Exam 4 Information

General information

- Meyer-Overton hypothesis —> refers to lipophilicity

- Mullins modification —> refers to lipophilicity and volumes

- GABA_A —> enhances binding, leading to increased CNS depression:

• E.g. propofol and midazolam

- Barbiturates increase GABA affinity to the receptor for depression

Stages of anesthesia

- Stage 1 - analgesia at low doses

- Stage 2 - excitement at increased doses (UNWANTED):

• Causes amnesia (good), delirium, irregular respiration, and vomiting

- Stage 3 - surgical (WANTED):

• Regular respiration —> wheeze regularly, lose consciousness, and pain insensitivity

- Stage 4 - medullary depression:

• Respiration stops —> death

Ideal inhalation anesthetics

- Nonflammable

- Good chemical and metabolic stability

- Low incidence of MI effects

- Low incidence of hepatic and renal damage

- Rapid induction and emergence from anesthesia

- Adequate skeletal muscle relaxation

- Wide margin of safety

- Blood gas partition coefficients (BGPCs):

• Enter lungs and distribute into the blood

• Low (0.5) —> more in the gas phase, which means less in the blood, leading to a faster recovery

- Minimum alveolar concentration (MAC):

• Low (1) —> only need 1% to produce activity in 50% (potent)

• If >100, need 100% of dose to achieve the effect (low potency)

Nitrous oxide

- Gas at room temperature

- Good analgesic properties

- Weak anesthetic

- BGPC = 0.47 —> low so 2x as much in the gas phase

- MAC = 104% —> high so it’s weak and needs O₂, so you can’t use 100%

- Always used in combination

- Very safe

- Fast onset

- Fast recovery because of low BGPC

- No hangover effect

- No skeletal muscle relaxation

Cyclopropane

- Gaseous anesthetic

- Produces anesthesia very quickly

- More potent —> very toxic

- When mixed with O₂, it becomes flammable

- Stored in cylinders, which are heavy and large —> bad for storage

- Rarely used

- MAC = 17.5%

- Skeletal muscle relaxation

Ethylene

- Gaseous anesthetic

- Safer with less side effects

- No skeletal muscle relaxation

- MAC = 80%

Halothane

- Volatile liquid anesthetic

- Prototype fluorene general anesthetic —> derived from ethane

- When mixed with O₂, it does NOT become flammable

- Increases molecular weight ineractions between molecules —> less volatile

- BP = 50.2 degrees Celsius —> liquid at room temperature

- BGPC = 2.5 —> favors the blood, so faster onset, but slower recovery

- MAC = 0.74% —> very potent and only need 0.74% of vapor in the airways

- Skeletal muscle relaxation

- Rapid induction and emergence

- 20% of the inhaled dose gets metabolized:

• Metabolites are very toxic —> the ions can cause MI effects, as well as kidney and liver damage

Ketamine

- NMDA receptor antagonist —> allosteric (not the same site as glutamate)/noncompetitive (whether glutamate is bound or not, this drug will bind)

- Only basic center is the N

- Chiral center is on the C under the ketone —> S>R

- Racemic mixture

- Highly water soluble —> aqueous solution

- IV

- Produces dissociative anesthesia without loss of consciousness

- No skeletal muscle relaxation

- Extensive, rapid metabolism —> demethylation at the N (active metabolite —> norketamine), hydroxylation to the right of the ketone, and glucuronidation

- Short duration of action —> 10-25 minutes

- C-III substance

- Can produce hallucinogenic effects even 24 hours after recovering —> because of its similarity in structure to phencyclidine

Esketamine

- Approved in 2019

- Nasal spray —> NOT IV

- Used to treat treatment-resistant depression

- Administered in the clinic under supervision of a HCP

- Used in combination with an anti-depressant

- 2x a week —> up to 84 mg

- Goes directly into the CNS —> faster onset

- C-III substance

Propofol

- NOT a controlled substance

- IV

- Works around GABA_A, but the binding site is unknown

- Used for the induction and maintenance of anesthesia and for continuous sedation in adults in the ICU

- 40 second onset

- Faster recovery

- Anti-emetic properties

- Drug of choice for ambulatory surgery in outpatients

- Skeletal muscle relaxation

- Limited water solubility —> need to increase the pH and reduce the lipid emulsion to keep it in solution

- Can cause allergies and can harbor microbial growth

- Extensively metabolized via sulfation and glucuronidation

Fospropofol

- Attaches a phosphate group to a methylene group

- Prodrug —> gets metabolized by alkaline phosphatases

- Slower onset than propofol —> 4-8 minutes

- Not as successful as propofol —> less used now

- C-IV substance

Midazolam

- Imidazolo-benzodiazepine

- GABA_A agonist —> more CNS inhibition

- Fluorine and chlorine substitution prevent metabolism

- Used for preoperative sedation and for induction of general anesthesia

- Slower onset than barbiturates —> <5 minutes for IV

- Prolonged CNS activity —> long recovery time

- Can cause amnesia and sedation

- Skeletal muscle relaxation

- Hydroxylation of the methyl on the imidazole ring

- C-IV substance

Remimazolam

- Benzodiazepine

- Soft drug —> the ester is active and it hydrolyzes via esterases to a carboxylic acid, making it more water-soluble and inactive

- Shorter duration of action compared to midazolam

- Approved in 2020

- The carboxylic acid is 300x less active at the GABA_A receptor

- Used for short procedures <30 minutes

- Ultra fast-acting

- Skeletal muscle relaxation

- IV

- C-IV substance

Etomidate

- Soft drug —> the ester is active and it hydrolyzes via esterases to a carboxylic acid, making it more water-soluble and inactive

- Used to induce general anesthesia and treat patients in cardioversion —> short procedures

- IV

- No analgesic activity

- Fewer CV and respiratory depressive events

- Produces hypnosis within 1 minute

- Short duration of action —> 3-5 minutes

- Can cause N/V

- No skeletal muscle relaxation

- NOT a controlled substance

Methohexital

- Barbiturate

- Ultra-short acting —> <3 hours

- IV —> <20 minutes duration of action

- No skeletal muscle relaxation

- C-IV substance

- 2 chiral centers —> one on the C between the two ketones and one to the right of the triple bond

Thiopental

- Barbiturate

- C-III substance

- No skeletal muscle relaxation

- No unsaturation unlike methohexital

- The S is more lipophilic —> brings it into the CNS quicker and exits the CNS more easily

- Ultra-short acting

- The S can be removed and replaced with an O —> less lipophilic, short-acting (3-4 hours), and can cause long-term sedation

- Used to be the most commonly used because of its cheapness —> not the drug of choice now because of how it deposits into the fat

- Can cause prolonged anesthesia with repeated use

Barbiturates and benzodiazepines

- Benzodiazepines are safer than barbiturates

- GABA_A and GABA_B agonists

- Benzodiazepines have specific GABA_A binding sites, whereas barbiturates do not

- GABA_A —> post-synaptic inhibition

- GABA_B —> pre-synaptic inhibition

Barbituric acid

- 2 imides —> 2 carbonyls between the N, making them acidic

- The CH₂ between the 2 carbonyls is also acidic

- Tautomerization can occur

- O at the bottom right can be replaced with an S —> increases lipophilicity

- Highly water soluble

- In order to have CNS activity, the 2 hydrogens have to be removed from the CH₂