CNS II: Sedative-hypnotic drugs Flashcards
What is a sedative? What is a hypnotic?
Sedative: Anxiolytic drug that reduces a person’s response to external stimuli, ie reduces anxiety and has calming effects with minimal depression of motor or mental functions.
Hypnotic: drowsiness and sleep like state
All anxiolytic drugs also cause sedation, therefore same drug is often used as both anti-anxiolytic (at a low dose) and hypnotic (at a high dose)
What are the three classes of sedative-hypnotics?
- Benzodiazepines (modern)
- Barbiturates (20th century)
- Sedative-autonomics (beta blockers, clonidine, TCAs, antipsychotics)
What is clonidine?
It is a sedative-hypnotic that can be used to treat hypotension and post menopausal symptoms like hot flashes in women.
It is a α2 adrenoreceptor agonist
Compare the dose response curve for barbiturates and benzodiazepines. Which is more dangerous.
The EC50 is about the same for both at sedation.
- Benzodiazepine stops giving effects after hypnosis and anesthesia
- Barbiturates will give effects into coma, linear dose response curve.
Because of this, benzodiazepines are much safer because their effect plateaus before respiratory depression. The lethal dose of benzodiazepines (such as diazepam) is over 1000 times greater than the typical therapeutic dose.
Describe the pharmacokinetics of benzodiazepines.
- Rapid onset because of lipid solubility and absorption in GI
- Rate at which BZ crosses BBB is dependent on protein binding, lipid solubility and ionization constant. Most cross easily (also cross placental barrier! Pregnant women shouldn’t take)
The half lifes of BZs are very important as duration of action determines use
Describe the metabolism and elimination of benzodiazepines
- Metabolized by hepatic (liver) microsomes to active compounds
- Apparent half life represents parent drug AND metabolites
Benzodiazepines are excreted in urine as glucuronides or oxidized metabolites (conjugated compounds need to be changed before excretion)
Why does triazolam (sedative-hypnotic/roofie) have short term action at a low dose?
Quickly creates lots of alpha-hydroxy metabolites that are quickly conjugated and excreted
With its short half-life, traizolam gives early morning insomnia, day time anxiety, amnesia and confusion.
This is no good for anxiolytic effect (obviously), which is better suited for drugs with low dose over longer periods.
Describe the metabolism of diazepam (valium)
- Diazepam
- Desmethyldiazepam
- oxazepam
- Conjugation and urinary excretion
The half life of any sedative-hypnotic is dictated by number of metabolites and activity of metabolites. Longer acting agents form active metabolites with long half lives.
Eg.
- Long acting (diazepam, chlordiazepoxide, flurazepam)
- Intermediate (alprazolam, lorazepam, temazepam)
- Short acting (oxazepam, triazolam)
Why should benzodiazepines NOT be mixed with other CNS depressants (eg. opioids, alcohol, benzodiazepine, barbiturates).
Why should they not be mixed with cigarettes?
SSRIs?
These all act at GABA receptor and there is cross tolerance (additive effects).
Can cause greater dependence (psychological seeking) and phsyiological of withdrawal symptoms
Dependence and tolerance is seen in all sedative-hypnotics, making them susceptible to abuse.
Smoking induces P450 2C enzyme, which metabolizes BZ, therefore smokers need larger doses of the drug.
SSRIs increase diazepam levels by altering clearance.
What are the two main adverse reactions to benzodiazepines?
- Drowsiness and confusion, ataxia (motor problems) and cognitive impairment at higher doses
- Withdrawal after abrupt discontinuation (confusion, anxiety, agitation, restlessness, insomnia and tension). Onset of withdrawal relates to half life of BZ (usually see withdrawal the most with short acting BZs).
Contrast desensitization and tachyphylaxis.
Desensitization: cellular action that underlies tolerance.
Tachyphylaxis: the effect on an organismal level
Describe the mech of action of benzodiazepines.
Positive allosteric modulators
There is enhanced Cl current when BZs bind due to more frequent channel openings (only when GABA is bound as well!).
BZ decrease EC50 for GABA induced Cl influx (response curve shifted to left)
List 5 therapeutic uses for benzodiazepines
- Anxiety
- Muscular disorders (eg. spasticity)
- Seizures (diazepam for epilepsy)
- Acute treatment of alcohol withdrawal
- Sleep disorders (BZ with short duration of action)
What are concerns with elderly and benzodiazepines? When is the only time the elderly are given BZs?
- Increased risk of dependence
- Sleep disorders from BZ comorbid with other age related disorders
- Increased sensitivity to adverse effects (daytime sedation, falls)
- Progressive worsening effects may resemble dementia, depression or anxiety syndromes
BZ given to elderly for anesthesia.
What is the only modern purpose for barbiturates?
Surgery anesthesia and some seizure disorders
Pentobarbital and phenobarbital
What do most adverse ‘side’ effects from barbiturates stem from?
The fact that they are potent inducers due to interaction with drug metabolizing enzymes
They are metabolized in the liver to inactive metabolites that are excreted in urine.
What is the mech of action of barbiturates?
Positive allosteric modulators, keep chloride channels open for longer when they are bound with GABA
Give four properties of barbiturates
- CNS depressant
- CNS depression is additive with alcohol and opiods
- No significant analgesic effect even at doses that produce general anesthesia (benzodiazepines do produce analgesia)
- Anti convulsive effects
What are three therapeutic uses of barbiturates?
- Anesthesia
- Anticonvulsant (phenobarbital used in long term management of tonic-clonic seizures, status epilepticus and eclampsia. Drug of choice in young chidren for febrile seizures.
- Anxiety
What is buspirone?
A anxiolytic agent that causes little sedation and has no anti-convulsant or muscle-relaxant properties.
Mechanism of action mediated by 5-HT1A receptors. Affinity for DA2 receptors shows.
Slow onset of action is a disadvantage.
What is zopidem?
An imidazopyridine derivative, unrelated to benzodiazepines, it has hypnotic actions.
It binds directly to GABAa receptor, close to where GABA binds.
Used for short-term treatment of insomnia.
What is Mother’s Little Helper?
Diazepam (valium)
