Benzodiazepines Summary PDF

Vladimir Aguilar BENZODIAZEPINES SUMMARY Benzodiazepines: - Exert five main pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia. Greater amnestic potency than sedative effects. Do not alter stored informatio...

Vladimir Aguilar BENZODIAZEPINES SUMMARY Benzodiazepines: - Exert five main pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia. Greater amnestic potency than sedative effects. Do not alter stored information (retrograde amnesia). Ineffective for surgical muscle relaxation. Widely used for anxiety and insomnia. Decreased use in chronic insomnia due to cognitive and mortality concerns. Advantageous over barbiturates due to safety, fewer drug interactions, and noninduction of hepatic microsomal enzymes. Less addictive compared to opioids, cocaine, amphetamines, or barbiturates. Specific Benzodiazepines - Midazolam: most commonly used in the perioperative period. Diazepam and lorazepam: prolonged context-sensitive half-times. Lorazepam: beneficial for sedation in critical care. Flumazenil: specific pharmacologic antagonist to benzodiazepines. Mechanism of Action - Enhance actions of GABA without activating the GABAA receptors. Increase in chloride conductance leads to hyperpolarization of the postsynaptic cell membrane. Bind between the α and γ subunits of the GABAA receptor. Interactions with various GABAA receptor types determine specific effects. Work synergistically with barbiturates, alcohol, and others on the GABAA receptor. Differences Among Benzodiazepines - Variances in potency, lipid solubility, and pharmacokinetics. High lipid solubility and significant protein binding. Effects may be enhanced in patients with hypoalbuminemia. Additional Information - Benzodiazepines decrease adenosine degradation. On the EEG, shift from α to β activity is observed. Common side effects include fatigue and drowsiness. Chronic use may not affect vital signs but caution with respiratory diseases. Concomitant use with alcohol may lead to profound amnesia. Influence anesthetic requirements and have interactions with opioids. May suppress the hypothalamic-pituitary-adrenal axis. Can lead to dependence with withdrawal symptoms. Glucuronidation is less affected by aging and liver disease. Elderly may have an enhanced response and cognitive decline with benzodiazepine use. Potential to inhibit platelet aggregation. 1 Vladimir Aguilar BENZODIAZEPINES SUMMARY Pharmacologic Effects of Benzodiazepines: - Anxiolysis: reduces anxiety. - Sedation: induces calmness or sleepiness. - Anticonvulsant actions: helps control seizures. - Skeletal muscle relaxation (spinal cord-mediated). - Anterograde amnesia: interferes with the ability to form new memories. Note: While they can cause anterograde amnesia, they don't cause retrograde amnesia (loss of already-formed memories). Usage and Prevalence: - Widely used due to their efficacy in treating anxiety and insomnia. - Many people use them at some point for sleep issues. - Their long-term use for chronic insomnia has been on the decline due to concerns about their impact on cognitive function and potential increase in mortality. Comparison to Other Drugs: - They are safer and less addictive than barbiturates. - They don't induce hepatic microsomal enzymes, unlike barbiturates. - While benzodiazepines have potential for addiction, they're considered less addicting than opioids, cocaine, amphetamines, or barbiturates. Specific Benzodiazepines: - Midazolam is frequently used in the perioperative period (around the time of surgery). - Diazepam and lorazepam have longer context-sensitive half-times, meaning they stay in the system longer. Therefore, lorazepam is sometimes chosen for sedating critically ill patients over extended periods. Antagonist: - Flumazenil is a specific antagonist for benzodiazepines. If someone has taken an overdose of a benzodiazepine or is experiencing undesirable side effects, flumazenil can be given to reverse the effects. Structural and Metabolic Features: - Benzodiazepines have structural similarities and many share active metabolites. - Their duration of action is based on how quickly they're metabolized and eliminated from the body, not on how they bind to receptors. - They do not lead to enzyme induction. 2 Vladimir Aguilar BENZODIAZEPINES SUMMARY Mechanism of Action of Benzodiazepines Facilitation of GABA Actions: - Benzodiazepines enhance the affinity of GABAA receptors for GABA. - GABA receptor affinity enhancement leads to increased probability of chloride channel openings. - This results in greater chloride conductance and hyperpolarization of postsynaptic cell membrane. - Enhanced resistance to excitation of postsynaptic neurons. Pharmacological Effects: - Benzodiazepines' mechanism of action underlies anxiolysis, sedation, anterograde amnesia, alcohol potentiation, anticonvulsant, and skeletal muscle relaxant effects. GABAA Receptor Interaction: - Benzodiazepines interact with a site between α and γ subunits of GABAA receptors. - Sedation linked to α1 and α5 subunits, anxiolytic activity to α2 and α5 subunitcontaining receptors. - α1-containing receptors are most abundant (60% in brain), α2 more restricted (hippocampus and amygdala), α5 mainly extrasynaptic for resting membrane potential modulation. Synergistic Effects and Safety: - Benzodiazepines, barbiturates, and alcohol act on different binding sites, producing synergistic effects. - Synergy can lead to increased CNS depression risk in combined overdose. - Benzodiazepines' built-in ceiling effect prevents exceeding GABA inhibition's physiologic maximum. - Low toxicity and clinical safety of benzodiazepines due to this limitation on GABAergic neurotransmission. Variability in Effects: - Onset and duration of action differences due to potency, lipid solubility, and pharmacokinetics. - High lipid solubility and plasma protein binding, mainly to albumin. - Hepatic cirrhosis or chronic renal failure may increase unbound benzodiazepine fraction, enhancing clinical effects. - Oral administration and IV injection result in rapid absorption into CNS and perfused organs. 3 Vladimir Aguilar BENZODIAZEPINES SUMMARY Nucleoside Transporter Systems: Benzodiazepine Effects on Adenosine Degradation: - Benzodiazepines inhibit the nucleoside transporter system. - This system is responsible for reuptake of adenosine into cells. - Adenosine degradation is decreased due to this inhibition. Physiological Effects of Adenosine: - Adenosine regulates cardiac function. - Slows heart rate, reducing cardiac oxygen demand. - Induces coronary vasodilation, increasing oxygen delivery. - Contributes to cardioprotection during myocardial ischemia. Effects of benzodiazepines on the EEG: Benzodiazepine Effects on EEG: - Benzodiazepines and barbiturates share similar effects on the EEG. - Decreased α activity and increased low-voltage rapid β activity. - Unlike barbiturates, benzodiazepines don't cause posterior spread of activity. - Shift from α to β activity is more prominent in frontal and rolandic areas. Tolerance and Midazolam: - Unlike barbiturates, tolerance to benzodiazepine effects on EEG does not develop. - Midazolam differs from barbiturates and propofol; it cannot induce an isoelectric EEG. Side effects of benzodiazepines: Common Side Effects: - Chronic use of benzodiazepines can lead to fatigue and drowsiness. - Initial sedation that might affect performance usually diminishes within 2 weeks of chronic treatment. Dosage Instructions: - Patients should take benzodiazepines before meals and without antacids, as these factors can impact absorption from the gastrointestinal tract. Cardiovascular and Ventilation Effects: - Chronic use of benzodiazepines doesn't negatively impact systemic blood pressure, heart rate, or cardiac rhythm. - While ventilation effects are generally absent, caution is advised for patients with chronic lung disease characterized by hypoventilation and decreased arterial oxygenation. 4 Vladimir Aguilar BENZODIAZEPINES SUMMARY Motor Coordination and Cognitive Impairment: - Benzodiazepines can cause decreased motor coordination and cognitive impairment. - Combining benzodiazepines with other CNS depressants may exacerbate these effects. Anterograde Amnesia and Alcohol Interaction: - Acute use of benzodiazepines might result in transient anterograde amnesia. - Combining benzodiazepines with alcohol, especially in acute settings, can lead to profound amnesia. Drug interactions involving benzodiazepines: Synergistic Sedative Effects: - Benzodiazepines have synergistic sedative effects with other CNS depressants like alcohol, anesthetics, opioids, and α2 agonists. Anesthetic Effects: - Benzodiazepines decrease anesthetic requirements for inhaled and injected anesthetics. Opioid Interactions: - Benzodiazepines potentiate the ventilatory depressant effects of opioids, particularly midazolam. - However, benzodiazepines reduce the analgesic actions of opioids. - Flumazenil, a benzodiazepine antagonist, enhances the analgesic effects of opioids. Long-term Opioid Therapy: - Concurrent use of opioids and benzodiazepines in long-term opioid therapy for chronic pain increases all-cause mortality significantly. Hypothalamic-Pituitary-Adrenal (HPA) Axis and benzodiazepines: HPA Axis Suppression: - Evidence supports that benzodiazepines suppress the hypothalamic-pituitary-adrenal (HPA) axis. - Treated patients show suppressed cortisol levels. Alprazolam and Cortisol: - Alprazolam, in animals, inhibits adrenocorticotrophic hormone and cortisol secretion. - Alprazolam's suppression is more pronounced compared to other benzodiazepines. Efficacy in Major Depression: - Alprazolam's unique efficacy in treating major depression may be attributed to its enhanced suppression of the HPA axis. 5 Vladimir Aguilar BENZODIAZEPINES SUMMARY Benzodiazepine dependence: Dependence and Symptoms: - Even therapeutic doses of benzodiazepines can lead to dependence. - Dependence is indicated by physical or psychological symptoms upon dosage reduction or discontinuation. Duration of Use and Dependence: - Symptoms of dependence can emerge after using low-potency benzodiazepines for over 6 months. Dependence vs. Addiction: - Dependence doesn't necessarily indicate addiction; inappropriate drug-seeking behaviors are needed to label it as addiction. Withdrawal Symptoms: - Withdrawal symptoms (irritability, insomnia, tremulousness) occur when discontinuing benzodiazepines. - Onset of withdrawal symptoms aligns with the drug's elimination half-life. - Short-acting benzodiazepines lead to symptoms within 1 to 2 days, while longer-acting drugs result in symptoms within 2 to 5 days. Aging and benzodiazepines: Metabolism and Aging: - Aging and liver disease impact glucuronidation less compared to oxidative metabolic pathways. - Lorazepam, oxazepam, and temazepam are solely metabolized via glucuronidation and lack active metabolites. Elderly Patients and Benzodiazepines: - In elderly patients, glucuronidation-metabolized benzodiazepines (like lorazepam, oxazepam, temazepam) might be preferred over those metabolized by hepatic microsomal enzymes (like diazepam with active metabolites). - Aging may lead to increased sensitivity to benzodiazepines due to both pharmacokinetic and pharmacodynamic factors. Cognitive Decline and Withdrawal: - Long-term benzodiazepine use might contribute to cognitive decline in elderly patients. - Benzodiazepine withdrawal symptoms in the elderly can include confusion. - Elderly long-term benzodiazepine users are more prone to postoperative confusion compared to short-term users or nonusers. 6 Vladimir Aguilar BENZODIAZEPINES SUMMARY Benzodiazepines and platelet aggregation: Platelet Aggregation Inhibition: - Benzodiazepines can inhibit platelet-activating factor-induced aggregation. - Midazolam can induce inhibition of platelet aggregation possibly through changes in platelet membrane conformation. Clinical Impact: - Although benzodiazepines significantly inhibit platelet aggregation in vitro, their effect on hemorrhagic complications in patients with severe, chemotherapy-induced thrombocytopenia is not substantial. - The clinical significance of benzodiazepine-induced platelet aggregation inhibition in surgical scenarios remains uncertain. Midazolam: Characteristics of Midazolam: - Midazolam is a water-soluble benzodiazepine. - It contains an imidazole ring, which contributes to its stability in aqueous solutions and rapid metabolism. Clinical Uses: - Midazolam is commonly used for preoperative medication and conscious sedation. - It has largely replaced diazepam in these applications. Amnestic Effects: - Similar to other benzodiazepines, midazolam's amnestic effects are more potent than its sedative effects. - Patients may be awake after receiving midazolam but still experience amnesia for events and conversations, such as postoperative instructions, for several hours. Commercial preparation of Midazolam: pK and Solubility: - Midazolam has a pK of 6.15, allowing for the preparation of water-soluble salts. - The parenteral solution of midazolam used clinically is buffered to an acidic pH of 3.5. pH-Dependent Phenomenon: - Midazolam exhibits a pH-dependent ring-opening phenomenon. - At pH values below 4, the ring remains open, maintaining water solubility. - At pH values above 4, as in physiological conditions, the ring closes, converting midazolam to a lipid-soluble form. 7 Vladimir Aguilar BENZODIAZEPINES SUMMARY Advantages in Formulation: - Midazolam's water solubility eliminates the need for solubilizing agents like propylene glycol. - Other benzodiazepines often require solubilizing agents that can cause venous irritation or interfere with IM injection absorption. Injection Comfort and Compatibility: - Midazolam causes minimal to no discomfort during or after IV or IM injection. - It's compatible with lactated Ringer solution and can be mixed with acidic salts of other drugs, such as opioids and anticholinergics. Pharmacokinetics of Midazolam: Absorption and Blood-Brain Barrier: - Midazolam is rapidly absorbed from the gastrointestinal tract. - It quickly crosses the blood-brain barrier. Effect-Site Equilibration Time: - Despite quick passage into the brain, midazolam has a relatively slow effect-site equilibration time (0.9-5.6 minutes) compared to other drugs like propofol and thiopental. - IV doses should be spaced sufficiently to allow the peak clinical effect before considering a repeat dose. First-Pass Hepatic Effect: - Only about 50% of an orally administered dose of midazolam reaches systemic circulation due to significant first-pass hepatic effect. Protein Binding and Duration of Action: - Midazolam is extensively bound to plasma proteins. - Short duration of action is due to rapid redistribution from the brain to inactive tissue sites and rapid hepatic clearance. Elimination Half-Time and Age: - Elimination half-time of midazolam is 1 to 4 hours, shorter than that of diazepam. 8 Vladimir Aguilar BENZODIAZEPINES SUMMARY - Elimination half-time may be doubled in elderly patients due to age-related decreases in hepatic blood flow and enzyme activity. Volume of Distribution (Vd): - Vd of midazolam is similar to diazepam, influenced by lipid solubility and protein binding. Clearance and CNS Effects: - Midazolam's clearance is faster than diazepam's, reflected in its context-sensitive halftime. - CNS effects of midazolam are expected to be shorter than those of diazepam. Cardiopulmonary Bypass: - Cardiopulmonary bypass affects plasma concentration and elimination half-time of midazolam due to changes in protein concentrations and pH. - Redistribution of priming fluid into tissues contributes to these changes. Metabolism of Midazolam: Metabolism Pathway: - Midazolam undergoes rapid metabolism via hepatic and small intestine cytochrome P450 (CYP3A4) enzymes. - These enzymes convert midazolam into active and inactive metabolites. Principal Metabolite and Activity: - The main metabolite, 1-hydroxymidazolam, has about half the activity of the parent compound. - It's quickly conjugated to 1-hydroxymidazolam glucuronide, which is then cleared by the kidneys. 9 Vladimir Aguilar BENZODIAZEPINES SUMMARY - In critically ill patients with renal insufficiency receiving continuous IV midazolam infusions, the glucuronide metabolite's high concentrations can lead to synergistic sedative effects with the parent compound. Other Active Metabolite: - Another active metabolite, 4-hydroxymidazolam, is not detectable in plasma following IV midazolam administration. Inhibition and Drug Interactions: - Metabolism of midazolam is affected by drugs that inhibit cytochrome P450 enzymes (cimetidine, erythromycin, calcium channel blockers, antifungal drugs), leading to unexpected CNS depression. - Fentanyl, used during general anesthesia, inhibits hepatic clearance of midazolam. - Cytochrome P450 3A enzymes also affect the metabolism of fentanyl. Hepatic Clearance: - Midazolam's hepatic clearance rate is much higher than that of lorazepam and diazepam, about 5 times greater than lorazepam and 10 times greater than diazepam. Renal clearance of Midazolam: Renal Clearance and Hepatic Metabolism: - Renal failure does not alter the elimination half-time, volume of distribution (Vd), or clearance of midazolam. - This is consistent with the fact that midazolam undergoes extensive hepatic metabolism. No Impact on Renal Function: - Unlike some drugs that are primarily eliminated through the kidneys, midazolam's pharmacokinetics remain largely unaffected by renal impairment. The effects of Midazolam on the central nervous system and other related aspects: Central Nervous System Effects: - Midazolam, like other benzodiazepines, reduces cerebral metabolic rate of oxygen consumption (CMRO2) and cerebral blood flow, similar to barbiturates and propofol. - Midazolam induces dose-related changes in regional cerebral blood flow, affecting areas linked to arousal, attention, and memory. Cerebral Vasomotor Responsiveness: - Midazolam anesthesia preserves cerebral vasomotor responsiveness to carbon dioxide. - Patients with decreased intracranial compliance experience minimal change in intracranial pressure (ICP) with midazolam doses. 10 Vladimir Aguilar BENZODIAZEPINES SUMMARY Induction in Intracranial Pathology: - Midazolam is a suitable alternative to barbiturates for inducing anesthesia in patients with intracranial pathology. - However, rapid administration of midazolam in patients with severe head trauma and ICP below 18 mm Hg might lead to an undesirable increase in ICP. Neuroprotective Activity and Seizures: - While midazolam improves neurologic outcome after incomplete ischemia, benzodiazepines lack proven neuroprotective activity in humans. - Midazolam is an effective anticonvulsant for treating status epilepticus. Prolonged Sedation and Withdrawal: - Extended sedation of infants with midazolam and fentanyl in critical care units can lead to encephalopathy upon benzodiazepine withdrawal. Paradoxical Excitement: - Less than 1% of patients experience paradoxical excitement when receiving midazolam. - This can be treated effectively with flumazenil, a specific benzodiazepine antagonist. Effects of Midazolam on ventilation: Ventilation Effects: - Midazolam causes dose-dependent reductions in ventilation. - At 0.15 mg/kg IV, midazolam has similar ventilatory effects as 0.3 mg/kg IV diazepam. Chronic Obstructive Pulmonary Disease (COPD): - Patients with chronic obstructive pulmonary disease experience even more significant depression of ventilation due to midazolam. Apnea and Large Doses: - Transient apnea might occur after rapid injection of large midazolam doses (>0.15 mg/kg IV), especially when combined with preoperative opioids. Interaction with Fentanyl: - Healthy volunteers experienced arterial hypoxemia and/or hypoventilation when given the combination of midazolam and fentanyl. Effects on Ventilation and Synergy: - Midazolam, when given alone at certain doses (0.05 or 0.075 mg/kg IV), reduces resting ventilation in healthy volunteers. - Spinal anesthesia stimulates resting ventilation, and combining spinal anesthesia with midazolam has a modest synergistic effect on depressing resting ventilation. 11 Vladimir Aguilar BENZODIAZEPINES SUMMARY Swallowing Reflex and Upper Airway: - Benzodiazepines like midazolam also suppress the swallowing reflex and reduce upper airway activity. The effects of Midazolam on the cardiovascular system: Historical Use as Anesthetic Induction: - Large IV doses of midazolam were tested for anesthetic induction but were not widely adopted. - Loss of consciousness is slow and unreliable with midazolam, and it doesn't reliably blunt the hemodynamic response to endotracheal intubation. Hemodynamic Effects: - Midazolam (0.2 mg/kg IV) for anesthesia induction produces greater systemic blood pressure decrease and heart rate increase compared to diazepam (0.5 mg/kg IV). - Similar hemodynamic changes occur with midazolam as with thiopental (3-4 mg/kg IV). - Midazolam-induced hemodynamic changes result from decreased systemic vascular resistance, while cardiac output remains unaffected. Beneficial Effects and Hypovolemia: - Benzodiazepines might improve cardiac output in congestive heart failure patients. - In hypovolemia, midazolam administration enhances blood pressure-lowering effects seen with other IV induction drugs. Response to Tracheal Intubation: - Midazolam doesn't prevent blood pressure and heart rate responses to tracheal intubation. - Mechanical stimulus from intubation may counteract blood pressure-lowering effects of large IV midazolam doses. Effect on Systemic Blood Pressure: - Midazolam's impact on systemic blood pressure is directly linked to its plasma concentration. - There's a ceiling effect where little further change in systemic blood pressure occurs once a certain plasma concentration is reached. Clinical uses of Midazolam: Preoperative Medication for Children: - Midazolam is commonly used as an oral preoperative medication for children. - Oral midazolam syrup (2 mg/mL) is effective for sedation and anxiolysis. 12 Vladimir Aguilar BENZODIAZEPINES SUMMARY - A dose of 0.25 mg/kg provides sedation and anxiolysis, even up to 1 mg/kg (maximum, 20 mg), with minimal effects on ventilation and oxygen saturation. Effective Dosing and Timing: - Oral midazolam (0.5 mg/kg) given 30 minutes before anesthesia induction reliably offers sedation and anxiolysis in children without causing delayed awakening. Comparison with Other Medications: - Oral midazolam is commonly used for mild to moderate sedation in children before surgery. - Recent comparative studies indicate that oral dexmedetomidine produces similar sedation while reducing emergence delirium. Timing and Anterograde Amnesia: - Although recommended to be administered at least 20 minutes before surgery, giving 0.5 mg/kg of oral midazolam 10 minutes before surgery also results in significant anterograde amnesia. Fetal Exposure: - Midazolam crosses the placenta, but its fetal-to-maternal ratio is lower compared to other benzodiazepines. The intravenous sedation uses of Midazolam: Intravenous Sedation: - Midazolam in doses of 1.0 to 2.5 mg IV is effective for sedation during regional anesthesia and brief therapeutic procedures. - Onset occurs within 30-60 seconds, peak effect is reached in 3-5 minutes, and the duration of sedation lasts 15-80 minutes. - The effect-site equilibrium time must be considered to anticipate the time of peak clinical effect and the possible need for additional doses. Ventilation and Side Effects: - The main side effect of midazolam during sedation is ventilation depression due to decreased hypoxic drive. - When combined with other anesthetic drugs, particularly opioids, midazolam-induced ventilation depression is exacerbated. - Patients with chronic obstructive pulmonary disease may experience amplified ventilation depression with benzodiazepine sedation. Pharmacodynamic Variability with Age: - Increasing age leads to greater pharmacodynamic variability. 13 Vladimir Aguilar BENZODIAZEPINES SUMMARY - Elderly patients are generally more sensitive to the hypnotic effects of midazolam, which may require dose adjustments. Induction of anesthesia using Midazolam: Induction of Anesthesia: - Midazolam can be used for inducing anesthesia, but it's not commonly used for this purpose nowadays. - Anesthesia induction with midazolam involves giving 0.1 to 0.2 mg/kg IV over 30 to 60 seconds. - Thiopental usually induces anesthesia 50% to 100% faster than midazolam. Enhancing Unconsciousness with Opioids: - Unconsciousness onset is facilitated when a small opioid dose (e.g., fentanyl, 50-100 μg IV) is administered 1 to 3 minutes before midazolam injection. Effects of Preoperative Medication and CNS Depressants: - The dose of midazolam needed for IV anesthesia induction is reduced when preoperative medication includes a CNS depressant drug. - In healthy patients receiving small benzodiazepine doses, cardiovascular depression is minimal. - Cardiovascular responses may reflect benzodiazepine-induced peripheral vasodilation, and these changes can be exaggerated in the presence of other CNS depressant drugs like propofol and thiopental. Maintenance of anesthesia using Midazolam: Supplementary Use in Maintenance: - Midazolam can be administered to supplement opioids, propofol, and/or inhaled anesthetics during the maintenance of anesthesia. Context-Sensitive Half-Time: - The context-sensitive half-time of midazolam moderately increases with the duration of continuous infusion. Effects on Anesthetic Requirements and Awakening: - Midazolam reduces anesthetic requirements for volatile anesthetics in a dosedependent manner. - General anesthesia with midazolam induction results in longer awakening times (1.0 to 2.5 times) compared to using thiopental for induction. 14 Vladimir Aguilar BENZODIAZEPINES SUMMARY Gradual Awakening and Side Effects: - Patients who receive midazolam for anesthesia induction experience gradual awakening. - Unlike other drugs, this gradual awakening is rarely associated with nausea, vomiting, or emergence excitement. Postoperative sedation using Midazolam: Long-Term IV Administration: - Long-term IV administration of midazolam (loading dose and maintenance dose) for postoperative sedation in intubated patients leads to saturation of peripheral tissues and changes in clearance. Changes in Clearance and Metabolism: - Clearance from the systemic circulation becomes less dependent on redistribution into peripheral tissues and more reliant on hepatic metabolism. Accumulation of Metabolites: - With prolonged IV administration, pharmacologically active metabolites of midazolam may accumulate. Delayed Emergence and Plasma Concentrations: - After discontinuation of IV infusion, plasma concentrations of midazolam decrease slowly, resulting in delayed emergence from sedation. - Emergence time is influenced by the plasma concentrations of midazolam at the time of IV infusion discontinuation. Impact of Analgesic Opioids: - Co-administration of analgesic doses of opioids reduces the required midazolam dose and speeds up recovery from sedation after the infusion is stopped. Factors Affecting Emergence Time: - Elderly patients, obese patients, and those with severe liver disease experience increased emergence time from midazolam infusion. Treating paradoxical vocal cord motion using Midazolam: Paradoxical Vocal Cord Motion: - Paradoxical vocal cord motion is a condition causing nonorganic upper airway obstruction and stridor, which can occur after surgery. Treatment with Midazolam: - Midazolam in doses of 0.5 to 1 mg IV may be used as an effective treatment for managing paradoxical vocal cord motion and its associated symptoms. 15 Vladimir Aguilar BENZODIAZEPINES SUMMARY Diazepam: Characteristics of Diazepam: - Diazepam is a benzodiazepine with high lipid solubility. - It has a longer duration of action compared to midazolam. Usage in Anesthetic Regimens: - Due to the advantageous properties of midazolam, parenteral diazepam is rarely used in modern anesthetic regimens. Commercial preparation and characteristics of Diazepam: Commercial Preparation: - Diazepam is not soluble in water and is dissolved in organic solvents like propylene glycol and sodium benzoate. - The solution has a pH of 6.6 to 6.9 and may be viscous. - Diazepam can be administered via IM or IV routes, but injection may be painful. - An IV injection formulation of diazepam made with soybean is available, associated with reduced pain and thrombophlebitis. Absorption and Distribution: - Diazepam is rapidly absorbed from the gastrointestinal tract after oral administration with nearly 100% bioavailability. - It reaches peak concentrations in about 1 hour (adults) or 15 to 30 minutes (children) after administration. - The drug is quickly taken up by the brain and then redistributed to inactive tissue sites, especially fat, due to its high lipid solubility. - Diazepam has a large volume of distribution (Vd), reflecting its extensive tissue uptake, and this Vd may be larger in women due to their higher body fat content. - It crosses the placenta rapidly, reaching fetal concentrations comparable to or higher than maternal levels. Protein Binding: - The extent of protein binding of benzodiazepines correlates with their lipid solubility. - Diazepam, being highly lipid-soluble, is extensively bound to proteins, most likely albumin. - Conditions like cirrhosis of the liver or renal insufficiency, which lead to decreased albumin levels in plasma, can result in reduced protein binding of diazepam. This could lead to increased side effects of the drug. - The significant protein binding limits the effectiveness of hemodialysis in treating diazepam overdose. 16 Vladimir Aguilar BENZODIAZEPINES SUMMARY Metabolism: - Diazepam undergoes hepatic metabolism mainly through an oxidative pathway called Ndemethylation. - The major metabolites of diazepam are desmethyldiazepam and oxazepam, with a smaller amount being metabolized to temazepam. - Desmethyldiazepam is metabolized more slowly than oxazepam and is only slightly less potent than diazepam. It contributes to the return of drowsiness that occurs 6 to 8 hours after diazepam administration. - Enterohepatic recirculation may also contribute to the recurrence of sedation. - The plasma concentration of diazepam decreases significantly over time due to rapid removal as a conjugate of glucuronic acid. - Desmethyldiazepam is eventually excreted in urine in the form of oxidized and glucuronide conjugated metabolites. Unchanged diazepam is not significantly excreted in urine. Elimination Half-Time: - The elimination half-time of diazepam ranges from 21 to 37 hours in healthy volunteers. - Cirrhosis of the liver can cause up to fivefold increases in the elimination half-time of diazepam. - The elimination half-time of diazepam increases with age, contributing to the increased sensitivity of elderly patients to the drug's sedative effects. - In cirrhosis, the prolonged elimination half-time of diazepam is due to decreased protein binding, leading to an increased volume of distribution (Vd), and decreased hepatic clearance due to reduced hepatic blood flow. - Compared to lorazepam, diazepam has a longer elimination half-time but a shorter duration of action because it dissociates more rapidly from GABAA receptors, allowing faster redistribution to inactive tissue sites. - The principal metabolite of diazepam, desmethyldiazepam, has an elimination half-time of 48 to 96 hours, which may exceed that of the parent drug. - Desmethyldiazepam can accumulate in plasma and tissues during chronic diazepam use, contributing to prolonged somnolence associated with high doses of diazepam. - It can take a week or more for elimination of diazepam and its metabolites from plasma after discontinuation of chronic diazepam therapy. 17 Vladimir Aguilar BENZODIAZEPINES SUMMARY Effects on Organ Systems: - Ventilation: o Diazepam, similar to other benzodiazepines, has significant effects on ventilation, causing dose-dependent depression of ventilation. This can lead to respiratory depression, particularly in patients with chronic obstructive pulmonary disease (COPD). - Systemic Circulation: o Diazepam has minimal effects on the systemic circulation. It does not produce significant changes in blood pressure or heart rate. - Hepatic and Renal Function: o Diazepam does not appreciably alter hepatic and renal functions. It does not have a significant impact on liver or kidney function. - Nausea and Vomiting: o Diazepam does not increase the incidence of nausea and vomiting. It is not associated with a higher likelihood of these gastrointestinal symptoms. - Stress-Responding Hormones: o The circulating plasma concentrations of stress-responding hormones such as catecholamines, arginine vasopressin, and cortisol remain unchanged in response to diazepam administration. Ventilation: - Diazepam's Effect on Ventilation: o Diazepam has minimal depressant effects on ventilation, with noticeable increases in arterial carbon dioxide (PaCO2) levels occurring only when relatively large doses (0.2 mg/kg IV) are administered. The slight increase in PaCO2 is primarily due to a decrease in tidal volume. However, small doses of diazepam (<10 mg IV) have rarely produced apnea. - Interaction with Other CNS Depressants: o When combined with other central nervous system (CNS) depressants such as opioids or alcohol, or when administered to patients with chronic obstructive airway disease, the depression of ventilation caused by diazepam can be exaggerated or prolonged. - Ventilatory Response to Carbon Dioxide: o Diazepam administration leads to a decrease in the slope of the line depicting the ventilatory response to carbon dioxide within a few minutes. This depression of the slope lasts for about 25 minutes and is related to the level of consciousness. Despite this decrease, the shape of the carbon dioxide response curve is not shifted to the right, unlike the effect observed with opioids. The depressant effects on ventilation are primarily due to CNS effects and do not significantly alter the mechanics of respiratory muscles. 18 Vladimir Aguilar BENZODIAZEPINES SUMMARY Cardiovascular System: - Hemodynamic Effects of Diazepam: o When used for induction of anesthesia in doses of 0.5 to 1 mg/kg IV, diazepam typically produces minimal decreases in systemic blood pressure, cardiac output, and systemic vascular resistance. These decreases are similar in magnitude to those observed during natural sleep, ranging from 10% to 20%. - Use in Cardiac Surgery: o Diazepam's relative hemodynamic stability made it a choice for high-dose use in cardiac surgery in the past. - Heart Rate Responses: o There is a transient depression of baroreceptor-mediated heart rate responses caused by diazepam. This depression is less significant than the depression caused by volatile anesthetics, but it could potentially interfere with optimal compensatory changes in hypovolemic patients. - Effects on Left Ventricular End-Diastolic Pressure: o In patients with increased left ventricular end-diastolic pressure, a small dose of diazepam can significantly decrease this pressure. - No Direct Action on Sympathetic Nervous System: o Diazepam does not have a direct action on the sympathetic nervous system, and it does not cause orthostatic hypotension. 19 Vladimir Aguilar BENZODIAZEPINES SUMMARY Skeletal Muscle Effects: - Mechanism of Skeletal Muscle Relaxation: o The skeletal muscle relaxant effects of diazepam are due to its actions on spinal internuncial neurons, not at the neuromuscular junction. It's believed that diazepam reduces the tonic facilitatory influence on spinal gamma neurons, leading to a decrease in skeletal muscle tone. - Tolerance: o Tolerance can develop to the skeletal muscle relaxant effects of benzodiazepines over time. Overdose: - CNS Intoxication: o CNS intoxication can occur when diazepam plasma concentrations exceed 1,000 ng/mL. - Severity of Overdose: o Despite massive overdoses of diazepam, serious consequences are unlikely if cardiac and pulmonary functions are supported and there are no other contributing factors like the presence of other drugs such as alcohol. Clinical Uses: - Preoperative Medication: o Diazepam is commonly used as an oral preoperative medication for adults. - Treatment of Local Anesthetic-Induced Seizures: o Diazepam is recommended for treating seizures induced by local anesthetics. - Management of Delirium Tremens: o Both diazepam and lorazepam are used to manage delirium tremens, a severe form of alcohol withdrawal. - Skeletal Muscle Relaxation: o Diazepam's muscle relaxant effects are utilized in the management of lumbar disc disease and may also be beneficial for patients experiencing tetany. - Shift to Midazolam: o Midazolam has largely replaced diazepam for IV sedation and preoperative medication in children. Anticonvulsant Activity: - Diazepam has anticonvulsant properties and can protect against the development of seizures caused by local anesthetic toxicity. - Diazepam is effective in abolishing seizure activity caused by various factors such as lidocaine toxicity, delirium tremens, and status epilepticus. - The anticonvulsant efficacy of diazepam is thought to be due to its ability to enhance the actions of the inhibitory neurotransmitter GABA. - Unlike barbiturates, which depress the CNS nonselectively, diazepam selectively inhibits activity in the limbic system, particularly the hippocampus. 20 Vladimir Aguilar BENZODIAZEPINES SUMMARY - When diazepam is administered to terminate seizures, a longer-acting antiepileptic drug like fosphenytoin is often given as well. Lorazepam: - Lorazepam is structurally similar to oxazepam, with the addition of an extra chloride atom on the ortho position of the 5-phenyl moiety. - Lorazepam is a benzodiazepine with potent sedative and amnesic properties. - Compared to midazolam and diazepam, lorazepam is more potent in terms of sedation and amnesia. - It has an intermediate duration of action between midazolam and diazepam. - Like other benzodiazepines, lorazepam produces effects on ventilation, the cardiovascular system, and skeletal muscles. Pharmacokinetics of Lorazepam: - Lorazepam is metabolized in the liver by conjugation with glucuronic acid to form pharmacologically inactive metabolites. - Unlike midazolam and diazepam, lorazepam does not form pharmacologically active metabolites. - The elimination half-time of lorazepam is 10 to 20 hours. - More than 80% of the injected dose of lorazepam is excreted in the urine as lorazepam glucuronide. - Lorazepam has slower metabolic clearance compared to midazolam, possibly due to slower hepatic glucuronidation. - Lorazepam's metabolism is less likely to be influenced by hepatic function, increasing age, or drugs that inhibit P450 enzymes. - The slower onset of action of lorazepam compared to midazolam or diazepam is due to its lower lipid solubility and slower entrance into the central nervous system. Clinical Uses of Lorazepam: - Lorazepam is reliably absorbed after oral and IM administration. - After oral administration, maximal plasma concentrations occur in 2 to 4 hours and persist for up to 24 to 48 hours. - The recommended oral dose of lorazepam for preoperative medication is 50 μg/kg, not to exceed 4 mg, resulting in maximal anterograde amnesia lasting up to 6 hours without excessive sedation. - Larger oral doses of lorazepam produce additional sedation without increasing amnesia. - The prolonged duration of action of lorazepam makes it less suitable for cases where rapid awakening at the end of surgery is desired. - After a single IV dose (1-4 mg), the onset of effect occurs within 1 to 2 minutes, with peak effect in 20 to 30 minutes, and sedative effects lasting 6 to 10 hours. - Infusions of lorazepam for postoperative sedation lead to significant delays in emergence from sedation compared to midazolam. - Lorazepam is effective in reducing emergence reactions after administration of ketamine. 21 Vladimir Aguilar BENZODIAZEPINES SUMMARY - Although it requires solvents for IV administration, lorazepam is reported to be less painful on injection and less likely to cause venous thrombosis compared to diazepam. Temazepam: - Temazepam is an orally active benzodiazepine used exclusively for treating insomnia. Oral absorption is complete, but peak plasma concentrations may take about 2.5 hours to occur after administration. It is metabolized in the liver to weakly active or inactive metabolites, which are then conjugated with glucuronic acid. The elimination half-life of temazepam is approximately 15 hours. Oral doses of 15 to 30 mg of temazepam do not alter the proportion of rapid eye movement (REM) sleep to total sleep in adults. Despite the relatively long elimination half-life, temazepam used for treating insomnia is unlikely to result in residual drowsiness the next morning. Tolerance or signs of withdrawal are not typically observed, even after consecutive nightly use for 30 days. Remimazolam: - Remimazolam is a newly developed ultrashort-acting benzodiazepine derivative. It belongs to the class of carboxylic acid esters and, similar to remifentanil, is rapidly metabolized by nonspecific tissue esterases to an inactive carboxylic acid. Remimazolam has a high affinity and selectivity for the benzodiazepine site of the GABAA receptor. The drug is currently undergoing development and seeking FDA approval for use as an anesthetic and sedative in gastrointestinal or pulmonary procedures. Recent studies have shown that remimazolam can lead to faster recovery of full alertness after short diagnostic procedures like bronchoscopy when compared to midazolam. The recovery time was 6.0 minutes for remimazolam versus 12 minutes for midazolam. Flumazenil: - Flumazenil is a 1,4-imidazobenzodiazepine derivative. It is a specific and exclusive benzodiazepine antagonist with a high affinity for benzodiazepine receptors. Flumazenil exerts minimal agonist activity and acts as a competitive antagonist. It can prevent or reverse the agonist effects of benzodiazepines in a dose-dependent manner. The drug is effective in reversing the benzodiazepine-induced ventilatory depression that occurs when benzodiazepines are combined with opioids. Flumazenil is metabolized by hepatic microsomal enzymes to inactive metabolites. Dose and Administration of Flumazenil: - The dose of flumazenil should be adjusted individually to achieve the desired level of consciousness. The recommended initial dose is 0.2 mg IV (8-15 μg/kg IV). 22 Vladimir Aguilar BENZODIAZEPINES SUMMARY - - - This initial dose typically reverses the effects of benzodiazepine agonists within about 2 minutes. Additional doses of 0.1 mg IV can be administered at 60-second intervals if needed, up to a total of 1 mg IV. Generally, total doses of 0.3 to 0.6 mg IV are sufficient to decrease sedation caused by benzodiazepines, while total doses of 0.5 to 1.0 mg IV can completely reverse the effects of therapeutic benzodiazepine doses. If a patient does not respond to IV doses of flumazenil exceeding 5 mg, it suggests involvement of substances other than benzodiazepines or the presence of organic disorders. The duration of action of flumazenil is 30 to 60 minutes, and additional doses may be needed to maintain the desired level of consciousness. For maintenance of wakefulness, a continuous low-dose infusion of flumazenil (0.1 to 0.4 mg per hour) can be used. Caution should be exercised when administering flumazenil to patients being treated with antiepileptic drugs to avoid precipitating acute withdrawal seizures. Side Effects of Flumazenil: - - - Flumazenil's antagonism of excess benzodiazepine effects does not lead to acute anxiety, hypertension, tachycardia, or a stress response in postoperative patients. Reversal of benzodiazepine effects with flumazenil does not result in changes in left ventricular systolic function or coronary hemodynamics in patients with coronary artery disease. Flumazenil's weak intrinsic agonist activity likely mitigates abrupt reversal of agonist effects. Flumazenil does not influence anesthetic requirements (minimum alveolar concentration) for volatile anesthetics, indicating that these anesthetics do not exert their effects on the CNS through GABAA receptors. At approximately ten times the clinically recommended dose, flumazenil has no agonist effects on resting ventilation or psychomotor performance in normal individuals. Short-Acting Nonbenzodiazepine Benzodiazepines: - - - The term "benzodiazepine" originally referred to a specific chemical structure comprising a benzene ring and a diazepine ring. However, the term has also come to represent a class of drugs that share clinical activity and a common binding site on the GABAA receptor, known as the benzodiazepine site. Some drugs exhibit the same pharmacology as benzodiazepines, binding to the GABAA receptor and producing similar effects, but they don't possess the benzodiazepine chemical structure. These drugs have been humorously named "nonbenzodiazepine benzodiazepines." Approved drugs in this category include zaleplon (Sonata), zolpidem (Ambien), and eszopiclone (Lunesta). Zaleplon, zolpidem, and eszopiclone act on the GABA receptor complex and exhibit more selectivity for certain subunits of GABA receptors. This leads to a clinical profile for 23 Vladimir Aguilar BENZODIAZEPINES SUMMARY - - treating sleep disorders that is more effective and has fewer side effects compared to conventional benzodiazepines. These drugs differ in their effects on sleep stages due to variations in their binding to GABA receptor subunits. Zaleplon has a rapid elimination, making it useful for patients with delayed onset of sleep. Zolpidem has a delayed elimination, potentially causing residual sedation and side effects but can be used for sustained treatment of insomnia with reduced waking during the night. Despite being slightly effective for insomnia, the overall clinical significance of their effects is questionable. The use of these agents has increased in recent years, with around 3% of Americans reporting their use. 24