Nervous System- Hypontics By Schriefer

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Nervous System- Hypontics by Schriefer

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Nervous System- Hypontics by Schriefer

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Major types of hypnotics

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BZD1 agonists
Melatonin receptor agonist
Benzodiazepines
others

All are CNS depressants, generally alter normal sleep pattern, generally potentiate other CNS depressants, and may have potential for abuse.

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Specific BZD1 agonists:

zolpidem (zol’ pi dem, Ambien),
zaleplon (zal’ e plon, Sonata) and
eszopiclone (Lunesta)

MoA
Pharm effects

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Mechanism – are not benzodiazepines (chemically) but bind to a subtype (BZD1) of the benzodiazepine receptor

Pharmacological effects –activation of the BZD1 receptor results in hypnosis but not anticonvulsant or muscle relaxing effects. Produce minimal rebound insomnia or disruption of deep sleep

type 1: makes you sleepy
type 2: anticonvulsant effects

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zolpidem effects on stages and REM

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induced sleep, in awake.
little change in stages 1-4 and REM

most like natural sleep

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Benzodiazepines effects on stages and REM

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induces sleep from awake
increases length of 1-4 stages
decreases length of REM

not as much like natural sleep

beware of REM rebound insomnia. they'll end up taking more. disturbing normal sleep more than the 'z' drugs

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Zolpidem
Zaleplon
Eszopiclone

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Drug Onset Duration

Zolpidem 30 min 6-8 hours
Zaleplon 20 min 4 hours
Eszopiclone 30 min 8 hours

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Specific BZD1 agonists adverse effects

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Adverse effects:
Headache and drowsiness upon awakening, dizziness, NVD
Memory impairment at higher dose
Bitter aftertaste with eszopiclone
Strange sleep-related behaviors
Severe allergic rxns and angioedema

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Melatonin Receptor Agonist:

Ramelteon

how does it work?
effects on sleep?
adverse effects?
drug interactions?

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Ramelteon (Rozerem) activates MT1 and MT2 receptors. MT1 regulates sleep and MT2 mediates phase shifting on circadian rhythm.

Effects on sleep – decreases sleep latency (desired effect), slight decreases in stage 3 & 4, does not help to stay asleep (duration 2-4 hrs). No tolerance, so ok for chronic use.

help go to sleep, not stay asleep.
Adverse effects: Somnolence, dizzy ,nausea, headache, hyperprolactinemia, NO rebound insomnia!!

Drug interactions – CYP1A2 inhibitors (eg fluvoxamine) increase ramelteon serum levels; they should not be used together.

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Benzodiazepine Hypnotics general characteristics

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General characteristics:
-High therapeutic index when administered alone, even a large overdose is seldom lethal
-Metabolized by microsomal drug metabolizing system but with chronic use, induction of the enzyme system is non-significant
-Should be avoided during pregnancy because of potential teratogenic effects
-Additive effect with alcohol and other CNS depressants
-Physical dependence and withdrawal are slower in onset and less severe than barbiturates
-Do alter normal sleep pattern
-May worsen obstructive sleep apnea
-Avoid in elderly (falls & confusion)

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Flurazepam (flure az’ e pam, Dalmane);
Quazepam (qua’ze pam, Doral)

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Relatively long T ½ - hangover effect
Effective for more than 28 days
Less REM rebound upon withdrawal
Forms active metabolite which may accumulate upon chronic use

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Temazepam

Oxazepam
Lorazepam

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Temazepam (te maz’ e pam, Restoril)
Intermediate duration of action

Oxazepam (ox a’ e pam, Serax) and Lorazepam (lor a’ ze pam, Ativan)
Safer for use in presence of liver dysfunction and in elderly patients

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don't use these:
Triazolam (tri a’ zo lam, Halcion) and Estazolam (es ta zo’ lam, Pro Som)

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-Fast onset, short T ½ (3-4 hours).
-Current controversy over safety. Thought to increase incidence of confusion and abnormal (disinhibited) behaviors; FDA says is safe at .125 - .25 mg. Also problem with early morning insomnia and increased likelihood of rebound insomnia when decreased.
-Potential of drug interaction with estazolam and inhibitors of CYP-3A4 inhibitors (e.g., ketoconazole).

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Barbiturates:

Qualitatively, all hypnotic barbiturates possess the same activity and differ only in onset and duration of action.

2nd or 3rd line

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Pentobarb (Nembutal)Secobarb (Secoal): short acting, to fall asleep

Amobarb (Amytal): intermediate acting, to stay asleep

Phenobarbital: long acting, daytime sedation, not drug of choice

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Barbiturates: MoA

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Enhance GABA effects. Barbiturates act at a site thought to be a GABA receptor-modulated ionophore.

at high doses they open the channel on their own, which allows them to cause more depression.

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Barbiturates pharm actions.

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CNS:
Hypnosis
-Hangover effect: more intense with long acting agents
-Paradoxical excitement – disinhibition
-↓ REM phase, ↑ duration of stage 2 NREM phase → REM rebound
Hyperalgesia
Anesthesia
Anticonvulsant: selective action unrelated to sedative effects

Respiration:
At anesthetic or toxic dose: respiratory depression at medullary respiratory center

Cardiovascular system:
At therapeutic dose: Slight ↓ BP, HR
At toxic dose: vasomotor depression may cause congestive heart failure, hypovolemic shock, and cardiac arrest

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Barbiturates and the liver.

what can barbiturates precipitate?

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Initial competitive inhibition of metabolism of drugs. Chronic administration may result in enzyme induction

Induction of other enzyme systems may precipitate acute intermittent porphyria

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acute overdose of barbs

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Acute overdose:
Symptoms – coma, decreased respiration, hypothermia, hypotension, pulmonary edema, renal or cardiovascular failure
Treatment – symptomatic support, gastric lavage, dialysis, pH alteration
Lethal dose for addicts not much greater than normal individuals

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tx of barbs

Clinical applications

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Treatment:
Slow withdrawal (10 days to 3 weeks)
Substitute with phenobarbital and gradually taper off
IV diazepam to manage status epilepticus

Clinical applications
As a sedative during illness in children
Anticonvulsant – phenobarbital
Induction anesthetic – thiopental

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Chloral Hydrate (Noctec, Somnos)

major side effects, and what doesn't it give you

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Metabolized by alcohol dehydrogenase to trichloroethanol which is the active form

Major side effects – GI irritation, disagreeable taste, but causes lesser hangover effect, REM suppression than barbiturates, and lacks marked respiratory and cardiovascular depression

Safe for use in children and elderly patients in whom BZDs or barbiturates can induce excitation

Knock-out drops or “Mickey Finn” – enhanced toxic effects when combined with ethanol

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Sodium oxybate is what. stimulates which receptors. what is it used to treat?

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Also known as gamma hydroxybutyrate (GHB). GHB is a breakdown product of GABA and functions as an endogenous neuromodulator with effects on vigilance and other behaviors.

It appears to stimulate GABAB and specific GHB receptors.

DATE RAPE DRUGFGFGG

Recently approved to treat cataplexy associated with narcolepsy. Thought to improve quality of nighttime sleep and thus decrease daytime sleepiness and cataplexy. May also help sleep problems associated with fibromyalgia.

Since GHB is a drug of abuse, there are strict regulations governing prescribing. Adverse effects include sleepwalking, incontinence, and respiratory depression and amnesia (esp. with alcohol).

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Trazodine

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Atypical antidepressant with pronounced sedative properties.

often used more as a sleep drug than antidepressant

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Over-The-Counter sleep aids

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Over-The-Counter sleep aids:

Antihistamines with weak sedative effects

Melatonin – natural hormone – chemically related to 5HT. Shows promise in treatment of jet lag and sleep disturbances. May help wean patients off benzodiazepine hypnotics. Controlled, clinical trials lacking.

Valerian – an herbal product possibly effective in producing sleep

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Practical aspects of treatment of insomnia

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-Explore patterns of insomnia and possible causes and treat accordingly. When appropriate, suggest measures such as backrub, warm drink, pleasant and quiet atmosphere instead of drugs to promote relaxation and sleep. Educate patient in ways to improve sleep habits and sleep environment
-Warn the patient about driving, operating machinery, or engaging in potentially hazardous activities when taking drugs
-Caution the patient that alcohol, barbiturates, non-barbiturate sedative-hypnotics, and other CNS depressants have additive depressing effects and should not be taken in combination without specific instructions from the physician.
-Administering barbiturates (especially by injection) to children or elderly patients may cause excitement and confusion
-Drugs do not possess analgesic activity and some may produce restlessness and increased sensitivity when given to patients in pain.
-Benzodiazepines should be avoided during early pregnancy because there is reason to suspect that this group of drugs are teratogenic
Patients with persistent insomnia often can benefit from sleep clinics, where specialists try to find and treat the underlying reason for their difficulties. Sometimes the patient’s insomnia stems primarily from psychologic factors such as negative conditioning, which can usually be overcome by reconditioning therapy.