Blood pressure variation in the left ventricle (Blue line) & aorta (Red line) showing the cyclic variations of systolic and diastolic pressure

Cushing Syndrome

 11β-hydroxysteroid dehydrogenase enzyme   mineralocorticoid   BP &   K +

vasogenic edema Metabolic Syndrome nephrosclerosis

o Sedentary lifestyle o Obesity o Insulin resistance o Metabolic syndrome o Aging o Alcohol o Vitamin-D deficiency

o Low birth-weight o Family history o Genetic o Na+ sensitivity o Sympathetic overactivity o Renin overactivity

DASH diet: (dietary approaches to stop hypertension) Rich in fruits & vegetables and low-fat or fat-free dairy foods.

Classification of Hypertension Systolic pressure Diastolic pressure mmHg Normal 90–11960–79 Pre-hypertension 120–13980–89 Stage 1 140–15990–99 Stage 2 ≥160≥100 Isolated systolic HT ≥140<90

UK Hypertension Guidelines Starting Treatment threshold Group Treatment Target >160/100All 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 >130/80Type-2 Diabetes alone.<130/80 >135/85Type-1 Diabetes alone.<130/80 >130/80 Type-1 or 2 Diabetes with microalbuminuria. Type-1 or 2 Diabetes with renal, eye or CV damage. <130/80 >130/80Chronic renal disease with Macroalbuminuria.<125/75

DIABETIC HYPERTENSION Diabetic Nephropathy with (Microalbuminuria)  ACEIs / ARBs. Diabetic Nephropathy with (Macroalbuminuria)  ARBs / ACEIs. Diabetic Hypertension without Nephropathy  ACEIs / ARBs +/- Thiazide +/- CCBs.

Definition: [  GFR  60 ml / min / 1.73 m 2 (= 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 m 2 (serum creatinine mg / 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 CCBs Symptomatic 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): Compelling Indications Diuretic ßBßBßBßBACEIARBCCBAA Heart failure Post-MI High CAD risk Diabetes Chronic kidney disease Recurrent stroke prevention

The Use of Diuretics Require Electrolyte & Acid-base Balance Monitoring

Osmotic mannitol glucose furosemide HCT chlortalidone spironolactone CAI acetazolamide

Adverse EffectType of DiureticsExampleClinical Effect HypovolemiaLoop Diuretic Thiazide Lasix HCT  25 mg/day Hypotension Thirst  GFR HypokalemiaLoop Diuretic Thiazide Carbonic Anhydrase Inhibitor Lasix HCT  25 mg/day Acetazolamide Muscle weakness Cardiac arrhythmia HyperkalemiaPotassium Sparing DiureticsSpironolactoneMuscle Cramps Cardiac arrhythmia HyponatremiaLoop Diuretic Thiazide Lasix HCT  25 mg/day Neurological manifestations Metabolic AlkalosisLoop Diuretic Thiazide Lasix HCT  25 mg/day CNS manifestations Cardiac arrhythmia Metabolic AcidosisPotassium Sparing Diuretics CAI Amilorides – triamterene Acetazolamide muscle weakness neurological symptoms seizures Decrease Ca++ ExcretionThiazideHCTPrevents Osteoporosis Prevents Renal calculi HyperuricemiaLoop DiureticLasixGout

α-adrenergic receptors are present in the smooth muscles e.g. prostate, arteries & veins. α 1 -adrenergic stimulation  smooth muscles contraction  vasoconstriction. α 1 -adrenergic blockers  Relaxing vascular smooth muscles  vasodilatation   vascular resistance  hypotension. α 1 -adrenergic blockers  Relaxing prostate & U.B. neck.

o β 2 : Bronchodilation. Vasodilatation. Affect Glycogen Breakdown in Liver & Skeletal muscles o β 3 : Lipolysis. Renin Release   BP. Stimulation of β -adrenergic Receptors: o β 1 : +ve Chronotropic on heart muscle. +ve Inotropic on heart muscle.

o Management of cardiac arrhythmias o Antihypertensive.

Other Side Effects of β -blockers : o Hyperkalemia. o Erectile dysfunction. o Bradicardia, heart failure, heart block. o Hypotension, orthostatic hypotension. o Tremors. o Insomnia

Mode of Action : Disrupt the calcium ions (Ca +2 ) transport at calcium channels: o In vascular smooth muscles o In cardiac muscle INDICATIONS : o Hypertension o Atrial flutter & AF o Angina

o At high doses CCBs block the effect of insulin.

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.

Direct Na + H 2 O retention water retention Blood

Direct Na + H 2 O retention water retention

Direct Na + H 2 O retention water retention

Direct Na + H 2 O retention water retention Blood water retention

Magdi El-ShalakanyMagdi El-Shalakany Mean Arterial Pressure (mm Hg) Intraglomerular Pressure Chronic hypertension with chronic renal disease Chronic hypertension Normal Low High with normal renal function

smooth muscle cells

1.Hypertension 2.  IGP 3.Renal Hyperfiltration 4.Renal Tissue injury 5.Structural & Morphological Changes : Mesangial tissue expansion Basement membrane thickening Podocyte pedicles’ detachment Intraglomerular Fibrosis 1.  BP 2.  IGP 3.  Renal t. injury 4.  GFR 5.Bradykinin S.E: Persist Dry Cough Inflammation symp Angio-edema 6.Tolerance Degradation

1. Hypertension 2. Left Ventricular remodeling  (CHF) 3.  IGP 4.Renal Hyper-filtration 5.Renal Tissue injury  Chronic renal disease 6.Structural & Morphological Changes : o Mesangial tissue expansion o Basement membrane thickening o Podocytes pedicles’ detachment o Intraglomerular Fibrosis

1.  BP 2.  sympathetic tone   peripheral resistance 3.  Na + & water retention   blood volume 4.  sympathetic tone   HR 5.  COP &  Heart work load & O 2 consumption 1. Hypertension 2. Heart Failure 3. Angina 4. Post myocardial infarction

6.  Intra-Glomerular Pressure (  IGP) 7.  Renal Hyper-filtration 8.  Renal Tissue injury 9.Improve functional & structural renal condition 10.  Structural & Morphological Changes 11.  micro & macro-albuminuria 5. Diabetic Nephropathy 6. Chronic renal disease

1. Bradykinin & inflammatory related S.E: o Persistent Dry Cough o Angio-edema o 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)

1.Hypertension 2.  IGP 3.Renal Hyperfiltration 4.Renal Tissue injury 5.Structural & Morphological Changes : Mesangial tissue expansion Basement membrane thickening Podocyte pedicles’ detachment Intraglomerular Fibrosis 1.  BP 2.  IGP 3.  Renal t. injury 4.  GFR   C Cr 5.Bradykinin S.E: Persist Dry Cough Inflammatory symptoms Angio-edema 6.Tolerance Degradation

1. No Bradykinin & inflammatory related S.E: o Persistent Dry Cough o Angio-edema o 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)

Diuretics α-blockers β-blockers CCBs ACE-Is/ARBs

 -blockers  -blockers Calcium antagonists AT 1 -receptor blockers Diuretics ACE inhibitors ESH Guidelines. J Hypertens. 2007;25: ESH= European Society of Hypertension

o 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. o Creatinine clearance rate ( C Cr or Cr Cl): “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 ( C Cr or Cr Cl) is then more accurate to measure suspected renal disease.

o 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 mg/24 hr urine; (can not be detected by usual urine dipstick methods). o Macroalbuminuria is a level  300 mg/24 hr urine.

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 / DBP 80-89) Require Lifestyle modifications to  CV Risk.

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.

8.Empathy & Motivating Patients are very important to reach Treatment Goal. 9.Responsible Physician’s Judgment remains paramount in the presence of these guidelines.