Sedatives & Anesthetics:Analgesics

Question 1

What are benzodiazepines

Answer 1

Sedatives-hypnotics

Question 2

MOA of Benzodiazepines

Answer 2

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.

Question 3

What is the naming convention of benzodiazepines (short and long acting)

Answer 3

Benzodiazepines end with ‘-pam’, short acting, ‘-azepam’ is for short acting such as lorazepam or oxazepam

Question 4

What are the 2 important properties of short acting benzos

Answer 4

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

Question 5

What is a clinical consequence of these properties of short acting benzos

Answer 5

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.

Question 6

Name the inhibitory neurotransmitters of CNS

Answer 6

GABA and glycine

Question 7

Explain the properties of GABA A receptor and what is its function

Answer 7

GABA A consists of 5 subtypes that together form a chloride channel that modulate neuronal excitability, mood changes, anxiety and sleep

Question 8

Explain MOA of alcohol

Answer 8

It also binds to an allosteric site to GABA A

Question 9

What are the clinical consequences of MOA of alcohol and how does it relate to benzos

Answer 9

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

Question 10

Explain the 3 stages of alcohol withdrawal

Answer 10

1. 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

Question 11

What are the 1st line for treatment of alcohol withdrawal if the liver is fine and when there is hepatic insufficiency

Answer 11

Long acting benzos if liver is fine and short acting when there is hepatic insufficiency

Question 12

What is the hallmark of alcohol withdrawal treatment

Answer 12

Treating and preventing seizures

Question 13

How are alcohol withdrawal seizures treated?

Answer 13

IV benzos

Question 14

What other seizures can be treated with IV benzos

Answer 14

Status epilepticus (generalized tonic clonic seizures > 30min)

Question 15

Anesthetic uses of benzos

Answer 15

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.

Question 16

Benzos used for insomnia?

Answer 16

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).

Question 17

What other CNS disorders can be treated with benzos?What are the adverse effects of benzos when treating these disorders?

Answer 17

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

Question 18

What is a major adverse effects of using benzos and what is the physiological mechanism behind it?What is a clinical concequence to it?

Answer 18

Tolerance, there is downregulation of GABA A receptor so this is pharmacodynamic tolerance. Same withdrawal effects as alcohol.

Question 19

Other AE of benzos?

Answer 19

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

Question 20

What drugs should not be taken with benzos?

Answer 20

Other CNS depressant such as alcohol, barbituates, neuroleptics and 1st gen anti histamines

Question 21

How to counter AE of benzos?

Answer 21

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.

Question 22

What is an AE of flumezanil?

Answer 22

Administration of flumanezil can precipitate withdrawl symptoms in people who have developed tolerance to benzos through chronic use

Question 23

What is increased GABA A (Cl ion channel) permeability (or conductance to Cl ions) associated with? Arousal or sedative effect?Explain why.

Answer 23

Increase in GABA A Cl ion conductance leads to sedative effect.Cl- channel hyperpolarizes and stabilizes membranes, making neurons less excitable.

Question 24

Name non benzos that are used for sleep therapy

Answer 24

Nonbenzodiazepine hypnotics help you catch some Zzz’s -> 3 Z’s Zolpidem, Zaleplon, and esZopiclone

Question 25

What is the first line of therapy for insomnia?

Answer 25

Non-pharm interventions such as behavior modification and cognitive therapy

Question 26

When should pharmacotherapy be used for insomnia?

Answer 26

As a 2nd line, pharmacotherapy can provide immediate relief but should generally be used for short-term management due to addictive/dependence

Question 27

MOA of non benzos

Answer 27

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

Question 28

How are non benzos different than benzos and what is a clinical consequence of this

Answer 28

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

Question 29

Explain the use of zaleplon and zolpidem

Answer 29

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

Question 30

Eszopliclone MOA and side effect

Answer 30

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)

Question 31

AE of non benzos

Answer 31

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

Question 32

What meds can non benzos not be used for?

Answer 32

Other CNS depressants (1st generation anti-histamines, barbs, benzos, alcohol).

Question 33

Explain the frequency of tolerance and withdrawal with non benzos than with benzos

Answer 33

Nonbenzodiazepines are less likely to cause tolerance than benzodiazepines. Less likely to cause physical dependence and withdrawal’s as well.

Question 34

Treatment for non benzos overdose and what is a concequence of this?

Answer 34

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

Question 35

What is the role of melatonin in inducing sleep?

Answer 35

Maintains circadian rhythm

Question 36

What is ramalteon

Answer 36

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.

Question 37

What are the side effects of ramalteon?

Answer 37

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

Question 38

What are barbiturates?

Answer 38

Sedatives-hypnotics

Question 39

barbiturates MOA and how are they principally different than other sedatives?

Answer 39

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

Question 40

What is the normal half life of barbiturates

Answer 40

Longer than other sedatives so hang over effect is more common

Question 41

Name a barbiturate that is still used clinically and explain its use

Answer 41

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

Question 42

What is another barbiturate that is still in clinical use and explain its therapeutic uses

Answer 42

Phenobarbital, management of seizures

Question 43

What is the duration for which thiopental works?

Answer 43

Thiopental acts within 1 minute -> making a patient unconscious, but lasts for only about 5 minutes

Question 44

Explain the short duration of action of thiopental. Is it due to rapid metabolism?

Answer 44

No, it is due to rapid redistribution. Accumulation of Thiopental in the brain is followed by redistribution into skeletal muscle and adipose tissue

Question 45

When exactly is phenobarbital used for the treatment of seizures?

Answer 45

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.

Question 46

Primadone

Answer 46

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

Question 47

What are the side effects of primadone that limits its use?

Answer 47

Significant sedating effects, hypotension, and respiratory depression. It has a very long half life.

Question 48

What are the AE of barbiturates and what is a clinical concequence of these AE

Answer 48

1. 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

Question 49

Name IV anesthetics

Answer 49

Propofol, etomidate, ketamine

Question 50

Propofol use and MOA

Answer 50

IV anesthetic, used for induction AND maintenance of anesthesia, potentiation of GABA A receptor is the proposed MOA

Question 51

Etomidate use and MOA

Answer 51

IV anesthetic, used only for induction of anesthesia, appears to act through the potentiation of GABA-A receptor

Question 52

What is a unique side effect of propofol

Answer 52

Causes profoung vasodilation (arterial and venous) -> reduced preload and afterload, leads to hypotension

Question 53

What is a unique property of etomidate and what is a clinical concequence of this?

Answer 53

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

Question 54

Ketamine

Answer 54

Inhibition of NMDA receptor so it stops potentiation

Question 55

What are the unique effects of ketamine as a result?

Answer 55

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

Question 56

What are the CV and respiratory effects of ketamine

Answer 56

Increases BP, HR and CO, minimal respiratory depression so especially useful as an anesthetic

Question 57

What anesthetics can be used periopertively for minor procedures?

Answer 57

IV benzos, like for colonoscopy

Question 58

When are inhaled anesthetics used

Answer 58

To deepen anesthesia after the induction of IV anesthetcis

Question 59

MOA of inhaled anesthetics

Answer 59

Unknown

Question 60

What inhaled anesthetic is gas at room temp?

Answer 60

nitrous oxide aka laughing gas

Question 61

Name volatile anesthetics and what is a unique physical property that they share?

Answer 61

suffix “-flurane” or “-ane” (e.g. enflurane, isoflurane, halothane), they all have higher boiling points and are liquid at room temperature

Question 62

What inhaled anesthetics are highly soluble in the blood?Which ones are not?

Answer 62

Volatile anesthetics such ads halothane are highly soluble, N2O is not

Question 63

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?

Answer 63

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

Question 64

Explain blood gas partition coefficient and its relationship with solubility

Answer 64

↑Blood:Gas Partition Coefficient = ↑Solubility↓Blood:Gas Partition Coefficient = ↓Solubility

Question 65

Explain MAC and how does it related to ED 50

Answer 65

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

Question 66

Explain potency and how does it relate to MAC

Answer 66

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

Question 67

What are the effects of inhaled anesthetics on CV system

Answer 67

inhaled anesthetics can cause myocardial depression leading to ↓CO and hypotension

Question 68

What are the effects of inhaled anesthetics on respiratory system

Answer 68

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).

Question 69

What are the effects of inhaled anesthetics on brain? Which ones have this effect?

Answer 69

Fluoronated anesthetics decrease cerebral vascular resistance, causing increased cerebral blood flow -> increases ICP!

Question 70

What unique complication is associated with halothane? Explain.

Answer 70

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

Question 71

What is malignant hyperthermia? What anesthetics are associated with it? Explain the pathophysiology of the disease.

Answer 71

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

Question 72

Explain the clinical presentation of malignant hyperthermia

Answer 72

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.

Question 73

Treatment of malignant hyperthermia

Answer 73

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

Question 74

What are the unique side effects of enflurane

Answer 74

Can be nephrotoxic and can cause convulsions

Question 75

Name the 3 opioid receptors.

Answer 75

μ, κ, and δ.

Question 76

Which of these 3 is the main opioid receptor

Answer 76

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).

Question 77

Explain the MOA of opioid receptors and how do they inhibit pain transmission

Answer 77

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

Question 78

Name 3 main opioid drugs and their clinical uses

Answer 78

Fentanyl, used for post operative and chronic painMorphine and hydromorphone

Question 79

Explain MOA of Tramadol and its clinical use

Answer 79

Tramadol (weak μ agonist); instead, it works primarily through serotonin and norepinephrine reuptake (“north-south compass”). Tramadol is commonly used for neuropathic pain, specifically.

Question 80

What are the effects and uses of opioids in the GI tract

Answer 80

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).

Question 81

What exactly does loperamide and diphenoxylate do in the GI tract?

Answer 81

Increases colonic phasic segmentation activity

Question 82

What is an antitussive?

Answer 82

Anti cough

Question 83

Name antitussive opioids

Answer 83

Codeine Dextromethorphan

Question 84

MOA of Dextromethorphan

Answer 84

antagonizes NMDA receptors

Question 85

AE of opioids

Answer 85

1. 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

Question 86

How can opioids cause pancreatitis?Why is this an important complication over long term treatment with opioids?

Answer 86

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

Question 87

What is opioid-induced hyperalgesia

Answer 87

Increased pain sensitivity d/t long term chronic μ-receptor stimulation from opioid use.

Question 88

Explain withdrawal symptoms associated with opioids and what is it called?

Answer 88

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.

Question 89

When does these symptoms starts?

Answer 89

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

Question 90

Explain methadone as treatment for opioid addiction

Answer 90

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.

Question 91

Buprenorphine use and MOA

Answer 91

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

Question 92

Explain neonatal abstinence syndrome and how is it treated?

Answer 92

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

Question 93

Name partial μ-agonists

Answer 93

Buprenorphine, nalbuphine, butorphanol

Question 94

What happens when a patient is switched to a partial agonist from a full μ-agonists

Answer 94

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.

Question 95

Naloxane

Answer 95

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.

Question 96

Naltrexone

Answer 96

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.