Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

An effective sedative (anxiolytic) agent should reduceanxiety and exert a calming effect with little or noeffect on motor or mental functions.

Sedation refers to decreased responsiveness to anylevel of stimulation and is associated with somedecrease in motar activity and ideation

A hypnotic drug should produce drowsiness andencourage the onset and maintenance of a state ofsleep that as far as possible resembles the naturalsleep state passive and highly suggestible

Awake

Amnesia

sedation

Hypnosis

Coma

Death

ACCORDING TO DURATIONOF ACTION :ULTRA SHORT ACTING(3-5 HOURS).TRIAZOLAM, MIDAZOLAMSHORH ACTING (6-24HOURS).

ALPRAZOLAM,NITRAZEPAMLORAZEPAMESTAZOLAMOXAZEPAMTEMAZEPAM

LONG ACTING:( 24-72 HOURS)

CHLORAZEPATECHLORDIAZEPOXIDEDIAZEPAMFLURAZEPAM.QUAZEPAMPRAZEPAM

Newer agents(non-benzodiazepines)ZOLPIDEM, ZALEPLON,ZOPICLONE, ESZOPICLONEBarbituratesPHENOBARBITONE, MEPHOBARBITONE,SECOBARBITONE,THIOBARBITONE, PENTOBARBITONE, THIOPENTONE,HEXOBARBITONEMiscellaneousPARALDEHYDE, CHLORAL HYDRATE, GLUTETHEMIDE,MELATONIN, RAMELTEON, MEPROBAMATE,

GABA –Gamma Amino Butyric Acid is a majorinhibitory neurotransmitter in CNS

Benzodiazepines potentiate GABA ergic inhibition atall levels of neuroxis—spinal cord, hypothalamus,hippocampus, substantia nigra, cerebellar cortex andcerebral cortex

Pentameric structure 5 subunits Macromolecular complex of ion channel

(1) Ultra-short-acting barbiturates: act within seconds,and their duration of action is 30min. Therapeutic useof Thiopental: anesthesia

(2) Short-acting barbiturates: have a duration of action ofabout 2h. The principal use of Secobarbital : sleep-inducing hypnotics.

Barbiturates share with benzodiazepines the ability toenhance the action of GABA, but they bind adifferent site on the GABA-receptor/chloride channel,and prolong the duration of the opening of GABA-activated chloride channels.

At high doses, barbiturates can inhibit the release ofthe Ca2+-dependent neurotransmitter

They exhibit a GABA mimetic action Depress action of excitatory glutamate

neurotransmitter by binding to AMPA receptor

High lipid solubility allows rapid transport across theblood-brain barrier and results in a short onset.

Removal from the brain occurs via redistribution tothe other tissues results in short duration of action.

Barbiturates and their metabolites excretion viathe renal route.

Alkalization of the urine expedites the excretion ofbarbiturates.

Treatment of acute over dosage: Sodiumbicarbonate and dialysis

Solution of sodium alkaline Cannot be given byIM/SC route necrosis and pain

Oral and IVWeakly acidic drugs

Metabolism-phase1- oxidationPhase 2-glucuronyl conjugation

Sedative-hypnotic agents Be used in the emergency treatment of

convulsions as in status epilepticus. Anesthetic (or be given before anesthetic) Combination with antipyretic-analgesic Treatment of hyperbilirubinemia and kernicterus

in the neonate Neonatal jaundice Preanaesthetic medication

After effect: hangover---dizzy, drowsiness, amnesia,impaired judgment, disorientation drug automatism

Tolerance: decreased responsiveness to a drugfollowing repeated exposure because of down-regulation of receptors and induction of hepatic drug-metabolising enzymes.

Have a narrow therapeutic-to-toxic dosage range.Suppress REM sleep.Tolerance develops relatively quickly.Have a high potential for physical dependence and

abuse drug automatismRespiratory depression and hypotension

Potent inducers of hepatic drug-metabolising enzymes.hyperalgesia

Dependence: including psychologic and physiologicdependence.

Withdrawal symptoms: excitation, insomnia, tremor,anxiety, hallucinations and sometimes convulsions.

Depressant effect on respiration: can cross theplacental barrier during pregnancy and secrete tobreast milk.

Others: Skin eruptions and porphyria Drug interaction-barbiturates metabolize OCPS

anticoagulants, theophylline, tolbutamide

An overdose can result in coma, diminished reflexes,severe respiratory depression, hypotension leadingto cardiovascular collapse, and renal failure.

Treatment(1) supporting respiration and circulation.(2) alkalinizing the urine and promoting diuresis.(3) Hemodialysis or peritoneal dialysis.

Benzodiazepines bind specifically to a regulatory site onthe receptor, distinct from the GABA binding site, andenhanced receptor affinity for GABA.

The GABAA-receptors is a ligand-gated ion channelconsisting of a pentameric assembly of subunits.

Benzodiazepines act very selectively on GABAA-receptors, which mediate the fast inhibitory synapticresponse produced by activity in GABA-ergic neurons.

The effect of benzodiazepines is to enhance theresponse to GABA, by facilitating the opening of GABA-activated chloride channels (an increase in thefrequency of channel opening, but no change in theconductance or mean open time).

Reasons for their extensive clinical use:1) great margin of safety;2) little effect on REM sleep;3) little hepatic microsomal drug-metabolizingenzymes4) slight physiologic and psychological dependenceand withdrawal syndrome5) less adverse effects such as residual drowsiness andincoordination movement.

1. Reduction of anxiety and aggression :affects the hippocampus and nucleus amygdalae

2. Sedation and induction of sleep:The latency of sleep onset is decreased;The duration of stage 2 NREM sleep is increased;The duration of slow-wave sleep is decreased.

3. Anticonvulsant and antiseizure

They are highly effective against chemicallyinduced convulsions caused by leptazol,bicuculline and similar drugs but less so againstelectrically induced convulsions.

They can enhance GABA-mediated synapticsystems and inhibit excitatory transmission.

PHARMACOLOGICAL EFFECTS

4. Muscle relaxationrelax contracted muscle in joint disease

or muscle spasm.5. Anticonvulsant effect: especially

diazepam, lorazepam, clorazepate,clonazepam, nitrazepam.

6. Other effectslead to temporary amnesiadecrease the dosage of anestheticdepress respiratory and cardiovascular function.

PHARMACOLOGICAL EFFECTS

Well absorbed when given orally;They bind strongly to plasma protein, and their highlipid solubility cause many of them to accumulategradually in body fat.

All Benzodiazepines are metabolized in the liverPhase I: ( liver microsomal system)Phase II: glucuronide conjugation and

excreted in the urine.

Dose reduction inLiver diseaseOld people.Synergistic effect with other CNS depressants

Drug interactionConcurrent with sodium valproate can provokepsychotic symptomsRifampicin (decreases half life)Cimetidine, isoniazid, OCPs (increases half life)

ContraindicationAlcohol and other CNS depressants, antihistamines

TRIAZOLAMused only for sedation in severe insomniasIt also has amnesic, anxiolytic anticonvulsant, musclerelaxant propertiesOral-44% sublingual-53%

OXAZEPAM-Used to relieve anxiety with alcohol withdrawalOral bioavailability is 95%Used in treatment of insomniasIt is a metabolite of Diazepam, PrazepamIt is amnesic, anxiolytic anticonvulsant, hypnoticUsed in Post traumatic stress disorderUsed in pre-menstrual syndrome10-15mg

MIDAZOLAMTreatment of acute seizures, insomniasAnxiolytic, hypnotic, anticonvulsantInduction and maintenance of anaesthesiaIntranasal, buccal routeUsed for endoscopy

Anxiety disorders: alprazolamGeneral anxiety disordersPanic attack - major depressive disorders

Sleep disorders (Insomnia).Estazolam, Lorazepam, temazepam:Flurazepam, QuazepamLong acting drugs can cause hangover.

3.To control withdrawal symptoms of alcoholsdiazepam- chlordiazepoxide.

4.Treatment of epilepsyDiazepam – Lorazepam: Status epilepticusClonazepam-Clorazepate: absence , myoclonicseizures.

5.Muscle relaxation: in spastic states (Diazepam)

In anesthesia1. Preanesthetic medication diazepam2. Induction of balanced anesthesia(Midazolam)3. Adjunct therapy during minor surgery

(endoscopy, bronchoscopy, dental surgery).

Acute toxicity: Benzodiazepines in acute overdose areconsiderably less dangerous than other sedative-hypnotic drugs.

Cause prolonged sleep, without serious depression ofrespiration or cardiovascular system

The availability of an effective antagonist, flumazenilcan avert toxicity reactions

Side-effects during therapeutic use: drowsiness,confusion, amnesia, impaired coordination. Maindisadvantages are interaction with alcohol, long-lasting hangover and the development ofdependence.

Tolerance and dependence: induction of hepaticdrug-metabolising enzymes; a change at thereceptor level

a selective competitive antagonist of BZDreceptors (Bz1).

Blocks action of benzodiazepines, zaleplon andzolpidem but not other sedative /hypnotics.

Blocks psychomotor, cognitive and memoryimpairment of BZs.

Has short duration of action T 1 /2 = 1 hourAbsorbed orally, need to be used repeatedly IV

Zopiclone is a cyclopyrrolone in structure.Acts at the GABAA-benzodiazepine receptorIt has a fairly fast (about 1 h) onset of actionwhich lasts for 6–8 h, making it an effective drugboth for initial and maintenance insomnia.Its duration of action is prolonged in the elderlyand in hepatic insufficiency.The dose is 3.75–7.5 mg orally

ZolpidemIt is an immidazopyridine in structureFast onset (30–60 min) and short duration of actionSleep latency is shortenedSleep duration is prolongedRelative lack of effect on sleep stages (REMsuppression)Zolpidem is nearly completely metabolised in liverDose-10-20mg

ZaleplonShortest acting newer non-BZD that inhibits BZDreceptors containing alfa1 subunitRapidly absorbedOral bioavailability is 30%Due to first pass metabolismT1/2-1hrDose-5-10mg HS

N-acetyl -5 methoxy tryptamine is principal hormone ofpineal glandHigh dose-80mg can induce sleepLow dose-2-10mg donot depress CNSIt has improved sleep quality in elderly insomniasMelatonin supplements may retard agingIt is tried in cluster headacheMeloset-3mg

Buspirone, Ipsapirone, GepironeThese drugs act through non-GABAergic systemSelective activation of inhibitory presynaptic 5HT1AReceptor, they suppress 5HT neurotransmissionthrough neuronal systemBUSPIRONEMinimal abuse liability and no withdrawal reactionsNo rebound anxiety, insomniaBuspirone causes less impairment of psychomotarskills

Buspirone does not potentiate the CNS depressanteffect of ethanol (non-sedating anxiolytic drug)

It has no muscle relaxant, anticonvulsant or hypnoticaction

It can cause tachycardia nervousness, GIT distressand parasthesias

PROPRANOLOLPropranolol helps to suppress such performanceanxiety by breaking vicious cycleBeta –blockers decreases palpitation, tremors, GITupset hypertension and blood lactic acid levels20mg TDSmay have associated CVS effectsmakesit unlikely to be used as potential anxiolytic agent

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