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  • Slide 1
  • 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 Antihypertensive Drugs Treatment Guidelines from The Medical Letter Drugs for Hypertension January 2009 Fall 09
  • Slide 2
  • Hypertension The most common cardiovascular disease Affecting ~50 million people in the US Defined as sustained systolic BP 140 mmHg and/or Sustained diastolic BP 90 mmHG Causes: ~90-95% unknown origin (essential or primary hypertension) ~5-10% due to renal, endocrine or neurogenic disease
  • Slide 3
  • Risks associated with chronic elevated BP Heart Disease Heart Failure Arrhythmias Myocardial Infarcts Stroke Renal Failure
  • Slide 4
  • 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)
  • Slide 5
  • AM Meds: Digitek (digoxin) 250 mcg Verapamil SR Tab, 180 mg Hydralazine 25mg Fish Oil 1000 units Enalapril Mal Tabs (5 mg in AM, 5mg in PM) ASA 350mg Chlorathalidone 25mg 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, 5mg in PM) Hydralazine 25mg Lipitor 10mg Fish Oil 1000 units Flomax.4mg Singulair 10mg 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, q4-6hr (rescue only) Claritin (generic) 10mg 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. Can you identify potential interactions among the drugs based on sympotoms?
  • Slide 6
  • Brenner Fig 10-1 == 4 SYMPATHOLYTICS VASODILATORS ANGIOTENSIN INHIBITORS Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin II receptor blockers Renin inhibitor DIURETICS 8
  • Slide 7
  • 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)
  • Slide 8
  • Relative Receptor Affinities Alpha agonists Phenylephrine 1 > 2 >>>> Clonidine 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
  • Slide 9
  • Lippincott Fig 19-7 ADH 11
  • Slide 10
  • Brenner Fig 8-1 Presynaptic inhibition of NE release vasodilation (Epi) vasoconstriction (NE) + inotropic + chronotropic NE blood glucose (from muscle and liver) bronchodilation Not on same tissue
  • Slide 11
  • -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 See Drugs for angina and heart failure for details Note: Nebivolol (approved 1/08) 1 -blocker with antioxidant and increases endothelial nitric oxide release (vasodilator)
  • Slide 12
  • 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 -blockers: Prazosin
  • Slide 13
  • Brenner Fig 9-4 Prazosin Intact feedback inhibition of NE release by 2 receptors unless dose is too high vascular 1 receptors 11
  • Slide 14
  • = ? blockers Brenner Fig 9-3 TPR CO MAP Before After
  • Slide 15
  • -Methyldopa (false neurotransmitter) Chronic therapy Replaces NE: Less effective for stimulating 1 -receptors More effective for stimulating 2 -receptors 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
  • Slide 16
  • -Methyldopa * *Clonidine X X 22 Brenner Fig 8-1
  • Slide 17
  • 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!!!!
  • Slide 18
  • Antidiuretic Hormone (ADH = vasopressin) Brain (AT 1 ) H 2 O retention & vasoconstriction Na + retention PGs NO + modified Brenner Fig 10-3 PGs = prostaglandins
  • Slide 19
  • 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?) Less effective in blacks unless combined with thiazide diuretics (Medline 2003; Circulation 2005; 112:3654-3666) Captopril (prototype) Highest oral bioavailability Shortest t 1/2 How would this affect dosing?
  • Slide 20
  • ACE-Inhibitors (cont) Side effects related to: Suppression of angiotensin II (AngII) (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)
  • Slide 21
  • Losartan Blocks AngII from binding to AT 1 receptors Allows AT 2 receptors to be stimulated by circulating AngII (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 ACE2 metabolizes AngII to Ang1-7 (a vasodilator), and there are non-ACE sources of AngII, therefore ARBs might be more effective than ACE-I (stay tuned, more data is needed) Less effective antihypertensive in blacks (same as with ACE-I)
  • Slide 22
  • 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 I, 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)
  • Slide 23
  • 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 hypertensionTx sodium nitroprusside (SNP): used for hypertensive emergencies and surgery) (cyanide toxicity due to metabolite obsolete story)
  • Slide 24
  • VASODILATORS (cont) 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?
  • Slide 25
  • Ca 2+ channel blockers (CCBs) Site of action