Anaesthetics: Pharmacology - Sedative-hypnotic drugs Flashcards
What is the difference between a sedative and a hypnotic?
Sedative: anxiolytic, exerts a calming effect
Hypnotic: produces drowsiness, encourages onset and maintenance of sleep (more pronounced CNS depression than sedation: may be achieved by increasing dose of sedative-hypnotic)
Describe the difference in dose-response curve between older and newer sedative hypnotics
Wtih older sedative-hypnotics (e.g. barbiturates, alcohol), increasing the dose above that needed for hypnosis may lead to general anaesthesia, and at still higher doses to depression of respiratory and vasomotor centres in medulla -> coma, death (i.e. linear dose-response relationship)
Newer sedative-hypnotics (e.g. benzodiazepines) require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis, and so are safer
Five classes of sedative-hypnotics
- Benzodiazepines
- Barbiturates
- Other simple drugs (e.g. alcohol, chloral hydrate, trichlorethanol, paraldehyde)
- Newer agents (e.g. buspirone, zolpidem, zaleplon)
- Drugs with sedative-hypnotic side effects (i.e. most antipsychotics, many antidepressants, some antihistamines)
Describe the structure of the GABA(A) receptor and its major isoform in the brain
Pentameric chloride channel
Major isoform in the brain is composed of 2x a1, 2x B2 and 1x y2 subunits
Where do benzodiazepines bind on the major GABA(A) receptor isoform in the brain?
Between a1 and y2 subunits
What is the mechanism of action of benzodiazepines?
Binds to molecular components of GABA(A) receptor and potentiates GABAergic inhibition at all levels of neuraxis (spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, cerebral cortex)
Achieves this by increasing frequency of channel opening (does not directly activate or open channel)
Describe the structure of benzodiazepine
7-membered heterocyclic ring, which for most benzodiazepines contains a carboxamide group
Describe the absorption of benzodiazepines
Variable, dependent on lipid solubility amongst other factors
Triazolam, diazepam, and active metabolite of clorazepate (nordiazepam) are more rapidly absorbed than other commonly used benzodiazepines
How is clorazepate absorbed?
Clorazepate is a prodrug: converted to active metabolite nordiazepam by acid hydrolysis in the stomach
Describe the distribution of benzodiazepines
Rate of entry to CNS dependent on lipid solubility (triazolam enters rapidly, has rapid onset of action)
All cross placental barrier and enter breast milk
Describe the metabolism of benzodiazepines
Transformed to water-soluble metabolites by microsomal enzyme systems in the liver:
- Phase I oxidation (often involves CYP3A4)
- Phase II conjugation to form glucuronides, which are then excreted in the urine
Elimination t1/2 dependent on rate of transformation
Describe the metabolism of diazepam
Undergoes phase I reaction to produce active metabolite desmethyldiazepam (nordiazepam)
Desmethyldiazepam transformed to active metabolite oxazepam
Oxazepam undergoes conjugation to form glucuronides which are then excreted in the urine
Which benzodiazepines do not produce active metabolites (i.e. are directly conjugated)?
Oxazepam
Lorazepam
Give two examples of phase I benzodiazepine metabolites. What are their elimination half-lives and what is the clinical significance of this?
Desmethyldiazepam (metabolite from oxidation of chlordiazepoxide, diazepam, prazepam and clorazepate): long elimination t1/2 >40hrs, can cause cumulative effects with repeated dosing
Alpha-hydroxy metabolites (from oxidation of alprazolam, triazolam): short elimination t1/2, 2-3hrs for triazolam (so more suited as a hypnotic than a sedative; can produce withdrawal symptoms between doses e.g. daytime anxiety)
What classes of drugs can affect metabolism of diazepam, midazolam, and triazolam?
P450 inhibitors/inducers
Seven organ system effects of benzodiazepines
- Sedation
- Hypnosis
- Anaesthesia: at high doses
- Anticonvulsant
- Muscle relaxation
- Respiratory depression
- Cardiovascular depression
What are the sedative effects of benzodiazepines?
Calming effects and reduced anxiety
Dose-dependent anterograde amnesia
May cause behavioural disinhibition
What are the effects of benzodiazepines on the sleep cycle?
Decreased sleep latency
Increased duration of stage 2 non-REM sleep
Decreased duration of stage 3 REM and stage 4 non-REM sleep
Over what time course does tolerance to effects of benzodiazepines on sleep develop?
Use for >1-2 weeks
Which four benzodiazepines are sufficiently selective to be useful in the management of seizures?
Nitrazepam
Clonazepam
Diazepam
Lorazepam
What is the mechanism of muscle relaxant activity of benzodiazepines?
Inhibitory effects on polysynaptic reflexes and internuncial transmission
At high doses may also depress transmission at skeletal NMJ
Describe the respiratory depression seen with benzodiazepine use
Comparable to normal sleep in healthy patients
Can produce more significant respiratory depression in those with pulmonary disease
Death from overdose is usually due to suppression of medullary respiratory centre
Describe the cardiovascular depression seen with benzodiazepine use
No significant effects in healthy patients in doses up to those causing hypnosis
Decreased contractility and vascular tone with high doses (especially IV) or with normal doses in the setting of hypovolaemia or pre-existing cardiovascular disease (e.g. heart failure)
Define tolerance vs physiologic dependence
Tolerance: decreased responsiveness to drug following repeated exposure
Physiologic dependence: altered physiologic state that requires continuous drug administration to prevent abstinence or withdrawal syndrome
Does cross-tolerance occur with sedative-hypnotics?
Yes: partial cross-tolerance seen between sedative-hypnotics and with alcohol
What are the possible mechanisms of sedative-hypnotic tolerance?
Metabolic tolerance: increased rate of metabolism (e.g. with chronic use of barbiturates due to enzyme induction)
Pharmacodynamic tolerance: changes in CNS responsiveness
In case of benzodiazepines, there is down-regulation of brain benzodiazepine receptors
Three features of sedative-hypnotic withdrawal syndrome
- Anxiety
- Insomnia
- CNS excitability (may progress to convulsions)
How does the dependence seen with newer sedative-hypnotics (e.g. zolpidem, zaleplon, eszopiclone) compare with that of benzodiazepines?
Less intense
How does the withdrawal syndrome seen in sedative-hypnotics with long half-lives compare with that of those with short half-lives?
Long half-lives: more gradual withdrawal syndrome
Short half-lives: may get withdrawal symptoms even between doses (e.g. daytime anxiety with use of triazolam for sleep)
Which benzodiazepine has slow oral absorption?
Temazepam
Describe the mechanism of action of barbiturates
Bind to multiple isoforms of GABA(A), but at different binding site to benzodiazepines
Increase duration of channel opening, and at higher doses may directly activate channels
Also have non-GABAergic effects:
- Bind to AMPA receptor to decrease excitatory glutaminergic transmission
- Can exert nonsynaptic membrane effects
Describe the pharmacokinetics of barbiturates
Absorption: most absorbed rapidly following oral administration
Distribution: as for benzodiazepines (enter CNS, cross placenta, found in breast milk)
Metabolism: oxidation by hepatic enzymes with metabolites appearing in urine as glucuronide conjugates, rate of metabolism usually slow (except thiobarbiturates), chronic use results in induction of hepatic microsomal enzymes
Excretion: only minor quantities excreted unchanged in urine with exception of phenobarbital (20-30% unchanged; excretion can be increased with urinary alkalinisation due to phenobarbital’s pKa of 7.4)
Half-life of phenobarbital
4-5 days
What is the difference in organ effects of barbiturates compared with benzodiazepines?
Don’t cause anterograde amnesia
Can be used in seizure management (phenobarbital and metharbital) but not first-line
No muscle relaxant effects
Mechanism of action of newer sedative-hypnotics (e.g. zolpidem, zaleplon, eszopiclone)
Interact only with GABA(A) receptor isoforms containing a1 subunits (more selective than benzodiazepines)
Describe the pharmacokinetics of newer sedative-hypnotics (e.g. zolpidem, zaleplon, eszopiclone)
Absorption: most absorbed rapidly after oral administration
Distribution: as for other sedative-hypnotics (enters CNS, crosses placenta, found in breast milk)
Metabolism: common enzyme involved is CYP3A4 (therefore metabolism of these drugs is influenced by enzyme inducers/inhibitors), elimination t1/2 of zolpidem increased in women and significantly in the elderly
Elimination: in urine
What is the difference in organ effects of newer sedative-hypnotics (e.g. zolpidem, zaleplon, eszopiclone) compared with other sedative-hypnotics?
No muscle relaxant effects
No anticonvulsant effects
Predominantly used for hypnosis over sedation (no REM rebound)
What is the mechanism of action of ramelteon?
Melatonin receptor agonist (no direct GABAergic effects)
What is the advantage of ramelteon over other sedative-hypnotics?
No rebound insomnia or significant withdrawal symptoms
Describe the metabolism of ramelteon
Extensive first-pass metabolism to active metabolite with longer t1/2 than parent drug
CYP1A2 and CYP2C9 involved in metabolism (avoid enzyme inhibitors e.g. fluvoxamine, or inducers)
Five adverse effects of ramelteon
- Avoid in hepatic disease
- Dizziness
- Somnolence
- Fatigue
- Endocrine changes
What is the mechanism of action of buspirone?
Selective anxiolytic effect without sedative, hypnotic or euphoric effects: mechanism of action may be related to partial agonism of 5HT-1A receptors in the brain, but also has affinity for D2 receptors
How long do the anxiolytic effects of buspirone take to be established?
3-4 weeks
What is the advantage of buspirone over other sedative-hypnotics?
Anxiolytic effects only
No rebound anxiety or withdrawal syndrome with abrupt cessation
Describe the pharmacokinetics of buspirone
Rapidly absorbed with extensive first-pass metabolism
Elimination t1/2 2-4hrs (increased with hepatic dysfunction and with P450 inhibitors; inducers decrease t1/2)
Five adverse effects of buspirone
- Non-specific chest pain
- Tachycardia, palpitations
- Paraesthesias
- Dose-dependent pupillary constriction
- Increased BP with MAOI use
Describe the pharmacokinetics of midazolam
Absorption: oral bioavailability 44%, IM bioavailability 80-100%
Distribution: highly lipophilic -> rapidly distributed into CNS
Metabolism: in liver to glucuronides (via active metabolites), higher metabolic clearance (short t1/2)
Excretion: urine (50-70% as metabolites)
Describe the CNS, respiratory, CVS and renal effects of midazolam
CNS effects: hypnosis, sedation, anterograde amnesia, but no studies on anticonvulsant activity
Respiratory effects: decreased TV and RR (little overall change in MV), apnoea in 10-77% when used as induction agent, impairs ventilatory response to hypercapnia
CVS effects: decreases SBP, DBP and TPR
Renal effects: decreases renal blood flow
Five clinical uses of midazolam
- Induction of anaesthesia
- Procedural sedation
- Hypnotic
- Premedication prior to general anaesthesia
- Chronic pain syndromes
What is the mechanism of action of flumazenil?
1,4-benzodiazepine derivative that acts as a competitive antagonist at benzodiazepine binding site on GABA(A) receptors to inhibit the actions of benzodiazepines, zolpidem, zaleplon and eszopiclone
Two clinical uses of flumazenil
- Reverse CNS depression in benzodiazepine overdose (less predictable effect on respiratory depression)
- Hasten recovery following use of benzodiazepines as adjuvant anaesthesia or sedation
Describe the pharmacokinetics of flumazenil
Absorption: well-absorbed orally but significant first-pass metabolism, acts rapidly when given IV
Distribution: widely distributed
Metabolism: rapid hepatic clearance, short t1/2 0.7-1.3hrs, sedation commonly recurs due to longer t1/2 of benzodiazepines (may need repeated dosing)
Elimination: 95% in urine as metabolites
Barbiturates are contraindicated in patients with a past history of what illness?
Porphyria (may precipitate acute porphyria)
List the following benzodiazepines in order of increasing half-life: diazepam, oxazepam, triazolam, clorazepate, lorazepam, alprazolam
Triazolam
Lorazepam
Oxazepam
Alprazolam
Diazepam
Clorazepate
Half-life of diazepam
20-80hrs
Half-life of triazolam
1-2hrs
What are some of the specific indications for alprazolam?
Panic disorder
Agoraphobia
What enzyme metabolises zaleplon?
Aldehyde dehydrogenase
What are the half-lives of the newer sedative-hypnotics?
All relatively short (zaleplon 1-2hrs, zolpidem 1-3hrs, eszopiclone 6hrs)
