ANTI ANXIETY DRUGS.(Sedative) Hypnotics, Psychoanalgesia)ANXIETY. Unpleasant emotional state associated with uneasiness & fearful concernabout future and behavioral changes in response to environmental events that are nonRewarding (when it is expected).PunishingFrustrating.SecondaryDiseases:MIPU (Peptic Ulcer)IHD (Ischemic heart Diseases)Situational Anxiety:Illness.Tragedy.Medical or surgical procedure.Other stressful events.Manifestations of Anxiety.PsychologicalBehaviouralPsysocilogical. a) Verbal complaints of being anxious (Anxiety) b) B) Somatic & Autonomic ffects: • vigilance. • Restlessness. • Agitation. • Motor tension. • Tachycardia. • Sweating • Emotional upset like weeping etc. • G-I upset (Abdominal pain, diasehea etc.) c). Interference with N0 productiove activity &^ stressful tasks like: * driving *Public speaking. * Playing instrument *Sitting in exams. * Surgery. * Sports.CONDITIONS RELATED TO ANXIETYPhobic anxityPanjic disorder.Generalized anxiety disorder.Excersive & unreasonable anxiety about N0 life circumstance.Post- transmatic stress disorders
ANXIOLYTIC SEDATIVE & HYNOTIC) 1) Benzodiazepines: Diazepam.2. 5-HT1A recap Agonists.Buspirone.Ipsapirone.GepironeTendospiron.3. Barbituates.(Obsoleted Now)4. B-Recep. Antagonists.Propranolol.5. X2 recep Agonists.Clonidine.From 6-10 gp No need to remember gp name.6) imidazopydine.Zolpidem.7. Pyrazolopyrimidine. Zaleplon.8. Cyclopynelone.ZopidoneEszopiclone.9. Melatonin recap. Against: Rameltcon.10. MISC:-Cacbamates:-MeprobamatePipecidinediones:-GlutethincideMethylprylon.ALCOHOLS (CJLORAL DERIVATIVES)Chloral hydrate.Trichloralethonal.Etheclorvynol.Cyclic Ethers:-Parcaldehyde.Sedative anti-histamines:_DiphenhydraminePyrilamineDoxylamine.PromethazineHydroxyzine.Other Drugs:-EthynamateClomethiazole.TCAEtomidate (I/V anaesthetic, in dose is used for sedation.
Antipsychotics.Anti- Narcoleptic Drugs: Modafinil.Inhibitory NYS in CNS.GabaGlycineTausine.DISTRIBUTION OF GABA.Transmitter at about 30% of synapses in CNS.Cerebellum, cerebral coirtex, hypothalainus.All newrons sentitive to Gaba.GABA RECEPTORS:Effects Gabaq-APost synptic inhibition,CT conductance.Gaba.Pre synaticInhibition Ca+2 conductance, IC conductance.Agonists.Gaba + +Balofen - +Muscimol. + _AntagonistsBicnculline CompetitivePicrotoxin Non-competitive Direct channel block.Phacloten - +Potentiation.Benzodiazzepines + -Bacebitucates + -Macrommolecular/supra. Competent.Contains Gaba A + benzodia zepeines binding site + ion channel CT channelBinding of Gaba-A & drug to their respective binding sites.Openinbg if ion channel occursCarring cl influxHyperpolacizationSo, stablise the cell.OTHER DRUGS INTERACTING WITH GABA RECEPTORS.Alcohol.
I/V anaesthetyics Alphyoxolone etomidate.Propfol.Inhalation anesthetics HalothanceAntiepilpticsGabapenter.Vigabation.Antihalmintics.Ivenmetion cause pacalyisi of wormCNS StimulantsBiccusculine.BENZODIAZEPINESCHEMISTRY:-A seven members ring fused jto an aromatic ring with 4 main substitution sites (R1---R4)A= BenzeneB= Diazepine ring (7 membered)C=5 aryl substituent(4 substrate sites R1—R4)A substitution in 7th position a Halogen or Nitro group is required for sedative hypnoticactivity.Triazolam & alprazolam include a triazolam & at 1,2 positionSeveral BDZ are synthesized by diff substitution.GABA- a RECEPTORS.Pentaminc structure assembled from 8 submits selected from sultiple polypeptide clonesi.e B V S which have multiple submits.Eg 6diff & 4B 3VGaba receptor displays heterogeneity in diff areas of CNS consisting of diff combinationof these essentiasl sub units In most areas Gaba A receptor is made up to 2 & 2B and oneV sub-unit.CCMuscule relaxainton.X5 Subunit:Memory impairment.BDZ- Recep interaction: 1. Agonist BDZS, zolpidem, zaleplon, zopiclone, E szopiclone. 2. Antagainst:- Funmezenil, antagonize all above but not bacbituraters, meprobanate, and ethanol. 3. Inverse against: 4. B- carbolines can procduce anxiety & seizures. 5. They can also blockl the effect of BDZ’s ] Basal activities recap has some activity always, not zzero activity any time. When recap. Has 2 conformations like BDZ recap. BDZ bind configueation shift. To the configureation to which BDZ can bind. BDZ against A configueration efficacy B-cacboline, Inverse against efficacy. Basal activity is ed basdal activity is responsible for day to day control of anxiety when B-A ed person become anxiogenic Inverse aginst:
Block effect of against antagonist effect Opposite to No clinical anxixoylic No sigrificance effect of BDZ. MOA 7 DISTRIBUTION OF RECEPTORS. BDZ potentiate Gaba ergic inhibition at all the levels of nerural axis. They are no Gabaergic not Gaba memetic Including:• Sp. Cord• Hypothalamus.• Hippocartnpus• Subst. Nigra• Cerbral cortex• Cerebellac cortex.SPECIFICITY.1. Structural related to structural.2. Biology, every recap has its own tissue distribution.Gaba bind b/w x & B- submunitBDZ bind b/w B&X subunit.1. .Both REM & NREM. Sleep imp for N0 physiological behaviors Dissemblance in anyone of them cause refreshment. PHARMACOLOGICAL EFFECT OF BDZ.a) CNS:2. Sedfation calming effect of anxious, resteress, against pt.3. Reduction of anxiety & aggervsion.4. Depression of psychormotol & congnitive fxns mental. Memory, leaving, recall.5. Diminish the punjishment suppressed behaviours in animals this disinhibited behavoin equates with anxioulytic action on human).6. Behavioueral disinhibijtory eff lead to impaired judgement loss of self control & some enphorient eff. Due to anxiety relief not enphoric effect.7. Anterograde Amnesia (Dose dependent)8. with small dose less events undec with laege dose more drug effect for some hrs.Retrogrfade Amensia by drugs:Hyoscine (Anti muscacinic)Induction of sleep from sedation hyprosis• Sleep latency (Pt goes to bed wait for hrs and tirs bt not sleep)• Duration NREM stfage-2 sleep• Sleep is not refreshing• Duration of total sleep• Intermitten awakening• Dueration of REM sleep• Duration of BREM stage-4Show wave. Sleep (Metab rate & adr. Steroid sec. are at lowerst & growth hormone athighest) No prominent eff on metabolic fxns & secretions but after prolonged.9. Anaesthersia- Diaz loraz, midaz & in combination with othert agents.(midazepam, Diazepam, Lorzepam)
Reduction of muscle tone & co-ordination- independent of se4dation. Fine movementlost Muscle tone Hypotonia. In pregnancyI/V ose is not practiced CZ resp support sudden apnea death should be present.For jendoscopy small period anaesthetics ishort procedures.10. Central muscle relaxant eff (BDZ) & meprobamate use of BDZ*epilepsyFor RX of dnig induced convulsion list line linedrugs.• spasticity disorderts.• Inhibit poly synaptic reflexes• Depren internucial transmission• High dose depress tramission in sk muscle.11. Anti convulsant eff. (leptfazole induced)RX of convulsionh:Diazepan, chlorazepam.Statis AbsenceEpi lepticus seizures.12. Anti depressant eff (Alprazolam)13. Tolerance & cross tolerancePh.K componentMemtabolismDyna plaer4ance due to recap denyelination.Defect in drug recap coupling.Psycholgivcal dependace 6-8 wks usePhysical dependence but not sever.Rebound eff withdrawal eff.14. Dependance: (more than 2-6 wks). Opiod just 1-2 days use cause dependence.WIDE SPREAD SAFETY MARGIN.B) CVS;Depressed.N0 no prominent phenonmen effect.If hypovolemica then prominent eff in ferson.b) RESP. SYSTEMNormal person not prominent eff.Pt suffering from COPD bdz leads to resp deprevsion death can occure.PHARMACOKINTICS OF BDZS.ABSOCPTION: oral injectable, I/MHighly lipid soluble abscbed from site of absorptionChlorfazepate undergo activations in stomach by hydrolysis.DISTRIBUTION.Groos top CNS cross BBB central effect. Aq humorBlood aqBlood milleBlood testis.Can be secreted in milk 16.6- 6.9Basic drugs are secrtelted in milk (non polac in blood) lipid shouble goes in milkbecome polar these and remain these.
BIO TRANSFUNATION.Dealkylation (Active)Hydroxylation Glu crnidation Active (inactivation)Occucin CYP 3 A4 in liverSo. Metabolism of most BDZ is affected by enz inducers & enz interibitos hepaticdysfxn & eldecly pt.No active metabolite with Lorazepam oxazepam & estazolam.FNZ inducers: ducation ½ liver dystxnEXCRENTION:Glucronideslinaetive by kidneys.No roles of kidney. CC CCCC They are of SD____lcrs. Chances of long overs Tolerance. Addictive pot Mental & physical impairment. BDZ ANTAGONISTYS: FLUMAZEIL:• Imidazo BDZ.• Ist discovered in 1981.• Competitive antagonist of against and inv agonists b/C it will bind recap in constitutive states.• At high doses partial agonistic activity.• Do not block eff of other sed hypnotics opiods, ethanol & gene anesthetic b/C only bind BDZ recap.Pharmaeokinetics.T1/2 0.7-1.3 hrs rapid hepatic collearance.Dosage 1-1omg.I/VUSES:BDZ & mixed CNS deprersion.Nevrological deficit in hepatic encephyalo pathy.Diagnosis of addiction.cc5HT1A AGONISTS AS ANXIOLYTICS:1. BUSPIRONE: 5mg TDS Act as partial against at 5ht recap. They are abundant in septohippo-campal region & receive projection. From midbrain raphae SHT neurons. They will the 5HT autoinhyibitory recap eff. Release of mediators so, they act indirectly. 5HTT1A recap are authionhibitory. Aslo bind doparmine recap. Chronic use adaptive reduction in cortical SHT recap activity.
So the eff onset is delayed so cannot used for acute conditions. Not eff in panic disorders & acute anxicty states. Also inhibit NA act of locus ceruleus neurons interfere e arousal reactions. ADV: No sedation> No motor incoordination no withdrwal symptoms. No anticonvulsant eff. No memory impairment. Addicitive potential. Tolerance potential. A/E Nausea, Dizziners, Headache, Restlessness. KINETICS. Well absorbed pec orally. Metabolism in liver by dealkylations & hydroxylation. Active metabolitie. Major is 1 (2 pyrimdyl) piprazine which also has antagonistic action on x-recep.2) ISAPIRONE. Has high selectively for 4HT1A recap.Also 5HT transmission iridirectly.NATI ENXIETY3) SUMOTRIPAN.4) GEPIRONE. All have similar action.5) TAMDPSPIRONEAll of them:- Less psychomotor impairment so Do not effect driving skill No sedation & hypnosis No above liability No motor in coordination No rebound anxiety No withdrawal effects No binding with GABA OR BDZ binding Sites No anti conwlsents No muscle relaxant effects No euphoriant potential Do not potential effect of other Sedatives, hypnotics, alcohol & Tricycles Elderly pts are not more sensitive . CI: MAO-I therapy (BP) Vses: Generalized anxity atates
Drug Innteraction:• Refampicin ½ Buspirone• Ketoconazole inhibit ayp 3A4 & 1+ ½MELATONIN RELEPTOR AGONISTRemelteon:-MDA:• Agonist at Melatorin receptors MT1 & MT2• Melatonin involved in maintaining circadian rhythm of sleep/wake cycles• Has MT1 & MT2DISTRIBUTION:Supra chiasmatics nucleiKINETICS: Well – absocbed per orally extensive, 1st pars effect by cyp-I A2 – active metabolite with long T1/2Action: Reduce sleep latency T sleep duration No rebound insomnia or withdrawl effect – ( particularly with short acting drugs)A/E: DIZZINESS Fatigue Somnolence Prolactines level is Testostecon lavelUses:Sleep disorder especially those with sleep latency & difficulty in falling sleepInteraction:Flurocamine which inhibits hepatic cyp 1A2BARBITURATES:a) long Acting: Phenopasbitone Mephobasbitoneb) Intermediate Acting: Butobasbitone Now obsolete Hexobasbitone Cyclobasbitone