洋地黄中毒幻灯片.ppt

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1、洋地黄中毒第1页,共24页,编辑于2022年,星期日Digitalis IntoxicationwCardiac glycoside poisoning is a potentially life-threatening problem wIn a series of 150 severely affected patients 50%were receiving long-term digitalis therapy,10%had taken an accidental large overdose,and 40%had ingested an overdose with suicidal

2、intent Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments.Final report of a multicenter study.Circulation 1990;81:1744第2页,共24页,编辑于2022年,星期日Digitalis IntoxicationwThe mortality in different studies has ranged from 3 to 40 percentwRecent adva

3、nces have considerably lowered the incidence of digitalis overdose in patients receiving chronic therapy.These include:A better understanding of pharmacokinetics,leading to more appropriate maintenance dosingIncreasing awareness of drugs that can affect digoxin metabolismThe development of radioimmu

4、noassays for plasma digoxin levels第3页,共24页,编辑于2022年,星期日PHARMACOLOGYwDigitalis acts at the subcellular level by inhibiting the membrane-bound Na-K-ATPase pumpwThe net effect is the intracellular loss of potassium and the gain of sodium and calciumwDrug action depends on the tissue conc.,which is rela

5、tively constant in relation to plasma levelswThus,plasma levels can be used to monitor compliance and toxicity 第4页,共24页,编辑于2022年,星期日PHARMACOLOGYwThe two digitalis preparations used in clinical practice today are digoxin and digitoxinwThe bioavailability of digoxin is about 80%and plasma half-life is

6、 1.6 dayswMajor depot for digitalis in humans is skeletal muscle wAs a result,dosage requirements and the likelihood of toxicity are related to muscle mass rather than total body weightwApproximately one-third of the body stores of digoxin is excreted per day 30%unchanged in the urine,and 3%as metab

7、olites in stool第5页,共24页,编辑于2022年,星期日PREDISPOSING FACTORS TO TOXICITY wDrug InteractionsA number of drugs can raise digitalis levels by interfering with its metabolism or renal excretionwRenal insufficiencyEnd-stage renal disease,prolongs the half-life of digoxin and reduces its volume of distributio

8、n There must be reductions both in the loading dose(by about 40 percent)and in the maintenance dose(by 50 to 75 percent)in this setting第6页,共24页,编辑于2022年,星期日PREDISPOSING FACTORS TO TOXICITYwFinally,there are a number of factors that can increase the sensitivity to digoxin and predispose to toxicity a

9、t plasma levels at the upper limits of normalold age,certain cardiac diseases-active ischemia,myocarditis,cardiomyopathy,cardiac amyloidosis,cor pulmonalemetabolic factors-hypokalemia,hypomagnesemia,hypoxemia,hypernatremia,hypercalcemia,and acid-base disturbances 第7页,共24页,编辑于2022年,星期日CLINICAL MANIFE

10、STATIONS wThere are multiple,mostly nonspecific manifestations of digitalis toxicity wThese include fatigue,blurred vision,disturbed color perception,anorexia,nausea,vomiting,diarrhea,abdominal pain,headache,dizziness,confusion,delirium,and occasionally hallucinations wCardiac arrhythmias are respon

11、sible for mortality in this setting and may take almost any form第8页,共24页,编辑于2022年,星期日CLINICAL MANIFESTATIONSwThe combination of SVT and AV block,for example,is highly suggestive of digitalis toxicity wAlthough hypokalemia predisposes to digitalis toxicity,massive overdose can lead to hyperkalemia as

12、 inhibition of the Na-K-ATPase pump impairs potassium entry into cells wPlasma digoxin levels are markedly elevated in these patients,usually being above 10 ng/mL Other signs of toxicity can occur at lower levels of 3 to 5 ng/mL第9页,共24页,编辑于2022年,星期日PLASMA DIGOXIN LEVELSwPlasma digoxin levels should

13、be measured at least 6 hours after the last dose,since this is the time required for attainment of the steady state wThe plasma digoxin concentration should be used only as a guide to appropriate therapeutic dosing wSeveral factors(importantly hypokalemia)can predispose to toxicity at levels below 2

14、 ng/mL,which is considered the upper limit of normal wOn the other hand,clearly elevated levels(above 3 ng/mL)can be seen in asymptomatic patients第10页,共24页,编辑于2022年,星期日PLASMA DIGOXIN LEVELSwFalse positive elevations of plasma digoxin can occur in newborns,pregnant women,and patients with chronic ren

15、al failure or hepatobiliary disease wThis problem is thought to result from increased levels of endogenous digoxin-like substanceswThe highest values(up to 4 ng/mL)are seen in neonateswSmaller errors of 0.6 to 1.8 ng/mL have been described in the third trimester of pregnancy,renal failure,and combin

16、ed hepatic and renal failure wLarge doses of steroid derivatives,such as spironolactone and methylprednisolone,can cross react with the digoxin radioimmunoassay第11页,共24页,编辑于2022年,星期日GENERAL PRINCIPLES OF THERAPY wGastrointestinal decontamination ipecac-induced emesis or lavage is carried out with ca

17、re to avoid vagal stimulation which may worsen existing conduction blockactivated charcoal effectively adsorbs digitalis,if ingestion has occurred within 6-8 hours repeated doses can be given to adsorb active metabolites as they are excreted by the biliary tract cholestyramine is an alternative to a

18、ctivated charcoalw 第12页,共24页,编辑于2022年,星期日GENERAL PRINCIPLES OF THERAPYwCorrection of electrolyte imbalancesHypokalemia,hypomagnesemia,and other electrolyte disorders should be corrected Potassium replacement should be given carefully,since raising the plasma potassium concentration can increase atri

19、oventricular blockSome acutely intoxicated patients present with severe hyperkalemia,requiring therapy with glucose and insulin and sodium bicarbonate第13页,共24页,编辑于2022年,星期日GENERAL PRINCIPLES OF THERAPYwManagement of cardiac arrythmiasSevere bradyarrhythmias are treated with atropine,electrical pacin

20、g is used in unresponsive patientsTherapy of cardiac ectopy is reserved for more complex formsLidocaine and phenytoin are antiarrhythmic drugs of first choiceVerapamil is useful for SVTsCardioversion should be limited to patients with life-threatening arrhythmias and used at the lowest effective ene

21、rgy level第14页,共24页,编辑于2022年,星期日DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS wDigoxin-specific antibody Fab fragments(Digibind),purified from sheep IgG,rapidly bind to circulating digoxin and are indicated in Ingestion of more than 10 mg of digoxin in adults or 4 mg in childrenPlasma digoxin concentration abo

22、ve 10 ng/mL A plasma potassium concentration above 5 meq/L in the presence of life-threatening arrhythmia ventricular tachycardia or fibrillation,progressive bradycardia,or high degree AV nodal block第15页,共24页,编辑于2022年,星期日Mechanism of action of DigibindwThe proposed sequence of events that occurs aft

23、er infusion of Fab fragments begins with rapid binding of intravascular digoxin and is followed by diffusion of the fragments into the interstitial space to bind free digoxin at that site wThe affinity of the fragments for digoxin is greater than the affinity of digoxin for Na-K ATPasewThe Fab fragm

24、ents are relatively small(mol wt 50,000)which allows them and bound digoxin to be rapidly excreted by glomerular filtration in patients with near-normal renal functionwThe elimination half-life of the fragments is 15 to 20 hours in this setting第16页,共24页,编辑于2022年,星期日DigibindwDigibind can also be succ

25、essfully in patients with renal insufficiency,including those on maintenance dialysis wIn the largest study,18 patients had a pretreatment plasma creatinine concentration of more than 5 mg/dL,including five who were on dialysis wThese patients responded to Digibind in a manner similar to patients wi

26、th normal renal function第17页,共24页,编辑于2022年,星期日Efficacy of DigibindwIn the largest series of 150 patients with life-threatening digitalis toxicity,80 percent had resolution of all signs and symptoms,10 percent improved,and 10 percent showed no response wThe median time to initial response was 19 minu

27、tes and the time to complete response was 88 minutes wOf the patients who experienced cardiac arrest,54 percent survived hospitalization第18页,共24页,编辑于2022年,星期日wSeveral factors which contribute to partial responses or resistance include,underlying heart disease that was the true cause of some of the p

28、resumed manifestations of digitalis toxicity,too low a dose of Fab,and treatment of patients who were already moribundwA dramatic fall in the plasma potassium concentration can occur after digibind therapy wThe decline in the plasma potassium concentration begins within one hour and is complete with

29、in 4 hrswThus,monitoring of the plasma potassium concentration should be performed in all patients receiving this therapy第19页,共24页,编辑于2022年,星期日Side effects of digibind therapywDespite the improvement induced by digibind,potentially important side effects can occur exacerbation of congestive heart fa

30、ilure,increased ventricular response in patients with A-fib.hypokalemia wIdiosyncratic allergic manifestations are very rare,occurring in less than one percent of caseswPlasma digoxin measurements are unreliable for one to two weeks after fragment therapy第20页,共24页,编辑于2022年,星期日Dosing regimen for digo

31、xin-specific antibody fragments wTotal body load of digitalis(TBL,in mg)=SDC(serum digitalis concentration)x volume of distribution x weight(kg)wThe serum digitalis concentration is measured in ng/mL and for digoxin,the volume of distribution is 5.6 L/kg,thereforeTBL =(SDC x 5.6 x weight)1000 wOne v

32、ial of digibind contains 40 mg,which neutralizes approximately 0.6 mg of digoxin第21页,共24页,编辑于2022年,星期日Dosing regimen for digoxin-specific antibody fragmentswNumber of vials =TBL 0.6OrwNumber of vials=(SDC x weight)100第22页,共24页,编辑于2022年,星期日wIf the amount ingested is known,then the TBL can be calculat

33、ed directly:wTBL =Dose ingested(mg)x 0.8 for digoxin which has 80 percent bioavailabilitywIf the SDC and the amount ingested are not known,then digibind is given empirically according to the following regimen wFor an acute overdose in adults:Give 10 vials;repeat with another 10 vials if indicatedwWi

34、th chronic toxicity:Give 6 vials to an adult,one vial to a child第23页,共24页,编辑于2022年,星期日EXTRACORPOREAL TECHNIQUESwHemodialysis or hemoperfusion can help control hyperkalemia or volume overload in patients with concurrent renal failurewThey are,however,of limited utility in removal of digoxin because of its extensive tissue binding and very large volume of distribution(5.6 L/kg)第24页,共24页,编辑于2022年,星期日

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