NEW PHARMACEUTICALS
| NEW PSYCHIATRIC PHARMACOLOGY —Sam S. Torbati, MD, Medical Director of Quality and Safety, and Attending
Emergency Physician, Cedars-Sinai Medical Center, Los Angeles, CA
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| Acutely agitated patients: manage behavior before doing anything else; need focused history and physical examination;
obtain as much information as possible about condition, including duration; determine cause of agitation (rule out
medical causes, eg, meningitis); how to approach patient—try to talk to patient; offer food or drink; if patient needs
medication, offer oral medication first; show of force possibly enough to control patient; concept of voluntary
medication—gives patient chance to cooperate; builds therapeutic alliance; allows patient to have self-respect; reduces
threat felt by patient; patient who has psychiatric disease and experience with taking medication more likely to take medication
long term; level of force used proportional to severity of patient’s agitation; if patient severely agitated, verbally
threatening, and hostile, offer medication; if patient refuses, hold down and give medication intramuscularly (IM); if patient
assaultive, restraints needed until IM medication given; concept in psychiatry that restraints harmful and should be
last resort (better to chemically sedate); restraints can have adverse physiologic and psychologic effects (meet criteria for
posttraumatic stress disorder); remove restraints as soon as patient sedated
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 | Lorazepam (Ativan): used extensively in emergency department (ED); well tolerated; few side effects; first-line treatment
for alcohol or sedative withdrawal and sympathomimetic toxicity; can combine with neuroleptic; multiple routes
of administration; rapid onset; earlier studies suggested antiagitation effects similar to those of haloperidol; can cause
oversedation if too much used; no true antipsychotic properties
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| Midazolam (Versed): effective for agitation; rapid absorption when given IM; shorter half-life than lorazepam; 5 mg midazolam
IM more effective than 10 mg haloperidol IM; more effective at calming agitated patients; associated with
procedural sedation (requires more paperwork)
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| Haloperidol (Haldol): good track record for efficacy and safety; given orally, intravenously (IV), or IM; superior to some
older antipsychotics; risks include extrapyramidal side effects, dystonia, akathisia, drug-induced parkinsonism, mild
degree of QT prolongation, and neuroleptic malignant syndrome (NMS); has sigmoidal dose-effect curve between 2.5
to 15 mg IM; after 15 mg, no added benefit and higher rate of adverse effects; “cocktail” often used includes haloperidol
and lorazepam, with or without histamine (H)1 blocker; can give haloperidol and lorazepam in same syringe as
long as given immediately (more efficacious than either alone); sometimes causes oversedation
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| Newer atypical antipsychotics
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| Olanzapine (Zyprexa): study of 200 agitated bipolar manic patients requiring IM medications; found olanzapine more effective
than lorazepam or placebo; in study of schizophrenic patients, olanzapine performed better and had more rapid onset;
studied IM in agitated dementia and shown better than lorazepam; when given orally, better than haloperidol in short-term
studies; has 0% dystonic rate, compared to ≈7% with haloperidol; associated with postural hypotension; combination with
benzodiazepines not recommended (reports of hypoventilatory response); replaces classic lorazepam and haloperidol
cocktail; with long-term use, causes obesity and metabolic dysregulation, including diabetes
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| Ziprasidone (Geodon): standard dose 10 to 20 mg; rapid onset of action; powder form; in double-blind studies, had no extrapyramidal
symptoms, not excessively sedating, and safe; no significant abnormalities on electrocardiography; better
than haloperidol in psychiatric patients; does not cause weight gain; ED study—110 agitated patients given 20 mg
ziprasidone IM; by 60 min, 95% of patients controlled, with reduction in time patient in restraints; another ED study—
compared efficacy and safety profile to droperidol and midazolam; showed midazolam had most rapid onset of action
but highest rate of respiratory depression (subclinical); effective and safe to use in ED
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| Risperidone (Risperdal): given orally (no IM formulation); effective in acute settings; cannot combine with lorazepam
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| NEW CARDIAC DRUGS —Eric R. Snoey, MD, Clinical Professor of Medicine, University of California, San Francisco,
School of Medicine, and Program Director, Emergency Medicine, Alameda County Medical Center, Oakland, CA
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Atrial Fibrillation (AF)
| Introduction: AF most common rhythm disturbance seen by ED physicians
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| Digoxin: not used as often; slow onset of action, but once peak effect reached, lasts long time; slows atrioventricular
(AV) node by increasing parasympathetic tone; study showed digoxin equivalent to placebo in controlling AF with
rapid venticular response (RVR) in ED
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| Diltiazem: effective alternative to digoxin; 10 to 20 mg slow IV push works within minutes; increase dose until appropriate
rate response obtained; mixed afterload and chronotropic agent; study—participants in intensive care unit (ICU)
with Swan-Ganz catheter, severe heart failure symptomatology, ejection fraction (EF) of 10% to 15%, and borderline
blood pressure (BP) received diltiazem for AF with RVR; had positive hemodynamic response; cardiac output increased;
wedge pressure and dyspnea scores decreased; can use diltiazem (with caution) specifically in AF with RVR,
even in patients whose left ventricle (LV) not normal; excellent agent for rate control; has negative inotropic effect; use
with caution in patients with borderline low BP or in established or suspicious poor LV function
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| Thromboembolic complications
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| Warfarin (Coumadin): resurgence of use due to growing incidence of AF; fibrillatory dysfunctional contractions lead to
eddy currents and stasis of blood in right and left sides of heart, particularly left atrium, leading to clot formation;
likelihood of clot formation increases longer patient in AF; biggest risk at moment of cardioversion; risk for thromboembolic
complications and embolic stroke 6% in following week; arbitrary cutoff of 48 hr; thought that at <48 hr
of AF, not enough time to develop left atrial clot and able to cardiovert patient without underlying anticoagulation;
caveat—not always true, particularly in patients with underlying congestive heart failure (CHF), mitral valve disease,
or history of thromboembolism (need anticoagulation, even if duration of AF just few minutes); if patient
meets criteria or has AF >48 hr—start warfarin immediately in ED, continue for 3 wk, then perform elective cardioversion,
followed by 4 more weeks of warfarin (to prevent atrial stunning, which leads to potentiation of more
clot formation); another option to perform transesophageal echocardiography, heparinize patient by giving enoxaparin
(Lovenox), then do cardioversion, followed by 4 wk of anticoagulation; long-term basal rate of thromboembolic
complications in AF ≈4 times that of age-matched general population (not consistent across all age groups )
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| American Heart Association recommendations: AF patient with mitral stenosis, hypertension, history of CHF, LV dysfunction,
or age >75 yr meets criteria for long-term warfarin therapy, regardless of status of AF; patients with AF
usually older, hypertensive, and probably have underlying CHF; ≈80% of patients with AF should be on warfarin
therapy or aspirin
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| Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial: 4000 participants
with new and chronic AF; first group received drugs to maintain normal sinus rhythm over study period (3 yr); second group
on warfarin and rate-controlling drug; results showed no difference in mortality, fewer hospitalizations, and better quality of
life for those in second group; only factor that mitigated or controlled risk for thromboembolic complications whether patient
on warfarin (not maintaining normal sinus rhythm); other than symptom relief, little evidence to support routine aggressive
efforts to maintain normal sinus rhythm; 20% to 30% of patients who are defibrillated and obtain normal sinus rhythm
have no recurrence of AF; gold standard for AF direct current cardioversion; basal rate of spontaneous cardioversion for
new-onset AF 70%
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| Antiarrhythmic drugs: meta-analysis of 91 trials—showed success rate 50% to 70% for converting patients with
new-onset AF, 30% for those with chronic AF; amiodarone—most commonly used drug in ED for conversion of AF;
originally approved for ventricular tachycardia; has β-blocking and antiarrhythmic effects; controls rate and rhythm; minimal
cardiac suppressive effect; neutral effect on BP, unlike procainamide, which consistently lowers BP; safe for use in
Wolff-Parkinson-White syndrome; efficacy unknown (success rate 4%- 100%); takes ≈10 hr to convert patient;
ibutilide—first drug developed exclusively to control AF and atrial flutter; rapid onset of action; highly effective; works
within 1 hr; no effect on heart rate and BP; causes torsades de pointes in 4% to 8% of patients, of whom 1.7% require intervention;
1 in 60 cases need intervention, assuming patients chosen appropriately and no contraindications (eg, prolonged
QT syndrome at baseline, low magnesium, concurrent use of type 1 agents, eg, quinidine, procainamide); if
cardioversion successful, observe for 4 to 6 hr; short half-life; RSD1235—in development; in clinical trials comparing to
placebo, drug effective in 61% of participants with 3- to 7-day duration of AF; mean conversion time 14 min; low relapse
rate (1%); few adverse effects
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Congestive Heart Failure
| High-dose nitroglycerin: diastolic dysfunction CHF—with excessive afterload, LV becomes stiff and no longer relaxes
during diastole, leading to increased end diastolic pressure (increased wedge pressure), which backs up into lungs, leading to
pulmonary edema; not typical volume-overloaded patients (BP problem); nitroglycerin—preload and afterload vasodilator;
one-third of oral nitroglycerin bioavailable, so 1.2-mg oral dose same as 300 µg IV; lasts ≈3 min; IV drip at 10 or 20 µg/min
one-fortieth of oral dose (should give 200- 400 µg/min); once BP decreased, titrate down to 25 to 50 µg/min
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| Fenoldopam: dopamine receptor agonist; rapid half-life; enhances renal blood flow; no cyanide toxicity;
disadvantages—highly potent (caution required); increases intraocular pressure and should be avoided in patients with
glaucoma
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| Nesiritide: reduces preload and afterload; improves cardiac index and diuresis; effective for decompensated systolic dysfunction
CHF, eg, in cardiomyopathies, with EF of 15%, and globular boggy nonfunctional heart; Vasodilation in the
Management of Acute CHF (VMAC) study—2 groups in ICU, most on Swan-Ganz catheters; one group given medications,
plus B-type natriuretic peptide; other group given medications plus IV nitroglycerin; statistically significant drop in
wedge pressure in nesiritide group; no change in cardiac index, dyspnea, mortality, or length of stay; less ventricular irritability,
compared to dobutamine; less need for dose manipulation; after ≈6 hr at fixed dose, nitroglycerin loses efficacy (tachyphylaxis;
must increase dose); disadvantage—hypotension (seen in ≤10% of patients) usually asymptomatic, but lasts
2.2 hr (unsafe in patients preload-dependent, eg, those with right ventricular infarct, inferior wall infarct, cor pulmonale,
pulmonary edema, cardiac tamponade); 90-day mortality nearly 40% higher, compared to nitroglycerin; more instances of
acute renal failure; 40-fold increase in cost; because of cost and potential danger, best reserved for ICU patients refractory
to traditional management and intolerant of inotropes
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Acute Coronary Syndrome (ACS)
| Management: 30% to 40% of time due to previously silent asymptomatic stenotic lesions that rupture, exposing
endothelium and leading to platelet aggregation and thrombosis; possible to change course of eventuality (myocardial infarction
[MI], usually transmural) by giving antithrombotic agents, platelet agents, antianginals, and anti-inflammatory
agents
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| Heparin: effective, but has narrow therapeutic index; number needed to treat, 40; significant bleeding risk (2:1 cost-risk
ratio); meta-analysis (2004; JAMA)—6 trials (22,000 patients); no mortality benefit to enoxaparin, but ≈17% reduction
in relative risk (RR) for cardiovascular death and MI; 7% risk for major bleeding; should be given only to high-risk group
with, eg, dynamic ECG changes and positive troponins; in one trial of high-risk patients who received invasive therapy,
bleeding rates significant; Enoxaparin and Thrombosis Reperfusion for Acute Myocardial InfarCtion Treatment, Thrombolysis
In Myocardial Infarction–Study 25 (ExTRACT-TIMI 25) trial—compared enoxaparin to unfractionated heparin
(UFH) for fibrinolysis; 33% reduction in RR with enoxaparin, compared to UFH; IV enoxaparin—target level of anti-
factor Xa activity 0.5 to 1.2 (therapeutic enoxaparin effect); takes 24 hr to achieve effect if given SQ (5 min if given IV);
caveats—do not give IV if patient has ST-segment elevation MI (STEMI) and >75 yr of age (unacceptably high risk for
bleeding); instead, mitigate SQ dose by 25% (0.75 mg/kg bid); if creatinine clearance 30 mL/min, give normal IV dose
and normal SQ dose (except SQ dose given q24h [rather than q12h])
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| Clopidogrel (Plavix): adenosine diphosphate (ADP) inhibitor; ≈20% of patients aspirin-nonresponders; Clopidogrel in
Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial—looked at non-Q wave MI and unstable angina;
2% absolute risk reduction; taken once daily for 9 mo; 25% of benefit seen over 9 mo present in first 24 hr of therapy; effect
comes at cost of increased bleeding (intraoperative coronary artery bypass Graft [CABG] bleeding); to avoid increased risk
for bleeding, not given until angiography performed to decide whether patient will have CABG; participants who received
clopidogrel and had CABG still did better; 1 in 3000 patients who receive clopidogrel have increased risk of bleeding in operating
room; many cardiac surgeons think that if CABG required urgently, 5- to 7-day wait not necessary; in presence of
STEMI, 36% reduction in RR for death, MI, and poor blood flow at angiography (20% at 30 days), with no increase in
bleeding; de rigueur drug for patients undergoing catheterization and percutaneous coronary intervention (PCI) for STEMIs;
with loading dose of 300 mg, 12 hr to peak effect; new recommended dose 600 mg (peak effect in 2 hr); in recent trial, dose
of 900 mg had even faster peak effect, with no increase in bleeding complications; has Class 1 recommendation for high-risk
non-STEMI and STEMI with or without PCI or CABG
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| Ranolazine: fatty acid metabolism inhibitor; allows heart to use glucose and create more adenosine triphosphate
(ATP), obviating ischemic symptomatology; for patients refractory to standard antianginal therapy; decreases number
(by 30%) and duration of anginal events; side effects minimal and uncommon
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| Statins: decrease low-density lipoprotein (LDL), increase high-density lipoprotein (HDL); prevent dementia and certain
cancers; anti-inflammatory and antithrombogenic; from PCI and CABG standpoint, plaque stabilizers; trial data show—
statins decrease death, MI, cardiopulmonary resuscitation, and recurrent ischemia
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Suggested Reading
Antman EM et al: Enoxaparin versus unfractionated heparin adjunctive antithrombin therapy in patients receiving fibrinolysis
for ST-elevation myocardial infarction. Design and rationale for the Enoxaparin and Thrombolysis Reperfusion
for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25). Am
Heart J 149:217, 2005; Antman EM et al: Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation
myocardial infarction. N Engl J Med 354:1477, 2006; Barbui C et al: Conventional vs. atypical antipsychotic medications.
N Engl J Med 354:972, 2006; DiMarco JP et al: Factors affecting bleeding risk during anticoagulant therapy in
patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management
(AFFIRM) study. Am Heart J 149:650, 2005; Fox KA et al: Benefits and risks of the combination of clopidogrel and aspirin
in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in
Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 110:1202, 2004; Friedman JH: Atypical
antipsychotics have very different adverse effect profiles and should not be lumped together. Arch Intern Med 166:586;
author reply 586, 2006; Gardner DM et al: Modern antipsychotic drugs: a critical overview. CMAJ 172:1703, 2005;
Krakowski MI et al: Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective
disorder. Arch Gen Psychiatry 63:622, 2006; Lafuente-Lafuente C et al: Antiarrhythmic drugs for maintaining
sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern
Med 166:719, 2006; McNamara RL et al: Management of atrial fibrillation: review of the evidence for the role of
pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 139:1018, 2003; Montalescot G
et al: A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary
syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation
and Ongoing Necrosis) trial. J Am Coll Cardiol 48:931, 2006; Roy D et al: A randomized, controlled trial of
RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol 44:2355,
2004; White HD et al: Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients
with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior
Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am
Heart J 152:1042, 2006; Erratum in: Am Heart J. 2007 Feb;153(2):327.
Educational Objectives
| The goal of this program is to improve the pharmacologic management of acutely agitated patients and patients with acute
coronary syndromes in the emergency department (ED). After hearing and assimilating this program, the clinician will be
better able to:
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| 1. Describe how to approach an acutely agitated patient in the ED.
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| 2. List advantages and disadvantages of the atypical antipsychotic drugs.
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| 3. Recommend the appropriate drug for a patient with atrial fibrillation.
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| 4. Prescribe the appropriate drug for treatment of congestive heart failure.
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| 5. Prescribe the appropriate drug for treatment of acute coronary syndrome.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Torbati was recorded at the 4th Annual Emergency Medicine Symposium, held December 1, 2006, in Los Angeles, CA,
and sponsored by the Cedars-Sinai Medical Center, Department of Emergency Medicine. Dr. Snoey was recorded at Topics
in Emergency Medicine, held November 6-9, 2006, in San Francisco, CA, and sponsored by the Division of Emergency
Medicine, University of California, San Francisco, School of Medicine. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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