Lectures 2-3: Sedative-Hypnotics, Anxiolytics, Muscle Relaxants

Phenobarbital and Overdose Treatment

Barbiturates

Increase duration of GABA action- channel stays open longer

Independent effect on Cl- influx

General CNS depressant

Low margin of safety

Overdose can cause death

Physical/psychological dependence

Dangerous with alcohol

W/ increasing drug concentration: Disinhibition → Sedation → Sleep → General Anesthesia → Coma → Death

Induce CYP450 enzymes → Anticonvulsant

Respiratory depression

Supportive care, diuresis, alkalinize urine

Contraindicated in porphyria

Contraindicated in pulmonary insufficiency

Severe withdrawal- life threatening

CYP450 inhibitors

Erythromycin, clarithromycin

Ritonavir, saquinavir

Ketoconazole, itraconazole

Cimetidine, grapefruit juice

Quinidine, quinine

Zafirlukast, zileuton

Buspirone

Valproic acid

Phenytoin

Fluoxetine, Paroxetine, Duloxetine

CYP450 Inducers

Rifampin (rifampicin)

St John’s Wort

Phenobarbital

Carbamazepine

Ethanol

Smoking

Benzodiazepines Drugs

Diazepam

Chlordiazepoxide

Alprazolam

Lorazepam

Oxazepam

Clonazepam

Midazolam

Triazolam

Benzodiazepines

anxiolytic- immediate, effective

sedative-hypnotic, anticonvulsant

Allosteric activator at GABAA receptor- intensify action of GABA (increase frequency of channel opening)

Act only when GABA present

At higher doses, GABA release is inhibited

Ceiling to the effect

very safe, even in overdose

Metabolized in the liver by CYP3A

Drugs with shorter half lives/reduced dose in elderly people

Dangerous with alcohol

Benzodiazepines Uses

Insomnia

Epilepsy / seizures

Sedation/ amnesia/ anesthesia

Muscle relaxation

Alcohol/ barbiturate withdrawal

Drug of choice for most types of anxiety

Exceptions: Use antidepressants

OCD and PTSD

Agoraphobia/panic attacks

Children/adolescents

Triazolam

Insomnia

less interference with REM sleep than barbiturates

all asleep, less “hangover”

rebound insomnia

Benzodiazepines for Epilepsy and seizures

clonazepam, diazepam, and lorazepam

Benzodiazepines for Sedation and anesthesia

midazolam: amnesia and sedation

Benzodiazepines for Muscle Relaxation

diazepam

Benzodiazepines for Alcohol withdrawal

alcohol also works at GABAA receptor

prevent DTs, seizures

chlordiazepoxide, diazepam, lorazepam

Benzodiazepines side effects and contraindications

Drowsiness, sedation → Tolerance generally develops

Sedation and confusion in elderly

Memory impairment in elderly and children

Respiratory depression- problem with sleep apnea

May cause birth defects

Withdrawal → anxiety and insomnia

Severe withdrawal → seizures, agitation

Overdose of BZ alone usually causes sleep- serious with EtOH

Contraindications: Pregnancy, Children, Sleep apnea, Alcohol

Caution in recovering alcoholics/addicts

Flumazenil

Benzodiazepine antagonist

Reverses effect of benzodiazepines, zolpidem, zaleplon, eszopiclone

Injected

Withdrawal/seizures possible in BZ, barbiturate, EtOH dependent patients, epilepsy, TCA overdose

Zolpidem, Zaleplon

Bind to BZ1 on GABAA receptor

VERY rapid action; “blackouts”

Little effect on REM sleep

Very short half lives/duration of action → Daytime effects low

Not recommended in elderly due to fall risk

metabolized in liver (CYP3A4)

GI upset, diarrhea

Drowsiness, dizziness, “blackouts”

Confusion, memory loss in elderly

Additive CNS depression with other drugs

Sleep-walking, -driving, -eating

Eszopiclone

Not as selective for BZ1 subtype

Longer half life (6 hrs), but overall, effects are similar to the others

Treatment of insomnia

Rebound insomnia or withdrawal (agitation, psychosis) if stop abruptly after chronic use

metabolized in liver (CYP3A4)

Ramelteon

Melatonin analogue binds to MT1/MT2 receptors

Resets sleep-wake cycle and promotes sleepiness

No effect on REM sleep

No addiction potential

Short t1/2 - no daytime sleepiness

Metabolized in liver by CYP1A2 or CYP2C9

Avoid in severe liver disease due to poor metabolism

Chronic use may increase prolactin, decrease testosterone, + cause adrenocortical insufficiency

Contraindicated in severe sleep apnea

Not recommended in pregnancy

Tasimelteon

Non-24-hour sleep disorder

Cause nightmares and headache, increase liver enzymes

Metabolized in liver by CYP1A2 or CYP2C9

Suvorexant, Lemborexant, Daridoexant

Orexin antagonists

Orexin neurons promote wakefulness

Metabolized by CYP3A-

Side effects: sleep paralysis, weakness, hallucinations, worsens depression

Patients with deficits in orexin often have narcolepsy

Contraindicated in narcolepsy

diphenhydramine/hydroxyzine

sedatives

Block H1 receptor

OK for occasional use- tolerance develops quickly

Pregabalin

Binds to Ca channels

Reduces neuronal hyperexcitability

Decreases transmitter release

Sedating

Fibromyalgia, restless legs, neuropathic pain

Drowsiness, dizziness, ataxia

Buspirone

partial agonist at postsynaptic 5-HT1A receptor

minor antidepressant effect through increased NE, DA

relieves anxiety

no sedation

effect takes 2-3 weeks

Used for anxiety, PMS, autism, recovering addicts/alcoholics

does not impair memory

will not prevent withdrawal from benzodiazepines or alcohol

low addiction potential

Dizziness/headache, restlessness, hypertension with MAOIs

Buspirone Drug Interactions

Monoamine oxidase inhibitors → hypertension

SSRIs → serotonin syndrome

CNS depressants → sedation

Inhibitors of CYP450

Baclofen

agonist at GABAB receptors

Inhibits cAMP formation

decreases release of excitatory transmitters in brain & spinal cord

decreases spasticity

reduces pain by inhibiting Substance P release

less sedating than diazepam

intrathecal administration may reduce peripheral side effects + increase effectiveness of treatment → respiratory depression

Side Effects: drowsiness, weakness, increased seizure activity

Diazepam

α1 - sedative effect + anticonvulsant

α2 - anxiolytic

α2 /α3 /α5 - muscle relaxant

facilitates GABA-mediated presynaptic inhibition in the spinal cord through stimulation of GABA A receptors

sedating if dose sufficient to relax muscles

useful for local muscle trauma

adjunct in chronic spasticity

Tizanidine

α2 receptor agonist

produces spinal cord pre + post synaptic inhibition to decrease muscle spasticity

inhibits pain transmission in dorsal horn

doesn’t cause too much muscle weakness

used for chronic and acute muscle spasms

Side Effects:

sedation, some hypotension

dry mouth, weakness, falls in elderly

Cyclobenzaprine; carisoprodol; chlorzoxazone; metaxalone; methocarbamol; Orphenadrine

Sedatives at brain stem

Used for acute muscle spasms

Not very effective

Cyclobenzaprine blocks muscarinic receptors:

Sedation, confusion common

Hallucinations

Carisoprodol

Decreases neuronal activity, reticular formation, spinal cord

Alter perception of pain

Rapidly metabolized to meprobamate, which is similar in action to barbiturates

Chronic use induces hepatic enzymes

Not very effective as muscle relaxant

Has been a drug of abuse

Caution in recovering addicts / alcoholics

OnabotuliniumtoxinA

Inhibits ACh release from nerve → degrades synaptic fusion proteins needed for release

Control muscle spasms following stroke or neurological injury, strabismus in the eye

Aberrant nerve regeneration or spread of toxin to unwanted areas

Drugs metabolized by CYP450

Benzodiazepines

Zolpidem

Zaleplon

Eszopiclone

Ramelteon

Tasimelteon

Suvorexant, Lemborexant, Daridoexant

Buspirone