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

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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


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


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


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

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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

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DASH Diet

20


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


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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Adverse Effects of β-Adrenoceptor Blockers


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

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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

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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

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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

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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)

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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

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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)

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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

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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

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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?

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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

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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

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Side Effects of ACEIs & ARBs


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

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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

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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

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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

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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)

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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)

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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

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HYPERTENSION ABC & Update Mahmoud Khattab, Ph.D. Professor of Pharmacology & Toxicology 1.

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