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99 Cards in this Set
- Front
- Back
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What is the function of sedative-hypnotics?
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Cause SEDATION or Encourage SLEEP
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An effective Sedative agent should...
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Reduce anxiety
Exert a calming effect With LITTLE or NO effect on Motor or Mental function |
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The degree of CNS depression caused by a sedative should be...
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The minimum consistent with therapeutic efficacy
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A HYPNOTIC drug should do what?
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Produce DROWSINESS
Encourage the ONset and MAINtenance of a state of sleep Sleep must resemble (as far as possible) Natural sleep state |
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Hypnotic effects involve....?
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A more pronounced DEPRESSION of the CNS than sedation
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How can most sedative drugs achieve Hypnotic effects?
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By Increasing the dose, Sedative drugs can cause CNS depression
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What is the dose response relationship for Sedative-hypnotics?
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They cause a GRADED Dose- Dependent depression of CNS function
Individual drugs differ in the relationship between Dose and CNS depression |
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What is the dose-response relationship for OLDER Sedative-hypnotics?
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Older sedative-hypnotics show a LINEAR dose-response curve
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The LINEAR dose-response curve means that.....
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Increasing the dose above what is needed for hypnosis causes- A General state of ANESTHESIA
Higher doses pass this state and may - Depress Respiratoy and Vasomotor centers in the MEDULLA This leads to Coma and Death |
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BENZODIAZEPENES show what kind of dose-response relationship?
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NON - LINEAR dose-response relationship
They are SAFER drugs |
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What are the categories of Sedative-hypnotics?
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Benzodiazepenes
Barbituates Non-benzodiazepene benzodiazepene receptor agonist 5HT1A receptor partial agonist Melatonin agonist Older drugs Other classes |
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What are the most widely used Anxiolytic drugs?
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Benzodiazepenes
They have largely replaced Barbituates for this reason - Benzos are Safer and More effective |
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What is the MOA of Benzos?
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They bind GABA (a) receptors in Neuronal membranes in the CNS
They enhance the GABA effect on the receptor This effect is an ALLOSTERIC effect. Benzos have no effect of its own without GABA being bound first The binding of Benzos cause an INCREASE in the FREQUENCY of the channel openings |
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What is GABA(a) receptor?
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It functions as a Cl- channel
GABA the inhibitory neurotransmitter binds and causes opening of the channels This leads to hyperpolarization of the neurons causing inhibition of the triggering of the axn potential |
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What is the structure of the GABA receptor?
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Pentameric - 2 alpha, 2 beta and 1 gamma
GABA binds between the adjacent a and b subunits |
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Where on the GABA receptor does Benzo bind?
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Between a and g subunits (alpha and gamma)
They sites are called Benzo receptors -BZ1 and BZ2 (thes are subtypes commonly found in CNS) |
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What effect does Benzos have on the EC50 for GABA induced Cl- influx ?
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Benzos
-DECREASE the EC50 -It makes GABA more potent -Less GABA is needed for Cl- conductance The Efficacy DOES NOT change |
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What r the 3 interactions with the Benzo receptors?
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Agonists (Positive allosteric modulator of GABA)
Antoagonists Inverse Agonists |
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What is the clinical use of the Benzos that are Agonists/Positive allosteric modulator of GABA?
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Anxiolytics
Anticonvulsants |
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Name the the Antagonist of the Benzo receptor
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Flumazenil
This is used as an Anitidote for Overdose on Benzo They bind BZ1 and BZ2 |
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What type of allosteric effects do the Inverse agonists have on the BZ receptors?
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Negative Allosteric modulator of GABA receptor function ( decrease the function of GABA at the GABA receptor)
They can cause Anxiety and Seizures - esp. the Beta-CARBOLINES These are only used Experimentally - Not for clincal use |
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All Benzos exhibit these reactions to a greater or lesser extent....namely
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Reduce anxiety
Sedative and Hypnotic action Anticonvulsants/ Siezure states Muscle Relaxant Anesthesia |
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At what dose is Benzos Anxiolytics?
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Low dosage
They are thought to do this by selectively inhibiting neuronal circuits in the Limbic system |
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Can Benzos provide anesthesia as a single drug?
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Diazepam and Midazolam are used in IV anesthesia but
NOT by themselves |
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How are the Benzos absorbed and distributed?
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Benzos are Lipophillic
Benzos are Rapidly absorbed after oral admin They are distributed through out the body |
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Name the Long acting Benzos?
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Flurazepam and Diazepam (1-3 days)
'FD'- Few Days They form active metabolites with long half lives |
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What is the t1/2 of the short acting BEnzos?
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3-8hrs
Oxazepam Triazolam 'OT' Only Three to.... |
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Alprazolam, Lorazepam, Temazepam are?
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Intermediate acting Benzos
'ALTe" ALTernating between long and short |
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Most Benzos undergo PHASE 1 reaction by ?
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CYP3A4
The metabolites are then conjugated in PHASE II reactions forming Glucoronides |
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The Phase II metabolites are excreted ...?
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In the urine
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Name some inhibitors of CYP3A4?
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Erythromycin, Clarithromycin
Itraconazole, Ketoconazole Nefazodone, Ritonavir Grapefruit Juice They can inhibit the metabolism of Benzos |
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Which 3 Benzos are not metabolized by P450?
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Oxazepam
Temazepam Lorazepam 'OTL' Out The Liver (although we know that it is in the liver) They are conjugated directly. They can be used in patients with liver disease - other Benzos may need dose adjustment |
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Which Phase reaction produces pharmacologically active metabolites?
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Phase 1
Desmethyl-diazepam is a metabolite of several Benzos with t1/2 of 40 hrs |
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What can be said about the half life of Benzos with active metabolites?
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The 'Apparent' half life is the combined actions of the Parent drug and its Metabolite
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What is the further metabolite of Desmethyldiazepam?
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Oxazepam
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The long acting Flurazepam is oxidized to a metabolite with a t1/2 ranging from?
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30 - 100 hrs
approx 1-4days |
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How is Clorazepate different from the other Benzos in its metabolism?
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It is a pro-drug
It is Decarboxylated to Desmethyldiazepam in GASTRIC JUICE This is NOT a PHASE 1 reaction |
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Which Benzo is useful in anxiety?
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Alprazolam (intermediate acting)
('A'lprazolam for 'A'nxiety) Widely used for PANIC disorders Only recommended for Short term or Intermittent use in anxiety disorders |
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What are the AE of Alprazolam?
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May cause REBOUND anxiety in between doses
Assoc. with withdrawal syndrome incl. Seizures |
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Which Benzo is used in Muscular disorders?
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Diazepam
Useful in treatment of *skeletal muscle spasms e.g from strains *Spasticity from degenerative disorders e.g MS and Cerebral Palsy |
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Which Benzo is used in 'Some' types of Epileptic seizures?
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Clonazepam
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Which Benzos is the DOC in 'Status Epilecticus'?
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LORAZEPAM
Diazepam can also be used |
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Management of Ethanol withdrawal?
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Diazepam, Oxazepam
Also: Clodiazepoxide and Clorazepate |
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Name 2 Benzos used as components in anesthesia protocols.
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Diazepam, Midazolan
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The 3 most prescribed Benzos for sleep disorders?
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Flurazepam -long acting
Temazepam -IM acting Triazolam -short acting 'FTT' -fight the tension, (go to sleep) |
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What are the 2 useful effects of sedative -hypnotics on sleep?
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Latency of sleep onset is decreased
Duration of stage 2 Non Rem sleep is increased They also decrease the duration of REM, and stage 4 NREM sleep (significance unclear) |
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What are the AE of Benzos?
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Drowsiness and confusion (2 most common side effects)
Ataxia -occurs at high doses Cognitive impairment - decr long term recall, and formation of new knowledge Adverse Psychological effects - paradoxical effects e.g anxiety, irritablity, hostility, rage, paranoia, derpession, suicide ideation (incidence rare and dose related) Dependence - if high doses are given over prolonged periods Abrupt discontinuation of Benzos can cause withdrawl symptoms -anxiety, agitation, confusion, insomnia, tension, restlestness |
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Flumatezil, the only Benzo antagonist available for clincal use is approved for?
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*Reversing the CNS depressant effects of Benzo overdose
*hasten recovery after use in anesthetics and diagnostic procedures ONSET: Rapid, but short duration t1/2 -1 hr due to rapid hepatic clearance |
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How is reversal of long acting Benzos maintained?
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Frequent administration of Flumatezil (due to short half life)
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What is the AE of Flumazenil?
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May preciptate Withdrawal in Phys. dependent patients
May cause Seizures in patient who use Benzo to control seizures |
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Why have Benzos replaced Barbituates as sedative-hypnotics?
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Barbituates induce
-tolerance -physical dependence -severe withdrawal symptoms -induce drug metabolizing enzymes Can cause COMA in high doses Benzos Overdose is seldom lethal, unless alcohol or other CNS depressants are taken concurrently |
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What is the MOA of Barbituates?
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They also act on GABA (a) receptors and enhance GABA effect (like Benzo)
But.. They increase the DURATION of the GABA gated Cl- channel opening (Benzo incr. frequency of opening) They bind at a site different from Benzos |
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What other receptors does Barbituates act on?
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Glutamate receptors -blockage
Hig frequency Sodium Channels- blockage (pentobarbital anesthetic amounts) Together the action on the 3 receptors may explain their use as *Surgical anesthetics *A more pronounced CNS depressant effect This is the reason for their low margin of safety |
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What are the effect of Barbs on the CNS using low or high dose?
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Low dose - Sedation
High dose - Hypnosis-->anesthesia-->Coma-->Death |
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How does Barbs cause Respiratory depression?
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They
*suppress the Hypoxic and chemoreceptor response to CO2 |
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Overdose of Barbs can cause?
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Coma and DEATH
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What is the effect of Barbs on the P450 enzymes?
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Induction of P450 Enzymes
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What Barb is Ultra-short acting? What is its use?
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THIOPENTAL - duration of action 30mins
'T'hiopental for 'T'id-bit of action Used IV to Induce Anesthesia |
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Which Barb has a duration of >1day and is used as an Anticonvulsant?
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PHENOBARBITAL
Used in long term mangement of Tonic-Clonic seizures, Status Epilepticus and Eclampsia |
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Which Barbs are useful as sedative-hypnotics?
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Secobabital
Pentobarbital Amobarbital Sleeping in a 'SPA' They are Short acting (3-8 hrs) |
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What drug have replaced Barbs for treatment of anxiety?
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Benzos
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What r the uses of Barbs in Liver metabolic states?
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*They increase Glucoronyl tranferase and Bilirubin binding Y protein
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Which Barb is used in Hyperbilirubinemia and Kernicterus?
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Phenobarbital
Phetharbital (N-phenylbarbital)works equally well |
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Which Barbituate is non depressant?
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Phetharbital (N-phenylbarbital)
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What is the mechanism for termination of effects of Barbs?
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Redistribution
This accounts for the Short duration of action of THIOPENTAL Barbs are metabolized in the liver (EXCEPT Phenobarbital) |
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What are the AE of Barbs?
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CNS - drowsiness, impaired conc. , mental and physical sluggishness
Paradoxical excitement -irritation, paranoia Hypersensitivity - esp in person with asthma Hangover Increase Porphyrin synthesis -C/I in patients with porphyrias |
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What is the effect of Barbs on patients with Pulm. Insuff.?
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Serious Resp. depression.
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How can Barbs cause CV collapse?
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Rapid IV injection
Even slow IV can produce APNEA and occasional LARINGOSPASM, COUGHING, RESP. difficulties |
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What is the AE of Barbs when given in the presence of PAIN?
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May worsen PAIN perception
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How is withdrawal from Barbs different to Opiod withdrawal?
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Withdrawal is more SEVERE from Barbituates
Abrupt withdrawal causes Tremors anxiety weakness seizures delirium Cardiac arrest Can result in DEATH |
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What is the leading cause of death among drug overdoses?
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Barb POISONING
Severe Resp. and central CV depression |
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Which site on the GABA (a) receptor do the Non-Benzodiazepene Benzodiazepene Receptor Agonists NBBRA bind?
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They bind the BZ1 subtype of Benzodiazepene receptors only
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What subunit does the BZ1 receptor contain?
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alpha 1 subunits
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Name the 3 NBBRA?
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ZOLPIDEM
ZALEPLON ESZOPICLONE |
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What is the duration of action of Zolpidem?
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Short duration of action
Short half-life (1.5-3.5hrs) |
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When is Zolpidem used?
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It is used as a HYPNOTIC
Short-term treatment of Insomnia Particularly for Sleep INITIATION |
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What other effects does Zolpidem have?
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Minimal Muscle relaxing and Anticonvulsant effects
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With prolonged use, can Zolpidem cause tolerance?
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Little or no tolerance develops
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What are the AE of Zolpidem?
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Low incidence of AE
Agitation, nightmares, headache, dizziness, drowsiness |
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Which 2 NBBRA are similar in their effects
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ZOLIPEDEM and ZALEPLON
Similar HYPNOTIC action Zaleplon is also indicated for Short term treatment of Insomnia |
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What are the characteristics of Zaleplon?
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Rapid onset
Short duration of action Elimination half-life - 1hr |
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Which entantiomer of Zopiclone is pharmacollogically active?
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S-entantiomer
Eszoplicone -has a 50 fold affinity for the receptor than R |
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What is the clinical use of Eszoplicone?
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Insomnia
It decreases sleep latency It Improves sleep MAINtenance |
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What is the elimination half-life of Eszoplicone
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6 hours (longer than the other 2)
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Name the 5-HT1A partial agonist
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BUSPIRONE
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What is the use of Buspirone?
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ANXIOLYTIC -onset 2-3 weeks
NO hypnotic, anticonvulsant or muscle relaxant properties |
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Does Buspirone bind GABA receptors?
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NO - MOA may be analagous to antidepressants
It is indicated for MANAGEMENT of anxiety disorders, NOT for Acute anxiety |
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What are the Advantages of Buspirone?
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LESS psychomotor impairment than Benzos
NO drug interaction with Ethanol, Benzo or other sedative-hypnotics NO rebound anxiety or Withdrawal signs on abrupt discontinuance NO Depencence |
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What is RAMELTEON?
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Agonist at MT1 and MT2 melatonin receptors
These receptors are located in the Suprachiasmatic nuclei of the brain |
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What is the clinical use of RAMELTEON?
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Treatment of INSOMNIA
Difficulty of Sleep ONSET |
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Which drug should not be used along with Ramelteon?
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Fluvoxamine (SSRI) - it inhibits CYP1A2 which metabolizes Ramelteon
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Which Sedative-Hypnotic is the only Category B drug in pregnancy?
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Buspirone
'B'uspirone for Category 'B' The others are category C, D or X |
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Older sedative-hypnotics?
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Chloral Hydrate
Meprobamate Paraldehyde |
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Name the OTHER classes of sedative-hypnotics?
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*Beta blocker
Propranolol *alpha 2 agonist Clonidine *Antihistaminics Hydoxyzine Diphenhydramine Doxylamine |
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Which Antihistamine has strong Antiemetic activity?
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Hydroxyzine
Used for Symptomatic relief of ANXIETY ( not for long term use) |
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Propranolol, the most lipophillic beta blocker is widely used to ..?
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Control Performance Anxiety
It has central effects but does not affect cognition |
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What alpha 2 agonist may also modify Autonomic expression of anxiety?
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CLONIDINE
Centrally acting partial alpha 2 agonist |
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Non prescription antihistamine, Diphenhydramine and
Doxylamine are effective in treating? |
MILD types of Insomnia
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Is it ending anytime soon??
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Yes..The end
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