Clinical Toxicology Lecture Notes 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 Drug of abuse Opioids When considering over doses of opioids (narcotics), heroin (diacetylmorphine) is probably the first drug that comes in mind, and we image users as long term habitual drug abusers of low socioeconomic status. The association is actually unjustified, since victims of opioid overdose may be at any age and represent all social and economic levels, and the drug may be obtained by illegal or legally obtained by prescription.  Mechanisms of toxicity and characteristics of acute opioid poisoning All opioid derivatives have the potential to produce severe toxicity that is dependent on the dose and route of administration. Clinical response of analgesia, euphoria, respiratory depression, and miosis are believed to result from occupation of the μ-receptors. A different type of analgesia results when the ĸ-receptors are involved. Psychogenic effects, such as dysphoria, delusion, and hallucinations, result from opioid action at the δ-receptors. In acute overdose, respiration will be severely depressed to a rate as low as 2 to 4 per min. Cyanosis becomes apparent and many victims have foamy pulmonary edema. In humans, death from an acute opioid overdose is almost always from respiratory arrest. Respiratory depression with acute overdose is further complicated by bradycardia and hypotension. Hypotension usually occurs in the later stages of poising and results from hypoxia.  Pinpoint pupils (miosis) are usually considered to be the classical sign of narcotic poisoning. The body temperature usually decreases and the skin feels cold and clammy this is due to suppression of the hypothalamic heat-regulation mechanisms. Skeletal muscles also become flaccid and sometime the jaw relaxes. The tongue may even fail to block the airway. There is decrease urinary output which can be related to release of antidiuretic hormone (ADH). Gastric motility and tone of both small and large intestine may be decreased, resulting in severe constipation. Death even in an addict, is almost always due to respiratory failure, complicated by such factors as pneumonia, shock, and pulmonary edema.  Management of toxicity Since victims of opioid overdoses are often comatose with depressed respiration, the major treatment objective is to maintain vital functions. Therefore, the first step is to provide adequate respiratory assistance and cardiovascular support. Opioid overdoses are treated readily with an ideal direct antagonists. The use of an antagonist brings about dramatic improvement in respiration within minutes. Overall, the antagonist will reverse CNS depression, analgesic, convulsion, psychotogenic, and dysphoric actions of opioids. Naloxone was the first pure opioid antagonist, and it is considered the drug of choice for the treatment of opioid intoxications. Dramatic improvement in respiration is seen within minutes after it is administered. Comatose patients must be awakened as quickly as possible. If hypoxia persists and adequate tissue oxygenation is not achieved quickly, capillary damage followed by shock is likely to ensue.  Patients with pulmonary edema are at special risk diuretics, digitalis, steroids, and antihistamine have all been recommended as supportive therapy. However, all have unsure efficacy. Respiratory depression lasts much longer than the antagonistic effect of naloxone so patient must, therefore, be closely monitored for at least the next 24 to 48 hr. Naloxone should if possible be used only to return respiration to normal. Naturally occurring opioids Codeine Codeine or methylmorphine, possesses analgesic and antitussive properties. It is less potent than morphine. Toxicity and death due to codeine alone are infrequently encountered. Acute toxic ingestions of codeine produce the typical characteristic of symptoms seen with morphine: coma, meiosis, and respiratory depression.  Synthetic opioids 1. Diphenoxylate Diphenoxylate is a mepridine congener used in combination with atropine in an antidiarrheal preparation. There is an extremely narrow dose range between therapeutic and toxic blood concentrations. Acute intoxications especially in children are characterized by anticholinergic effects. These may consist of hyperpyrexia, flushing of the skin, lethargy, hallucination, urinary retention, and tachycardia. This phase is followed by meiosis, respiratory depression, and coma due to the opioid activity. 2. Fentanyl Alpha-methyl fentanyl is 200 times as potent as morphine, and the minimum lethal dose is about 125 μg. 3-Methyl-fentanyl is 7000 times as potent as morphine, and the minimum lethal dose reported at 5 μg. As with other opioids, the most significant acute toxic effect of fentanyl derivatives is respiratory depression, which is dose dependent and may last up to 30 min. The hemodynamic effects include bradycardia and hypotension. The remaining characteristics of toxicity include chest wall rigidity, nausea, vomiting, hypothermia, and seizures.  3. Meperidine Meperidine hydrochloride is a pure opioid agonist. It is the most commonly used opioid analgesic. Its structure is different to morphine, but similar to fentanyl. When meperidine is prescribed for postoperative or chronic pain, it is often necessary to increase the dose to obtain the therapeutic response. However, a potential problem may result from cumulative doses of meperidine, which related to its pharmacokinetic properties. 4. Pentazocine It exert its major actions on the CNS and smooth muscle. CNS effects include analgesia, sedation, and respiratory depression. Psychiatric disturbance include dysphoria, depression, confusion and hallucination. The cardiovascular response to pentazocine differ from other opioids in that high doses cause increased blood pressure and heart rate, flushing, chills, and sweating.  5. Propoxyphene It is synthetic analog of methadone and if taken in overdose, causes all the classic signs of opioid poisoning. As with diphenoxylate containing products, most people do not consider the toxic potential of propoxyphene to be great. Too frequently, large quantities are being used for minor pain without advising the recipient of the potential for toxicity. One special concern is ingestion of a product that also contains acetaminophen. Clinical symptoms caused by propoxyphene overdose may completely dominate those of a toxic acetaminophen ingestion. 6. Cocaine Central stimulation is one of cocaine's major pharmacological and toxic actions. Most cocaine use occurs by intranasal insufflation or inhalation of freebase cocaine, crack. A survey of cocaine users discovered that 61% were intranasal users, 21% smoked the free base form, and 18% were IV users. Most fatalities follow intravenous use. Cocaine death have also been associated with body packing.  Mechanism of toxicity Cocaine interferes with reuptake of norepinephrine at adrenergic nerve endings. Cocaine has also been shown to block reuptake of dopamine and interfere with serotonin activity. Characteristic of poisoning Feeling of euphoria or dysphoria may occur. Motor coordination is not usually hampered at lower doses. With large doses, stimulation extends to the lower motor centers and cord reflexes. Muscular twitching is noted first and may be followed by tonic-clonic convulsions. Death from high doses is usually a result of medullary depression producing respiratory failure.  The most prominent cardiovascular feature is sinus tachycardia which may produce ventricular arrhythmia. Vasoconstriction, combined with increased heart rate, produces hypertension. Hyperpyrexia may occur and be a combination factor in cocaine death. The effect of cocaine on the respiratory system follows the same progression: initial stimulation resulting in tachypnea, followed by dyspnea and respiratory failure. Management Diazepam is the drug of first choice to control cocaine-induced seizures. When seizure control is inadequate phenobarbital may be substituted. Cardiovascular effects must be treated aggressively Propranolol, a beta- adrenergic blocking agent, will normally reverse and control hypertension and tachycardia.  If the victim is in the depression stage of poisoning (hypotension), attention must be directed immediately toward raising the blood pressure. Intravenous fluids and vasopressors such as dopamine are indicated at this point. Hyperthermia must also be controlled. Cocaine-induced psychosis with hallucination paranoia, and hyper- excitability requires treatment. Neurologic agents have been used with success. More recently, lithium has been used. Marijuana Tetra-hydro-cannabinol is rapidly absorbed into the blood after inhalation, producing subjective effects within seconds to minutes that last at least 2 to 3 hr. After a single usage, only 5% to 10% of an oral dose of THC is absorbed. Onset of effects may be delayed for 30 min, but last as long as 5 hr or more. Characteristics of marijuana poisoning Low doses of THC (2 mg) will generally produce a sense of relaxation, mild euphoria, and increased auditory, visual, perception. Periods of hilarity may be followed by silence.  With moderate doses (5-7 mg) a progression to disturbance in thought processes and time perception, impairment in short-term memory, and ataxia may be prominent. High doses (15 mg) may induce feeling of depersonalization, disorientation, paranoia, and marked sensory distortion. Cardiovascular effects may include dose-related sinus tachycardia, but blood pressure is usually not significantly affected. Impaired pulmonary function is evidenced by bronchitis, pharyngitis, cough, and an asthma-like condition. Marijuana smoking may cause cancer due to its high tar content. Management Management of marijuana-induced reactions is purely supportive and symptomatic. Ingested material should be removed from the stomach with emesis, lavage, or activated charcoal. If the patient is disoriented or experiencing hallucinations or panic reactions, a prolonged talk down period may be necessary. Since acute toxic reactions due to marijuana alone are rare. Thank you