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!