Illustrated Handbook of Toxicology (eBook)

Alkaloids

Atropine

The tertiary nitrogen compound atropine (A) is a pharmaceutical drug used as an antidote for poisoning with parathion (E605). It is also used as an anticholinergic, bronchodilator, antispasmodic, antiparkinsonian, and mydriatic.

Atropine is potentially deadly. Eating as few as 3–5 berries of the deadly nightshade Atropa belladonna (A) can kill a child, and 10–20 berries are lethal for adults. Especially in children, intoxication is frequently caused when medication is confused with eye drops containing atropine. Nevertheless, lethal incidents are rare despite the dramatic symptoms, thanks to the characteristic symptoms of poisoning, the wide therapeutic window (or index), and the excellent treatment options.

The alkaloid hyoscyamine (see p. 268) undergoes racemization into atropine, and this explains why the two compounds lead to similar symptoms of poisoning. Hyoscyamine is found in several species of the nightshade family (see p. 268).

Signs of intoxication. Typical symptoms of poisoning (B) include parasympatholytic (anticholinergic) peripheral and central effects, depending on the dose of atropine administered. A dose of 0.5–1.0 mg causes mild bradycardia, dry mouth and skin, and minor dilatation of the pupils. Doses of 2.0 mg and more result in tachycardia, accelerated pulse, intense thirst, mydriasis, and impaired accommodation. With doses of 5.0 mg and more, the above symptoms are more pronounced, and the inhibition of glandular secretion results in hoarseness, difficulty in swallowing, and impaired speech; restlessness and headache are also observed, and body temperature may rise (hyperthermia) as the result of impaired sweat secretion. Because of disturbed regulation, the skin appears dry, hot, and bright red, especially in the face. Effects on the intestinal muscles manifest themselves as reduced intestinal peristalsis (obstipation) and lack of tonus, and/or effect on the genitourinary tract as voiding difficulties leading to urinary retention. Doses of 10 mg and more have additional effects on the central nervous system, such as restlessness, clonic spasms, frenzy, confusion, delirium, and hallucination. This phase of excitement may turn into a state of exhaustion associated with deep unconsciousness. Death occurs as the result of central respiratory paralysis.

Above a dose of 1.5 mg/kg BW, atropine is life-threatening to adults. A dose of 10–20 mg/ kg BW is definitely fatal; the lethal dose for children is 1–10 mg/kg BW.

Therapy. The initial treatment of atropine poisoning (C) consists of general measures, such as gastric lavage and administration of activated charcoal to prevent further absorption of the poison. In addition, the vital functions of respiration, body temperature, and micturition must be maintained by artificial respiration, thermolytic physical measures (e.g., a cold bath), and forced diuresis by means of a bladder catheter. Oral and ocular mucosae need to be moistened. Small IV doses of benzodiazepines (diazepam) or short-acting barbiturates are administered for sedation. The indirect parasympathomimetic physostigmine salicylate is considered the most effective antidote. This cholinesterase inhibitor can abolish the peripheral symptoms and, unlike pyridostigmine and neostigmine, also the central symptoms. It is administered by means of IM injection or slow IV infusion at a dose of 0.5–2.0 mg/kg BW for adults and 0.02 mg/kg BW for children. Since the antagonist is rapidly metabolized, one repeat administration of 1 mg/20 min (preferably as a brief infusion) is indicated if there is prolonged decrease in vigilance.

Colchicine

The alkaloid of the meadow saffron Colchicum autumnale (A) is a mitotic poison. It is also the drug of choice for treating acute attacks of gout. Most cases of poisoning are therefore not caused by accidental ingestion of seeds and leaves but by therapeutic overdosage.

The lethal dose is 20 mg colchicine (5 g of seeds) for adults and 5mg (1.25 g of seeds) for children.

Signs of intoxication. The symptom-free latency period lasts for up to 6 hours after ingestion. It is followed by acute symptoms of poisoning (B), such as gastrointestinal problems (bloody diarrhea, colicky abdominal pain, nausea, and vomiting). Cholera-like diarrhea with vomiting is accompanied by symptoms that manifest themselves first in the mouth and throat as a scratchy feeling, burning, and difficulty in swallowing, and then as a choking feeling and cyanosis (C). Later in the course of poisoning, the symptoms include bone marrow depression, blood clotting disorders, kidney damage, hepatonecrosis, dehydration, electrolyte imbalances, generalized spasms, and ascending paralysis. Death occurs after 2 or 3 days due to cardiac arrest, respiratory failure, or sepsis.

Therapy. Emergency procedures include detoxification by induction of vomiting, administration of activated charcoal, and gastric lavage. To interrupt enterohepatic cycling, an indwelling duodenal catheter is used for continuous aspiration of the duodenal juice. Plasma volume expanders are administered for shock treatment.

Morphine and Opioids

These drugs (D) have a central stimulant action and are potent analgesics. Because of the potential risk of causing addiction, they are subject to national drug regulations, e.g., the Controlled Substances Act in the United States.

Signs of intoxication. The cardinal symptoms of acute poisoning (E) include extreme miosis, somnolence or coma, and respiratory depression (2–4 breaths/min). The central respiratory paralysis (hypoxia) usually observed after 7–12 h is often preceded by Cheyne-Stokes respiration and cyanosis. Furthermore, there are symptoms of circulatory collapse, hypotension, bradycardia, hypothermia, loss of tone, areflexia, flush, and pulmonary edema. Plasma concentrations of 0.1 mg/L and higher are toxic, and concentrations above 0.5 mg/L are dangerous. The lethal dose of morphine in adults is >0.1 g after parenteral application and 0.3–1.5 g after oral application (maximum daily dose 200 mg). Infants are much more sensitive (lethal dose 30 mg).

Chronic morphine poisoning (E) is called morphinism, a state of physical and emotional dependence. Opioid addicts suffer from spastic obstipation and disturbed micturition, and they have constricted (“pinpoint”) pupils. Characteristic changes also include weight loss, impotence, all kinds of infections, and physical and mental deterioration.

Therapy. In acute cases of poisoning with morphine or its derivatives (as well as synthetic opioid analogs such as pethidine, methadone, and pentazocine), emergency procedures include artificial ventilation with oxygen and shock treatment. Administration of the specific antidote naloxone hydrochloride (0.4 mg/mL) (D) is used to counteract oxygen deprivation as quickly as possible. Intravenous application of this short-acting opioid antagonist abolishes the central depressant and peripheral effects of opioids within minutes. The initial dose is 0.4 mg IV or IM (for children 10 µg/kg BW) every 2–3 min until the respiratory depression ceases and a maximum dose of 2–4mg in total is reached. Since morphine antagonists trigger life-threatening withdrawal symptoms in morphine addicts (ventricular fibrillation, collapse), the dose of the antagonist in such cases should be reduced and the dosage interval shortened. Stimulation of central a2-receptors by clonidine (17 µg/kg BW per day) diminishes the norepinephrine-mediated withdrawal symptoms.

Ergot Alkaloids

These mycotoxins occur in the sclerotium (A) of the ergot fungus Claviceps purpurea, which grows as a parasite in the ears of cereal plants, especially rye (Secale cereale). The isolated alkaloids are used as pharmaceuticals for treating circulatory disorders, headaches, and migraine, and for stopping postpartum hemorrhages.

In medieval times, epidemic mass poisonings with ergot-contaminated rye frequently caused ergotism, associated with gangrene and central nervous system disorders. Peripheral vasoconstriction caused hands and feet to die off, with dry gangrene accompanied by burning pain.

Signs of intoxication. The most potent of these vasoconstrictive alkaloids is ergotamine (B), a derivative of lysergic acid (see p. 92). Acute poisoning by ingestion is characterized by nausea, vomiting, abdominal pain, diarrhea, paresthesia (tingling in fingers and toes), coldness and numbness in the extremities, and central nervous system symptoms, such as headache, vertigo, anxiety, spasms, dyspnea, and mydriasis (C). Exceeding the maximum daily dose of ergotamine (>10 mg) results in circulatory collapse and unconsciousness. Respiratory paralysis and cardiac arrest may then lead to death. As a result of long-term use at high dosage (chronic poisoning), irreversible vascular damage occurs, thus leading to gangrenous tissue (C). However, this occurs only after extensive vasospasms, ischemia, necrosis, and endothelial damage associated with thrombus formation.

Therapy. Treatment of acute poisoning after ingestion consists of eliminating the poison by administration of activated charcoal, gastric lavage with sodium sulfate, and hemostatic measures, such as dextran infusion and heparin administration. Arterial vasospasms associated with ergotism are treated with organic nitrites (e.g., amyl nitrite), nitroglycerine (0.4 mg sublingually), or papaverine (30–60 mg...