Antihypertensive Drugs Fall 09 DIURETICS only those used

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Antihypertensive Drugs Fall ‘ 09 DIURETICS (only those used for antihypertensive therapy) SYMPATHOLYTICS Peripheral

Antihypertensive Drugs Fall ‘ 09 DIURETICS (only those used for antihypertensive therapy) SYMPATHOLYTICS Peripheral adrenergic receptor blockers Centrally acting RENIN-ANGIOTENSIN SYSTEM INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin II receptor blockers VASODILATORS Ca 2+ -channel blockers Others Treatment Guidelines from The Medical Letter Drugs for Hypertension January 2009

Hypertension The most common cardiovascular disease • Affecting ~50 million people in the US

Hypertension The most common cardiovascular disease • Affecting ~50 million people in the US • Defined as sustained systolic BP 140 mm. Hg and/or • Sustained diastolic BP 90 mm. HG Causes: ~90 -95% unknown origin (essential or primary hypertension) ~5 -10% due to renal, endocrine or neurogenic disease

Risks associated with chronic elevated BP Stroke Heart Disease Heart Failure Arrhythmias Myocardial Infarcts

Risks associated with chronic elevated BP Stroke Heart Disease Heart Failure Arrhythmias Myocardial Infarcts Renal Failure

Strategies for treating hypertension Stepped care approach: • Life style changes (e. g. ,

Strategies for treating hypertension Stepped care approach: • Life style changes (e. g. , lower dietary Na+, weight loss) • Single-drug therapy • Multiple-drug therapy Careful consideration should be taken when patients present with co-morbidities: diabetes, lipid disorders, ischemic heart disease and failure, migraines, asthma, etc. . . Specific patients may respond better to certain therapies (factors include; ethnicity, age, etc…)

JDM is an 81 year old caucasian male who has been active until the

JDM is an 81 year old caucasian male who has been active until the last 6 months. He lives in New England for 4 months of the year, and in the Bahamas for the remainder of the year. He exercises every day (typically a long walk), fishes and gardens. His longstanding PCP retired last year, and complains to his new PCP that he has bouts of light headedness and elevated heart rates. His wife is a retired nurse so she makes him take his blood pressure and heart rate often. Systolic pressure is usually normal, but diastolic pressure is low. AM Meds: Digitek (digoxin) 250 mcg Verapamil SR Tab, 180 mg Hydralazine 25 mg Fish Oil 1000 units Enalapril Mal Tabs (5 mg in AM, 5 mg in PM) ASA 350 mg Chlorathalidone 25 mg Multivitamin Ester C 1000 units/ MSM 1000 units Glucosamine/chondroitin/MSM 1000 units Acetaminophen 1000 mg (for arthritis discomfort) PM Meds: Terazosin (5 mg at noon, 5 mg in PM) Hydralazine 25 mg Lipitor 10 mg Fish Oil 1000 units Flomax. 4 mg Singulair 10 mg Acetaminophen 1000 mg (for arthritis discomfort) Glucosamine/chondroitin 1000 units/ MSM 1000 units For allergies/ asthma: Advair Discus 100/50, 1 one puff in AM, PM Fluticasone, 2 puffs each nostril once a day Maxair Autohailer, q 4 -6 hr (rescue only) Claritin (generic) 10 mg Can you identify potential interactions among the drugs based on sympotoms?

= 4 SYMPATHOLYTICS VASODILATORS ANGIOTENSIN INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin II receptor

= 4 SYMPATHOLYTICS VASODILATORS ANGIOTENSIN INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin II receptor blockers Renin inhibitor DIURETICS 8 Brenner Fig 10 -1

SYMPATHOLYTICS (see Table 9 -1, Brenner) Peripheral adrenergic receptor blockers -blockers: propranolol, pindolol, metoprolol,

SYMPATHOLYTICS (see Table 9 -1, Brenner) Peripheral adrenergic receptor blockers -blockers: propranolol, pindolol, metoprolol, atenolol -blockers: prazosin ( 1 -blocker), phenoxybenzamine ( 1 - and 2 -blocker) 1 -, 2 - and 1 - blockers: carvedilol, labetalol Centrally acting drugs clonidine ( 2 -agonist) methyldopa (false transmitter) Ganglionic blockers: trimethaphan (rarely used in the US, if at all, only for hypertensive emergencies only)

Relative Receptor Affinities Alpha agonists Phenylephrine Clonidine 1> 2>>>> 2 > 1>>>> Mixed alpha

Relative Receptor Affinities Alpha agonists Phenylephrine Clonidine 1> 2>>>> 2 > 1>>>> Mixed alpha and beta agonists Norepinephrine (NE) 1= 2; 1>> 2 Epinephrine (Epi) 1= 2; 1= 2 Beta agonist Dobutamine 1> 2 >>>> Dopamine agonist Dopamine D 1=D 2>> >> modified from Katzung Table 9 -2

 1 ADH Lippincott Fig 19 -7

1 ADH Lippincott Fig 19 -7

Not on same tissue vasoconstriction (NE) vasodilation Presynaptic inhibition (Epi) of NE release NE

Not on same tissue vasoconstriction (NE) vasodilation Presynaptic inhibition (Epi) of NE release NE blood glucose (from muscle and liver) Brenner Fig 8 -1 bronchodilation + inotropic + chronotropic

See Drugs for angina and heart failure for details -Adrenergic Receptor Blockers Non-selective: 1

See Drugs for angina and heart failure for details -Adrenergic Receptor Blockers Non-selective: 1 -, 2 -blocker propranolol Selective: 1 -blocker metoprolol, atenolol 1 -, 2 - and 1 - blocker: carvedilol, labetalol both indicated for hypertension carvedilol also approved for heart failure patients Note: Nebivolol (approved 1/08) 1 -blocker with antioxidant and increases endothelial nitric oxide release (vasodilator)

 -blockers: Prazosin Selective 1 -blockers • TPR because of vasodilation (not typically first

-blockers: Prazosin Selective 1 -blockers • TPR because of vasodilation (not typically first line drugs) • No adverse metabolic or lipid effects **therefore, advantage over –blockers with co-morbidities • Side effects: (Why might these be expected? ) Postural hypotension (especially after first dose) Occasional reflex tachycardia – tries to compensate Fluid retention Doxazosin significant increase in CHF compared to diuretics alone (ALLHAT) perhaps because of fluid retention

Intact feedback inhibition of NE release by 2 receptors vascular 1 receptors Prazosin 1

Intact feedback inhibition of NE release by 2 receptors vascular 1 receptors Prazosin 1 Brenner Fig 9 -4 unless dose is too high

= ? blockers TPR Before After CO MAP Brenner Fig 9 -3 = ?

= ? blockers TPR Before After CO MAP Brenner Fig 9 -3 = ? blockers

Centrally acting sympatholytics: TPR Clonidine ( 2 -agonist) For severe, refractory hypertension Side effects

Centrally acting sympatholytics: TPR Clonidine ( 2 -agonist) For severe, refractory hypertension Side effects include: sedation, dry mouth, and rebound hypertension upon withdrawal after chronic use -Methyldopa (false neurotransmitter) Chronic therapy Replaces NE: Less effective for stimulating 1 -receptors More effective for stimulating 2 -receptors

*Clonidine * X 2 X -Methyldopa Brenner Fig 8 -1

*Clonidine * X 2 X -Methyldopa Brenner Fig 8 -1

RENIN-ANGIOTENSIN SYSTEM INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors: Captopril, Lisinopril (many on the market:

RENIN-ANGIOTENSIN SYSTEM INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors: Captopril, Lisinopril (many on the market: enalapril, ramipril. . . ) Angiotensin II receptor blockers (ARBs): Losartan (many on the market: candesartan, irbesartan, valsartan. . . ) Direct renin inhibitor (DRI): Aliskiren Examples of indications and clinical uses: Mild/moderate essential hypertension Heart Failure (especially early stages) Diabetic nephropathy!!!!

PGs = prostaglandins PGs + NO Brain Antidiuretic Hormone (ADH = vasopressin) H 2

PGs = prostaglandins PGs + NO Brain Antidiuretic Hormone (ADH = vasopressin) H 2 O retention & vasoconstriction (AT 1) Na+ retention modified Brenner Fig 10 -3

ACE-Inhibitors • Differ in their pharmacokinetics Half-life (T 1/2), metabolism • No adverse effects

ACE-Inhibitors • Differ in their pharmacokinetics Half-life (T 1/2), metabolism • No adverse effects on lipid profiles or glycemic control • All have cardioprotection independent of BP especially in CAD patients (HOPE Trials, NEJM 2000) • Also effective in reducing vascular complications associated with diabetes (type 1 definitely, maybe type 2) especially effective with nephropathies (via anti-inflammatory mechanisms? ) Captopril (prototype) • Highest oral bioavailability • Shortest t 1/2 How would this affect dosing? Less effective in blacks unless combined with thiazide diuretics (Medline 2003; Circulation 2005; 112: 3654 -3666)

ACE-Inhibitors (con’t) Side effects related to: Suppression of angiotensin II (Ang. II) (hypotension and

ACE-Inhibitors (con’t) Side effects related to: Suppression of angiotensin II (Ang. II) (hypotension and renal insufficiency) Increased in bradykinin (cough and edema) Why? Also: Hyperkalemia (caution with K+ sparing diuretics) Fetotoxic (do not use with pregnancies) Renal failure (with bilateral renal a. stenosis) Bonus: Bradykinin stimulates vasodilation and Prostraglandin/NO vasodilation (high doses of NSAIDs may interfere with PGI 2 -mediated vasodilation)

Losartan Blocks Ang. II from binding to AT 1 receptors Allows AT 2 receptors

Losartan Blocks Ang. II from binding to AT 1 receptors Allows AT 2 receptors to be stimulated by circulating Ang. II (promoting vasodilation? ? ) Relatively few side effects less cough than with ACE-I but fetotoxic like ACE-I Diabetes: slows progression of nephropathy (RENNAAL) Cardioprotection (maybe? ? ): reduces cardiac remodeling Typically reserved for patients who do not tolerate ACE-I Some evidence ACE 2 metabolizes Ang. II to Ang 1 -7 (a vasodilator), and there are non-ACE sources of Ang. II, therefore ARB’s might be more effective than ACE-I (stay tuned, more data is needed) Less effective antihypertensive in blacks (same as with ACE-I)

Aliskiren: Direct renin inhibitor (DRI) New class of nonpeptide, oral inhibitor Binds to a

Aliskiren: Direct renin inhibitor (DRI) New class of nonpeptide, oral inhibitor Binds to a site on renin, preventing formation of angiotensin (Ang) I Lowers plasma renin activity, Ang II, and aldosterone Safety and tolerance appear similar to ACE-I and ARBs Significance of inhibiting renin? ACE-I and ARBs may increase renin (because no negative feedback) Hydrochlorothiazides also increase renin Pro(renin) receptors were recently identified • Activate MAP kinases and profibrotic signaling • May be involved in vascular remodeling (e. g. , with diabetes)

VASODILATORS Ca 2+ -channel blockers: DHPs: amlodipine, nifedipine Diltiazem Verapamil Others: less frequently used

VASODILATORS Ca 2+ -channel blockers: DHPs: amlodipine, nifedipine Diltiazem Verapamil Others: less frequently used for chronic Tx Hydralazine Minoxidil Note: nitrates not used for chronic hypertension. Tx sodium nitroprusside (SNP): used for hypertensive emergencies and surgery) (cyanide toxicity due to metabolite – obsolete story)

VASODILATORS (con’t) • Promote vascular smooth muscle relaxation, TPR • Most (not all) produce

VASODILATORS (con’t) • Promote vascular smooth muscle relaxation, TPR • Most (not all) produce concomitant reflexes if not dosed properly: cardiac contractility and HR myocardial O 2 consumption renin-angiotensin-aldosterone system • Usually no effects on serum lipids Why would this be an advantage over other drugs such as -blockers?

Ca 2+ channel blockers (CCBs) Site of action dependent on tissue selectivity • Verapamil

Ca 2+ channel blockers (CCBs) Site of action dependent on tissue selectivity • Verapamil most cardiac selective (nodal cells and myocytes) • Diltiazem intermediate selectivity • Dihydropyridines (DHPs) most vascular selective All have some coronary vasodilatory effects Which is most likely used for antihypertensive therapy? Which is most likely to cause reflex tachycardia? See also Angina drug & Antiarrhythmic drug lectures

Toxicities associated with DHPs (selected) Short acting DHPs Immediate-release nifedipine, nisoldipine, felodipine May cause

Toxicities associated with DHPs (selected) Short acting DHPs Immediate-release nifedipine, nisoldipine, felodipine May cause reflex tachycardia Longer acting DHPs Sustained-release nifedipine, amlodipine, isradipine Do not cause significant increases in HR (neither do verapamil or diltiazem) Why? Side effects of DHPs include: • Headaches • Peripheral edema Doses to achieve BP goals will likely differ from anti-anginal goals, therefore side effects may be different

Hydralazine and Minoxidil • Typically reserved for severe hypertension • Often co-administered with a

Hydralazine and Minoxidil • Typically reserved for severe hypertension • Often co-administered with a diuretic and/or -blocker • Dilates arterioles, not veins contraindicated for patients with angina, ischemic heart disease Hydralazine • May act by increasing c. GMP (similar to NO) (in combination with isosorbide dinitrate – see HF lecture) Minoxidil (oral, not topical) • Opens KATP channels, thus hyperpolarizes cells

Vascular Smooth Muscle Cell sites of antihypertensive CCB drug action DHP hibitor ARB Losartan

Vascular Smooth Muscle Cell sites of antihypertensive CCB drug action DHP hibitor ARB Losartan A 1 Blocker Prazosin NE Sildenafil c. GMP PDE 5 inhibitor (not used for systemic hypertension, but maybe pulmonary arterial hypertension) blocker agonist Ca 2+ Minoxidil 1 AII AT 1 K+ATP Ca 2+ SR Ca 2+ PDE GMP contraction MLCK PDE c. AMP 2 Hydralazine Endothelial cell NO PDE = phosphodiesterase Epi Acetylcholine Bradykinin

DIURETICS: (those used for antihypertensive therapy) • Thiazide diuretics: hydrochlorothiazide • Loop diuretics: furosemide

DIURETICS: (those used for antihypertensive therapy) • Thiazide diuretics: hydrochlorothiazide • Loop diuretics: furosemide • Potassium-sparing diuretics: amiloride, spironolactone, eplerenone Discussed previously

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Int Med 2008,

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Int Med 2008, 168(2) update Thiazides are DOC in hypertensive patients with metabolic syndrome No evidence that ACEI, CCB, alpha blockers offer any advantage of clinical outcomes over thiazides in these patients (particularly in blacks with metabolic syndrome) chlorthalidone, lisinopril, amlodipine, doxazosin Doxazosin arm stopped early because of increased CV events, with 2 x more HF compared to thiazide group

JNC VII Compelling Indications for Drug Classes Compelling Indication Initial Therapy Options Clinical-Trial Basis

JNC VII Compelling Indications for Drug Classes Compelling Indication Initial Therapy Options Clinical-Trial Basis Heart Failure Diuretic, BB, ACEI, ARB, Aldo Ant MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-He. FT, RALES Post-MI BB, ACEI, Aldo Ant ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS High CAD Risk Diuretic, BB, ACEI, CCB ALLHAT, HOPE, ANBP 2, LIFE, CONVINCE Diabetes Mellitus ACEI, Diuretic, BB, ARB, CCB Chronic Kidney Disease ACEI, ARB Recurrent Stroke Prevention Diuretic, ACEI NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction Chobanian AV et al. JAMA. 2003; 289: 2560 -2572

Clinical considerations: Most effective treatment, ethnicity differences* Least side effects (most patients are asymptomatic)

Clinical considerations: Most effective treatment, ethnicity differences* Least side effects (most patients are asymptomatic) Frequency of dosing Cost Fixed-drug combinations: -blocker and thiazide diuretic ACE inhibitor and thiazide diuretic AII receptor blocker and diuretic Ca 2+ channel blocker and ACE inhibitor What are advantages and disadvantages of fixed-drug combinations?

Presence of co-morbidities (considerations) Thiazide diuretics and -blockers: • Often used in combination •

Presence of co-morbidities (considerations) Thiazide diuretics and -blockers: • Often used in combination • However, both may adversely affect lipid profiles and insulin sensitivity (exaccerbate CAD, atherosclerosis, type 2 diabetes) ACE inhibitors: • May also be beneficial for diabetic nephropathies ACE inhibitors and diuretics: • Useful for patients with CHF -blockers or Ca 2+ channel blockers: • Useful for patients with angina Diuretics and Ca 2+ channel blockers: • Blacks respond better to each, rather than to -blockers and ACE inhibitors

Antihypertensive Targets (-) ARBs = angiotensin receptor blockers; AT-1 = angiotensin II sub-type 1;

Antihypertensive Targets (-) ARBs = angiotensin receptor blockers; AT-1 = angiotensin II sub-type 1; DHPs = dihydropyridines; SVR = systemic vascular resistance. (LH Opie, 2004. )

Guidelines for treatment and prevention of hypertension are published by the Joint National Committee

Guidelines for treatment and prevention of hypertension are published by the Joint National Committee (JNC) on the Detection, Prevention and Treatment of Hypertension http: //www. nhlbi. nih. gov/guidelines/hypertension/ Guidelines and updates (including power point presentations, treatment algorhythms, etc…) can be found (free) through the NHLBI website http: //www. nhlbi. nih. gov/health/prof/heart/index. htm#hbp