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Medical Training
SPC & PIL
Pharmaco-vigilance
Medical Affairs Department
HYPERTENSIONhigh blood pressure
Definition of Hypertension
Chronic elevation of blood pressure.
140/90 mmHg
“Systemic, Arterial Blood Pressure”
Blood pressure variation in the left ventricle (Blue line) & aorta (Red line) showing the cyclic variations of systolic and diastolic pressure
elastic recoil
Etiology of Hypertension
• Primary Hypertension “Essential Hypertension”
• Secondary Hypertension
95%
2ry to another medical condition
No identifiable cause
Pheochromocytoma catecholamine
Cushing syndrome cortisol
Secondary Hypertension
Suprarenal: adenoma
Cushing Syndrome
Suprarenal: adenoma
Secondary Hypertension
Suprarenal: adenoma
Cushing Syndrome
Polycystic Kidney
Secondary Hypertension
Renal: Tumors
Secondary Hypertension
Renal: Renal Artery Stenosis
Coarctation of Aorta
Secondary Hypertension
Liquorice 11β-hydroxysteroid dehydrogenase enzyme mineralocorticoid® BP &® K+
Drugs
Secondary Hypertension
NSAIDsCOX2 selectiveSteroids
Pregnancy
Secondary Hypertension
PIHPreclampsia “EPH gestosis”
Sleeping Disturbance
Secondary Hypertension
• Tonsil enlargement
• Postnasal adenoma
• DNS
• Obesity.
Sleeping Disturbance
Secondary Hypertension
Management:Mandibular Advancement Splint (MAS), tonsillectomy, adenoidectomy, septoplasty or weight loss.
Secondary Hypertension
Hyperthyroidism
Hypothyroidism
Ca
Other Causes:
Rebound hypertension
Secondary Hypertension
Withdrawal ofClonidineBBs
Diagnosis of Hypertension
Korotkoff sounds
K1K2K3K4K5
Symptoms & Signso No symptomso Symptoms of 1ry Cause (2ry hypertension)o Headache, Fatigue, Blurred Vision, Epistaxiso Nausea – Vomiting.o Retina : copper or silver wire appearance, exudates, hemorrhages or papilledema.
Complications of Hypertension
vasogenic edema
Metabolic Syndrome
nephrosclerosis
Risk Factors of 1ry Hypertension
Risk Factors
Primary Hypertensionno identifiable reversible cause
o Sedentary lifestyleo Obesityo Insulin resistanceo Metabolic syndromeo Agingo Alcoholo Vitamin-D deficiency
Risk Factors
Primary Hypertension
o Low birth-weighto Family historyo Genetico Na+ sensitivityo Sympathetic overactivityo Renin overactivity
no identifiable reversible cause
Pathophysiology Hypertension
Factors Affecting Arterial Blood Pressure
Management of Hypertension
ResistantHypertension
Failure to reduce blood pressure to the appropriate level after taking a 3-drug regimen including thiazide.
Management of
Hypertension
Prevention
Lifestyle advice (non-pharmacological control)
Should be offered to the patient, before initiation of any drug therapy.
Lifestyle Changes
Healthy Diet
Salt Restriction
DASH diet: (dietary approaches to
stop hypertension)
Rich in fruits & vegetables and low-fat or fat-free dairy foods.
Weight Reduction
More ExerciseExercise
Reduce Stresses
HypertensionManagement
Guidelines
Lifestyle Changes “American & British Guidelines” suggest that:
Lifestyle changes should be explored in all patients who are hypertensive or pre-hypertensive.
Classification of
Hypertension
Classification of Hypertension
Systolic pressure
Diastolic pressure
mmHg mmHg
Normal 90–119 60–79
Pre-hypertension 120–139 80–89
Stage 1 140–159 90–99
Stage 2 ≥160 ≥100
Isolated systolic HT ≥140 <90
&
&
or
oror
STROKEMIHF BY 40%
25%50%
AMERICAN GUIDELINES
UK Hypertension GuidelinesStarting
Treatment threshold
GroupTreatment Target
>160/100 All those with such persisting readings >160/100. <140/90
>140/90
Have established cardiovascular disease, or Have C.V. Risk (>20% per 10 years), or Have evidence end-organ damage without D.M., or Ch. renal dis., without Macroalbuminuria (or D.M.)
<140/90
>130/80 Type-2 Diabetes alone. <130/80
>135/85 Type-1 Diabetes alone. <130/80
>130/80Type-1 or 2 Diabetes with microalbuminuria. Type-1 or 2 Diabetes with renal, eye or CV damage.
<130/80
>130/80 Chronic renal disease with Macroalbuminuria. <125/75
COMPELLINGINDICATIONS
Urine ALB/CR 2
DIABETIC HYPERTENSION
Diabetic Nephropathy with (Microalbuminuria)
ACEIs / ARBs.
Diabetic Nephropathy with (Macroalbuminuria)
ARBs / ACEIs.
Diabetic Hypertension without Nephropathy
ACEIs / ARBs +/- Thiazide +/- CCBs.
Urine ALB/CR 2
Definition: [ GFR 60 ml / min / 1.73 m2 (= serum creatinine 1.5 mg / dL or 1.3 mg / dL )] [Albuminuria 300 mg/day (macroalbuminuria)].
Treatment Goal: Aggressive BP Lowering 125/75
Compelling Drug: ACEIs or ARBs (Diabetic or non-Diabetic Nephropathy). N.B. GFR (serum creatinine) up to 35% from baseline is acceptable , And is NOT a reason to withhold treatment unless hyperkalemia develops.
In Advanced Renal Disease: [= GFR 30 ml / min / 1.73 m2 (serum creatinine 2.5 - 3mg / dL)]:Increasing dose of loop diuretic is usually needed with ARBs or ACEIs)
CHRONIC RENAL DISEASE
HEART FAILURE
Asymptomatic HF ACEIs / ARBs + BBs.
Advanced HF ACEIs / ARBs + BBs + Diuretic.
CEREBRO-VASCULAR STROKE
Risks & Benefits of ACUTE Lowering of BP DURING acute CV Stroke are still unclear.
Control of BP at intermediate levels (approximately 160/100 mmHg) is appropriate until condition is stabilized or improved.
Stroke rates are lowered better by ACEIs / ARBs + Thiazide.
ISCHEMIC HEART DISEASE
Asymptomatic Angina: BBs or CCBsSymptomatic Angina: ACE-Is / ARBs
(ARBs in Patients can’t tolerate ACE-Is)Acute MI (elevated ST segment): ACE-Is / ARBs + BBs
(ARBs in Patients can’t tolerate ACE-Is)
N.B. CCBs if given there should be extreme cautious to avoid heart failure.
AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; βB, ß-blocker; CCB, calcium channel blocker; MI, myocardial infarction; CAD, coronary artery disease.
JAMA. 2004;289(19):2560-2572.
The Seventh Report of the Joint National Committee
Compelling Indications Diuretic ßB ACEI ARB CCB AA
Heart failure Post-MI
High CAD risk Diabetes
Chronic kidneydisease
Recurrent stroke
prevention
Difference Between American & British Guidelines
Thiazide
ACE-I ARB CCB BB
BB
ThiazideACE-I ARB CCB
American Guidelines
British Guidelines
AntihypertensiveDrugs
CLASSES OFANTIHYPERTENSIVE
DRUGS
DIURETICS
DIURETICSDrugs used to do forced diuresis.
INDICATIONS:
o Treatment of Heart Failure.o Treatment of Hypertension.o Treatment of Liver cirrhosis.o Treatment of Certain Renal Conditions.o Urine Alkalinization To Treat Aspirin overdose:Acetazolamide ( carbonic anhydase H+ excretion)
The Use of Diuretics Require Electrolyte &
Acid-base Balance Monitoring
DIURETICSTHIAZIDE DIURETIC:
o Antihypertensive independent from its diuretic effect At a dose that causes diuresis. Due to Direct Vasodilator Effect Peripheral Resistance BP Afterload
At dose causing diuresis Blood Volumevenous return Preload
o Compelling Indication in HF
o Least S.E.
DIURETICSAdvantages of thiazide diuretic:
o Least S.E.o Drug of 1st Choice in JNC7.o Causes synergism when combined with any antihypertensive therapy. o Compelling indication in HF.o Also Ca sparing diuretic.
Osmoticmannitol glucose
furosemide
HCTchlortalidone spironolactone
CAIacetazolamide
Loop Diuretics
Lasix
o High Ceiling diuretic: “cause up to 20% increase in Na+ filtration load”
o Safer for Short term use only
Potassium Sparing Diureticso Used mainly to Correct Hypokalaemia “caused by other diuretics or digitalis”.
o Spironolactone AA: A compelling indication in HF.
Adverse Effect Type of Diuretics Example Clinical EffectHypovolemia Loop Diuretic
ThiazideLasixHCT 25 mg/day
HypotensionThirst GFR
Hypokalemia Loop DiureticThiazideCarbonic Anhydrase Inhibitor
LasixHCT 25 mg/dayAcetazolamide
Muscle weaknessCardiac arrhythmia
Hyperkalemia Potassium Sparing Diuretics Spironolactone Muscle CrampsCardiac arrhythmia
Hyponatremia Loop DiureticThiazide
LasixHCT 25 mg/day
Neurological manifestations
Metabolic Alkalosis Loop DiureticThiazide
LasixHCT 25 mg/day
CNS manifestationsCardiac arrhythmia
Metabolic Acidosis Potassium Sparing Diuretics
CAI
Amilorides – triamtereneAcetazolamide
muscle weakness neurological symptomsseizures
Decrease Ca++ Excretion Thiazide HCT Prevents OsteoporosisPrevents Renal calculi
Hyperuricemia Loop Diuretic Lasix Gout
α-blockers
α-adrenergic receptors are present in the smooth muscles e.g. prostate, arteries & veins. α1 -adrenergic stimulation smooth muscles contraction vasoconstriction.α1-adrenergic blockers Relaxing vascular smooth muscles vasodilatation vascular resistance hypotension.α1-adrenergic blockers Relaxing prostate & U.B. neck.
α-blockers(α1 blockers or α1 antagonists)
α-blockers(α1 blockers or α1 antagonists)
Other minor effects:Relaxing cardiac muscle COP hypotension.
Side effects:o Relaxing cardiac muscle Heart Failure.o Appetite obesityo Dryness of moutho Weak antihypertensive
( HF events - ALLHAT)
β-blockers
β-blockers(β-blockers or β-antagonists)
β-adrenergic Receptors Location:o β1-adrenergic receptors mainly in : Heart & kidneys.
o β2-adrenergic receptors mainly in : Smooth muscles, (vascular – bronchial) Liver & Sk. Muscles.o β3-adrenergic receptors : Fat cells.
β-blockers(β-blockers or β-antagonists)
o β2 : Bronchodilation. Vasodilatation. Affect Glycogen Breakdown in Liver & Skeletal muscles
o β3 : Lipolysis.
Renin Release BP.
Stimulation of β-adrenergic Receptors:o β1 : +ve Chronotropic on heart muscle. +ve Inotropic on heart muscle.
β-blockers(β-blockers or β-antagonists)
Blocking of β-adrenergic Receptors By β-blockers :o β1 : Stress & Physical exertion effect on heart muscle. HR & Cardiac contractility force. Renin Release BP.
o β2 : Bronchospasm induces asthma Vasospasm BP. NB. (non selective β-blockers induce overall hypotension)
o β3 : Diabetogenic.
β-blockers(β-blockers or β-antagonists)
( cardiac workload oxygen demand)
o Management of cardiac arrhythmias
( conduction & HR)
o Antihypertensive. ( COP & vascular resistance)
Indications of β-adrenergic blockers:o Cardio-protection after MI
β-blockers(β-blockers or β-antagonists)
Side Effects of β-blockers :o Bronchospasm & dyspnea.o Diabetogenic Risk: disturbed glucose & lipid metabolism:Recent studies revealed that: Diuretics and β-blockers risk of diabetes ACE inhibitors & ARBs risk of diabetes.
That is why UK clinical guidelines :recommend avoiding diuretics and β-blockers as first-line treatment of hypertension.
β-blockers(β-blockers or β-antagonists)
Other Side Effects of β-blockers :oHyperkalemia.o Erectile dysfunction.o Bradicardia, heart failure, heart block.o Hypotension, orthostatic hypotension.o Tremors.o Insomnia
Anti-Renin Effect
melatonin.
CCBs
Calcium Channel-blockers (CCBs)Mode of Action: Disrupt the calcium ions (Ca+2) transport at calcium channels:o In vascular smooth muscles o In cardiac muscle
vascular resistance.
contractility Stroke volume COP.o In cardiac muscle HR
INDICATIONS:o Hypertension o Atrial flutter & AF BBs are better than CCBs
CCBs are better than BBs
o Angina vascular resistance BP contractility
Work load & O2 demand
Calcium Channel-blockers (CCBs)Side effects :o Headache. o Flushing. o Lower limb edema
o At high doses CCBs block the effect of insulin.
Contraindicated in HFo Direct Bradycardia.o Reflex Tachicardia:Direct vasodilatation stimulate baroreceptors HR(That’s why BBs are better in controlling AF)(That’s why CCBs better avoided in MI)
Side effects :o Headache. o Flushing. o Lower limb edema
AnginaAF
Hypertension+ cardiotropic
ACE-Is & ARBs
Renin Angiotensin
Aldosterone
System
Renin Angiotensin
Aldosterone
System
R A AS
Anatomy & PhysiologyOf Renal
Glomerulus
Nephron
GFRIGP
Glomerular Corpuscle
Juxta glomerular cells
macula densa
Afferent arteriole
Efferent arteriole
Distal convoluted tubule
Urinary chamber
Bowman’s capsule
Basement membrane -Podocytes
Proximal convoluted tubule
Urinary excretion: Fluid & electrolyte filtration from capillary side to urinary side through the basement membrane & podocytes to the urinary chamber of the glomerulus.
RENIN
BP
Na
BP
GFR
GFR
Direct Na+ H2O retention
water retention Bl
ood
Bloo
d
Bloo
d
urine
urine
BP
GFR
Direct Na+ H2O retention
water retention Bl
ood
Bloo
d
Bloo
d
urine
urine
BP
GFR
Direct Na+ H2O retention
water retention
Bloo
dBl
ood
Bl
ood
urine
urine
BP
GFR
GFRIGPAfferent vasodilatation
Efferent vasoconstriction
BP
RENIN
Functional & Structural Changes of RAAS Activation
Direct Na+ H2O retention
water retention Bl
ood
Bloo
d
Bloo
d
urine
urine
water retention
BP
GFR
BLOOD VOL
GFRIGPAfferent vasodilatation
Efferent vasoconstriction
RENIN
BP
Functional ChangesIn HemodynamicsRenal Hyper-Filtration
Magdi El-ShalakanyMean Arterial Pressure (mm Hg)
Intr
aglo
mer
ular
Pre
ssur
e
Chronic hypertension with chronic
renal disease
Chronic hypertensionNormal
Low
High
80 120 160 18014010060
Renal Autoregulatory Curve
with normal renal function
The Continuum of Diabetic
Nephropathy
Structural Changes of RAAS Activation
RENAL CORPUSCLE
podocytesbasement membrane
Bowman's capsule
PCT
DCT
urinary Space
mesangial tissue
Juxtaglomerular cells
Macula densa
Juxta-Glomerular Apparatus
Renin
smooth muscle
cells
glomerular capillaries
(afferent)(efferent)
RAAS STIMULATION1. Hypertension2. IGP3. Renal Hyperfiltration4. Renal Tissue injury5. Structural & Morphological
Changes :• Mesangial tissue expansion• Basement membrane thickening• Podocyte pedicles’ detachment• Intraglomerular Fibrosis
ACE-I1. BP2. IGP3. Renal t. injury4. GFR5. Bradykinin S.E:• Persist Dry Cough• Inflammation symp• Angio-edema
6. Tolerance
Degradation
RAAS STIMULATION1. Hypertension2. Left Ventricular remodeling (CHF)3. IGP4.Renal Hyper-filtration5.Renal Tissue injury Chronic renal disease6.Structural & Morphological Changes :o Mesangial tissue expansiono Basement membrane thickeningo Podocytes pedicles’ detachmento Intraglomerular Fibrosis
ACE-I EFFECTS1. BP2. sympathetic tone peripheral resistance3. Na+ & water retention blood volume 4. sympathetic tone HR5. COP & Heart work load & O2 consumption
ACE-I INDICATIONS1. Hypertension2. Heart Failure3. Angina4. Post myocardial infarction
Prophylaxis in Acute Coronary Syndrome
ACE-I EFFECTS6. Intra-Glomerular Pressure (IGP)7. Renal Hyper-filtration8. Renal Tissue injury9. Improve functional & structural renal condition10. Structural & Morphological Changes11. micro & macro-albuminuria
ACE-I INDICATIONS5. Diabetic Nephropathy6. Chronic renal disease
Both due to BP & also independent to its Antihypertensive Effect
ACE-I SIDE-EFFECTS1. Bradykinin & inflammatory related S.E:o Persistent Dry Cougho Angio-edemao Rash o Inflammation-related Pain
2. GFR Creatinine Clearance Rate (Ccr or C C) serum Creatinine
GFR (serum creatinine) up to 35% from baseline is acceptable & is NOT a reason to withhold treatment unless hyperkalemia develops.
3. Hyperkalemia
4. Metallic Taste (sulfhydryl part in Captopril molecule)
1. Renal artery stenosis (bilateral)
2. Renal artery stenosis (Unilateral)3. Impaired renal function (ACE-Is may GFR).4. Aortic valve stenosis or cardiac outflow obstruction (ACE-I COP). 5. Hypovolemia or dehydration (ACE-Is diuresis ( fluid volume)
& BP).
6. Pregnancy (category D)
ACE-I ContraindicationsAbsolute Contraindications
Relative Contraindications
ACE-I is Contraindicated in Pregnancy
Why ARBs Are Better than ACE-Is?
(afferent)(efferent)
RAAS STIMULATION1. Hypertension2. IGP3. Renal Hyperfiltration4. Renal Tissue injury5. Structural & Morphological
Changes :• Mesangial tissue expansion• Basement membrane thickening• Podocyte pedicles’ detachment• Intraglomerular Fibrosis
ACE-I1. BP2. IGP3. Renal t. injury4. GFR C Cr5. Bradykinin S.E:• Persist Dry Cough• Inflammatory symptoms• Angio-edema
6. Tolerance
Degradation
ARBs are better than ACE-Is1. No Bradykinin & inflammatory related S.E:
o Persistent Dry Cougho Angio-edemao Rash o Inflammation-related Pain
2. ARBs prevent excessive GFR Creatinine Clearance Rate which serum creatinine.
It Keeps the Drop in GFR & C cr (if occur) 35% from baseline which is acceptable & So No Need to Withhold treatment.
3. No Decline of Anti-Hypertensive Effect
4. No Metallic Taste (sulfhydryl part in Captopril molecule)
Beside All Benefits of ACE-Is
Factors Affecting Arterial Blood Pressure
Diuretics
Diuretics
α-blockers
β-blockers
β-blockers
CCBs
CCBs
CCBs
ACE-Is/ARBs
ACE-Is/ARBsACE-Is/ARBs
ACE-Is/ARBs
ESH 2010: Possible Drug Combinations of Different Classes of Antihypertensive Agents
-blockers
-blockersCalcium
antagonists
AT1-receptorblockers
Diuretics
ACE inhibitors
The most effective and well tolerated combinations are shown as solid lines
ESH Guidelines. J Hypertens. 2007;25:1105-1087. ESH= European Society of Hypertension
THANKYOU
Renal Functions &
Renal Disease
Renal Disease Terminologyo CRD = Chronic Renal Disease.o GFR = Glomerular Filtration Rate.o BUN = Blood Urea Nitrogen = Uremia = Azotemia.o ESRD = End Stage Renal Disease (= Need for Dialysis or Kidney Transplant)
o Plasma concentrations of creatinine and urea (BUN = Blood Urea Nitrogen) are used to measure renal function.
Kidney Function Tests
o Creatinine clearance rate (CCr or CrCl): “A measure for GFR”.
o BUN and serum creatinine will not be raised normal Until 60% of total kidney function is lost.
o Creatinine clearance (CCr or CrCl) is then more accurate to measure suspected renal disease.
Kidney Function Testso Proteinuria (elevated level of protein (albumin) in urine) : It is an important Prognostic marker for renal disease. o Albumin level 30 mg/24 hr urine is diagnostic for chronic kidney disease o Microalbuminuria is a level of 30-300 mg/24 hr urine; (can not be detected by usual urine dipstick methods).o Macroalbuminuria is a level 300 mg/24 hr urine.
KEY MESSAGES OF AMERICAN GUIDELINES AND BRITISH GUIDLINES
KEY MESSAGES OF AMERICAN GUIDELINES “JNC7”
1. In patients 50 yr : SBP ( 140 mmHg) is much more important Risk Factor for CVD than DBP.
2. CVD Risk doubles with each increment of 20/10 mmHg (above normal).
3. Pre-hypertensive patients (SBP 120-139 / DBP 80-89) Require Lifestyle modifications to CV Risk.
KEY MESSAGES OF AMERICAN GUIDELINES “JNC7”
4. Thiazide diuretic is drug of First choice for most patients with uncomplicated hypertension.
5. Certain Risk conditions are Compelling Indications For Other Anti-hypertensive Agents (e.g. ACE-Is , ARBs , CCBs , BBs …. etc)
6. Most hypertensive patients will require 2 or more antihypertensive agents to Achieve Treatment Goals:
( 140/90 mmHg, or 130/80 mmHg for Diabetic or Chronic Renal disease patients )
7. If BP is 20/10 mmHg above Goal, consider additional agent therapy, one of which should be thiazide.
KEY MESSAGES OF AMERICAN GUIDELINES “JNC7”
8. Empathy & Motivating Patients are very important to reach Treatment Goal.
9. Responsible Physician’s Judgment remains paramount in the presence of these guidelines.
What Are The Main Differences In British
Guidelines?
UK Guidelines Recommendations
1. In hypertensive patients aged 55 or black patients of any age, the first choice for initial therapy should be either a CCB or a thiazide-type diuretic .
2. In hypertensive patients younger than 55, the first choice for initial therapy should be an ACE inhibitor /(ARBs).
UK Guidelines Recommendations
3. If initial therapy is a CCB or a thiazide diuretic & a second drug is required, an ACE inhibitor /(ARBs) should be added.
4. If initial therapy was with an ACE-I or a CCB, a thiazide diuretic should be added.
UK Guidelines Recommendations
5. If treatment with three drugs is required, the combination of ACE-I /(ARBs) , CCB, and thiazide diuretic should be used.6. If a fourth drug is required, one of the following should be considered:
a- A higher dose thiazide diuretic,
b- Another diuretic (with careful monitoring),
c- β-blockers, d- α-blockers.
UK Guidelines Recommendations
8. Beta blockers are not preferred as initial therapy of hypertension.
β-blockers may be considered in young
age, and those with intolerance or
contraindication to ACE inhibitors and ARBs: e.g. women with child-bearing potential.
UK Guidelines Recommendations
9. When a β-blockers is withdrawn, dose should be stepped down gradually.
β-blockers should NOT be withdrawn in patients with compelling indications for β-blockers:
e.g. those who have symptomatic angina or who have had myocardial infarction.