1. BARBITURATES
Guide:- Dr. Archana
Tripathi
Presenter:- Dr. Khushboo

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. 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. 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. STRUCTURE
Oxybarbiturates
Thiobarbiturates
THIOPENTONE:5-ethyl,5[methyl,butyl]2-thiobarbiturate
METHOHEXITONE:1-methyl-5-allyl5[methyl,pentynyl]
2-oxybarbiturate

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. 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. THIOPENTONE METHOHEXITONE
1.PHYSICAL PROPERTIES
-Yellowish powder -White powder
-Bitter in taste
-Faint garlic smell
-pKa-7.6 -pKa-7.9
-pH-10.5 -pH-11
2.PREPARATION
-2.5% solution
-1% solution
3.STABILITY(Powder form
stable indefinitely)
-Refrigerated solution stable -refrigerated solution
upto 2weeks stable upto 6weeks
-at Room temperature stable
for 6days .

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. GABA creates a negative change in the
transmembrane potential(hyperpolarization).
This makes it an Inhibitory neurotransmitter

GABA binding site
Barbiturate binding site

11.  At low conc.-GABA-facilitator
 At high conc.- GABA-mimetic(barbiturate
anesthesia)
 Block AMPA receptor which is sensitive to
glutamate,excitatory neurotransmitter


12. PHAMACOKINETICS
 Absorption
 Protien binding
 Distribution
 Ionization
 Metabolism
 Renal excretion
 USUAL DOSE-First order kinetics
 HIGH DOSE-Zero order kinetics

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. DISTRIBUTION
FACTORS 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. Compartment model
Induction dose
rapid mixing of drug with central blood volume
quick 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. 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. METABOLISM
A.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. 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. COMPARATIVE PHARMACOKINETICS
Thiopentone Methohexitol
Rapid COMPARATIVE
 distribution 8.5 5.6
T½(min)
PHARMACOKINETIC
Slow distribution 62.7 58.3
T½(min.)
I
T½ Elimination (Hrs.) 11.6 3.9
CL (ml/kg/min.) 3.4 10.9
Vd(L/kg) 2.5 2.2
 Distribution t½ , protein binding &Vd of both drug is similar
 Elimination T½ & Cl differ

20.  Earlier awakening In pediatric due to rapid
total clearance
 Delayed awakening in elderly due to
increased CNS sensitivity,altered metabolism
and decreased Vd
IMP. Points about PK of methohexitol
 Lesser lipid soluble
 More metabolized
 Rapid hepatic clearance &
 recovery rapid than thiopentone

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. 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.  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.  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.  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. CLINICAL INDICATIONS
1. Principal clinical uses of barbiturates:
 Induction and maintenance of anesthesia
 Treatment of increased intracranial pressure
1. Preanesthetic medication (replaced by BZDs)
2. Status epilepticus and treatment of grand mal seizures,
but benzodiazepines are probably superior
3. Cardioversion
4. ECT
5. Narcoanalysis,Narcotherapy or truth spells
6. Cerebroprotective agent in trauma patients and focal
cerebral ischemia
7. T/t of hyperbilirubinemia & kernicterus

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.  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. ADVERSE EFFECTS
A.COMPLICATIONS
1.On injection-garlic or onion taste
2.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 inj
3.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. 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 destruction
Prev:-give inj at dorsum of hand in adult;scalp vein in infants
-avoid inj at antecubital fossa
-always use 2.5%soln.

31. T/t :-1.Leave the needle at site;dilution of drug by saline
4p’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. B.SYSTEMIC ADVERSE EFFECTS
1.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 hydration
2.RESP-Transient apnea(t/t:no m/m but if >20sec IPPV)
-Laryngospasm & Bronchospasm
3.CNS –continuous infusion of thiopentone 4mgkg causes
Isoelectric EEG
4.KIDNEY –Decrease in urine output

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 metabolism
6.TOLERANCE AND PHYSICAL DEPENDENCE
7.IMMUNOSUPPRESION-
-increased incidence of nosocomial infection
-bone marrow suppression and leucopenia

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. PREPARATIONS
 0.5gm is diluted with 20cc of distilled water to
make 2.5% concentration
 1gm preparation is also available

36. DOSE VARIABILITY
 LOWER INDUCTION DOSE REQUIREMENTS:-
A.Less bood volume -Hemorrhagic shock
-dehydration
-decreased cardiac output
B.Less lean body mass-obese
-elderly
-female
C.Other condition -severe anemia, uremia
-burns, intestinal obstuction
-malnutrition ,ulcerative colitis

37.  INCREASED DOSE REQUIREMENT
A.urbans people
B. chronic alcoholics
C. Children >1yr after thermal injury

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. COMPARISON
THIOPENTONE PROPOFOL
A.PROPERTIES
1.Ultra short acting barbiturate 1.Short acting propyl phenol
2.Available as yellow powder 2.Available as white emulsion
3.Soluble in water 3.Insoluble in water
4.Stable,sterile at r.t. 6days 4.Discard in 6hrs
5.Bacteriostatic 5.Good bacterial culture
6 pH=10.5 6 pH=7
7.2.5%soln 7.1%soln
8.Contain Na2CO3 8.Contain Na edatate/metabisulphite
B.PHARMACOKINETIC
OA:15sec OA:15sec
DOA:8-10min DOA:2-8min
Elimination:10hr Elimination:3-4hrs
Recovery:delayed Recovery:rapid and smooth

40. THIOPENTONE PROPOFOL
C.ACTIONS
1.Sedation,hypnosis,antianalgesia 1.hypnosis, amnesia,noanalgesia
2.CNS:Maintain CPP 2.CNS:Decrease CPP
3.CVS:BP both central and peripheral 3.CVS:BP only peripheral
4.Resp:bronchospasm/laryngospasm 4.Resp:bronchodilation,apnea
5.GIT: risk of aspiration 5.GIT: vomiting
6.Pregnancy:safe upto 4mg/kg 6.preg:neonatal depression
7.Muscle:localise spasm 7.Muscle:no effect
8.Antioxidant:no 8.Antioxidant effect
9.Stress response:no effect 9.Stress response:block
D.SIDE EFFECT
1.More hangover 1.Less
2. More vascular compromise 2.Less
3.Tissue necrosis 3.No tissue necrosis

41. THIOPENTONE PROPOFOL
E.INDICATIONS
1.Induction 1.Induction
2.Anticonvulsant 2.Maintenance
3.Control ICP 3.ICU sedation
4.Antiemetic
5.Antipruritic
6.Anticonvulsant
7.Antioxidant
8.Control ICP
F. C/I:
AIP Shock
G.DOSE:
5mg/kg 2mg/kg

43. THANK U