PHCT FINALS

• CNS Drugs (Anti-convulsants)

  • Sedative-hypnotic Drugs
  • Barbiturates
  • Benzodiazepines
  • Other sedative-hypnotics
• Sedative


  A substance that moderates activity and excitement while inducing a calming effect (subdues excitement> calmness)
• Hypnotic


  A substance that causes drowsiness and facilitates the onset and maintenance of natural sleep
• Sedative-hypnotic drugs


  • Barbiturates
  • Benzodiazepines
  • Other sedative-hypnotics
• Uses of sedative-hypnotics


  • Relief of anxiety
  • Insomnia
  • Sedation and amnesia before medical and surgical procedures
  • Treatment of epilepsy and seizure states
  • Component of balanced anesthesia
  • Control of ethanol or other sedative-hypnotic withdrawal states
  • Muscle relaxation in specific neuromuscular disorders
  • Diagnostic aids or for treatment in psychiatry
• Barbiturates


  • Used as hypnotic and sedative
  • For induction of anesthesia and for the treatment of epilepsy and status epilepticus
• Barbiturate groups by duration of action

  • Ultrashort-acting
  • Short-acting
  • Intermediate-acting
  • Long acting
• Barbiturates


  • They appear to increase the duration of the GABA-gated chloride channel openings
• Mechanism of toxicity (barbiturates)

  All barbiturates cause generalized depression of neuronal activity in the brain achieved through enhanced GABA-mediated synaptic inhibition
• Generally, toxicity is likely to happen when the barbiturate dose exceeds 5-10 times the hypnotic dose
• Fatal dose for shorter-acting barbiturates is > 2-3 g, for Phenobarbital is > 6-10 g, and for Methohexital is > IV injections of 1-3 mg/kg in young women undergoing abortion
• Clinical presentation of barbiturate intoxication

  • Mild to moderate: Lethargy, slurred speech, ataxia, nystagmus
  • Higher doses: Hypotension, Coma, Respiratory arrest
• Diagnosis of barbiturate poisoning

  • Usually based on history of ingestion
  • Specific levels: > 60-80 mg/L associated with coma, > 150-200 mg/L with severe hypotension for Phenobarbital, > 20-30 mg/L coma likely for short-acting barbiturates
• Treatment of barbiturate poisoning

  • Emergency and supportive measures
  • Specific drugs and antidotes (no specific antidote)
  • Decontamination: Activated charcoal, ipecac-induced emesis, cathartic
  • Enhanced elimination: Urine alkalinization for Phenobarbital, repeat-dose activated charcoal, hemoperfusion
• Benzodiazepines


  Family of depressant (sedative) drugs, also known as minor tranquilizers, developed by Roche as safer alternatives to barbiturates, enhance GABA-A receptor function to promote sleep and sedation
• Benzodiazepines


  • They appear to increase the FREQUENCY of the GABA-gated chloride channel openings
• Mechanism of benzodiazepine toxicity

  Cause generalized depression of spinal reflexes and the reticular activating system, may cause coma and respiratory arrest
• The toxic therapeutic ratio for benzodiazepines is very high, they are prone to dependence
• Clinical presentation of benzodiazepine intoxication

  • Lethargy, Slurred speech, Ataxia, Coma, Respiratory arrest, Hypothermia, Hyporeflexia, Midposition or small pupils
• Flumazenil


  A specific benzodiazepine receptor antagonist that can rapidly reverse coma, but may induce seizures or withdrawal, and resedation is common
• Benzodiazepines with no active metabolites

  • Alprazolam, Clonazepam, Estazolam, Halazepam, Lorazepam, Oxazepam, Temazepam, Triazolam
• Benzodiazepines with active metabolites

  • Chlordiazepoxide, Clorazepate, Diazepam, Flurazepam, Midazolam, Quazepam
• Chloral hydrate


  Metabolized to trichloroethanol, which also has CNS-depressant activity and may sensitize the myocardium to catecholamines
• Glutethimide


  Sedative introduced as a safer alternative to barbiturates for insomnia, often produces anticholinergic effects
• Meprobamate


  Hypotension is more common with this agent than with other sedative-hypnotics, used for anxiety
• Methaqualone


  Unusual among sedative-hypnotics in frequently causing muscular hypertonicity, clonus, and hypereflexia, overdose can cause delirium, convulsion, vomiting, kidney failure and death
• Seizure


  Excessive abnormal electrical discharge from the cortical neurons, can be a single occurrence or recurrent (epilepsy)
• Types of seizures


  • Partial seizure: Simple partial, Complex partial
  • Generalized seizure: Tonic-clonic, Absence, Myoclonic
• Mechanisms of action of anti-seizure drugs

  • Sodium channel blockers, Calcium channel blockers, GABA-mediated
• Indications for anti-seizure drugs

  • Generalized tonic-clonic and partial seizures, Absence seizures, Myoclonic seizures, Status epilepticus, Febrile seizures
• Phenytoin


  One of the most effective drugs against partial seizures and generalized tonic-clonic seizures, used IV to treat status epilepticus and as an antiarrhythmic, blocks sodium channels and inhibits repetitive neuronal firing
• Phenytoin toxicity


  • Alters neuronal ion fluxes, increasing refractory periods and decreasing repetitive neuronal firing, toxic levels usually cause CNS depression
  • Propylene glycol diluent in parenteral preparations may cause myocardial depression
• Valproate


  For absence with GTC
• Specific agents


  • Phenytoin
• Phenytoin


  • One of the most effective drugs against partial seizures and generalized tonic-clonic seizures
  • IV phenytoin is used to treat status epilepticus and occasionally as an antiarrhythmic agent
  • The oldest non-sedative anti-seizure drug
• Phenytoin


  AKA diphenylhydantoin, diphenyl substituted hydantoin
• Side effects of phenytoin

  • CNS: ataxia, nystagmus, diplopia
  • Connective: hirsutism, gingival hyperplasia
  • FHS (fetal hydantoin syndrome) – cleft palate, congenital heart disease, microcephaly, growth and mental retardation
  • CYP 450 inducer
  • May displace protein binding of ASA and Sulfonamides
• Mechanism of action of phenytoin

  Block sodium channels and inhibit the generation of repetitive action potentials
• Mechanism of toxicity of phenytoin

  1. Phenytoin alters neuronal ion fluxes, increasing refractory periods and decreasing repetitive neuronal firing

  2. Propylene glycol diluent in parenteral preparations may cause myocardial depression and cardiac arrest when infused rapidly (> 40-50 mg/min [0.5-1 mg/kg/min])
• Minimum acute toxic oral overdose of phenytoin

  Approximately 20 mg/kg