension treatment
 Chronotherapeutic Verapamil: Circadian
rhythm of BP & MI incidence can be targeted by
designed formulations
61
Calcium Channel Blockers
Compelling Indications
 High Coronary Disease Risk
 CCBs can be used as alternatives, after β-blockers
in chronic angina, unstable angina, and non-ST
elevation MI when intolerance occurs
 Diabetes: CCBs are option in hypertensive
diabetics; no effect on glucose/insulin
 Stroke risk is reduced by DHPs (clinical evidence)
 ACEIs have more CV protection than CCBS
(FACET & ABCD trials)
62
Fixed-Dose Combinations for
Hypertension
COMBINATION
TYPE
FIXED‐DOSE COMBINATION (mg/mg)*
ACEI and CCB
Amlodipine/benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20)
Enalapril/felodipine (5/5)
Trandolapril/verapamil (2/180, 1/240, 2/240, 4/240)
ACEI and Diuretic Benazepril/hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25)
Captopril/hydrochlorothiazide (25/25, 25/25, 50/15, 50/25)
Enalapril/hydrochlorothiazide (5/12.5, 10/25)
Fosinopril/hydrochlorothiazide (10/12.5, 20/12.5)
Lisinopril/hydrochlorothiazide (10/12.5, 20/12.5, 20/25)
Moexipril/hydrochlorothiazide (7.5/12.5, 15/25)
Quinapril/hydrochlorothiazide (10/12.5, 20/12.5, 20/25)
ARB and Diuretic Candesartan/hydrochlorothiazide (16/12.5, 32/12.5)
Eprosartan/hydrochlorothiazide (600/12.5, 600/25)
Irbesartan/hydrochlorothiazide (150/12.5, 300/12.5)
Losartan/hydrochlorothiazide (50/12.5, 100/25
Olmesartan medoxomil/hydrochlorothiazide (20/12.5, 40/12.5,
40/25)
Valsartan/hydrochlorothiazide (80/12.5, 160/12.5, 160/25)
Telmisartan/hydrochlorothiazide (40/12.5, 80/12.5)
63
Fixed-Dose Combinations for
Hypertension
Beta-blocker &
Diuretic
Atenolol/chlorthalidone (50/25, 100/25)
Bisoprolol/hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25)
Metoprolol/hydrochlorothiazide (50/25, 100/25)
Nadolol/bendroflumethiazide (40/5, 80/5)
Propranolol LA/hydrochlorothiazide (40/25, 80/25)
Timolol/hydrochlorothiazide (10/25)
Centrally Acting Drug Methyldopa/hydrochlorothiazide (250/15, 250/25, 500/30,
500/50)
& Diuretic
Reserpine/chlorthalidone (0.125/25, 0.25/50)
Reserpine/chlorothiazide (0.125/250, 0.25/500)
Reserpine/hydrochlorothiazide (0.125/25, 0.125/50)
Diuretic & K+-sparing
Amiloride/hydrochlorothiazide (5/50)
Diuretic
Spironolactone/hydrochlorothiazide (25/25, 50/50)
Triamterene/hydrochlorothiazide (37.5/25, 75/50)
64
Special Populations
 Black patients (JNC& & AHA 2007):
 Black patients have higher HTN incidence, more need
for combination therapy
 As monotherapy, thiazide diuretic and CCB are highly
effective
 ACEI, ARB, or β-blockers are less effective in black
patients but addition of a thiazide diuretic greatly
improve efficacy
 Elderly Patients:
 Patients of ≥65 years old have lower BP control
 Patients of ≥75 years old respond best to thiazes & CCB
and less to ACEI, ARB, and β-blockers
65
Recall (Self-Assessment)
Questions
 Define different stages of HTN according to JNC-7 2003
 Enumerate the first-line HTN therapeutics according to









AHA 2007 guideline.
Mention five HTN-related target organ damage.
Outline pharmacological HTN treatment algorithm
For Each of the 1st & 2nd line HTN therapeutics:
Mention the name of two drugs
Three harmful adverse effects and a contraindication
Compelling indication (s) for each group
Drugs most- & least-effective in black & elderly patients
JAMA; 289: 2534 (2003) JNC-7
66
Circulation; 115: 2761 (2007) AHA guidelines