Drugs -Sedative Hypnotics (Kinder)

Question 1

Prototype Benzodiazepines

Answer 1

Alprazolam
Clonazepam
Diazepam
Midazolam 
Triazolam

Question 2

Flumazenil

Answer 2

Benzodiazepine Antagonist

Question 3

Phenobarbital

Answer 3

barbituate

“barbital”

Question 4

what is a sedative

Answer 4

i) Reduces anxiety and exerts a calming effect
ii) Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antidepressants, antihistamines, neuroleptics/antipsychotics)
iii) Agents that produce sedation as a side effect can intensify the effects of CNS depressants

Question 5

what is a hypnotic

Answer 5

i) Produces drowsiness and facilitates the onset and maintenance of a state of sleep
ii) Hypnotic effects involve more pronounced depression of the CNS, which can be achieved with many sedative-hypnotics by increasing the dose

Question 6

MOA of benzodiazepines

Answer 6

i) MOA: promotes binding of γ-aminobutyric acid (GABA), major inhibitory neurotransmitter, to the GABAA receptor; enhances GABA-induced ion currents (increases frequency of channel opening)

sedation, hypnosis, muscle relaxation, anxiolytic and anticonvulsant effects

iv) Because of their low capacity to produce fatal CNS depression, benzodiazepines have displaced barbiturates as preferred sedative-hypnotic agents

NOTE:
(2) The benzodiazepines DO NOT substitute for GABA but enhance the effects of GABA allosterically (bind to the receptor at a site other than the active site) without directly activating GABAA receptors or opening the chloride channel

Question 7

how do benzodiazepines (newer) versus barbituates and older typical type sedative-hypnotics differ in dose response curve

Answer 7

Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics. The linear slope of drug A is typical of many of the older sedative-hypnotics, such as barbiturates and alcohols. Drug B represents benzodiazepines and certain newer hypnotics, where proportionately greater dosage increments are required to achieve CNS depression that is more profound than hypnosis.

Question 8

MOA of barbituates

Answer 8

i) MOA: bind to GABAA receptors and potentiate GABA-induced chloride currents (increases duration of channel opening)
ii) Can activate the channel directly by acting as a GABA-mimetic at high concentrations
iii) Capable of causing a wide spectrum of effects, from mild sedation to anesthesia, including anxiolytic, hypnotic and anticonvulsant effects
iv) Barbiturates possess a narrow therapeutic index and it is often not possible to achieve a desired effect without evidence of general depression of the CNS

Question 9

Ramelteon

Answer 9

Activates melatonin receptors MT1 and MT2

Question 10

metabolism of benzodiazepines

Answer 10

(1) Hepatic metabolism accounts for the clearance of all benzodiazepines; most undergo phase I reactions, predominantly by CYP3A4, then glucuronidation (phase II)

Question 11

what type of receptor is GABA A and what is its function

Answer 11

i) The GABAA receptor is a ligand-gated ion channel (ionotropic) made up of five subunits that, when activated by the endogenous compound GABA, allows chloride ions to enter the cell
ii) One major isoform of the GABAA receptor in the brain is composed of two α1 subunits, two β2 subunits, and one γ2 subunit
iii) Under normal physiological conditions, GABA activation causes normal chloride influx and polarization; reduces the number of action potentials
iv) GABAA receptors are responsible for most inhibitory transmission in the CNS

Question 12

what type of receptor is GABA A and what is its function

Answer 12

i) The GABAA receptor is a ligand-gated ion channel (ionotropic) made up of five subunits that, when activated by the endogenous compound GABA, allows chloride ions to enter the cell
ii) One major isoform of the GABAA receptor in the brain is composed of two α1 subunits, two β2 subunits, and one γ2 subunit
iii) Under normal physiological conditions, GABA activation causes normal chloride influx and polarization; reduces the number of action potentials
iv) GABAA receptors are responsible for most inhibitory transmission in the CNS

Question 13

why doesn’t flumazenil work as a barbituate antagonist

Answer 13

(a) Block the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem but do not antagonize the actions of barbiturates, meprobamate, or ethanol because these compounds bind at a different site

Question 14

Buspirone

Answer 14

stimulates 5-HT1A receptors

Question 15

use of sedative hypnotics in anesthesia

Answer 15

(1) High doses of certain sedative-hypnotic agents, particularly the barbiturates and older sedative-hypnotics, depress the CNS to the point known as stage III general anesthesia

Question 16

effects of sedative hypnotics on the resp and CV system

Answer 16

(1) Sedative-hypnotics can produce significant dose-dependent respiratory depression in patients with pulmonary disease
(2) Depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics

(3) At normal doses, sedative-hypnotics can cause cardiovascular depression in patients with diseases that impair cardiovascular function (heart failure, hypovolemia), most likely a result of depression of the medullary vasomotor centers
(4) At toxic doses, myocardial contractility and vascular tone may both be depressed and could lead to circulatory collapse
(5) Effects on respiration and cardiovascular function are more marked when agents are given intravenously

Question 17

pharmacodynamic example of tolerance

Answer 17

(1) Pharmacodynamic example: benzodiazepine tolerance in animals has been associated with down-regulation of brain GABAA receptors. Down-regulation of receptors leads to hyperexcitability of the CNS during periods of withdrawal, leading to the symptoms characteristic of sedative-hypnotic withdrawal.

Question 18

pharmacokinetic example of tolerance

Answer 18

(2) Pharmacokinetic example: barbiturates stimulate the production of higher levels of hepatic CYPs, causing more rapid removal and breakdown of barbiturates from the circulation. This results in a decrease in their efficacy.

Question 19

what are the overall actions of sedative-hypnotic drugs

Answer 19

sedation
hypnotic
anesthesia
anticonvulsants
muscle relaxation 
resp and CV depression

Question 20

what schedule are most the sedative hypnotic drugs

Answer 20

schedule III or IV drugs

III Less than I or II Current accepted medical use. Moderate or low potential for physical dependence and high potential for psychologic dependence.

IV Less than III Current accepted medical use. Limited potential for dependence.

Question 21

why must you taper sedative hypnotics

Answer 21

• abrupt withdrawal leads to more serious withdrawal signs
  (2) To avoid withdrawal symptoms (particularly in patients taking benzodiazepines and/or barbiturates), the dose of sedative-hypnotics are tapered gradually over time

Question 22

why is it important to know that flumazenil’s t1/2 is shorter than benzo’s t1/2

Answer 22

b) PK: short t1/2 due to hepatic clearance (0.7-1.3 hours); longer t1/2 of benzodiazepines cause the recurrence of sedation and requires repeated administration of flumazenil

Question 23

treatment of anxiety states

Answer 23

i) Benzodiazepines are widely used for the management of acute anxiety states (situational anxiety) and rapid control of panic attacks as well as long-term management of generalized anxiety disorder and panic disorders

iv) Currently, use of newer antidepressants [selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)] preferred in treatment of generalized anxiety disorders/certain phobias, although benzodiazepines still used for acute anxiety states
v) Concomitant treatment of anxiety on a short-term basis with benzodiazepines and SSRIs is useful until SSRIs become effective (on the order of 4-6 weeks, after which benzodiazepines would be removed from treatment)

Question 24

benefits of using benzo’s for anxiety

Answer 24

(1) Risk of dependence
(2) Depression of CNS functions
(3) Amnestic effects
(4) Additional CNS depression when combined with other drugs (including ethanol)

Question 25

disadvantages of using benzo’s for anxiety

Answer 25

(1) Risk of dependence
(2) Depression of CNS functions
(3) Amnestic effects
(4) Additional CNS depression when combined with other drugs (including ethanol)

Question 26

treatment of sleep disorders

Answer 26

(4) Zaleplon and eszopiclone may cause less amnesia or day-after somnolence than zolpidem or benzodiazepines at recommended doses
(5) The t1/2 of zaleplon and zolpidem are fairly similar (1-2 hours and 1.5-3.5 hours, respectively) and are appropriate agents for individuals who have trouble falling asleep
(6) Eszopiclone has a t1/2 of approximately 6 hours and is more effective treating individuals who awaken early and have difficulty sleeping through the night

Question 27

what are some concerns in using sedative hypnotics in sleep disorders

Answer 27

v) Abrupt discontinuation of sedative-hypnotic drug treatment may lead to rebound insomnia
vi) Note: Long-term use of hypnotics is an irrational and dangerous medical practice. The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Non-pharmacologic therapies include proper diet and

exercise, avoiding stimulants before retiring, ensuring a comfortable sleeping environment, and retiring at a regular time each night.

Question 28

what are some direct toxic actions of sedative hypnotics

Answer 28

(1) Many common adverse effects of sedative-hypnotics result from dose-related depression of the CNS
(2) Low doses may lead to drowsiness, impaired judgment, and diminished motor skills that can lead to impacts on driving ability, job performance, and personal relationships
(3) An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment and in older patients (doses approximately half of those used in younger adults are safer and usually as effective)
(4) Sedative-hypnotics are the drugs most frequently involved in deliberate overdoses (benzodiazepines are considered safer because they have flatter dose-response curves)
(5) With severe toxicity, respiratory depression from central actions of the drug may be complicated by aspiration of gastric contents in the unattended patient (more pronounced if ethanol is present)
(6) Barbiturates enhance porphyrin synthesis and are contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or symptomatic porphyria

Question 29

what others substances interact with sedative hypnotics

Answer 29

(2) Examples of drug interactions: alcoholic beverages, opioid analgesics, anticonvulsants, phenothiazines, and some antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class

Question 30

which sedative hypnotics cause cytochrome P450 induction

Answer 30

(a) Phenobarbital and meprobamate can induce P450 induction with long-term use

Question 31

what must you NOT co-administor with ramelteon

Answer 31

iv) Avoid co-administration with fluvoxamine (SSRI) because it is an inhibitor of CYP1A2

Question 32

ADR’s of ramelteon

Answer 32

v) ADRs: dizziness, somnolence, fatigue, and endocrine changes (decreases in serum cortisol, decreases in testosterone, and increases in prolactin)

Question 33

uses of buspirone and MOA

Answer 33

i) Approved for the treatment of generalized anxiety disorder (anxiolytic effects may take 3-4 weeks to become established, making buspirone less effective in acute panic disorders)
ii) Does not cause sedation, hypnotic, euphoric, anticonvulsant, or muscle relaxant effects
iii) MOA: unknown; effects may be mediated by a variety of CNS receptor systems including serotonergic or dopaminergic systems

Question 34

ADR’s of buspirone

Answer 34

(1) Extensive metabolism by CYP3A4; use with caution in patients with hepatic impairment
v) ADRs: tachycardia, palpitations, nervousness, gastrointestinal distress, paresthesias, and dose-dependent papillary constriction

Question 35

biotransformation of benzodiazepines

Answer 35

-hepatic metabolism for all

most undergo phase I reactions (CYP3A4) followed by glucuronidation (phase II) to increase metabolite to being more water soluble

cumulative toxicity of the metabolites from breakdown (these have long half lives)

Question 36

what drugs are examples of CYP3A4 inhibitors that will cause increased concentrations of benzo’s if given with benzo’s

Answer 36

amiodarone

erythromycin

antifungals (ruconazole)

diltiazem and verapamil (CCB)

imatinib, conivaptan

Question 37

biotransformation of barbituates

Answer 37

hepatic metabolism (Most) and excrted in urine as glucuronide conjugates

EXCEPT phenobarbital which is 20-30 % excreted unchanged - adjust in renal failure

cumulative toxicity

Question 38

biotransformation of zolpidem, zaleplon, eszopiclone

Answer 38

short half life - useful for sleep aid’s

CYP3A4 plays a role in metabolism

Question 39

diazepam half life

Answer 39

100 hour 1/2 life

active metabolite

very fast rate of onset

very lipid soluble and redistributes

oxidation

Question 40

alprazolam 1/2 life

Answer 40

12-15 hrs

insignificant active metabolite

fast rate of onset after oral administration

oxidate

Question 41

lorazepam 1/2 life and onset

Answer 41

10-20 hr

intermediate onset

undergoes conjugation

Question 42

how are lorazepam, oxazepam and temazepam metaoblized

Answer 42

conjugated (no hepatic metabolism)

good for pt’s with hepatic impairment

Question 43

tolerance of sedative hypnotics

Answer 43

decrease in response to drug following repeated exposure

ALSO cross tolerance - repeated use of a drug produces tolerance to that drug but also drugs in same structural/mechanistic class

Question 44

atropine

Answer 44

antimuscarinic

block effects of AChE inhibitor overdose