Pharmacology of Sedative-Hypnotics and Anti-Epileptiics
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Transcript of 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.