General Anesthetic Med Chem (Exam 2 Cut Off)

Question 1

Sedatives

Answer 1

• Drugs which decrease activity, moderate excitement, and calm recipient
• Produce state of sedation without sleep

Question 2

Hypnotics

Answer 2

• Drugs that produce drowsiness and facilitate onset/maintenance of sleep
• Resembles natural sleep in EEG and recipient can be easily aroused

Question 3

Anesthesia Spectrum

Answer 3

• No strict line between sedation, hypnotic, and anesthesia
• Increasing depths of a continuing spectrum of CNS depression
• Most drugs can produce general anesthesia at higher doses
• Widespread CNS depression is why they are often used as AED, muscle relaxants, antianxiety, and adjuncts to anesthesia

Question 4

Choral Hydrate

Answer 4

• From late 1800s
• Active form: trichloroethanol
• Disagreeable taste and irritants
• Prodrugs helped reduce these negatives (EX: triclofos)

Question 5

Barbiturates

Answer 5

• Barbital and phenobarbital were introduced in early 1900s
• As a group, barbiturates dominated the sedative/hypnotic market into the mid 1900s
• MUST BE: weakly acidic and posses a lipid-water partition coefficient within certain limits

Question 6

Barb Acidity

Answer 6

• Generally contributed to lactam-lactim and keto-enol tautomerism
• In 5,5-disubstituted barbs, only lactam-lactim is possible and these compounds have mildly acidic properties
• Becoming tri or tetra substituted doesn’t change or abolishes activity respectively

Question 7

Barbs Lipophilicity

Answer 7

• Important for CNS activity
• Want the total number of carbons on C5 to be between 6-10
• Further additions diminishes hypnotic activity

Question 8

Barb + Sulfur

Answer 8

• Replacement of oxygen at C2 with sulfur increases lipid solubility
• Creates quick onset and short duration
• Replacing more with sulfurs decreases the hypnotic activity

Question 9

Barbs + Metabolism

Answer 9

• Long acting generally used as anticonvulsants and sedatives
• Short-intermediate usually used as hypnotics
• Ultra-short usually used as IV anesthetics
• Durations of actions tend to be determined by relative rates of metabolism for barbs (excluding ultra-short)

Question 10

Aliphatic Oxidation

Answer 10

• Barb metabolism pathway
• w-1 hydroxylation at C5 if the chain has 4-5 carbons
• Faster for compounds with longer chains
• Can be hindered at w-1 site if branching occurs there

Question 11

Aromatic Oxidation

Answer 11

• Barb metabolism pathway
• Phenobarbital undergoes hydroxylation at para position on phenyl ring
• Very slow process compared to aliphatic (1/2 life ~100 hours)

Question 12

Barb SAR Summary

Answer 12

• Maximal activity: 6-10 carbons on C5
• Two groups are necessary on C5
• Substitution at N1 and N3 destroys activity (no salts)
• Sulfur on C2 yields quick onset and short duration (more = decreased activity)

Question 13

Benzo Spectrum

Answer 13

• Possess a wide spectrum of therapeutic utility

- Muscle relaxants, anesthesia induction agents, antianxiety, AED, sedative/hyponotic

Question 14

Benzos + Sedative/Hypnotics

Answer 14

• Can’t be solely a hypnotic agent based on pharmacological props
• Still primarily promoted as sleep inducers
• Based on speed on onset and duration of action

Question 15

Benzo SE

Answer 15

• Light headedness, confusion, dry mouth
• Impairment of locomotor and some mental functions
• Drug interactions relatively infrequent
• Low rate of abuse and dependence

Question 16

Zolpidem

Answer 16

• Imidazopyridine
• Chemically unrelated to benzos and barb, but interacts with GABA-A receptor complex a shares from pharmacologic properties with benzos
• Interacts more selectively with GABA-benzo receptor subtypes than benzos themselves

Question 17

Antihistamines

Answer 17

• Sometimes used as sedative/hypnotics
• Tend to be principal SE
• In some drugs, this effect has been exploited as desired therapeutic effect (Benadryl, doxylamine)

Question 18

Phenothiazines

Answer 18

• Sometimes used as a sedative/hypnotic
• Drowsiness is well known SE
• Propiomazine (used before labor) and Promethazine both known for sedative/hypnotic effects

Question 19

Anxiety

Answer 19

• Emotional state characterized by disquietude of mind and fearful anticipation of events
• Varying levels of anxiety recognized by intensity, pervasiveness, persistence, interference, and rationale

Question 20

Historical Antianxiety

Answer 20

• Barbs were first introduced for anxiety but there was concern over the tolerance, dependence, and overdose associated with them
• Propranediol carbamates (meprobamate) initially were then accepted but then found to have more undesirable properties like barbas
• Chlordiazpoxide (benzo) was then revolutionary for anxiety and at one point accounted for 75% of all antianxiety prescriptions

Question 21

Benzo Structure

Answer 21

• R1: alkyl subs are common but not necessary
• R2: Aryl or cyclohexanyl subs are important at this position (electron withdrawing group enhances potency)
• R3: Electron withdrawing group enhances potency

Question 22

Benzo MoA

Answer 22

• All effects result from actions on CNS
• Most prominently sedation, hypnosis, muscle relaxation, anticonvulsion, and decreased anxiety
• Stimulate GABA which acts as a major inhibitory neurotransmitter in the brain

Question 23

5HT1A Anti-Anxiety

Answer 23

• Buspirone is first in azaspirodecanediones
• Unrelated to benzos
• No AED/muscle relaxing properties and only mild sedation
• Main effects are agonist activity on 5HT1A receptors
• Metabolized by hydroxyolation and N-dealkylation to active metabolism
• 1-PP (active metabolite interacts and concentrates in the brain)
• Low abuse potential and doesn’t cause withdrawal effects

Question 24

Benzos + Old/Liver Problems

Answer 24

• Metabolism is markedly slower in elderly patients with hepatic dysfunction
• Agents like oxazepam then preferred since it is directy conjugated for hepatic issues
• Triazolam has relative short duration and less hangover effects for elderly patients