L’eggo My Benzo! Benzodiazepines, Flumazenil

1.1 "L'eggo my Benzo!" Benzodiazepines, flumazenil Physiology GABA, along with glycine, is one of the major CNS inhibitory neurotransmitters ("Take it easy" sign on cab). GABA receptors are divided into A, B, & C subtypes. GABA-A is a chloride ion channel formed of 5 subunits ("Chlo-rider" sign on cab). GABA-A is the main site of action for many sedative/hypnotics including benzodiazepines, alcohol, and barbiturates (Ben's diner, drinking guy, and barbershop respectively) Mediates Mood changes, neuronal excitability, sleep, anxiety. Alcohol Allosterically binds GABA-A receptor (separate site from benzos) (Cab-A outside, with guy drinking on the trunk). Functions to enhance inhibitory action of GABA. Chronic ingestion induces downregulation of GABA A receptor complex & decreased GABA sensitivity & tolerance ("All are welcome" banner). So have to increase alcohol intake to have same effects. Withdrawal: Abrupt cessation in intake will cause a decrease in GABA mediated inhibitory tone → CNS excitation. 3 stages (demonstrated by patrons at the bar with lots of bottles): Start within 8-12 hours. Insomnia, tremor, ANS hyperactivity (diaphoresis, variable BP, tachycardia) (closest patron with brown shirt) 12-48 hour: seizures (middle patron) 48-96: delirium tremens. Includes fever, disorientation, severe agitation. (farthest, angry patron) Benzodiazepines (Ben's Diner) Many of the names end in-pam (diazepam, oxazepam, diazepam) ("Best PAM-cakes" sign) or -olam suffix for the short acting benzos (triazolam, alprazolam, midazolam) ("All A.M."). MOA: allosterically bind GABA-A receptor (separate site from alcohol) (Cab-A outside). Potentiate GABA A transmission throughout the CNS (special delivery of pam-cakes increasing cab driver effects). Major inhibitory CNS neurotransmitter (along with glycine) (CNS & "take it easy" signs on cab). Activated GABA-A receptor is a chloride channel (Chlo-rider cap). ↑chloride conductance inhibits synaptic transmission → CNS depression (CNS light on cab). Increased permeability hyperpolarizes & stabilizes membrane potential, making less excitable. Chloride channel conductance is d/t an increase in frequency of opening rather than increased duration ("Now Open More Frequently") All are metabolized by the liver (liver on ox). Short acting: Rapidly metabolized & inactivated Long acting: form active metabolites that have very long half-lives and exert effects of their own. Note that effects can be cumulative with repeat dosing, which is important when considering the half-lives of the different formulations. Active metabolites tend to accumulate with liver disfunction, leading to increased sedation Short-acting: Alprazolam, Triazolam, Oxazepam, Midazolam (ATOM) Short serum half-life, fast acting (Better Act fast!). Makes more addictive & likely to lead to dependence ("Addictive Flavor") Duration of action of common benzos (per UWorld) Short (half-life <6h) Triazolam, midazolam Intermediate (half-life 6-50h) Oxazepam, alprazolam, lorazepam, clonazepam Long (half-life > 50h) Diazepam, chlordiazepoxide, flurazepam Clinical indications Benzos are first line treatment for alcohol withdrawal. Long acting preferred d/t self-tapering effects which smoother course of withdrawal. (long tapering flag). In patients with severe liver disease, may use short acting agents to prevent accumulation of active metabolites in liver disease. treatment of seizures is one of the major concerns with alcohol withdrawal; hence IV administration is indicated in EtOH withdrawal. IV administration used for seizures, including epilepsy, alcohol withdrawal. This is especially useful with continuous seizure activity (i.e. status epilepticus). (Construction worker with jackhammer next to ivy-bound pole; workmate pulling the plug.). Anesthesia: Causes muscle relaxation & amnesia. Can be used for general anesthesia, e.g. rapid sequence intubation (sleeping guy with straw) Can be used for a state of conscious sedation for minor procedures & surgeries (guy drinking a Lite) Commonly used for short term treatment of insomnia (sleeping guy). Not first line d/t physical dependence. Can be helpful in childhood parasomnias (crying kid with pajamas) Central muscle relaxants. Diazepam especially can help with spasticity d/t UMN disorders including MS, stroke, spinal cord trauma, even tetanus. However, will produce sedation at the dosing needed to relax muscle tone (very relaxed guy reclining in booth, sleeping) Used for management of acute anxiety states GAD (anxious date). SSRIs & SNRIs are first line for long-term management. Can be useful in the management of somatic symptoms of acute anxiety (e.g. headache, insomnia, other) (sweating, shaking date clutching head). Panic disorder (Edvard Munch's Scream). SSRIs & SNRIs are first line for long-term management. Side effects/toxicities Dose related CNS depression. Should not be coadministered with any other CNS depressants, including alcohol, barbiturates, neuroleptics, first gen antihistamines (bee swatter). Significant dose related anterograde amnesia (useful clinically during sedation) (question mark on sleeping man's hat) Elderly patients are more sensitive to adverse effects. Most common reversible cause of confused states in the elderly is the overuse of sedative hypnotics; may present with somnolence, confusion, disorientation (confused elderly man) Can cause central ataxia. ↑fall risk in the elderly. Included in BEERS criteria. (Falling stack of pancakes in front of older man) High dependence & withdrawal potential Chronic use induces downregulation of GABA-A receptor complex & decreased GABA sensitivity & tolerance ("All are welcome" banner). Withdrawal may look like alcohol withdrawal, d/t similar CNS effects. Can include tremors, anxiety, perceptual disturbances, dysphoria, seizures, psychosis. Flumazenil (fluffy muzzled dog) Competitive antagonist at the BZD receptor (dog is antagonizing man with pancakes). Used for reversal of BZD induced sedation. Use in OD is controversial. May precipitate seizures d/t withdrawal symptoms in patients who've developed tolerance.