toxicity mediated by interference with membrane pumps - underlying mechanisms of cardiac glycoside...
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Toxicity mediated by interference with membrane pumps
- underlying mechanisms of
cardiac glycoside toxicity
Michael Eddleston
Scottish Poisons Information BureauRoyal Infirmary of Edinburgh, UK
Cardiac glycoside poisoning
• Epidemiology of cardiac glycoside poisoning
• Standard treatment = pharmacokinetics
• Mechanisms of toxicity
• Possibilities for treatment that result from this knowledge
• Future research??
Cardiac glycoside medication poisoning
Deaths uncommon in industrialised countries
• Schaper et al Eur J Intern Med 2006;17:474.GIZ-Nord Poison Center consulted in 168,000 cases.142 deaths (0.08% of cases)None due to cardiac glycosides
• AAPCC data from USA 2005 Clin Tox 2006;44:803.61 poison centres consulted in 2,424,180 cases1261 deaths (0.05% of cases)20 (1.6%) primarily due to cardiac glycosides(10 due to therapeutic error, 3 ADR, only 3 intentional)
Self-poisoning in north central Sri Lanka
Prospective cohort of acutely poisoned patients started
in March 2002 in 2 district hospitals. Now contains over
13,000 patients.
Up to mid-2005: 8383 cases98% due to self-harm
Pesticides: 3848 (45.9% of total)
Oleander seeds: 2423 (28.9% of total)
Other common poisons: medicines & hydrocarbons
All treated using a standard protocol
Case fatality for different classes of poison
0.0 2.5 5.0 7.5 10.0 12.5 15.0
kerosene
oleander seeds
pesticides
all poisons
Case fatality ratio (95% CI)
Case series of oleander poisoning
• Jaffna, Sri Lanka, 1980 - 170 patients over 3 years, with 7 deaths (CFR 4.1%).
• Bankura, W Bengal, 1985 – 300 patients over 5 years, with 14 deaths (CFR 4.7%).
• Anuradhapura, Sri Lanka, 1995 – 79 patients over 4 months, with 6 deaths (CFR 7.6%)
• North Central Province, Sri Lanka 2005 – 2423 patients over 3 years, with 109 deaths (CFR 4.5%)
Symptoms of substantial oleander poisoning (n=66)Cardiac dysrhythmias 100%
Nausea 100%Vomiting 100%Weakness 88%Fatigue 86%Diarrhoea 80%Dizziness 67%Abdominal Pain 59%Visual Symptoms 36%Headache 34%Sweating 20%Confusion 19%Fever and/or Chills 5%Anxiety 3%Abnormal Dreams 3%
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or o reducing absorption
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or o reducing absorption
The introduction of Fab fragments The introduction of Fab fragments for digoxin poisoningfor digoxin poisoning
• first reported in humans in April 1976
• reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific ovine antibodies
• Ingested dose = 22.5 mg of digoxin
• serum potassium initially 8.7 mmol/l
Time course of :total serum digoxin ( )Free serum digoxin ( )Fab fragments ( ) serum potassium ( ) after iv administration of DA in a 39-year-old manwith severe digoxin poisoning.
Smith TW et al. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797-800.
Effect of Fab in oleander poisoning
Effect of anti-digoxin Fab on dysrhythmias
Effect of Fab on serum potassium
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab
• Activated charcoal
Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by:
o speeding elimination and/or o reducing absorption
Odds Ratio
Favours Treated with AC Favours Not treated with AC
.1 .5 1 1.5 2 2.5 4
Odds ratio (95% CI)
No. of events/ No. of participants Treated AC Untreated AC
Overall 0.98 ( 0.75, 1.28) 186/2811 95/1405
Poison Organophosphate 0.85 ( 0.57, 1.27) 74/624 45/330 Oleander 1.00 ( 0.60, 1.67) 46/1010 23/505 Other or NK Pesticide/Paraquat 1.10 ( 0.63, 1.89) 44/640 20/317 Other substances 1.50 ( 0.63, 3.56) 22/537 7/253
Severity Asymptomatic 1.24 ( 0.66, 2.32) 35/1325 14/654 Symptomatic GCS 14/15 1.10 ( 0.71, 1.71) 67/1157 31/586 Symptomatic GCS <14 0.79 ( 0.52, 1.19) 84/329 50/165
Time since ingestion
Missing 0.29 ( 0.04, 2.01) 2/27 3/14
<= 2 hours 0.79 ( 0.49, 1.29) 46/615 29/313 3-4 hours 1.10 ( 0.69, 1.74) 61/887 28/444 5-7 hours 1.04 ( 0.58, 1.86) 37/636 18/321 >=8 hours 1.15 ( 0.64, 2.06) 40/646 17/313
Test of Interaction
P=0.7
P=0.4
P=0.6
Treated with Activated Charcoal vs Not Treated with Activated Charcoal
Comparison of two published RCTs
de Silva MDAC 5/201 [2·5%] vs SDAC 16/200 [8%] RR 0.31 (95% CI 0.12 to 0.83)
SACTRCMDAC 22/505 [4·4%] vs SDAC 24/505 [4.8%] RR 0.92 (95% CI 0.52 to 1.60)
Fixed effects model, test of heterogeneity P=0.06
Why? Different regimen? Poor compliance?
Time from hospital admission to death in RCT
0 12 24 36 48 60 72 84 96 108 120
MDAC
SDAC
No AC
Time from admission to death (hrs)
Standard treatment
Only two interventions have been carefully studied
• Anti-digoxin/digitoxin Fab• Activated charcoal
Current situation:Anti-digoxin Fab are too expensive for widespread useThe evidence for activated charcoal is ? negative
Are there other options?Here we need to understand the mechanism of
toxicity
Ion channels of cardiac muscle
Function of Na+/K+ ATPase
Effect of cardiac glycosides
Consequences of cardiac glycoside binding 1
• Rises in intracellular Ca2+ and Na+ concentrations
• Partial membrane depolarisation and increased automaticity (QTc interval shortening)
• Generation of early after-depolarisations (u waves) that may trigger dysrhythmias
• Variable Na+ channel block, altered sympathetic activity, & increased vascular tone.
Consequences of cardiac glycoside binding 2
• Decrease in conduction through the SA and AV nodes
• Due to increase in vagal parasympathetic tone and by direct depression of this tissue
• Seen as decrease in ventricular response to SV rhythms and PR interval prolongation
• In very high dose poisoning, Ca2+ load may overwhelm the sarcoplasmic reticulum’s capacity to sequester it, resulting in systolic arrest – ‘stone heart’
Yellow oleander cardiotoxicity
Potassium effects 1
• Hyperkalaemia is a feature of poisoning, due to inhibition of the Na+/K+ ATPase. Causes hyperpolarisation of cardiac tissue, enhancing AV block.
• Study of 91 acutely digitoxin poisoned patients before use of anti-digoxin Fab (Bismuth, Paris):
• All with [K+] >5.5 mmol/L died• 50% of those with [K+] 5.0-5.5 mmol/L died• None of those with [K+] <5.0 mmol/L died
However, Rx of hyperkalaemia ‘does not improve outcome’
Potassium effects 2
• Pre-existing hypokalaemia also inhibits the ATPase & enhances myocardial automaticity, increasing the risk of glycoside induced dysrhythmias
• Effect of hypokalaemia may be in part due to reduced competition at the ATPase binding site
• Hypokalaemia <2.5 mmol/L slows the Na pump, exacerbating glycoside induced pump inhibition.
What other treatment options are available?
• Anti-arrhythmics – lidocaine & phenytoin
• Atropine & pacemakers
• Correction of electrolyte abnormalities
• Correction of hyperkalaemia
• Fructose 1,6 diphosphate
Unfortunately, as yet, no RCTs to guide treatment
Classic treatments
• Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction.
Phenytoin reported to terminate digoxin-induced SVTs.
• Atropine – given for bradycardias.
• Temporary pacemaker – to increase heart rate, but cannot prevent ‘stone heart’. Also insertion of pacemaker may trigger VF in sensitive heart. Now not recommended where Fab is available.
Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine
40 50 60 70 80 90 1005060708090
100110120130140
baseline rate
Rat
e at
5 m
in
40 50 60 70 80 90 10060708090
100110120130140
baseline rate
Rat
e at
15
min
Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine
Importance of the nervous system
• In animals, spinal cord transection reduces the toxicity of cardiac glycosides
• Administration of the 2-adrenoceptor agonist clonidine increases the dose of cardiac glycoside required to induce dysrhythmias and death. Inhibited by administration of yohimbine.
• Can this information be confirmed in humans? Is this partly how atropine is working?
Classic treatments
• Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction.
Phenytoin reported to terminate digoxin-induced SVTs.
• Atropine – given for bradycardias.
• Temporary pacemaker – to increase heart rate, but cannot prevent ‘stone heart’. Also insertion of pacemaker may trigger VF in sensitive heart. Now not recommended where Fab is available.
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+.
• However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon.
• Hypomagnesaemia. Serum [Mg2+] is not related to severity in oleander poisoning. However, low [Mg2+] will make replacing K+ difficult.
• Theoretically, giving Mg2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).
Serum potassium on admission
0 1 2 3 4 52
3
4
5
6
7
8
mild or no cardiotoxicitysevere cardiotoxicity
[cardiac glycoside] (nmol/L)
seru
m p
otas
sium
mm
ol/L
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+.
• However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon.
• Hypomagnesaemia. Serum [Mg2+] is not related to severity in oleander poisoning. However, low [Mg2+] will make replacing K+ difficult.
• Theoretically, giving Mg2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).
Serum magnesium on admission
0 1 2 3 4 50.40
0.65
0.90
1.15
mild or no cardiotoxicitysevere cardiotoxicity
[cardiac glycoside] (nmol/L)
seru
m m
agne
sium
mm
ol/L
Correction of electrolyte disturbances
• Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K+.
• However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon.
• Hypomagnesaemia. Serum [Mg2+] is not related to severity in oleander poisoning. However, low [Mg2+] will make replacing K+ difficult.
• Theoretically, giving Mg2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).
Correction ofhyperkalaem
ia-
dangerous or
beneficial?
Cerbera manghas poisoning(pink-eyed cerbera, odallam, kaduru, or sea mango)
Use of insulin/dextrose for hyperkalemia
• Van Deusen 2003 – single case. No effect – neither dangerous nor beneficial.
• Reports from India of ‘successfully’ treating yellow oleander poisoning with insulin dextrose when no other therapies were available.
• Oubaassine and colleagues 2006 – reported case of combined digoxin (17.5 mg) & insulin (50 iu) poisoning with no substantial cardiac effects and no hyperkalaemia.
Might lowering [K+] > 5.5 mmol/L be beneficial???
Oubaassine 2006 – rat work
• Rats were infused with 0.625 mg/hr digoxin.
• After 20 mins, half received high dose glucose and insulin to keep glucose between 5.5 to 6.6 mmol/L.
• Time to death recorded
• Thirty minutes after digoxin infusion, plasma [K+] had risen in control group compared to insulin glucose group: 6.9 ± 0.5 mmol/L vs 4.9 ± 0.3 mmol/L.
• Effect on clinically important outcomes?
Effect of insulin dextrose on survival
0 30 60 90 120 150 1800
2
4
6
8
10 ControlInsulin glucose
insulinglucose/salinestarts
digoxin starts
Time
Surv
ival
Fructose 1,6 diphosphate (FDP) 1
• Intermediate of muscle metabolism – mechanism??
• Markov 1999, Vet Hum Toxicol. Effect of FDP in dog Nerium oleander poisoning.
• 12 dogs infused with 40mg/kg oleander extract over 5min
• Then half the dogs were infused with 50mg/kg FDP by slow IV bolus, followed by constant infusions.
Fructose 1,6 diphosphate (FDP) 1
• Intermediate of muscle metabolism – mechanism??
• Markov 1999, Vet Hum Toxicol. Effect of FDP in dog Nerium oleander poisoning.
• 12 dogs infused with 40mg/kg oleander extract over 5min
• Then half the dogs were infused with 50mg/kg FDP by slow IV bolus, followed by constant infusions.
Response of dysrhythmias to FDP
0 30 60 90 120 150 180 210 240
0
1
2
3
4
5
6
ControlFDP
Time (mins post oleander)
Num
ber
of d
ogs
with
dysr
hyth
mia
Response of blood pressure to FDP
Response of plasma [K+] to FDP
Conclusions
• Cardiac glycoside toxicity is a common global problem
• Anti-digoxin Fab are an effective PK Rx but expensive
• Treatments based on a mechanistic understanding may also be effective but none have been trialed, perhaps due to the effectiveness of Fab
• FDP – if found to be effective, its safety and price make it a very attractive future therapy. Unfortunately, we do not yet know how FDP works!
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