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Pharmacology of Hypertension

Pharmacology of Hypertension. Vicki Groo , Pharm.d . Clinical Associate Professor Clinical pharmacist, heart center. vjust@uic.edu 413-0928. objectives. Classify hypertension and define treatment goals

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Pharmacology of Hypertension

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  1. Pharmacology of Hypertension Vicki Groo, Pharm.d. Clinical Associate Professor Clinical pharmacist, heart center vjust@uic.edu 413-0928

  2. objectives • Classify hypertension and define treatment goals • Be able to describe the pharmacology of oral antihypertensives with considerations in drug choice and compelling indications • Be able to describe the pharmacology of intravenous antihypertensives used in the treatment of hypertensive emergency

  3. CLASSIFICATION **Adults (18 yo) **Avg of 2 readings, 2 mins apart, on 2 occasions Secondary HTN only accounts for 5-10% of population JAMA 2003;289:2560-2572

  4. epidemiology • 31% of US population with HTN • 30% of US population with pre-HTN • Present in: • 69% of patients who present with 1st MI • 77% of patients who present with 1st stroke • 74% of patients with heart failure • Only 47% have BP under control • http://www.cdc.gov/bloodpressure/facts.htm

  5. National Health & Nutrition Examination Survey 2007-2008 81% 73% 50%

  6. TREATMENT GOALS JNC-7 • REDUCE MORBIDITY AND MORTALITY • Measurable goal: • Prehypertension: <120/80 • HTN w/ diabetes or renal disease: <130/80 • Others: <140/90 • Minimize/ control other CV risk factors • Reduce/ minimize adverse drug effects JAMA 2003;289:2560-2572

  7. AHA BP targets 2007: • For prevention and management of ischemic heart disease: *Don’t worry about learning these for now. They may change Circulation 2007:115:2761-88

  8. Without Compelling Indications With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist. Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices JNC VII JAMA 2003;289:2560-2572

  9. Drug Therapy Considerations • Clinical trial data • Over 2/3 of patients will require ≥2 drugs • Cost/ adverse effects • JAMA 2003;289:2560-2572

  10. Limit salt intake Physical activity Lifestyle Modifications DASH eating Plan Lose weight Limit alcohol intake

  11. Pharmacology of Antihypertensives • Diuretics: • Deplete sodium thereby decreasing blood volume • Agents that block production or action of angiotensin • Reduce peripheral vascular resistance • Potentially ↓ blood volume • Sympathoplegic agents: • ↓ peripheral vascular resistance • Inhibit cardiac function • ↑ venous pooling in capacitance vessels • Direct vasodilators: • Relax vascular smooth muscle, thus dilating resistance vessels

  12. Diuretic moa

  13. Diuretic Comparison P = 0.054 and 0.009 for 24 hr and pm BP respectively Indapamide Hypertension 2004;43:4-9,

  14. Diuretic Considerations Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

  15. diuretics • Compelling Indications: • Heart Failure • High CAD risk • Diabetes • Recurrent Stroke Prevention • Monitoring • Electrolytes after initiation or dose increases • Every 6-12 months • K sparing, every 3 months if also on RAAS inhibitor • Side Effects • Increase glucose • Increase uric acid— precipitate gout • dehydration— orthostatic hypotension • Spironolactone— gynecomastia

  16. Mechanism of Action

  17. ACE Inhibitors ARBs * generic Combining with thiazide usually more effective than dose increase • Direct Renin Inhibitors • Aliskiren(Tekturna) • 150-300 mg/day • As effective as ACE or ARB in HTN * Dual elimination: liver & kidney Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

  18. ACE Inhibitors and ARB • Compelling Indications • Systolic Heart Failure • DM • CKD with Proteinuria • CAD • Monitoring • 1-2 weeks after initiation or dose change for K & Cr • Every 6 months on stable doses • Side Effects • Dry Cough  Switch to ARB • Angioedema: ARB likely okay, consider severity • Hyperkalemia: supplements, diet, worsening renal fxn • Combining RAAS inhibitors is generally not recommended • No added benefit CV or renal outcomes / Increased toxicity • ACE or ARB + aldosterone antagonist is the exception • Avoid in Pregnancy

  19. Beta Blockers • MOA: Sympatholytic  ↓ HR and CO / ↓ release of renin Avoid sudden discontinuation Rebound HTN d/t up regulation of ᵦ receptors Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

  20. Beta Blockers • Compelling Indications • CAD • Systolic Heart Failure • Monitoring • ECG if bradycardic- AV block • Avoid combining with other AV nodal blocking agents • Side Effects • Bronchoconstriction—Reactive Airway Disease • Choose B1 selective agent and keep at lower doses • Metabolic—↓HDL, ↑ LDL and triglycerides • Diabetes—↓ insulin sensitivity • Mask symptoms of hypoglycemia, delay recovery • Carvedilol may have advantage as it ↑’s insulin sensitivity • Peripheral Vascular Disease—↑ symptoms, use B1 selective • Depression—Choose agent with low lipid solubility • Fatigue

  21. Calcium channel blockers • http://www.accesspharmacy.com/content.aspx?aID=6543820 • http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html

  22. CCB Considerations ^ Do not use short acting agents in treatment of HTN # Do not combine with beta-blockers: increased risk of bradycardia Doses provided in DrDiDomenico’s lecture on angina Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com

  23. Calcium channel blockers • Compelling Indications • High CAD risk • Diabetes • Monitoring / Side Effects • Dihydropyridine (DHP) • peripheral edema • reflex tachycardia • dizziness • Non DHP • Bradycardia • Contra-indicated in heart failure • Constipation (especially verapamil)

  24. Vasodilators: alpha-1 blockers Doxazosin: start 1 mg daily: max 8 mg daily Prazosin: start 1 mg bid-tid: max 15 mg/day Terazosin: start 1 mg qhs: max 20 mg/day http://cvpharmacology.com/vasodilator/alpha.htm

  25. Vasodilators: alpha-1 blockers • Compelling Indications: None • Second line therapy • Also used to treat BPH (benign prostatic hypertrophy) • Monitoring: • Na and H20 retention with high doses • Side Effects: • Dizziness —Orthostatic hypotension, first dose syncope • Headaches • Reflex tachycardia • Fatigue

  26. Vasodilators: direct • MOA: vascular smooth muscle relaxation • Compelling Indications: None • Second line therapy: Resistant HTN • Hydralazine • 10 – 50 mg qid; max 300 mg /day • Often dosed bid or tid to improve adherence • Rare but serious SE: Lupus erythematosus, blood dyscrasias, peripheral neuritis • Headaches, tachycardia, angina, nausea, diarrhea, rash • Minoxidil • Start 5 mg daily; usual 10-40 mg daily; max 100 mg daily • Rare but serious SE: Stevens-Johnson syndrome • Hypertrichosis— used topically to promote hair growth • Headache, edema, tachycardia, paresthesia

  27. Vasodilators: direct Caution: Increased myocardial work Use in combination with B-blocker / diuretic to combat these effects

  28. Central alpha 2 agonists • Bind to and activate α2 receptors in the brain • ↓ sympathetic outflow to the heart → CO and HR • ↓ sympathetic outflow to vasculature → ↓ vascular tone http://www.cvpharmacology.com/vasodilator/Central-acting.htm

  29. Central alpha 2 agonists • Compelling Indications: None • Second line therapy: Resistant HTN • Clonidine • Start 0.1 mg bid, titrate up weekly: max 2.4 mg/day • Available as a transdermal patch changed weekly • Severe rebound HTN if stopped abruptly • Side Effects: sedation, depression, bradycardia + many more • Methyldopa • Start 250-500 mg bid-tid, adjust every 2-3 days, max 3gm/day • Can be used in pregnancy • Serious but uncommon SE: blood dyscrasias, myocarditis, pancreatitis • Side effects: sedation, orthostatic hypotension + many more

  30. Antihypertensives: • α 1 blocker: • Prazosin, Doxazosin, Terazosin • Dizziness, edema • Centrally Acting: • Methlydopa • Clonidine • Sedation, dry mouth • Vascular Smooth Muscle: • Hydralazine, Minoxidil • CCBs • Headache, Dizziness, edema, • B-blockers: • Atenolol • Carvedilol • Metoprolol • Propranolol • Bradycardia • Diuretics: • Thiazide • Loop • Other • hypokalemia Renin ACE Angiotensinogen Angiotensin I Angiotensin II ARBs Aliskiren ACE Inhibitors Hyperkalemia, dry cough

  31. Without Compelling Indications With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist. Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices JNC VII JAMA 2003;289:2560-2572

  32. Inadequate BP Response with Initial Agent • Increase dose • Substitute new drug from different class • Little to no response to initial drug • No compelling indication for the drug • Troublesome SE • Add a new drug from a different class • Initial drug produces some response and is well tolerated • Compelling indication for the initial drug • Add thiazide if not used initially

  33. HTN: Special Populations • Elderly • Isolated systolic HTN common • SBP rises and DPB declines with aging • Generally salt sensitive • Use lower initial drug doses and slower dose titration • Avoid 1-blockers, labetalol, central 2 agonists • JNC-8 – higher BP goal? • AHA Consensus Statement on the Elderly 2011 • Goal SBP < 140 mm Hg • Age > 80, goal SBP < 150 mmHg • No evidence for lower BP goals for elderly patients at high risk, eg DM, CAD, CKD. • Maintain DBP > 65 mmHg --- coronary perfusion Circulation 2011;123:2434-2506

  34. HTN Elderly Guidelines • Canada 2013 • In the very elderly (age ≥ 80), the target for SBP should be < 150 (grade C) • No changes for those age 65-79; ie goal remains at < 140/90 • Europe 2013 • In elderly < 80 years old with SBP ≥160 mmHg there is solid evidence to reducing SBP to 150 and 140 mmHg (IA) • In fit elderly patients < 80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability (IIb C) • If > 80 years and with initial SBP ≥160 mmHg, it is recommended to reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental conditions (IB) • Benefit in treating elderly, ↓ stroke, CV events, heart failure Canadian Journal of Cardiology 2013;29:528-542

  35. HTN: Special Populations • African Americans • Prevalence, severity and impact increased compared to other populations • Onset at younger age • More Na+ sensitive, lower plasma renin activity • Good response to Na restriction and diuretic therapy •  response to ACE inhibitors, ARBs, and -blockers as monotherapy • HOWEVER, can be overcome by adding a diuretic • Still indicated if compelling indication exists! • ACE inhibitor angioedema 2-4 x more frequent

  36. Hypertensive crisis

  37. EMERGENCY BP >180/120 Acute Target Organ Damage Life threatening GOAL:  BP now IV therapy URGENCY BP >180/120 No Target Organ Damage Not life-threatening GOAL:  BP over days Oral therapy HYPERTENSION CRISES

  38. HYPERTENSIVE EMERGENCIES • Heart • Acute coronary syndrome • Acute heart failure with pulmonary edema • Dissecting aortic aneurysm • CNS • Intra-cerebral hemorrhage / CVA • Encephalopathy • Eclampsia • Acute Renal Failure • Eyes: • Papilledema, hemorrhage

  39. IV Vasodilators Sodium Nitroprusside Nicardipine Nitroglycerin Enalaprilat Fenoldopam Hydralazine IV Adrenergic Inhibitors Labetalol Esmolol Phentolamine Treatment for Hypertensive Emergencies • Goal: • Lower MAP no greater than 20-25% in a few hours • Maintain DBP 100-110 mmHg • Too rapid or too much  cerebral hypoperfusion • Continuous BP monitoring

  40. IV vasodilators * See next slide

  41. IV vasodilators: MOA Fenoldopam D1 receptor agonist moderate affinity α2 vasodilation Release Pro drug • Nitroprusside: • arteriole and venous • No tolerance • Less effect on HR • Nitroglycerin • 1° venodilator • Arteriole dilator at high doses • + tolerance http://cvpharmacology.com/vasodilator/nitrodilator%20mech.gif http://www.drugabuse.gov/sites/default/files/imagecache/content_image_landscape/images/colorbox/dopamine.gif

  42. IV vasodilators Duration of action varies from 1-2 min to 6 hours

  43. Nitroprusside Toxicity Metabolism releases Cyanide • Increased Risk if: • Rate at ≥ 5 ug/kg/min • 2 ug/kg/min for prolonged use (24-48 hours) • Renal insufficiency • Can administer Na Thiosulfate to enhance metabolism of cyanide • Cyanide Toxicity • Weakness • Headaches • Vertigo • Confusion / giddiness • Perceived difficulty breathing • Thiocyanate Toxicity • Anorexia / nausea • Fatigue • Toxic psychosis http://www.biomedcentral.com/content/figures/1471-2253-13-9-1-l.jpg

  44. IV adrenergic blockers Duration of action varies from 3-10 min to 6 hours

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