sedative-hypnotics.pdf

8/10/2019 Sedative-Hypnotics.pdf

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sweetpotatoMD 1

SEDATIVE HYPNOTICS

What is the purpose of giving anxiolytic/ sedative

agent?

- To relax the patient

- To calm the patient

What about the hypnotic agents/ drugs?

- To induce sleep

Ang problema lamang with the hypnotic sedative

drugs, if you give in large amount it can cause

respiratory depression, cardiovascular depression,

coma, even death.

Sedative/Anxiolytic Agent

Reduce anxiety

Exert a calming effect

Mild CNS depression (psychomotor and cognitive

function): minimum consistent with therapeutic

efficacy

Dose-dependent anterograde amnesia

Anterograde amnesia

- caused by BENZODIAZEPINES

- while having the medication, the patient cannot

recall what had happened

MANIFESTATIONS OF ANXIETY

Pervasive feeling of apprehension

Feeling of helplessness

Difficulty in concentratingIrritability / Insomnia

GIT disturbance / Muscle tension

Excessive perspiration / HR/ RR

Nausea, palpitations, dry mouth

ANXIETY DISORDERS

Panic disorders

Obsessivecompulsive disorder

Posttraumatic stress disorder

Social phobia

Social Anxiety disorder

Generalized Anxiety disorder

Specific phobias

Hypnotic Drug

Produce drowsinessEncourage the onset and maintenance of a state

of sleep can cause:

latency of sleep (time to fall asleep

reduced)

duration of stage 2 NREM sleep

duration of REM sleep

duration of stage 4 NREM slow-wave

sleep

Pronounced depression of the CNS

WHY DO WE NEED TO SLEEP?

RESTORATIVEfunction

Allows the body to recover from all the work

that it did while it was awake

REM sleep: memory and learning (helps

process & strengthens memories)

ADAPTIVEfunction

The need of the animals to protect

themselves

Search for food & water during the day

Save energy, avoid getting eaten

Avoid falling off a cliff

PHASES OF SLEEP

NREM & REM

3-6 cycles per night

Lasts approximately 1.5 2 hours per cycle

NREM

Occurs at the onset of sleep

4 stages STAGE 1

The individuals body movements lessen

HR and eye movements slow down

BP goes down

The person would still be aware of voices of

people and noises around him

easily awakened

Lasts for 1-7 minutes


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STAGE 2(also called QUIET SLEEP)

The brain activity slows down

Body temperature decreases

Lasts for 10-25 minutes

STAGES 3 and4 (called SLOW WAVE or DEEP SLEEP)

EEGdominated by delta waves

Persons muscles are totally relaxed

BP and HR: lowest point

Provide the refreshing phase

Stage 3lasts for few minutes

Stage 4lasts for 20-40 minutes

REM(PARADOXICAL SLEEP)

Sleep is deep

Total muscle relaxation is observed

Skeletal muscle atonia

Brain is active

Characterized by EEG activation

Burst of autonomic activity is present

Episodic rapid eye movements

Dreams/ Nightmares take place

Play a role: convert short-termmemory to

long-termmemory

INSOMNIA: A DISEASE OR A SYMPTOM?

PRIMARYINSOMNIA

Difficulty initiating or maintaining sleep for at

least one month

Significant distress and/or impairment in

daytime functioning

Cannot be accounted for by other primary

disorders

If more than 4 monthsof INSOMNIA:

-

usually PSYCHOLOGICALin nature.

SLEEP DISORDERS THAT CAUSE INSOMNIA

Sleep apnea

Paranomnias

Somnambulism(sleep walking)

Somniloquy(sleep talking)

Bruxism(teeth gnashing)

Nightmares(sleep terrors)

Unfamiliar or non-conducive sleep environments

Extreme heat or cold

Stress, Conditions associated with pain

Alcohol, caffeine, prohibited drugs

Psychiatric disorders (insomnia > 4 weeks)

MEDICATIONS ASSOCIATED WITH INSOMNIA

CNS Stimulants

Dextroamphetamine, Methylphenidate, Pemoline

Antihypertensives

Alpha-blockers, Beta blockers, Methyldopa, Reserpine

Respiratory Medications

Albuterol, Theophylline

ChemotherapyDecongestants

Phenylpropanolamine,Phenylephrine, Pseudoephedrine

Hormones

Corticosteroids, Thyroid medications

Psychotropics

Antidepressants, Selective Serotonin Reuptake Inhibitors

TREATMENT OF INSOMNIA

3 Main Goals:

Treat the underlying cause

Improve nighttime sleep

Improve daytime functioning

SEDATIVE-HYPNOTIC DRUGS

I. BENZODIAZEPINES

II. BARBITURATES

III. MISCELLANEOUS DRUGS:

-

BUSPIRONE/ZOLPIDEM/ZALEPLON

-

RAMELTEON, ESZOPICLONE

Other Miscellaneous S/H Drugs

CHLORAL HYDRATE

PARALDEHYDE

ETHCHLORYNOL

PIPERIDINEDIONES:

GLUTETHIMIDE, METHYPRYLON

CARBAMATES: MEPROBAMATE

BENZODIAZEPINE CLASSIFICATION (nice to know daw)

Anxiolytic Benzodiazepines

Aprazolam, Diazepam, Oxazepam

Chlordiazepoxide, Halazepam, PrazepamClorazepate, Lorazepam, Temazepam

Clonazepam, Midazolam, Triazolam

Hypnotic Benzodiazepines

Nitrazepam

Flurazepam


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BENZODIAZEPINE CLASSIFICATION

I. SHORTACTING (3-8 hrs)

Midazolam (x)

Triazolam (x)

Oxazepam (xxx)

II. INTERMEDIATEACTING (10-20 hrs)

Alprazolam

Lorazepam

Estazolam

Temazepam (XXX)

III. LONGACTING (1-3 days)

Diazepam

Flurazepam (x), Clorazepate (X)

Halazepam (XX)

Chlordiazepoxide (XX)

CHEMICAL CLASSIFICATION

Benzodiazepines

1, 4 benzodiazepines

Contain a carboxamide group in the 7- member

heterocyclic ring structure

Substituent in the 7 position( a halogen or nitro):

needed for sedative-hypnotic effect

Triazole ring at the 1,2 position

(triazolobenzodiazepines) :

triazolam & alprazolam

The chemical structure of Benzodiazepines lacks sedative

hypnotic property but with the presence of nitro and

alkyl group, this will have the hypnotic/ sedative

properties.

BARBITURATES CLASSIFICATION

LONG-acting (1-2 days)

Phenobarbital, Mephobarbital

Barbital, Metharbital

INTERMEDIATE-acting

Amobarbital, Butabarbital

SHORT-acting (3-8hrs)

Pentobarbital, Secobarbital

ULTRA-SHORT-acting (20 minutes)

Thiopental, Hexobarbital,

Methohexical, Thiamylal

BARBITURATE STRUCTURE

- Dun sa position 2, mayroong OXYGEN don (refer to

Katzung), it should be replaced by SULFUR to become

MORE LIPID SOLUBLE itong THIOPENTAL. Kaya if there is

substitution of sulfur to that oxygen, this Thiopental wil

become highly lipid soluble. And this lipid can penetrate

in the BRAIN BARRIER and use also as ANESTHETIC

AGENT.

CHEMICAL CLASSIFICATIONNewer Drugs

Zolpidem an imidazopyridine

Zaleplon a pyrazolopyridine

Eszopiclone a cyclopyrrolone

Ramelteon a melatonin receptor agonist

Buspironeslow onset anxiolytic agent

PHARMACOKINETICS ABSORPTION AND DISTRIBUTION

Rates: differ# of factors: lipophilicity

Triazolam: extremelyrapid

Diazepam & active metabolite of clorazepate

more rapid

Clorazepateactive form: desmethyldiazepam

(nordiazepam) by acid hydrolysis in the stomach

Barbiturates & newer hypnotics: rapidly into the

blood

Lipid solubility

onset of CNS effects

Triazolam

Thiopentalundergoes redistribution

Eszopiclone

Zaleplon

Zolpidem

All cross the placental barrier

Also detectable in breast milk

CHLORDIAZEPOXIDE

DIAZEPAM

PRAZEPAM

CHLORAZEPATE

- is converted to their active metaboliteDESMETHYLDIAZEPAM

has a half-life of about 40 hours

Lalo na yung CHLORDIAZEPOXIDEhas LONGER half life

kasi mas napupunta sya sa ibang substance/compound

that would lead to DYSMETHYLDIAZEPAM.

converted to

OXAZEPAM


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and then will undergo CONJUGATION that will make

these drugs easily eliminated into the urinary system.

Same with ALPRAZOLAM and TRIAZOLAM. These 2

directly undergoes elimination. Also has SHORT HALF

LIFE.

BIOTRANSFORMATION

Benzodiazepines

Hepatic metabolism

- Phase I and phase II

Barbiturates

Hepatic metabolism

Oxidationalcohol, acids, ketones

Elimination t1/2:

18-48 hrsSecobarbital & Pentobarbital

4-5 daysPhenobarbital

Newer Hypnotics

Zolpidem

PPC: 1.6 hours

Elimination t1/2: 1.5-3.5 hours

Zaleplon

t1/2: 1 hour

CimetidineINHIBITS aldehyde hydrogenase

& CYP3A4

Eszopiclone

Elimination t1/2: 6 hours

KetoconazoleINHIBITS CYP3A4

RifampicinINDUCE CYP3A4

EXCRETION

Kidney

Barbiturates (Phenobarbital): enhanced by

alkalinization of the urine

CLORAZEPATELONGEST

Elimination Half-life: 50-100 hrs.

ZALEPLONSHORTEST Peak Blood Level:


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BENZODIAZEPINES: Increase frequency of the

opening of GABA chloride channel

BARBITURATES: Prolong the duration of the

opening of the GABA chloride channels

We have the LIGANDS:

-

AGONIST

-

ANTAGONIST(Flumazenil)

-

INVERSE AGONIST (B-carbolines n-butyl--

carboline-3-carboxylate (-CCB)

Ano ang functions ng mga LIGANDS?

Once we say

AGONISTBIND & ACTIVATE

ANTAGONISTBLOCKS THE EFFECTS OF

BENZODIAZEPINES

- FLUMAZENIL- Antagonist for BenzodiazepineOverdosage

Kung halimbawa, na-overdose yung patient

nagkaroon ng Respiratory Depression,

Cardiovascular Depression, you give FLUMAZENIL to

bring back to normal function yung nadepress.

INVERSE AGONISTBLOCKS THE EFFECTS OF

BENZODIAZEPINES

BUSPIRONE 5HT1A RECEPTOR AGONISTS

Has affinity for brain D2 receptors

No rebound or withdrawal signs

No sedation, no motor in coordination, no withdrawal

effects

May cause nausea, dizziness, headache & restlessness

Rifampin t1/2

Erythromycin, ketoconazole, grapefruit juice,

nefazodone t1/2

Used to treat ANXIETY, the advantage of this isagainst the Benzodiazepines is that there is NO

REBOUND or WITHDRAWAL SIGNS

ZOLPIDEM Imidazopyrimidine derivative

Binds to BZ 1 (omega receptors)

Minor effects on sleep architecture

Less tolerance & dependence

T is 1.5 to 3.5 hrs

Rifampin decrease its half life

Headache, dizziness, confusion, ataxia

ZALEPLON Similar to zolpidem

t: 1 hour

Metabolism inhibited by cimetidine

Decreases sleep latency; Has little effect on total sleep

or sleep architecture

Rapid onset & short duration of action

Back/chest pain, migraine, nervousness, headache,

dizziness

RAMELTEON

Agonist at MT1 & MT2 melatonin receptors at the

suprachiasmatic nuclei of the brain

Reduce the latency (the time of falling asleep) of sleep

w/ no effects on sleep architecture , no rebound

insomnia or significant withdrawal symptoms

Adverse effect: dizziness, somnolence, fatigue

endocrine changes, decrease in testosterone, increase

in prolactin

RAMELTEON - DRUG INTERACTIONS

CYP1A2 : Ciprofloxacin, Fluvoxamine,

Tacrine, Zileuton

CYP2C9: Fluconazole

Caution in liver dysfunction

Rifampicin induces its metabolism

ORGAN LEVEL EFFECTS

SEDATION


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sweetpotatoMD 6

ALL

-

Benzodiazepines

-

Barbiturates

-

Older Sedative Hypnotic Drugs

can EXERT CALMING EFFECTS. REDUCTION OF

ANXIETY, DEPRESSANT EFFECT ON PSYCHOMOTOR

& COGNITIVE FUNCTION.

But ONLY BENZODIAZEPINES can cause DOSE-

DEPENDENT ANTEROGRADE AMNESIA.

ORGAN LEVEL EFFECTS

HYPNOSIS

REBOUND INSOMNIA: ZOLPIDEM/ZALEPLON

ORGAN LEVEL EFFECTS

ANESTHESIASTAGE III of general anesthesia

Depends mainly on the physiochemical

properties (rapid onset and duration of effects)

ULTRA-SHORT ACTING

THIOPENTAL

METHOHEXITAL

Large doses contribute to persistent

respiratory depression long t1/2 & active

metabolite

DIAZEPAM, LORAZEPAM, MIDAZOLAM

ANTICONVULSANT EFFECTS inhibiting the

development and spread of epileptiform

electrical activity in the CNS

Clonazepam, Nitrazepam, Lorazepam,

& Diazepam

Phenobarbital & Metharbital

MUSCLE RELAXATION

Carbamate (meprobamate)

Benzodiazepines

Exert inhibitory effects on polysynaptic

reflexes and internuncial transmission

High doses: depress transmission at

the skeletal neuromuscular junction

RESPIRATORY FUNCTION

Healthy individual: comparable to changes

during natural sleep

Pulmonary disease: respiratory depression

Dose-related

Depression of the medulary respiratory cente

CARDIOVASCULAR FUNCTION

No significant effect at hypnotic dose (healthy

individual)

Cardiovascular depression: hypovolemic states

actions on the medullary vasomotor centers

Toxic doses: myocardial contractility & vascula

tone: depressed

TOLERANCE & DEPENDENCE

Tolerance decreased responsiveness to a drugfollowing repeated exposure

Dependence altered physiologic state that requires

continuous drug administration to prevent an abstinence

or withdrawal syndrome

BENZODIAZEPINES ANTAGONIST

FLUMAZENIL

Antagonist at BZ binding sites on the GABAA

receptor

t is 0.7 to 1.3 hrs

Rapid hepatic clearance

Agitation, Confusion, Dizziness & Nausea

CLINICAL USES OF SEDATIVE-HYPNOTICS

FOR RELIEF OF ANXIETY

FOR INSOMNIA

FOR SEDATION & AMNESIA BEFORE AND DURING

MEDICAL & SURGICAL PROCEDURES

FOR TREATMENT OF EPILEPSY & SEIZURE STATES

AS A COMPONENT OF BALANCED ANESTHESIA (IV) FOR CONTROL OF ETHANOL OR OTHER SEDATIVE

HYPNOTIC WITHDRAWAL STATES

FOR MUSCLE RELAXATION IN SPECIFIC

NEUROMUSCULAR DISORDERS

AS DIAGNOSTIC AIDS OR FOR TREATMENT IN

PSYCHIATRY


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THERAPEUTIC USES:

1. Anxiety & Agarophobia: ALPRAZOLAM

2. Insomnia: TRIAZOLAM, QUAZEPAM, TEMAZEPAN,

FLURAZEPAM, ESTAZOLAM

3. Anxiety, status Epilepticus, Anesthetic Premedication,

Muscle Relaxation: DIAZEPAM

4. Anxiety, Preanesthetic Medication: LORAZEPAM

5. Pre-anesthetic & intraoperative medication:

MIDAZOLAM

6. Seizure, acute mania, movement disorder:

CLONAZEPAM

7. Ethanol Withdrawal: CHLORDIAZEPOXIDE,

DIAZEPAM, PHENOBARBITAL

8. Delirium Tremens: PARENTERAL LORAZEPAM

9. Central muscle relaxant: MEPROBAMATE and

BENZODIAZEPINES

10. Psychiatric uses (mania control of drug-induced

hyperexcitability states

PHENCYCLIDINE INTOXICATION:BENZODIAZEPINES

Dosages of Drugs Used Commonly

for Sedation and Hypnosis

DRUG DOSAGE FOR SEDATION

Alprazolam 0.250.5 mg 2-3 x daily

Buspirone 5-10 mg 2-3 x daily

Chlordiazepoxide 1020 mg 2-3 x daily

Chlorazepate 57.5 mg twice daily

Diazepam 5 mg twice daily

Halazepam 2040 mg 3-4 x a dayLorazepam 12 mg once or twice/d

Oxazepam 1530 mg 3-4 x a day

Phenobarbital 1530 mg 2-3 x a day

DRUG DOSAGE FOR HYPNOSIS At Bedtime

Chloral hydrate 5001000 mg

Estazolam 0.52 mg

Eszopiclone 13 mg

Lorazepam 24 mg

Quazepam 7.515 mg

Secobarbital 100200 mg

Temazepam 7.530 mg

Triazolam 0.1250.5 mg

Zaleplon 520 mg

Zolpidem 510 mg

CLINICAL TOXICOLOGY OF S/Hs

Results from dose-related depression of CNS

Low doses:

Drowsiness

Impaired judgment

Diminished motor skills

Driving ability

Job performance

Personal relationships

Significant anterograde amnesia (BZ)

Effortful cognitive processes

Date rape

Results from long half-lives

Hangover effects

MIDAZOLAMwould NOT manifest HANGOVER effects

Overuse of S/H

Confusional states in elderly

Higher dosesLethargy or a state of exhaustion

Can exacerbate breathing problem

(COPD/symptomatic sleep apnea)

OverdosageAlprazolam

Severe toxicity

Respiratory depression from central actions

complicated by aspiration of gastric contents

Cardiovascular depression

Ensure airway with mechanical ventilation,

Maintenance of plasma volume,

Renal output, and cardiac function

Use of positive inotropic drugs

Hemodialysis or hemoperfusion

Flumazenil (BZ overdosage)

Not referable to their CNS actions (infrequent)

Hypersensitivity reactions (skin rashes)

Teratogenicity (fetal deformation)

Benzodiazepines Category D or X

Barbiturates Category D

Eszopiclone, Ramelteon,Zaleplon, Zolpidem

Category C

Buspirone Category B

CONTRAINDICATIONS

Barbiturates

History of acute intermittent porphyria,

Variegate porphyria,

Hereditary coproporphyria, or

Symptomatic porphyria


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sweetpotatoMD 8

DRUG INTERACTIONS

Additive effectenhanced depression: alcohol,

opioid analgesics, anticonvulsants, & Phenothiazines,

antihistamines, antihypertensive agents, tricyclic

antidepressant drugs

P450 inhibitor: cimetidine, oral contraceptives,

prolong BZ t

Cisapride s concentration of Triazolam, Alprazolam,

Midazolam

THE ALCOHOL

Widely consumed

Low to moderate amounts: relieves anxiety and

fosters a feeling of well-being or even euphoria

Most common abused drugalcohol abuse

Alcoholism

END.

I am only one but I am one. I cannot do everything, but I

can do something. What I can do, I ought to do. And with

the grace of God, I will do it.

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