Exam 2 Drugs: Sedative-Hypnotics (30)

Question 1

Benzodiazepines (general info mech, effects, interactions, metabolism)

Answer 1

• substitute at 7 position for sed-hyp activity
• hepatic metabolism
• metabolized to more h20 soluble
• undergo phase I metabolism oxidation (n-dealkylation and allipathic hydroxylation), phase II metabolites conjugated to form glucoronides
• CYP3A4 especially active
• mech: bind to specific GABAa receptor subunits @ CNS neuronal synapes facilitating GABA-mediated Cl ion channel opening which enhances membrane hyperpol.
• Does not substitute for GABA, enhances GABA effects allosterically
• Benzos bind BZ site on GABAa receptor, bind isoforms with alpha 2,3, and 5.
• alpha 2,3: anxiolytic and muscle-relaxing actions
• alpha 5: memory impairment
• low affinity for GABAb
• effects: dose-dependent depressant effects on the CNS, sedation, relief of anxiety, amnesia, hypnosis, anesthesia, coma, resp depression
• dependence liability
• interactions: additive CNS depression w/ ethanol and many other drugs
• Benzos potentiate GABAergic inhib at all levels (spinal cord, hypo, hippo, cortex)
• low risk drug interactions, minimal effects on CV or autonomic function
• relatively high therapeutic index and flumazenil for overdose (contraversial)
• benzos considered safer in terms of deliberate overdose

Question 2

Alprazolam

Answer 2

• Benzodiazepine
• Triazole ring at 1,2 position
• hepatic metabolism: undergoes alpha-hydroxylation to form active metabolites w/ short t1/2 then become inactive glucuronides
• oral dosage, rapid onset
• withdrawal symptoms especially severe, more toxic in overdose than other benzodiazepines
• clinical app: anxiety disorders, agoraphobia (more selective in these disorders than other benzodiazepines)

Question 3

Chlordiazepoxide

Answer 3

• Benzo
• phase I metabolite t1/2 > 40 hours –> desmethyldiazepam (nordiazepam)
• oral, IM, IV
• clinical app: anxiety disorders, management alcohol withdrawal and sedative-hypnotic withdrawal, anesthetic premedication
• long-acting and self tapering b/c of active metabolites
• to treat withdrawal, administered in progressively decreasing doses

Question 4

Clorazepate

Answer 4

• Benzo
• more rapid oral absorption (of active metabolite) than other benzos
• converted to active metabolite desmethyldiazepam (nordiazepam) BY ACID HYDROLYSIS IN STOMACH
• prodrug –> not biologically active
• active metabolite long acting, t1/2 >40 hours
• nor diazepam metabolized to Oxazepam before glucurronidation
• clinical app: anxiety and seizure disorders

Question 5

Clonazepam

Answer 5

• Benzo
• oral
• N-desalkyl compound, metabolized by reduction of 7-NO2 group to the corresponding amine (inactive) followed by acetylation
• long acting (t1/2 > 24 hours)
• clinical app: seizure disorders, adjuctive treatment in acute mania and certain movement disorders
• tolerance develops to anti-seizure effects

Question 6

Diazepam

Answer 6

• Benzo
• more rapid oral absorption than other benzos
• active metabolite: nordiazepam
• metabolism affected by inhib of P450s
• long-acting
• clinical app: anxiety disorders, status epilepticus, skeletal muscle relaxation, anesthetic premedication
• prototypical benzo
• oral, IV, IM, rectal
• used IV in anesthesia (often in combo with other agents)
• large doses in general anesthesia may lead to post-anesthetic resp depression
• can be used in treatment of alcohol or sedative-hypnotic withdrawal
• can relax muscles w/o much sedation
• incidence of drug-related deaths 0.3 per million tablets

Question 7

Estazolam

Answer 7

• Benzo
• primary action through Estazolam but is metabolized to 3-hydroxyderv. before glucuronidation
• short (intermed) t1/2, less sedative effect
• oral dosage
• treats insomnia
• contains triazole ring : adverse similar to triazolam

Question 8

Flurazepam

Answer 8

• Benzo
• actual drug short-acting but overall long-acting (3-intermed before glucuronidation)
• oral dosage
• insomnia
• active metabolites accumulate w/ chronic use
• daytime sedation common
• biotransformed to active metabolites

Question 9

Lorazepam

Answer 9

• Benzodiazepine
• short-acting; less sedative effect
• metabolized straight to glucuronidation (phase II conjugation)
• oral, IM, IV
• treats anxiety disorders, preanesthetic
• used IV in anesthesia (often in combo with other agents) –> large doses used, may lead to post anesthetic resp depression
• clinically useful in management of seizures
• day-time sedation common ?
• parenteral use for suppressing symptoms of delirium tremens

Question 10

Midazolam

Answer 10

• Benzo
• affected by inhibitors and inducers of P450s
• IV and IM admin
• clinical app: preanesthetic and intra-operative medication
• rapidly inactivated
• IV in anesthesia: often in combo with other agents, large doses used, may lead to post-anesthetic resp depression

Question 11

Oxazepam

Answer 11

• Benzo
• short-acting, less sedative effect
• oral
• clinical app: anxiety disorders

Question 12

Quazepam

Answer 12

• Benzo
• long-acting
• bio-transformed to active metabolite
• oral
• clinical app: insomnia
• active metabolites accumulate with chronic use
• daytime sedation common

Question 13

Temazepam

Answer 13

• Benzo
• metabolized directly to conjugation (glucuronidation)
• oral
• t1/2 ~10 hours
• clinical app: insomnia

Question 14

Triazolam

Answer 14

• Benzo
• triazole ring @ 1,2-position
• extremely rapid oral absorption, high lipophilic compound compared to other benzos
• rapid onset CNS effects
• undergo alpha-hydroxylation –> metabolites short-acting due to rapid conjugation
• short elim t1/2: 4 hours
• favors use as hypnotic rather than sedative
• affected by inhibition and inducers of P450s
• oral
• clinical app: insomnia
• REM rebound with abrupt cessation
• Causes daytime anxiety when used to treat sleep disorders