Barbiturates toxicity power point presentation

It contains information about barbiturates and benzodiazepines toxicity

1. Barbiturate Toxicity

2. Barbiturates are sedative-hypnotic drugs. Barbiturates have been used for a broad spectrum of indications Insomnia, psychiatric disorders, anesthesia , alcohol withdrawal, seizures, and elevated intracranial pressure. barbiturate toxicity is still a prevalent cause of significant morbidity and mortality that requires prompt and effective care to mitigate   Physical dependence can also develop with sustained barbiturate use and place patients at higher risk of toxicity due to the need for escalating doses to achieve the desired effect(s). Barbiturate toxicity can also be iatrogenic

3. PATHOPHYSIOLOGY Barbiturates enhance the activation of gamma-amino-butyric-acid type A (GABA A ) receptors, GABA A  chloride channels are open This leads to hyperpolarization of the postsynaptic neuronal cell membrane, which causes inhibition of excitatory cells in the central nervous system Barbiturates also diminish responses to the excitatory neurotransmitter, glutamate, by inhibiting the glutamate receptor subtype alpha-amino-3-hydoroxy-5-methyl-4-isoxalolepropionic acid (AMPA) in the central nervous system. These drugs also decrease calcium conductance via their effect on membrane calcium channels. Depression of the respiratory medullary centers can cause decreased ventilation and apnea. Barbiturates affect the cardiovascular system via vasodilation of peripheral blood vessels, depression of the brain’s cardiac and vasomotor centers, and a direct negative ionotropic effect on the heart. Barbiturates can also cause hypothermia by depressing the temperature-regulating mechanism in the pons

4. Toxicokinetics ultra–short-acting - Thiopental and methohexital) are given intravenously and used as anesthetics.  short-acting-pentobarbital and secobarbital) have durations of effect of 2 to 6 hours and are used as sleeping aids and sedatives. intermediate-acting- long-acting agents-have durations of effect of greater than 6 hours and are used as antiepileptic agents and in the treatment of alcohol withdrawal All barbiturates are absorbed rapidly after oral ingestion and undergo enterohepatic recirculation small proportion of barbiturate drugs are excreted unchanged in the urine.  Barbiturates also induce the hepatic cytochrome P450 (CYP) enzyme system, which increases the metabolism of drugs that are CYP substrates shorter-acting agents are more lipid soluble, protein-bound, and undergo more hepatic metabolism

5.   Respiratory acidosis brought about by respiratory depression may allow any barbiturate to cross the blood-brain barrier more easily. short-acting agents undergo more hepatic metabolism than longer-acting agents, large ingestions of these agents may overwhelm saturable hepatic enzymes and prolong metabolism time. Finally, as barbiturate levels decrease, gastrointestinal motility may improve, which can lead to increased enterohepatic recirculation, barbiturate reabsorption, and further toxic effects

6. History and Physical Assessment of the airway, breathing, circulation, and neurologic deficits should take priority for a patient with suspected barbiturate toxicity. Physical examination findings consistent with a sedative-hypnotic toxidrome include decreased ventilation, decreased blood pressure, abnormal heart rate, decreased bowel sounds, dry skin, and hypothermia

7. EVALUATION   A point-of-care glucose level should be determined for any patient with altered mental status to assess for hypoglycemia. A complete blood count and comprehensive metabolic panel should be obtained to further evaluate for hepatic disease, renal insufficiency, or other metabolic derangements. A pregnancy test should be conducted for any woman of childbearing age.  A serum lactic acid level can help assess for cellular hypoperfusion. Creatine phosphokinase can identify rhabdomyolysis and should be drawn for unresponsive patients ( ie , at risk for muscle compression) or present with physical trauma. Troponin can aid in assessing cardiac ischemia from hypoperfusion. An electrocardiogram can assess for abnormal heart rate and rhythm, and ischemia and give insight into the possibility of co-ingestion of other substances ( eg , prolonged QTc interval and suspicion for tricyclic antidepressant co-ingestions). Laboratory screening for co-ingested agents should occur and include a blood ethanol level, urine drug screen inclusive of qualitative barbiturate testing, and acetaminophen and salicylate levels

8. TREATMENT   consists mainly of supportive care clinicians should administer intravenous or intranasal naloxone if there is suspicion of opioid co-ingestion and impending respiratory failure. Endotracheal intubation and mechanical ventilation are necessary for patients who cannot protect their airways or progress to respiratory failure.  Hypotension should be treated with aggressive crystalloid fluid repletion and vasopressors. Hypothermia should be corrected with external rewarming. Enhanced elimination is only recommended for barbiturate toxicity with coma, need for respiratory support, or need for cardiovascular support ( ie , when clinical benefits are likely to outweigh the risks of treatment) Multiple-dose activated charcoal may decrease the elimination half-life in severe toxicity with long-acting barbiturates like phenobarbital. Intermittent hemodialysis may benefit patients with toxicity from long-acting barbiturates as these agents may be more likely to be removed according to their pharmacokinetic properties

9. Benzodiazepine Toxicity

10. Benzodiazepines are currently used to treat anxiety, seizures, withdrawal states, insomnia, agitation and are commonly used for procedural sedation. Due to their many uses and addictive properties, benzodiazepines have been widely prescribed and abused since their development several decades ago.

11. PATHOPHYSIOLOGY Benzodiazepines are organic bases with a benzene ring and a 7-member diazepine moiety, with variable side chains that determine the potency, duration of action, metabolite activity, and rate of elimination effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, the primary inhibitory neurotransmitter in the central nervous system. The GABA-A receptor, depending on various arrangements of its subunits, determines its affinity for various agents that bind to the receptor. Benzodiazepines bind at the interface of the GABA-A receptor and subsequently lock the receptor into a configuration that increases its affinity for GABA. Benzodiazepines do not alter the production, release, or metabolism of GABA but instead potentiates its inhibitory actions by augmenting or enhancing receptor binding. This binding ultimately increases the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization, which decreases the ability to generate an action potential.

12. TOXICOKINETICS Benzodiazepines taken in toxic doses without other coingestants rarely cause a significant toxidrome. Classic symptoms include slurred speech, ataxia, and altered mental status. Respiratory compromise is uncommon in isolated benzodiazepine ingestions, but if taken with coingestants such as ethanol or other drugs/medications, respiratory depression can be noted. It is important to note that most intentional ingestions of benzodiazepines do involve coingestants, the most common being ethanol, leading to substantial respiratory depression and airway compromise Patients with severe toxicity will present in a stuporous or comatose state, and immediate airway management and mechanical ventilation may be required. Patients with severe toxicity will present in a stuporous or comatose state, and immediate airway management and mechanical ventilation may be required. Propylene glycol is the diluent used in the parenteral formulations for these two benzodiazepines, and prolonged use can cause propylene glycol toxicity, which includes skin and soft tissue necrosis, haemolysis, cardiac dysrhythmias, hypotension, significant lactic acidosis, seizure, and multisystem organ failure. 

13. HISTORY AND PHYSICAL Patients with benzodiazepine toxicity will primarily present with central nervous system depression ranging from mild drowsiness to a coma-like, stuporous state. The classic presentation of an isolated benzodiazepine overdose consists of CNS depression with normal vital signs. Cardiac-related effects and fatalities are rare in pure benzodiazepine toxicities. Respiratory depression or compromise, while less common when compared to barbiturates, is the most important adverse effect requiring immediate intervention. Life-threatening respiratory depression can be seen with large oral ingestions with or without coingestants. Iatrogenic causes of toxicity can be seen when benzodiazepines are combined with other drugs during procedural sedation, particularly with opiates such as fentanyl

14. EVALUATION Benzodiazepine overdose is usually suspected or diagnosed based on clinical presentation Before any diagnostic tests are ordered in the patient presenting with altered mental status with suspected overdose or toxicity, any respiratory or abnormal vital signs should be addressed first. Mechanical ventilation may be required to address respiratory compromise and intravenous fluids administered to manage hemodynamic instability. An ECG should be ordered to rule out the ingestion of drugs that may widen the QRS or QTc intervals and may precipitate arrhythmias. A pregnancy test should be ordered for all women of childbearing age. A head CT without contrast may be considered to rule out an intracranial abnormality related to the patient presenting with an acutely altered mental status.

15. The mainstay treatment for acute benzodiazepine toxicity is supportive care, which may include endotracheal intubation to provide definitive airway management. Single-dose or multi-dose activated charcoal, hemodialysis , or whole bowel irrigation play no role in managing benzodiazepine toxicity. Flumazenil is a nonspecific competitive antagonist at the benzodiazepine receptor that can reverse benzodiazepine-induced sedation Seizures and cardiac dysrhythmias, particularly PSVT, can occur after flumazenil administration, and many fatalities have been reported. Flumazenil can precipitate acute withdrawal syndromes in those with chronic benzodiazepine dependence, which can be life-threatening. TREATMENT

16. Flumazenil can be safely administered to non-habituated users of benzodiazepines. This situation classically occurs in the pediatric population with accidental ingestion or after procedural sedation. It is recommended that the decision to use flumazenil be based on the balance of risk versus benefit in the assessment and treatment of a patient that is a non-habituated user of benzodiazepines, as most people with a benzodiazepine  overdose will do well with supportive care and time alone