CNS Depressants PDF

Acute intoxication with CNS depressants (Opioids, Benzodiazepines, TCAs) Fte in Dr. Asmaa Sharif Associate professor of Forensic Medicine and Clinical toxicology College of Medicine, DAU 10/29/2024 1  Lear...

Acute intoxication with CNS depressants (Opioids, Benzodiazepines, TCAs) Fte in Dr. Asmaa Sharif Associate professor of Forensic Medicine and Clinical toxicology College of Medicine, DAU 10/29/2024 1  Learning objectives Understand opioids overdose pathophysiology. Presentations of opioids toxicity Diagnostic strategies of opioids toxicity Management of opioids toxicity Diagnosis and Management of opioids withdrawal Understand Benzodiazepines overdose. Master the clinical presentation of Benzodiazepines toxicity. Aware of Benzodiazepines toxicity management. Diagnosis and Management of Benzodiazepines withdrawal Understand metabolism of cyclic antidepressants overdose. Master the clinical presentation of TCA toxicity. Aware of TCA toxicity management. Use of HCO3 in TCA and managing its side effects.  Central nervous system (CNS) depressants Are drugs that slow down brain activity, making them effective for treating many conditions. Central nervous system depressants are used to treat different disorders, including: insomnia, anxiety , panic attacks , stress , sleep disorders , pain , and seizures. There are three major types of CNS depressants: sedatives hypnotics, and tranquilizers. Drugs that are classified as CNS depressants include: Alcohol Barbiturates Benzodiazepines Opioids Are 1) Opioids  Opioids Opioids are a class of drugs derived from the opium poppy plant or synthetic with similar properties. They are primarily used for their pain-relieving and euphoric effects, acting on specific opioid receptors in brain, spinal cord and throughout the body. Opioids include natural substances like morphine and codeine, as well as semisynthetic and synthetic drugs like oxycodone, hydrocodone, fentanyl, and methadone. 1) Naturally occurring opioids: e.g. morphine and codeine. 2) Semi-synthetic opioid :e.g. heroin, Apo-morphine. 3) Synthetic opioids: e.g. methadone, and pethidine.  Circumstances of exposure - Accidental is the most common route - An opioid overdose It can be diagnosed by some symptoms and signs such as decreased level of consciousness and pinpoint pupil - Opioid-induced intolerance It may be described as a desensitization process where opioids desensitize the receptors, with greater opioid dosing needed to to produce the original chronic pain relief effect. - "Drug idiosyncrasy" Refers to reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy.  Mechanism of action of opioids Specific opioid receptor binding 1)Receptor Types: a) Mu (m). I)Most opioid analgesics: act at the Mu receptor b) Delta (d). c) Kappa (k). I)Mu (m) :Analgesia, euphoria, respiratory depression, physiological dependence II) Delta (d) and Kappa (k): Spinal analgesia  Mechanism of action of opioids Toxicological actions of Opioids 1- Depressed Respiratory Function 2- Altered Consciousness and Sedation 3- Cardiovascular suppression (depress VMC) 4- Gastrointestinal Complications (constipation) 5- Metabolic Disturbances (hypoventilation and metabolic acidosis)  Actions of opioid a)CNS: combined stimulation & depression - Stimulatory effects: 1) CTZ 3) Third cranial nerve nucleus 4) Euphoria and state of feeling of well- being. seressipinpointPuritt - Depressant effects: 1) On cerebral cortex: i) Analgesia ii) Sedation, drowsiness, mood changes 2) On cough center euphoria 3) On respiratory center Invent 4) On heat regulating center: hypothermia  Actions of opioid 5- On respiratory center: slow shallow respiration due to decreased sensitivity of RC to arterial CO2 tension. It can be seen in patient on opioids that: - Have developed acute renal failure and is not able to excrete the opioid. - Have had the dose of opioid increased despite severe sedation. b) CVS: Suppress VMC and produce shock c) GIT effects: Increase segmental GIT motility gastric acid secretion (Constipation) tone of antrum and first part duodenum Dry mouth the amount of saliva gut motor activity Constipation stool transit time ileo-cecal valve & anal sphincter tone propulsive intestinal motility X-ray showing impacted stool (white) surrounded by gases bowel  Actions of opioid morphine histtie d) Biliary tract (aggravate biliary colic) itching e) Genito-urinary (urine retention) - Tone and amplitude of ureter contractions. - detrusor muscle tone. - Tone of external sphincter and volume of bladder. - Urinary retention especially in the elderly male with prostatic hypertrophy. f) Bronchi Bronchospasm h) Skin Itching due to histamine release Uncommon adverse effects Bad dreams Seizures Hallucinations  Diagnosis of opioid toxicity Diagnosis Circumstantial Clinical History Investigations evidence examination 1-Circumstantial evidence: Signs of acute intoxication in addict.  Accidental poisoning in children, or iatrogenic poisoning. 2-History: Recent prescription or intake of opiates.  Diagnosis of opioid toxicity 3-Clinical examination: Any patient comes with respiratory depression, hypotension, hypothermia, pinpoint pupil is of high suspect to be opiate poisoned (Opioid toxidrome)  4- Investigations Diagnosis of opioid toxicity Toxicological Non-toxicological skullbffature distitst wingscreening confirmatory Opioid drugs have a wide biodistribution and can be identified in virtually all parts of the body and in all body fluids. The drugs are typically metabolized by the liver, producing metabolites that are often longer lasting and detectable at higher levels than the parent drug. Screening tests are Inexpensive immunoassay screening tests and thin layer chromatography are usually used to detect the presence of opiates. Confirmatory tests are Gas chromatography/ mass spectrometry which is a more expensive laboratory test that is available for confirmation of the results and/or detection of synthetic opioids not usually included in screening immunoassays.  Diagnosis of opioid toxicity 2-Non toxicological investigations (DD) 1- Ordering radiographic images for cerebral bleeding 2- Electrocardiograms to monitor bradycardia. 3- Order arterial blood gases, 4- Electrolytes analysis 5- Blood glucose, renal function tests.  Treatment of opioid overdose First of all, hospitalization is mandatory. Treatment of an opioid overdose should focus on (1) maintaining a patent airway (2) Making sure the patient is adequately oxygenated (3) Supporting the pulse and blood pressure (4) Monitoring for complications. Note : Bradycardia is seldom severe enough to require intervention, but if the patient’s hemodynamic status were compromised because of a slow heart rate, atropine would be the drug of choice.  Treatment of opioid overdose Once the ABCs have been stabilized, consider gastric decontamination. Decontamination (1) Syrup of ipecac. Due to the potential for CNS depression and loss of gag reflex in the patient with an opioid overdose, ipecac should never be used in these situations. (2) Lavage. Studies have shown that to be effective it must be performed within an hour of an ingestion (may be delayed to six hours because of diminished gastric motility and pyloric spasm). (3) Whole bowel irrigation. This technique instills a large amount (1-2 liters per hour) of isotonic fluid into the gut to mechanically remove any toxin that remains in the stomach or intestines. Again, situations in which whole bowel irrigation would be appropriate for an opioid overdose (except for body packers and stuffers) would be very unusual. (4) Activated charcoal. Activated charcoal adsorbs drug that is in the stomach and intestine, but it is only useful if it is used within a few hours of ingestion.  Treatment of opioid overdose The next step is to administer the antidote of choice which is naloxone. Naloxone is a specific antidote for opioid poisoning. Naloxone is a derivative of oxymorphone and it is a competitive antagonist at the mu opioid receptors. It also has a lesser effect on the kappa receptors and the delta receptors. Naloxone binds to the opioid receptors and prevents opioid from binding to them and it (essentially) produces no pharmacological action of its own. It will effectively reduce central nervous system depression, respiratory depression, and bradycardia caused by an opioid. Dose: A standard dose is often listed as 0.4-0.8 mg as an IV bolus, and a similar dose for children. This dose can be repeated. Adverse effects: they are all rare may be due to massive catecholamine surge or interference with endogenous endorphins: 1- asystole/ventricular irritability. 2- hypertension. 3- pulmonary edema. 4- gastrointestinal effects. 2) Benzodiazepines  seditisis Benzodiazepines Benzodiazepines remain among the most widely prescribed class of drugs. Majority of benzodiazepine overdoses follow a relatively benign clinical course. Benzodiazepines produce sedative, hypnotic, anxiolytic, and anticonvulsant effects by enhancing the inhibitory actions of GABA. b to subtrope  Benzodiazepines toxicokinetics Benzodiazepines are rapidly well absorbed orally, and parenterally Following absorption, benzodiazepines distribute readily Penetration of the blood-brain barrier is facilitated by their highly lipophilic structure. In plasma, benzodiazepines are highly protein-bound. Metabolism of all benzodiazepines occurs in the liver through HME. (diazepam is metabolized into an active metabolite: nordiazepam) Elderly patients or those with liver disease, leading to prolonged elimination of some benzodiazepines Mechanism of action of Benzodiazepines  Pathophysiology of Benzodiazepines toxicity Addiction  Central nervous system depression is common  Significant respiratory depression with large oral overdoses  Other complications include aspiration pneumonia and pressure necrosis of skin and muscles. Clinical pitcure of Benzodiazepines acute toxicity  Management of Benzodiazepines toxicity 1. General supportive treatment: (A-B-C) 2. Decontamination (D): Gastric lavage (if in coma, insert cuffed endotracheal tube). Repeated doses of activated charcoal are recommended. 3- Elimination (E): Diuresis, peritoneal dialysis and hemodialysis are not effective due to large VD and high plasma protein bindings 4. Antidote (Flumazenil) I  a nonspecific competitive antagonist of the benzodiazepine receptor,  Can reverse benzodiazepine-induced sedation after general anesthesia, procedural sedation, and overdose, but is not recommended for the reversal of benzodiazepine overdose in addicts (Refractory seizures, can be induced) Patients remaining asymptomatic after 4 to 6 hours of observation may be medically cleared. For cases of deliberate overdose, appropriate psychiatric consultation should be obtained. p Benzodiazepines withdrwal 3)Tricyclic antidepressants (TCA) (Psychoanaleptics)  TCA Toxicokinetic Well absorbed from GIT, ( anticholinergic effect → delay absorption ) Metabolized in the liver by cytochrome oxidase to active metabolites. Most of them are highly plasma & tissue protein bound. Large volumes of distribution. Little excreted unchanged in urine. Little gastric & biliary excretion ( enterohepatic circulation)  Mechanism of action of TCA 1-Inhibit the reuptake of neurotransmitters (adrenaline, noradrenaline, dopamine, serotonin) at the presynaptic terminals: Increase their levels and induce an anti depressant effect. 2-Block histamine receptors: Sedation 3-Sodium channel blockade (Quinidine like action on the heart): Arrhythmia 4- Block muscarinic acetylcholine receptors (Anticholinergic Effects) Dilated pupils Blurred vision Dry skin Tachycardia Hypertension Hyperthermia Urinary retention Ileus Dry mouth Agitation Delirium Confusion Hallucinations Slurred speech Coma Mechanism of action of TCA 5- α-Adrenergic Receptor Antagonism: Inhibits both central and peripheral receptors α1 (Sedation, Orthostatic hypotension) 6- block GABA receptors seizures  Clinical picture of TCA toxicity cardio toxicity no bicarb 1- CVS: - Hypotension is caused by direct myocardial depression and peripheral vasodilation from α- adrenergic blockade - Cardiac arrhythmias, (sinus tachycardia, ventricular dysrhythmia ) with ECG changes, (widening of QRS complex, depression of ST segment, abnormal t wave, prolonged PR & QT intervals). 2-CNS: Stimulation followed by depression - Seizures and altered mental status, delirium, disorientation, agitation, hallucination. - Lethargy and coma in severe cases. 3- Anticholinergic manifestation. 4- Others: Hyperthermia and acidosis may develop rapidly due to agitation and seizure. Pulmonary edema is common due to aspiration Clinical picture of TCA toxicity Anticholinergic toxidVome Suspect TCA poisoning in the following Patients who have an anticholinergic toxidrome Decreased level of consciousness, QRS prolongation (>100 msec)  Investigations of TCA toxicity 1- Toxicological: assess serum ldrug evel. 2- Non toxicological: - Acid-base status, blood gases. - ECG., X- ray chest. - Glucose, electrolytes, kidney function.  Treatment of TCA toxicity 1- A B: Early intubation is advised for patients with CNS depression and/or hemodynamic instability. 2- C: The patient should be attached to a cardiac monitor Treat hypotension Antidotefor TCA Treat cardiac arrhythmias by sodium bicarbonate I.V. which is the first drug of choice. Lidocaine is the 2nd drug of choice. 3- Decontamination: No emesis (coma or convulsion ), do lavage, gut dialysis & cathartic 4- Elimination has no role (large VD) 5- Treat convulsion & hyperthermia.