Post on 02-Jun-2018
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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