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CNS DEPRESSANTSSEDATIVE-HYPNOTIC

DRUGSDr. Hiwa K. Saaed, BSc, HD, MSc, PhD

Department of Pharmacology & ToxicologyCollege of Pharmacy/ University of Sulaimani

2018-19

ANXIETY

Mental features:• worry, • fear, • difficulty concentration, • sleep problems.

Physical symptoms:are similar to those of fear (sympathetic activation)

• Tachycardia; • sweating, • muscle aches, • nausea, • shortness of breath, • trembling, • and palpitations.

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Anxiety the most common mental disorders, is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). It usually involves both: Mental & Physical Symptoms

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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 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 warfare)

Secondary due tomedical causes or substances

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SEDATIVE-HYPNOTIC DRUGS

a chemically heterogeneous class of drug.The most important are:

Benzodiazepines (BZs),

Barbiturates: phenobarbital,

Other hypnotics: – Non benzodiazepines: zolpidem, Zaleplon and Eszopiclone– Antihistamines: diphenhydramine, hydroxyzine, and doxylamine– antidepressants: Doxepin – Melatonin agonist: Ramelteon

Other Anxiolytics: – Buspirone, – antidepressants: SSRIs, such as escitalopram or paroxetine– or serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine

or duloxetine)

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(BZs) Alprazolam, Chlordiazepoxide, Clonazepam Clorazepate, Diazepam, Estazolam, Flurazepam, Lorazepam, Midazolam, Oxazepam, Quazepam, Temazepam Triazolam

THE EFFECTS OF CNS DEPRESSANTS

Sedatives cause mild depression and relaxationAnxiolytic—drugs that relieve anxiety, Site of action is on the limbic system which regulates thought and mental function.

Hypnotics induce drowsiness and encourage sleepAmnesiac effects can cause the loss of memorySite of action is on the midbrain and ascending RAS which maintain wakefulness.

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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BENZODIZEPINES

• Benzodiazepines are widely used anxiolytic drugs. • They have largely replaced barbiturates and meprobamate

in the treatment of anxiety and insomnia, because benzodiazepines are generally considered to be safer and more effective.

• Selective serotonin reuptake inhibitors (SSRI), are preferred in in many cases

• Nonbenzodiazepine hypnotics and antihistamines may be preferable for insomnia.

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BENZODIAZEPINEMECHANISMS OF ACTION

The GABAA receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic membrane. For each subunit, many subtypes exist (for example, there are six subtypes of the α subunit). 10/25/18 9

The targets for benzodiazepine actions are the GABAA receptors. GABA is the major inhibitory neurotransmitter in the CNS.

BENZODIAZEPINEMECHANISMS OF ACTION

• Benzodiazepines modulate GABA effects by binding to a

specific, high-affinity site (distinct from the GABA-binding site)

located at the interface of the α subunit and the γ subunit on

the GABAA receptor

• Common BZ receptor subtypes in the CNS are designated as

BZ1 or BZ2 depending on whether the binding site includes an

α1 or α2 subunit, respectively.

• Benzodiazepines increase the frequency of channel openings

produced by GABA.

• Binding of a benzodiazepine to its receptor site increases the

affinity of GABA for the GABA-binding site (and vice versa).

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BENZODIAZEPINEMECHANISMS OF ACTION

BZs 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.

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BZ ReceptorBZ1 receptors: mainly in the cerebellum and are related to anxiety and sedation. BZ2 receptors: mainly in the basal ganglia and hippocampus and are associated with muscle relaxation, as well as memory and learning. This helps explain; why some are superior as anxiolytics and some as hypnotics. For example, midazolam strongly acts on the BZ2 receptors, causing amnesia. Other receptors in this complex are associated with seizure activity. This explains the use of some of the benzodiazepines in epilepsy and in other convulsive conditions.

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ACTIONS

All benzodiazepines exhibit the following actions to some

extent:

1. Reduction of anxiety: At low doses, the benzodiazepines

are anxiolytic, by selectively enhancing GABAergic

transmission in neurons having the α2 subunit in their

GABAA receptors, in the limbic system of the brain.

2. Sedative/hypnotic: All benzodiazepines have sedative

and calming properties, and some can produce hypnosis

(artificially produced sleep) at higher doses. The

hypnotic effects are mediated by the α1-GABAA

receptors.

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ACTIONS

3. Anterograde amnesia: Temporary impairment of memory with use of the benzodiazepines is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired.

4. Anticonvulsant: This effect is partially, although not completely, mediated by α1-GABAA receptors.

5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located.

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THERAPEUTIC USES1. Anxiety disorders:

– anxiety symptoms secondary to panic disorder, alprazolam

– generalized anxiety disorder (GAD),

– social anxiety disorder, performance anxiety,

– posttraumatic stress disorder (PTSD),

– obsessive–compulsive disorder (OCD),

– anxiety related to depression and schizophrenia,

– and extreme anxiety associated with phobias, such as fear of flying.

The longer-acting agents, such as clonazepam, lorazepam, and diazepam, are

often preferred in those patients with anxiety that may require prolonged

treatment.

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THERAPEUTIC USES

2. Sleep disorders: A few of the benzodiazepines are useful as hypnotic agents. Commonly prescribed benzodiazepines for sleep disorders include:

• intermediate-acting temazepam• short-acting triazolam. • Long-acting flurazepam: is rarely used, due to its extended half-life,

which may result in excessive daytime sedation and accumulation of the drug, especially in the elderly.

Estazolam (intermediate) and quazepam (long-acting agents). In the treatment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon awakening.

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THERAPEUTIC USES

a. Temazepam: This drug is useful in patients who experience frequent wakening. However, because the peak sedative effect occurs 1 to 3 hours after an oral dose, it should be given 1 to 2 hours before bedtime.

b. Triazolam: • is effective in treating individuals who have difficulty in going to sleep. • Tolerance frequently develops within a few days, and withdrawal of the

drug often results in rebound insomnia. • Therefore, this drug is not a preferred agent, and it is best used

intermittently. In general, hypnotics should be given for only a limited time, usually less than 2 to 4 weeks.

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THERAPEUTIC USES

3. Amnesia: – The shorter-acting agents are often employed as premedication for

anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty.

– They cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures.

– Midazolam is a benzodiazepine used to facilitate amnesia while causing sedation prior to anesthesia.

4. Seizures: – Clonazepam is occasionally used as an adjunctive therapy for certain

types of seizures, – whereas lorazepam and diazepam are the drugs of choice in

terminating status epilepticus.

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THERAPEUTIC USES

3. alcohol withdrawal-related seizures: Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are useful in the acute treatment.

4. Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.

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PHARMACOKINETICS

Ø Most of them are well absorbed orally.Ø Bzs are lipid soluble and widely distributedØ Redistribution from CNS to skeletal muscles, adipose tissue.

Ø Cross placental barrier during pregnancy and areexcreted in milk (Fetal & neonatal depression).

Ø Highly bound to plasma protein.

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DURATION OF ACTION OF BZS

Short acting (2-8 hrs)midazolam triazolamIntermediate (10-20 hrs)temazepam, lorazepam, alprazolam, oxazepam, nitrazepam, estrazolamLong acting (1-3 days):chlordiazepoxide, diazepam, flurazepam, clonazepam, chlorazepate

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PHARMACOKINETICS

Ø All Bzs are metabolized in the liverPhase I: ( liver microsomal system)Phase II: glucouronide conjugation and excreted in the urine.

Ø Many of Phase I metabolites are active: Increase eliminationhalf life of the parent compound, cumulative effect withmultiple doses.

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

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METABOLISM

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

• Tolerance (that is, decreased responsiveness to repeated doses of the drug) occurs when used for more than 1 to 2 weeks. Tolerance is associated with a decrease in GABA receptor density.

• Cross-tolerance exists between the benzodiazepines and ethanol.

• 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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Tolerance & Dependence

WITHDRAWAL SYMPTOMSAbrupt discontinuation, particularly if high doses used for

prolong period. WD symptoms with BZs are less intense than with ethanol or barbiturates.

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WITHDRAWAL SYMPTOMS

• Confusion, • anxiety, • agitation, • restlessness• insomnia • tension

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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FLUMAZENILBZS ANTAGONIST

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

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Other Hypnotic AgentsNON BENZODIAZEPINES Zolpidem and Zaleplon

• act on BZ1 (a subtype of BZ receptor family), are more selective

hypnotics, 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

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

• 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 chronic generalized anxiety disorders but takes 1 to 2 weeks to exert anxiolytic effects. It is not effective for short-term or “as-needed” treatment of acute anxiety states.

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

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

BARBITURATES

The barbiturates were formerly the mainstay of treatment to sedate patients or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, primarily 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 discoverer 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 RAS 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) AnticonvulsantPhenobarbital; • Short (3-8hrs) Sedative & HypnoticPentobarbital, secobarbital and amobarbital:• Ultrashort (20 min) I.V induction of

anesthesia: Thiopental

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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, absorbedorally. distribute throughout the body

• Thiopentone is highly lipid soluble (high rate of entry intoCNS- quick onset of action).

• All barbiturates redistribute from the brain to thesplanchnic areas, to skeletal muscle, and, finally, to adiposetissue.

• metabolized in the liver to inactive metabolites• Excreted in the urine.• Alkalinization increases excretion (NaHCO3)• Cross the placenta (pregnancy).

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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 BARBITURATESo They do not produce anesthesia in high

doses & patient can be aroused.o These are not enzyme inducers,o Very low abuse liability.o Lesser distortion of normal hypnogram.o Bzs have no hyperalgesia.o Bzs can be used as day time anxiolytic.o Do not effect respiratory or CVS function.o There is a specific antagonist-Flumazenil.

o Produce loss of consciousness and have low margin of safety

o enzyme inducers.o High abuse liability.o Marked suppression of REM sleep.o Hyperalgesic action.o Unacceptable drowsiness is seen.o Causes respiratory and depression &

hypotension.o No specific antagonist.

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Other anxiolytics 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.

• 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: is the first and only medication that's been proven to treat people with Non-24-Hour Sleep-Wake Disorder.

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MISCELLANEOUS

• PROPRANOLOL has efficacy in performance anxiety and social phobias.• Antidepressants: The use of sedating antidepressants with strong

antihistamine profiles has been ongoing for decades. Doxepin, an older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action, was recently approved at low doses for the management of insomnia. Other antidepressants, such as trazodone, mirtazapine and other older TCA with strong antihistamine properties are used off-label for the treatment of insomnia.

• 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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