Pharmacology of Sedative-Hypnotics and Anti-Epileptiics

Introduction to CNSAndSedative-HypnoticsAndAnti-epileptics

Dr.U.P.RathnakarMD. 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

Basics same as in ANSNeurotransmitters4 processes of neurotransmission

EPSP & IPSP*

Neurotransmitters

Excitatory amino acids L-Glutamate, Aspartate, Homocystate Inhibitory AA GABA, Glycine OthersNA, DA, 5HT, Ach, Purines[Adenosine &

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

A

Neurotransmitters

NT Rec Ago Antago Exc/Inh

ACh

M1 Atr, Pirenz. Ex

M2 Bethanecol

Atro Inh

N Nicotine Exc

DA D1 PhenothiInhD2 Bromo Phenothi

GABA GABA A Biccuculine Inh

GABAB Baclofen Saclofen

Glycine Strychnine Inh

5HT 5HT KetanserinOndansetron

Exc(Inh)

NT Contd….

NT Rec Ago Antago Exc/Inh

NA α1 Phenyl Prazo Exc

α2 Clonidine Yohimbine Inh

β1β2

DobutamineAlbuterol

Atenolol ExcInh

Histamine H1 Mepyramine ExcExcH2 Ranitidine

H3 InhInhOpioids Mu,delta,

KapaNaloxone

Endocanab CB1 & 2 Rimonobant Inh

Neurotrnsmission-4 processes1. Neurotransmission NT Released by neurones Criteria Immediate EPSP oR IPSP2. Neuromodulators NT released by neurones and astrocytes Long duration Long term changes in synaptic

transmission [Synaptic plasticity] Eg. CO2, Adenosine, PG, NO*

Neurotrnsmission-4 processes3. Neuromediators: II messengers [cAMP, cGMP, Inositol

phosphate]4. Neurotropic factors: Released by Neurones, astrocytes, microglia Longer duration Regulates growth & morphology of neurones Eg.Cytokines, Chemokines, growth factorsNeurohormones: released circulation-Vsopressin,

oxytocin*

EPSP &IPSP

EPSP•Opening-Na+ channels•↓Cond. Of Cl-channels•↓Cond.of K+channels•Changes in int.metabolism

IPSP•Opening Cl-channels•↑Cond. K+chnnels•Activation of enzymes-those ↑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 balanceAmong neuron

•Sleep-NREM &REM•NREM 90’-I,II,III,IV REM 5-30’Cycle repeates REM prolongsWake up from•Children-sleep & growth

Physiology of sleep

NREM REM Peacefull P.Symp+ BMR, CO, HR, PVR-Low Infrequent dreams-no

recall α rhythm Muscle relax-except RS

Hypotension No eye ball movement GH in stage 3 & 4*

Not Symp act+ High Vivid, bizarre,

sexual Β Rhythm Muscle

flacid(Ob.apnoea) Hypertension Rapid eye ball

movement*

Benzodiazepines[BZD]

1. Hypnotics: Diazepam, Nitrazepam, Alprazolam, Temazepam, Triazolam

2. Ant-anxiety: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam

3. Anti-convulsants: Diazepam, lorazepam, Clonazepam, Clobazam

4. 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

SleepDep.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, FlurazepamOnly 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]1. Transient: <3 days. Stress. Sleep hygeine2. Short term:3d-3weeks. Grief.Illness3. 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/mtIf does not respond suspect

other drugs along with BZD like alcohol*

BarbituratesLong 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 SedationSleep 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

solublePenetrates 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 toxicityo Uses Pheno-Epilepsy Thiopentone- i.v. anesthetic, Narcoanalysis Cong.non-hemolytic jaundice Not as hypnotico 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 seizuresSeizure type Features

Partial1. Simple

partial [SPS]

2. Complex partial[CPS]

3. Partial secondarily generalized-tonic-clonic

Conciousness ++20-60Sec.Motor or sensoryConciousness impaired30-120 SecPurposeless movementsLoss of conciousnessSPS, CPS-evolves generalized1-2 Mts.

Classification of epileptic seizures contd…..Seizure type Features

Generalized•Absence[Petitmal]

Myoclonic

Tonic-clnic[Grandmal]

Abrupt loss of conciousnessStaring, cessation of activities30-60 secBrief [A Second], shock like contraction of musclesA part or general, General tonic-clonicNot preceded by partial

Clinical classification of anti-seizure drugs

Seizure type Conventional New drugs

1. SPS

2. CPS

3. Partial….

generalized

1. Carbamazapine

2. Phenytoin

3. Valproate

‘ Same as above’

Carbamazapine

Phenobarbitone

Phenytoin

Primidone

Valproate

GapapentineLamotrigineLevetiracetamTiagabineTopiramateZonisamide

‘Same as above’

‘Same as above’

Clinical classification of anti-seizure drugs

Seizure type Conventional New drugsAbsence

Myoclonic

Tonic-clonic

Ethosuximide Valproate

Valproate

Carbamazapine Phenobarbitone Phenytoin Primidone Valproate

Lamotrigine

LamotrigineTopiramate

LamotrigineTopiramate

Clinical classification of anti-seizure drugs

Seizure Drugs Second choice

Febrile

Status epilepticus

Diazepam rectal

Diazepam i.v.Lorazepam i.v.

Fosphenytoin i.v.Pheno i.v.

Movie!

MOA of antiseizure drugs Reduce excitationReduce EPSP Enhance

Na or Ca channel inactivation

Carbamazapine LamotriginePhenytoin ValproateTopiramate Zonisamide

ValproateEthosuximideTrimethadione

MOA of antiseizure drugs

Promote inhibition Promote IPSP Enhance GABA transmission [Cl channels]

BZDGABA binding sites

Barbiturates

GABA ↓ GABA-TSuccinic semialdehyde ↓ DehydrogenaseMetabolites

GAT-1GABA

Vigabatrine

ValproateTiagabine

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 orderupto 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-erraticallyMetabolized 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 inducerOCP, 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

Prodrug10-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 + LoreazepamAbsence status• Uses-Broad spectrum Absence, Myoclonic, Partial, GTC 15mg/kg 60mg.kg. *

Valproic acid toxicity

GI disturbance Neurological-Ataxia, Blurred

vision, Alopecia Fulminant hepatitisChildren

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 RecurrenceAnother 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.