HYPERTENSION ABC & Update Mahmoud Khattab, Ph.D. Professor of Pharmacology & Toxicology 1.
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Transcript of HYPERTENSION ABC & Update Mahmoud Khattab, Ph.D. Professor of Pharmacology & Toxicology 1.
HYPERTENSIONABC & 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 sensitivityo Increased activation of second messengers or ion
channelso Apparent increased sensitivity due to effects of
structure or function to increase resistance o Hypertrophy or hyperplasiao Decreased endothelial-dependent vasodilator
mechanisms 5
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 SBP
(mm Hg)
DBP
(mm Hg)
Normal <120 AND <80
Pre-hypertension
120-139 OR 80-89
Stage 1 Hypertension
140-159 OR 90-99
Stage 2 Hypertension
≥160 OR ≥100
7
Classification and Goal
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)
JAMA 2003;289:2560–2572
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 CVDo 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
EYEo Hypertension can induce
retinopathy that may proceed to blindness
o G 1: arterial vasoconstriction
o G2: Arteriovenous nicking (atherosclerosis)
o 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. Absence or presence of various forms of hypertension-related target organ damage
II. Identifiable (secondary) causes of hypertension
III. Concomitant major CV risk factors, other disorders, and assessment of lifestyle habits
17
HYPERTENSION THERAPYLifestyle 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 8-148-14 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 4-94-9 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
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
Unproven Modifications High levels of K+, Ca2+, &
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 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:o Need to continue treatmento Control does not mean cureo 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%), All-cause 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
27
Algorithm for Treatment of Hypertension
Beta-blockers NOT 1st line in 2007 AHA guidelines
28
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
29
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)
Hypertension with Compelling Indications
Compelling Indication
1ST Line Sequential Therapy
Diabetes Mellitus ACEI/ARB thiazide diuretic, CCB or β-blockers
Chronic Kidney Disease
ACEI/ARB
Acute/Chronic CAD β-blockers & ACEI (or ARB)
thiazide diuretic for BP control, CCB for ischemia control
Prior Ischemic Stroke ACEI & thiazide diuretic, or ARB
Left Ventricular Dysfunction
ACEI (or ARB) & thiazide (loop) diuretic & β-blockers
Aldosterone antagonist in severe HF, Hydralazine/dinitrate in black30
31
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
32
Starting Drug TherapySEQUENTIAL 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
33
THERAPY MONITORING
Four aspects are considered upon monitoring: BP control evaluated 1-4 weeks after therapy
initiation/modificationo Initial BP lowering needs 1-2 weeks, but steady BP up to 4
weekso Average of 2 measurements is usedo Standing BP measurement for orthostatic hypotension
evaluation (whenever dizziness occurs) Compliance (adherence) Progression of the disease; target-organ damage points
to therapy modification Toxicity
34
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
35
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
36
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
37
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
38
DiureticsSide-Effects
Annoying Harmful Contraindication
Thiazide-Diuretics
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
Aldosterone Antagonists
Hirsutism, menstrual irregularities, gynecomastia, GIT upset
Hyperkalemia, hyponatremia Kidney failure, hyperkalemia, hyponatremia
39
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 low- to moderate-doses
40
Pharmacologic Characteristics of β-Blockers
β1-SELECTIVITY ISA α-BLOCKADE
Acebutolol + + −
Alprenolol − + −
Atenolol + − −
Betaxolol + − −
Bisoprolol + − −
Bopindolol − + −
Carvedilol + − +
Celiprolol + +β2 −
Dilevolol + +β2 −
Labetalol − − +
Metoprolol + − −
Nadolol − − −
Nebivolol + − −
Oxprenolol − + −
Pindolol − + −
Propranolol − − −
Sotalol − − −
Timolol − −
NO-Donotaing
41
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
42
Adverse Effects of β-Adrenoceptor Blockers
Annoying Harmful Contraindication
Beta
Blockers
Bradycardia, Weakness, Lethargy,
GIT disturbance
•Systolic heart failure (carvedilol & 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
•Asthma (Severe)•2nd/3rd degree heart block•Systolic HF exacerbation•“Brittle” diabetes mellitus
43
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 non-ISA β-blockers
ISA β-Blockers should be avoided in patients with MI history where agonistic properties may worsen the cardiac function
44
β-Blockers
Lipid Solubility Lipid solubility is of max clinical relevance in
patients with renal/hepatic impairmento 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
45
β-BlockersCompelling 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
46
β-BlockersCompelling 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
47
ACE InhibitorsEffects 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
48
ACE InhibitorsClinical 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
49
ACE InhibitorsRisk 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- & race-related poor response
50
ACE InhibitorsCompelling 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 non-ST elevation MI & Unstable angina (as β-blocker)
o In chronic angina: ACEI can be added after β-blocker or non-DHP CCB
Diabetes ACEIs reduced hypertension-related CV events & nephropathy in diabetic (mostly type 2) patients (HOPE & UKPDS studies)
51
ACE Inhibitors: Compelling IndicationsDiabetes
ACEIs are comparable or better than diuretics & better than CCBS in reduction of CV risk
NO adverse effect on glucose metabolismChronic 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
function in diabetes type-1 & -2
52
ACE Inhibitors: Compelling IndicationsRecurrent Stroke Prevention
ACEI + Thiazide diuretic reduced the incidence of stroke & total vascular events in hypertensive/non-hypertensive 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)
53
Angiotensin II Type-1 Receptor Blockers (ARBs)
Pharmacological Profile ARBs are the newest class of
antihypertensive agents ARBs selectively block the effects
of Angiotensin II (ANG II) on type-1 receptors
Type-1 receptors mediate vasoconstriction, aldosterone secretion (salt & water retention), myocyte and SM hypertrophy & sympathetic NS stimulation
Type-2 receptors mediate anti-profilerative actions, tissue repair, & cell differentiation
Generic Name
Trade Name
Losartan Cozaar
Valsartan Diovan
Candesartan Atacand
Eprosartan Teveten
Irbesartan Aprovel
Olmesartan Benicar
Temisartan Micardis
54
ARBsPharmacological 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
55
ARBsPharmacological 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 & diuretic-treated or volume-depleted patients?
56
ARBs Compelling Indications
Heart Failure ARBs are probable
alternatives in hypertension + HF ACEI-intolerant patients (ACEI-induced angioedema; AHA & ACC)
o ACEIs & ARBs are equivalent in symptomatic HF relief, but ARBs are of similar or weaker mortality rate reduction
o Val-HeFT study: Patients with systolic HF treated with valsartan have less combined morbidity/ mortality vs placebo
Diabetes ARB reduce diabetic
nephropathy progression especially in type2 diabetes more than CCBs
o ARBs are the only antihypertensive agent showing evidence of reduction of renal failure in type 2 diabetes & nephropathy
o Benefits are BP lowering-independent
o ARBs are recommended to lower nephropathy in HTN, diabetes & proteinuria (American Diabetes Association
57
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
58
Side Effects of ACEIs & ARBs
Annoying Harmful Contraindication
ACE Inhibitor
Dizziness, faintness, lightheaded-ness, cough, taste changes
Hypotension (elderly), skin rash (disappear or discontinue), proteinuria, leukopenia
Bilateral renal stenosis, volume depletion, hyponatremia, pregnancy
ARBs As ACEIs Except cough
Same as ACEIs Same as ACEIs
59
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
60
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
61
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
62
Calcium Channel BlockersCompelling 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)
63
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)
64
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 & Diuretic
Methyldopa/hydrochlorothiazide (250/15, 250/25, 500/30, 500/50)
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 Diuretic
Amiloride/hydrochlorothiazide (5/50)
Spironolactone/hydrochlorothiazide (25/25, 50/50)
Triamterene/hydrochlorothiazide (37.5/25, 75/50)
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 Circulation; 115: 2761 (2007) AHA guidelines
66