MODULE 2 | CNS DEPRESSANTS Flashcards
are group of drugs that may enhance the activity of inhibitory neurotransmitters in the brain (GABA) and spinal cord (GLYCINE) or inhibit excitatory neurotransmitters (GLUTAMATE), and block the production of excitatory action potential
CNS depressants
most common mental disorders
anxiety
an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or unknown source
ANXIETY
drugs used to treat anxiety are called
anxiolytics
- induction of a relaxed easy state, i.e. allays irritability, nervousenss, or excitement
SEDATION
SEDATIVES
reduce anxiety and exert a calming effect on motor and mental function
sedatives
induction of sleep
HYPNOSIS
HYPNOSIS
produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep
hypnotics
inability to fall asleep and/or maintain a state of sleep
insomnia
one of the applications of sedative-hypnotics
insomnia
STAGES OF SLEEP
- very light sleep
- muscle activity slows down
stage 1
STAGES OF SLEEP
- breathing pattern and heart rate slows down
- body temperature decreases slightly
stage 2
STAGES OF SLEEP
- deep sleep starts
- brain starts to generate slow delta waves
sstage 3
STAGES OF SLEEP
- very deep sleep
- muscle activity is limited
stage 4
STAGES OF SLEEP
- REM sleep
- brainwaves speed up and dreams occur
- heart rate increases
stage 5
REM meaning
rapid eye movement
the sleep cycle is divided into (2)
NREM
REM
STAGES OF SLEEP
drowsy transition from waking to sleeping, still awake
stage 1 nrem
STAGES OF SLEEP
no longer aware but are easily awakened
stage 2 NREM
STAGES OF SLEEP
slow-wave sleep
stage 3 nrem
STAGES OF SLEEP
- deep sleep
- brain acvitivity decreases
- heart rate is slow
- BP is decreased
- breathing decreases
stage 4 NREM
the NREM sleep usually takes how many mins
60-90mins
STAGES OF SLEEP
- increase autonomic activity
- increase breathing, BP and HR
- increase blood flow to the brain
- dreaming episodes occur
stage 5 REM
the REM sleep occupies how many % of the total sleep
20-25%
BENZODIAZEPINES
SHORT ACTING (2-8hrs)
Oxazepam
Midazolam
Triazolam
BENZODIAZEPINES
INTERMEDIATE-ACTING (10-20hrs)
Lorazepam
Alprazolam
Temazepam
Estazolam
BENZODIAZEPINES
LONG-ACTING (1-3days)
Chlordiazepoxide
DIAZEPAM
Flurazepam
Chlorazepate
Quazepam
an active metabolite of Diazepam, Chlordiazepoxide, and Chlorazepate
Nordazepam
Benzodiazepines support what GABA receptor
GABA A
Barbiturates support what GABA receptor
GABA B
BARBITURATES
ULTRA SHORT-ACTING (30mins)
Thipental
Thiamylal
Methohexital
ThiThiMo
BARBITURATES
SHORT-ACTING (2 hours)
Pentobarbital
Hexobarbital
Secobarbital
5-6-7
BARBITURATES
INTERMEDIATE-ACTING (3-5hrs)
Amobabital
Butabarbital
BARBITURATES
LONG-ACTING (>6hours)
Phenobarbital
Barbital
MISCELLANEOUS AGENTS
- 5-HT1A partial agonist
- D2 antagonist
Buspirone
MISCELLANEOUS AGENTS
- novel hypnotic drug
- melatonin receptor agonist
RAMELTEON
MISCELLANEOUS AGENTS
melatonin receptor agonist
TASIMELTEON
MISCELLANEOUS AGENTS
orexin antagonist
Almorexant
Suvorexant
which has extremely rapid absorption
TRAZOLAM or DIAZEPAM
TRIAZOLAM
the absorption of the active metabolite of ____ is more rapid than other common used benzodiazepens
clorazepate
active form of Clorazepate (a prodrug)
desmethyldiazepam
(nordiazepam)
major requirement to enter BBB
lipophilic
all sedative-hypnotics cross the ____ during pregnancy
placental barrier
sedative-hypnotics are also detectable in ____ and may exert depressant effeects in the nursing infant
breast milk
BENZODIAZEPINES
are metabolized by ____ systems of the liver
microsomal drug-metabolizing enzyme
BENZODIAZEPINES
DESMETHYLDIAZEPAM:
elimination half life
more than 40hrs
BENZODIAZEPINES
Alprazolam, Triazolam undergo ____
a-hydroxylation
BENZODIAZEPINES
parent drug or active metabolites with ____
long halflives
BENZODIAZEPINES
ESTAZOLAM ,OXAZEPAM, LORAZEPAM:
are metabolized directly into ____
inactice glucuronides
BENZODIAZEPINES
affected by inhibitors and inducers of hepatic P450 isozymes
Diazepam
Midazolam
Triazolam
Barbiturates increase ____
bilirubin conjugation
BARBITURATES
oxidation by ____ to form alcohols, acids, and ketones
hepatic enzymes
BARBITURATES
metabolites appear in the urine as ____
glucoronide conjugates
BARBITURATES
SECOBARBITAL and PHENOBARBITAL:
elimination half lives
18 - 48 hrs
BARBITURATES
PHENOBARBITAL:
elimination half lives
4-5 days
ZOLPIDEM (NEWER HYPNOTICS)
reches peak plasma levels in ____
1-3 hrs
ZOLPIDEM (NEWER HYPNOTICS)
formulations available
sublingual & oral spray
ZOLPIDEM (NEWER HYPNOTICS)
rapidly metabolized to inactive metabolites via oxiation and hydroxylation by ____
hepatic CYP3A4
ZOLPIDEM (NEWER HYPNOTICS)
the elimination half life is greater in ____
women
ZOLPIDEM (NEWER HYPNOTICS)
the elimination half life is increased significantly in the ____
elderly
(NEWER HYPNOTICS)
is metabolized to inactive metabolites mainly by** hepatic aldehyde oxidase** and partly by the cytochrome P450 isoform CYP3A4
ZALEPLON
NEWER HYPNOTICS
- metabolized by hepatic CYP450 (CYP3A4) to form the inactive N-oxidde derivative and weakly active demethyleszopiclone
- elimination half life is prolonged in the elderly and in the presence of inhibitors of CYP3A4 (ketoconazole)
- inducers of CYP3A4 (rifampin) increase its hepatic metabolism
ESZOPICLONE
excreted unchanged in the urine to a certain extent (20-30%) in humans
PHENOBARBITAL
PHENOBARBITAL
its elimination rate can be increased significantly by ____ of the urine
mgmt. of phenobarbital toxicity
alkalanization
bc phenobarb is a weak acid
PHENOBARBITAL
pKa
weak acid - 7.4
MOA OF SEDATIVE-HYPNOTICS
the precursor in the synthesis of GABA
GLUTAMINE
MOA OF SEDATIVE-HYPNOTICS
GABA synthesis is facilitated by what enzyme
GLUTAMIC ACID DECARBOXYLASE
MOA OF SEDATIVE-HYPNOTICS
prevention of metabolism/degradation of GABA
storage into vesicles
MOA OF SEDATIVE-HYPNOTICS
how will the GABA produce its effect
by binding to the postsynaptic receptor
MOA OF SEDATIVE-HYPNOTICS
GABA inactivation via
GABA transaminase
key difference between GABA A and GABA B
GABA A - ionotropic
GABA B - metabotropic, GPRC
increase frequency of chloride ion channel opening
Benzodiazepines (Zolpidem)
- a benzodiazepine antagonist
- can reverse the hypnotic effects of zolpidem
FLUMAZENIL
bind to other sites distinct from benzodiazepines and other sedatives increasing the duration of chloride ion channel opening
Barbiturates (Phenobarbital)
- a negative mdoulator
- acts at the same site as BZDs through competitive binding
FLUMANEZIL
potentiate GABAergic inhibition
benzodiazepines
enhance GABA’s effects allosterically without directly activating GABA A receptors or opening the associated Cl channels
benzodiazepenes
what will happen if GABA and benzodiazepine interacts
increase the frequencey of channel-opening events
increase Cl conductane
increase the duration of the GABA-gated Cl channel openings
barbiturates
whis is more toxic
BENZODIAZEPINE or BARBITURATES
barbiturates
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS
- low doses: BZDs, barbiturates, and older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety
- the anxiolytic actions are accompanied by some depressant effects on psychomotor and cognitive functions (side effects)
SEDATION
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | SEDATION
exert dose-dependent anterograde amnesic effects (MIDAZOLIN) – inability to remember events occuring during the durg’s duration of action (used during surgeries, e.g. CS)
BENZODIAZEPINES
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS
- manifest when high doses are given
HYPNOSIS
EFFECTS OF BZDs AND SHs
the latency of sleep onset is ____
time to fall asleep
decreased
can sleep faster
EFFECTS OF BZDs AND SHs
the duration of stage 2 NREM is ____
increased
EFFECTS OF BZDs AND SHs
the duration of REM sleep is ____
decreased
EFFECTS OF BZDs AND OLDER SHs
the duration of stage 4 NREM slow-wave sleep is ____
decreased
EFFECTS OF NEWER SHs
decreases REM sleep but has minimal effect on slow-wave sleep
ZOLPIDEM
EFFECTS OF NEWER SHs
decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep
ZALEPLON
EFFECTS OF NEWER SHs
increases total sleep time mainly via increases in stage 2 NREM sleep
ESZOPICLONE
EFFECTS OF NEWER SHs
ESZOPICLONE:
low doses
little effect on sleep patterns
EFFECTS OF NEWER SHs
ESZOPICLONE:
highest recommended dose
decreases REM sleep
all hypnotics can cause deliberate ____
interruption of REM sleep
REM rebound is commonly observed in what drug
TRIAZOLAM
anxiety and irritability followed by REM rebound is commonly associated with ____
older sedativehypnotics
occurs with both Zolpidem and Zaleplon at higher doses
rebound insomnia
use of sedative-hypnotics for more than 1-2 weeks leads to some ____ to their effcts on sleep patterns
tolerance
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | ANESTHESIA
high doses of certain SHs depress the CNS to the point known as ____
STAGE III OF GENERAL ANESTHESI
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | ANESTHESIA
- very lipid-soluble, penetrating brain tissue rapidly
- makes them useful for the induction of anesthesia
THIOPENTAL & METHOHEXITAL
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | ANESTHESIA
- used IV
- given in large doses
- long half lives and formation of active metabolites contributes to post-anesthetic respiratory depression
- can be reversed by Flumazenil
BZDs
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS
- inhibit the development and spread of epileptiform electrical activity in the CNS
anticonvulsant effect
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | ANTICONVULSANT
selective to be clinically useful in the management of seizures
BZDs
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | ANTICONVULSANT
- effective in the treatment of generalized tonic-clonic seizures (not the drug of first choice)
BARBITURATES
ORGAN LEVEL EFFECTS OF SEDATIVE-HYPNOTICS | MUSCLE RELAXANT
- exert inhibitory effects
- may depress transmission at the skeletal neuromuscular junction at high doses
Carbamate and BZDs
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
can produce significant respiratory depression in patients with ____ at therapeutic doses
pulmonary diseasse
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
usual cause of death due to overdose of SHs
depression od the medullary respiratory center
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
no significant effects in ____ of healthy patients
cardiovascular system
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
AT NORMAL DOSE:
* in ____ states, heart failure and other disease that impair CV function may appear
HYPOVOLEMIC
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
AT TOXIC DOSE:
* may cause depression of ____ and ____ leading to circulatory collapse
myocardial contractility & vascular tone
ORGAN LEVEL EFFECTS OF SHs | RESPIRATION & CARDIOVASCULAR
respiratory and cardiovascular effects are more marked when given ____
IV
available in a biphasic release formulation that provides sustained drug levels for sleep maintenance
ZOLPIDEM
have value in the management of patients who awaken early in the sleep cycle
ZALEPLON
cause less amnesia or day-after somnolence than zolpidem / BZDs
Zaleplon & Eszopiclone
- orexin antagonists
- sleep enabling drugs
Almorexant
Suvorexant
- agonist at MT1 and MT2 melatonin receptors
- have no direct effects on GABAergic neurotransmission in the CNS
Ramelteon
Tasimelteon
approved for non-24hr sleep-wake disorder
Tasimelteon
- reduce the latency of persistent sleep
- no rebound insomnia
- no effect on sleep architecture
- rapidly absorbed; undergoes extensive first pass metab
Ramelteon
useful relaxant effects in skeletal muslces spasticity of central origin
DIAZEPAM
CLINICAL USES OF BZDs
anesthesia
Midazolam
antegrade amnesia
CLINICAL USES OF BZDs
anxiety
BZD
CLINICAL USES OF BZDs
muscle relaxant
alcohol withdrawal
DIAZEPAM
CLINICAL USES OF BZDs
anticonvulsant
Diazepam
Clonazepam
Clorazepate
CLINICAL USES OF BZDs
panic disorders
Alprazolam
CLINICAL USES OF BZDs
status epilepticus
Diazepam
seizure should be NMT 5 days
why is MIDAZOLAM preferred over other BZDs for anesthesia
- shorter onset of action
- greater potency
- more rapid elimination
CLINICAL USES OF BZDs
sleep disorders (insomnia)
lorazepam
temazepam
CLINICAL USES OF BZDs
alcohol withdrawal
diazepam
CLINICAL USES OF BABRITURATES
anticonvulsant
hypnosis
phenobarbital
CLINICAL USES OF BABRITURATES
anesthesia
sedation
thiopental
CLINICAL TOXICOLOGY OF SHs
- drowsiness, impaired judgement, diminished motor skills
- w impact on driving ability, job performance, personal relationships
- anterograde amnesia
- hangover effects
low doses
CLINICAL TOXICOLOGY OF SHs
- lethargy or state of exhaustion
- as gross symptom equivalent to those of ethanol intoxication
- exacerbate breathing problems in px w/ COPD
high doses
CLINICAL TOXICOLOGY OF SHs
a dose as low as ten times the hypnotic dose may be ____
fatal
except BZDs and newer hypnotics
TERATOGENECITY
individual BZDs category
D or X
TERATOGENECITY
Barbiturates are FDA pregnancy category ____
D
TERATOGENECITY
Eszopiclone, Ramelteon, Zaleplon, and Zolpidem are category
C
TERATOGENECITY
Buspirone, an anxiolytic, is caategory ____
C
ADVEERSE EFFECTS
Barbiturates enhance ____ synthesis
* contraindicated in patients with porphyria
porphyrin
which drug does tolerance rapidly develops
BARBITURATES or BZDs
barbiturates
____ usually develops when used continuously at therapeutic doses
PHYSICOLOGIC DEPENDENCE
____ may result to abstinence or withdrawal syndrome
abrupt withdrawal
it is advised that withdrawal should be done ____
gradually
which does have high potential for physical dependence and abuse
BARBITURATES or BENZODIAZEPINES
BARBITURATES
Due to high abuse potential, most sedative-hypnotic drugs are classified as ____ or ____ drugs
schedule III or IV
over how many % of alcohol is oxidized in the liver
90%
the rate of oxidation of alcohol follows ____
ZERO-ORDER KINETICS
inhibits alcohol dehydrogenase
Fomepizole
inhibits aldehyde dehydrogenase
Disulfiram
alcohol produces ____
dose-dependent depression
primary mechanism to account for the CNS depressant property of alcohol
enhance the action of GABA at GABA A receptor
alcohol inhibits the ability of ____ to open the cation channel
glutamate
accounts for the blackouts episodes
EFFECTS OF ALCHOL
induces ____ in the skin resulting to flushed sensation
dilation of blood vessels
EFFECTS OF ALCHOL
stimulates secretion of ____ and ____
saliva and gastric juices
EFFECTS OF ALCHOL
blocks secreetion of ____
ADH - antidiuretic hormone
antidiuretic hormone
vasopressin
CONSEQUENCES OF CHRONIC ALCOHOLISM
Alcoholics suffer from ____ resulting to WERNICKES-KORSAKOFF’S SYNDROME
thiamine deficiency
CONSEQUENCES OF CHRONIC ALCOHOLISM
characterized by paralysis of the external eye muscles, ataxia and confused state than can progress to coma & death
WERNICKES-KROSAKOFF’S SYNDROME
chronic alcoholinsm causes enzyme ____
induction
acute alcoholinsm causes enzyme
inhibition
TREATMENT OF ALCOHOLISM
opioid antagonists can cause dose-dependent hepatotoxicity, thus should be used with caution in patients with eviidence of abnormalities in serum aminotransferase activity
NALTREXONE
TREATMENT OF ALCOHOLISM
reduces short term and long term (more than 6mos) relapse rates when combined with psychotherapy
Acamprostate
- should be taken with alcohol; has little effect when given alone
- inhibits aldehyde dehydrogenase resulting accumulation of acetaldehyde causing extreme discomfort in patients
- this causes flushing, throbbing headache, N&V, sweating, hypotnesion, and confusion – may last for 30mins in mild cases and several hours in severe ones
Disulfiram
TREATMENT OF ALCOHOLISM
5 HT3 antagonist
Ondansetron
TREATMENT OF ALCOHOLISM
antiseizure
Topiramate
employed in conditions collectively known as neurosis
anxiolytics
an accumulation of anxiety and tension which leads to emotional changes and abnormal behavior
neurosis
commonly used anxiolytic
Buspirone
ANXIETY STATES
- psychic awareness of anxiety
- accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity
PRIMARY
ANXIETY STATES
- results from circumstances that may** have to be dealt with only once or a few times**
Situational anxiety
- excessive or unreasonable anxiety about life circumstances
- managed by drug therapy, sometimes in conjunction with psychotherapy
GENERALIZED ANXIETY DISORDER
Triggered by certain circumstances, such as open spaces, social interactions or spiders
Phobic anxiety
Attacks of overwhelming fear occur in association with marked somatic symptoms, such as sweating, tachycardia, chest pain, trembling, choking, etc
Panic disorder
- Widely used for the management of acute anxiety states and for rapid control of panic attacks
- Also used, though less commonly, in the long-term management of GAD and panic disorders
BZDs
selectively used for the treatment of panic disorders and agoraphobia
Alprazolam
preferred for patients with anxiety that may require treatment for prolonged period of time
Diazepam
- 5HT1A partial agonist, **D2 antagonist **
- Has selective anxiolytic effect without causing marked sedative, hypnotic, or euphoric effects
- Mainly for generalized anxiety states, less effective in panic disorders
BUSPIRONE
- Used mainly to reduce physical symptoms of anxiety (tremors, palpitations, etc.)
- No effect on affective component
BETA BLOCKERS
