CNS DEPRESSANTSSEDATIVE-HYPNOTIC DRUGS

Dr. Hiwa K. Saaed, BSc, HD, MSc. PhDDepartment of Pharmacology & Toxicology

College of Pharmacy/ University of Sulaimani

2014-2015

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ANXIETY

• Unlike other mental disorders, anxiety can be both:– a normal emotion – and a psychiatric illness.

• It is a universal human emotion, and a certain amount is useful to the individual, acting as a stimulant and increasing efficiency.

• but when it becomes excessive and disproportionate to the situation, an anxiety state develops; it becomes a pathological (disabling) and needs treatment.

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ANXIETY DISORDERSIt usually involves both: • Mental features

– worry, fear, difficulty concentration, sleep problems.

• Physical symptoms – Tachycardia; muscle aches, nausea, shortness of

breath, trembling, pacing

ANXIETY CLASSIFICATION

#Primary• Generalized anxiety disorder (GAD): apprehensive and

tense for no particular reason.• Panic disorder: unexpected attacks of anxiety.• Phobic disorders: fears certain situation “agoraphobia”• Obsessive compulsive disorder: repetitive, anxiety

driven behavior or obsessive thoughts and doubts (check things more than once)

• Post-traumatic stress disorder (rape or warefare)

#Secondary due to medical causes or substances

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SEDATIVE-HYPNOTIC DRUGSThe sedative-hypnotics belong to a

chemically heterogeneous class of drug.

The most important are:• Benzodiazepines (BZs), Diazepam, • Non benzodiazepines:

buspirone, zolpidem, and Zaleplon• Barbiturates: phenobarbital, • Miscellaneous: carbamates, alcohol

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SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultrashort

acting acting

Intermediate Short Buspirone

acting acting Chloral hydrate

Long Long Zaleplon

acting acting Zolpidem

Ramelteon

Tasimelteon

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THE EFFECTS OF CNS DEPRESSANTS

– Sedatives cause mild depression and relaxation• Anxiolytic—drugs that relieve anxietySite of action is on the limbic system which regulates thought and mental function.

– Hypnotics induce drowsiness and encourage sleep• Amnesiac effects can cause the loss of

memorySite of action is on the midbrain and ascending RAS which maintain wakefulness.

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THE EFFECTS OF CNS DEPRESSANTS (continued)

• The same drug can cause different effects based on dose.– Low dose (sedatives—relieve anxiety and promote

relaxation)– Higher doses (hypnotics—can cause drowsiness

and promote sleep)– Even higher doses (anesthetics—can cause

anesthesia and are used for patient management during surgery)

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DOSE-DEPENDENT DEPRESSION OF CNS

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• Most S-H drugs facilitate the actions of GABA, a major inhibitory transmitter in the CNS,

• GABAA receptor activation leads to increased Cl- ion influx;

• GABAB receptor activation causes increased efflux of K+.

• Both mechanisms result in membrane hyperpolarization.

SEDATIVE HYPNOTICMECHANISMS OF ACTION

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GABAA RECEPTOR The pentapeptide structure of the GABAA receptor has binding sites for BZs and for other drugs, including Barbiturates and ethanol.

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BENZODIZEPINES

Sedative (Anxiolytics) : Alprazolam Chlordiazepoxide oxazepam Diazepam lorazepam

Hypnotics : Triazolam Diazepam Alprazolam

Lorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam Preanesthetics :  Diazepam - Midazolam Leo sternback

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DURATION OF ACTION OF BZS

• Short acting (2-8 hrs)midazolam triazolam

• Intermediate (10-20 hrs) temazepam, lorazepam, alprazolam, oxazepam, nitrazepam, estrazolam

• Long acting (1-3 days): chlordiazepoxide, diazepam, flurazepam, clonazepam, chlorazepate

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BENZODIAZEPINEMECHANISMS OF ACTION Affect neurons that have receptors for the neurotransmitter GABABZs potentiate GABA → increase frequency of Cl- ion channel opening→ causes hyperpolarization→ raise firing threshold→ and thus inhibits the formation of action potentials inhibitory effect on different sites of the brain especially motor cortex, and limbic system.

GABA—inhibitory transmitter in brain regions– Limbic system (alter mood)– RAS (cause drowsiness)– Motor cortex (relax muscles)

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PHARMACOKINETICS

Most of them are well absorbed orally.

Bzs are lipid soluble and widely distributed

Redistribution from CNS to skeletal muscles, adipose tissue.

Cross placental barrier during pregnancy and are excreted

in milk (Fetal & neonatal depression).

Highly bound to plasma protein.

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PHARMACOKINETICS

 All Bzs are metabolized in the liver

Phase I: ( liver microsomal system)

Phase II: glucouronide conjugation and excreted in the urine. Many of Phase I metabolites are active: Increase

elimination half life of the parent compound , cumulative effect with multiple doses.

EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam.

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METABOLISM

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BZs have neither antipsychotic activity nor analgesic. They don’t affect ANS

Reduction of anxiety at low dose: alprazolam, lorazepam, oxazepam, diazepam and chlordiazepoxide.

Alprazolam has anxiolytic-antidepressant effect. Diazepam is preferred in acute panic-anxiety. Chlordiazepoxide is preferred in chronic anxiety states.

Sedative and hypnotic actions at higher dose:

not all, three most commonly prescribed BZs are:– long acting flurazepam, – intermediate temazepam – short acting triazolam.

and Two non BZs: – Zolpidem & Zaleplon.

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ACTIONS AND THERAPEUTIC DOSES:

• Anterograde amnesia: short acting BZs used in premedication for endoscopic, bronchoscopic, angioplasty.

In anesthesia :

Preanesthetic medication diazepam

Induction of balanced anesthesia (Midazolam)

• Anticonvulsant: Treatment of epilepsyDiazepam – Lorazepam: Status epilepticus

Clonazepam-Clorazepate: absence , myoclonic seizures.

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ACTIONS AND THERAPEUTIC DOSES:

• To control Alcohol withdrawal symptoms:

chlordiazepoxide, chlorazepate, diazepam & oxazepam• Muscle relaxant at higher doses; diazepam is

useful in the Rx of skeletal muscle spasm• Other actions: in higher doses BZs decrease BP

and increase HR. diazepam decreases nocturnal gastric acid secretion

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ACTIONS AND THERAPEUTIC DOSES:

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INDICATIONS AND DRUG CHARACTERISTICS

• Tolerance: reduction in drug effect requiring an increase in dosage to maintain the same response.

• Chronic use leads to tolerance (cross with other S-H drugs), possibly via downregulation of BZ receptors.

• The antianxiety effects of the BZ are less subject to tolerance than sedative and hypnotic effects.

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TOLERANCETOLERANCE

DEPENDENCE• Physiological dependence: removal of the

drug evokes unpleasant symptoms, usually the opposite of the drugs effects

• Psychological dependence: the drug taker feels compelled to use the drug & suffers anxiety when separated from drug.

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WITHDRAWAL SYMPTOMSAbrupt discontinuation, particularly if high doses

used for prolong period.

1. Confusion,

2. anxiety,

3. agitation,

4. restlessness,

5. insomnia

6. tension

WD symptoms with BZs are less intense than with ethanol or barbiturates;

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ADVERSE EFFECTS OF BZS

• Drowsiness and confusion• Ataxia at high doses-precludes activities

like driving• Cognitive impairment:

↓long term recall,

↓acquisition of knowledge

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FLUMAZENIL BZS ANTAGONIST

Flumazenil: I.V only, reverses the effect of the BZs (competitive antagonist), onset is rapid, and duration is short.

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MISCELLANEOUS; NON BENZODIAZEPINES

Zolpidem and Zaleplon they:• act on BZ1 (a subtype of BZ receptor family),

• are more selective hypnotics• are not effective in chronic anxiety, seizure

disorders, or muscle relaxing.• Possibly less tolerance occur with prolong use • and lower abuse liability and dependence than

BZs. • they show no withdrawal effects, Minimal

rebound insomnia

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ZOLPIDEM AND ZALEPLON

• Rapidly absorbed, rapid onset with short duration (2-3 hrs)

• Zaleplon is very similar to zolpidem in its hypnotic action,

• but ZALEPLON causes fewer residual effect on pseudomotor and cognitive function compared with zolpidem or the BZs due to short t1/2 < 1hr

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BUSPIRONE

totally different anxiolytic from BZs, no effects on GABA systems, possible partial agonist at 5-HT1A receptors some affinity for D2 & 5-HT2A.

Indication:• Indicated for generalized anxiety disorders but

takes 1 to 2 weeks to exert anxiolytic effects.

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Buspirone lucks anticonvulsant and Muscle relaxant property of BZs and cause minimal sedation. • No additive CNS depression with other drugs.

Adverse effects:hypothermia, increase prolactin, headache, dizziness, nervousness

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BUSPIRONE

BARBITURATES

• Formerly used as sedative hypnotic replaced by BZs, because barbiturates induce:

1. tolerance,

2. drug metabolizing enzyme,

3. physical dependence

4. and very severe withdrawal symptom.

5. Flumazenil does not block the effects of barbiturates.

Bayere dicoverer of barbiturates.

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• interact with GABA receptors, the binding site is distinct from that of the BZs.

• potentiate GABA action on Cl- entry into the neuron by increase the duration of Cl- ion channel opening.

• In addition, barbiturates can block excitatory glutamate receptor (sub anesthetic dose).

• at high doses (anesthetics conc. of pentobarbital-reticular

activating system inhibition), also– open Cl- ion channels directly – and block high frequency Na+ channels).

BARBITURATES MECHANISM OF ACTION

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Duration of Action of Barbiturates

• Long acting (1-2 days) Anticonvulsant

Phenobarbital; • Short (3-8hrs) Sedative & Hypnotic Pentobarbital, secobarbital and amobarbital:• Ultrashort (20 min) I.V induction

of anesthesiaThiopental

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ADVERSE EFFECTS OF BARBITURATES

• Dose-dependent CNS depression, with nystagmus and ataxia progressing to respiratory depression, coma, and possible mortality.

• no specific antidote in overdose. • Additive CNS depression with other drugs.

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PHARMACOKINETICS

All barbiturates are weak acids, lipid soluble, absorbed

orally. distribute throughout the body

Thiopentone is highly lipid soluble (high rate of entry into

CNS- quick onset of action). Redistribute in the body from the brain to skeletal muscles-

adipose tissues. metabolized in the liver to inactive metabolites Excreted in the urine. Alkalinization increases excretion (NaHCO3) Cross the placenta ( pregnancy).04/18/2023 36

METABOLISM

• Hepatic metabolism (some to active metabolite). • Induction of Cytochrome P450 is characteristic and may

lead to drug interactions. • Because of increase heme synthesis, they are

contraindicated in porphyrias • Porphyrias: a hereditary disorder of hemoglobin

metabolism causing:

-mental disturbance,

-extreme sensitivity to light

-and excretion of dark pigments in the urine.

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WHY BENZODIZEPINES HAS REPLACED BARBITURATES?

BZS BARBITURATES They do not produce anesthesia in

high doses & patient can be aroused. These are not enzyme inducers, Very low abuse liability. Lesser distortion of normal

hypnogram. Bzs have no hyperalgesia. Bzs can be used as day time

anxiolytic. Do not effect respiratory or cvs

function. There is a specific antagonist-

Flumazenil.

Produce loss of consciousness and have low margin of safety

enzyme inducers. High abuse liability. Marked suppression of REM sleep. Hyperalgesic action. Unacceptable drowsiness is seen.

Causes respiratory and depression & hypotension.

No specific antagonist.

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MISCELLANEOUS • Antihistamines:

it has low tendency for habituation and thus is useful for patients wit anxiety who have a history of drug abuse. – hydroxyzine, – diphenhydramine – doxylamine;

• Melatonin: synthesized from 5HT, significant role in diurnal cycles and sleep-wake behavior.

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MISCELLANEOUS

• Ramelteon: melatonin receptor (MT1 and MT2) agonist with sleep promoting activities. – It has been approved for chronic insomnia and

considered free from dependence potential.

• Tasimelteon• PROPRANOLOL has efficacy in performance anxiety

and social phobias.• Tricyclicantidepressants (TCA) and SSRI• Opiod analgesics• Ethanol

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SOME OUTDATED HYPNOTICS:

• Chloral hydrate: – is a trichlorinated derivative of acetaldehyde that is

converted to the active metabolite, trichloroethanol in the body.

• Paraldehyde: – little effect on respiration and BP in therapeutic dose. – Large doses suppress all type of convulsions with

rapid onset of action. – It has strong aromatic odor and unpleasant taste.

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Thank you

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