sedative hypnotic drugs€¦ · propranolol, particularly somatic anxiety controversy. •...
TRANSCRIPT
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Sedative Hypnotic Drugs
dr. Annisa Fitria/dr. H.M. Bakhriansyah, M.Kes, M.Med.Ed
Department of Pharmacology
Medical Faculty
Lambung Mangkurat University
Terminology
Sedative state Hypnotic state
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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
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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 tetracyclic anti 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
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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
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• Alprazolam
• Bromazepam
• Chlorazepate
• Chlordiazepoxide
• Diazepam
• Estazolam
• Flurazepam
• Halazepam
• Lorazepam
• Midazolam
• Nitrazepam
• Oxazepam
• Prazepam
• Temazepam
• Triazolam
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.
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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)
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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
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BARBITURATES
• Accidental ingestion � suicides
• Having serious and lethal interaction with
other drugs
• Depressing CNS: sedation – general
anesthesia
• Clinical use: insomnia, anxiety, epilepsy,
seizure, anesthesia.
• Side effects : laryngospasm
• Interaction : oral contraceptive,
phenytoin, digitoxin, quinidine etc.
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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).
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• 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 monotherapy does not work
• Avoiding the sudden withdrawal
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Treatment flowchart for status epilepticus
Medications
BarbituratBenzodiazepinAsam valproatGabapentin
Lamotrigin
FenitoinKarbamazepinAsam valproatEtosuksimid
FenitoinKarbamazepin
GABA
Glutamate
Ca
Na
STATUS EPILEPTICUS
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Karbamazepin
• Stabilize neural membrane by decreasing Na, Ca and K flows through it.
• avoid to be given with MAO inhibitor consecutively
Fenitoin
• Difenilhidantoin derivate
• 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
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Phenobarbital
• Stimulating GABA receptor
• SE: sedation, nistagmus, ataxia and allergy
• Inducing enzym P450
Primidon
• Mechanism of actions are unknown
• Its active metabolit has long half life
Gabapentin
• GABA agonist
• Adjuvant therapy
Lamotrigin
• Stabilizing neuron and affecting glutamate release
• Adjuvant therapy
• SE: rash (prominent)
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Klonazepam
• Stimulating GABA receptor
Felbamat
• Stimulating GABA receptor and inhibiting NMDA receptor
• Used un-frequently
Parkinson disease
• A progressive neurodegenerative disorder associated with loss of dopaminergic nigrostriatal neurons.
• Distinctive features:– Resting tremor, rigidity,
bradikinetia, and postural instability
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Principle therapy
• Increasing the synthesis and release of dopamine (L-dopa+karbidopa, amantadin)
• Inhibiting dopamin metabolism (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 cholinergicAmantadine
L-dopa+karbidopa
Dopamine agonists drugsMAO B inhibitors
Protocol of therapy
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L-dova (levodopa)
• Dopamine precursor � inactive form
• Activated by decarboxilase enzyme;– Brain
– Lever & kidneys � can not pass through BBB � bioavailability countered by karbidopa/benserazide.
• Interaction: piridoxine increases decarboxilated reaction.
• 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
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Trihexiphenidile & benzotropine
• Action: less than L-dopa
• Adjuvant therapy
• Tapering dose
Diphenhidramine
• Anti cholinergic effect at central level
• Anti histamine
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.