Hypertension – Drug therapy

Hypertension – Drug therapy : 

Hypertension – Drug therapy Dr. Girish Vaswani D.N.B. ( Med ) Consulting Physician Bhatia hospital Dalvi hospital

What to look for before therapy? : 

What to look for before therapy? The level of the pressure Any identifiabale cause Evidence of target organs damages Other risk factors

Classifying Blood Pressure by Readings : 

Classifying Blood Pressure by Readings High Blood Pressure = Elevated systolic pressure and/or elevated diastolic pressure The highest reading dictates classification Elevated readings must occur on multiple occasions to be diagnosed

White coat hypertension : 

White coat hypertension Normal out-of-office BP readings Present in 20 % Poses cardiovascular hazard

Masked hypertension : 

Masked hypertension Normal in-office BP readings Out-of-office readings high Present in 20 % Hazards similar to sustained HT

Morning BP surge : 

Morning BP surge Occurs within 2 hrs of awakening Poses increased cardiovascular and stroke risk as well SCD

Nocturnal Dip : 

Nocturnal Dip May be attenuated Increased risk of cardiovascular events and sudden cardiac deaths

Primary Hypertension : 

Primary Hypertension In 90 – 95 % cases no cause is detected. This is essential HT With or without wide pulse pressure Includes TOP, AIP Treatment is necessary

Identifiable causes of hypertension : 

Identifiable causes of hypertension Renal - macro / microvascular, parenchymal, APCKD, renin producing tumors, obstr uropathy Endocrinal - Cushing’s, Conn’s, Phaeo, enzyme defects, acromegaly, hypothyroidism, hypercalcemia Drugs – estrogens, adrenal steroids, decongestants, apetite suppr, TCA, NSAID, MAO inhibitors, cyclosporine Wide pulse pressure – AR, AVF, PDA, Thyrotox

Identifiable causes of hypertension : 

Identifiable causes of hypertension Co-arctation aorta Obstructive sleep apnea Pregnancy Neurogenic- psychogenic, raised ICT, acute spinal injury, dysautonomias, polyneritis

Other CVD risk factors : 

Other CVD risk factors Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria or estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD (men under age 55 or women under age 65) *Components of the metabolic syndrome.

Laboratory Tests : 

Laboratory Tests Routine Tests Electrocardiogram Urinalysis Blood glucose, and hematocrit Serum potassium, creatinine, or the corresponding estimated GFR, and calcium Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides Optional tests Measurement of urinary albumin excretion or albumin/creatinine ratio More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved

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Renal function Blood volume Venous tone Venous return Heart rate Nervous control Muscular responsiveness Myocardial contractility Stroke volume Cardiac output CNS factors Renin release Angiontensin II formation Intrinsic vascular responsiveness Peripheral resistance Nervous control Renal function Mean arterial pressure Factors that Govern the Mean Arterial Pressure

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Mean Arterial Pressure MAP = CO CO = HR X SV SNS Blood volume Heart contactility Venous tone X PVR myogenic tone vascular responsivenes nervous control vasoactive metabolites endothelial factors circulating hormones

Which drug ? : 

Which drug ? A – Ace inhibitors, ARB, aldosterone antagonists, alpha blockers B – Beta blockers C – Ca entry blockers, Central agents D – Diuretics E – Extras : periph dilators, reserpine

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Choice of Treatment

Treatment Goals for BP levels : 

Treatment Goals for BP levels Less than 130/85 in all patients With nephropathy less than 120/80 With cardiac disease not to lower greater than 110/70 J – curve Most never reach TARGET

Diuretics-Disadvantages : 

Diuretics-Disadvantages Hypovolemia Electrolyte imbalances Acid – base imbalances Hyperlipidemia Hyperglycemia Hyperuricemia Others – skin rashes, bone marrow, GI symps, sulfa allergies No effect LVH

Diuretics – Best used : 

Diuretics – Best used Elderly, black Mild to moderate HT Those with renal and cardiac failure & fluid overloaded states Good potentiators of other anti-hypertensives

Diuretics - mechanism : 

Diuretics - mechanism BP = CO x PVR So dehydrate Duration short Escape Ceiling effect

Diuretics - Types : 

Diuretics - Types Thiazides Loop Aldosterone antagonists Osmotic Carbonic anhydrase inhibitors

Beta blockers-disadvantages : 

Beta blockers-disadvantages Cardiac – SA node, AV node, ventricle Vascular – PVD, gangrene, vasculitides, Raynaud’s, TAO Pulmonary Renal Liver CNS Metabolic – sugar, lipids, K

Beta blockers – best used : 

Beta blockers – best used All stages of ischemic heart disease Tachycardias – supraventricular, ventricular MVP, HOCMP, LVH Thyrotoxicosis Pheochromocytoma already on alpha block Heart failure

Two groups : 

Two groups Non DHP - primary action on heart Dihydropyridines - primary action on arterioles nifedipine nimodipine amlodipine felodipine isradipine

Ca channel blockers : 

Ca channel blockers

Ca channel blockers : 

Ca channel blockers

Ca channel blockers : 

Ca channel blockers

CCBs-Common SE : 

CCBs-Common SE Headache Edema (nifedipine) Constipation (verapamil) Gingival hyperplasia AV block & heart failure (verapamil and diltiazem) Drug interactions: beta blockers (verapamil and diltiazem), cimetidine

Calcium Channel Blockers : 

Calcium Channel Blockers Divided into 2 groups chemically and pharmacologically Common property: they all antagonize Ca++ movement across cell membranes by blocking L type channels decrease frequency of opening in response to depolarization Also called: Slow Ca++ channel blockers Ca++ channel antagonists Ca++ entry blockers

Cardiac effects : 

Cardiac effects Verapamil and diltiazem type reduce Ca++ entry in the heart Slow pacemaker activity - HR decreases Slows conduction between atria and ventricles Lessens strength of contraction - decreased stroke volume Dihydropyridines have minimal effects on Ca++ entry in heart muscle

Vascular effects : 

Vascular effects dihydropyridines Arteries and arterioles dilate more than veins Fall in BP due to reduced TPVR Reflex tachycardia verapamil and diltiazem - lesser effect on arterioles and more depression of heart (no tachycardia)

CCB Safety : 

CCB Safety DO NOT USE SHORT ACTING DHP’S!!!!!! DHP except plendil and norvasc may be detrimental in CHF Discontinue slowly tapering dose if used for angina Diltiaziem/verapamil contraindicated in sick sinus syndrome, 2nd or 3rd degree heart block, severe CHF, cardiogenic shock, interact with statins…dramatically increasing levels (except pravachol and lescol)

Ace inhibitors/ArBs : 

Ace inhibitors/ArBs Serum Na < 125 Creatinine normal No dehydration or other acute unstable renal or cardiac condition Stenotic valvular heart disease, HOCMP Renal artery stenosis Sensitivity to drug

Ace inhibitors / Arbs - Beware : 

Ace inhibitors / Arbs - Beware Angioedema Cough Hyperkalemia Metabolic acidosis Skin rashes Neutropenia

Ace inhibitors / ArBs – best used : 

Ace inhibitors / ArBs – best used Diabetes Heart disease Peripheral vasc disease Renal disease Respiratory Metabolic – sugar, lipids, uric acid Proteinuria

Ace v/s AT2RA : 

Ace v/s AT2RA More cough For microalb Better cardiac failure CNS AT2RA better Less cough For macroalb No added adv Better CNS

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Angiotensinogen Angiotensin I Angiotensin II Angiotensin III Renin ACE Aminopeptidase Non-ACE (eg. Chymase in heart) Endopeptidase Angiotensin 1-7 Releases ADH; ↑ PG; Natriuretic; ↓ RVR; ↓ BP (brain stem inj.) ? Role in effects of ACEI 1 2 3 7 8 9 10 NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 9 10 NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8 NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH + 1. ↓ Renal Perfusion Pressure 2. ↓ Na at Macula Densa cells 3. ↑ Sympathetic nerve activity (ß-1) ±PG The Renin-Angiotensin System

LV remodelling : 

LV remodelling Myocyte hpertrophy Altered contractile properties Myocyte necrosis, apoptosis and autophagia Beta adrenergic desensitisation Abnormal myocardial metabolism Collagen and extracellular matrix disorganisation and dissolution

AT2 - Actions : 

AT2 - Actions Cardiac-hypertrophy, fibrosis Vasc-endoth dysfunc Renal-Incr IGP, protein leak, growth & fibr Adrenals-aldosterone excess Coagulation system-incr fibrinogen & PAI

Regulatory Functions of the EndotheliumNormal Dysfunction : 

Regulatory Functions of the EndotheliumNormal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis Platelet Disaggregation NO, PGI2 Adhesion Molecules CAMs, P,E Selectins Antiproliferation NO, PGI2, TGF-, Hep Growth Factors ET-1, A-II, PDGF, ILGF, ILs Lipolysis Inflammation ROS, NF-B PAI-1, TF-α, Tx-A2 tPA, Protein C, TF-I, vWF LPL Vogel R

Endothelial functions : 

Endothelial functions Vasodilatation Antiplatelet Antithrombotic Profibrinolytic Antioxidant Anti inflammatory antiproliferative Vasoconstriction Pro-aggregatory Prothrombotic Antifirinolytic Pro-oxidant Pro-inflammatory Pro-proliferative

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Angiotensin II Vasoconstriction Aldosterone Secretion Direct Renal Sodium Retention ↑ Thirst ADH Release ↑ Cardiac Contractility Sympathetic Facilitation: Central Nerve terminal (ganglionic ?) Cardiac & Vascular Hypertrophy All known physiologic effects are mediated by the angiotensin II type 1 receptor ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE

Circulating and local (tissue) RAS influence on the cardiovascular system : 

Circulating and local (tissue) RAS influence on the cardiovascular system Circulating RAS Short-term effects Sodium/water reabsorption via aldosterone secretion Local RAS Long-term effects Intraglomerular hypertension Vascular hypertrophy Heart Heart Vasoconstriction Positive chronotropic effects/ arrhythmogenic effects Myocardial hypertrophy ANGIOTENSIN II

ACEI : 

ACEI Bradykinin Angiotensin I Angiotensin II ACE inhibitor Inactive metabolites AT1-blocker Vasodilation Natriuresis Extracellular matrix degradation Cough Angioedema Hypertension Aldosterone Transforming growth factor  Plasminogen activator Vasodilatation Natriuresis Antiproliferative effects AT1Receptor AT2Receptor

Angiotensin II Interaction With Secondary Mediators : 

Angiotensin II Interaction With Secondary Mediators Yusuf. Am J Cardiol. 2002;89(suppl):18A-26A. LDL  BP  Diabetes Smoking Oxidative stress Endothelial dysfunction and smooth muscle activation NO  Local mediators  Tissue ACE  AII Endothelin catecholamines PAI-1, platelet aggregation, tissue factor VCAM/ICAMcytokines Proteolysis inflammation Growth factors cytokines matrix Vasoconstriction Thrombosis Inflammation Plaque rupture Vascular lesion and remodeling

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Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X

ACE Inhibitors : 

ACE Inhibitors

Alpha blockers - Fears : 

Alpha blockers - Fears Postural hypotension Reflex tachycardia May aggravate angina

Alpha blockers – best used : 

Alpha blockers – best used Phaeochromocytoma Peripheral vascular disease Pregnancy Prostatic hypertrophy, renal disease Early morning BP surge Metabolically neutral drug

Pregnancy and hypertensives : 

Pregnancy and hypertensives Safely use CCB, AB, labetolol and methyldopa Never use diuretics, BB, Ace/Arb and other agents

Causes of Resistant Hypertension : 

Causes of Resistant Hypertension Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication Inadequate doses Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) Over-the-counter (OTC) drugs and herbal supplements Excess alcohol intake Identifiable causes of HTN

Antihypertensive treatment: Preferred drugs as per new European guidelines : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy ESRD=end-stage renal disease PAD=peripheral arterial disease ISH=isolated systolic hypertension

Antihypertensive treatment: Preferred drugs as per new European guidelines : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy ESRD=end-stage renal disease PAD=peripheral arterial disease ISH=isolated systolic hypertension

Antihypertensive treatment: Preferred drugs as per new European guidelines : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy ESRD=end-stage renal disease PAD=peripheral arterial disease ISH=isolated systolic hypertension

Antihypertensive treatment: Preferred drugs as per new European guidelines : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy ESRD=end-stage renal disease PAD=peripheral arterial disease ISH=isolated systolic hypertension

Summary : 

Summary Left ventricular hypertrophy LV faliure, cardiac failure ACS HOCMP MVP, regurgitant valve Indapamide, and all except diuretics AceI, ArB, diuretics, BB, vasodilators BB, Ace/Arb BB, nonDHP Ace/Arb, diuretics, BB

Summary : 

Summary Stenotic cardiac valves Aortic dissection B/L RAS CNS disease, stroke, hemorrhage Thyrotoxicosis Pheochromocytoma Avoid Ace/Arb, D BB, Ace/ Arb. Avoid Ace/ARB Avoid central agent, BB. Arb over Ace. BB AB + BB

Summary : 

Summary Renal failure Hyperkalemia Periph vasc disease Hyperlipidemia Hyperglycemia Hyperuricemia CCB, D, Ace/Arb Avoid Ace/Arb, BB Avoid BB. USE AB Avoid BB, D Avoid BB, D Avoid D

Slide 61: 

Consider prescription if: • Sustained diastolic blood pressure of > 90 mm Hg or • Isolated systolic hypertension of > 160 mm Hg and • No other risk factors Prescribe if: • Target-organ damage or CVD, or • Concomitant diseases such as diabetes mellitus or • Other cardiovascular risk factors Prescribe if: • Diastolic blood pressure readings average > 100 mm Hg, regardless of other factors Indications for PharmacotherapyAdults under 60 years (summary)

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Standardized Therapy AlgorithmAdults over 60 years

Slide 64: 

Standardized Therapy Algorithm Adults under 60 years

ARBs Uses : 

ARBs Uses Usually Secondary to ACEi Hypertension CHF Renal Insufficiency Diabetes Migraine prophylaxis

MOA of ACE Inhibitors : 

MOA of ACE Inhibitors Block formation of angiotensin II Lowers TPVR Reduces the release of aldosterone Increases Na+ excretion Increases K+ retention

Blocking the Renin-Angiotensin System : 

Blocking the Renin-Angiotensin System BP decreases MAINLY by lowered TPVR Cardiac output is usually NOT significantly affected For some reason, reflex sympathetic stimulation DOES NOT OCCUR Absence of cardiostimulation makes these drugs safe in patients with ischemia

ACE Inhibitors- Side Effects : 

ACE Inhibitors- Side Effects Angioedema possible (0.1%) Hypotension (especially with diuretics) Acute renal failure in patients with renal artery stenosis (what with NSAIDs) Hyperkalemia in patients taking potassium supplements or potassium sparing diuretics

ACE Inhibitors- Side Effects : 

ACE Inhibitors- Side Effects Dry, non-productive cough – 25% incidence Alteration of taste Allergic skin rashes, drug fevers Absolutely contraindicated during 2nd and 3rd trimesters of pregnancy Fetal hypotension Fetal renal failure Fetal malformation or death

Angiotensin Receptor Blockers : 

Angiotensin Receptor Blockers

Angiotensin Receptor Blockers: Mechanisms : 

Angiotensin Receptor Blockers: Mechanisms Agents block Angiotensin type 1 receptors (NOT angiotensin I receptors!!!) Have no effect on bradykinin metabolism Probably reduced cough and angioedema possibilities Contraindicated during pregnancy Losartan (Cozaar) and Valsartan (Diovan)

Slide 72: 

Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X X

ARB Side effects : 

ARB Side effects Hyperkalemia Precipitate renal failure in bilateral renal artery stenosis Contraindicated in patients experiencing angioedema from ACEi Contraindicated during pregnancy

ARB Efficacy : 

ARB Efficacy ADA recommends ARBs for type 2 diabetics with microalbuminuria As effective in blood pressure lowering as ACEi May reduce overall cardiovascular death in diabetics with LVH, and in non-deabetic hypertensives (LIFE) Decreases progression of microalbuminuria in type 2 diabetics Decreases mortality in CHF (ELITE)

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Indications for PharmacotherapyAdults under 60 years

Slide 76: 

Indications for PharmacotherapyAdults under 60 years

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Indications for PharmacotherapyAdults under 60 years

Indications for Pharmacotherapy Adults over 60 years : 

Indications for Pharmacotherapy Adults over 60 years

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Indications for PharmacotherapyDiabetics

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Indications for PharmacotherapyDiabetics

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Symp. Activity (alpha adrenergic activity) Baroreceptor sensitivity RAARAASS activity Plasma cortisol, catecholamine levels MBPS Thromboembolic tendency Platelet aggregation Hematocrit Fibrinogen, PAI-1 Blood viscosity Hypercoagulability Fibrinolytic activity Impaired endothelial function NO production atherosclerosis Shear stress on vascular wall Vascular tone Cardiovascular events MI Sudden cardiac death Ventricular fibrillation Ventricular tachyarrhythmia Stroke Target organ damage Hypertension 2005;45:485-86 AJH 2005; 18: 145-181