Introduction to CNS

And
Sedative-Hypnotics
And
Anti-epileptics

Dr.U.P.Rathnakar
MD. DIH. PGDHM
 CNS

 Humans Animals
 ↓ ↓
 Intelligence Instinct
 [Physiology of BRAIN]
 Defines differences*
 Action of drugs on CNS challenging

 Major th.importance-20% of all Rx –

Analgesics
 Self administration-Coffee, alcohol, nicotine,
canabis
 Gulf between drug action at cellular level &
behavioral level is wide
 “ Throwing candy-floss across Grand
canyon!”*
Some actions are well established

 DA pathway & Parkinsonism

 NA, 5HT and depression

 DA & Schizo. Less well

established
 Link bet. Cellular disturbances

and epilepsy –Simple- not

established
 Anatomy of CNS

 Frontal lobe→ Higher functions, motor cortex

 Parietal → Somato-sensory
 Thalamus →Relay center for sensory pathway
 Hypo →Autonomic, emotion, circardian, thirst,
hunger- CONTROL
 Limbic →Learning, memory, emotion, addiction
 Basal ganglion →Extrapyramidal control
 Reticular formation →Sleep-wakefullness
 Midbrain →Vision, hearing
 Medulla →Vital functions
 Cerebellum →Posture, balance
 Sp.cord →integration????? *
 BBB
 Tight junction & Glial cells around capillaries
 Absent- Floor of iv vent[CTZ-area post rema],
Pineal gland, around pitutary
 Defecient in new born
 Pathological →HTN, Inflammation, heat/cold
stress, infection, radiation
 Do not cross →Mol.wt.>60000, polar, Lipid
soluble cross
 Imp →Precursors-levodopa, AMA-intrathecally*
Neuro-chemical transmission

 Basicssame as in ANS
 Neurotransmitters

 4 processes of

neurotransmission
 EPSP & IPSP*
 Neurotransmitters

 Excitatory amino acids

 L-Glutamate, Aspartate, Homocystate

 Inhibitory AA

 GABA, Glycine

 Others

NA, DA, 5HT, Ach, Purines[Adenosine &

ATP], Histamine, Melatonin, NO,
Arachidonic acid, Anandamide*
A

Neurotransmitters
NT Rec Ago Antago Exc/Inh
M1 Atr, Pirenz. Ex
M2 Bethanecol Atro Inh
ACh
N Nicotine Exc
DA D1 Phenothi
D2 Bromo Phenothi Inh

GABA GABA A Biccuculine Inh

GABAB Baclofen Saclofen
Glycine Strychnine Inh
5HT 5HT Ketanserin Exc
Ondansetron (Inh)
NT Contd….

NT Rec Ago Antago Exc/Inh

NA α1 Phenyl Prazo Exc
α2 Clonidine Yohimbine Inh

β1 Dobutamine Atenolol Exc

β2 Albuterol Inh
Histamine H1 Mepyramine Exc
H2 Ranitidine Exc

H3 Inh
Opioids Mu,delta, Naloxone Inh
Kapa
Endocanab CB1 & 2 Rimonobant Inh
 Neurotrnsmission-4 processes
1. Neurotransmission
 NT Released by neurones
 Criteria
 Immediate EPSP oR IPSP
2. Neuromodulators
 NT released by neurones and astrocytes
 Long duration
 Long term changes in synaptic transmission
[Synaptic plasticity]
 Eg. CO2, Adenosine, PG, NO*
 Neurotrnsmission-4 processes
n Neuromediators:
 II messengers [cAMP, cGMP, Inositol phosphate]
n Neurotropic factors:
 Released by Neurones, astrocytes, microglia
 Longer duration
 Regulates growth & morphology of neurones
 Eg.Cytokines, Chemokines, growth factors
Neurohormones: released circulation-Vsopressin,
oxytocin*
 EPSP &IPSP

EPSP
IPSP
•Opening-Na+ channels
•Opening Cl-channels
•↓Cond. Of Cl-channels
•↑Cond. K+chnnels
•↓Cond.of K+channels
•Activation of enzymes-those
•Changes in int.metabolism ↑inhibitory rec. or that ↓Exc.rec.
Sedative-Hypnotics
 Sedative-Hypnotics
 Sedatives: Deppresses CNS-Calmness &
Drowsiness(Sedation). Slow acting
 Hypnotics: Produces drowsines-

facilitates onset and maintainance of

sleep. Resembles natural sleep with EEG
charecterstics
 HYPNOSIS; Passive state of

sugestibility by artificial means*

 History
 Alcohol & Herbs→ Since antiquity
 Bromide, Chloral hydrate, Paraldehyde

 Phenibarbital →1912

 2500 brbiturates tested, 50

commercially available
 Upto 1960 →No others

 Then came chlordiazepoxide and other

benzodiazepines*
CNS DEP: Sedation →Sleep →Unconciousness →SA →Dep. Of CVS & RS →
Death
 Physiology of sleep

•Sleep-Absence wakefulness
•Active process
•1/3 of life spent in sleep
•Biological clock regulates
•Restoration of natural balance
Among neuron
•Sleep-NREM &REM
•NREM 90’-I,II,III,IV →REM 5-30
→Cycle repeates →REM prolongs
→Wake up from
•Children-sleep & growth

Physiology of sleep
 NREM REM
 Peacefull  Not
 P.Symp+  Symp act+
 BMR, CO, HR, PVR-Low  High
 Infrequent dreams-no  Vivid, bizarre, sexual
recall
 α rhythm
 Β Rhythm
 Muscle relax-except RS  Muscle
flacid(Ob.apnoea)
 Hypotension  Hypertension
 No eye ball movement  Rapid eye ball
 GH in stage 3 & 4* movement*
 Benzodiazepines[BZD]
n Hypnotics: Diazepam, Nitrazepam,
Alprazolam, Temazepam, Triazolam
n Ant-anxiety: Diazepam,
Chlordiazepoxide, Oxazepam,
Lorazepam, Alprazolam
n Anti-convulsants: Diazepam, lorazepam,
Clonazepam, Clobazam
n Non[Novel]-Benzodizapine hypnotics:
Zopiclone, Zolpidem, Zaleplon*
 Benzodiazepines
 Benzene + Diazepine ring
 Ph.Action:
 CNS: Peripheral
• Sedative > Coronary vaso.dil.
• Hypnotic > N.M.Block
• Anxiolytic
• Muscle relaxant
• Anterograde amnesia*
 Ph.action contd…
 CNS:
 Not a general depressant
 Action profile of all BZD same-selectivity difft.
 Does not produce total anesthesia
 Antianxiety profile not dependent on sedation
 Anticonvulsant-Tolerance
 Sk.Muscle relaxation-central
 Analgesia-Only Diazepam-i.v.
 No hyperalgesia*
 Ph.action contd…
 Sleep;
 Onset hastened
 Total sleeping time increased [stages 3&4 ↓]
 REM cycle increases ↑ but duration of REM
↓
 Night terrors decrease
 Wakes up refreshed
• RS: Hypnotic doses no effect. Higher doses
depress vent. & acidocis
• CVS: Low doses no effect. High-hpotension,
tachycardia. i.v. increases cor.flow*
Sites of action

 Sleep→Dep.of ascending reticular

formation
 Effect on mental function →Limbic

system
 Muscle relaxation →Medulla.

 Ataxia →Cerebellum*
 MOA

 GABA Inhibition By action on GABA

rec.
 GABA rec. A & B & C

 A. [Cl.channel] B [GPCR] C Cl.Channel]

 GABA is primary ligand.

 BZD binds to difft site & enhances

GABA binding action

 BZD ↑ frequency of Cl- channel opening

 GABA facilitatory-Not GABA mimetic*

 PK
 Absorption:
 Absorbrd completely
 Clorazepate-Gastrijuice-Nordazepam(Active)
 Prazepam, Flurazepam→Only active ingredients
reach Syst.circulation

 Metabolism
 Metabolized by CYP3a4 &CYP219
 Some yield active metabolites
 Eliminated after conjugation
 Enzyme inhibitors prolong action*
 Toxicity
 Safe drugs
 Light headedness, increased reaction time, motor
incordination,-IMPAIRS DRIVING-DANGEROUS
WITH ACOHOL
 Daytime sleepines
 Weakness, headache, blurred vision, vertigo, nausea,
vomiting, diarrhea, Jt.pain, incontinence
 Anticonvulsants may increase seizures
 Dependence-less than Barbiturates
 FLUNITRAZEPAM {ROHYPNOL]-
 Date rape drug*
 Drug interactions
 BZD + Alcohol→ Excessive CNS dep;.
 BZD + Valproate → psychotic symptoms
 CYP3A4 inhibitors →Prolong metabolism of BZD
 Duration of action:
 Ultra short acting → Midazolam
 Short acting →Triazolam-(Zolpidem)
 Intermediate acting[6-24h) →Estazolam,
Temazepam
 Long acting (>24h) →Diazepam, Flunazepam,
Quazepam*
 Novel Benzodiazepine receptor agonists
{Non-Benzodiazepine Hypnotics}

 Chemical structure does not resemble

 Agonists at BZD sites on GABA rec.

 Short half life(1-2h)

 Zaleplon. Zolpidem.Zopiclone.

Eszopiclone
 Amnesia, rarely hallucinations

 Short term use*

 Uses of BZD
 Insomnia[Dyssomnia]
2. Transient: <3 days. Stress. Sleep hygeine
3. Short term:3d-3weeks. Grief.Illness
4. Long term: >3 weeks. Medical problems,
psychiatric disorders.
 Anxiolytic . Status epilepticus.
Muscle relaxant. Short
procedures. Alcohol withdrawal.
With analgesics. FDC banned*
Ideal hypnotic
 Will not disturb sleep
architecture
 No next day effects

 No drug interactions

 No dependence

 REGULAR MOD. EX. IS IDEAL! *

 Treatment of insomnia
 Psychological:
 Go to bed only when sleepy
 Use bed & bed room only for sleeping & sex
 If awake after 20 mts leave the bed room
 Getup same time every morning-regardless of
sleep at night
 Discontinue coffee & Nicotine (at least
evenings)
 Reg.ex.regimen
 Avoid alcohol
 Relaxation therapy*
Treatment of insomnia
 Lorazepam-0.5mg.HS
 Temazepam-7.5-15mg HS

 Zolpidem, Zaleplon- 5-10mg. HS

 Younger-Double dose

 1-2 weeks.

 Intermittent therapy

 No Barbiturates*
 Flumazanil
 BZd receptor antagonist
 Against both agonist & inverse agonist

 High I pass metabolism

 Only i.v.

 Used to reverse BZD anesthesia

 BZD over dose

 0.2mg/mt→If does not respond suspect

other drugs along with BZD like alcohol*

Barbiturates
 Long acting:
Phenobarbitone
 Short: Butobarbitone,
Pentobarbitone,
 Ultra short acting:
Thiopentone,
Methohexitone*
 MOA
 Site of action: General global CNS
depression
 ↑Duration of opening of Cl- channels-
GABA facilitatory
 Higher concn. GABA mimetic

 Inhibit AMPA rec.

 Depress Na & K channels

 Multiple neuronal targets*

 Pharmacological actions
 CNS: Dose dependent depression
 Sedation→Sleep →Anesthesia →Coma → death.
 ↓Time taken to sleep
 ↑Sleep duration
 Hangover common
 Impairs learning
 Hyperalgesia(No analgesia)
 Anticonvulsant
 CVS: Hypotension
 RS: Depression*
 PK
 Well absorbed
 CNS entry depend on lipid solubility
 Termination of action-Metabolism, excretion,
redistribution
 Thiopentone-Highly lipid soluble→Penetrates
CNS in 6-10 sec. →Anesthesia →
Redistribution to other organs →Plasma
concn.falls →Back diffuses from brain →
Conciousness 6-10mts →Ultimate disposal by
metabolism*
 Uses and toxicity
o Uses
 Pheno-Epilepsy
 Thiopentone- i.v. anesthetic, Narcoanalysis
 Cong.non-hemolytic jaundice
 Not as hypnotic
o Toxicity
 Hangover
 PK & PD tolerance, dependence
 Confusion, paradoxical excitement
 Abuse liability, withdrawal symptoms,
hypersensitivity*
 Barbiturate poisoning
 Suicidal or accidental
 Gastric lavage with activated

charcoal
 Supportive-Airway, BP, Fluids

 Alkaline diuresis

 Hemodialysis

 No anti dote*
 CI And DI
 C.I.

 Intermittent porphyria

 Liver and kidney disease

 COPD

 Sleep apnoea

• D.I.
 Enzyme inducer→ reduces effectiveness of
Warfarin, OCP, Tolbutamide, Chloramphenicol
 Complex interaction with Phenytoin-
Competitively inhibits and induces*
 Why BZDs preferred

 High TI- Very high dose not fatal

 Hypnotic doses- other systems not

effected
 Sleep architecture not disturbed

 Rebound phenomenon less common

 Does not induce enzymes

 Lower abuse potential

 Antidote available*
Pharmacotherapy
of the epilepsies
 Pharmacotherapy of the epilepsies
 Seizure: Transient alteration of behaviour Due
to Disordered synchronous rhythmic of Brain
neurones
 Epilepsy: Disorder of brain function
characterized by periodic, unpredictable
occurrence of seizures
 Seizures “ Non-epileptic”- Evoked in normal
brain by electroshock or chemical convulsants
 Seizures “ Epileptic”- When occuring without
provocation*
Classification of epileptic seizures
Seizure type Features
 Partial Conciousness ++
 Simple 20-60Sec.

partial [SPS] Motor

or sensory
Conciousness impaired
 Complex 30-120 Sec
partial[CPS] Purposeless movements
 Partial Loss of conciousness
secondarily
SPS, CPS-evolves generalized
generalized-
tonic-clonic 1-2 Mts.
 Classification of epileptic seizures contd…..
Seizure type Features

Generalized

•Absence Abrupt loss of conciousness

[Petitmal] Staring, cessation of activities
30-60 sec
Myoclonic Brief [A Second], shock like

contraction of muscles
A part or general,

Tonic-clnic General tonic-clonic

[Grandmal] Not preceded by partial
 Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs

• SPS 1. Carbamazapine Gapapentine

2. Phenytoin Lamotrigine

3. Valproate Levetiracetam

Tiagabine

Topiramate

Zonisamide

• CPS ‘ Same as above’ ‘Same as above’

• Partial…. Carbamazapine
generalized Phenobarbitone ‘Same as above’
Phenytoin
Primidone
Valproate
 Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs
Absence  Ethosuximide Lamotrigine

 Valproate

Myoclonic  Valproate Lamotrigine

Topiramate

 Carbamazapine
Tonic-clonic  Phenobarbitone Lamotrigine

 Phenytoin Topiramate

 Primidone
 Valproate
Clinical classification of anti-seizure drugs

Seizure Drugs Second choice

Febrile Diazepam rectal

Status Diazepam i.v. Fosphenytoin i.v.

epilepticus Lorazepam i.v. Pheno i.v.

Movie!
 MOA of antiseizure drugs
 Reduce excitation→Reduce EPSP →Enhance
Na or Ca channel inactivation

Carbamazapine Lamotrigine Valproate

Phenytoin Valproate Ethosuximide
Topiramate Zonisamide Trimethadione
 MOA of antiseizure drugs
 Promote inhibition → Promote IPSP →
Enhance GABA transmission [Cl channels]
GABA
Vigabatrine ↓ GABA-T
Succinic semialdehyde
Valproate ↓ Dehydrogenase
Tiagabine Metabolites
GAT-1
GABA GABA
BZD binding sites

Barbiturates
 Phenytoin[Diphenylhydantoin]
 Earlier drugs –sedatives with
antiseizure properties
 Phenytoin is not a sedative

 Prompted researchers look for

selective antiseizure drugs-not

gen.CNS depressants*
 Ph.Properties-Phenytoin
 Antiseizure activity without

gen.CNS dep.
 MOA:

 Slows rate of recovery of

inactivated Na channels
 Toxic concn.-Ca channels and Cl

channels. Toxic effect than

Th.effect*
 Phenytoin-PK
 Highly protein bound-90%
 Non-linear elimination kinetics
 First order→upto 10 ug →Zero order
 Half life- 6h →60h
 Small adjustment in dosage →Plasma
concn.disproportanately↑
 Metabolism-CYP2C9/10-saturable
 Other substrates inhibit Phenytoin metabo.
 Phenytoin may also inhibit others →
Warfarin*
 Phenytoin-PK

 Enzyme inducer of →CYP3A4 → OCP →

Unplanned pregnancy.
 Imp-Phenytoin is teratogenic
 Low water solubility →Fosphenytoin →
Prodrug →i.v.use*
 Phenytoin-Toxicity
 Gingival hyperplasia-20% on chronic therapy
 Due to altered collagen metabolism
 Toothless portion not affected
 Good oral hygiene minimizes
 Hirsutism, coarse facial features
 Megaloblastic anemia-FA absorption &
excretion
 Osteomalacia-↓Ca absorption,↓Response of
tissues to Vit D
 Hypersensitivity-Neutropenia, liver toxicity,
SLE, skin rashes*
Gum Hyperplasia-Phenytoin toxicity
 Phenytoin-Toxicity Contd…
 Terratogenicity-Hydantoin syndrome
 Increased metabolism of Vit K- affects Ca
metabolism. Osteomalacia does not respond
to Vit D.
 Cerebellar, vestibular manifestations-Ataxia,
vertigo, diplopia, nystagmus
 i.v-Hypotension
 Plasma concn:
 10μg →Good seizure control
 20 μg →Toxic affects appear*
 Drug Interactions-Phenytoin
 Pheno & Phenytoin: Both induce enzymes→
metabolism of each other →Result
unpredictable
 CBMZP & Phenytoin →Induce each others
metabolism
 Valproate →Displaces phenytoin → Also
decreases metabolism! →Phenytoin toxicity
 Chloromphenicol, Cimetidine etc. inhibit
Phenytoin metabolism
 Phenytoin inhibits Warfarin metabolism
 OCP and Phenytoin*
Phenytoin-Uses
 SPS, CPS, Tonic-Clonic seizures
 Not in absence

 Status epilepticus

 Trigeminal neuralgia(Second-

CRBMZP)
 100 mg bd-TDM

 Cardiac arrhythmia. *
 Phenobarbitone
 Tonic-clonic, SPS, CPS
 Advantages-Low cost, low toxicity, Effective
 Behavioral disturb. In children
 Sedation
 60mg. 1-3 times a day

 Primidone: Prodrug. Converted Pheno and

PhenylEthylMelanamine in liver[both active].
Uses same as Pheno. *
 Carbamezepine
 Iminostilben
 MOA:

 Slows rate of recovery of inactivated

Na channels →Prevents repetitive firing

of AP.
• Ph.effects:

 Similar to phenytoin

 Effective in MDP [Phenytoin is not]

 Antidiuretic effect*
Carbamazepine-PK
 Absorbed slowly-erratically
 Metabolized in liver[CYP3A4]

 10-11 epoxy product is active

 Enz. inducer-CYP2C, CYP3A,

UGT,→OCP *
 Carbamazepine-Toxicity
 Neuro: Drowisiness, Ataxia, Diplopia,
Blurred vision →Gradual increase in
dosage →Tolerance
 Hematological: Agranulocytosis, Aplastic

anemia, Leukopenia, Neutropenia.

 Hypersensitivity: Dermatitis,

Eosinophelia, Lymphadenopathy,
Splenomegaly
 Water retension*
Carbamazepine-DI
 Enzyme inducer→OCP, Lamotrgine,
Haloperidol
 Pheno., Phenytoin →Increase

metabolism
 Enz. Inhibitors →Inhibit CRBMZP

metabolism*
Carbamazepine-Uses

 CPS, GTC, SPS

 Neuralgias- Not an analgesic,

blocks afferent impulse.

 MDP

 200-400mg TID. SR tablets*

Oxycarbazepine

 Prodrug→10-monohydroxy
derivative
 Not an enzyme inducer

 Less potent than Carbamazepine*

 Ethosuximide
 Reduces Ca flow in ‘T’ type Ca channels
 Reduces 3Hz spikes[EEG] from

thalamus neurones
 Effective in absence seizures only[ No

action on Na and GABA]

 ADE- GI, Behavioral effects[Anxiety,

inability to concentrate]
 250-300mg./day. →Increase 25 every

week*
 Valproic acid
 Carboxylic acid

 MOA-Multiple

 Na channels

 Ca channels

 Increases synthesis, Decreases

degradation of GABA
 PK: well absorbed*
 Valproic acid-toxicity

 GIT
 Alopecia

 Neurological:- Ataxia, blurred vision

 Fulminant hepatitis- Children below

2y, with other antiepileptics

 Fetus-Spina bifida, neural tube

defects*
 Valproic acid-DI & uses
 DI:
 Inhibits metabolism of Phenytoin & Pheno
 Inhibits UGT-Lamotrigine, Lorezepam
 Displaces & Inhibits metabolism of Phenytoin
 Valproic + Loreazepam→Absence status
• Uses-Broad spectrum
 Absence, Myoclonic, Partial, GTC
 15mg/kg →60mg.kg. *
Valproic acid toxicity

 GI disturbance
 Neurological-Ataxia, Blurred

vision,
 Alopecia

 Fulminant hepatitis→Children

below 2 years with other

antiepileptics*
 Benzodiazepines
 Clonazepam →Absence & Myoclonic
 Diazepam & Lorazepam →Status
 Clobazam, Clorazepate + Other drugs → Partial
seizures
 Diazepam:
 Not used in long term[Sedation, tolerance]
 Control of convulsions[Epilepsy & others]
 0,2-0.5mg/kg slow i.v. →100mg/day
 ADE-Fall of BP, Resp.dep.,
 Rectally in children-Febrile
 Lorazepam: 0.1mg/kg-i.v.-Long duration*
Other [new] Anti epileptics
 Gabapentine-
 Increses GABA release
 Used in Partial seizures
 Vigabatrine
 Inhibits GABA transaminase
 Used as adjuant
 Tiagabine
 Inhibits GABA Tpt-GAT 1
 ADD on in Partial seizures*
Lamotrigine

 Developed as antifolate agent

 Anticonvlsant axction-not related to

antifolate
 MOA-Na channels

 Moa as broad spectrum not understood

 Others: Levetiracetam, Topiramate,

Felbamate, Zonisamide, Acetazolamide*

 Principle of management
 Attend causative factor- Tumor
 Educate-Disease, Duration,

Toxicity, Compliance
 Avoid-Alcohol,Sleep deprivation,

stress
 Anticipate natural

variation-’Catamenial’
 Justify drug therapy*
 Guidelines to drug therapy
 Start with single, well tried safe drug
 According to type of seizure
 Age, sex-Hirsutism, terratogenicity,
hepatitis
 Single drug → Failure →SUBSTITUTE with
second[difft.MOA] →withdrawal of First
gradual
 Three drug hardly useful
 Dosage increased at particular time*
Dosage and administration

 Once or twice daily

 Small dose → increased two weekly

→ To Minimum effective dose →

further increase depends on
occurrence of seizures

 TDM: Important for Phenytoin*

 Drug withdrawal
 Seizure free for 2 years
 Factors decide recurrence:
 Type of epilepsy
 Early remission better outlook
 Single drug or multiple drug for remission
 Underlying lesion
 Associated neurological deficit
 20% relapse early- 20% Relapse in 5 years
 Withdrawn over 6 months
 Recurrence→Another 2 years of tt. *
Spl.Situations
 Status epilepticus: Diazepam, Lorazepam →
Pheno 100-200mg, i.m/i.v. →
Fosphenytoin25/50mg/Mt i.v. infusion,
max.1000mg. → i.v.Midazolam, Propofol,
Thiapentone, Curarization, G.A
 Care of unconscious
 Febrile: Rectal diazepam during fever in high
risk children*
 Spl. situations
1. Pregnancy:
 OCP failure
 Terratogenic
 Folate supplementation 0.4 mg/day
 Trial of drug free interval in women who
want to be pregnant
 Monotherapy if possible
 Vit K in last month
 Carbamazepine safest*
 50% of seizures are eliminated by
medication,
 30% of seizures are reduced in intensity and
frequency by medication,
 20% of seizures are resistant to medication.