1

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

2

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

3

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

4

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

5

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

6

• 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.

7

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)

8

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

9

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.

10

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).

11

• 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

12

Treatment flowchart for status epilepticus

Medications

BarbituratBenzodiazepinAsam valproatGabapentin

Lamotrigin

FenitoinKarbamazepinAsam valproatEtosuksimid

FenitoinKarbamazepin

GABA

Glutamate

Ca

Na

STATUS EPILEPTICUS

13

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

14

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)

15

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

16

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

17

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

18

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.