SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS

ANTISEIZURE DRUGS
M.O.A Enhancement of GABA -increase GABA actions at receptor: BZD, phenobarbital
action
- inhibits GABA transaminase: vigabatrin

- blocks GABA uptake: tiagabin

Inhibition of sodium -phenytoin, carbamazepine, valproic acid, lamotrigine

channel function

Inhibition of Calcium T- Ethosuximide

type channels

Only enhances GABAergic Gabapentin

action

target synaptic vesicle Levetiracetam

protein SV2A

USES Drugs used in Partial Phenytoin, Carbamazepine, Lamotrigine, Vigabatrin, Gabapentin, Topiamate
seizures and Generalized
tonic-clonic seizures

Drugs used in Generalized Ethosuximide, Valproic acid, trimethadione

seizures

Other drugs used in Benzodiazepines; Acetazolamide

epilepsy
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
SODIUM CHANNEL BLOCKER
•
Phenytoin, • They stabilize & prolong the inactivated state of Na+ channels
• Carbamazepine preventing entry of Na+ for a long time.
• Lamotrigine

EXAMPLES CLINICAL USES M.O.A ADVERSE EFFECTS

Phenytoin for generalized tonic *Absorption is slow & complete, in the *gingival hyperplasia
clonic (grand mal) duodenum only. Highly bound to plasma *mild peripheral
seizures. albumin (90%). Metabolized in liver by neuropathy
microsomal enzymes *osteomalacia
*Elimination: first-order at low dose, zero- *hirsutism
order at higher dose. Excreted in urine. *diplopia
*Induction of liver microsomal enzymes *megaloblastic anaemia
 Drug interactions (↓plasma level) with *cleft palate
Isoniazid, cimetidine, sulfonamides, warfarin

Carbamazepine Drug of choice for *Similar to that of phenytoin Dose related:

partial seizures *acts presynaptically to decrease synaptic *Diplopia and ataxia (Rx
Generalized tonic- transmission rearrange divided doses)
clonic seizures *Mild GI disturbances
Trigeminal neuralgia *Drowsiness (at much
 Mania higher doses)
*Hyponatremia and
water intoxication

Idiosyncratic:
*Skin rash (the most
common)
*blood dyscrasias in the
form of:
aplastic anaemia and
agranulocytosis
leukopenia (requires
careful monitoring)

Lamotrigine *Monotherapy in blockage of voltage dependent sodium *Dizziness headache and

partial seizures. channels (similar to phenytoin). somnolence
*Add on therapy actions on voltage-activated Ca⁺²channels *Diplopia
*Absence seizures in (accounting for its efficacy in absence *Nausea
children. seizures) *Skin rash
(hypersensitivity).
*Life-threatening
dermatitis

Vigabatrin Add-on drug for cases *irreversible inhibitor of GABA-transaminase eye check needed as the
(inhibits GABA not responding to (covalent binding)  ↑GABA drug may cause
transaminase) other drug *short plasma t ½ but long acting peripheral visual field
defect on long-term
Gabapentin *effective against *aminoacid analog of GABA,
Pregabalin partial seizures *Not metabolized, excreted in urine. Does not
(Only enhances induce liver enzymes
GABAergic action)

Topiamate for partial and

generalized seizures
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS

ENHANCEMENT OF GABA ACTION

EXAMPLES CLINICAL USES M.O.A ADVERSE EFFECTS
Valproic acid *Absence seizures *Block voltage-dependent sodium *Hepatic failure,
(Sodium Valproate) *myoclonic seizure channels & T-type Calcium channel specially children
*partial seizures with *Increase in brain GABA <2yrs
complex symptoms (A) facilitate GAD *Neural tube defects
(enzyme for synthesis of GABA) when pregnant
(B) Inhibit GABA transporter GAT-1 mother given in 1st
*increase membrane potassium trimester
conductance leading to hyperpolarization *Thinning and curly
of the neuronal membrane. hair
Pharmacokinetics
• well absorbed following an oral
dose
• Valproic acid is 90% bound to
plasma proteins
Drug interactions:
1. Valproic acid inhibits the
metabolism of several drugs,
including phenobarbital,
carbamazepine, and phenytoin,
leading to an increased blood
level of these compounds.
2. At high doses, valproic acid can
inhibit its own metabolism.

CALCIUM T-TYPE CHANNELS INHIBITORS

EXAMPLES CLINICAL USES M.O.A ADVERSE EFFECTS
Ethosuximide Used for absence seizure inhibits Ca2+ currents (low threshold T- May exacerbate other
(pure petit mal drug) type) that mediate thalamocortical types of epilepsy
oscillations (3/sec firing rhythm) seen in
absence seizure

PHARMACOKINETICS:
complete absorption, NOT protein-
bound, completely metabolized by
hydroxylation, t ½ 40 hr

-Diazepam i.v. up to 20-
30 mg (the effect is not
lasting)
STATUS EPILEPTICUS
-Lorazepam i.v. -Midazolem i.m. -Phenytoin i.v. (long-lasting)
(longer lasting) (slower onset, short- -Phenytoin is precipitated by
action) glucose; Need to monitor cardiac
rhythm (d/t propylene glycol in
which drug is dissolved)

-Fosphenytoin is freely -Phenobarbital 100- For Absence status epilepticus:

soluble, alternative 200 mg i.v. up to 800 BZD are drug of choice
mg, but monitor
respiratory
depression.
DRUG RESISTANT EPILEPSY
*High risk of premature *Combination therapy: *Newer Drugs: *Early evaluation for surgery- anterior
death, injuries & One drug should be Na+ new Na channel lobectomy for resistant temporal lobe
psychosocial dysfunction in channel blocker & the blockers- epilepsy
these patients. other drug with lacosamide,
GABAergic properties. eslicarbazepine
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
SEDATIVE-HYPNOTIC DRUGS
SEDATIVE (anxiolytic) drug reduces anxiety, moderates excitement and calms the recipient.

HYPNOTIC drug produces drowsiness and facilitates the onset and maintenance of a state of
sleep and from which the recipient can be aroused easily

SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS CLASSIFICATION

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra short

acting acting
Intermediate Short Buspirone
acting acting Chloral hydrate
Long Long Zaleplon
acting acting Zolpidem
Ramelteon

CHARACTERISTIC • Lipid soluble

• Absorbed well from the GIT
• Good distribution to the brain
• Metabolized before elimination from the body by hepatic enzymes
DRUG A - BARBITURATES

DRUG B - BDZ
- flatter dose response
curve
- greater margin of safety

↑DOSE =
↑ CNS DEPRESSION

• Dose dependent depression of CNS.

• Cross tolerance and cross dependence between
all CNS sedatives (Barbiturates, BZD, Ethanol)

All sedative-hypnotics:
• Cross the placenta  fetal depression.
• detectable in breast milk  depress infant CNS

NORMAL  RELIEF FROM ANXIETY  DISINHIBITION

SEDATION HYPNOTICS  G.A  COMA DEATH

CLINICAL USES • Acute & chronic anxiety disorders

• Insomnia
• Epilepsy & seizures
• Sedation, Amnesia, Anesthesia
• Muscle relaxation
• Alcohol & Sedative Hypnotic withdrawal
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
Benzodiazepines (BZD)
MODE OF • Bind to an allosteric site on GABA receptor (pocket between  &  subunit)
ACTION • Promote binding of GABA to two binding sites between  &  subunits of GABAA receptor.
• This triggers ligand-gated chloride channel opening (↑frequency), with resulting
membrane hyperpolarization.
• Neuronal firing is decreased as a result, producing observed CNS depressant effects.

GABAA • The GABA-A receptor is a ligand gated ion channel receptor

Receptors • GABA binding causes the channel to open and Cl enters into the neuron
• Creates a negative charge in the transmembrane potential.
• This makes GABA an Inhibitory neurotransmitter

Binding sites: GABA / BZD / Flumazenil / Zolpidem / Barbiturates

PHARMCO. CNS (uses) Peripheral

ACTION • Sedation • Coronary vasodilation (after i.v. of
• Decreased anxiety diazepam)
• Hypnosis • Neuromuscular Blockade (overdose)
• Anticonvulsant activity
• Muscle-Relaxation
• Anterograde amnesia

ADVERSE • BZD have few SE (vs other • Overdose: Rare fatalities if BZD alone
EFFECTS psychotropics) • Severe CNS & Respiratory Depression if
• Sedation, CNS Depression combined with:
– Worse if combined with EtOH – alcohol
• Behavioral Disinhibition – barbiturates
– Irritab, excitement, aggression – narcotics
(<1%), rage – tricyclic antidepressants
• Psychomotor & Cognitive Impairment
– coordination, attention (driving)
– poor visual-spatial ability (not
aware of it)
– Ataxia, confusion

ANTEDOTE: • Drug used to treat BZD over dosage.

FLUMAZENIL • It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine
binding site on the GABAA receptor
• It has been found to be effective in overdoses of non-benzodiazepine sleep enhancers,
zolpidem and zaleplon
• Action lasts 2 hr, caution: shorter action than BZDs - repeat dose might be needed
• convulsion rarely occurs, esp. patient taking TCA
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
DRUG ROA T½ (H) INDICATION COMMENT

Short-Acting Oral 3+1 Insomnia Daytime side

effects
Triazolem (Halcion) IM, IV 2+0.6 Insomnia
Rapid metabolism
Midazolem (Versed)

Intermediate-Acting Oral 12+2 Anxiety, agoraphobia Severe withdrawal

$
Alprazolam (Xanax) Oral 11+6 Insomnia
Metab.Conjugation
Temazepam (Restoril) O,IM, IV 10+3 Anxiety, alcohol w/d
Chlordiazepoxide anaesthetic premed. Active metabolite
O,IM, IV 14+5
(Librium)
Anxiety, premed. Metab.Conjugation
Lorazepam (Ativan)

Long-Acting O,IM, IV, 43+13 Status epilepticus, Prototype BZD

Rectal anxiety, sk. muscle
Diazepam (Valium) 74+24 relaxation, premed. Active metab.
Oral
Flurazepam (Dalmane) 23+5 Insomnia Tolerance to anti-
O,IM, IV convulsant effect
Clonazepam (Klonopin) Seizures, acute mania
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
BARBITURATES
INTRO • Main hypnotics until 60s
• Depresses CNS  CVS collapse (no more used as anxiolytic / hypnotic)
• Those with 6 -12hrs duration of action (e.g. pentobarbital) sparingly used
• Phenobarbital still used as anticonvulsant and Thiopental for induction of anaesthesia

KINETICS • Well absorbed in GIT

• It is a weak acid  alkaline urine  ionisation and elimination
• Induces hepatic enzymes  conc. of several drugs e.g. steroids, oral contraceptives,
warfarin, tricyclic antidepressants

MODE OF • Barbiturates bind to the GABA-A

ACTION receptor at a nearby site
• Potentiate the effect of GABA in
increasing the Cl- flow
• Barbiturates also block the AMPA
receptor which is sensitive to
glutamate, the excitatory
neurotransmitter, (opposite effect from
GABA)

CLINICAL  Epilepsy (pnenobarbitone)

USES  overdose of stimulants e.g. amphetamine;
 Induction of anaesthesia (thiopental i.v.)

ADVERSE • Sedation (within therapeutic dose)

EFFECTS • Tolerance (not enough to cancel motor and cognitive impairment)
• Megaloblastic anemia
• Mild hypersensitivity
• Osteomalacia
• Overdose  Resp and CVS failure  coma
• Precipitates porphyria
• Withdrawal Sx: anxiety, nausea, vomiting, hypotension, seizure, psychosis, CVS collapse &
death
 SEDATIVE, HYPNOTICS, & ANTI-CONVULSANT DRUGS
OTHER DRUGS
BUSPIRONE • 5HT1A agonist, no hypnotic but little sedative action
• Doesn’t potentiate CNS depressant effect of sedative hypnotics
• No rebound anxiety
• Anxiolysis may take > 1 wk (mainly for generalised anxiety states, not suitable for
panic disorders, phobia; administered p.o.)
• Related compounds:
Ipsapirone, Gepirone, Tandospirone
ZOLPIDEM • Structurally unrelated to BZD
• Zolpidem, zaleplon, eszopiclone bind to 1 subunit of GABAA R enhancing GABA
effect
• Produces deep sleep
• Minimal anxiolytic, muscle relaxant and anticonvulsant effect
• Use: short-term Rx of insomnia
• High doses depress resp (esp with other CNS depressants, alcohol)
• Less risk of dependence (cf BZD)
• Metabolized in liver

RAMELTEON • Indicated for patient with difficulty in falling asleep

• Agonist action at MT1 & MT2 melatonin receptors in the suprachiasmatic nuclei of
brain
• No direct effect on GABAergic neurotransmission
• PK: rapid absorption, metabolized by CYP1A2 (mainly) and CYP2C9, metabolite also
active.
• SE: dizziness, somnolence, fatigue.

ANTIHISTAMINES • Sedation is a side effect of their antihistaminic effect

Diphenhydramine
Promethazine

Β-ADRENAGIC • Treat anxiety due to somatic symptoms or performance anxiety (stage fright)
BLOCKERS