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H YPERTENSION I N T HE I NPATIENT S ETTING Mechanisms and Pharmacologic Management

H YPERTENSION I N T HE I NPATIENT S ETTING Mechanisms and Pharmacologic Management. Dedicated to the memory of L EON I . G OLDBERG, MD , P H D A pioneer in the research of dopamine receptor pharmacology and physiology. Learning Objectives.

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H YPERTENSION I N T HE I NPATIENT S ETTING Mechanisms and Pharmacologic Management

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  1. HYPERTENSION IN THEINPATIENT SETTINGMechanisms and Pharmacologic Management

  2. Dedicated to the memory ofLEON I. GOLDBERG, MD, PHDA pioneer in the research of dopaminereceptor pharmacology and physiology

  3. Learning Objectives Outline the prevalence, pathology, and pathophysiology of hypertension in the inpatient setting. Identify treatment goals and treatment options for the severely hypertensive patient. Discuss the pharmacologic profile and potential benefits of fenoldopam in the treatment of hypertension.

  4. Situations Requiring InpatientAntihypertensive Treatment Preexisting Hypertension • Primary / Essential • Secondary No Preexisting Hypertension • Acute Crisis • Perioperative

  5. Epidemiology and Relevance • At least 45% of hospitalized patients have preexisting hypertension • About 25% of surgical patients have preexisting hypertension • Hypertensive patients frequently have coexisting cardiac and vascular disease Goldman L, et al. N Engl J Med 1977;297:845-850

  6. Parenteral Treatment of HypertensionMay be Required in ... • EM • MICU • SICU • OR • PACU • Obstetrics Suite

  7. Parenteral Treatment of HypertensionMay be Required for Medical Emergencies • Uncontrolled or Malignant Hypertension • Drug-Induced Hypertension • cocaine, amphetamines • drug withdrawal • drug-drug interactions • Endocrine Disorders

  8. Parenteral Treatment of Hypertension May Be Required During/After Perioperative Period • Cardiac Surgery • Major Vascular Surgery • carotid endarterectomy • aortic surgery • Neurosurgery • Head and Neck Surgery • Renal Transplantation • Major Trauma - Burns or Head Injury

  9. Factors in the Development ofAcute Hypertension ER/CC Myocardial Ischemia Hypercarbia/ Hypoxemia Reduced organ perfusion -Renal -Cerebral OR Vascular clamping (afterload) Hyperdynamic Myocardium Malignant Hyperthermia Diastolic Dysfunction PACU Pain Anxiety Distended Bladder Hypervolemia Vasoconstriction

  10. Adverse Consequences ofUncontrolled Hypertension • Postsurgical • Hemorrhage • Suture line disruption • Aortic dissection • End Organ Injury • Myocardial ischemia • Stroke • Renal failure • Pulmonary Edema

  11. Sympathetic Nervous System Regulation of Blood Pressure CNS Adrenal Gland Adrenergic Tone Catecholamines Baroreceptor Reflexes Veins Arteries Capacitance Resistance Afterload Preload Volume/Pressure Cardiac Output Renin/Angiotensin Heart Kidney Blood Pressure

  12. Renin-Angiotensin-Aldosterone Regulation of Blood Pressure Renin Substrate Angiotensin I Angiotensin II Renin Aldosterone Vasoconstriction Kidney Adrenal Cortex Blood Pressure Sodium & Water Reabsorption

  13. Preoperative Hypertension “Effective intraoperative management may be more important than preoperative hypertensive control in terms of decreasing clinically significant blood pressure lability and cardiovascular complications in patients who have mild to moderate hypertension.” Goldman L, Caldera DL. Anesthesiology 1979;50:285-292

  14. Inpatient Hypertension:Therapeutic Considerations Therapy • Treat the underlying cause • Provide adequate anesthesia/analgesia • Administer antihypertensive medications

  15. Hypertension in the United States • 50 million adults have high blood pressure • 25% are unaware of this condition • 72.6% are not well controlled at goal of <140/90 • Majority have additional CV risk factors JNC VI. Arch Intern Med 1997;157:2413-2448

  16. Classification of Blood Pressure* Hypertensive+ Stage 1 140-159 Or 90-99 Stage 2 160-179 Or 100-109 Stage3** Or 180 110 ³ *When SBP and DBP fall into different categories, use higher classification.+Based on average of at least two readings or at least two visits.**Assess for presence of risk factors and target organ disease. JNC VI. Arch Intern Med 1997;157:2413-2448

  17. Classification of Severe Hypertension Uncomplicated Stage 3 HTN Hypertensive Crises • urgencies • emergencies JNC VI. Arch Intern Med 1997;157:2413-2448

  18. Hypertensive Urgencies: Defined by Effects or Setting • Hypertension with •  Progressive target organ damage

  19. Hypertensive Emergencies: Defined by Effects Severe HTN with acute end organ damage:  Central nervous system  Myocardial ischemia or heart failure  Renal damage  Active hemorrhage  Eclampsia  Microangiopathic hemolytic anemia  Aortic dissection

  20. Hypertensive Emergencies Are More Than Blood Pressure Measurement • Hypertensive emergencies generally occur with DBP 140 mm Hg, but can be much lower • Baseline level of hypertension and rate of rise are also important • There is much overlap between groups and categories, i.e., cannot be defined by BP alone Kincaid-Smith P. Aust N Z J Med 1981;11(Suppl 1):64-68

  21. Hypertensive Emergencies: Common Etiologies • Medication noncompliance / withdrawal • Accelerated hypertension in a patient with preexisting hypertension • Renovascular hypertension • Acute glomerulonephritis

  22. Hypertensive Emergencies: Other Etiologies  Sympathomimetic drug poisonings  Eclampsia  Pheochromocytoma  MAO inhibitor interactions

  23. Treatment Guidelines* •  Hypertensive Emergencies • Initiate treatment immediately •  Hypertensive Urgencies • Reduce BP within a few hours •  Non-urgent Stage 3 Hypertension • Reduce BP within one week *JNC VI. Arch Intern Med 1997;157:2413-2448

  24. Hypertensive Emergencies: Initial Approach  Multiple confirmations of BP, including all four extremities  Assess target organ involvement  Frequent monitoring of vital signs  Initiate treatment immediately  Use titratable therapy (parenteral)

  25. Endpoints of Antihypertensive Therapy Reduce MAP by 20-25%or Reduce MAP to 110-120 mmHg(whichever is higher) Achieve target BP within 2-4 hours

  26. Hypertensive Emergencies:Control the BP for Patients with . . . • Aortic dissection • Active arterial hemorrhage • Acute myocardial infarction • Intracranial hemorrhage

  27. IV Therapeutics • Alpha Blockers • ACE Inhibitors • Beta Blockers • Calcium Channel Blockers • Diuretics • Dopamine-1 Agonists • Ganglionic Blockers • Nitrovasodilators • Other Vasodilators

  28. Intravenous Agents for Hypertensive Emergencies Common Vasodilators Advantages Disadvantages Agent Onset Duration Nitroprusside Nitroglycerin Fenoldopam Hydralazine Nicardipine Enalaprilat Immediate 2-5 min <5 min 10-20 min 5-15 min 15-30 min 1-2 min 3-5 min 5-10 min 3-8 hrs 1-4 hrs 6 hr Cyanide, Thiocyanate Potent, Titratable Tolerance, Variable Efficacy Coronary Perfusion Renal Perfusion Increased IOP Tachycardia, Headache Eclampsia Avoid in CHF or Cardiac Ischemia CNS Protection CHF, Acute LV Failure Avoid in MI Modified from the 6th Joint National Commission Reports, NIH, 1997

  29. Intravenous Agents for Hypertensive Emergencies Adrenergic Antagonists Advantages Disadvantages Agent Onset Duration Labetalol Phentolamine Esmolol 5-10 min 1-2 min 2 min 3-6 hrs 3-10 min 10-20 min Beta Blocker Effects Heart Block, Acute CHF Combines Beta Blockade With Vasodilation Catecholamine Excess Tachycardia Beta Blocker Effects Heart Block, Acute CHF Aortic Dissection, Perioperative Modified from the 6th Joint National Commission Reports, NIH, 1997

  30. Acute Hypertensive Situations Ideal Therapeutic Agent Parenteral administration  Rapid onset and offset (minutes)  Easy titratability  Reliable efficacy  Safe across patient populations •  Ease of use •  Cost effectiveness

  31. Sodium Nitroprusside Profile Advantages • Immediate onset • Short duration of action • Potent Limitations • Light sensitive • Arterial catheter usually recommended • ICU-level care usually required

  32. Sodium Nitroprusside Adverse Effects • Excessive Hypotension • Tachyphylaxis (hyperdynamic response) • Redistribution of Flow • Intrapulmonary Shunt • Coronary Steal • Reduced Renal Blood Flow • Platelet Dysfunction • Toxicity • Cyanide • Thiocyanate

  33. Metabolism of Sodium Nitroprusside Nitroprusside Oxyhemoglobin Non-enzymatic Nitroprusside Radical Methemoglobin Cyanmethemoglobin CN- Thiosulfate Cytochrome Oxidases Hepatic Rhodanase Inactive Cytochromes Thiocyanate (SCN-) TOXICITY Renal Excretion Tinker JH, Michenfelder JD. Anesthesiology1976;45:340-354

  34. NO+ CN- CN- CN- 2 Na+ Fe++ CN- CN- Sodium Nitroprusside 4 of the 5 CN ions are promptly released 44% of fractional weight is cyanide

  35. Signs Of Cyanide Toxicity • Increased mixed venous saturation • Increased metabolic acidosis • Loss of consciousness and abnormal breathing patterns • Death may be very rapid

  36. Additional Costs Often Associated With Nitroprusside Infusions • Arterial blood gas measurements • Lactate concentrations • Cyanide / thiocyanate monitoring • Invasive blood pressure monitoring

  37. Nitroglycerin • Coronary vasodilator • Direct venodilator (variable arterial effects) • Requires special tubing for administration • Side effects: headaches and tachycardia • Variable efficacy and tachyphylaxis • Methemoglobinemia

  38. Esmolol: Characteristics • Easy to titrate • Short t½ (8 min.) • 1 selective antagonist • Quick onset of action • Metabolized by red blood cell esterases • Myocardial depression • Caution in patients with reactive airway disease

  39. Labetalol: Characteristics • Combined alpha-beta blocker • Half-life 4-6 hours • Dose response is variable • Blunts reflex tachycardia • Myocardial depression • Caution in patients with reactive airway disease

  40. Nifedipine Capsules: Characteristics • Provides non-oral route for NPO patients • Requires breaking capsule, sublingual administration • Absorption variable - Abrupt hypotension may occur - May exacerbate myocardial ischemia

  41. Nicardipine: Characteristics • Dihydropyridine • Water soluble and light stable (allows for IV infusion) • Slow onset and offset • Arterial catheter not mandatory • May accumulate • Variable duration of hypertensive effect

  42. Dopamine and Fenoldopam Cl HO HO NH · CH3SO3H NH2 HO HO DOPAMINE FENOLDOPAM MESYLATE OH

  43. Receptor Profiles of Dopamine and Fenoldopam Similarities • Both drugs agonize peripheral DA1 receptors • Blood pressure reduction (vasodilation) • Increased renal blood flow and Na excretion • Maintenance of or increase in GFR Differences • Dopamine also agonizes DA2 receptors • Blood pressure reduction (if high, norepinephrine) • Decreased renal blood flow and Na excretion • Decreased GFR • Dopamine also agonizes B1 and alpha1 receptors • Blood pressure elevation (vasoconstriction) • Chronotropy • Inotropy

  44. Dopamine Receptor Agonists Actions of Dopaminergic Agonists Fenoldopam Dopamine DA1 (vasodilation) +++ +++ DA2 (vasodilation, emesis +++ - inhibits prolactin)  (vasoconstriction) ++ - 1 (inotropic, chronotropic ) +++ - 2 (vasodilation) + - +++ = Major action ++ = Moderate action + = Minimal action - = No action Frishman WH, Hotchkiss H. Am Heart J, 1996;132:861-867

  45. Peripheral Dopamine Receptor Subtypes DA1 DA2 • Postsynaptic smooth muscle • Proximal tubule • Cortical collecting duct • Presynaptic • Glomerulus • Renal nerves • Adrenal cortex Location Secondary Messenger G-protein linked increased adenylate cyclase Inhibition of adenylate cyclase decreased NE release Systemic Effects Peripheral vasodilation Peripheral vasodilation • Increased RBF • Increased GFR or no change • Natriuresis (inhibition of NA/K ATPase via protein kinase C and NA/H exchanger via adenyl cyclase) • Diuresis • Decreased RBF • Decreased GFR • Decreased Na and H20 excretion • Decreased aldosterone Renal Effects* * Carey RM, et al. Am J Hypertens, 1990;3(6Pt2):59S-63S

  46. Dopamine: Lack of Pharmacological Specificity • BP effects variable, dose-dependent • 1: increased heart rate, tachyarrhythmias • 1:vasoconstriction • Minute ventilation decreases • Possible respiratory depression

  47. Physiologic Effects Fenoldopam Does not cross BBB Systemic Vasodilation • Coronary Vasodilation • without “steal” • (in animals) • Reflex tachycardia • Metabolized by conjugation • No P450 interaction •  RBF •  Na excretion •  H2O excretion • Maintains GFR during BP lowering • Mesenteric vasodilation •  Mucosal PO2 • (in animals)

  48. Dopamine Receptor Affinities GOLDBERG and RAJFER

  49. Fenoldopam Receptor Activity • Selective peripheral dopamine-1 (DA1) receptor agonism • Systemic vasodilation • Regional vasodilation (especially renal) • Renal proximal and distal tubular effects • No binding to DA2 or beta-adrenergic receptors • No alpha-adrenergic agonism, but is an alpha1 antagonist • Does not cross blood brain barrier

  50. Mechanism of Action of Fenoldopam Fenoldopam infusion Selective stimulation of D1-dopamine receptors Direct increase in sodium excretion Adenylyl cyclase activation Increase in intracellular concentration of cAMP Vascular smooth muscle relaxation Vasodilation of renal arteries Vasodilation of coronary arteries Vasodilation of mesenteric arteries Vasodilation of systemic arteries Decrease in systemic vascular resistance Maintenance of blood flow to vital organs Decrease in blood pressure

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