Verapamil
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. Additional information |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
PHARMACEUTICALS
1. NAME
1.1 Substance
Verapamil
1.2 Group
Therapeutic group : calcium channel blockers; Class IV
antiarrhythmic drugs
1.3 Synonyms
Valeronitrile,5-((3,4-Dimethoxyphenethyl)
Methylamino)-2-(3,4-Dimethoxy-phenyl)-2-Isopropyl
5-((3,4-Dimethoxyphenethyl)Methylamino)-2-(3,4-Dimethoxy-
phenyl)-2-Isopropylvaleronitrile
[3-[ [2-(3,4-dimethoxyphenyl) ethyl]-methylamino] propyl]-3,4-
dimethoxy- -(1-methylethyl)benzeneacetonitrile
isopropyl- -(N-methyl-N-Homoveratryl)- -aminopropyl]-
3,4-dimethoxyphenylacetonitrile
Iproveratril, Isoptin, D 365, CP-16533-1
1.4 Identification numbers
1.4.1 CAS number
52 - 53 - 9
1.4.2 Other numbers
NIOSH/RTECS : YV 8300 000
UPDT : 7907
1.5 Brand names, Trade names
Calan (Searle); Cardibeltin (Pharma - Schwarz - Germany);
Cordilox (Knoll AG, Germany; Abbott); Cardimil; Dilacoron
(Knoll AG, Germany); Ikacor (Ikapharm, Israel); Isoptin (Knoll
AG, Germany; Isoptine (Biosédra, France); Manidon (Knoll AG,
Germany; Medinsa, Spain); Vasolan (Knoll AG, Germany); Veramil
(Yurtoglu, Turkey); Verapamil (Erco, Danemark; Orion, Finland)
Generic products are also available
1.6 Manufacturers, Importers
See section 1.5
2. SUMMARY
2.1 Main risks and target organs
The principal effects of verapamil are on the cardiovascular
system. It decreases atrioventricular conduction and has a
negative inotropic effect. It has a vasodilating action on
the vascular system.
2.2 Summary of clinical effects
Toxic effects occur usually after a delay of 1 to 5 hours
following ingestion. After IV injection, symptoms appear
after a few minutes.
The main cardiovascular symptoms are :
bradycardia and atrioventricular block (in 82 % of cases)
hypotension and cardiogenic shock (in 78 % of cases)
cardiac arrest (in 18 % of cases)
Pulmonary oedema may occur
Impairement of consciousness and seizures may occur and are
related to a low cardiac output.
Nausea and vomiting may be observed.
2.3 Diagnosis
The principal symptoms are due to the effects of verapamil on
the cardiovascula system. They include bradycardia,
atrioventricular block, hypotension, cardiogenic shock and
cardiac arrest. Pulmonary oedema, impairment of consciousness
and seizures may also occur.
ECG is the most relevant investigation in verapamil poisoning.
Measurement of blood verapamil concentrations are not useful
for clinical management.
Therapeutic blood concentrations may vary from 50 to 350
microgram/l
Metabolic acidosis due to shock and hyperglycaemia may occur.
2.4 First aid measures and management principles
Patients with verapamil overdose should be closely monitored
preferably in an Intensive Care Unit
Monitor vital signs : ECG, blood pressure, respiration,
diuresis, central venous pressure
Treatment may include :
emesis, early gastric lavage and oral activated charcoal
correction of hypotension and shock by alpha or/and beta
sympathomimetic agents
correction of atrioventricular block by betamimetic agents or
ventricular pacing
artificial ventilation and treatment of metabolic acidosis in
case of cardiogenic shock
treatment of cardiac arrest
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic substance
3.2 Chemical structure
C27H38N2O4
Formula
Molecular weight : 454.59
3.3 Physical properties
3.3.1 Properties of the substance
Viscous, pale yellow oil
Boiling point: 243-246°C
Practically insoluble in water, sparingly
soluble in hexane, soluble in benzene, ether,
freely soluble in the lower alcohols, acetone,
ethylacetate, chloroform
Verapamil hydrochloride: C27H39ClN2O4
Crystals, decompose at 138.5-140.5°C. The pH of
a 0.1 % aqueous solution is 5.25. Sparingly
soluble in chloroform. Soluble in ethanol,
isopropanol, acetone, ethyl acetate; freely
soluble in methanol.
3.3.2 Properties of the locally available formulation
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Shelf-life of the locally available formulation
To be added by PCC.
3.4.3 Storage conditions
Store tablets and ampoules at room temperature. Protect
ampoules from light.
3.4.4 Bioavailability
3.4.5 Specific properties and composition
4. USES
4.1 Indications
(Martindale, Goodman and Gillman, Drugdex)
Paroxysmal supraventricular tachycardia (PSVT):
Verapamil is the drug of choice for prevention and
treatment of PSVT.
Angina: Verapamil has been shown to be effective in the
treatment of angina pectoris.
Hypertension: Verapamil may be used as an alternative
treatment for mild or moderate hypertension. Verapamil
seems to be as effective as nifedipine or nicardipine
and does not produce reflex tachycardia. There is no
contraindication in patients with bronchospastic
diseases.
4.2 Therapeutic dosage
4.2.1 Adults
In arrhythmias
The initial dose for supraventricular tachycardia,
atrial fibrillation or atrial flutter is 5 to 10 mg
(0.075 to 0.15 mg/Kg) given as an IV bolus over 2
minutes (3 minutes in the elderly). A further dose of 5-
10 mg may be administered after 30 minutes if no
response is observed.
In angina pectoris
The daily oral dose ranges between 240 and 360 mg (80 to
120 mg three times daily). The half-life is prolonged
during chronic treatment; smaller doses may therefore
be given after 3 to 5 days of treatment (Shand 81,
Schwarz 82).
In hypertension
The initial recommended dose is one tablet (240 mg) of
sustained release verapamil, once daily. If necessary,
the daily dose should be increased to 480 mg.
Dosage in renal failure
No dosage adjustment is recommended in patients with
renal failure (Hamann et al, 1984)
Dosage in hepatic insufficiency
Dose reductions are required in hepatic insufficiency.
Dosage should be reduced to 20 - 30 % of the normal
oral dose (Drugdex; Somogyi et al, 1981) Intravenous
single doses should be reduced by half (Hamann et al,
1984)
Dosage in congestive heart failure
Dosage may be reduced due to a decrease of liver blood
flow.
4.2.2 Children
Infants up to 1 year
The recommended initial dose is 0.1-0.2 mg/Kg given as
an IV bolus under continuous ECG monitoring. This dose
may be repeated after 30 minutes if necessary. The
oral maintenance dose is 4-8 mg/kg/day.
Children 1-15 years
An initial dose of 0.1-0.3 mg/kg/day given as an IV
bolus is recommended. Doses should not exceed 5 mg. A
second dose may be administred after 30 minutes. The
oral maintenance dose is 4-8 mg/kg/day.
4.3 Contraindications
- Severe heart failure
- Second or third degree atrioventricular block
- Cardiogenic shock
- Severe hypotension
- Sick sinus syndrome
- Severe left ventricular dysfunction
- Hypersensitivity to verapamil
5. ROUTES OF ENTRY
5.1 Oral
Oral absorption is the most frequent cause of intoxication
5.2 Inhalation
Not relevant
5.3 Dermal
Not relevant
5.4 Eye
Not relevant
5.5 Parenteral
Cardiovascular toxicity was reported with IV doses much lower
than oral toxic doses (Benaim et al, 1972, Vaughan-Neil et al,
1972, Hattori et al, 1982, Lipman et al, 1982)
5.6 Other
Not relevant
6. KINETICS
6.1 Absorption by route of exposure
Oral: About 90 % of verapamil is absorbed from the
gastrointestinal tract. Absorption is rapid and the peak
plasma concentration is reached 30-120 minutes following an
oral dose. In a case of acute poisoning the calculated
half-time of absorption was 1.5 hours (Sauder et al, 1990).
Verapamil undergoes extensive first-pass metabolism by the
liver. Bioavailability ranges from 20 to 35% (Eichelbaum et
al, 1981) but it may vary in patients with underlying
disease: 13-14% in cardiac failure; 35 % in atrial
fibrillation; and 50-55% in cirrhosis (Drugdex; Somogyi et al,
1981).
6.2 Distribution by route of exposure
Oral: The volume of distribution is 2.4-6.2 l/Kg (Schomerus et
al, 1976; Mc Allister et al, 1982). In cirrhotic patients,
the apparent volume of distribution is higher than in control
patients (9.17 vs 6.15 l/Kg) (Somogyi et al, 1981)
Parenteral: Volume of distribution is 2.5-6.76 l/Kg (Dominic
et al, 1981; Mc.Allister et al, 1982; Eichelbaum et al, 1981)
in normal subjects, and this doubles in patients with
cirrhosis (Somogyi et al, 1981). 90 % of plasma verapamil is
bound to plasma protein. Verapamil crosses the placental
barrier and has also been found in breast milk.
6.3 Biological half-life by route of exposure
Parent Compound
Oral: The mean elimination half-life following single oral
doses is 2.8-7.4 hours (Shomerus et al, 1976; Knoll
Pharmaceuticals, 1984). After repeated or chronic doses,
the half-life increases to 4.5-12.0 hours (Knoll
pharmaceuticals, 1984; Schwartz et al, 1982; Shand et al,
1981). Sauder et al (1990) reported an elimination half-life
of 7.9 and 13.2 hours in two cases of acute poisoning.
Parenteral: Following IV administration, Dominic et al (1981)
reported a distribution half-life of 3.5 minutes and an
elimination half-life of 110.5 minutes.
Metabolites
The main metabolite is norverapamil which has an elimination
half-life very similar to that of the parent compound,
ranging from 4 to 8 hours (Reynolds, 1982; Mc.Allister et al,
1982; Piotrowski et al, 1986; Barberi et al, 1985)
6.4 Metabolism
Verapamil undergoes an extensive hepatic metabolism. Due to a
large hepatic first-pass effect, bioavailability does not
exceed 20 - 35% in normal subjects. Twelve metabolites have
been described. The main metabolite is norverapamil and the
others are various N- and 0-dealkylated metabolites (Knoll
Pharmaceuticals, 1984; Shomerus et al, 1976).
6.5 Elimination by route of exposure
Kidney
About 70% of the administered dose is excreted in urine within
5 days as metabolites, of which 3-4% is excreted as unchanged
drug (Eichelbaum et al, 1979; Knoll Pharmaceuticals, 1984).
Faeces
About 16% of the ingested dose is excreted within 5 days in
faeces as metabolites (Eichelbaum et al, 1979; Prod Info,
1984)
Breast milk
Verapamil may appear in breast milk.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
(Goodman and Gilman; Jaeger et al, 1990)
Verapamil is a calcium channel blocker and inhibits the
entry of calcium through calcium channels into
cardiovascular cells. Verapamil reduces the magnitude
of the calcium current entry and decreases the rate of
recovery of the channel. Channel blockade by verapamil
is enhanced as the frequency of stimulation increases.
Its action on cardiac tissue results in antiarrythmic
and negative inotropic effects.
Verapamil slows the spontaneous firing of pacemaker
cells in the sinus node in vitro. In vivo, this effect
is partially abolished by an increase in the
sympathetic activity due to arterial dilatation.
Verapamil decreases the rate of phase 4 spontaneous
depolarization in cardiac Purkinje cells. The most
marked effect of verapamil is a reduction in conduction
velocity through the A.V. node and a significant
increase in the functional refractory period.
Verapamil decreases peripheral vascular and coronary
resistance but it is a less potent vasodilator than
nifedipine. In contrast, its cardiac effects are more
prominent than those of nifedipine. At doses necessary
to produce arterial vasodilatation, verapamil has much
greater negative chronotropic, dromotropic and inotropic
effects than nifedipine. The intrinsic negative
inotropic effect of verapamil is partially offset by
the decrease in afterload and the reflex increase in
sympathic activity.
At toxic doses, calcium channel inhibition by verapamil
results in three principal effects:
hypotension due to arterial vasodilatation;
cardiogenic shock secondary to a negative inotropic
effect;
bradycardia and atrio-ventricular block.
7.1.2 Pharmacodynamics
The therapeutic effects of verapamil on hypertension and
angina pectoris are due to arterial systemic and
coronary vasodilatation. The antiarrhythmic activity of
verapamil is due to a delay in impulse transmission
through the AV node by a direct action.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
(Kozlowski et al, 1988; Coaldrake et al, 1984;
Mc Millan et al, 1987; Immonen et al, 1981;
Defaire et al, 1976; Hruby and Missliwetz 1985;
Moroni et al, 1980; Perkins 1978; Woie et al,
1985; Madera and Wenger 1977; Enyart et al,
1983; Mayer et al, 1985; Da Silva et al, 1979;
Candell et al, 1979; Terwee et al, 1985; Haegy
et al, 1979; Grosch and Zweigle 1979; Eckert et
al, 1988; Orr et al, 1982; Gris et al, 1989;
Hendren et al, 1989; Sauder et al, 1990)
Toxicity may occur after ingestion of 1 g.
Haemodynamic disturbances are dose-dependent:
hypotension or cardiogenic shock occurred in
45% of the cases when the dose ingested was 2 g
and in 100% of the cases when the dose exceeded
2 g (Sauder et al, 1990). Deaths have been
reported after overdoses of 1.4., 2.4. and 2.8 g
(Hendren et al, 1989; Madera et al, 1977; Mayer
et al, 1985). Recovery has been reported with
doses above 6 g (Immoney et al, 1981, Mc Millan
et al, 1988 : Coaldrake et al, 1984; Kozlowski
et al, 1988).
7.2.1.2 Children
No data available
7.2.2 Relevant animal data
Experimental IV intoxication has been described in rat,
dog or cat models (Strubelt et al, 1984; Hamann et al,
1987; Gay et al, 1984; Jolly et al, 1987; Agoston et al,
1984). In a dog intoxication model, an IV bolus of 200
g/kg followed with an infusion of 16 g/kg/min of verapamil
produced an hyperdynamic shock with severe hypotension, a
decrease in vascular resistance and an increase of cardiac
output. Heart rate was significantly reduced as the PR
interval increased. Higher doses in a similar protocol
(bolus of 720 g/kg and infusion dose of 110 g/kg/mn)
produced cardiogenic shock (Gay et al, 1984). These data
suggest that experimental overdosage in animal should
produce two different degrees of severity:
the first degree appears at "low" toxic doses and is
characterized by a cardiovascular collapse due to
decreased vascular resistance eventually associated
with bradycardia and/or atrioventricular block;
the second degree appears when toxic doses are increased
(Gay et al, 1984) or when beta-blocking agents are
given in association (Hamann et al, 1987; Jolly et al,
1987). This stage is characterized by a predominent
negative inotropic effect responsible for a cardiogenic
shock.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Verapamil is classified as Category C (United States
Pregnancy Classification) by the manufacturer (Knoll
Pharmaceuticals, 1987).
7.5 Mutagenicity
No data available.
7.6 Interactions
(Reynolds, 1982; Meyler; Drugdex)
Beta-blockers: Hypotension, atrioventricular block, left
ventricular failure and asystole have been reported after IV
administration of verapamil to patients receiving beta-
blockers. Combined IV beta-blocker and IV verapamil
therapy is contraindicated. Although oral verapamil combined
with oral beta-blockers has been recommended in some cases of
angina, this combination should be avoided in patients with
impaired left ventricular function.
Digoxin: Increase in digoxin half-life. Impairment of renal
and extra-renal clearance of digoxin.
Amiodarone: Sinus arrest and A-V block
Calcium salts: Antagonism of the effects of calcium channel
blockers.
Quinidine: Hypotension in patients with hypertrophic
cardiomyopathy.
Theophylline: Increase in serum theophylline levels may give
symptoms of toxicity.
Disopyramide: Additive negative inotropic effects.
Antibiotics: Reduction of verapamil concentrations in
tuberculous patients treated with rifampicin, isoniazid and
ethambutol. It is sugggested that the metabolism of verapamil
is enhanced by induction of hepatic enzymes by rifampicin.
Carbamazepine: Increase of plasma carbamazepine levels by
inhibition of carbamazepine metabolisation with subsequent
neurotoxicity.
Cimeditine: Controversial data concerning effects on verapamil
bioavailability have been reported.
Cyclosporin: Increase in serum cyclosporin concentrations due
to inhibition of cyclosporin metabolism.
Dantrolene: Hyperkalaemia and cardiac depression
Lithium: Decrease of serum lithium concentration with
exacerbation of manic psychosis.
Oral hypoglycaemic drugs: Improvement of glucose tolerance in
non-insulin dependent diabetes mellitus.
7.7 Main adverse effects
The following adverse reactions have been reported during
verapamil treatment:
Cardiovascular
Hypotension is the most frequent side effect associated with
intravenous verapamil injection; hypotension was also reported
after oral administration of verapamil.
Heart failure has been reported in patients with impaired
cardiac function and in patients treated with beta-blockers
and verapamil.
Supraventricular tachycardia
Heart block: atrioventricular block has been reported after
verapamil IV injection in patients on digitalis treatment.
Ventricular fibrillation and cardiac arrest: 5 cases of
cardiac arrest after IV verapamil injection in patients with
Wolf-Parkison-White syndrome have been reported (Mac Govern et
al, 1986)
Central nervous system
Rare episodes of dizziness, headache, drowsiness and fatigue
have been described after oral administration. One case of
dystonia with jerking movements has been reported (Hicks and
Abraham, 1985).
Endocrine - metabolic
Lipid abnormalities: an increase in triglycerides and VLDL-C
levels in patients with hyperlipidemia.
Gynaecomastia: 18 cases reported during prolonged verapamil
treatment.
Gastrointestinal
Nausea, diarrhoea and constipation (6.3%) are sometimes
reported.
Hepatoxicity
Transient elevation of SGOT and SGPT
Rare cases of hepatotoxicity have been reported in patients
after 2-3 weeks treatment
Respiratory
In a series of 120 patients treated with verapamil for a
cardiomyopathy, 8 developed pulmonary oedema with a fatal
outcome in 3 cases.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
Routine biomedical investigations, i.e. sodium,
potassium, creatinine and/or urea, glucose.
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
Should be performed.
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
Hyperglycaemia has been reported. Acidosis may occur in
shock. Verapamil may be measured in biological fluids
but levels are not useful or necessary for the
management of verapamil poisoning.
Plasma
Following chronic administration, therapeutic plasma
concentrations of verapamil are 50-350 g/l.
In 6 patients with acute verapamil poisoning, plasma
levels ranged from 845 to 7,266 g/l (Enyart et al,
1983; Gris et al, 1989; Kozlowski et al, 1988; Orr et
al, 1982; Ter Wee et al, 1985; Woie & Storstein 1981).
Higher levels (up to 85,000 g/l) were measured in
fatal overdose.
Urine
Verapamil concentrations in urine are 3,300-25,204 g/l
during the first 24 hours after ingestion (Sauder et al,
1990). The renal clearance of verapamil is less than
2% of total body clearance (Sauder et al, 1990)
Tissues
Tissue analyses in patients with fatal outcome show very
high concentrations in the liver (29-400 mg/kg) and in
the kidney (30-140 mg/kg) (Chan et al, 1987; Weller and
Wolf, 1984; Thompson and Ranneil, 1981).
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Symptoms usually appear within 1 to 5 hours of ingestion
and may include hypotension, bradycardia,
atrioventricular block, cardiogenic shock, cardiac
arrest.
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
The effects are similar to those observed after
ingestion.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
9.2.2 Inhalation
9.2.3 Skin exposure
9.2.4 Eye contact
9.2.5 Parenteral exposure
9.2.6 Other
9.3 Course, prognosis, cause of death
Course: Symptoms appear within 1-5 hours after ingestion and
may persist for up to 48 hours (Haegy et al, 1979)
Prognosis is worse if:
the dose was higher than 2 g
cardiogenic shock occurs
other cardiotoxic drugs, especially beta-blockers, have also
been ingested
there is an underlying cardiac insufficiency
If the patient has not developed cardiac arrest or postanoxic
coma during the 48 first hours, recovery is usual.
Death may occur within a few hours after ingestion. It is
associated with irreversible shock and/or atrioventricular
block (Madera et al, 1977; Meyer et al, 1989; Orr et al,
1982).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute:
Cardiovascular symptoms are dose-dependent; they occur
in 45% of the cases when the dose ingested is less than
2 g, and in 100% of the cases when the dose exceeds 2 g
(Sauder et al, 1990).
Hypotension
Hypotension is due to arterial vasodilatation and the
negative inotropic effect of verapamil. In a review of
28 cases of acute verapamil poisoning in adults,
hypotension was present in 22 cases (mean
systolic arterial pressure 54 mmHg) (Sauder et al,
1990). In a series of 21 cases (7 adults and 14
children) reported by Schlagenhaufen and Keller (1987),
hypotension was present in 18 cases.
Cardiogenic shock
In the cases reviewed by Sauder et al (1990), 11 of the
22 patients who had hypotension developed cardiogenic
shock.
Sauder et al (1990) reported cardiogenic shock in 2
patients who had ingested verapamil and beta-blockers.
A haemodynamic study performed in one case showed a
strong decrease in cardiac index (1.3 l/min/m›) despite
treatment with positive inotropic agents (epinephrine
0.8 g/kg/min and isoproterenol
0.2 g/kg/min).
Bradycardia
Bradycardia is the commonest symptom and occurs within
the first hour of ingestion. In the 28 cases reviewed
by Sauder et al (1990), heart rate ranged between 30
and 100 beats/min with a mean of 55 beats/min.
Bradycardia is often associated with atrioventricular
block.
Atrioventricular block
Atrioventricular block, associated mainly with a
junctional rhythm, is a frequent feature and is present
in 82% of cases (Sauder et al, 1990). There is no
correlation between the ingested dose and
atrioventricular conduction disturbances which may be
seen with doses lower than 1 g (Hruby et al, 1985;
Immoven et al, 1981; Eckert et al, 1988). Third degree
AV block occurred in 90% of cases; first or second
degree AV block is less frequent (10% of the cases).
Recovery of normal sinus rythm occurs between 5 and 48
hours.
Cardiac arrest
In the cases reviewed by Sauder et al (1990), 5 patients
developed cardiac arrest with a fatal outcome in 3
cases (Immonen et al, 1981; Madera et al, 1977; Mayer
et al, 1985; Hruby et al, 1985; Orr 1982).
Chronic: No data available.
9.4.2 Respiratory
Acute: Pulmonary oedema may occur and is due to
cardiogenic shock.
Chronic: No data available.
9.4.3 Neurological
9.4.3.1 CNS
Acute
Drowsiness and confusion have been reported.
Coma due to cerebral hypoxaemia may occur in
severe shock.
Seizures occured in a child who had ingested 400
mg verapamil (Passel & Crespin, 1984).
Chronic: No data available.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Acute: Nausea and vomiting are common.
Chronic: No data available.
9.4.5 Hepatic
No data available.
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
No data available.
9.4.9 Eye, ear, nose, throat: local effects
No data available.
9.4.10 Haematological
No data available.
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Acidosis may be seen in cardiogenic shock.
9.4.12.2 Fluid and electrolyte disturbances
No data available.
9.4.12.3 Others
Hyperglycaemia may occur but is rather rare
(Mc Millan et al, 1987; Enyart et al, 1983;
Da Silva et al, 1979; Gris et al, 1989).
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
No data available.
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Patients with verapamil overdose should be closely monitored
preferably in an intensive care unit. Monitor vital signs,
including ECG, blood pressure, central venous pressure,
urine
output and respiration.
Treatment may include correction of hypotension or shock, AV
block and artificial ventilation. Early gastric lavage
and/or emesis is indicated in recent ingestion. Forced
diuresis and extrarenal elimination are ineffective and not
recommended.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood samples for verapamil analysis should be drawn
in plastic tubes with heparin.
10.2.2 Biomedical analysis
A biochemical profile including glucose, BUN,
electrolytes, creatinine, enzymes and blood gases
should be obtained on admission.
10.2.3 Toxicological analysis
Verapamil analysis in biological fluids is not
necessary for management of the poisoning.
10.2.4 Other investigations
10.3 Life supportive procedures and symptomatic/specific
treatment
Observation and monitoring
Monitor vital signs systematically, including ECG, blood
pressure and central venous pressure. Insert a venous
catheter for hydration and drug injection. If shock is
present, a haemodynamic study by a Swan Ganz catheter may
be useful for guiding treatment.
Hypotension and shock
Experimental studies on verapamil intoxication showed that
sympathomimetic agents are the drugs of choice for the
treatment of haemodynamic and conduction disturbances. Beta
agonists reverse the negative inotropic, dromotropic and
chronotropic effects. However, beta agonists are effective
in reversing hypotension only if they are combined with
alpha agonists (Schomerus et al, 1976). Calcium salts
reverse
haemodynamic effects of verapamil but are ineffective in
A.V. block. Drugs which directly or indirectly enhance
intracellular calcium availability should have a
complementary effect; these include calcium salts, glucagon,
phosphodiesterase III inhibitors (Amrinone, Enoximone,
Milrinone), beta agonists (dobutamine, orciprenaline,
isoproterenol).
In an experimental model of verapamil toxicity, 4-
amidopyrine
increased the heart rate and the blood pressure (Shand et al,
1981).
Apha and beta agonists (sympathomimetics)
Alpha and beta sympathomimetic drugs such as dopamine or
epinephrine are recommended at very high doses if
necessary. Dopamine should be given at a dose of 10
g/kg/min and increased up to 20 - 30 g./kg/min if necessary.
Epinephrine is a better alternative and should be used at a
dose of 0.25 g/kg/min which should be increased up to 1
g/kg/min if needed (Sauder et al, 1990).
It may be necessary to monitor haemodynamic parameters with
a
thermodilution Swan-Ganz catheter to evaluate the relative
importance of arterial vasodilatation and of negative
inotropic effects. If arterial vasodilatation is dominant,
it should be corrected with an alpha agonist such as
norepinephrine, which should be given at high doses
sufficient to restore the normal level of systemic vascular
resistance. However, if negative inotropic effects are
dominant, it is justifiable to increase the dose of
epinephrine to normalize the cardiac output.
Calcium salts
Calcium gluconate 10% may be given at a dose of 0.2 to 0.5
ml/kg over 5 to 10 minutes and may be repeated as needed.
Calcium chloride 10% may be used at a dose of 10 to 20 ml
in adults and 20 mg/kg in children.
Glucagon has been used in some cases (Hruby et al, 1985)
Amrinone was used successfully in one case (Sauder et al,
1990). An IV bolus of 1 mg/kg over 5 minutes increased the
cardiac index significantly from 2.22 to 3.43 l/min/m›, and
the left ventricular stroke work index from 21 to 39
gm/m›/beat, in a patient who was treated with
epinephrine 0.8 g/kg/min and with isoproterenol 1.3
g/kg/min.
Atrioventricular block
Atropine is ineffective. Complete AV block should be treated
with high doses of beta agonists such as isoproterenol.
Administer isoproterenol at a dose of 0.3 g/kg/min and
increase in 0.2 g/kg/min increments as needed; epinephrine
may also be effective. Calcium salts are not very effective
in AV block. If the conduction disturbances do not respond
to
beta agonists, cardiac pacing may be necessary.
Respiratory failure - pulmonary oedema
Respiratory failure should be treated by artificial
ventilation. Early artificial ventilation is also
indicated in patients with cardiogenic shock.
10.4 Decontamination
Emesis is indicated in recent ingestion.
Gastric lavage is indicated in recent ingestion and should
be
performed under strict ECG and blood pressure monitoring.
The efficacy of activated charcoal has not been established.
However, it is reportedly useful in diltiazem poisoning
(Jaeger et al, 1990a). Repeated doses of activated
charcoal may be useful in cases of poisoning with verapamil
sustained-release forms.
10.5 Elimination
Forced diuresis is ineffective. Toxicokinetic studies show
that less than 2% of the dose ingested is eliminated in the
urine (Sauder et al, 1990).
Haemodialysis was ineffective in one case of acute verapamil
poisoning (Ter Wee et al, 1985).
10.6 Antidote treatment
10.6.1 Adults
The benefit of calcium salts has not been established
in acute verapamil intoxication (See section 10.3.).
10.6.2 Children
10.7 Management discussion
Patients with verapamil poisoning should be closely
monitored, preferably in an intensive care unit as soon as
possible.
Outside of an intensive care unit
Recent ingestion and no cardiotoxic symptoms: perform
emesis
and/or gastric lavage and give oral activated charcoal
Cardiotoxicity present: atrioventricular block - give
isoproterenol; shock - treat with dopamine or epinephrine.
Transfer the patient to an intensive care unit.
In the intensive care unit
Monitor vital signs (ECG, blood pressure, central venous
pressure, respiration) and biochemical parameters
Gastric lavage and oral activated charcoal in recent
ingestion. Symptomatic treatment of respiratory distress.
Atrioventricular block: give isoproterenol
Hypotension, shock: give sympathomimetic drugs with alpha
and
beta agonists such as dopamine or preferably epinephrine.
Calcium salts, glucagon or phosphodiesterase inhibitors may
be given. If the shock does not respond to these measures,
perform a haemodynamic study in order to adapt the
treatment.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Schlagenhaufen and Keller (1987) reported a series of 21
cases of acute verapamil poisoning (7 adults and 14
children) collected by the Swiss Toxicological Information
Center. Hypotension was present in 18 cases, AV block
occured in 11 cases, fatal outcome was reported in 2 cases.
Korlowski et al (1988) reported a case of acute poisoning
with 9.6 g of sustained-release verapamil. The patient
developed cardiogenic shock (blood pressure 40 mmHg) and
3rd degree atrioventricular block. Peak serum verapamil
concentration was 2,814 g/l. Supportive treatment included
isoprenaline, dopamine, calcium salts and ventricular
pacing. The patient recovered.
Mayer et al (1985) reported a case of fatal poisoning with
2.4 g of a substained-release form of verapamil in a 60 year-
old woman. Haemodynamic study showed 2 stages: first, a
hyperdynamic state with decreased systemic vascular
resistance; then cardiogenic shock with decreased
contractility which became rapidly unresponsive to inotropic
agents.
Passal and Crespin (1984) reported a case of accidental
intoxication with 400 mg of verapamil in a 11 month-old
girl. She developed coma, seizures, respiratory depression,
bradycardia and hypotension. She was successfully
resuscitated with intravenous calcium chloride,
isoproterenol and dopamine.
11.2 Internally extracted data on cases
Sauder et al (1990) reported six cases of verapamil
poisoning with doses of 1.2-9.6 g. Cardiogenic shock was
present in two cases and AV block in four cases. The two
patients who presented with cardiogenic shock had also
ingested beta-blockers. All patients recovered without any
complications.
A toxicokinetic study was performed in two cases and showed
peak serum levels of 951 and 185 g/l; serum half-lives of
7.9 and 13.2 hours, total body clearances of 425 and 298
ml/min, respectively. Only 2% of the ingested dose was
eliminated in urine.
A haemodynamic study performed in one patient with
cardiogenic shock showed a marked decrease in cardiac index
(1.3 l/min/m2) and in left ventricular stroke work index
(11 gm/m2/beat). Haemodynamic parameters improved with
treatment with high doses of epinephrine, isoproterenol,
amrinone and calcium salts.
11.3 Internal cases
To be added by the PCC.
12. Additional information
12.1 Availability of antidotes
12.2 Specific preventive measures
12.3 Other
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Sauder Ph, Kopferschmitt J, Flesch F, Jaeger A
Service de Réanimation Médicale et Centre Anti-Poisons
CHU, Pavillon Pasteur
67091 Strasbourg Cedex
France
Tel: 33-88161144
Fax: 33-88161330
Date: 27 March 1991
Peer Review: Adelaide, Australia, April 1991