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Sedative H ypnotic D rugsSedative H ypnotic D rugsSedative H ypnotic D rugsSedative H ypnotic D rugs

H M Bakhriansyah, dr., M.Kes., M.Med.Ed

Department of Pharmacology

Medical Faculty

Lambung Mangkurat University

Terminology

Sedative state Hypnotic state

Sleeping

NREM� 4 phases� Physical processes

decreased � For relieving physical

tiredness � Non recalling of and non

detail dream � Night terror and sleep

walking

� 5HT, adenosin, GABA

REM� 1 phase� Physical processes

increased � For relieving mental

tiredness� Detail, non logical and

bizarre dream �nightmare

� ACh

Wakefulness

Wakefulness

�Driven by formation reticulare brain steam and hypothalamus

�Neurotransmitters:�Excitation: NE, dopamine, histamine

�Inhibition: 5HT, GABA, adenosine

Insomnia

� Difficultly to fall into sleep or sleep cycle incompletely leading to symptoms and life disturbances �diminishing of working ability, social and daily life

� Classification:�Transient insomnia : 2-3 days

�Short term insomnia : ≤ 3 weeks

�Long term insomnia : > 3 weeks

� Initial insomnia : difficult to fall into sleep

� Delayed insomnia : easy to wake up and difficult to gain into sleep again

� Broken insomnia : multiple awakening

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Short acting benzodiazepine

Initial insomniaInitial insomnia

AnxietyAnxiety Depression syndromeDepression syndrome Psychosocial stressPsychosocial stress

Tricyclic and tetracyclicanti depressants agents

• Long acting benzodiazepine• Phenobarbital

Delayed insomniaDelayed insomnia Broken insomniaBroken insomnia

Consideration

�Given 15-30 minutes before night sleeping

�Dose is increased gradually

�Optimal dose is maintained for 1-2 weeks followed by tapering off

�Elderly: dose is reduced or given 2-3 times per week

SEDATIVE – HYPNOTIC AGENTS

�BENZODIAZEPIN DERIVATES

�BARBITURATE DERIVATES

�OTHERS:�CHLORALHIDRATE

�PARALDEHIDE

�ANTIHISTAMINE: Diphenhidramine, doxylamine

�NEWER DRUGS: zolpidem, zaleplon, zolpiklon

BENZODIAZEPINE DERIVATES

�Bind to its receptors (close to GABA receptors) � inhibitory neurotransmitter within the CNS

�The receptors-drugs interaction regulates the entrance of Cl into the post synaptic cells.

�Commonly used: wide range of safety

BARBBDZ

Diminish synaptic transmission

Intensify Cl conductance mediated by GABA

Prolong GABA effects

� Alprazolam

� Bromazepam

� Chlorazepate

� Chlordiazepoxide

� Diazepam

� Estazolam

� Flurazepam

� Halazepam

� Lorazepam

� Midazolam

� Nitrazepam

� Oxazepam

� Prazepam

� Temazepam

� Triazolam

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Pharmacodynamic

� Depression the CNS�Low therapeutic dose

�Relief of anxiety, drowsiness, sluggishness

�Increased dose

�Muscle relaxation, hypnosis

� Relatively safe: distinctive dose for therapy and death

� Side effects: minimal related to lacking of GABA neurons in the periphery.

Clinical Uses

� Anxiety�Pharmacotherapy

accomplished by counseling

�Using the lowest effective dose and the shortest duration

�Chosen drug based on half life unless for depression based anxiety (ALPRAZOLAM)

� Insomnia�Altering the normal distribution of REM phase and

NREM sleep.

� Epilepsy and seizures (clonazepam, diazepam)

� Sedation, retrograde amnesia and anesthesia

� Muscle relaxant (diazepam)

� Alcohol and sedative hypnotic withdrawal (diazepam and chlordiazepoxide)

Clinical Problems

�Cross tolerance

�Dependency (physically and mentally)

�Drug abuse

�Withdrawal syndrome particularly for barbiturate � rebound insomnia, anxiety

�Side effects are related to their ability to produce CNS depression: excessive sedation, confusion, impaired motor coordination � suppress breathing center, allergy and death.

�Interaction: alcohol, other CNS depressants

BARBITURATES

�Accidental ingestion � suicides

�Having serious and lethal interaction with other drugs

�Depressing CNS: sedation – general anesthesia

�Clinical use: insomnia, anxiety, epilepsy, seizure, anesthesia.

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�Side effects : laryngospasm

�Interaction : oral contraceptive, phenytoin, digitoxin, quinidine etc.

Other drugs

�Azapirones such as buspirone (5HT)

�Antihistamines such as diphenhidramine, promethazine, hydroxyzine, etc

�B-adrenergic blocking agents such as propranolol, particularly somatic anxiety � controversy.

�Antipsychotic and antidepressants such as chlorpromazine and amitriptyline.

Status Epilepticus

� SE : �Continues seizures

occuring 30 minutes (epilepsi foundation)

�More than 30 minutes of continues seizures activity or 2 or more sequential seizures without full recovery of consciousness between seizures (Dodson, 1993).

� Systemic and primary brain changes � related to morbidity and mortality rates�Decreasing GABA inhibition.

�Increasing blood pressure (early stage) � decreasing

�Acidosis (+)

�Pulmonary edema

�Hyperthermia

�Mild leukocytosis

�GABAergic mechanism fails

� Goal of therapy: to treat the epilepsy and to minimalise the side effects

Principal therapy:

� Monotherapy is better than polypharmacy

� Dosage is increased until the therapeutic effect or toxicity effect are met.

� Polypharmacy is introduced when monotherapydoes not work

� Avoiding the sudden withdrawal

Treatment flowchart for status epilepticus

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Medications

BarbituratBenzodiazepin

Asam valproatGabapentin

Lamotrigin

Fenitoin

KarbamazepinAsam valproat

Etosuksimid

FenitoinKarbamazepin

GABA

Glutamate

Ca

Na

STATUS EPILEPTICUS

Karbamazepin

� Stabilize neural membrane by decreasing Na, Ca and K flows through it.

� avoid to be given with MAO inhibitor consecutively

Fenitoin

� Difenilhidantoinderivate

� Mechanism of actions are similar to Karbamazepin

� Could be given orally, intra venous and intra muscular

Valproic Acid

� Increasing GABA transmission

� Sedation effect is minimal

Etosuksimid

� Mechanism of action is unknown

� Probably by inhibiting Ca channel

Phenobarbital

� Stimulating GABA receptor

� SE: sedation, nistagmus, ataxia and allergy

� Inducing enzym P450

Primidon

� Mechanism of actions are unknown

� Its active metabolithas long half life

Gabapentin

� GABA agonist

� Adjuvant therapy

Lamotrigin

� Stabilizing neuron and affecting glutamate release

� Adjuvant therapy

� SE: rash (prominent)

Klonazepam

� Stimulating GABA receptor

Felbamat

� Stimulating GABA receptor and inhibiting NMDA receptor

� Used un-frequently

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Parkinson disease

� A progressive neurodegenerative disorder associated with loss of dopaminergicnigrostriatal neurons.

� Distinctive features:�Resting tremor,

rigidity, bradikinetia, and postural instability

Principle therapy

� Increasing the synthesis and release of dopamine (L-dopa+karbidopa, amantadin)

� Inhibiting dopaminmetabolism (selegilin/deprenil)

� Activating dopamine receptor (bromocriptine, pergolide)

� Blocking muscarinic/ cholinergic receptor (trihexiphenidile, benzathropine, diphenhidramine)

To facilitate action of dopaminergic To suppress action of cholinergic

Anti cholinergic

Amantadine

L-dopa+karbidopa

Dopamine agonists drugsMAO B inhibitors

Protocol of therapy

L-dova (levodopa)

� Dopamine precursor � inactive form

� Activated by decarboxilaseenzyme;�Brain

�Lever & kidneys � can not pass through BBB � bioavailability countered by karbidopa/benserazide.

� Interaction: piridoxine increases decarboxilatedreaction.

� On/off phenomenon (+) after 3-5 years application �mechanism ??? Desensitization of dopamine receptor

� Not a first line therapy

Selegiline (deprenil)

� Instead of inhibiting metabolism of dopamine:

� Stimulating dopamine release.

�Neuro-protective effect

� + MOA inhibitors �crisis of hypertension.

Bromociptine & Pergolide

� Dopamine receptor agonists

� Action: Lesser than L-dopa

� As a single therapy at the early stage

� Combination with L-dopa at the moderate and late stage.

� Tapering dose

Trihexiphenidile & benzotropine

� Action: less than L-dopa

� Adjuvant therapy

� Tapering dose

Diphenhidramine

� Anti cholinergic effect at central level

� Anti histamine

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Amantadine

� Anti virus

� Mechanism: ??? May be by facilitating dopamine release

� Action:

�Less than L-dopa

�Better than anti cholinergic

� Early stage:

�Anti cholinergic or

�Amantadine

� When early stage therapy is not effective, L-dopa+karbidopa are started.

� Final stage: dopamine agonists medications and MAO inhibitors.