question

commonly found to overshadow environmental problems

answer

world peace and economic concerns

question

what type of effects do BDZs produce, and are these effects dose-dependent

answer

BDZs fall into group known as sedative-hypnotics that produce dose-dependent CNS depressant effects

question

what term is recently replacing the term "sedative" in sedative-hypnotic drugs, and why

answer

anxiolytic - more accurately describes the effects - reduced activity, excitement, and calming effect

question

what are hypnotics

answer

drugs that produce drowsiness and facilitate sleep

question

at what concentration do anxiolytic effects occur compared to hypnotic effects, in sedative/anxiolytic benzodiazepenes

answer

anxiolytic effects occur at much lower concentration

question

what is the difference with hypnotic benzodiazepenes

answer

concentrations at which anxiolytic and hypnotic effects occur are much closer

question

what type of effects occur with BDZs at even higher doses than hypnotic effects

answer

some anesthetic actions

question

what part of the CNS do BDZs cause little depression of

answer

medullary centers controlling respiration

question

what is the implication of this

answer

BDZs are safe when used alone

question

what can occur when they are combined with other sedative/hypnotic drugs (i.e. alcohol)

answer

fatal overdose

question

what drugs were said to be general CNS depressants (no "flattening out" of curve representing CNS effects as dose gets to high levels)

answer

barbiturates - BDZs level off

question

how many times greater is the lethal dose compared to the typical therapeutic dose for BDZs

answer

1000x

question

what is the chemical structure of BDZs like

answer

three ring structure - "benzodiazepene" refers to a benzene ring fused to a diazepine ring - all clinically relevant BDZs also contain a 5-aryl ring

question

are these drugs lipophilic, and what variation exists

answer

lipophilic, but lipophilicity can vary by 50 fold

question

what is determined by the level of lipophilicity

answer

rate of onset of action

question

which BDZ is the most lipophilic

answer

diazepam (Valium)

question

what are the targets of BDZs

answer

GABA-A receptors in the CNS (gamma subunit)

question

what is the structore of GABA-A receptors like

answer

they are chloride channels

question

when GABA binds to the receptor, what does it cause to happen to chloride flow, and what is the result

answer

chloride influx into cell, resulting in hyperpolarization and inhibition of cell's activity

question

what does the GABA-A receptor mediate

answer

most of rapid, inhibitory transmission in the CNS

question

what is the other GABA receptor in the brain, and what effect do BDZs have on this receptor

answer

GABA-B receptor - BDZs have no actions, and this is not a chloride channel

question

what other substance do BDZs require to function, and why

answer

require GABA, as they enhance GABA binding to the receptor - BDZs are unable to directly open the channel themselves

question

what do BDZs cause by increasing GABA affinity for the receptor

answer

increase in opening frequency of GABA-A receptor/ion channels and increased chloride influx

question

what do barbiturates, such as phenobarbital, cause to happen at the GABA-A receptor

answer

prolonged duration of opening, rather than increased frequency caused by BDZs

question

what are six classes of disease or purposes that BDZs can be used for

answer

1) anxiety disorders; 2) insomnia; 3) muscle spasms; 4) epilepsy/seizures; 5) sedation for medical/surgical procedures; 6) ethanol withdrawal

question

what group should be given a lower dose of BDZ, and how much lower

answer

patients over 65 - give 1/2 to 1/3 as much

question

what is the most potent benzodiazepene

answer

triazolam (halcion)

question

what fraction of patients with pathological anxiety seek treatment

answer

one third

question

in what ways can pathological anxiety occur (4)

answer

1) primary anxiety disorder; 2) secondary anxiety disorder; 3) response to acute stress; 4) with other psychiatric illness

question

for what common and serious medical problem was treatment of anxiety said to reduce risk of recurrence

answer

MI

question

what commonly used drug often causes anxiety

answer

caffeine

question

for what primary anxiety disorders are benodiazepenes first line treatments of (2)

answer

1) GAD (generalized anxiety disorder); 2) panic disorder

question

what other primary anxiety disorders were mentioned (3)

answer

1) phobic disorders; 2) OCD; 3) PTSD

question

for generalized anxiety disorder, what BDZ is most effective

answer

all are equally effective in preventing anxiety

question

what is the most frequently prescribed anxiolytic in the US

answer

alprazolam (Xanax)

question

what are three other most frequently prescribed BDZs

answer

1) lorazepam (Ativan); 2) diazepam (Valium); 3) clonazepam (Klonopin)

question

what are the primary differences among BDZs

answer

pharmacokinetic properties

question

what can BDZs be classified according to

answer

half life

question

do any have very long half lives

answer

yes, many

question

what factors should be considered when prescribing a BDZ (4 - unrelated to illness BDZ is being prescribed for)

answer

1) half-life; 2) age of patient; 3) presence of liver disease; 4) presence of other drugs which compete for metabolism

question

what are criteria for diagnosis of panic disorder (2)

answer

1) at least two unexpected attacks; 2) persistent worry about having another panic attack

question

what is the term for panic attacks that are more likely to occur, but not always, in response to a certain situation

answer

situationally predisposed

question

what else can panic attacks occur with or without

answer

agoraphobia (fear of places from which escape may be difficult)

question

what are the FDA approved BDZs for treatment of panic disorder

answer

1) alprazolam; 2) clonazepam

question

what are times until onset like for these drugs

answer

quick

question

what should be remembered about dosing for panic disorder, compared to GAD

answer

higher doses of alprazolam are required for treatment of panic disorder compared to GAD

question

what is often msitaken for panic attack

answer

PSVT (paroxysmal supraventricular tachycardia)

question

what classes of phobic disorders are there (2)

answer

1) simple phobia; 2) social phobia

question

what drug is used for simple phobia

answer

drugs contraindicated

question

how is social phobia differentiated from agoraphobia

answer

social phobia involves fear of humiliation, rather than fear of being unable to escape

question

what is the first line treatment for social phobia

answer

SSRIs

question

what BDZs are used (2) but are second line treatments

answer

1) alprazolam; 2) clonazepam

question

what secondary problem has increased incidence in social phobics

answer

alcoholism (25% increase)

question

what is contraindicated in these cases

answer

BDZs

question

what type of benzodiazepene treatment course should be used for insomnia

answer

between one to four weeks

question

what two undesirable problems develop

answer

1) tolerance to hypnotic effects; 2) physial dependence

question

what are desirable characteristics for hypnotic agents (3)

answer

1) rapid onset; 2) sustained action to facilitate sleep; 3) no residual action by morning

question

of the BDZs, which fits these criteria the best

answer

triazolam (halcion)

question

what are the advantages of triazolam (2)

answer

1) short duration of action; 2) effective for people who have difficulty going to sleep

question

what are disadvantages of triazolam (4)

answer

1) tolerance develops within a few days; 2) early morning insomnia; 3) rebound insomnia upon discontinuation; 4) REM sleep rebound (blocks REM)

question

what problem arises from blocked REM

answer

underlying anger gets expressed (violence)

question

what BDZ is useful for people with frequent wakening, and why

answer

temazepam - peak effect is 2-3 hours after oral dose - intermediate rate of onset

question

what other advantage does temazepam have

answer

no hepatic metabolism

question

what is a very long acting BDZ hypnotic that is used primarily for inpatients (half life is over 100 hours)

answer

flurazepam

question

how long can it be effective

answer

up to four weeks

question

what is one disadvantage

answer

causes daytime sedation

question

how does it affect sleep (3)

answer

1) shortens time to onset; 2) decreases number of wakenings; 3) increases duration

question

what is another fast acting BDZ with a considerably long half life (39 hours)

answer

quazepam

question

how potent are quazepam and flurazepam

answer

low potency compared to other BDZ

question

what should be noted about quazepam and flurazepam's effects on sleep

answer

these less potent and more slowly eliminated drugs continue to improve sleep even after discontinuation

question

what is an intermediate onset BDZ with a half life ranging from 8-31 hours

answer

estazolam

question

who are BDZs contraindicated in for insomnia, and why

answer

patients with obstructive sleep apnea - they decrease muscular tone in upper airway and exaggerate the impact of episodes of apnea

question

what are the muscle relaxant actions of BDZs due to, and where does this action take place

answer

increase in presynaptic inhibition in the spinal cord

question

what BDZs are indicated for muscle spasms/spasticity (2)

answer

1) diazepam; 2) clonazepam

question

in what situations are these drugs used for spasms/spasticity (2)

answer

1) muscle injuries; 2) degenerative disorders

question

what degenerative disorders were mentioned (2)

answer

1) cerebral palsy; 2) MS

question

which of these drugs has an advantage, and what is that advantage

answer

clonazepam has the advantage that it can be used to reduce spasticity at non-sedative doses

question

what BDZs are used for epilepsy (2)

answer

1) clonazepam; 2) clorazepate

question

what type of seizures is clonazepam used for

answer

absence seizures

question

what problem can occur, and when does it

answer

tolerance within 1-6 months

question

what type of seizures is clorazepate used for

answer

partial seizures

question

in what strategy is clorazepate used

answer

used with other anticonvulsants

question

what BDZs are used for acute seizures / status epilepticus (2)

answer

1) lorazepam; 2) diazepam

question

what line of treatment are these drugs

answer

DOCs for status epilepticus

question

which stops seizures in the shortest time, how long does it take, and why

answer

diazepam (IV) stops seizures in one minute (reaches brain in 10 seconds) because it is the most lipophilic

question

what is the half life of diazepam (IV)

answer

15 minutes

question

what should diazepam be followed by

answer

phenytoin

question

how long does lorazepam (IV) take to stop seizures, and what is its half life

answer

stops seizures in about five minutes, half life 12-15 hours

question

what BDZ is used for sedation prior to invasive procedures

answer

midazolam

question

what effects does it produce that are useful for this purpose (3)

answer

1) conscious sedation; 2) muscle relaxation; 3) anterograde amnesia

question

what doses are required for anterograde amnesia

answer

preanesthetic doses

question

what doses are required to cause general anesthesia

answer

does not cause general anesthesia by itself

question

what serious problem has midazolam caused during use for conscious sedation, and in what patient groups (2)

answer

death due to respiratory arrest in: 1) patients premedicated with narcotics; 2) patients with COPD

question

what problem occurs frequently upon withdrawal of chronic alcohol that can be treated with BDZs

answer

seizures

question

what BDZs are used for the management of acute effects of alcohol withdrawal (4)

answer

1) chlordiazepoxide; 2) diazepam; 3) clorazepate; 4) oxazepam

question

how is dosing determined

answer

doses are titrated so that only a tremor is present during withdrawal

question

what dose usually needs to be given, and why

answer

because of cross-tolerance at GABA-A receptor, you need to give max therapeutic dose of BDZ

question

how well are almost all BDZs absorbed, and from where

answer

quickly, from the gut

question

what is the exception, and what is different about its absorption

answer

clorazepate - it is decarboxylated in gastric juice to an active metabolite which is completely absorbed

question

what is the implication of the high lipid solubility of BDZs

answer

taken up rapidly into brain (and other highly perfused organs) then redistributed to tissues less well perfused

question

what BDZs have fastest redistribution

answer

highest lipid solubility

question

how important is redistribution from brain to other tissues in terminating CNS effects

answer

can be as important as metabolism in terminating CNS effects

question

do BDZs cross the placenta, and are they secreted into breast milk

answer

yes, yes

question

what transformation, and where, is necessary for elimination of BDZs

answer

hepatic metabolism to water-soluble compounds

question

what important compounds are many BDZs metabolized to

answer

active metabolites

question

what is the half time of the active metabolite like, compared to parent compound

answer

longer

question

what is the implication of the longer half life of active metabolite

answer

long half-lives can cause cumulative effects with multiple doses

question

what was said to be true about metabolism of those with short half lives (one of two things)

answer

1) don't have active metabolites; 2) active metabolites are quickly eliminated

question

what class of BDZs usually don't have active metabolites

answer

hypnotic BDZs

question

what exception must we know

answer

flurazepam is a hypnotic with active metabolites and a long half life

question

what is an ultra-short acting BDZ

answer

midazolam (half life 1-2 hours)

question

what is a short acting BDZ

answer

halcion

question

what are four long-acting BDZs mentioned

answer

1) chlordiazepoxide; 2) diazepam; 3) flurazepam; 4) quazepam

question

how many phases does hepatic metabolism of most BDZs occur in

answer

three

question

what is phase one, and what does it result in

answer

initial oxidation step results in N-desalkylated active metabolites

question

what is phase two, and what does it result in

answer

hydroxylation at R3 yields another active metabolite

question

what is phase three, and what does it result in

answer

conjugation of hydroxyl compounds with glucuronic acid yeilding inactive metabolites which are excreted in the urine

question

what is the fastest, second-fastest, and slowest reaction

answer

phase 1 (fastest), phase 3, phase 2 (slowest)

question

what phase(s) are often bypassed in drugs with shorter half lives

answer

phase 1, 2

question

in what patients are phase 1 and 2 reactions often reduced in (2)

answer

1) elderly; 2) liver disease

question

what related drugs were said to be able to increase their own metabolism, and how

answer

barbiturates increase their own metabolism by inducing the hepatic microsomal enzymes

question

what three substances were mentioned to reduce or slow down phase 1 and 2 reactions (3)

answer

1) cimetidine; 2) oral contraceptives; 3) grapefruit juice

question

what BDZs have no active metabolites (3)

answer

1) lorazepam; 2) oxazepam; 3) temazepam

question

who would these be good options for (2)

answer

1) elderly; 2) liver disease

question

what effects of BDZ effects does tolerance develop more for (3)

answer

1) hypnotic; 2) muscle relaxant; 3) anti-convulsant (not anxiolytic effects)

question

when does physical dependence occur with BDZ treatment

answer

if BDZs are given for long periods

question

which BDZs are physical dependence more likely with (what characteristics - 2)

answer

1) shorter acting; 2) more potent

question

what four were mentioned to be shorter acting and more potent

answer

1) alprazolam; 2) klonazepam; 3) lorazepam; 4) triazolam

question

what are symptoms of withdrawal from BDZs like

answer

similar to those for which the BDZ was originally prescribed

question

what group of BDZs do not produce as severe withdrawal symptoms

answer

those with longer half lives

question

what is indicated for people on BDZs for prolonged periods who are to stop taking them

answer

gradual withdrawal

question

what are the two most common adverse effects

answer

1) drowsiness; 2) confusion

question

what are three other adverse effects

answer

1) motor incoordination; 2) cognitive impairment; 3) anterograde amnesia

question

when is anterograde particularly common

answer

when BDZs are used with alcohol

question

how should doses for elderly be adjusted, and what BDZs are more appropriate

answer

doses should be one third to a half of those typically prescribed, and BDZs with a shorter half life are more appropriate

question

what other problems can BDZs cause in the elderly

answer

increased risk of falling (even with those drugs that have shorter half lives)

question

what are BDZs used during pregnancy linked to

answer

cleft palate

question

besides pregnancy, when should women always avoid BDZs

answer

when nursing

question

what drugs have an additive effect with BDZs (2)

answer

1) alcohol; 2) other sedative hypnotics

question

what can these cause when combined

answer

respiratory depression

question

in what diseases are BDZs contraindicated (3)

answer

1) liver disease; 2) COPD; 3) obstructive sleep apnea

question

what is the problem in liver disease

answer

effects are potentiated because of decreased metabolism

question

what BDZs are more appropriate for patients with liver disease

answer

those without active metabolites

question

what drug was said to cause problems in patients with COPD (asthma, chronic bronchitis, and emphysema) and what problem does it casue

answer

effects of midazolam on respiration are exaggerated in these patients

question

why are BDZs bad in sleep apnea

answer

muscle relaxant effects aggravates disroders - use with caution in people who snore a lot, too

question

what non-benzodiazepene is useful for anxiety

answer

buspirone (Buspar)

question

what is the MOA of buspirone

answer

partial agonist at 5HT1A receptors (also has affinity for DA receptors, possibly a mixed agonist/antagonist)

question

what undesirable properties of BDZs is it missing (4)

answer

1) physical dependence; 2) withdrawal; 3) no cross-tolerance; 4) no interaction with alcohol

question

what else is a major difference between buspirone and BDZs

answer

buspirone has a slow onset of action (2-4 weeks)

question

who is buspirone good for (2)

answer

1) elderly; 2) patients with substance abuse problems

question

what main non-benzodiazepene is good for insomnia

answer

zolpidem (Ambien)

question

what is onset and half life like

answer

quick onset (within 1-2 hours), half life of 2.5 hours

question

how do the effects of zolpidem compare to BDZs (what effects of BDZs does and doesn't it have)

answer

it has selective hypnotic effect, but minimal anxiolytic, anticonvulsant, and muscle relaxant effects

question

who should doses be adjusted for, and how

answer

should be adjusted down for elderly

question

what are side effects (4)

answer

1) dizziness; 2) headache; 3) confusion; 4) sleepiness

question

what drug can zolpidem interact with

answer

alcohol

question

what is a similar option to zolpidem

answer

zaleplon (Sonata)

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