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Clinical Toxicology Lec=4 • CNS Stimulants :Camphor •CNS Depressants: oBarbiturates oMoth • , Benzodiazepines &Chlorahydrate Repellent Camphor  Camphor has long been used externally as a rubefacient, mild analgesic, antipruritic, and counterirritant . However, the variety of proprietary...

Clinical Toxicology Lec=4 • CNS Stimulants :Camphor •CNS Depressants: oBarbiturates oMoth • , Benzodiazepines &Chlorahydrate Repellent Camphor  Camphor has long been used externally as a rubefacient, mild analgesic, antipruritic, and counterirritant . However, the variety of proprietary products containing camphor (Acne products, Analgesic (external) products, Antitiussive; congestion products, and Hemorrhoidal products). Camphorated oil(180mg/ml) has been the largest single cause of camphor-related poisonings. Most poisonings have  occurred because victims mistook it for castor oil. One teaspoonful of camphorated oil may result in serious toxicity in adults Mechanism of Toxicity The precise mechanism for inducing toxic symptoms is elusive. Camphor stimulates the brain at all levels. Signs and symptoms of camphor poisoning may appear within 5 to 15 min after ingestion, or be delayed for several hours on a full stomach. Because it is highly lipid soluble, camphor enters the CNS quickly. Burning in mouth, throat, and stomach ,Dizziness , hallucinations, Dyspnea .Cold, clammy skin Face alternately pale and flushed, Pulse rapid and weak. Irritation, excitement, convulsions ,Depression following CNS stimulation. Muscle tremors and rigidity, Urinary retention, anuria Transient hepatic damage. Any odor of camphor on the breath or in urine should be considered positive for camphor poisoning. Death is from status epilepticus or respiratory failure. If the victim survives, there are usually no residual problems extending beyond the initial encounter  Camphor must be removed from the stomach as quickly as possible. Immediate emesis or gastric lavage is indicated (before convulsions and generalized stimulation occur). Activated charcoal should follow. Lavage should be continued until the odor of camphor is no longer detected.  It has been suggested that whenever the quantity ingested is unknown, it should be assumed the amount was greater than 1 g, and the patient should be vigorously treated .  Barbiturates have long been used to control convulsions, but diazepam is generally preferred because it produces less respiratory depression.  Hemodialysis will hasten removal of camphor from the blood.  Succinylcholine may be used to help control muscular rigidity andspasm. As with any other CNS stimulant, the patient must be kept quiet and at minimum sensory input. CNS Depressants Numerous drugs possess CNS-depressant activity. These include many sedative-hypnotic agents (Table 14.1). Dozens of other drugs that are used for various pharmacologic purposes produce sedation as an adverse effect. Also, many chemicals cause drowsiness and CNS depression as a major component of toxicity. drugs used for sedative (anti-anxiety) and hypnotic (sleep producing) effects. sedative drugs were the agents to treat a wide variety of neurologic and psychologic disorders ranging from minor anxiety and pain, to epilepsy, hypertension, and psychosis Initially, opioids, bromides, and alcohol were used, but were later replaced by barbiturates, chloral hydrate, meprobamate, and similar compounds. More recently, benzodiazepine derivatives have dominated the market. A newer hypnotic, zolpidem, has been marketed recently as an agent that has even less potential to cause toxicity in overdose. Today, most sedative-hypnotic drug-related poisonings are due to barbiturates or benzodiazepines. Whereas poisoning with a barbiturate requires intensive care, benzodiazepine intoxications do not normally require aggressive treatment for survival. Barbiturates These drugs were divided into three groups based on latency of onset and duration of action. • Short-acting barbiturates include: pentobarbital and secobarbital. • Intermediate-acting barbiturates include: amobarbital and butabarbital. • Long-acting barbiturates, such as phénobarbital and barbital. Their major action is the production of sedation, hypnosis, or anesthesia through CNS depression. The effect, however, depends largely on the dose, mental status of the patient or individual at the time of ingestion, duration of action of the drug, the physical environment while under the influence, and tolerance of the individual to this class of drugs. Shorter-acting barbiturates are more lipid soluble. Hence, they reach higher CNS concentrations and cause greater depression than phenobarbital. Furthermore, toxic blood concentrations of phenobarbital are more readily decreased by hemodialysis and alkaline diuresis than similar blood concentrations of shortacting barbiturates Barbiturate poisonings are common in intentional (suicidal) poisonings, but less frequently encountered in accidental Poisoning. One of the reported contributing factors to barbiturate poisoning is drug automatism.To illustrate, assume that an individual consumes a prescribed dose of sedative and becomes drowsy. Later, not remembering that he has already taken a previous dose(s), he swallows another dose. This act may be repeated again and again until a potentially lethal quantity has been consumed Mechanism of Toxicity CNS depression accounts for all of the toxic manifestations of barbiturate poisoning. The drugs bind to an allosteric site on the GABA-Cl- ionophore complex (gamma-aminobutyric acid), an inhibitory neurotransmitter, in presynaptic or postsynaptic neuronal terminals in the CNS. This complex formation prolongs the opening of the chloride channel. Ultimately, by binding to GABAA receptors, barbiturates diminish the action of facilitated neurons and enhance the action of inhibitory neurons. • Respiratory depression is the major toxic event that follows barbiturate ingestion and usually causes early death. At a dose approximately three times greater than needed for hypnosis, the body’s neurogenic driving force for breathing is eliminated . Hypoxic and chemoreceptor forces are also depressed. This, then, contributes to acid-base imbalances characteristic of barbiturate poisoning. • Hypothermia is another potentially serious problem that follows toxic ingestions of barbiturates. Lowered body temperature results from direct depressant action on the thermoregulatory centre. It potentiates acidosis, hypoxia, and shock. • Sympathetic ganglia are depressed with larger doses. This may help explain why toxic barbiturate doses reduce the blood pressure. Normal doses do not cause significant cardiovascular effects, but only slight decreases in blood pressure and heart rate, as would be expected during sleep. • High concentrations have direct myocardial suppressant actions, causing decreased force of contraction with reduced cardiac output. Decreased gastrointestinal motility and tone, which may lead to increased drug absorption. • Bullous lesions on the fingers, buttocks, and around the knees have been reported in about 6% of all patients with acute barbiturate poisonings and may be helpful in differential diagnosis of an unconscious patient. • Chronic barbiturate (ab)use is associated with the development of tolerance which is responsible for decreasing the therapeutic to toxic index. An addict may obtain therapeutic benefit only with 5 to 6 times the normal dose. Abrupt withdrawal results in anorexia, tremor, insomnia, cramps, seizures, delirium, and orthostatic hypotension. Signs and symptoms of acute toxicity Signs and symptoms of barbiturate poisoning are related directly to CNS and cardiovascular depression. Reactions are dose-dependent and vary from mild sedation to complete paralysis. Clinical signs and symptoms are more reliable indicators of clinical toxicity than plasma concentrations. This is especially true when CNS depression does not correlate with plasma concentrations, an indication that other CNS depressants may be involved. Clinical management of acute overdose  Gastric lavage can be done with benefit upto 12 to 24 hours postingestion.  Multiple dose activated charcoal has been shown to greatly increase phenobarbitone elimination  Forced alkaline diuresis is said to be particularly useful in Phenobarbitone . no value in the treatment of short acting barbiturate  intoxication. Barbiturate elimination can be increased by haemodialysis and should be reserved for patients with haemodynamic compromise refractory to aggressive supportive care.  For hypotension: First administer isotonic intravenous fluids and place in Trendelenburg position.. If the patient is unresponsive to isotonic fluid therapy administer a vasopressor. Dopamine or noradrenaline  Supportive measures: supplemental assisted ventilation, IV fluids. oxygen, intubation, Benzodiazepines Benzodiazepines have a high therapeutic index and are the safest of all sedative-hypnotic drugs. In other words, the range between therapeutic dose and toxic or lethal dose is extremely wide. Increasing dosage, even to massive amounts, will not cause general anesthesia, as opposed to other sedative drugs . Consequently, their overall potential for toxicity is low, and patients with benzodiazepine overdose present with fewer problems. Mechanism of Toxicity Benzodiazepines bind to an allosteric site of the E and/or b subunits of the GABAA-Cl- ionophore complex. This action increases the frequency of the opening of the chloride channels. Ultimately, the drugs enhance the affinity of GABA for GABAA receptors and potentiate the effects of GABA throughout the nervous system. The effects of GABA-mediated actions account for benzodiazepines’ sedative/hypnotic, anticonvulsant, and skeletal muscle relaxation properties. At high doses, benzodiazepines induce neuromuscular blockade and cause vasodilation and hypotension (after i.v administration). The compounds do not significantly alter ventilation, except in patients with respiratory complications, in the elderly population, and in the presence of alcohol or other sedativehypnotic . There is also minimal effect on cardiovascular integrity. Signs and symptoms of acute toxicity  Although signs and symptoms are generally nonspecific, apparent toxicity depends on the extent of intoxication. Serum toxic concentrations of benzodiazepines do not correlate well with signs and symptoms ,for diazepam, toxic blood concentrations are between 0.5 and 2.0 mg/dL.  Effects on motor performance are more prominent than cognition Mild toxicity is characterized by ataxia, drowsiness, and motor incoordination. In moderate toxicity, the patient is aroused by verbal stimulation, although he or she may enter coma stage 1 or 2. Patients in respiratory depression and hypotension are rare. Severe toxicity are unresponsive except to deep pain stimulation, consistent with coma stage 1 or 2. Tolerance to benzodiazepines can occur after chronic ingestion. There may be cross tolerance to barbiturates, and ethanol. Administration of benzodiazepines to a pregnant woman prior to delivery may produce signs of poisoning in the neonate. A condition called “floppy infant syndrome”, characterised by hypotonia that may last several days, may occur following maternal diazepam use. • Clinical management is symptomatic, and may also incorporate the use of a specific antidote. Flumazenil,, is a benzodiazepine antagonist. It competitively antagonizes the binding and allosteric effects of benzodiazepines. • Most patients achieve complete reversal of benzodiazepine effect with a total slow IV dose of just 1 mg. • Some investigators suggest that flumazenil is better administered in a series of smaller doses in an incremental manner beginning with 0.2 mg and progressively increasing by 0.1 to 0.2 mg every minute until a cumulative total dose of 3.5 mg is reached. • Flumazenil has also been reported to reverse cardiovascular depression secondary to benzodiazepine use. • Flumazenil does not reverse respiratory depression very well and hence fundamental procedures such as supplemental oxygen, endotracheal intubation, and ventilation must not be neglected. • Flumazenil is generally well tolerated. Adverse effects are usually mild, consisting mainly of nausea and vomiting Chloral Hydrate Chloral hydrate, as well as chloral betaine and triclofos sodium, are potent CNS sedatives. Chloral hydrate is converted to its active metabolite, trichloroethanol. Chloral betaine and triclofos are converted to chloral hydrate and trichloroethanol, respectively. Chloral hydrate and metabolites of chloral betaine and triclofos are lipid soluble and readily enter the CNS. Poisoning resembles barbiturate intoxication. Lethal doses are between 5 and 10 g Chloral hydrate and ethanol in combination are referred to as the infamous Mickey Finn(Knock-out drops) Whether intense CNS depression that results is additive or synergistic to the depressants is not known, it has been suggested that each drug inhibits the metabolism of the other . If this is true, the overall effect may be more than additive. The corrosive action of chloral hydrate may cause gastritis, nausea, and vomiting. arrhythmias , cardiac arrest, respiratory depression, and coma. Non-cardiogenic pulmonary oedema and aspiration pneumonitis have been reported after massive overdose. In addition, it has been shown to be nephrotoxic and Institute continuous cardiac monitoring and obtain an ECG after significant overdose. Monitor pulse oximetry and/or arterial blood gases in patients with CNS or respiratory depression. Emesis is not recommended. Chloral hydrate is rapidly absorbed, particularly after ingestion of liquid formulations. Gastric lavage is also unlikely to be of benefit in most cases. If performed, lavage should be done carefully because of the risk of perforation. In the case of liquid ingestions a small flexible tube may be indicated to prevent oesophageal damage. Moth Repellent • Naphthalene or paradichlorobenzene are the active ingredient of moth repellents. • Many cases of poisoning was reported , the exposure was oral, but dermal and inhalation exposures were also reported. • Naphthalene, a bicyclic aromatic hydrocarbon, is a natural component of fossil fuels, such as petroleum and coal. It is also produced when wood and tobacco are burned. • Paradichlorobenzene, an organochlorine insecticide, is considered to be half as toxic as naphthalene.  Many moth repellent products contain nearly 100% naphthalene or paradichlorobenzene. The products can be formulated into balls, crystals, or flakes.  1 One mothball of either type weighs about 5 g. Less than one naphthalene mothball may cause clinical signs of toxicosis in children, but accidentally ingesting up to paradichlorobenzene mothball is generally well-tolerated. one Naphthalene evaporates easily and has a strong odor that repels moths. It can be inhaled, ingested, or absorbed transdermally. It is soluble in oils and fats, so dermal absorption is increased if oils have been previously applied to the skin. Similarly, oral absorption increases when naphthalene is co- administered with a fatty product such as corn oil. Naphthalene itself is not responsible for the toxic effects. Its metabolites alpha and beta naphthol as well as naphthoquinone are powerful haemolytic agents. Individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are especially vulnerable to the toxicity of these metabolites.  Paradichlorobenzene also has a characteristic penetrating odor and is well-absorbed orally and by inhalation also drinking milk or eating a fatty meal after oral exposure to paradichlorobenzene increases its absorption.  Mothballs of either type may take several days to dissolve in the gastrointestinal tract, so prolonged absorption is possible.  Both chemicals widely distributed throughout the body, both metabolized by the liver via CYP450 , and the metabolite excreted primarily through urine. Clinical signs of toxicity  Oral exposure to naphthalene can cause gastrointestinal signs, including vomiting, nausea, abdominal pain, and diarrhea.  Hemolytic anemia and cataract formation have also been reported. An association exists between glucose-6-phosphate dehydrogenase deficiency and the hematologic effects of naphthalene.  Inhaling naphthalene can gastrointestinal effects in people. also cause hemolysis and  Paradichlorobenzene ingestion can cause nausea and vomiting. Hepatotoxicity is also possible but uncommon .  Paradichlorobenzene vapors are irritating to the nose and eyes, and central nervous system depression.  With dermal contact, produces a burning sensation but causes only slight skin irritation. anemia has been seen with longterm exposures  Paradichlorobenzene may cause cataract formation Treatment  When treating moth repellent exposure, assess and stabilize the patient.  If the patient is dyspneic, provide supplemental oxygen and place an intravenous catheter.  Induce emesis only in asymptomatic patients and only if ingestion occurred less than two hours before presentation and no contraindications to inducing emesis exist. After the vomiting has subsided, administer activated charcoal effective up to 1 hour , and a saline cathartic , may be beneficial up to 24 hours after mothball ingestion because mothballs dissolve slowly in the gastrointestinal tract.  In general, naphthalene ingestion requires more aggressive treatment than paradichlorobenzene.  If the type of mothball ingested is unknown and the owner has brought in a sample, perform the following test. Add three heaping tablespoons of table salt to tepid water, and mix vigorously until the salt will no longer dissolve. Place the mothball in the saturated salt water. Naphthalene mothballs float.   Antiemetic for vomiting , Sucralfate to reduced GIT irritation . PPIs or H2 antagonist to decrease gastric acid production.  Seizures may be controlled with diazepam.  Blood transfusions may be needed in patients with severe methemoglobinemia.. Alkaline Diuresis for naphtalene : Should be performed if there is evidence of haemolysis. This may prevent renal deposition of red blood cell break down products in the renal tubules and resultant renal failure. Treat haemolysis with blood transfusion, packed red cell transfusions,