117: Strychnine

Strychnine alkaloid occurs naturally in Strychnos nux-vomica, a tree native to tropical Asia and North Australia, and in Strychnos ignatii and Strychnos tiente, trees native to South Asia. The alkaloid was first isolated in 1818 by Pelletier and Caventou.^5,15 It is an odorless and colorless crystalline powder that has a bitter taste when dissolved in water. Besides strychnine, the dried seeds of S. nux-vomica contain brucine, a structurally similar, although less potent, alkaloid.⁸⁸ Strychnine is available from commercial sources in its salt form, usually as nitrate, sulfate, or phosphate.

Strychnine was first introduced as a rodenticide in 1540, and in subsequent centuries was used medically as a cardiac, respiratory, and digestive stimulant,⁴⁵ as an analeptic,⁹² and as an antidote to barbiturate⁹¹ and opioid overdoses.⁵⁹ Nonketotic hyperglycemia,^9,36,80 sleep apnea,⁷⁶ and snake bites¹⁵ were also once considered indications for strychnine use. In 1982, at least 172 commercial products were found to contain strychnine, including 77 rodenticides, 25 veterinary products, and 41 products made for human use.⁸³ However, the use of strychnine was substantially decreased; some countries such as the European Union banned its use as a rodenticide in 2006, and most of its prior medicinal indications are no longer utilized. Currently, strychnine is used as a rodenticide (for moles, gophers, and pigeons) and a research tool for the study of glycine receptors. Most commercially available strychnine-containing products contain about 0.25% to 0.5% strychnine by weight.⁸³

Between 1926 and 1928, strychnine killed more than three Americans every week.^5,27 In 1932, it was the most common cause of lethal poisoning in children,^5,83,98 and one-third of the unintentional poison-related deaths in children younger than 5 years were attributed to strychnine.⁶⁰ Currently, strychnine poisoning is rare and continues to decrease in the United States, although deaths are still reported. The Toxic Exposure Surveillance System (TESS) and National Poison Data System (NPDS) data of the American Association of Poison Control Centers (AAPCC) reported 1414 strychnine exposures during the past 10 years (2002–2011), with only eight deaths (Chap. 136).

Strychnine poisoning has resulted from deliberate exposure with suicidal and homicidal intent,^27,50 as well as from unintentional poisoning by a Chinese herbal medicine (Maqianzi)¹⁶ and a Cambodian traditional remedy (slang nut).^47,49,51,86 Maqianzi is used to treat limb paralysis, severe rheumatism, and inflammatory disease, whereas slang nut is used to treat gastrointestinal illness. The bitter taste of strychnine allows it to be used to adulterate heroin⁴³ and cocaine.^13,22,64 There are also reports of strychnine poisoning from adulterated amphetamines,²²3,4-methylenedioxymethamphetamine (MDMA),²⁵ Spanish fly,¹² and from the ingestion of gopher bait.⁵²

Standard references list the lethal dose of strychnine as approximately 50 to 100 mg^{18,33,34,70,94} (1–2 mg/kg). However, mortality resulting from doses as low as 5 to 10 mg and, alternatively, survival following ingestions of 1 to 15 g of strychnine are reported.^6,18,82,97 Some of this variation may be attributed to the route of administration, with parenteral administration being more toxic than oral, and the limitations of self-reported exposure quantities.

Strychnine is rapidly absorbed from the gastrointestinal tract and mucous membranes. There is a case of reported poisoning as a result of dermal absorption of strychnine from an alkaline solution, in which strychnine exists in the nonionized, alkaloid form.³⁵ Protein binding is minimal, and strychnine is rapidly distributed to peripheral tissues⁹³ with a large volume of distribution (13 L/kg).⁴⁰ Based on postmortem findings, the highest concentrations of strychnine are found in the liver,^57,70,78 bile,⁷⁰ blood,⁷⁰ and gastric contents.^70,78 Relatively less strychnine is identified in kidney, urine, and brain.⁷⁸

Strychnine is metabolized by hepatic cytochrome P450 isozymes, mainly CYP3A4^1,53,61 producing strychnine-N-oxide as the major metabolite,¹ the toxicity of which is about one-tenth of that of the original alkaloid.⁵⁵ This metabolism is increased by P450 induction.^44,48 Several urinary metabolites are identified,⁶⁵ and 1% to 30% of strychnine is excreted unchanged in urine,^10,39,69 in decreasing proportions when larger amounts are ingested.^81,93 Strychnine follows first-order kinetics with an elimination half-life of 10 to 16 hours.^26,69,95

Glycine, one of the major inhibitory neurotransmitters in the spinal cord, opens a ligand-gated chloride (Cl^–) channel, thus allowing the inward flow of Cl^– (Fig. 14–12).²⁰ As Cl^– moves inward, the cell becomes hyperpolarized, reducing neuronal excitability. Strychnine competitively inhibits the binding of glycine to the α-subunit of the glycinergic chloride ­channel.^13,19,96,98 Although strychnine affects all parts of the central nervous ­system in which glycine receptors are found, the most significant effect is in the spinal cord. With loss of the glycine inhibition at the motor neurons in the ventral horn, there is a loss of inhibitory influence on the normally suppressed reflex arc. The result is increased impulse transmission to the muscles, producing generalized muscular contraction. Rabbits pretreated with glycine had a 40% increase in the strychnine “seizure” threshold, illustrating the competitive nature of strychnine and glycine activity on the glycinergic ­chloride channel.^17,77 Tetanus toxin (tetanospasmin) causes an identical clinical syndrome of muscular contractions but does so by preventing the release of presynaptic glycine and does not function as a competitive antagonist. In dogs, strychnine also has positive chronotropic and inotropic effects on the heart,⁸⁴ but this effect is unlikely to exert a major effect in human poisoning.

Oral strychnine poisoning is characterized by a rapid onset of signs and symptoms beginning within 15 to 60 minutes of ingestion³² and, although less well documented, effects begin even sooner after parenteral or nasal administration. Delayed onset of clinical effects are rarely reported.^23,34 The typical findings of poisoning are involuntary, generalized muscular contractions resulting in neck, back, and limb pain. The contractions are easily triggered by trivial stimuli (such as turning on a light), and each episode usually lasts for 30 seconds to 2 minutes.⁸³ These episodes may recur for as long as 12 to 24 hours. Differences in the strength of various opposing muscle groups result in the classic signs of opisthotonus, facial trismus, and risus sardonicus, with flexion of the upper limbs and extension of lower limbs predominating. Hyperreflexia, clonus, and nystagmus^11,62 are also evident on examination. Because strychnine affects glycine inhibition mainly in the spinal cord, the patient typically remains fully alert until metabolic complications arise. The combination of convulsive motor activity involving both sides of the body in the conscious patient has often resulted in imprecise descriptions such as “conscious seizure” or “spinal seizure.” Hemodynamically, both hypotension,^24,26,64 or hypertension^13,29,63 in the presence of bradycardia^14,24,26,64 or tachycardia^13,14 are reported. Hyperthermia, presumably from increased muscular activity, is typical, and temperatures as high as 109.4°F (43°C) are reported.¹³ Other nonspecific signs and symptoms include dizziness, vomiting, and chest and abdominal pain.⁶²

Early in the course of strychnine poisoning, mortality is mainly due to hypoventilation and hypoxia secondary to muscular contractions.²⁹ Life-threatening complications include rhabdomyolysis with subsequent myoglobinuria and acute kidney injury,¹⁴ hypoxia or hyperthermia-induced multiorgan failure, aspiration pneumonitis,⁸⁵ anoxic brain injury, and pancreatitis.⁴² Rarely, local neuromuscular sequelae such as weakness, myalgia, and anterior tibial compartment syndrome are reported.¹³ As might be expected, the prognosis is related to the duration and extent of the episodes of muscle contractions.³¹

The diagnosis of strychnine poisoning is mainly established on clinical grounds, based on exposure history and compatible clinical manifestations, but can be confirmed by detection of strychnine in biological specimens. Several diagnoses need to be considered, the most important of which is tetanus because it produces similar muscular hyperactivity. In a patient with tetanus, however, the onset of symptoms is more gradual and the duration much longer than in the case of strychnine poisoning. Frequently, the diagnosis of tetanus is suggested by a history of recent injury, or the finding of an obvious wound. In general, patients with tetanus have either undocumented or incomplete tetanus immunization.

Strychnine poisoning can be differentiated from generalized seizures by the presence of a normal sensorium during the period of diffuse convulsions. That is, most patients with bilateral convulsions are having generalized seizures, which by definition involve the reticular activating system, producing unconsciousness. It is conceivable, although extraordinarily rare, to have bilateral focal seizures producing apparent “generalized” convulsions. In this case, because the reticular activating system may not be involved, the mental status of the patient may be preserved. The presence of consciousness in a patient with a generalized convulsion may be sufficient to establish the diagnosis of strychnine poisoning or tetanus at least in the early phase of the clinical course. As time progresses and management is delayed this finding may be obscured by metabolically induced alterations in sensorium.¹⁷ When there is an alteration in the level of consciousness, an electroencephalogram may be helpful, to document the presence or absence of a seizure focus. A computed tomography scan of the head can help to exclude structural brain lesions, and a lumbar puncture is helpful to exclude meningitis or encephalitis. Hypocalcemia, hyperventilation, and myoclonus secondary to kidney or liver failure are evaluated by appropriate routine laboratory testing. Although a drug induced dystonic reaction should be considered when there is a relevant history, dystonic reactions are usually static, whereas strychnine poisoning results in dynamic muscular activity. Serotonin toxicity, malignant hyperthermia, neuroleptic malignant syndrome, and stimulant associated toxicity should be considered if the medical history is supportive.

Respiratory and metabolic acidosis both occur commonly in strychnine-poisoned patients. Metabolic acidosis is associated with elevated serum lactate concentrations,¹³ whereas respiratory acidosis secondary to hypoventilation results from diaphragmatic and respiratory muscle failure. Survival of patients with serum pHs in the range of 6.5 to 6.6 is well documented.^{13,29,30,32,54,95} The lowest pH and highest lactate concentration reported in a patient who subsequently had full recovery was 6.5 and 32 μmol/L,^13,95 respectively. Thus, profound acidemia in strychnine poisoning is not necessarily associated with a poor prognosis.^7,8,13,73 In contrast to the metabolic acidosis with elevated lactate concentration that occurs in shock, the elevated lactate concentration of strychnine poisoning results from overactivity of the muscle instead of undersupply or underutilization of oxygen and nutrients.

Besides acidemia, other laboratory abnormalities expected from prolonged muscular activity include hyperkalemia and those associated with rhabdomyolysis and acute kidney injury.¹³ There is also stress-induced leukocytosis,^13,42 elevated liver enzyme concentrations,^42,62,90 hypocalcemia,^13,40 hypernatremia,³² and hypokalemia.^28,62,85 The electrocardiogram is expected to remain normal or reflect changes consistent with the above electrolyte disturbances.⁴⁰ Chest radiography may show evidence of aspiration pneumonitis or acute respiratory distress syndrome.

Strychnine can be detected by a variety of methods such as thin-layer chromatography,^66,89 high-performance liquid chromatography,² ultraviolet spectrometry,⁶⁶ a simple colorimetric reaction,⁶⁶ gas chromatography–mass spectrometry,^14,57,69,78 gas chromatography flame ionization detector,⁹⁴ and capillary electrophoresis.⁹⁹ With the exception of the bedside colorimetric reaction, none of these tests are routinely available in a time frame useful to assist in clinical decisions. Strychnine is also detectable in amounts as low as 0.01 mg/L in tissue,^2,21,58,72 and strychnine resists postmortem putrefaction. Additionally, even when available, quantitative concentrations do not correlate with clinical toxicity. Reported blood strychnine concentrations in fatal poisoning ranged from 0.5 to 61 mg/L.⁹⁴ Conversely, the highest initial blood concentration associated with survival was 4.73 mg/L from blood drawn 1.5 hours postingestion⁹⁵; a concentration as low as 0.06 mg/L was found in a patient who solely had muscular irritability.²⁶

In patients with strychnine poisoning, inducing vomiting is absolutely contraindicated because of the risk of aspiration and loss of airway control following rapid onset of muscle contractions. Gastric lavage should be considered on an individual basis after evaluating potential benefits and risks.³ When gastric lavage is thought to be indicated, it may be important to protect and secure the airway with an endotracheal tube before attempting lavage. Activated charcoal (AC) binds strychnine effectively at a ratio of approximately 1:1; 1 g of AC will bind 950 mg of strychnine.^4,88 In animal models, pretreatment⁶⁷ and posttreatment⁷¹ with AC increase the median lethal dose in 50% of test subjects (LD₅₀) for strychnine. Clinical evidence of the effectiveness of AC for strychnine ingestion was first demonstrated in 1831, when Professor Touery survived the ingestion of a lethal dose of strychnine by using AC in a demonstration before the French Academy of Medicine.

Currently, there is no evidence to recommend the use of multiple-dose AC or whole-bowel irrigation for strychnine poisoning. Although forced diuresis was once suggested as an effective means of enhancing the elimination of strychnine,⁸⁸ subsequent data failed to demonstrate an increase in clearance⁸¹ and it is therefore no longer recommended. Peritoneal dialysis, hemodialysis, and hemoperfusion have not been extensively studied. However, because strychnine is rapidly distributed to the tissues⁹³ with a large volume of distribution (13 L/kg), extracorporeal drug elimination procedures are unlikely to be useful and therefore not justified given their risks.

Supportive treatment remains the most important aspect of management in the majority of cases. The focus of care is to stop the muscular hyperactivity as soon as possible to prevent the metabolic and respiratory complications. At all times, unnecessary stimuli and manipulation of the patient should be avoided, as these activities trigger muscle contractions. Benzodiazepines remain the first line treatment for strychnine induced muscular hyperactivity.^83,95 Although much of the evidence concerning the efficacy of benzodiazepines is based on clinical experience with diazepam,^38,46,64 any of the other commonly used benzodiazepines (midazolam or lorazepam) would likely have similar effects. The initial dose of the benzodiazepine chosen should be the standard dose used for other indications, although doses of more than 1 mg/kg diazepam or its equivalent may be needed.^41,56 In case of failed intravenous access, lorazepam or midazolam can be given intramuscularly or intraosseously. Dosing should be repeated until the patient demonstrates muscle relaxation and the contractions cease. In addition to benzodiazepines, barbiturates and propofol are also effective, although considered secondary therapies, in stopping the strychnine-induced hyperactivity.^37,51,74,87 Benzodiazepines and barbiturates both work through agonism of γ-aminobutyric acid (GABA) receptor chloride complexes to increase the inhibitory neurotransmission to the spinal cord from the brain, and thus raise the reflex arc threshold.⁷⁹ If these measures fail to control the muscular hyperactivity, a nondepolarizing neuromuscular blocker (NMB) should be administered. Only nondepolarizing NMBs should be used, as succinylcholine itself, a depolarizing NMB, induces muscle contractions.^{13,26,51,64,81} It is important to remember that strychnine has no direct effects on consciousness, so that sedation must always accompany neuromuscular blockade. Generally, therapy is continued for about 24 hours, at which time the benzodiazepines and or NMBs can be tapered as tolerated.

The most important therapy for the metabolic complications of strychnine poisoning is to expeditiously stop the production of metabolic byproducts by terminating the muscular hyperactivity. Hyperthermia should be treated rapidly by active cooling with ice water immersion, cooling blanket, or mist and fan, depending on the magnitude of temperature elevation. Means to prevent rhabdomyolysis induced acute kidney injury include adequate fluid administration to ensure good urine output (> 1 mL/kg/h), the potential use of urinary alkalinization with sodium bicarbonate,⁷⁵ and temporary renal replacement therapy, if acute kidney failure occurs. Metabolic acidemia rapidly resolves when muscular activity is controlled.^13,68

Effective management in the first few hours of strychnine poisoning is crucial for survival. If the patient can be supported adequately for the first 6 hours, this may be considered a good prognostic sign.^13,34 All significantly poisoned patients should be managed in an intensive care unit with the help of a regional poison center or a medical toxicologist. For patients unintentionally exposed to strychnine who remain asymptomatic, an observation period of 12 hours is sufficient to exclude significant risk.

• Strychnine is a lethal poison that is no longer frequently encountered, except in areas where it is used as a rodenticide.

• A “conscious seizure” is the characteristic presentation of strychnine toxicity, and is rapidly followed by life threatening metabolic and respiratory consequences.

• The mainstay of treatment is supportive care with the goal of rapidly terminating muscular contractions, providing adequate airway management, and rapidly treating hyperthermia and or metabolic abnormalities.

• Although benzodiazepines are generally sufficient, neuromuscular paralysis with a nondepolarizing NMB may be required.

• Generally, the prognosis of strychnine poisoning is good, if the patient can be adequately supported and survives the first few hours of toxicity.

References