MVAL
• Many gradients exist:
• Oxygen
• Zone 1 = oxygen rich; Zone 3 = hypoxic
• Bile Salts
• Bilirubin
• Many organic ions
• Gradients of enzymes involved in detoxification also exist:
• Zone 1: Glutathione
• Zone 3: Cytochrome p450 proteins
• Why do many hepatotoxins preferentially damage one type of liver cell?
• Specialized processes are located in the liver
• Example: Cocaine an acetaminophen cause Zone 3 hepatocellular necrosis
• Zone 3 is site of high levels of cytochrome p450
• P450 enzymes produce harmful metabolites of these two drugs
• Cytochrome p450 enzymes may bioactivate many toxins to free radicals
• Conditions in which cytochrome p450 is depleted has been shown to decrease liver damage during exposure to certain hepatotoxins
• Activation of Kupffer cells increases ROS and reactive nitrogen species in the liver
• Example: LPS
• In addition, migration (infiltration) of neutrophils, lymphocytes, and other inflammatory cells may occur to combat infection but also may add to damage by depleting glutathione, etc., through release of excessive amounts of ROS and proteases, etc.
• Liver cells are vulnerable to same types of insult that injure other tissues
• Preferential liver damage occurs due to the location of the liver and due to its high capacity for converting chemicals to reactive entities
• Liver is susceptible to toxicological insult because of:
• The liver’s proximity and involvement with the GI tract
• The liver’s diverse and vital functions
• Bile formation
• Detoxification reactions
• Extraction of diverse substances
Acute Liver Failure and Cirrhosis: Pathophysiology and the Role of Ativan and Versed
Acute Liver Failure (ALF)
• Definition: A rapid decline in liver function characterized by coagulopathy (elevated INR) and hepatic encephalopathy in a patient without pre-existing liver disease.
• Pathophysiology:
o Zonal Damage:
Zone 3 (centrilobular hepatocytes): Susceptible to injury from toxins metabolized by cytochrome P450 enzymes.
Example: Acetaminophen toxicity generates reactive metabolites (e.g., NAPQI) through CYP enzymes, leading to oxidative stress and glutathione depletion.
Kupffer Cell Activation: Release of reactive oxygen species (ROS) and inflammatory mediators exacerbates hepatocyte damage.
o Hypoxia:
Zone 3 is relatively hypoxic compared to oxygen-rich Zone 1, further increasing vulnerability during ischemic or toxic insults.
o Impaired Detoxification:
Loss of phase I and phase II detoxification capacity leads to the accumulation of ammonia, bilirubin, and reactive metabolites, contributing to encephalopathy and systemic toxicity.
Cirrhosis
• Definition: Chronic, progressive fibrosis and loss of normal hepatic architecture due to ongoing liver injury.
• Pathophysiology:
o Impaired Blood Flow:
Fibrosis restricts blood flow, exacerbating hypoxia in centrilobular regions (Zone 3).
o Loss of Hepatocyte Function:
Decreased cytochrome P450 activity (Phase I metabolism) and impaired conjugation (Phase II metabolism) reduce the liver's ability to metabolize drugs and toxins.
o Kupffer Cell and Inflammatory Activation:
Chronic inflammation perpetuates oxidative stress and hepatocyte apoptosis, worsening fibrosis.
o Detoxification Failure:
Impaired ammonia clearance leads to hepatic encephalopathy.
Accumulation of bile salts and bilirubin contributes to jaundice and pruritus.
Role of Ativan and Versed in ALF and Cirrhosis
Ativan (Lorazepam)
• Phase II Metabolism (Glucuronidation):
o Lorazepam undergoes conjugation with glucuronic acid, which is preserved longer than CYP-mediated processes in cirrhosis and ALF.
• Advantages in Liver Dysfunction:
o Safe in patients with impaired Phase I metabolism as its clearance is less reliant on cytochrome P450.
o Minimal accumulation, reducing the risk of prolonged sedation or toxicity.
• Clinical Use:
o Preferred for sedation in patients with hepatic encephalopathy or ALF to avoid exacerbating neurological dysfunction.
Versed (Midazolam)
• Phase I Metabolism (Cytochrome P450):
o Metabolized by CYP3A4 enzymes predominantly in Zone 3 hepatocytes.
• Disadvantages in Liver Dysfunction:
o Reduced CYP activity in cirrhosis and ALF slows metabolism, leading to prolonged half-life and increased sedation risk.
o Accumulation of active metabolites may worsen encephalopathy.
• Clinical Use:
o Requires caution or avoidance in advanced liver disease due to the risk of oversedation and drug toxicity.
Preferential Liver Damage in Zone 3
• Susceptibility:
o High cytochrome P450 activity in Zone 3 increases the generation of toxic metabolites, such as those from acetaminophen or cocaine.
o Low oxygen levels make Zone 3 cells vulnerable to ischemia.
• Kupffer Cell Activation:
o Inflammatory cells release ROS and reactive nitrogen species, depleting antioxidants like glutathione and worsening injury.
• Protective Adaptation:
o Conditions reducing cytochrome P450 activity (e.g., pre-existing liver damage) can paradoxically protect against toxins that rely on bioactivation to cause harm.
Summary
• Ativan (Phase II metabolism) is safer for sedation in ALF and cirrhosis due to preserved glucuronidation pathways.
• Versed (Phase I metabolism) poses a higher risk of toxicity due to impaired CYP activity in liver dysfunction.
• Understanding the zonal distribution of liver enzymes (e.g., CYP in Zone 3) and the mechanisms of injury (e.g., ROS, hypoxia) is critical in managing liver disease and drug metabolism effectively.
Acute Liver Failure and Cirrhosis: Pathophysiology and the Role of Ativan and Versed
Acute Liver Failure (ALF)
• Definition: A rapid decline in liver function characterized by coagulopathy (elevated INR) and hepatic encephalopathy in a patient without pre-existing liver disease.
• Pathophysiology:
o Zonal Damage:
Zone 3 (centrilobular hepatocytes): Susceptible to injury from toxins metabolized by cytochrome P450 enzymes.
Example: Acetaminophen toxicity generates reactive metabolites (e.g., NAPQI) through CYP enzymes, leading to oxidative stress and glutathione depletion.
Kupffer Cell Activation: Release of reactive oxygen species (ROS) and inflammatory mediators exacerbates hepatocyte damage.
o Hypoxia:
Zone 3 is relatively hypoxic compared to oxygen-rich Zone 1, further increasing vulnerability during ischemic or toxic insults.
o Impaired Detoxification:
Loss of phase I and phase II detoxification capacity leads to the accumulation of ammonia, bilirubin, and reactive metabolites, contributing to encephalopathy and systemic toxicity.
Cirrhosis
• Definition: Chronic, progressive fibrosis and loss of normal hepatic architecture due to ongoing liver injury.
• Pathophysiology:
o Impaired Blood Flow:
Fibrosis restricts blood flow, exacerbating hypoxia in centrilobular regions (Zone 3).
o Loss of Hepatocyte Function:
Decreased cytochrome P450 activity (Phase I metabolism) and impaired conjugation (Phase II metabolism) reduce the liver's ability to metabolize drugs and toxins.
o Kupffer Cell and Inflammatory Activation:
Chronic inflammation perpetuates oxidative stress and hepatocyte apoptosis, worsening fibrosis.
o Detoxification Failure:
Impaired ammonia clearance leads to hepatic encephalopathy.
Accumulation of bile salts and bilirubin contributes to jaundice and pruritus.
Role of Ativan and Versed in ALF and Cirrhosis
Ativan (Lorazepam)
• Phase II Metabolism (Glucuronidation):
o Lorazepam undergoes conjugation with glucuronic acid, which is preserved longer than CYP-mediated processes in cirrhosis and ALF.
• Advantages in Liver Dysfunction:
o Safe in patients with impaired Phase I metabolism as its clearance is less reliant on cytochrome P450.
o Minimal accumulation, reducing the risk of prolonged sedation or toxicity.
• Clinical Use:
o Preferred for sedation in patients with hepatic encephalopathy or ALF to avoid exacerbating neurological dysfunction.
Versed (Midazolam)
• Phase I Metabolism (Cytochrome P450):
o Metabolized by CYP3A4 enzymes predominantly in Zone 3 hepatocytes.
• Disadvantages in Liver Dysfunction:
o Reduced CYP activity in cirrhosis and ALF slows metabolism, leading to prolonged half-life and increased sedation risk.
o Accumulation of active metabolites may worsen encephalopathy.
• Clinical Use:
o Requires caution or avoidance in advanced liver disease due to the risk of oversedation and drug toxicity.
Preferential Liver Damage in Zone 3
• Susceptibility:
o High cytochrome P450 activity in Zone 3 increases the generation of toxic metabolites, such as those from acetaminophen or cocaine.
o Low oxygen levels make Zone 3 cells vulnerable to ischemia.
• Kupffer Cell Activation:
o Inflammatory cells release ROS and reactive nitrogen species, depleting antioxidants like glutathione and worsening injury.
• Protective Adaptation:
o Conditions reducing cytochrome P450 activity (e.g., pre-existing liver damage) can paradoxically protect against toxins that rely on bioactivation to cause harm.
Summary
• Ativan (Phase II metabolism) is safer for sedation in ALF and cirrhosis due to preserved glucuronidation pathways.
• Versed (Phase I metabolism) poses a higher risk of toxicity due to impaired CYP activity in liver dysfunction.
• Understanding the zonal distribution of liver enzymes (e.g., CYP in Zone 3) and the mechanisms of injury (e.g., ROS, hypoxia) is critical in managing liver disease and drug metabolism effectively.
Benzodiazepines
Elderly metabolize/eliminate benzodiazepines at a slower rate due to {{c1::reduced OXIDATIVE reduction}}, therefore they are unaffected by certain benzodiazepines {{c1::LOT (lorazepam, oxazepam, temazepam)}} because {{c1::they undergo ONLY GLUCURONIDE conjugation (preserved in elderly and LIVER DISEASE)}}
TOOOOOO HIGH YIELD
LOT
Lorazepam, oxazepam, temazepam
What test can be used to help diagnose catatonia?
{{c1::Lorazepam challenge test}}
Catatonia is a syndrome (not a specific disorder) of marked psychomotor disturbance that occurs in severely ill patients with mood disorders with psychotic features, psychotic disorders, autism spectrum disorder, and medical conditions (infectious, metabolic, neurologic, rheumatologic). Common features include decreased motor activity, lack of responsiveness during interview, and posturing. Catatonia can range from stupor to marked agitation (catatonic excitement), which contributes to difficulties in recognition.
Treatment of catatonia includes benzodiazepines and/or electroconvulsive therapy (ECT). A lorazepam challenge test (lorazepam 1-2 mg IV) resulting in partial, temporary relief within 5-10 minutes confirms the diagnosis. Catatonia generally responds to benzodiazepines within a week; ECT is the treatment of choice in patients who do not improve.
-) Antipsychotics can worsen catatonia and should be avoided. Clozapine is generally reserved for treatment-refractory psychosis due to the risk of severe neutropenia. Treatment of this patient's underlying bipolar disorder with risperidone should be deferred until his catatonia resolves with lorazepam.
What is treatment of catatonia?
{{c1::1. Benzodiazpines
2. Electroconvulsive therapy}}
Catatonia is a syndrome (not a specific disorder) of marked psychomotor disturbance that occurs in severely ill patients with mood disorders with psychotic features, psychotic disorders, autism spectrum disorder, and medical conditions (infectious, metabolic, neurologic, rheumatologic). Common features include decreased motor activity, lack of responsiveness during interview, and posturing. Catatonia can range from stupor to marked agitation (catatonic excitement), which contributes to difficulties in recognition.
Treatment of catatonia includes benzodiazepines and/or electroconvulsive therapy (ECT). A lorazepam challenge test (lorazepam 1-2 mg IV) resulting in partial, temporary relief within 5-10 minutes confirms the diagnosis. Catatonia generally responds to benzodiazepines within a week; ECT is the treatment of choice in patients who do not improve.
-) Antipsychotics can worsen catatonia and should be avoided. Clozapine is generally reserved for treatment-refractory psychosis due to the risk of severe neutropenia. Treatment of this patient's underlying bipolar disorder with risperidone should be deferred until his catatonia resolves with lorazepam.
Which benzodiazepine is safe to use for alcohol withdrawal in patients with liver disease?
{{c1::Lorazepam}}
Chlordiazepoxide has multiple active metabolites and is less safe in liver disease patients.
What drug is used to treat alcohol withdrawal?
{{c1::Lorazepam}}
Lorazepam, an intermediate-duration benzodiazepine, often given intravenously, is preferred in the hospital setting. It is safer in patients with possible liver disease and has no active metabolites. Adjunctive management includes intravenous fluids, frequent monitoring of vital signs, thiamine, folate, and nutritional support.
Chlordiazepoxide is a very long-acting benzodiazepine with multiple active metabolites that is used to treat alcohol withdrawal. However, it is less preferred in medically hospitalized patients and in those with possible liver disease, such as this patient.
Midazolam has a relatively short half-life of {{c1::2 to 3 hours::hours range}}, lorazepam has an intermediate half-life of {{c2::10 to 20 hours::hours range}}, and diazepam has a long half-life of {{c3::20 to 50 hours::hours range}}.
The benzodiazepines are metabolized in the liver where the parent compounds undergo extensive biotransformation.
Diazepam undergoes biotransformation to a number of products, two of which (oxazepam and desmethyldiazepam) are potent and long-acting BNZ receptor agonists. These metabolites result in the prolonged sedative effect seen with diazepam.
Lorazepam is also highly metabolized, but its metabolites are rapidly excreted by the kidneys and none have significant clinical activity.
Midazolam is biotransformed to compounds known as hydroxymidazolams, but controversy exists regarding whether these compounds have any benzodiazepine activity. Several studies in elderly patients and the critically ill have shown prolongation of midazolam’s t1/2β and its sedative effect. This is caused by several factors, including increased volume of distribution and extensive fatty tissue uptake after prolonged infusion.
One study investigating the effect of prolonged midazolam infusions in critically ill patients found that the mean time from administration to awakening in patients with renal failure was approximately 44 hours (control, 13 hours). The time to awakening in two patients with renal and hepatic failure was greater than 120 hours. Although these same factors could affect lorazepam, its lower lipid solubility and inactive metabolites appear to make it less likely to cause prolonged sedation.
Midazolam has a relatively short half-life of {{c1::2 to 3 hours::hours range}}, lorazepam has an intermediate half-life of {{c2::10 to 20 hours::hours range}}, and diazepam has a long half-life of {{c3::20 to 50 hours::hours range}}.
The benzodiazepines are metabolized in the liver where the parent compounds undergo extensive biotransformation.
Diazepam undergoes biotransformation to a number of products, two of which (oxazepam and desmethyldiazepam) are potent and long-acting BNZ receptor agonists. These metabolites result in the prolonged sedative effect seen with diazepam.
Lorazepam is also highly metabolized, but its metabolites are rapidly excreted by the kidneys and none have significant clinical activity.
Midazolam is biotransformed to compounds known as hydroxymidazolams, but controversy exists regarding whether these compounds have any benzodiazepine activity. Several studies in elderly patients and the critically ill have shown prolongation of midazolam’s t1/2β and its sedative effect. This is caused by several factors, including increased volume of distribution and extensive fatty tissue uptake after prolonged infusion.
One study investigating the effect of prolonged midazolam infusions in critically ill patients found that the mean time from administration to awakening in patients with renal failure was approximately 44 hours (control, 13 hours). The time to awakening in two patients with renal and hepatic failure was greater than 120 hours. Although these same factors could affect lorazepam, its lower lipid solubility and inactive metabolites appear to make it less likely to cause prolonged sedation.
The preferred first-line antiepileptic drug (AED) is {{c1::lorazepam}}, based on its rapid onset and prolonged action. {{c1::Lorazepam}} is superior to {{c2::diazepam}} in controlling seizures at the prehospital and in-hospital levels.
In a study by the Veterans Affairs Status Epilepticus Cooperative Study Group, treatment with lorazepam resulted in a 65% success rate versus treatment with phenobarbital (58%), diazepam plus phenytoin (56%), and phenytoin (44%); the proportion of complications, including respiratory depression, was not different among the 4 groups at 30 days.
In a landmark randomized controlled clinical trial, respiratory depression was less associated with benzodiazepine use in the management of SE. In the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) study, intramuscular midazolam was found to be at least as effective as IV lorazepam in prehospitalized patients with SE.
About 80% of patients will respond to first-line AEDs if treatment is delivered within 30 minutes of onset, but less than 40% will respond if treated within 2 hours of onset.
Most experts agree that a patient is in SE if seizures persist for more than 5 minutes or if the patient’s state of consciousness does not recover between seizures.
Lorazepam’s 2- to 3-h half-life and avid GABA receptor binding provide seizure protection for up to {{c1::24 h::hours}}.
Initial IV doses of lorazepam (0.1 mg/kg) are very effective (60%–90%) in terminating seizure activity within minutes.
What is the treatment of choice for patients with alcohol withdrawal?
{{c1::Benzodiazepines (e.g. lorazepam)}}
Ben's Diner, "order status;"
barbershop
Narrow spectrum antiepileptic agents: carbamazepine, phenytoin, gabapentin, tiagabine, vigabatrin ("Seize the Night")
Status epilepticus is treated acutely w/ benzodiazepines (e.g. diazepan, lorazepam); then phenytoin is used for maintenance/prophylaxis
Phenobarbital (barbiturate) can be used to treat refractory status epilepticus
{{c2::Benzodiazepines (diazepam, lorazepam)}} are first line for acute attacks of {{c1::status epilepticus}}, while {{c2::Phenytoin}} is first line for prophylaxis of {{c1::status epilepticus}}
"ben's"
status epilepticus = > 5 minutes of generalized convulsive seizures or > 2 seizure episodes without recovery of consciousness
Given that midazolam has an active metabolite which is {{c1::renally eliminated::hepatic/renal cleared}}, the use of midazolam in patients with combined liver and kidney impairment can further prolong sedation and should be avoided.
Should a benzodiazepine be necessary, lorazepam is generally thought to be the drug of choice because its primary mechanism of metabolism, conjugation, is a process less affected by liver dysfunction. When using lorazepam in patients with liver disease, the dose should be empirically reduced and given less frequently, thus utilizing the lowest effective dose to minimize undesirable adverse effects. Midazolam use should be avoided.
There is no single ideal drug regimen for terminating seizures; however, {{c1::benzodiazepines::RX class}}, specifically {{c1::lorazepam}}, represent excellent initial choices because of their effectiveness, rapid action, and wide therapeutic margin.
For patients who experience a solitary seizure or several brief seizures with known precipitant, long-term anticonvulsants are usually not necessary; however, there is agreement that status epilepticus should be pharmacologically ended as rapidly as possible.
Drugs that bind GABA receptors are the most effective seizure-quashing drugs.
{{c1::Flumazenil}} is a short-acting negative allosteric modifier at the γ-aminobutyric acid type A (GABAA) receptor and reverses the sedative effects of most {{c2::benzodiazepines (e.g., lorazepam, midazolam, and diazepam)::anxiolytic}}.
It can also reverse the effects of other similar non-benzodiazepine drugs that bind the same site on the GABAA receptor: zopiclone and zolpidem.
Flumazenil has no reversal effect on other GABAA agonists that bind to other sites on the receptor, such as barbiturates, propofol, ethanol, and inhaled anesthetics. Flumazenil is indicated for the diagnosis and treatment of benzodiazepine intoxication/overdose. Most experts agree that the major indication for flumazenil is in the setting of severe benzodiazepine overdose in a patient who is not benzodiazepine dependent. Typical doses are 0.2 mg intravenously every 1 to 2 minutes titrated to clinical effect.
The major risk with flumazenil is the potential to induce benzodiazepine withdrawal, which can lead to seizures and agitation. Therefore, flumazenil should not be used in polysubstance intoxications involving proconvulsant drugs. In clinical practice, flumazenil is used infre?uently, because most benzodiazepine overdoses occur in patients expected to be dependent as the result of chronic use, and patients generally do well with supportive care.
Flumazenil should only be used in select circumstances where the poisoning is severe and the risk of seizure or withdrawal is felt to be low, ideally in consultation with a toxicologist.
Initial IV doses of {{c1::lorazepam (0.1 mg/kg)::RX name & dose}} are very effective ({{c2::60%–90%::%}}) in terminating seizure activity within minutes.
Benzodiaz-epines cannot be expected to provide long-term seizure control by themselves, but can ‘‘break’’ seizures long enough to accomplish intubation if necessary and to initiate therapy with a longer acting drug.
Drugs that bind GABA receptors are the most effective seizure-quashing drugs.
For patients who experience a solitary seizure or several brief seizures with known precipitant, long-term anticonvulsants are usually not necessary; however, there is agreement that status epilepticus should be pharmacologically ended as rapidly as possible.
Options for pharmacological management of an acutely agitated patient include the administration of a(n) {{c1::benzodiazepine}} and/or an antipsychotic agent
The benzodiazepine lorazepam is often used due to its rapid onset of action and intramuscular formulation
{{c2::Benzodiazepines (diazepam, lorazepam)}} are first line for acute attacks of {{c1::status epilepticus}}.
status epilepticus = > 5 minutes of generalized convulsive seizures or > 2 seizure episodes without recovery of consciousness
What is the treatment of choice for patients with alcohol withdrawal?
{{c1::Benzodiazepines (e.g. lorazepam)}}
{{c2::Benzodiazepines (diazepam, lorazepam)}} are first line for acute attacks of {{c1::status epilepticus}}, while {{c2::phenytoin}} is first line for prophylaxis of {{c1::status epilepticus}}.
Status epilepticus → 5 minutes of generalized convulsive seizures or > 2 seizure episodes without recovery of consciousness
{{c2::Benzodiazepines (diazepam, lorazepam)}} are first line for acute attacks of {{c1::status epilepticus}}, while {{c2::phenytoin}} is first line for prophylaxis of {{c1::status epilepticus}}.
Status epilepticus → 5 minutes of generalized convulsive seizures or > 2 seizure episodes without recovery of consciousness
Which type of generalized seizure is acutely treated with benzodiazepines?
{{c1::Status epilepticus}}
What is the choice in pharmacotherapy for a patient with specific phobia who refuses CBT or if CBT is not available?
{{c1::Benzodiazepines (i.e. lorazepam)}}
CBT is the preferred first-line therapy
Short-acting benzos are favorable. Take 30 minutes before boarding plane, for example.
What is the treatment of delirium tremens?
{{c1::IV benzodiazepines (Lorazepam)}}
Keep giving until level of sedation is achieved; titrate dose down slowly to avoid life threatening withdrawal
{{c1::Long-acting benzodiazepines such as diazepam and chlordiazepoxide}} can be used to treat alcohol withdrawal.
What is the choice in a patient with hepatic disease (ie. chronic alcoholic) or in inpatient setting? {{c1::Lorazepam*}}
What is the most likely explanation for a patient who stopped taking his fluoxetine and lorazepam after 2 years and is now anxious and irritable and complains of insomnia, dysphoria, and anxiety?
{{c1::Benzodiazepine withdrawal}}
- Abrupt discontinuation of benzos can result in life-threatening withdrawal syndrome and cause early rebound effects of insomnia and anxiety and it can be hard to differentiate between the return of the anxiety disorder; also increases risk for seizures
- Lorazepam withdrawal → may produce sxs within 1-2 days
- Fluoxetine withdrawal → 4-6 days (longer half-life)
The benzodiazepines that are safe to use in patients with liver disease may be remembered with the mnemonic "LOT":
L: {{c1::Lorazepam}}
O: {{c1::Oxazepam}}
T: {{c1::Temazepam}}
Long-acting benzodiazepines such as {{c1::diazepam}} and {{c1::chlordiazepoxide}} can be used to treat alcohol withdrawal.
What is the choice in a patient with hepatic disease (e.g. chronic alcoholic) or in inpatient setting? {{c1::Lorazepam*}}
Acute stimulant intoxication UpToDate treatments:
Initial: {{c1::IV lorazepam/diazepam}}
Agitation: {{c1::ziprasidone/haloperidol}}
Hypertension: {{c1::vasodilators (nitroprusside/nitroglycerin) or alpha blockers (phentolamine)}}
Tachycardia: {{c1::calcium blockers (diltiazem)}}
Hyperthermia: {{c1::nondepolarizing agents (rocuronium/vecuronium) -> intubation}}
Alprazolam, Lorazepam, Temazepam, and Oxazepam are benzodiazepines that have {{c1::intermediate}} half lifes
this is 6-24 hours; ALT-M(edium)
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