SUBJECT FORENSIC SCIENCE

Paper No. and Title PAPER No.10: Forensic Toxicology

Module No. and Title MODULE No. 17: Cardiac Poisons

Module Tag FSC_P10_M17

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction and Forensic Issues

3. Classification of Cardiac Poisons

3.1 Cardiotoxic Plant Poisons

3.2 Diuretics

3.3 Antihypertensives

3.4 Antiarrhythmics

4. Summary

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

1. Learning Outcomes

After studying this module, you shall be able know about-

 The significance of Cardiac Poisons  The classification of Cardiac Poisons  The forensic importance of Cardiac Poisons

2. Introduction and Forensic Issues

Cardiac poisons have mainly actions on the heart, either directly on the musculature or through its nerve supply. These poisons generally produce deleterious effect on the action of the heart, due to poisoning of the cardiac muscle or of its conducting system. Mostly, the cases reported before a forensic laboratory related to Cardiac poisons are due to accidental poisoning by plants containing certain compounds (glycosides or alkaloids) which are poisonous in nature and effect. In this line the best known cardioactive glycoside is Digitalis purpurea (foxglove). However, others exist in the lily family, such as squill, which contains scillaren, and lily of the valley which contains convallatoxin in the bulbs, that have actions similar to digitalis. Also, milkweeds (Asclepias species, Asclepiadaceae) contain glycosides. The desglucouzarin in Asclepias asperula, like digitalis, inhibits Sodium- Potassium - ATPase. Two plants in the Apocynaceae also contain cardioactive glycosides. Apart from the plant borne poisons certain chemical compositions are also responsible for deaths due to cardiac abnormalities. Such chemicals may be involved in medical practice, e.g., Medicines related to Blood Pressure and other Cardiac irregularities. Most cases of antihypertensive drug overdose are accidental (for e.g. in children), or suicidal. Paediatric poisoning arises out of parental negligence rendering these and other dangerous pharmaceutical preparations easily accessible to toddlers. Tragically, deaths have occurred in some cases. Among the various antihypertensives, the beta blockers have frequently been implicated in serious poisoning, with propranolol being the commonest agent implicated. Reserpine increases suicidal tendency among patients. Extended or sustained release antihypertensives are generally associated with prolonged and more profound effects in overdose. Similarly, use of Diuretics may disbalance the osmoregulation of the body system which may ultimately affect the cardiovascular functioning. There are certain drugs which are although taken for the treatment of Cardiac dysfunctioning, but they may affect adversely which could be lethal.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3. Classification of Cardiac Poisons

3.1 CARDIOTOXIC PLANT POISONS

3.1.1 Nicotiana tabacum (Tobacco) Nicotine is a colourless, hygroscopic liquid alkaloid. Preparations of nicotine are extensively used in agriculture and horticulture for fumigating and spraying, as insecticides, fumigants, vermin paste, worm-powder, sheep dip etc. The dried leaves of the plant Solanaceae comprise of the tobacco used for smoking. These leaves of tobacco (tambaku) contain 1-8% of nicotine and are used in the form of smoking, snuff and for chewing. They are used for the preparation of cigars, cigarettes, bidis and powdered tobacco is used as a snuff. The tobacco is also consumed by mixing with lime alone (khaini) or with lime and betel. Nicotiana species contains Nicotine, Nornicotine, Anabasine and Anabatine as alkaloids. By far, the commonest source of nicotine poisoning, whether acute or chronic, results from smoking tobacco in the form of cigarettes. When a cigarette is lit and inhaled, the smoker is exposed to both gaseous and particulate matter. Nicotine is very toxic and exists in all parts of the plant, in combination with malic acid and citric acid. Poisoning is usually accidental resulting from excessive smoking or application of leaves or juice to the wound or abraded surface may lead to the absorption of the poison. Suicidal and homicidal poisoning is rare. Concentrated liquid nicotine is exceedingly dangerous. However, tobacco is much less poisonous than would be expected from its nicotine content when smoked. Nicotine poisoning can occur from ingestion or application over skin and by inhalation. Nicotine binds to nicotinic receptors, which are present mainly on the CNS, spinal cord and neuromuscular junctions. It also binds to Autonomic Nervous System and adrenal medulla. It first stimulates the vagus nerve, and then depresses the autonomic, central and spinal nervous system. In small doses, it contracts pupil but in larger doses, it causes dilatation. Cardiovascular manifestations include slow pulse at first and then rapid, Blood Pressure is raised and arrhythmias also develop. Death occurs due to respiratory failure. The Fatal dose is 60-100 mg of nicotine and 15-30 gm of crude tobacco, whereas the fatal period is 5-15 minutes.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3.1.2 Digitalis Purpurea Digitalis purpurea or commonly known as Foxglove is cultivated in whole of Jammu and Kashmir of India and all over the World. The entire plant of digitalis purpurea is toxic. Only leaves are used for medicinal purposes. The active principles in the form of glycosides are present in the leaves, roots and seeds of the plant. There are about more than thirty glycosides out of which only four are important, of this Digitalin, Digitoxin and are cardiac stimulants whereas Digitonin is cardiac depressant. The poisoning by digitalis is mostly accidental as it is used in different types of cardiac diseases and over doses do occur. Poisoning occurs due to intake of overdose of medicinal preparation accidentally but also it is sometimes used for homicidal purposes. Digitalis being a cumulative poison, accidental death may occur in susceptible individuals. The chief action of the poison is on the heart due to its glycosides content. In the heart, it prolongs the period of systole in cardiac cycle, regulates the rhythm of the heart by depressing both excitability and conductivity, shortens the period of diastole and causes rise of blood pressure. In toxic doses, there is increased impulsiveness of the heart, toxic arrhythmias and develops leading to . The poison first acts on the gastro intestinal tract then the cardiovascular system.

3.1.3 Aconite Commonly, Aconite is known as Mitha bish, Mitha zahar, Bikh, Monk’s hood, Blue Rocket, Bear’s foot. The plant Aconite is grown in garden for its attractive flowers in the Himalayan ranges in India. Aconitum napellus belongs to the family Ranunculaciae. All parts of nearly all the varieties of the plant are poisonous but the root is chiefly used as poison. There are several species of aconite out of which aconitum ferox and aconitum napellus are commonly used as poison. It has no odour but is sweetish in taste hence the name Mitha Bish. On chewing, tingling and numbness in the tongue, lips and mouth is felt. Aconite species contain diterpene and norditerpene alkaloids, the nitrogen molecule of which is usually ethylated or methylated to make them alkamines. Diterpenes are relatively low in , but the esterified, norditerpene bases have high toxicity. Indian species contain hypoaconitine and mesoaconitine which are less potent. The poison first stimulates the sensory nerve endings, producing tingling sensation then paralyzing them causing numbness. It produces similar effect on the motor and secretory nerve endings, the centres of the medulla and cord, while the higher centres are always left out.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

The alkaloids depress the myocardium, smooth muscles and skeletal muscles. Its depressant effect on motor ganglia and cardiac muscles produces heart block. As aconite is largely used as medicine, accidental poisoning is common. It is also given with betel leaf to mask its taste and sometimes added with liquor to increase its intoxicating effect. It is used as arrow poison in hilly areas.

3.1.4 Nerium odorum The plant grows wildly all over the country. It is also grown in gardens for its beautiful pink and white flowers. All parts of the plant are poisonous. Powdered roots are used for the treatment of venereal diseases, epilepsy, malaria, skin diseases and menstrual disorders by the quacks. The powdered roots are also applied as paste to treat ulcerations and cancerous growths. Decoction of the leaves may be applied to reduce swelling of body. The known active principles are Nerin, Oleandrin and Karabin. The fatal Dose for Powdered root is 15- 20gm, whereas, for Neriodorin and karabin it is150 mg. The signs and symptoms of nerium poisoning includes slow Pulse rate which becomes weak and feeble in late stages, fall of blood pressure and cardiac arrhythmias. Exhaustion and drowsiness leads to insensibility, collapse and coma. Death occurs from heart failure.

3.1.5 Cerbera thevetia The plant is also known by the names of Bastard oleander, Pila kaner etc. Similar to Nerium odorum, Cerebra is widely cultivated in gardens in India. All parts of the plant are highly poisonous. The powdered bark of the plant may be used as an antipyretic like Cinchona in the dose of 125mg but in little bigger dose, it acts as an emetic and purgative and in further bigger dose, it is poisonous. The milky juice from nearly all parts of the plant gives out the active principles which are cardiac glycosides, of these Thevetin and Thevetoxin can be recovered from the kernels of seeds. Cerberine, another alkaloid, is a neurotoxic and acts in a similar manner as of strychnine. Thevetin is a powerful cardiac . The action of Thevetoxin and Nerifolin is similar to digitalis. Thevetin contained in the acid ether extract obtained by subjecting the viscera of suspected yellow oleander poisoning to Stas-Otto procedure can be recognized by Keller’s Test. Accidental poisoning of Cerebra can occur from ingestion of powdered root or decoction for treatment and common in children. The powdered roots, decoction of leaves or paste of the fruit may be ingested for committing suicide. It is not used for homicidal purpose but commonly used as cattle poison that is given mixed with the cattle fodder. The paste is commonly smeared on the abortion stick to be used as an abortifacient. The powdered root or seeds are taken after mixing with food or drink to cause abortion.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3.1.6 Cerbera odallam This plant closely resembles that of Cerbera thevetia that grows wild in the swamps and the creeks of the seacoasts of India. The plant has a dark, fleshy lanceolate leaves similar to jasmine and the fruit resembles unripe mango. Milky juice exudes out from all parts of the plant. The kernels yield non-poisonous oil that is used for burning. The kernel contains a glycoside Cerberine and alkaloid Cerebroside that has digitalis like action. Usually in poisoning cases, death results from heart failure.

3.1.7 Hydrocyanic Acid Hydrocyanic acid is a vegetable acid that is widely distributed in nature in many fruits and leaves. Here it exists in the form of harmless glucoside known as amygdalin, which, coexist with the enzyme emulsion in the kernels of various fruits such as peaches, plums, apricots, bitter almonds, Bamboo shoots, certain oil seeds and beans and leaves of cherry laurel and bitter almonds. The emulsion can readily hydrolyse amygdalin in presence of water to form hydrocyanic acid, glucose and benzaldehyde. It is present in the leaves of Cherry laurel in the strength of .08-0.1% and 10% in oil of bitter almonds. Several people suffer from the effects of hydrocyanic acid poisoning after eating some of bitter almonds. Liquid hydrocyanic acid when pure is a highly volatile colourless liquid having a peculiar odour of bitter almonds or peach-kernels. The hydrocyanic acid is usually obtained by distilling Potassium Cyanide or Potassium Ferrocyanide with dilute Sulphuric Acid. Hydrocyanic Acid is decomposed in neutral or alkaline solution with formation of ammonia.

3.2 DIURETICS

Diuretics are the drugs that increase the rate of urine formation. In general, the diuretics act directly on the kidney tubules to yield the desired clinical effects. Clinically, diuretics are used to control hypertension, to reduce oedema and as an adjunct in treating congestive heart failure. Despite the widespread use of diuretics in medical practice, acute overdoses involving these agents are fortunately quite rare. Most reported cases of toxicity are actually related to chronic use. Long-term diuretic use to treat hypertension has recently been associated with the development of type 2 diabetes. Cardiovascular abnormalities include bradycardia, conduction defects, sinus arrest, and hypotension. Cardiovascular symptoms have only been reported after chronic therapy and not from an acute ingestion.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3.3 ANTIHYPERTENSIVES

Antihypertensives are a class of drugs that are used to treat hypertension or commonly known as high blood pressure.

3.3.1 Reserpine

Reserpine, an alkaloid present in the root of the Indian plant Rauwolfia serpentina, has been used for treating hypertension for decades. Related alkaloids include alseroxylon, deserpidine, raubasine, and rescinnamine. Reserpine is readily absorbed following oral and intramuscular dosing. Reserpine and its congeners reduce catecholamines and serotonin superficially and centrally from nerve terminal fibers. The resulting responses exhibit as CNS depression and peripheral sympatholysis. The adverse effects of reserpine include orthostatic hypotension, dizziness, blurred vision, bradycardia, nausea, vomiting, diarrhoea, and impotence. In addition, it often induces depression. Overdose produces reflective CNS depression. Victims may initially demonstrate hypertension and for up to one day followed by hypotension and bradycardia.

3.3.2 Methyldopa

Methyldopa acts centrally through an active metabolite, alphamethyl- noradrenaline, to lower blood pressure. It is an antihypertensive, whose specific mechanism of action is uncertain. However, Methyldopa may induce life-threatening effects such as haemolytic anaemia, hepatitis, pancreatitis, and myocarditis, apart from a myriad other lesser effects including headache, drowsiness, depression, oedema, bradycardia, nasal stuffiness, nightmares, disorders of sexual function, gynaecomastia, galactorrhoea, dryness of mouth, and nightmares. Acute overdosage of methyldopa may result in severe hypothermia, dry mouth, nausea, vomiting, hypotension, dizziness, weakness, lethargy, coma and bradycardia. Paraesthesias, headache, weakness, involuntary movements, and psychic disturbances have been reported.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3.3.3 Clonidine

Clonidine is an imidazoline compound with potent alpha 2- adrenergic agonist effects. At high doses, it has been shown to act as a peripheral partial alpha-adrenergic receptor agonist, resulting in stimulation of the peripheral post-synaptic alpha2- receptors, thus temporarily increasing blood pressure and pulse rate. Apart from its utility in hypertension, clonidine is also used in the treatment of attention deficit disorder, prophylaxis of migraine, and management of ethanol, opiate, and nicotine withdrawal. Its adverse effects include Dry mouth, drowsiness, orthostatic hypotension, insomnia, agitation, myalgia, arrhythmias, and Gastro-intestinal distress. Abrupt withdrawal of clonidine can be life-threatening. Withdrawal effects include agitation, tremor, palpitations, insomnia, severe hypertension, nausea, and vomiting. Even otherwise, rebound hypertension is common.

3.4 ANTIARRHYTHMICS

The antiarrhythmic drugs are primarily used to treat cardiac arrhythmias. A cardiac arrhythmia is a disturbance or irregularity in the heart rate, rhythm, or both, which requires administration of one of the antiarrhythmic drugs. An arrhythmia may occur as a result of heart disease or from a disorder that affects cardiovascular function. Conditions such as emotional stress, hypoxia, and electrolyte imbalance also may trigger an arrhythmia. General adverse reactions common to most antiarrhythmic drugs include light-headedness, weakness, hypotension, bradycardia, and drowsiness. All antiarrhythmic drugs may cause new arrhythmias or worsen existing arrhythmias, even though they are administered to resolve an existing arrhythmia. This phenomenon is called the proarrhythmic effect. This effect ranges from an increase in frequency of premature ventricular contractions (PVCs), to the development of more severe ventricular tachycardia, to ventricular fibrillation, and may lead to death.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

3.4.1 Procainamide

Procainamide is an antiarrhythmic agent with electrophysiologic properties similar to that of quinidine. Its primary effects on the heart are to decrease electrical impulse conduction velocity through atrial and ventricular tissue. Overdose of procainamide results in arrhythmias (ventricular tachycardia, junctional tachycardia),

3.4.2 Lignocaine

Lignocaine is an aminoacyl amide, and is a synthetic derivative of cocaine. It is used as an anaesthetic agent as well as antiarrhythmic agent. It is effective in controlling ventricular arrhythmias. Adverse Effects includes vertigo, drowsiness, confusion, ataxia, dysarthria, hearing loss, visual disturbances, agitation, convulsions, cardiovascular collapse, and coma.

3.4.3 Fenopraine

Fenopraine or Propafenone is an antiarrhythmic drug which blocks the fast sodium channel of the myocardial cell. It has some negative inotropic and beta-adrenoceptor blocking activity. Propafenone is structurally related to propranolol and is administered orally for the treatment of life-threatening ventricular arrhythmias. Adverse Effects includes Bradycardia, cardiac conduction anomalies, hypotension, proarrhythmias, worsening of heart failure, vertigo and headache.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons

4. Summary

 Common Cardiotoxic plants include the following: aconite, azalea, death camas, false hellebore, foxglove, lily of the valley, meadow saffron, mountain laurel, common oleander, yellow oleander, rhododendron, suicide tree, and yew.

 Several of the cardiotoxic plants contain various cardiac glycosides which act in similar fashion. Some of these glycosides are useful in pharmacotherapeutics (e.g. digitalis derived from foxglove).

 Both digoxin and digitoxin are well absorbed orally, but while the former is only moderately protein bound. Digitalis glycosides inhibit active transport of sodium ion and potassium ion across cell membranes by binding onto a specific site on the extracytoplasmic face of the alpha subunit of Na+-K+- ATPase.

 Poisoning with aconite has never been common. Most reported cases are accidental in nature, resulting from therapeutic misadventures.

 Accidental poisoning from Nerium is due to its use in traditional medicine. Suicidal ingestion of decoction prepared from leaves or root is fairly common in rural areas. All the glycosides of Nerium have digoxin-like effects as they also inhibit sodium-potassium ATPase.

 Hydrocyanic acid is the liquefied form of hydrogen cyanide, and is a bluish-white liquid with a faint, bitter almond odour.

 Overdose of Anti-hypertensives like Clonidine may result in bradycardia progressing to heart block, hypotension, hypothermia, CNS depression and sporadic apnoea. Sometimes there is inconsistent hypertension. Clonidine poisoning is much more severe in children as compared to adults.

FORENSIC SCIENCE PAPER No. 10: Forensic Toxicology MODULE No. 17: Cardiac Poisons