HYPERTENSION ABC

1
HYPERTENSIONABC Update

• Mahmoud Khattab, Ph.D.
• Professor of Pharmacology Toxicology

2
Development of Structural and Functional
Alterations in the Hypertensive Vessel Wall
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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

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Linkage Between Structural Functional Changes
Poiseuilles Law Resistance a 1/r4
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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)
• True increased sensitivity to vasoconstrictors 
• Increased receptor sensitivity
• Increased activation of second messengers or ion
  channels
• Apparent increased sensitivity due to effects of
  structure or function to increase resistance 
• Hypertrophy or hyperplasia
• Decreased endothelial-dependent vasodilator
  mechanisms

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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

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AHA Classification
Classification SBP (mm Hg) DBP (mm Hg)
Normal lt120 AND lt80
Pre-hypertension 120-139 OR 80-89
Stage 1 Hypertension 140-159 OR 90-99
Stage 2 Hypertension 160 OR 100
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Classification and Goal
JAMA 200328925602572

• 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 (HPLVH CHF)

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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

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Hypertension -related Target Organ Damage

• Heart
• Promoting atherosclerotic changes (indirectly)
• Pressure-related
• Enhancement of CVD
• Increase risk for IHD (angina MI)
• Antihypertensive therapy reduce such risks
• Enhance the progress of LVH (LVHHP 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

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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 (gt300 mg/day or 200 mg albumin/g
  creatinine) indicates target organ damage

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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

• 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

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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

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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

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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 lt120/80
• These patients are at high risk for target organ
  damage

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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

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Patient Evaluation/Risk Assessment

1. Absence or presence of various forms of
   hypertension-related target organ damage
2. Identifiable (secondary) causes of hypertension
3. Concomitant major CV risk factors, other
   disorders, and assessment of lifestyle habits

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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 8-14 mm Hg reduction in SBP can be produced

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DASH Diet
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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

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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 (ß
  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

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Algorithm for Treatment of Hypertension
Beta-blockers not first-line in AHA guidelines
2007
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Patient Education About Treatment

• Assess patients understanding and acceptance of
  the diagnosis of hypertension
• Discuss patients 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

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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
• 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)

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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)

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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
• JAMA289 2534 (2003)

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Hypertension with Compelling Indications
Sequential Therapy 1ST Line Compelling Indication
thiazide diuretic, CCB or ß-blockers ACEI/ARB Diabetes Mellitus
ACEI/ARB Chronic Kidney Disease
thiazide diuretic for BP control, CCB for ischemia control ß-blockers ACEI (or ARB) Acute/Chronic CAD
ACEI thiazide diuretic, or ARB Prior Ischemic Stroke
Aldosterone antagonist in severe HF, Hydralazine/dinitrate in black ACEI (or ARB) thiazide (loop) diuretic ß-blockers Left Ventricular Dysfunction
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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,
• A single drug is chosen dose increased till BP
  control occurred, max dose reached, or
  dose-limiting toxicity
• A second drug from a different class is added

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Starting Drug Therapy

• SEQUENTIAL THERAPY
• If goal BP is not achieved an alternative drug is
  chosen, to replace an initial one
• 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/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
• 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

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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

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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

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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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ß-Adrenoceptor Blockers

• ß-Blockers reduce morbidity mortality in
  hypertensive patients with compelling
  indications CHF, post-MI, high-risk CHD,
  diabetes
• All ß-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 ß-Blockers
NO-Donotaing
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Hemodynamic Response to ß-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 ß-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

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ß-Blockers

• Nonselective ß-Blockers are preferred in patients
  with non-CV indications like migraine
  prophylaxis/tremor
• ISA ß-Blockers are indicated for patients
  responding with severe bradycardia to non-ISA
  ß-blockers
• ISA ß-Blockers should be avoided in patients with
  MI history where agonistic properties may worsen
  the cardiac function

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ß-BlockersLipid Solubility

• Lipid solubility is of max clinical relevance in
  patients with renal/hepatic impairment
• High lipid sol drugs like propranolol are
  hepatically cleared
• Hydrophilic ones (atenolol) have main renal
  excretion (require dose adjustment)
• 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
ß-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
• Decreased HR, contractility myocardial O2
  demand produced by ß-blockers reduce the risk

46
ß-BlockersCompelling Indications

• Diabetes a cardio-selective agent is preferred
• ß-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
• ß-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

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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 ACEIß-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
  ß-blocker)
• In chronic angina ACEI can be added after
  ß-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 metabolism

• Chronic Kidney Disease (CKD)
• CKD increased intra-glomerular
  pressuremesangial 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- ß-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

54
ARBsPharmacological Profile vs ACI

• Unlike ARBs, ACE inhibition suppresses
  stimulation of both ANG II type-1 -2 receptors
• Hence, it is possible that ARBs are superior to
  ACEIs in amelioration of HTN-related damage
• 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)
• ACEIs ARBs are equivalent in symptomatic HF
  relief, but ARBs are of similar or weaker
  mortality rate reduction
• 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
• ARBs are the only antihypertensive agent showing
  evidence of reduction of renal failure in type 2
  diabetes nephropathy
• Benefits are BP lowering-independent
• 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
• Both ACEIs ARBs dilate the efferent arteriole
• 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 ß-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
  ß-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
64
Fixed-Dose Combinations for Hypertension
65
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 ß-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 ß-blockers

66
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