sedatives - dr lazaro.pdf

8/10/2019 SEDATIVES - DR LAZARO.pdf

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ANXIETY! Pervasive feeling of apprehension! Feelings of helplessness! Difficulties in concentrating! Irritability / Insomnia! GIT dist / Muscle tension! Excessive perspiration / ! HR / ! RR! Nausea, palpitations, dry mouth!

Org dse (acute MI, Ang P, GIT ul)


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SEDATIVE-HYPNOTIC DRUGS

! I. BENZODIAZEPINES

! II. BARBITURATES

! MISCELLANEOUS DRUGS:! BUSPIRONE/ZOLPIDEM/ZALEPLON

! RAMELTEON, ESZOPICLONE


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Other Miscellaneous Drugs! CHLORAL HYDRATE!

PARALDEHYDE! ETHCHLORYNOL! PIPERIDINEDIONES:

GLUTETHIMIDE, METHYPRYLON! CARBAMATES: MEPROBAMATE


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ANXIOLYTIC DISORDERS! BENZODIAZEPINES

! BUSPIRONE! ANTIDEPRESSANTS!

BETA ADRENERGIC BLOCKERS


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FOR INSOMNIA! BENZODIAZEPINES

! SUBTYPE-SELECTIVE BZ AGONISTS! ANTIHISTAMINES! ANTIDEPRESSANTS


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BENZODIAZEPINES!

1, 4 benzodiazepines! Contain a carboxamide group in the

7 membered heterocyclic ring structure! Substituent in the 7 position( a halogen

or nitro) : needed for sedative-hypnoticeffect

! Triazole ring at the 1,2 - position

(triazolobenzodiazepines) : triazolam &alprazolam


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BENZODIAZEPINECLASSIFICATION

I. SHORT ACTING ( 3-8 hrs)! Midazolam(X) Triazolam (x)! Oxazepam(xxx)

II. INTERMEDIATE ACTING (10-20 hrs)! Alprazolam Lorazepam! Estazolam Temazepam (XXX)III. LONG ACTING ( 1-3 days)! Diazepam Flurazepam (X)

Clorazepate(X) Halazepam(XX)! Chlordiazepoxide(XX)


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PHARMACODYNAMICS! BZ: increase frequency of the

opening of GABA chloride channels! BARB: prolong the duration of the

opening of the GABA chloridechannels

! BZ: agonist, antagonist , inverseagonist


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BENZODIAZEPINES

PHARMACOKINETICS! Oral absorption differ in Lipophilicity! diazepam & triazolam more lipid soluble! IM erratic! All cross the placental barrier during

pregnancy! Detectable in breast milk! Bind to plasma proteins! Displacement of warfarin from its

binding site


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BENZODIAZEPINESBIOTRANSFORMATION

CHLORDIAZEPOXIDE DIAZEPAM PRAZEPAM CHLORAZEPATE

Desmethylchlordiazepoxide

Demoxepam DESMETHYLDIAZEPAM ALPRAZOLAM & TRIAZOLAM

OXAZEPAM Alpha-hydroxy metabolite

Hydroxyethylflurazepam

FLURAZEPAM CONJUGATION LORAZEPAM

DesalkylFlurazepam

U RINARY EXCRETION

CONJUGATION


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BENZODIAZEPINESPHARMACOLOGIC EFFECTS

I. SEDATION: calming effectswith concomitant reductionof anxiety

II. HYPNOSIS1. ! sleep latency

2. " stage 2 NREM sleep3. ! REM sleep4. ! stage 3/ 4 NREM sleep


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Effects on Respiration & CVS! Effects on resp are dose related! Usual cause of death is depression

of the medullary center! CVS : no significant effect at

hypnotic dose! Marked if H-S is given by IV


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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 OTHERSEDATIVE HYPNOTIC WITHDRAWAL STATES! FOR MUSCLE RELAXATION IN SPECIFIC

NEUROMUSCULAR DISORDERS! AS DIAGNOSTIC AIDS OR FOR TREATMENT IN

PSYCHIATRY


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BZ

S THERAPEUTIC USES

1. anxiety & agarophobia: ALPRAZOLAM2. insomnia: TRIAZOLAM, QUAZEPAM,

TEMAZEPAN, FLURAZEPAM, ESTAZOLAM

3. anxiety, status epilepticus, anestheticpremedication, muscle relaxation:DIAZEPAM

4. anxiety, preanesthetic medication:LORAZEPAM

5. preanesthetic & intraoperativemedication: MIDAZOLAM

6. seizure, acute mania, movementdisorder: CLONAZEPAM


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BENZODIAZEPINES ADVERSE

EFFECTS! Prolonged sleep, Ataxia, lethargy! Impaired judgment, drowsiness,

impaired motor skill! Anterograde amnesia! Confusional state

! Disadvantages: interaction with alcohol,long-lasting hangover effects,development of dependence


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BZ

s Drug Interactions

! Additive effect : alcohol , other CNSdepressants

! P450 inhibitor: cimetidine, oralcontraceptives, prolong BZ t !

! Cisapride increases conc oftriazolam, Alprazolam, midazolam


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BENZODIAZEPINES ANTAGONIST

! FLUMAZENIL! t ! is 0.7 to 3 hrs! Rapid hepatic clearance! Agitation, Confusion, Dizzinesss &

dyspnea


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BARBITURATES CLASSIFICATION

I. ULTRA SHORT ACTING (20minutes)

! thiopental

II. SHORT ACTING (3-8hrs)! Amobarbital, pentobarbital

III. LONG ACTING (1-2 days)! phenobarbital


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MECHANISM OF ACTION! INCREASE DURATION OF THE GABA-

GATED CHANNELS OPENING! GABA MIMETIC, directly activating

chloride channels! DEPRESS EXCITATORY

NEUROTRANSMITTERS & exertnonsynaptic membrane effects

! Can induce full surgical anesthesia


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BARBITURATES

PHARMACOKINETICS! Phenobarbital: oral, IV! Phenobarbital is excreted

unchanged in the urine( 20-30%)elimination rate is increased byalkalinization of the urine

!

Thiopental: IV! Thiopental undergo by

redistribution


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BARBITURATES CLINICAL USES

PHENOBARBITAL: ANTICONVULSANT

THIOPENTAL: IV ANESTHETIC


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BARBITURATES ADVERSE EFFECTS

! Potent inducer of hepaticmicrosomal enzymes

! Tolerance, dependence! Absolutely contraindicated in

patients with history of hereditary

coproporphyria, acute intermittentporphyria, variegate porphyria,! Or symptomatic porphyria


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DRUG DOSAGE FOR ! Alprazolam! Buspirone! Chlordiazepoxide! Chlorazepate! Diazepam! Halazepam! Lorazepam! Oxazepam! Phenobarbital

SEDATION" 0.25 0.5 mg 2-3 x daily" 5-10 mg 2-3 x daily" 10 20 mg 2-3 x daily" 5 7.5 mg twice daily" 5 mg twice daily" 20 40 mg 3-4 x a day" 1 2 mg once or twice" 15 30 mg 3-4 x a day" 15 30 mg 2-3 x a day


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DRUG DOSAGE FOR ! Chloral hydrate! Estazolam! Eszopiclone! Lorazepam! Quazepam! Secobarbital! Temazepam! Triazolam! Zaleplon!

Zolpidem

HYPNOSIS At Bedtime" 500 1000 mg" 0.5 2 mg" 1 3 mg" 2 4 mg" 7.5 15 mg" 100 200 mg" 7.5 30 mg" 0.125 0.5 mg" 5 20 mg"

5 10 mg


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NEWER DRUGS FOR ANXIETY &SLEEP DISORDER

I. BUSPIRONE

II. ZOLPIDEM

III. ZALEPLON


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BUSPIRONE! 5HT1A RECEPTOR AGONISTS (partial)! Has affinity for brain D2 receptors! No rebound or withdrawal signs! 1-(2-pyrimidyl)-piperazine (1-PP)! Used in generalized anxiety disorder! No sedation, no motor incoordination,

no withdrawal effects! May cause nausea, dizziness, headache

& restlessness! Rifampin ! its t 1/2,! Erythromycin, ketoconazole, grapefruit

juice, nefazodone " its t 1/2


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ZOLPIDEM! Imidazopyrimidine derivative! Similar to Benzodiazepines! 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


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ZALEPLON! Similar to zolpidem! T ! is one 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


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RAMELTEON

! Agonist at MT1 & MT2 melatonin receptorsat the suprachiasmatic nuclei of the brain

! Reduce the latency of sleep w/ no effects onsleep architecture , no rebound insomnia orsignificant withdrawal symptoms

! Adverse effect: dizziness, somnolence,fatigue, endocrine changes, decreases intestosterone, increases in prolactin


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RAMELTEONDRUG INTERACTIONS

! CYP1A2 : ciprofloxacin,

fluvoxamine, tacrine, zileuton! CYP2C9: fluconazole! Caution in liver dysfunction! Rifampin induces its metabolism

sedatives - dr lazaro.pdf

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