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BARBITURATES  Guide:- Dr. Archana         TripathiPresenter:- Dr.   Khushboo
INTRODUCTION IV Anesthetic induction agent 1st IV anesthetic agent used in clinical practice Deriatives of barbituric a...
HISTORY First created in 1864 by a German scientist named  Adolf von Baeyer. It was a combination of urea from  animals a...
CLASSIFICATION A.Ultrashort acting:-       C.Intermediate acting:-  (acts within seconds and     (effects last 3-5hrs)  ...
STRUCTURE                     Oxybarbiturates                     ThiobarbituratesTHIOPENTONE:5-ethyl,5[methyl,butyl]2-thi...
STRUCTURE ACTIVITY       RELATIONSHIP Keto-enol tautomerization(enol form active and allow    solubility)   Either oxyge...
PHYSICOCHEMICAL         PROPERTIES Prepared commercially as sodium salts readily    soluble in water or saline   Decreas...
THIOPENTONE                           METHOHEXITONE1.PHYSICAL PROPERTIES   -Yellowish powder                  -White powde...
MECHANISM OF ACTION Preferentially affect the function of nerve synapses rather  than axons   1.Enhance action of inhibit...
GABA creates a negative change in the    transmembrane potential(hyperpolarization).    This makes it an Inhibitory neurot...
 At low conc.-GABA-facilitator At high conc.- GABA-mimetic(barbiturate  anesthesia) Block AMPA receptor which is sensit...
PHAMACOKINETICS Absorption Protien binding Distribution Ionization Metabolism Renal excretion USUAL DOSE-First orde...
PROTEIN BINDING Depends on lipid solubility Thiopentone is highly lipid soluble barbiturate Most avidly PP BOUND Decre...
DISTRIBUTIONFACTORS AFFECTING PP binding:Low PP binding more free form Lipid solubility:High lipid solubility readily cr...
Compartment model                       Induction dose            rapid mixing of drug with central blood volumequick dist...
IONIZATION Thiopentone has pk 7.6 that is near blood ph Acidosis thus favour non ionised drugs Acidosis increase the in...
METABOLISMA.Thiobarbiturate –Hepatic & Extrahepatic(kidney and CNS)B.Oxybarbiturates-Hepatic BIOTRANSFORMATION   1.Oxidat...
EXCRETION:- Renal excretion is limited to water-soluble end products  of hepatic biotransformation <1% of administered t...
COMPARATIVE PHARMACOKINETICS                               Thiopentone               MethohexitolRapid    COMPARATIVE dis...
 Earlier awakening In pediatric due to rapid  total clearance Delayed awakening in elderly due to  increased CNS sensiti...
CLINICAL CONSIDERATIONS Prompt awakening in 5-10min after a single dose of  thiopental or methohexital reflects redistrib...
EFFECTS ON ORGAN SYSTEMS  Cerebral metabolism: Decreases CBF and ICP but CPP preserved CMRO2 and ATP consumption decreas...
 Cardiovascular:  -CV depression by both central and peripheral effects  -Peripheral vasodilation and fall in BP   -Decre...
 Hepatic:     Hepatic blood flow is modestly decreased    Induction doses do not alter postoperative LFTs    Enzyme in...
 Immunologic:    Thiopentone inhibit nuclear transcription factor κB    Impair neutrophil function    Anaphylactic and...
CLINICAL                INDICATIONS1. Principal clinical uses of barbiturates:      Induction and maintenance of anesthes...
CONTRAINDICATIONS A.ABSOLUTE   Porphyria B.RELATIVE 1. Bronchial asthma,ch. Bronchitis, smoker’s  cough 2.Shock 3.Res...
 6. Severely anemic and Acidotic patients 7.Jaundice, severe hepatic or renal disease 8. Previous hypersensitivity reac...
ADVERSE EFFECTSA.COMPLICATIONS1.On injection-garlic or onion taste2.Perivenous and Intramuscular injections-Local tissue  ...
6. Intraarterial Inj.-Degree of injury related to conc. of drug   s/s: pt.complains of intense burning pain down to the in...
T/t :-1.Leave the needle at site;dilution of drug by saline4p’s-2. 5-10ml of plain xylocaine1%(old drug-procaine)     -3.P...
B.SYSTEMIC ADVERSE EFFECTS1.CVS -mild decrease SBP d/t vasodilation       -profound hypotension d/t nonimmunologically    ...
5.LIVER- Enzyme induction so a.accelerate metabolism of drug e.g;oral anticoagulants,    phenytoin and TCAs b.accelerate m...
RECOMMENDED DOSES  DRUG          INDUCTION      ONSET(sec)     IV                DOSE(mg/kg)                   MAINTENANCE...
PREPARATIONS 0.5gm is diluted with 20cc of distilled water to  make 2.5% concentration 1gm preparation is also available
DOSE VARIABILITY LOWER INDUCTION DOSE REQUIREMENTS:-A.Less bood volume -Hemorrhagic shock                       -dehydrat...
 INCREASED DOSE REQUIREMENT A.urbans people B. chronic alcoholics C. Children >1yr after thermal injury
MEDICATION INTERACTIONS Contrast media, sulfonamides,  aspirin,coumarin anticoagulants and other  drugs that occupy the s...
COMPARISONTHIOPENTONE                         PROPOFOLA.PROPERTIES1.Ultra short acting barbiturate   1.Short acting propyl...
THIOPENTONE                              PROPOFOLC.ACTIONS1.Sedation,hypnosis,antianalgesia      1.hypnosis, amnesia,noana...
THIOPENTONE        PROPOFOLE.INDICATIONS1.Induction        1.Induction2.Anticonvulsant   2.Maintenance3.Control ICP      3...
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Barbiturates
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Barbiturates

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Barbiturates

  1. 1. BARBITURATES Guide:- Dr. Archana TripathiPresenter:- Dr. Khushboo
  2. 2. INTRODUCTION IV Anesthetic induction agent 1st IV anesthetic agent used in clinical practice Deriatives of barbituric acids(2,4,6- trioxohexahydropyrimidine) Water soluble salts, alkaline in nature Can be used as hypnotics, sedatives, anticonvulsants and anesthetics Depressant for all excitable cells,CNS most sensitive Three clinically important drugs in anesthesia thiopentone, thiamylal and methohexitone
  3. 3. HISTORY First created in 1864 by a German scientist named Adolf von Baeyer. It was a combination of urea from animals and malonic acid from apples. used to put dogs to sleep Also popular and abused in pop culture because of their alcohol like effects Introduced clinically by Water and Lundy in 1934 Interesting facts:-• Caused the death of many celebrities such as Jimi Hendrix and Marilyn Monroe• Used by the Nazis during WWII for euthanasia
  4. 4. CLASSIFICATION A.Ultrashort acting:-  C.Intermediate acting:- (acts within seconds and (effects last 3-5hrs) duration of action -Amobarbitone 30min) -Methohexital -Butabarbitone sodium -Thiamylal sodium -Thiopental  D.Long acting:-(effects sodium lasts 6hrs) B.Short acting:-(acts -Phenobarbitone within minutes and -mephobarbitone duration of action 2hrs) #only ultra short acting are -Hexobarbitone useful as anesthetic agent
  5. 5. STRUCTURE Oxybarbiturates ThiobarbituratesTHIOPENTONE:5-ethyl,5[methyl,butyl]2-thiobarbiturateMETHOHEXITONE:1-methyl-5-allyl5[methyl,pentynyl] 2-oxybarbiturate
  6. 6. STRUCTURE ACTIVITY RELATIONSHIP Keto-enol tautomerization(enol form active and allow solubility) Either oxygen or sulphur at position 2 Sulphur at position 2 produces more lipid solublity,rapid onset,greater hypnotic potency but shorter duration of action eg;thiopentone Phenyl group at position 5 produces anticonvulsant property eg;phenobarbitone Increase in length of side chain atC5 increases hypnotic potency eg;pentobarbital Addition of methyl group at C1 produces rapid onset of action, but excitatory side effects eg;methohexital
  7. 7. PHYSICOCHEMICAL PROPERTIES Prepared commercially as sodium salts readily soluble in water or saline Decrease in alkalinity of solution precipitation Incompatible for mixture with acidic solution -ringer lactate -drugs pancuronium, vecuronium, atracurium, alfentanil, sufentanil and midazolam. Bacteriostatic property due to alkaline pH Mixed with 6%anhydrous sodium carbonate to prevent precipitation of insoluble acid form of barbiturate by atmospheric CO2. Sulphur is hygroscopis so,Vaccum is created in vial with removal of oxygen
  8. 8. THIOPENTONE METHOHEXITONE1.PHYSICAL PROPERTIES -Yellowish powder -White powder -Bitter in taste -Faint garlic smell -pKa-7.6 -pKa-7.9 -pH-10.5 -pH-112.PREPARATION -2.5% solution -1% solution3.STABILITY(Powder form stable indefinitely) -Refrigerated solution stable -refrigerated solution upto 2weeks stable upto 6weeks -at Room temperature stable for 6days .
  9. 9. MECHANISM OF ACTION Preferentially affect the function of nerve synapses rather than axons 1.Enhance action of inhibitory neurotransmitters 2.Suppress action of excitatory neurotransmitters Interact with GABAA receptors → Decrease rate of dissociation of GABA → Increase duration of GABA activated opening of Chloride channels → depresses RAS → decrease wakefulness Interferes with transmitter release (presynaptic) and stereoselectively interacting with receptors (postsynaptic) Barbiturates also targets other receptors – Adenosine recptors and n Ach receptors
  10. 10. GABA creates a negative change in the transmembrane potential(hyperpolarization). This makes it an Inhibitory neurotransmitter GABA binding site Barbiturate binding site
  11. 11.  At low conc.-GABA-facilitator At high conc.- GABA-mimetic(barbiturate anesthesia) Block AMPA receptor which is sensitive to glutamate,excitatory neurotransmitter
  12. 12. PHAMACOKINETICS Absorption Protien binding Distribution Ionization Metabolism Renal excretion USUAL DOSE-First order kinetics HIGH DOSE-Zero order kinetics
  13. 13. PROTEIN BINDING Depends on lipid solubility Thiopentone is highly lipid soluble barbiturate Most avidly PP BOUND Decreased protein binding in uremia &cirrhosis of liver In cirrhosis of liver due to hypoalbuminemia PP binding decreases but clearance rate not altered because adequate protein present still at advanced stage In neonate pp binding half of adult -reason for increased sensitivity to thiopentone. In stressful delivery (fetal acidosis ) unbound fraction further increases.
  14. 14. DISTRIBUTIONFACTORS AFFECTING PP binding:Low PP binding more free form Lipid solubility:High lipid solubility readily crooss BBB Degree of ionization:Low ionization readily cross BBB Dose and Rate of administration Tissue blood flow:in hypovolemia exaggerated cerebral and cardiac depression Volume of disribution-larger in females and pregnancy -smaller in elderly and hypovolemia
  15. 15. Compartment model Induction dose rapid mixing of drug with central blood volumequick distribution to highly perfused,low voume tissues(i.e.,brain)in 30sec slower redistribution of drug to lean tissue(muscle) termination of effect of induction dose(rapid recovery)in 5-10 mins Continuous infusion slower process of uptake into adipose tissue after 30sec elimination clearance through hepatic metabolism delay of recovery
  16. 16. IONIZATION Thiopentone has pk 7.6 that is near blood ph Acidosis thus favour non ionised drugs Acidosis increase the intensity of barbiturate effect More effected by metabolism induced alteration in pH
  17. 17. METABOLISMA.Thiobarbiturate –Hepatic & Extrahepatic(kidney and CNS)B.Oxybarbiturates-Hepatic BIOTRANSFORMATION 1.Oxidation of alkyl,aryl, or phenyl moiety at C5(most imp) 2.N-dealkylation 3.Desulfuration of thiobarbiturate at C2 4.Destruction of barbituric acid ring Metabolites-polar alcohols,ketones,phenols,carboxylic acids -inactive,water soluble and readily excreted in urine -glucuronide conjugation in bile Drugs that induce oxidative microsome enhance metabolism Long term administration induce enzymes
  18. 18. EXCRETION:- Renal excretion is limited to water-soluble end products of hepatic biotransformation <1% of administered thiopental or methohexital is excreted unchanged in the urine Renal excretion is important in the elimination of phenobarbital only Alkalinization of urine with bicarbonate enhance renal excretion of phenobarbital
  19. 19. COMPARATIVE PHARMACOKINETICS Thiopentone MethohexitolRapid COMPARATIVE distribution 8.5 5.6T½(min) PHARMACOKINETICSlow distribution 62.7 58.3T½(min.)IT½ Elimination (Hrs.) 11.6 3.9CL (ml/kg/min.) 3.4 10.9Vd(L/kg) 2.5 2.2 Distribution t½ , protein binding &Vd of both drug is similar Elimination T½ & Cl differ
  20. 20.  Earlier awakening In pediatric due to rapid total clearance Delayed awakening in elderly due to increased CNS sensitivity,altered metabolism and decreased VdIMP. Points about PK of methohexitol Lesser lipid soluble More metabolized Rapid hepatic clearance & recovery rapid than thiopentone
  21. 21. CLINICAL CONSIDERATIONS Prompt awakening in 5-10min after a single dose of thiopental or methohexital reflects redistribution of these drugs from brain to inactive tissues Elimination from the body depends almost entirely on metabolism So abnormal skills for 8hrs and residual CNS impairment for about 1 day
  22. 22. EFFECTS ON ORGAN SYSTEMS Cerebral metabolism: Decreases CBF and ICP but CPP preserved CMRO2 and ATP consumption decreased Metabolic activity concerned with neuronal signaling and impulse traffic reduced by barbiturates but not metabolic function CNS: progressive cns depression EEG changes-Low-voltage fast activity- small dose -High-voltage slow activity- large dose Potent hypnotic and anticonvulsant poor analgesic(at low dose antianalgesic- threshold)
  23. 23.  Cardiovascular: -CV depression by both central and peripheral effects -Peripheral vasodilation and fall in BP -Decreased myocardial contractility and CO -increase in HR(baroreceptor mediated sympth reflex) -CV effects vary markedly depending on volume status, baseline autonomic tone and preexisting CV ds Respiratory:  Depression of medullary and pontine ventilatory centres  Decreased response to hypercapnia and hypoxia  Leads to upper airway obstruction and double apnea  Laryngeal reflex and cough reflex are not depressed  Laryngospasm and bronchospasm
  24. 24.  Hepatic:  Hepatic blood flow is modestly decreased  Induction doses do not alter postoperative LFTs  Enzyme induction Renal:  Reduce RBF and GFR in proportion to fall in BP  Liberation of ADH and decrease urine output Skeletal muscle -Tone is reduced at high dose -When used as sole anesth agent poor muscle relaxation Eye -IOP reduced approx. 40%
  25. 25.  Immunologic:  Thiopentone inhibit nuclear transcription factor κB  Impair neutrophil function  Anaphylactic and anaphylactoid reactions are rare  Some evoke mast cell histamine release Uterus: contractions suppressed at high dose  Placenta: Maternal doses of thiopental up to 4 mg/Kg IV probably do not result in excessive concentrations of barbiturates in fetal brain Other:  Antithyroid(d/t thio-urea group) and Hypokalemia
  26. 26. CLINICAL INDICATIONS1. Principal clinical uses of barbiturates:  Induction and maintenance of anesthesia  Treatment of increased intracranial pressure1. Preanesthetic medication (replaced by BZDs)2. Status epilepticus and treatment of grand mal seizures, but benzodiazepines are probably superior3. Cardioversion4. ECT5. Narcoanalysis,Narcotherapy or truth spells6. Cerebroprotective agent in trauma patients and focal cerebral ischemia7. T/t of hyperbilirubinemia & kernicterus
  27. 27. CONTRAINDICATIONS A.ABSOLUTE Porphyria B.RELATIVE 1. Bronchial asthma,ch. Bronchitis, smoker’s cough 2.Shock 3.Respiratory obstruction or Inadequate airway 4.Fixed CV lesions-valvular stenosis,heart block,constrictive pericarditis coronary artery disease
  28. 28.  6. Severely anemic and Acidotic patients 7.Jaundice, severe hepatic or renal disease 8. Previous hypersensitivity reactions 9.Dystrophia myotonica, FPP 10.Hypothyroid and myxoedema pt. 11.Without proper iv or airway equipment 12.H/o convulsion for methohexitol
  29. 29. ADVERSE EFFECTSA.COMPLICATIONS1.On injection-garlic or onion taste2.Perivenous and Intramuscular injections-Local tissue irritation tissue necrosis ulceration(more with thiopentone) mechanism-crystal precipitation in alkaline pH t/t-10ml of 1%lignocaine with 100unit of hyalase inj3.Pain on injection and phlebitis (more with methohexital)4.Allergic rkn-Urticarial rash on head,neck and trunk,lasts a few mins;sometime severe reactions- facial edema, hives, bronchospasm and anaphylaxis (T/t- symptomatic, epinephrine and fluid replacement)5.Excitatory symptoms-cough,hiccough,tremors,twitching (5times more with methohexital)
  30. 30. 6. Intraarterial Inj.-Degree of injury related to conc. of drug s/s: pt.complains of intense burning pain down to the inj site followed by pallor,cyanosis,edema and finally necrosis 1st symptom-pain 1st sign-white hand with cyanosis of nail Mechanism-release norad locally so vasoconstriction -pptation in arterial pH→crystal formation →embolization in arteriole→occlusion → Ischemia → gangrene -inflammation and endothelial cell destructionPrev:-give inj at dorsum of hand in adult;scalp vein in infants -avoid inj at antecubital fossa -always use 2.5%soln.
  31. 31. T/t :-1.Leave the needle at site;dilution of drug by saline4p’s-2. 5-10ml of plain xylocaine1%(old drug-procaine) -3.Papaverine 40-80mg in 10-20ml saline for vasodilatation -4.Tolazoline(priscol)5ml- alpha blocking agent or phenoxybenzamine 0.5mg-ganglion blocking agent -5.Inject 500units of heparin to prevent thrombosis -6.Sympathectomy by stellate ganglion block or brachial plexus block relieve vasoconstriction and pain -7.Urokinase to improve blood flow -8.Oral anticoagulants for 7-10 days -9.Elective surgery cancelled only emergency Sx done
  32. 32. B.SYSTEMIC ADVERSE EFFECTS1.CVS -mild decrease SBP d/t vasodilation -profound hypotension d/t nonimmunologically mediated histamine release m/m-Consider slow rate of injection and adequate preoperative hydration2.RESP-Transient apnea(t/t:no m/m but if >20sec IPPV) -Laryngospasm & Bronchospasm3.CNS –continuous infusion of thiopentone 4mgkg causes Isoelectric EEG4.KIDNEY –Decrease in urine output
  33. 33. 5.LIVER- Enzyme induction so a.accelerate metabolism of drug e.g;oral anticoagulants, phenytoin and TCAs b.accelerate metabolism of endogenous substances as, corticosteroids, bile salts and vit.k c.stimulate ALA synthatase and exacerbate porphyria d. tolerance by inducing own metabolism6.TOLERANCE AND PHYSICAL DEPENDENCE7.IMMUNOSUPPRESION- -increased incidence of nosocomial infection -bone marrow suppression and leucopenia
  34. 34. RECOMMENDED DOSES DRUG INDUCTION ONSET(sec) IV DOSE(mg/kg) MAINTENANCE INFUSION THIOPENTAL 3-4 10-30 50-100mg every (2.5%) 10-12 min METHOHEXITAL 1-1.5 10-30 20-40mg every 4- (1%) 7 min Adult and pediatric dose are roughly same Methohexital can be given rectally in pediatric patients as 20-25 mg/kg/dose Thiopentone in 5% or 10% solution may be used in children basal narcosis
  35. 35. PREPARATIONS 0.5gm is diluted with 20cc of distilled water to make 2.5% concentration 1gm preparation is also available
  36. 36. DOSE VARIABILITY LOWER INDUCTION DOSE REQUIREMENTS:-A.Less bood volume -Hemorrhagic shock -dehydration -decreased cardiac outputB.Less lean body mass-obese -elderly -femaleC.Other condition -severe anemia, uremia -burns, intestinal obstuction -malnutrition ,ulcerative colitis
  37. 37.  INCREASED DOSE REQUIREMENT A.urbans people B. chronic alcoholics C. Children >1yr after thermal injury
  38. 38. MEDICATION INTERACTIONS Contrast media, sulfonamides, aspirin,coumarin anticoagulants and other drugs that occupy the same protein-binding sites as thiopental will increase the amount of free drug available Alcohol, narcotics, antihistamines, and other CNS depressants potentiate the sedative effects of barbiturates Chronic alcohol abuse
  39. 39. COMPARISONTHIOPENTONE PROPOFOLA.PROPERTIES1.Ultra short acting barbiturate 1.Short acting propyl phenol2.Available as yellow powder 2.Available as white emulsion3.Soluble in water 3.Insoluble in water4.Stable,sterile at r.t. 6days 4.Discard in 6hrs5.Bacteriostatic 5.Good bacterial culture6 pH=10.5 6 pH=77.2.5%soln 7.1%soln8.Contain Na2CO3 8.Contain Na edatate/metabisulphiteB.PHARMACOKINETICOA:15sec OA:15secDOA:8-10min DOA:2-8minElimination:10hr Elimination:3-4hrsRecovery:delayed Recovery:rapid and smooth
  40. 40. THIOPENTONE PROPOFOLC.ACTIONS1.Sedation,hypnosis,antianalgesia 1.hypnosis, amnesia,noanalgesia2.CNS:Maintain CPP 2.CNS:Decrease CPP3.CVS:BP both central and peripheral 3.CVS:BP only peripheral4.Resp:bronchospasm/laryngospasm 4.Resp:bronchodilation,apnea5.GIT: risk of aspiration 5.GIT: vomiting6.Pregnancy:safe upto 4mg/kg 6.preg:neonatal depression7.Muscle:localise spasm 7.Muscle:no effect8.Antioxidant:no 8.Antioxidant effect9.Stress response:no effect 9.Stress response:blockD.SIDE EFFECT1.More hangover 1.Less2. More vascular compromise 2.Less3.Tissue necrosis 3.No tissue necrosis
  41. 41. THIOPENTONE PROPOFOLE.INDICATIONS1.Induction 1.Induction2.Anticonvulsant 2.Maintenance3.Control ICP 3.ICU sedation 4.Antiemetic 5.Antipruritic 6.Anticonvulsant 7.Antioxidant 8.Control ICPF. C/I:AIP ShockG.DOSE:5mg/kg 2mg/kg
  42. 42. THANK U

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