Clinical Toxicology Lecture Notes 2024 - 2025 PDF

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at college of Pharmacy...

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at college of Pharmacy Uruk University 2024 - 2025 Central nervous system depressants Barbiturates Barbiturates divided to three types: 1. Short-acting - duration of action of 4 to 6 hr - ex: secobarbital, pentobarbital 2. intermediate acting – duration of action 8-10 – ex: amobarbital. 3. Long-acting,- duration of action of 12 to 24 hr. – ex: phenobarbital. The short duration of action of certain barbiturates associated with decreased toxicity potential. T or F and why ?  The short duration of action of certain barbiturates cannot be associated with decreased toxicity potential. In fact, just the opposite is true Shorter-acting barbiturates are more lipid soluble so 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 short acting barbiturates Mechanism of barbiturate toxicity Act directly on gamma-amino-butyric acid (GABA)-like effect, or to stimulation of GABA release. GABA is an inhibitory neurotransmitter within the CNS. When released, central depression is noted.  Respiratory depression is the major toxic event that follows barbiturate ingestion and usually causes early death. Hypothermia is another potentially serious problem that follows toxic ingestion of barbiturates. Lowered body temperature results from direct depressant action on the thermo-regulatory center. Potentiates acidosis, hypoxia and shock. Sympathetic ganglia are depressed with larger doses. This may help explain why toxic barbiturate doses reduce the blood pressure. Other clinical toxicity of barbiturate include decreased gastrointestinal motility and tone, which may lead to increased drug absorption. Characteristics of barbiturate poisoning Short-acting barbiturates are highly lipid soluble and potentially more than long acting barbiturates, which are less lipid soluble. Lethal doses of short–acting barbiturates produce death in a short period of time. In suicides, victims are often found dead at the scene or they die shortly thereafter. In contrast, patients who overdose on long-acting barbiturates generally die later in the hospital.  Benzodiazepines Benzodiazepines have a high therapeutic index and are the safest of all sedative-hypnotic drugs. In other words, the range between therapeutic dose or 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 problem. Mechanism of benzodiazepine toxicity Most toxic effects of benzodiazepines result from their sedative action on the CNS. At extremely high doses, neuromuscular blockade may occur. Within the CNS, benzodiazepines are selective for polysynaptic pathways. They inhibit presynaptic transmission by stimulating the inhibitory neurotransmitter, GABA.  Characteristics of benzodiazepine poisoning Effects on motor performance are more prominent than cognition. On occasion, severe paranoia, psychosis, hallucinations, and hypomania behavior are noted. Chloral hydrate Chloral hydrate, widely used as a sedative in both adults and children. Chloral hydrate is converted to its active metabolite, tri-chloro-ethanol. Chloral hydrate and its metabolite are lipid soluble and readily enter the CNS. Poisoning resemble barbiturate intoxication. The corrosive action of chloral hydrate may cause gastritis, nausea, and vomiting.  Antihistamines With introduction of antihistamines in the late 1940's, it was realized that these drugs produces a variety of effects centered around CNS depression. Sedation is the most common side effects of most antihistamines in adults. In overdose, CNS depression leading to coma may result. However, additional symptoms that resemble anticholinergic action may also be present and may be more significant than the degree of depression these include mydriasis, flushing, fever, dry mouth, and blurred vision. Children usually experience central stimulation, hallucinations, tonic-clonic convulsions, and hyperpyrexia, rather than depression. Management of CNS depression overdose The highest priority in treating any victim of depressant poisoning is to stabilize respiratory and correct anoxia because if the brain suffers damage from insufficient oxygenation other procedure will be little benefit. Oxygen should be given and the patient ventilated mechanically, if needed. A cuffed endotracheal tube should be used in Stage 4 coma to decrease risk of aspiration pneumonia during lavage. To help prevent hypostatic pneumonia, the victim should be turned frequently.  Since circulatory collapse is a major threat after ingestion of massive doses of CNS depressants, cardiovascular function must be assessed quickly and deficiency corrected. Renal failure is the cause of one-sixth of all death. Therefore, kidney function must be monitored constantly. Signs of uremia may be an indication for hemoperfusion or hemodialysis. 1. Prevent further absorption of the poison Ipecac-induces emesis should be considered If no contraindication be present. In a comatose individual, gastric lavage is appropriate. Activated charcoal adsorbs barbiturates and most common CNS- depressant drugs. A slurry can be instilled into the stomach though a nasogastric tube. 2. Increase excretion of absorbed drug Barbiturates are weak acids thus alkalinization will promote ionization of at least half the drug in the glomerular filtrate and cause it to be excreted more readily. Multiple doses of activated charcoal starting 10 hr after phenobarbital ingestion in healthy individuals significantly reduce blood concentrations. Hemodialysis is variably effective in removing significant amounts of CNS depressant from blood in cases of toxic/lethal ingestion. 3. Benzodiazepine antidote Flumazenil is an antagonism that can reduce or terminate the sedative, anxiolytic, anticonvulsant, ataxic, anesthetic, and muscle relaxant effects of benzodiazepines in a dose related manner. Thank you