高血压英文ppt精品课件hypertension in the inpatient

HYPERTENSION IN THE INPATIENT SETTING Mechanisms and Pharmacologic Management,Dedicated to the memory of LEON I. GOLDBERG, MD, PHD A pioneer in the research of dopamine receptor pharmacology and physiology,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.,Situations Requiring Inpatient Antihypertensive Treatment,Preexisting Hypertension Primary / Essential Secondary,No Preexisting Hypertension Acute Crisis Perioperative,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,Epidemiology and Relevance,EM MICU SICU OR PACU Obstetrics Suite,Parenteral Treatment of Hypertension May be Required in .,Uncontrolled or Malignant Hypertension Drug-Induced Hypertension cocaine, amphetamines drug withdrawal drug-drug interactions Endocrine Disorders,Parenteral Treatment of Hypertension May be Required for Medical Emergencies,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,Factors in the Development of Acute Hypertension,PACU Pain Anxiety Distended Bladder Hypervolemia Vasoconstriction,ER/CC Myocardial Ischemia Hypercarbia/ Hypoxemia Reduced organ perfusion -Renal -Cerebral,OR Vascular clamping (afterload) Hyperdynamic Myocardium Malignant Hyperthermia Diastolic Dysfunction,Adverse Consequences of Uncontrolled Hypertension,Postsurgical Hemorrhage Suture line disruption Aortic dissection End Organ Injury Myocardial ischemia Stroke Renal failure Pulmonary Edema,Adrenergic Tone,Baroreceptor Reflexes,Volume/Pressure,Renin/Angiotensin,Preload,Cardiac Output,Blood Pressure,Catecholamines,Adrenal Gland,CNS,Veins,Arteries,Capacitance,Resistance,Sympathetic Nervous System Regulation of Blood Pressure,Heart,Kidney,Afterload,Renin-Angiotensin-Aldosterone Regulation of Blood Pressure,Blood Pressure,Kidney,Vasoconstriction,Angiotensin I,Renin Substrate,Angiotensin II,Renin,Sodium & Water Reabsorption,Aldosterone,Adrenal Cortex,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,Therapy Treat the underlying cause Provide adequate anesthesia/analgesia Administer antihypertensive medications,Inpatient Hypertension: Therapeutic Considerations,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,Hypertension in the United States,JNC VI. Arch Intern Med 1997;157:2413-2448,Classification of Blood Pressure*,Hypertensive+,Stage 1,140-159,Or,90-99,Stage 2,160-179,Or,100-109,Stage3*,180,Or,110,*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,Uncomplicated Stage 3 HTN Hypertensive Crises urgencies emergencies,Classification of Severe Hypertension,JNC VI. Arch Intern Med 1997;157:2413-2448,Hypertension with Progressive target organ damage,Hypertensive Urgencies: Defined by Effects or Setting,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,Hypertensive Emergencies: Defined by Effects,Hypertensive Emergencies Are More Than Blood Pressure Measurement,Kincaid-Smith P. Aust N Z J Med 1981;11(Suppl 1):64-68,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,Hypertensive Emergencies: Common Etiologies,Medication noncompliance / withdrawal Accelerated hypertension in a patient with preexisting hypertension Renovascular hypertension Acute glomerulonephritis, Sympathomimetic drug poisonings Eclampsia Pheochromocytoma MAO inhibitor interactions,Hypertensive Emergencies: Other Etiologies, Hypertensive Emergencies Initiate treatment immediately Hypertensive Urgencies Reduce BP within a few hours Non-urgent Stage 3 Hypertension Reduce BP within one week,Treatment Guidelines*,*JNC VI. Arch Intern Med 1997;157:2413-2448, Multiple confirmations of BP, including all four extremities Assess target organ involvement Frequent monitoring of vital signs Initiate treatment immediately Use titratable therapy (parenteral),Hypertensive Emergencies: Initial Approach,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,Hypertensive Emergencies: Control the BP for Patients with . . .,Aortic dissection Active arterial hemorrhage Acute myocardial infarction,Intracranial hemorrhage,IV Therapeutics,Alpha Blockers ACE Inhibitors Beta Blockers Calcium Channel Blockers Diuretics Dopamine-1 Agonists Ganglionic Blockers Nitrovasodilators Other Vasodilators,Common Vasodilators,Intravenous Agents for Hypertensive Emergencies,Agent,Onset,Duration,Disadvantages,Cyanide, Thiocyanate,1-2 min 3-5 min 5-10 min 3-8 hrs 1-4 hrs 6 hr,Immediate 2-5 min 5 min 10-20 min 5-15 min 15-30 min,Nitroprusside Nitroglycerin Fenoldopam Hydralazine Nicardipine Enalaprilat,Advantages,Tolerance, Variable Efficacy,Increased IOP,Tachycardia, Headache,Avoid in CHF or Cardiac Ischemia,Avoid in MI,Potent, Titratable,Coronary Perfusion,Renal Perfusion,Eclampsia,CNS Protection,CHF, Acute LV Failure,Modified from the 6th Joint National Commission Reports, NIH, 1997,Adrenergic Antagonists,Intravenous Agents for Hypertensive Emergencies,Agent,Onset,Duration,Disadvantages,Beta Blocker Effects Heart Block, Acute CHF,3-6 hrs 3-10 min 10-20 min,5-10 min 1-2 min 2 min,Labetalol Phentolamine Esmolol,Modified from the 6th Joint National Commission Reports, NIH, 1997,Advantages,Tachycardia,Beta Blocker Effects Heart Block, Acute CHF,Combines Beta Blockade With Vasodilation,Catecholamine Excess,Aortic Dissection, Perioperative, Parenteral administration Rapid onset and offset (minutes) Easy titratability Reliable efficacy Safe across patient populations Ease of use Cost effectiveness,Acute Hypertensive Situations Ideal Therapeutic Agent,Sodium Nitroprusside Profile,Advantages Immediate onset Short duration of action Potent Limitations Light sensitive Arterial catheter usually recommended ICU-level care usually required,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,Metabolism of Sodium Nitroprusside,Tinker JH, Michenfelder JD. Anesthesiology 1976;45:340-354,Thiocyanate (SCN-),Thiosulfate,Renal Excretion,Cytochrome Oxidases,Inactive Cytochromes,CN-,TOXICITY,Hepatic Rhodanase,Nitroprusside,Nitroprusside Radical,Oxyhemoglobin,Methemoglobin,Non-enzymatic,Cyanmethemoglobin,44% of fractional weight is cyanide,4 of the 5 CN ions are promptly released,Sodium Nitroprusside,Signs Of Cyanide Toxicity,Increased mixed venous saturation Increased metabolic acidosis Loss of consciousness and abnormal breathing patterns Death may be very rapid,Additional Costs Often Associated With Nitroprusside Infusions,Arterial blood gas measurements Lactate concentrations Cyanide / thiocyanate monitoring Invasive blood pressure monitoring,Nitroglycerin,Coronary vasodilator Direct venodilator (variable arterial effects) Requires special tubing for administration Side effects: headaches and tachycardia Variable efficacy and tachyphylaxis Methemoglobinemia,Esmolol: Characteristics,Easy to titrate Short t (8 min.) 1 selective antagonist Quick onset of action Metabolized by red blood cell esterases Myocardial depression Caution in patients with reactive airway disease,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,Provides non-oral route for NPO patients Requires breaking capsule, sublingual administration Absorption variable - Abrupt hypotension may occur - May exacerbate myocardial ischemia,Nifedipine Capsules: Characteristics,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,Dopamine and Fenoldopam,HO,HO,DOPAMINE,NH CH3SO3H,OH,HO,HO,Cl,FENOLDOPAM MESYLATE,NH2,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,Dopamine Receptor Agonists,Dopamine,Fenoldopam,DA1 (vasodilation) + + DA2 (vasodilation, emesis + - inhibits prolactin) (vasoconstriction) + - 1 (inotropic, chronotropic ) + - 2 (vasodilation) + -,Actions of Dopaminergic Agonists,+ = Major action + = Moderate action + = Minimal action - = No action,Frishman WH, Hotchkiss H. Am Heart J, 1996;132:861-867,Peripheral Dopamine Receptor Subtypes,DA1,DA2,Location,Postsynaptic smooth muscle Proximal tubule Cortical collecting duct,Presynaptic Glomerulus Renal nerves Adrenal cortex,Secondary Messenger,G-protein linked increased adenylate cyclase,Inhibition of adenylate cyclase decreased NE release,Systemic Effects,Peripheral vasodilation,Peripheral vasodilation,Renal Effects*,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,* Carey RM, et al. Am J Hypertens, 1990;3(6Pt2):59S-63S,Dopamine: Lack of Pharmacological Specificity,BP effects variable, dose-dependent 1: increased heart rate, tachyarrhythmias 1: vasoconstriction Minute ventilation decreases Possible respiratory depression,Physiologic Effects Fenoldopam,Systemic Vasodilation,Does not cross BBB,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),Dopamine Receptor Affinities,GOLDBERG and RAJFER,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,Mechanism of Action of Fenoldopam,Fenoldopam infusion,Selective stimulation of D1-dopamine receptors,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,Maintenance of blood flow to vital organs,Decrease in systemic vascular resistance,Decrease in blood pressure,Direct increase in sodium excretion,Fenoldopam Metabolism: Conjugation Without Cytochrome P450 Interaction,NH,OH,Cl,HO,CH O,3,NH,OH,Cl,HO,3,CH O,NH,OH,Cl,HO,HO,NH,OH,Cl,HO,O SO,3,2,NH,OH,Cl,HO,O SO,3,2,NH,OH,Cl,HO,O,OH,OH,HO,COOH,O,Fenoldopam-8-O-Methyl,Fenoldopam-7-O-Methyl,Fenoldopam-8-Sulfate,Fenoldopam-7-Sulfate,(1R),(1S)Fenoldopam-7-O-B-Glucuronide,Fenoldopam Metabolism,Metabolism via conjugation Metabolites pharmacologically inactive No cytochrome P450 interactions No known metabolic drug interactions 88% albumin bound Elimination: 90% urine, 10% feces No dose adjustment for renal or hepatic impairment,Pharmacokinetics,Time (hr),0,1,2,3,4,5,6,0,10,20,30,40,Onset,Plasma Fenoldopam (ng/ml),48,49,50,51,52,53,54,Offset,0,10,20,30,40,Time (hr),Neurex: data on file,Time (Minutes),Mean Diastolic Blood Pressure - (mmHg) +/- Standard Error,65,70,75,80,85,90,95,10,20,30,40,50,60,Fenoldopam Time of Onset Of Antihypertensive Effect,Neurex: data on file,Time (hr),Plasma Fenoldopam (ng/ml),0,10,20,30,40,0,6,12,18,24,30,36,42,48,54,60,66,72,Dose 0.00 mg/kg/min,Dose 0.04 mg/kg/min,Dose 0.1 mg/kg/min,Dose 0.4 mg/kg/min,Dose 0.8 mg/kg/min,Dose-Dependent Pharmacokinetics,t1/2 = 5 min,Vd = 42 L,Neurex: data on file, t ( 5 min) Small volume of distribution Rapid attainment of steady state ( 30 min) Plasma concentrations proportional to dose No alteration in pharmacokinetics over 48 hr infusion Rapid elimination upon discontinuation,Fenoldopam: Pharmacokinetics, Predictable hemodynamic effect Rapid onset of effect Predictable dose response for lowering BP No rebound hypertension,Fenoldopam: Pharmacodynamics, Rapid, predictable, dose-dependent blood pressure decrease (without overshoot) Short t, rapid attainment of steady state titration Linear pharmacokinetics No cytochrome P450 interactions Dose-response curves well defined No dosing adjustment for pre-existing renal or hepatic impairment Increases renal blood flow and maintains GFR Ease of use,Fenoldopam: Potential Benefits,Overall efficacy,Comparison of Fenoldopam and Nitroprusside: Summary of Randomized Clinical Trials in Patients with Acute Severe Hypertension,Bednarczyk et al. Am J Cardiol 1989,Reisin et al. Hypertension 1990,Panacek et al. Acad Emerg Med 1995,Pilmer et al. J Clin Pharmacol 1993,White et al. Nieren Hoch 1991,Reference,n,Mean dosage g/kg/min,BP (mmHg) Pre Post,17 16 75 78 15 18 9 9 6 5,FND 0.6 SNP 2.0 FND 0.41 SNP 1.67 FND 0.5 SNP 1.2 FND 0.1-1.5 SNP 0.5-3.5 FND 0.32 SNP 0.93,FNDSNP FNDSNP FNDSNP FNDSNP FNDSNP,FND=fenoldopam SNP=sodium nitroprusside, Prospective, randomized, open-label, multicenter clinical trial 183 patients enrolled with balanced demographics (153 completed) FND efficacy equal to SNP Similar adverse event profile,Randomized Prospective Trial Fenoldopam vs. Sodium Nitroprusside in Treatment of Acute Severe Hypertension,Panacek EA, et al. Acad Emerg Med 1995;2:959-965,70,90,110,100,150,200,250,Baseline,Start,0.5,1.0,2.0,4.0,6.0,End,Comparative Effects of Fenoldopam and Nitroprusside on BP and HR During 6 Hour Infusion,Blood Pressure (mmHg),Maintenance Time (Hours),Heart Rate (bpm),= p 0.05; FNP vs SNP,Nitroprusside,Fenoldopam,*,Panacek EA, et al. Acad Emerg Med 1995;2:959,Nitroprusside,Comparative Effects of Fenoldopam and Nitroprusside on BP and HR after 12 Hours of Infusion,Panacek EA, et al. Acad Emerg Med 1995;2:959-965,9 229 8 148 6 94 5,-54 10 -45 5 -7 5,Fenoldopam,8 225 10 134 2 86 4,-45 10 -32 6 -6 4,Baseline ( SEM),Change ( SEM),n SBP DBP HR,SBP DBP HR,Hypertensive Emergency Trial,Ellis D, et al. Crit Care Med 1998;26(Suppl):A23 (abstract),Study Design,Determine pharmacokinetic/pharmacodynamic parameters Patients with end organ damage and DBP 120 mmHg Double-blind, constant infusion, 4 rates 0.01, 0.03, 0.1, 0.3 mg/kg/min 24-hour infusion, transition to PO after 18 hours No target BP specified Reduction in DBP at 4 hours primary endpoint Statistical comparison vs. 0.01 dose group,Efficacy Endpoint,Ellis D, et al. (abstract),4 Hour Systolic Blood Pressure,Ellis D, et al. (abstract),4 Hour Heart Rate,Ellis D, et al. (abstract),Objective End Organ Damage Malignant Hypertension Trial,Hematuria,CHF,Papilledema,Myocardial Ischemia,Renal Insufficiency,Retinal,Encephalopathy,0,5,10,15,20,25,30,35,Number of Patients,(Confusion, TIA),(III-IV, hemorrhage),(Cr 2.4),(ECG, chest pain),(Pulmonary),(edema, CXR, rales),Ellis D, et al. (abstract), No evidence of rebound effects Rapid disappearance of drug Administration before or after discontinuation of infusion Wide variety of drugs used Generally successful transfer to oral drugs,Transition to Oral Medications,Safety in Postoperative Hypertensio