Exam 3 - Lecture 27 & 28 General anesthetics, anxiolytics & sedatives, hypnotic drugs Flashcards
General anesthetics
Can induce a state of systemic anesthesia, lack of feeling
Anxiolytics
reduce anxiety
Sedatives (tranquillizers)
CNS depressants that induce calm
Hypnotics (soporifics or sleeping pills)
Typically psychoactive drugs that induce sleep
Modes of Drug delivery Anesthetics
Inhalation or injection
What is MAC
MAC - Minimum alveolar concentration, equivalent of potency
The lower the MAC, more potent the anesthetic
MAC is ~20% higher in red heads, due to mutations in melanocortin-1 receptor
Moving MAC curve left
Hypoatraemia (low sodium), increased age, pregnancy, opioid use, benzo, intoxication
Moving MAC curve right
Chronic amphetamine, cocaine, ephedrine, chronic alcohol use, decreased age
MAC: Zur Theorie def Alkoholnarkose Arguments for
Simple, diverse structures argues against obvious SAR
Suggest physicochemical mechanisms of action;
Bilayer thickness, curvature, fluidity
MAC: Zur Theorie def Alkoholnarkose Arguments against
Stereoisomers have similar oil:gas partition coefficients but different MAC
Many lipophilic drugs are not anesthetics
Change in body temp alter membrane fluidity but is not anesthetic
Changes in chain length increase lipophilicity but not MAC
Using EEG to measure anesthesia?
Distinction between anesthesia and sleep
If sleeping you can be arousable but if you’re anesthetized then you are unarousable.
Nonphysiological Oscillations in anesthesia
physiological Oscillations in Sleep
MAC value
The lower the better it will cross from Alveoli, into blood and then into Brain.
For example, drug with MAC 0.47 will cross better than one with a MAC of 2.3
Other considerations besides MAC for potency
The age and life-style of the patient
How fat
Other medications
Hair color
Blood/Gas partition coefficients and induction/recovery rate
The lower the blood/gas partition coefficient, the faster the induction of effect and recovery rate
Effect of isoflurane on Nav Channels
Inhibiting Nav channels in CNS neurons reduces excitability
Concentration dependent,
decreasing excitability in the brain
Effects on K2P channels
Activating K2P channels in CNS neurons reduces excitability
Open channel = less excitability, decreasing epilepsy and increasing anesthesia effects
K2P channel structure
not voltage gated
2 subunits
Subunit made of 4 Transmembrane proteins, 2 P loops
Ether
Cheap & easy to make, no longer recommended by WHO
MoA:
Positive Allosteric modulator at GABAa receptor
Agonist at GABAa-receptor at higher dose
Sympathomimetic effect, maintains BP
Side effect:
Post operative nausea and vomiting
Seizures and tremors
V flammable and explosive mixed with Oxygen
Nitrous Oxide
Laughing gas, non-flammable roomtemp
MAC >100%
Fast acting, can cause euphoria
MoA:
Weak PAM of GABAa and glycine receptor
Weak activator K2P, blocker NMDA, AMPA, kainite and GABAc
Halothane (fluothane)
MoA: #1 - Agonist at GABAa receptors Agonist at glycine receptors Antagonist at NMDA receptors and Nav channels Activates K2P channels
Side effect:
Arrhythmia
Respiratory depression
Hepatoxicity (metabolized into trichloroacetic acid = 30-70% mortality)
Not used in US anymore
Isoflurane (forane)
Widely used, non explosive
MoA: #1 Agonist at GABAa receptors Agonist at glycine receptors Antagonist at NMDA receptors and Nav channels Activates K2P channels
side effect:
Cardiac arrhythmia
Respiratory depression
Sevoflurane (Ultane, sojourn)
widely used, expensive bc hard to make
MoA:
#1 Positive allosetic modulator at GABAa (and GlyR?) receptors
NMDA receptor antagonist
Activated K2P channels
side effect:
Amongst safest agents available
All gas anesthetics associated with neurotoxicity
Neurodev/behavior abnormalities in kids?
Etomidate change % in BP/Heart Rate
- BP (low, ~2%)/ + Heart Rate
Injectable Anesthetics
More potent than gas ones
Not appropriate for long surgery, often used to induce anesthesia
Sodium Thiopental
Barbiturate sedative/anesthetic injection
Rapid onset (20-45s) and rapid recovery (<10Min) very short acting
Used to break status epileptics
increases open time of GABAa receptor channels
“truth serum”, used Euthanasia
distributes into greasier tissues due to its greasiness
Methohexital (Brevital)
Used for ECT, lowers threshold for seizures but other anesthetics must be used to break seizures
Used to induce anesthesia, fast recovery
Increase open time of GABAa receptor channels
Methohexital (Brevital)
Used for ECT, lowers threshold for seizures but other anesthetics must be used to break seizures
Used to induce anesthesia, fast recovery
Increase open time of GABAa receptor channels
Propofol (milk of amnesia)
Most used induction agent
Anti emetic, and anti seizure…often used to break induced seizures or status epileptics
MoA:
Positive allosteric modulator at GABAa receptors, Nav channel blocker
Side effect: Drop BP Cause irregular breathing Pain at injection site Vasodilation - have to give with a drug to bring BP up
Etomidate
R 10X more potent than S
Used in pt where history unclear/ BP is unstable
MoA:
PAM at B2, B3 GABAa receptors
GABAa receptor agonist at higher conc
side effect:
Adreno-cortical insufficiency = lower cortisone production and more susceptible to infection
Paradoxical effect = causes opposite effects of what is usually seen
Ketamine
Commonly used Europe for Off-site trauma..not much US
MoA:
NMDA-R antagonist with low potency effects at many other sites, including nAChRs and d and mORs = reduce excitation
Side effect:
Altered heart rhythms
Hallucination
Adverse drug interactions
Potential for depression treatment but also drug of abuse
Ketamine treat depression?
Ketamine is a dissociative anesthetic - make patient feel removed from their problems
Esketamine (Spravato)
metabolite of ketamine
MoA:
Non-competitive antagonist at NMDA-receptor
Suitable for induction in patients with hemorrhagic, anaphylactic or septic shock
Why regional anesthesia better?
Cheaper
Fewer post-op issues
Patient can be fully awake or sedated
no risk of general anesthesia
Decreased chance of DVT
No drug-drug considerations
Why regional anesthesia better?
Cheaper
Fewer post-op issues
Patient can be fully awake or sedated
no risk of general anesthesia
Decreased chance of DVT
No drug-drug considerations
Xenon
MoA:
Antagonist at NMDA receptor ( no hallucination on emergence)
Side effects:
Very expensive….recycle?( isn’t altered via metabolism)
Minimal, including no nausea
Methoxycarbonyl - Etomidate
Removes the decrease in cortisone
Keeps rapid onset of etomidate
Maintain hemodynamic stability of etomidate
Rapid metabolism by esterase’s into etomidate, causing decrease cortisone later
Long acting Benzo
Diazepam
Chlordiazepoxide
Chlorazepate
Flurazepam
Long acting = many active metabolite formed
Intermediate acting Benzo
metabolized into glucuronides often, not usually active
Alprazolam Lorazepam Oxazepam Temazepam Clonazepam Estazolam Quazepam Clobazam
Short acting Benzo
Hydroxylated and eliminated fast relatively
Midazolam
Triazolam
Alprazolam (Xanax)
Triazolobenzodiazepine - Triazole ring stops it from having same metabolism as diazepam
Used for:
Anxiety + panic attacks
Chemo nausea
side effect:
Sleepy, depression, memory problems
Drug of abuse
Diazepam (valium)
classic sedative
High chance for abuse and addiction, OD common due to street version of drug
Side effect:
Can change brainwave patterns, where patient uses it to sleep but then it’ll cause worse sleep
impair motor function, coordination and balance…in cerebellum
Midazolam (versed)
Commonly used in ICU/ critical care med
Has diazole ring preventing diazepam metabolism pathway
Most hydrophilic BDZ so can be used in saline infusion
Used for people on vent, not much anymore
Used for deep sedation of patients who are suffering and end of life care.
Used as sedative for euthanasia
Side effect: Paradoxical reaction Amnesia Tolerance and dependence OD possible
Mechanism of tolerance/addiction Benzos
Increase GABA signaling decreases receptor density (increase amount internalized or decrease amount brought to membrane)
Leads to equilibrium between higher conc of GABA and lower receptors
Decrease GABA conc (withdrawal) and GABAergic inhibition of excitability is lost
Alcohol Withdrawal syndrome
Minor Withdrawal: Onset 6 - 36 hrs last drink
Seizures: Onset 6 - 48 hrs last drink
Alcoholic hallucinosis: Onset 12 - 48 hrs
Delirium tremens: Onset 48 to 96 hrs
Alcohol Withdrawal syndrome treatment
preference is long-lasting benzo (Diazepam)
In patients with cirrhosis or acute alcohol hepatitis then Lorazepam is preferred
Benzo bind to which subunits
Between alpha and gamma, increase open frequency (number of times open)
Barbiturate bind to which subunits
Between alpha and beta, increase amount of time each time it opens
Pentobarbital (Nembutal)
Used for euthanasia, Human (execution) and vet
Sedative, hypnotic, short term anesthetic
Active metabolite of thiopental
Potential for OD
Street drug - yellow jackets
Can give Thiopental, gets metabolized into pentobarbital but then harder to predict how much you are giving in terms of dose
Meyer-Overton correlation for anesthetics
The lower the Mac value (more potent) the higher the Oil:gas partition coefficient (more lipophilic)
MAC Mechanisms of action
Easier something partitions into brain, faster it works
How to measure Mac
Measured at sea level due to pressure
After 15 minute equilibration
By end-tidal volume of the gas
Mac partition
Quickest partition between arterial blood and brain
Over time it will leave brain to try and reach equilibrium with other tissues
Multimodal
Multiple low affinity receptor targets with complimentary effects
Phencyclidine (PCP)
antagonist NMDA receptor
Agonist D2 and sigma2
associated with hallucination
dissociative anesthetic
Thiopental % change in BP/HR
-8%, +14%
Methohexital % change in BP/HR
-8%, +15%
Propofol % change in BP/HR
-17%, +8%
Ketamine % change in BP/HR
+28%, +33%
