1、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
2、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 Prima
3、ry / Essential Secondary,No Preexisting Hypertension Acute Crisis Perioperative,At least 45% of hospitalized patients have preexisting hypertensionAbout 25% of surgical patients have preexisting hypertensionHypertensive patients frequently have coexisting cardiac and vascular disease,Goldman L, et a
4、l. 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 Disorder
5、s,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
6、Major Trauma - Burns or Head Injury,Factors in the Development of Acute Hypertension,PACUPainAnxietyDistended BladderHypervolemiaVasoconstriction,ER/CC Myocardial IschemiaHypercarbia/ HypoxemiaReduced organ perfusion -Renal -Cerebral,ORVascular clamping (afterload)Hyperdynamic MyocardiumMalignant Hy
7、perthermiaDiastolic Dysfunction,Adverse Consequences of Uncontrolled Hypertension,Postsurgical Hemorrhage Suture line disruption Aortic dissectionEnd Organ Injury Myocardial ischemia Stroke Renal failurePulmonary Edema,Adrenergic Tone,Baroreceptor Reflexes,Volume/Pressure,Renin/Angiotensin,Preload,C
8、ardiac 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 Sub
9、strate,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 comp
10、lications 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 h
11、ave high blood pressure25% are unaware of this condition72.6% are not well controlled at goal of 140/90Majority 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
12、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,Uncomplica
13、ted Stage 3 HTNHypertensive Crisesurgenciesemergencies,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 syst
14、em 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,H
15、ypertensive 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 noncomp
16、liance / 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 EmergenciesInitia
17、te treatment immediately Hypertensive UrgenciesReduce BP within a few hours Non-urgent Stage 3 HypertensionReduce 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 Frequen
18、t 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 Eme
19、rgencies: 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 O
20、ther 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 Nicardip
21、ine 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,
22、1997,Adrenergic Antagonists,Intravenous Agents for Hypertensive Emergencies,Agent,Onset,Duration,Disadvantages,Beta Blocker Effects Heart Block, Acute CHF,3-6 hrs3-10 min10-20 min,5-10 min1-2 min2 min,LabetalolPhentolamineEsmolol,Modified from the 6th Joint National Commission Reports, NIH, 1997,Adv
23、antages,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
24、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,Exce
25、ssive Hypotension Tachyphylaxis (hyperdynamic response) Redistribution of FlowIntrapulmonary Shunt Coronary StealReduced Renal Blood Flow Platelet Dysfunction ToxicityCyanide Thiocyanate,Metabolism of Sodium Nitroprusside,Tinker JH, Michenfelder JD. Anesthesiology 1976;45:340-354,Thiocyanate (SCN-),
26、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
27、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
28、 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 t
29、itrate 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 tachy
30、cardia Myocardial depression Caution in patients with reactive airway disease,Provides non-oral route for NPO patientsRequires breaking capsule, sublingual administrationAbsorption variable - Abrupt hypotension may occur - May exacerbate myocardial ischemia,Nifedipine Capsules: Characteristics,Nicar
31、dipine: 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
32、 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, nore
33、pinephrine) 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
34、) (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,Postsyna
35、ptic 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
36、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,Dopam
37、ine: 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 Vasodilationwithout
38、 “steal”(in animals)Reflex tachycardia,Metabolized by conjugationNo P450 interaction, RBF Na excretion H2O excretionMaintains GFR during BP lowering,Mesenteric vasodilation Mucosal PO2(in animals),Dopamine Receptor Affinities,GOLDBERG and RAJFER,Fenoldopam Receptor Activity,Selective peripheral dopa
39、mine-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 Fen
40、oldopam,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 o
41、f 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,H
42、O,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 interac
43、tions 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
44、 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,Do
45、se 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 pharm
46、acokinetics 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,
