sedative hypnotic drugs psik - drug addicts · sedative hypnotic drugs h m bakhriansyah, dr.,...
TRANSCRIPT
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Terminology
Sedative state Hypnotic state
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Wakefulness
�Driven by formation reticulare brain steam and hypothalamus
�Neurotransmitters:�Excitation: NE, dopamine, histamine
�Inhibition: 5HT, GABA, adenosine
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Insomnia
� Difficultly to fall into sleep or sleep cycle incompletely leading to symptoms and life disturbances �diminishing of working ability, social and daily life
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
� 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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
SEDATIVE – HYPNOTIC AGENTS
�BENZODIAZEPIN DERIVATES
�BARBITURATE DERIVATES
�OTHERS:�CHLORALHIDRATE
�PARALDEHIDE
�ANTIHISTAMINE: Diphenhidramine, doxylamine
�NEWER DRUGS: zolpidem, zaleplon, zolpiklon
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
BARBBDZ
Diminish synaptic transmission
Intensify Cl conductance
mediated by GABAProlong GABA effects
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
� Alprazolam
� Bromazepam
� Chlorazepate
� Chlordiazepoxide
� Diazepam
� Estazolam
� Flurazepam
� Halazepam
� Lorazepam
� Midazolam
� Nitrazepam
� Oxazepam
� Prazepam
� Temazepam
� Triazolam
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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.
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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)
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
� 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)
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Clinical Problems
�Cross tolerance
�Dependency (physically and mentally)
�Drug abuse
�Withdrawal syndrome particularly for barbiturate � rebound insomnia, anxiety
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
�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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
BARBITURATES
�Accidental ingestion � suicides
�Having serious and lethal interaction with other drugs
�Depressing CNS: sedation – general anesthesia
�Clinical use: insomnia, anxiety, epilepsy, seizure, anesthesia.
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
�Side effects : laryngospasm
� Interaction : oral contraceptive, phenytoin, digitoxin, quinidine etc.
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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.
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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).
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
� 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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
� 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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Treatment flowchart for status epilepticus
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Medications
BarbituratBenzodiazepinAsam valproatGabapentin
Lamotrigin
FenitoinKarbamazepinAsam valproatEtosuksimid
FenitoinKarbamazepin
GABA
Glutamate
Ca
Na
STATUS EPILEPTICUS
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Valproic Acid
� Increasing GABA transmission
� Sedation effect is minimal
Etosuksimid
� Mechanism of action is unknown
� Probably by inhibiting Ca channel
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Gabapentin
� GABA agonist
� Adjuvant therapy
Lamotrigin
� Stabilizing neuron and affecting glutamate release
� Adjuvant therapy
� SE: rash (prominent)
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Klonazepam
� Stimulating GABA receptor
Felbamat
� Stimulating GABA receptor and inhibiting NMDA receptor
� Used un-frequently
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Parkinson disease
� A progressive neurodegenerative disorder associated with loss of dopaminergicnigrostriatal neurons.
� Distinctive features:�Resting tremor,
rigidity, bradikinetia, and postural instability
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Anti cholinergicAmantadine
L-dopa+karbidopa
Dopamine agonists drugsMAO B inhibitors
Protocol of therapy
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
Trihexiphenidile & benzotropine
� Action: less than L-dopa
� Adjuvant therapy
� Tapering dose
Diphenhidramine
� Anti cholinergic effect at central level
� Anti histamine
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008
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.
HaMBaHaMBaHaMBaHaMBa ---- 2008200820082008