Pharmacological_treatment_of_HT_PDF.pdf

Pharmacological Treatment of Hypertension MD3001 Dr. Morag K. Mansley School of Medicine Please log onto Vevox polling: or via vevox.app ID: 128-738-822 OVERVIEW • TREATMENT OF HYPERTENSION • NICE GUIDELINES • ANTIHYPERTENSIVE THERAPEUTICS: i. ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS...

Pharmacological Treatment of Hypertension MD3001 Dr. Morag K. Mansley School of Medicine Please log onto Vevox polling: or via vevox.app ID: 128-738-822 OVERVIEW • TREATMENT OF HYPERTENSION • NICE GUIDELINES • ANTIHYPERTENSIVE THERAPEUTICS: i. ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) ii. DIURECTICS iii. CALCIUM CHANNEL BLOCKERS iv. b1-ADRENOCEPTOR ANTAGONISTS • RESISTANT HYPERTENSION • LEARNING OBJECTIVES WHEN TO TREAT HYPERTENSION? WHEN TO TREAT HYPERTENSION? DIAGNOSIS (REMINDER): • • Clinic BP AND ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) average day time • • End organ damage? Secondary hypertension diagnosis? STAGE 1 HYPERTENSION • • • • • End organ damage? (<80 years old?) Cardiovascular disease? Renal disease? Diabetes? 10 year CV risk of ≥10% STAGE 2 HYPERTENSION No • Lifestyle modifications • Monitor BP Yes • Lifestyle modifications • Therapeutic interventions TREATMENT STRATEGIES LIFESTYLE MODIFICATIONS • Weight loss • Reduced salt (Na+) intake <6g/day • Reduced alcohol consumption • Increased aerobic exercise • Increased fruit and vegetable intake • Smoking cessation • (Stress reduction / relaxation techniques) TREATMENT OF HYPERTENSION THERAPEUTICS: • Angiotensin converting enzyme inhibitors (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Diuretics • Calcium channel blockers (CCBs) • b1-adrenergic receptor blockers NICE / BRITISH HYPERTENSION SOCIETY GUIDELINES With diabetes STEP 1 <55 years old >55 years old A C* STEP 2 A + C* STEP 3 A+C+D STEP 4 RESISTANT HYPERTENSION A + C + D + further diuretic** OR b1 blocker -seek specialist advice A – ACE inhibitor / ARB African/Caribbean descent C – Ca2+ channel blocker *where C is not tolerated, replace with D **low dose spironolactone or >D D – Thiazide diuretic BLOOD PRESSURE TARGETS *Rockwood Frailty Score nice.org.uk BLOOD PRESSURE CONTROL (REMINDER) Cardiac output: The heart Total peripheral resistance: Blood vessels http://healthfavo.com http://upload.wikimedia.org The brain The kidneys http://i.telegraph.co.uk/multimedia/archive TREATMENT OF HYPERTENSION •Antihypertensive drugs: • Angiotensin converting enzyme inhibitors (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Thiazide diuretics • K+ sparing diuretics • a-adrenergic receptor blocker • b-adrenergic receptor blocker • Calcium channel blockers (CCBs) National Institute for Health and Care Excellence (NICE). Clinical management of primary hypertension in adults. August 2011. guidance.nice.org.uk/cg127 Filtration / reabsorption in the kidney Reabsorption (as well as secretion) of ions, solutes and water occurs along the length of the tubule Blood is filtered at the glomerulus Ultrafiltrate enters tubule and flows along distinct segments Reminder: movement of Na+ important for determining blood volume. Excretion must match intake (balance). Remainder of ultrafiltrate flows to bladder and will leave as urine Na+ reabsorption in the kidney Distal convoluted tubule (DCT) Cortical collecting duct (CCD) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Na+ is reabsorbed in distinct segments along the tubule of the nephron • Creates an osmotic gradient for H2O to follow TREATMENT OF HYPERTENSION •Antihypertensive drugs: • Angiotensin converting enzyme inhibitors (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Thiazide diuretics • K+ sparing diuretics • a-adrenergic receptor blocker • b-adrenergic receptor blocker • Calcium channel blockers (CCBs) National Institute for Health and Care Excellence (NICE). Clinical management of primary hypertension in adults. August 2011. guidance.nice.org.uk/cg127 ANGIOTENSIN II AT1 receptors Vascular smooth muscle cells of blood vessels Hypothalamus Vasoconstriction release of vasopressin (ADH) TPR reabsorption H2O in kidneys ECV Zona glomerulosa of adrenal glands Renal tubules of the kidney stimulates secretion of aldosterone from adrenal glands Na+ reabsorption in the kidney ECV ANGIOTENSIN II – salt retention Distal convoluted tubule (DCT) Cortical collecting duct (CCD) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle ANGIOTENSIN II – salt retention Distal convoluted tubule (DCT) Cortical collecting duct (CCD) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Angiotensin II stimulates Na+ absorption, particularly in the proximal convoluted tubule (PCT) ANGIOTENSIN II – salt retention Distal convoluted tubule (DCT) Proximal convoluted tubule (PCT) Cortical collecting duct (CCD) Thick Ascending Limb (TAL), Loop of Henle Angiotensin II stimulates Na+ absorption, particularly in the proximal convoluted tubule (PCT) • Ang II stimulates aldosterone release which further stimulates Na+ reabsorption in the cortical collecting duct (CCD) • ACE INHIBITORS • First or second line anti-hypertensive treatment • e.g. ramipril, captopril, enalapril, perindopril, lisinopril Angiotensin I Angiotensin converting enzyme (ACE) Angiotensin II 1. Vasoconstriction TPR 2. 3. Water retention Na+ retention ECV ECV BP *1st and 2nd choice drugs as per Fife formulary ACE: BRADYKININ • ACE is involved in another process: • • • • B2 receptors Kininogen the kinin-kallikrein system Kallikrein cleaves kininogen to Bradykinin Bradykinin is a vasodilator ACE breaks down bradykinin into an inactive metabolite Vasodilation • PGI2 production • NO production Kallikrein Bradykinin Angiotensin converting enzyme (ACE) Inactive metabolite ACE INHIBITORS • First or second line anti-hypertensive treatment • e.g. ramipril, captopril, enalapril, perindopril, lisinopril Angiotensin I Bradykinin Angiotensin converting enzyme (ACE) Angiotensin converting enzyme (ACE) Inactive metabolite Angiotensin II Vasoconstriction TPR Water retention ECV Salt retention ECV Vasodilation TPR BP N.B. Increased bradykinin can cause bronchoconstriction which can give rise to a dry cough. Often patients are then prescribed an ARB instead. ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) • Also first or second line anti-hypertensive treatment • e.g. losartan, irbesartan, valsartan, olmesartan, candesartan Angiotensin I Bradykinin Angiotensin converting enzyme (ACE) Angiotensin II Angiotensin converting enzyme (ACE) Inactive metabolite AT1 receptors Vasoconstriction TPR Water retention ECV Na+ retention ECV • Due to specific effects on AT1 receptors, there are no effects on bradykinin, therefore no side-effect of cough BP TREATMENT OF HYPERTENSION •Antihypertensive drugs: • Angiotensin converting enzyme (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Thiazide diuretics • K+ sparing diuretics • a-adrenergic receptor blocker • b-adrenergic receptor blocker • Calcium channel blockers (CCBs) National Institute for Health and Care Excellence (NICE). Clinical management of primary hypertension in adults. August 2011. guidance.nice.org.uk/cg127 DIURETICS • Diuretics – substances that help the body get rid of water (target Na+ absorption to do this) • Reduce blood pressure by decreasing ECV 1. LOOP DIURETICS 2. THIAZIDE DIURETICS 3. K+ SPARING DIURETICS LOOP DIURETICS Distal convoluted tubule (DCT) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Most powerful class of diuretic • “torrential urine flow” • e.g. Furosemide, Bumetanide Cortical collecting duct (CCD) LOOP DIURETICS Distal convoluted tubule (DCT) NKCC2 Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Most powerful class of diuretic • “torrential urine flow” • e.g. Furosemide, Bumetanide Cortical collecting duct (CCD) • Only used in treatment of hypertension where renal function is impaired • Sometimes used in other fluid overload conditions e.g. heart • Inhibits the NKCC2 (Na+/K+/2Cl- co-transporter) in TAL LoH failure THIAZIDE DIURETICS Distal convoluted tubule (DCT) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Less powerful than loop diuretics • e.g. Bendroflumethiazide, Indapamide, Hydrochlorothiazide Cortical collecting duct (CCD) Hydrochlorothiazide THIAZIDE DIURETICS Distal convoluted tubule (DCT) Hydrochlorothiazide NCC Proximal convoluted tubule (PCT) Cortical collecting duct (CCD) Thick Ascending Limb (TAL), Loop of Henle • Less powerful than loop diuretics • Inhibits the NCC in the DCT • e.g. Bendroflumethiazide, Indapamide, Hydrochlorothiazide (Na+/Cl- co-transporter) • 2nd / 3rd line treatment K+ SPARING DIURETICS Distal convoluted tubule (DCT) Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle • Limited diuretic action alone, but powerful in combination with loop/thiazide diuretics Cortical collecting duct (CCD) K+ SPARING DIURETICS Distal convoluted tubule (DCT) ENaC Proximal convoluted tubule (PCT) Thick Ascending Limb (TAL), Loop of Henle Cortical collecting duct (CCD) 2 types: Aldosterone antagonists • Spironolactone, eplerenone ENaC inhibitors Limited diuretic action alone, but • Amiloride, triamterene powerful in combination with loop/thiazide diuretics • Rarely used due to also blocking K+ excretion (coupled to ENaC), causing • Inhibits ENaC in the CCD hyperkalaemia (K+ sparing) (Epithelial Na+ channel) • TREATMENT OF HYPERTENSION •Antihypertensive drugs: • Angiotensin converting enzyme (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Thiazide diuretics • Spironolactone and K+ sparing diuretics • a-adrenergic receptor blocker • b-adrenergic receptor blocker • Calcium channel blockers (CCBs) National Institute for Health and Care Excellence (NICE). Clinical management of primary hypertension in adults. August 2011. guidance.nice.org.uk/cg127 CALCIUM CHANNEL BLOCKERS (CCBs) • Inhibits contraction • Cardiac muscle • Vascular smooth muscle CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Na+ Ca+ Ca+ T-type VGCC Ca+ Ca+ Na+ Na+ Ca+ Na+ L-type VGCC Na+ Na+ K K+ + Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K Gap junction K+ K+ K+ Na+ K+ K+ Na+ K+ K+ Kleak Ca+ Na+ K+ Na+ K+ K+ Ca+ Na+ Na+ Na+ K+ K+ Na+ CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Na+ Ca+ Ca+ T-type VGCC Ca+ Ca+ Na+ Na+ Ca+ Na+ L-type VGCC Na+ Na+ K K+ + Na+ Gap junction K+ Na+ K+ K+ Ca+ Ca+ Na+ K+ K+ Na+ K+ Na+ K+ K+ Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K K+ K+ Kleak Ca+ Na+ Na+ Ca+ Na+ Na+ Na+ K+ K+ Na+ • Na+ enters cell via slow Na+ channel in pacemaker cell (funny current) • Small depolarisation CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Ca+ Ca+ T-type VGCC Ca+ Ca+ Na+ Na+ Ca+ Na+ L-type VGCC Na+ Na+ K K+ + Na+ Gap junction K+ Na+ K+ K+ Ca+ Ca+ Ca+ Na+ K+ K+ Na+ K+ Na+ K+ K+ Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K K+ K+ Kleak Ca+ Na+ Na+ Ca+ Na+ Na+ Na+ K+ K+ Na+ • Ca2+ enters cell via T-type voltage gated Ca2+ channel (VGCC) • Further depolarisation CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Gap junction Na+ Ca+ Ca+ Ca+ Ca+ + K + + Na K Na+ K+ K+ Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K K+ K+ Kleak Na+ K+ Ca+ Na+ Na+ Na+ K+ K+ Na+ • Ca2+ enters cell via L-type voltage gated Ca2+ channel (VGCC) • Large depolarisation Na+ + Na+ K+ Na+ K Ca+ Ca+ Na+ Na+ Ca+ Na+ L-type VGCC Ca+ K+ K+ Ca+ Ca+ Na+ Ca+ T-type VGCC Na+ K+ Na+ Ca+ CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Gap junction Na+ K+ K+ Na+ Na+ Ca+ Na+ L-type VGCC Ca+ Ca+ Ca+ Ca+ + K + + Na K Ca+ K+ K+ Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K K+ K+ Kleak Na+ K+ Na+ + Na+ K+ Na+ K Ca+ Ca+ Na+ Ca+ Ca+ Na+ Ca+ T-type VGCC Na+ K+ Na+ Ca+ Ca+ Na+ • Depolarisation spreads through gap junctions • To both pacemaker and contractile cells Na+ Na+ K+ K+ Na+ CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Gap junction Na+ K+ K+ Na+ Na+ Ca+ Na+ L-type VGCC Ca+ Ca+ Ca+ Ca+ + K + + Na K Ca+ K+ K+ • Depolarisation occurs in neighbouring cell Ca+ Ca+ Ca+ SR Ca+Ca+ K+ + + Na K K+ K+ Kleak Na+ K+ Na+ + Na+ K+ Na+ K Ca+ Ca+ Na+ Ca+ Ca+ Na+ Ca+ T-type VGCC Na+ K+ Na+ Ca+ Ca+ Na+ Na+ Na+ K+ K+ Na+ CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Gap junction Na+ K+ K+ Na+ Na+ Ca+ Na+ L-type VGCC Ca+ Ca+ Ca+ Ca+ + K + + Na K Ca+ K Ca+ + Na+ K+ K+ K+ Kleak Ca+ Na+ Ca+ Ca+ Na+ Ca+ T-type VGCC Na+ K+ Na+ Ca+ Na+ K+ K+ Ca+ Na+ Na+ Ca+ K+ Ca+ + Ca+ Ca+ SR Ca Ca+Ca+ Ca+ K+ + + Na K Ca+ Na+ Na+ Na+ K+ K+ Na+ • Contractile cells also contain L-type Ca2+ channels • Ca2+ is further released from sarcoplasmic reticulum (SR) via RyRs CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Ca+ T-type VGCC Na+ Gap junction K+ Na+ Ca+ Na+ K+ K+ Na+ Na+ Na+ Ca+ L-type VGCC Ca+ Ca+ Ca+ Ca+ Ca+ + K + + Na K Ca+ K+ Na+ K+ K+ Na+ Na+ Kcontraction Ca+ K+ + Ca+ Na+ Ca+ + Ca+ Ca+ SR Ca Ca+Ca+ Ca+ + K+ + K + Na K K+ Kleak Ca+ Na+ Ca+ Ca+ Na+ Ca+ Na+ • This causes CONTRACTION of the cardiomyocyte Na+ Na+ K+ K+ Na+ CALCIUM IN THE HEART Na+ Na+ Na+ Na+ Ca+ Slow Na+ (If) Ca+ T-type VGCC Na+ Gap junction K+ Na+ Ca+ Na+ K+ K+ Na+ Na+ Na+ Ca+ L-type VGCC Ca+ Ca+ Ca+ Ca+ Ca+ + K + + Na K Ca+ K+ Na+ K+ K+ Na+ Na+ Kcontraction Ca+ K+ + Ca+ Na+ Ca+ + Ca+ Ca+ SR Ca Ca+Ca+ Ca+ + K+ + K + Na K K+ Kleak Ca+ Na+ Ca+ Ca+ Na+ Ca+ Na+ Na+ Na+ K+ K+ Na+ Calcium channel blockers (CCBs) inhibit L-type voltage gated Ca2+ channels Same concept in vascular smooth muscle contraction CALCIUM CHANNEL BLOCKERS (CCBs) NON-DIHYDROPYRIDINES Phenylalkylamines Verapamil DIHYDROPYRIDINES Benzothiazepines Diltiazem Amlodipine Felodipine Nicardipine Nimodipine CARDIAC EFFECTS: SMOOTH MUSCLE: • contractility • coronary artery constriction • • heart rate conduction velocity CO • peripheral vessel constriction BP TPR TREATMENT OF HYPERTENSION •Antihypertensive drugs: • Angiotensin converting enzyme (ACE inhibitors) • Angiotensin II receptor blockers (ARBs) • Thiazide diuretics • K+ sparing diuretics • a-adrenergic receptor blocker • b-adrenergic receptor blocker • Calcium channel blockers (CCBs) National Institute for Health and Care Excellence (NICE). Clinical management of primary hypertension in adults. August 2011. guidance.nice.org.uk/cg127 SYMPATHETIC NERVOUS SYSTEM (REMINDER) Sympathetic neurotransmitters: NORADRENALINE ADRENALINE Bind adrenoceptors: a1 a1 - Vascular smooth muscle a2 a2 - Brain (vascular smooth muscle) b1 b1 - Heart b2 b2 - Vascular smooth muscle b-ADRENOCEPTOR ANTAGONISM • non-selective b-adrenoceptor antagonists have side effects • E.g. bronchoconstriction, important in asthmatics • b1-selective antagonists: • Bisoprolol, Atenolol HR/force of contraction • • BP Also inhibits renin release from granular cells Ang II • CO Atenolol vasoconstriction & Na+ and H2O retention TPR ECF BP Why are b-blockers not first line treatment? • • Less effective than comparators in reducing CV risk Less effective than ACEis and CCBs at reducing risk of diabetes • Less well tolerated than ACE inhibitors/ARBs However, they are useful for antihypertensive patients with additional need for b-blockade including angina or heart failure NICE / BRITISH HYPERTENSION SOCIETY GUIDELINES With diabetes STEP 1 <55 years old African/Caribbean descent >55 years old A C* *where C is not tolerated, replace with D STEP 2 A + C* STEP 3 A+C+D STEP 4 RESISTANT RESISTANT HYPERTENSION HYPERTENSION A A+ +C C+ +D D+ + further further diuretic** diuretic** OR b1 blocker OR alpha blockerOR beta blocker -seek specialist advice A – ACE inhibitor / ARB C – Ca2+ channel blocker **low dose spironolactone or >D D – Thiazide diuretic SIDE EFFECTS ARBs Dizziness CALCIUM CHANNEL BLOCKERS Flushes Headaches Ankle oedema Dizziness Headaches ACE inhibitors Persistent dry cough Dizziness Tiredness Headaches THIAZIDE DIURETICS Back/leg pain Hyperkalaemia Renal impairment Avoid in bilateral artery stenosis Teratogenic Hypokalaemia Risk of angioedema (Afro-Caribbean ) Hyponatraemia Risk of hyperkalaemia K+ SPARING DIURETICS Gout Renal impairment Hyperkalaemia Impotence Avoid in bilateral artery stenosis Renal impairment Monitor for dehydration teratogenic GI upset Ineffective in moderate to severe renal impairement Spironolactone – oestrogen related side effects LEARNING OUTCOMES TO DESCRIBE THE STEPPED PHARMACOLOGICAL MANAGEMENT OF HYPERTENSION TO UNDERSTAND THE MECHANISM AND ACTION OF: ACE INHIBITORS AND ARBs DIURETICS CALCIUM CHANNEL BLOCKERS b1-ADRENOCEPTOR ANTAGONISTS