Pharmacology Of Sedative-hypnotics And Anti-epileptiics

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 

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

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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  

 



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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 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

NT

Rec

Neurotransmitters Ago Antago

M1 ACh DA

Bethanecol Atro

Inh

N

Nicotine

Exc

D1

Phenothi Bromo

GABA A GABAB

Glycine 5HT

Ex

M2

D2 GABA

Atr, Pirenz.

Exc/Inh

Baclofen

Phenothi

Inh

Biccuculine

Inh

Saclofen Strychnine

5HT

Inh

Ketanserin Exc Ondansetron (Inh)

NT Contd…. NT

Rec

Ago

Antago

Exc/Inh

NA

α1

Phenyl

Prazo

Exc

α2

Clonidine

Yohimbine

Inh

β1 β2

Dobutamine Albuterol

Atenolol

Exc Inh

H1

Mepyramine

H2

Ranitidine

Exc Exc

Histamine

Opioids

Mu,delta, Kapa

Naloxone

Inh Inh

Endocanab

CB1 & 2

Rimonobant

Inh

H3

Neurotrnsmission-4 processes

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* 1.

Neurotrnsmission-4 processes

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* n

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 drowsinesfacilitates 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 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*

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    



Not Symp act+ High Vivid, bizarre, sexual Β Rhythm Muscle flacid(Ob.apnoea) Hypertension Rapid eye ball movement*

Benzodiazepines[BZD] n

n

n

n

Hypnotics: Diazepam, Nitrazepam, Alprazolam, Temazepam, Triazolam Ant-anxiety: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam Anti-convulsants: Diazepam, lorazepam, Clonazepam, Clobazam Non[Novel]-Benzodizapine hypnotics: Zopiclone, Zolpidem, Zaleplon*

Benzodiazepines 

Benzene + Diazepine ring



Ph.Action:

 • • • • •

CNS: Sedative Hypnotic Anxiolytic Muscle relaxant Anterograde amnesia*

Peripheral > Coronary vaso.dil. > N.M.Block

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   

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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  2. 3. 4.



Insomnia[Dyssomnia] Transient: <3 days. Stress. Sleep hygeine Short term:3d-3weeks. Grief.Illness 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     

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  

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- channelsGABA 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     o    

Uses Pheno-Epilepsy Thiopentone- i.v. anesthetic, Narcoanalysis Cong.non-hemolytic jaundice Not as hypnotic 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 PhenytoinCompetitively 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 

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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  





Partial Simple partial [SPS]

Features Conciousness

++

20-60Sec. Motor

or sensory Conciousness impaired Complex 30-120 Sec partial[CPS] Purposeless movements Partial Loss of conciousness secondarily SPS, CPS-evolves generalized generalizedtonic-clonic 1-2 Mts.

Classification of epileptic seizures contd….. Seizure type

Features

Generalized •Absence

[Petitmal] Myoclonic

Tonic-clnic [Grandmal]

Abrupt loss of conciousness Staring, cessation of activities 30-60 sec Brief [A Second], shock like contraction of muscles A part or general, General tonic-clonic Not preceded by partial

Clinical classification of anti-seizure drugs Seizure type •

SPS

Conventional 1. 2. 3.

Carbamazapine Phenytoin Valproate

New drugs Gapapentine Lamotrigine Levetiracetam Tiagabine Topiramate Zonisamide

CPS

‘ Same as above’

Partial…. generalized

Carbamazapine Phenobarbitone Phenytoin Primidone Valproate

•

•

‘Same as above’

‘Same as above’

Clinical classification of anti-seizure drugs

Seizure type Absence

Conventional  

Myoclonic



New drugs

Ethosuximide Valproate

Lamotrigine

Valproate

Lamotrigine Topiramate

 Tonic-clonic

   

Carbamazapine Phenobarbitone Phenytoin Primidone Valproate

Lamotrigine Topiramate

Clinical classification of anti-seizure drugs

Seizure

Drugs

Febrile

Diazepam

Status

Diazepam

epilepticus

Movie!

Second choice

rectal

i.v. Lorazepam i.v.

Fosphenytoin Pheno

i.v.

i.v.

MOA of antiseizure drugs 

Reduce excitation→Reduce EPSP →Enhance Na or Ca channel inactivation

Carbamazapine Lamotrigine Phenytoin Valproate Topiramate Zonisamide

Valproate Ethosuximide Trimethadione

MOA of antiseizure drugs 

Promote inhibition → Promote IPSP → Enhance GABA transmission [Cl channels] Vigabatrine Valproate

Tiagabine GABA

GAT-1 BZD

GABA binding sites Barbiturates

GABA ↓ GABA-T Succinic semialdehyde ↓ Dehydrogenase Metabolites

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 life6h →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(SecondCRBMZP)  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         

GabapentineIncreses 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.