Transcript Calcium channel blockers

Calcium channel blockers
Professor Ian Whyte
Hunter Area Toxicology Service
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Calcium channel blockers
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Phenylalkylamines
– verapamil
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Benzothiazepines
– diltiazem
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Dihydropyridines
– nifedipine, felodipine, nimodipine,
nicardipine, amlodipine, lercanidipine
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Calcium channel blockers
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Block calcium channels (L-type) in
heart and blood vessels
– prolong depolarisation
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↑QRS width
– block SA and AV node conduction
heart block
 asystole
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– vasodilators
– cerebral protection
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Calcium channel blockers
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Hypotension
– peripheral vasodilatation and myocardial
depression
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Bradycardia
– AV and SA node block
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Antidotes
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Correction of acidosis
Calcium loading
Glucagon
Insulin-dextrose euglycaemia
Atropine
Inotropic agents
Cardiac pacing
Bay K 8644 (calcium channel agonist)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Correction of acidosis
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Correct acidosis to a pH within the normal
range
– L calcium channel function is impaired when the
pH falls outside the physiological range
– acidosis enhances the effect of verapamil and
decreases the effect of calcium
– sodium bicarbonate significantly improved
myocardial contractility and cardiac output in a
swine model of verapamil poisoning
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Calcium loading
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Calcium loading is the most logical
and appears to be the most effective
agent to use in calcium channel
blocker poisoning
It is primarily indicated in patients
with heart block (who have usually
taken verapamil or diltiazem)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Glucagon
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Glucagon is a well-accepted antidote
for beta-blocker poisoning
The rationale for its use in CCB
poisoning is that it activates myosin
kinase independent of calcium flux
Clinical experience suggests it is less
effective in this setting than in betablocker poisoning
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin-dextrose euglycaemia
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Insulin infusions should be used to treat
hyperglycaemia or hyperkalaemia
Insulin-dextrose euglycaemia is more
effective in animal models than calcium,
adrenaline or glucagon
Effective in a case series of clinically
serious poisonings
Hypotension that is refractory to volume
loading, correction of acidosis and calcium
salts
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin-Euglycaemia
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Insulin as an inotrope
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–
myocardial ischaemia/infarction
endotoxic shock
cardiogenic shock post cardiopulmonary bypass
CCB and –blocker induced myocardial depression
Yuan TH, Kerns WP, Tomaszewski CA,Ford MD, Kline
JA. Insulin-glucose as adjunctive therapy for severe calcium
channel antagonist poisoning. J Tox Clin Tox 1999; 37(4):
463–474
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin-Euglycaemia
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Rationale
– In unstressed, aerobic state the
myocardium relies primarily on free fatty
acids (FFAs) for mechanical energy
– During shock, substrate preference shifts
from FFAs to carbohydrate oxidation
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin-Euglycaemia
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In the presence of
– inhibition of insulin release
– insulin resistance
– poor tissue perfusion
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impaired glycolysis and carbohydrate
delivery
Systemic hyperglycaemia and
inefficient myocardial energy transfer
– myocardial depression
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Insulin-Euglycaemia
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Hypokalaemia
– Shift of extracellular K+ to intracellular via
Na+/K+ pump
– Na+ shift means resting membrane potential
becomes more negative (hyperpolarisation)
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decrease arrhythmias
– Prolongs plateau phase of action potential
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increases calcium entry
– Aim for K+ 2.8–3.2
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Replace if K+ < 2.5
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Atropine
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Vagal tone is increase by vomiting and
gastrointestinal decontamination
Atropine should be given to all
patients who are vomiting or having
GI decontamination
Atropine should be given to all
patients with bradycardia
A response may only occur after
calcium loading
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Inotropic agents
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Dopamine is the initial pressor agent of
choice (75% response) for diltiazem
overdose
Isoprenaline produces a therapeutic response
in 50% of patients
Action is predominantly through increasing
the frequency of impulses originating in the
SA node
These agents are often ineffective as
chronotropic agents when there is a high
degree of conduction block
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Cardiac pacing
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Ventricular rather than atrial pacing
In severe poisoning the heart may fail
to capture and pharmacological
therapy will still be required
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Calcium channel agonists
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Calcium channel agonists (eg. Bay K
8644) would appear to be a logical
antidote
Animal studies using these compounds
have not been very promising
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital