Sedatives & Anesthetics:Analgesics Flashcards
What are benzodiazepines
Sedatives-hypnotics
MOA of Benzodiazepines
Benzodiazepines work by binding to an allosteric site on the GABA-A receptor, enhancing GABA activity. The GABA-A receptor is a chloride channel. GABA-A channel activation leads to increased Cl conductance -> Cl- channel hyperpolarizes and stabilizes membranes, making neurons less excitable.It is important to know that benzodiazepines cause potentiation of GABA-A by allowing it to open more frequently, NOT by prolonging the time for which the ion channel is open.
What is the naming convention of benzodiazepines (short and long acting)
Benzodiazepines end with ‘-pam’, short acting, ‘-azepam’ is for short acting such as lorazepam or oxazepam
What are the 2 important properties of short acting benzos
They have a shorter half life and have 2 important properties: inactivated by liver (whereas long acting are activated by liver) and more likely to develop physical dependence due to their short duration of action
What is a clinical consequence of these properties of short acting benzos
Short acting are inactivated by liver, long acting are activated by liver, as a result in people with hepatic insufficiency we administer short acting ones for example when treating alcohol withdrawal symptoms.
Name the inhibitory neurotransmitters of CNS
GABA and glycine
Explain the properties of GABA A receptor and what is its function
GABA A consists of 5 subtypes that together form a chloride channel that modulate neuronal excitability, mood changes, anxiety and sleep
Explain MOA of alcohol
It also binds to an allosteric site to GABA A
What are the clinical consequences of MOA of alcohol and how does it relate to benzos
Alcohol withdrawal have the same symptoms as benzos withdrawal, alcohol and benzos can have synergistic effects, benzos can be used to treat alcohol withdrawal symptoms
Explain the 3 stages of alcohol withdrawal
- 8 hrs. Insomnia, tremulousness, anxiety, autonomic instability (which manifests as increase in blood pressure, diaphoresis and tachycardia)2. Seizures3. 48-96 hrs. Delirium tremens - this consists of fever, disorientation and severe agitation
What are the 1st line for treatment of alcohol withdrawal if the liver is fine and when there is hepatic insufficiency
Long acting benzos if liver is fine and short acting when there is hepatic insufficiency
What is the hallmark of alcohol withdrawal treatment
Treating and preventing seizures
How are alcohol withdrawal seizures treated?
IV benzos
What other seizures can be treated with IV benzos
Status epilepticus (generalized tonic clonic seizures > 30min)
Anesthetic uses of benzos
IV benzos can be used for general or light anesthesia (for intubation of an airway for example). Can induce conscious sedation for minor procedures and surgeries.
Benzos used for insomnia?
Can be used to treat insomnia for short term treatment, cannot be used long term due to side effects such as toleranceCan treat parasomnias in children (sleepwalking, night terrors).
What other CNS disorders can be treated with benzos?What are the adverse effects of benzos when treating these disorders?
Benzos can be used as a muscle relaxant, so for example can treat spasticity caused by upper motor neuron injury. We have to be careful as at the same dosage it can have sedative effects.Can be used to treat generalized anxiety disorder but SSRIs and SNRIs are the first line due to benzos side effects
What is a major adverse effects of using benzos and what is the physiological mechanism behind it?What is a clinical concequence to it?
Tolerance, there is downregulation of GABA A receptor so this is pharmacodynamic tolerance. Same withdrawal effects as alcohol.
Other AE of benzos?
Sedative effect, cause dose related anterograde amnesia so impairs the ability to learn new information, elderly are more susceptible to these effects, impairs coordination and balance, can cause central ataxia
What drugs should not be taken with benzos?
Other CNS depressant such as alcohol, barbituates, neuroleptics and 1st gen anti histamines
How to counter AE of benzos?
In order to treat someone with acute over dose of benzos we can use the drug flumazenil, it is a benzodiazepines receptor antagonist, reverses sedation caused by benzos.
What is an AE of flumezanil?
Administration of flumanezil can precipitate withdrawl symptoms in people who have developed tolerance to benzos through chronic use
What is increased GABA A (Cl ion channel) permeability (or conductance to Cl ions) associated with? Arousal or sedative effect?Explain why.
Increase in GABA A Cl ion conductance leads to sedative effect.Cl- channel hyperpolarizes and stabilizes membranes, making neurons less excitable.
Name non benzos that are used for sleep therapy
Nonbenzodiazepine hypnotics help you catch some Zzz’s -> 3 Z’s Zolpidem, Zaleplon, and esZopiclone
What is the first line of therapy for insomnia?
Non-pharm interventions such as behavior modification and cognitive therapy
When should pharmacotherapy be used for insomnia?
As a 2nd line, pharmacotherapy can provide immediate relief but should generally be used for short-term management due to addictive/dependence
MOA of non benzos
These drugs have a similar method of action to benzodiazepines. They work by binding to an allosteric site on the GABA-A receptor (an ionotropic Cl- channel) -> enhances the frequency* of Cl- channel opening in response to GABA -> increased flow of Cl- ions across the membrane, causing CNS depression
How are non benzos different than benzos and what is a clinical consequence of this
Different structure than benzos, as a result bind more specifically with GABA A and hence have less anti anxiety and anti convulsive activity, AE are less frequent and less severe
Explain the use of zaleplon and zolpidem
Rapid onset of action and short half life since they are rapidly metabolized by CYP450, good for helping them fall asleep but does NOT help them stay asleep due to short duration of action
Eszopliclone MOA and side effect
Has the longest half-life of the 5 to 7 hours, so it works to both initiate and maintain sleep. Due to its longer half life it is more likely to cause hang over (still sleepy the next day)
AE of non benzos
Elderly patients are more sensitive to non-benzos, leading to cognitive impairment and delirium, night wandering and agitation, it also increases risk of ataxia and falls
What meds can non benzos not be used for?
Other CNS depressants (1st generation anti-histamines, barbs, benzos, alcohol).
Explain the frequency of tolerance and withdrawal with non benzos than with benzos
Nonbenzodiazepines are less likely to cause tolerance than benzodiazepines. Less likely to cause physical dependence and withdrawal’s as well.
Treatment for non benzos overdose and what is a concequence of this?
Flumazenil (a competitive antagonist at the BZD receptor) reverses the sedative actions of nonbenzo hypnotics, but precipiates seizures - controversal to use it in cases of nonbenzo/benzo overdose
What is the role of melatonin in inducing sleep?
Maintains circadian rhythm
What is ramalteon
Used for insomnia, melatonin receptor agonists, binds to MT1 and MT2 melatonin receptors located in the suprachiasmatic nucleus of the hypothalamus. They have NO effects on GABA A receptors.
What are the side effects of ramalteon?
There are few side effects and are safe in elderly patients. Doesn’t affect sleep architecture, doesn’t cause rebound insomnia, and doesn’t cause withdrawal symptoms
What are barbiturates?
Sedatives-hypnotics
barbiturates MOA and how are they principally different than other sedatives?
Bind to an allosteric site on the GABA-A receptor. Benzos & non-benzos bind at a different allosteric site. Alcohol has its own allosteric binding site.Barbiturates work by prolonging the duration of Cl- channel opening in response to GABA, not the frequency
What is the normal half life of barbiturates
Longer than other sedatives so hang over effect is more common
Name a barbiturate that is still used clinically and explain its use
Thiopental, ultra short duration barbiturate with rapid onset, it is highly lipophilic so can cross the BBB to cause sedative effect, used for induction of anesthesia
What is another barbiturate that is still in clinical use and explain its therapeutic uses
Phenobarbital, management of seizures
What is the duration for which thiopental works?
Thiopental acts within 1 minute -> making a patient unconscious, but lasts for only about 5 minutes
Explain the short duration of action of thiopental. Is it due to rapid metabolism?
No, it is due to rapid redistribution. Accumulation of Thiopental in the brain is followed by redistribution into skeletal muscle and adipose tissue
When exactly is phenobarbital used for the treatment of seizures?
1st line of treatment of seizures in neonates but not for the elderly b/c administration is slow, it causes prolonged sedation, and it may involve a higher risk of hypoventilation and hypotension than other agents.
Primadone
Anti seizure medication, one of its active metabolites is phenobarbital, so it can be used to treat seizures. It is also 1st line therapy w/ Propranolol (β-blocker) to treat essential tremor
What are the side effects of primadone that limits its use?
Significant sedating effects, hypotension, and respiratory depression. It has a very long half life.
What are the AE of barbiturates and what is a clinical concequence of these AE
- Cause severe CNS depression such that it can lead to coma2. Synergistic effects with alcohol, 1st gen anti Histamine, benzos and non benzos3. Causes tolerance and withdrawal symptoms to develop4. Potent inducers of CYP450
Name IV anesthetics
Propofol, etomidate, ketamine
Propofol use and MOA
IV anesthetic, used for induction AND maintenance of anesthesia, potentiation of GABA A receptor is the proposed MOA
Etomidate use and MOA
IV anesthetic, used only for induction of anesthesia, appears to act through the potentiation of GABA-A receptor
What is a unique side effect of propofol
Causes profoung vasodilation (arterial and venous) -> reduced preload and afterload, leads to hypotension
What is a unique property of etomidate and what is a clinical concequence of this?
A unique characteristic of etomidate is its ability to preserve cardiovascular stability after bollus injection -> minimal changes in BP, HR, & CO; useful for induction of anesthesia in patients with compromised myocardial contractility
Ketamine
Inhibition of NMDA receptor so it stops potentiation
What are the unique effects of ketamine as a result?
Ketamine causes a dissociative anesthesia, can cause unpleasant emergence reactions such as vivid colorful dreams, hallucinations, fear, confusion, and out of body experiences, illicitly used as a euphoric
What are the CV and respiratory effects of ketamine
Increases BP, HR and CO, minimal respiratory depression so especially useful as an anesthetic
What anesthetics can be used periopertively for minor procedures?
IV benzos, like for colonoscopy
When are inhaled anesthetics used
To deepen anesthesia after the induction of IV anesthetcis
MOA of inhaled anesthetics
Unknown
What inhaled anesthetic is gas at room temp?
nitrous oxide aka laughing gas
Name volatile anesthetics and what is a unique physical property that they share?
suffix “-flurane” or “-ane” (e.g. enflurane, isoflurane, halothane), they all have higher boiling points and are liquid at room temperature
What inhaled anesthetics are highly soluble in the blood?Which ones are not?
Volatile anesthetics such ads halothane are highly soluble, N2O is not
Explain solubility of anesthetics in blood and how does that relate to their duration of onset.How does this explain the time it takes to recover from anesthesia?
Less soluble inhaled anesthetics (e.g. N2O) have a faster onset of action. If an agent has poor solubility, the amount of gas it takes to saturate the blood will be small -> so brain saturation will occur very quickly -> partial pressure of gas will rise quickly -> Less soluble anesthetics (e.g. NO2) have a faster onset and a faster recovery.Highly soluble inhaled anesthetics require more gas concentration to saturate the blood -> takes longer to saturate the blood and brain -> takes longer to raise partial pressure of gas -> highly soluble inhaled anesthetics (e.g. halothane) have a slower onset of action and a longer half-life -> longer recovery time
Explain blood gas partition coefficient and its relationship with solubility
↑Blood:Gas Partition Coefficient = ↑Solubility↓Blood:Gas Partition Coefficient = ↓Solubility
Explain MAC and how does it related to ED 50
Refers to the % of anesthetic in the expired gas mixture that renders 50% of patients unresponsive - corresponds to the dose of anesthetic that causes 50% of patients to become unresponsive to painful stimuliMAC is the same as ED 50
Explain potency and how does it relate to MAC
Potency - determined by the minimal concentration that reaches the brain that is necessary to achieve an adequate level of anesthesia. It is inversely proportional to MAC. The lower the MAC -> the more potent the anesthetic
What are the effects of inhaled anesthetics on CV system
inhaled anesthetics can cause myocardial depression leading to ↓CO and hypotension
What are the effects of inhaled anesthetics on respiratory system
All volatile anesthetics are respiratory depressants -> ↓minute ventilation, ↓tidal volume, and cause hypercapnia (↑pCO2). They also suppress mucociliary clearance, which may contribute to post-operative atelectasis (complete or partial lung collapse).
What are the effects of inhaled anesthetics on brain? Which ones have this effect?
Fluoronated anesthetics decrease cerebral vascular resistance, causing increased cerebral blood flow -> increases ICP!
What unique complication is associated with halothane? Explain.
Halothane, specifically, can cause severe liver damage, including massive hepatic necrosis. Hepatic necrosis can present from 2 days to up to 4 weeks. Liver tenderness, hepatomegaly and elevated LFTs are characteristic, light microscopy of liver biopsy shows widespread central lobular hepatic necrosis, it has up to 80% mortality rate if hepatic necrosis occurs
What is malignant hyperthermia? What anesthetics are associated with it? Explain the pathophysiology of the disease.
Only occurs with volatile anesthetics and succinylcholine, does NOT occur with N2O.It happens due to defective ryanodine receptors. These receptors act to let out Ca2+ from the SR of skeletal muscle for contraction. Abnormal Ryanodine receptors release large amount of Ca2+ in response to fluorinated anesthetics -> this requires excessive ATP dependant reuptake of the Ca2+ by the SR -> excessive consumption of ATP produces heat; loss of ATP along with the generation of excessive heat produces muscle damage - causes rhabdomyolysis
Explain the clinical presentation of malignant hyperthermia
Muscle rigidity, fever right after surgery under general anesthesia, tachycardia and HTN are also characteristic, blood work shows elevated CK, It can be life threatening.
Treatment of malignant hyperthermia
Requires treatment with dantrolene It is a muscle relaxant that acts on Ryanodine Receptors and prevents the release of Ca2+ into the cytoplasm of skeletal muscle fibers
What are the unique side effects of enflurane
Can be nephrotoxic and can cause convulsions
Name the 3 opioid receptors.
μ, κ, and δ.
Which of these 3 is the main opioid receptor
μ-opioid receptor is the main analgesic receptor - it mediates most of the clinical and the adverse effects (e.g. analgesia, sedation, constipation, respiratory depression).
Explain the MOA of opioid receptors and how do they inhibit pain transmission
Opioid receptors work through Gi-proteins to affect ion channel gating. In neurons, it causes K+ channels to open -> K+ leaves the cell, leading to hyperpolarization of the cell -> inhibition of signal transmission. Opioid receptor activation also causes the closure of voltage gated Ca2+ channels on pre-synaptic nerve terminals, preventing neurotransmitter release (such as glutamate, acetylcholine, NE, serotonin, substance P) so overall opioids are stopping pain transmission to the brain
Name 3 main opioid drugs and their clinical uses
Fentanyl, used for post operative and chronic painMorphine and hydromorphone
Explain MOA of Tramadol and its clinical use
Tramadol (weak μ agonist); instead, it works primarily through serotonin and norepinephrine reuptake (“north-south compass”). Tramadol is commonly used for neuropathic pain, specifically.
What are the effects and uses of opioids in the GI tract
μ-opioid receptors exist in high density in the GI tract where they modulate the activity of the enteric system to delay stool transit (decreased motility & increased tone) and increase absorption of water and constipation. -> Opioids can be used as antidiarrheals (e.g. loperamid, diphenoxylate).
What exactly does loperamide and diphenoxylate do in the GI tract?
Increases colonic phasic segmentation activity
What is an antitussive?
Anti cough
Name antitussive opioids
Codeine Dextromethorphan
MOA of Dextromethorphan
antagonizes NMDA receptors
AE of opioids
- SIGNIFICANT CNS depression2. SIGNFICANT respiratory sedation, which is dose-dependant, this can be fatal in patients with compromised lung function such as those with COPD3. Virtually all opiates cause miosis (constricted pupils) and constipation which does NOT change with tolerance
How can opioids cause pancreatitis?Why is this an important complication over long term treatment with opioids?
Opiates can cause biliary colic (contract biliary sphincter of Odi) -> reflux of biliary and pancreatic secretions -> elevate plasma amylase and lipase.Patients develop tolerance so they start taking more and more drug for the same effect which can eventually lead to acute pancreatitis
What is opioid-induced hyperalgesia
Increased pain sensitivity d/t long term chronic μ-receptor stimulation from opioid use.
Explain withdrawal symptoms associated with opioids and what is it called?
Physical dependance can occur with opioid use which leads to withdrawal symptoms: rhinorrhea, lacrimation, yawning, hyperventilation, hyperthermia, muscle aches, vomiting, diarrhea, and anxiety = This is called Abstinence Syndrome.
When does these symptoms starts?
With Morphine or Heroin, withdrawal symptoms usually start within 6-10hrs after the last dose and peak effects are typically seen at 36hrs, afterwhich, symptoms slowly subside after a few days
Explain methadone as treatment for opioid addiction
Methadone is a potent μ-receptor agonist used for weaning patients off of heroin or opioids. Methadone is a long-acting (long half-life) opioid and immediately attenuates withdrawal symptoms. The long half-life allows the patient to slowly wean off the opioid effects as the methadone is tapered off.
Buprenorphine use and MOA
Buprenorphine “blueprint” - is a long-acting (long half-life) partial μ-agonist used to attenuate withdrawal symptoms. Since it is only a partial μ-agonist, Buprenophine is a safer drug to use than Methadone for attenuating withdrawal symptoms
Explain neonatal abstinence syndrome and how is it treated?
Neonate suffering from withdrawal symptoms due to the mother being an opioid addict. The baby will be an irritable, moist, and tachypneic baby with diarrhea, sweating, sneezing, and crying).Usually Morphine or Methadone is used for neonatal abstinence syndrome
Name partial μ-agonists
Buprenorphine, nalbuphine, butorphanol
What happens when a patient is switched to a partial agonist from a full μ-agonists
If a patient is already being treated for opioid withdrawal symptoms using a full μ-agonist (e.g. morphine, methadone), then switching them to a partial μ-agonist will further their withdrawal symptoms.
Naloxane
Naloxone is a μ-antagonist used to reverse acute opioid toxicity and its associated symptoms. Can precipitate withdrawals; do not use for someone who is addicted/dependent on opioids.
Naltrexone
Naltrexone is a μ-antagonist that helps maintain abstinence in heroin addicts by blocking the μ-receptors, preventing heroin action. Useful for abstinence in patients to maintain abstinence long-term. Naltrexone also helps to reduce cravings for alcohol and nicotine. Naltrexone an also help with weight loss.
