Barbiturates

barbiturates.

1. BARBITURATES DR ZIKRULLAH

2. INTRODUCTION Barbiturates are drugs derived from barbituric acid. Barbituric acid was first created by Adolf Von Baeyer in 1864 by combining Urea and Malonic acid. Introduced clinically by Water and Lundy in 1934.

3. CLASSIFICATION A. Long acting barbiturates Phenobarbitone Barbitone Methylphenobarbitone B. Intermediate acting barbiturates Amylobarbitone Butobarbitone Cyclobarbitone Pentobarbitone C. Short acting barbiturates Quinal barbitone D. Ultra short acting barbiturates Thiopentone sodium Methohexital Thymilal

4. STRUCTURE ACTIVITY RELATIONSHIP Barbituric acid itself doesn’t have CNS activity. Branched chain substitution at C 5 leads to greater hypnotic activity Phenyl group at C 5 – greater anticonvulsant activity ( Phenobarbitone ) Methyl group at C 5 – convulsant activity ( Methohexital ) ‘O’ atom at C 2 - oxybarbiturate ( pentobarbitone ) ‘S’ atom at C 2 - thiobarbiturate ( thiopentone )

5. THIOPENTONE SODIUM A thiobarbiturate of ultra short acting type used for intravenous induction of anaesthesia . Its structural name is sodium 5-ethyl,5-methyl,1-butyl thiobarbiturate , empirically it is NaSC 11 H 17 O 2 N 2 .

6. PREPARATION Sodium thiopentone (aka thiopental or pentothal) is prepared by dissolving yellowish powder in sterile water to provide a 2.5% solution ( i.e 25mg/ml) Available in 500mg & 1g strength. Stability Powder- indefinite period Reconstituted – a) room temperature: 1 week b) refrigerated: 2 weeks 6

7. Commercial preparations contain a mixture of six parts of anhydrous sodium carbonate to prevent precipitation of insoluble acid form of barbiturate by atmospheric CO 2 . The solution is alkaline and can be irritating and painful if accidentally injected into tissues. pH of 2.5% solution of thiopentone is 10.5. 7

8. Should not be mixed in the same syringe with other drugs, as it may cause formation of a cloudy precipitate and inactivate the drug. Alkaline pH is responsible for their bacteriostatic properties.

9. Diluent used for reconstitution for hygroscopic thiopentone powder - 0.9% NS - Sterile water - 5% dextrose solution Routes of administration : a) Intravenous b) Rectal 9

10. MECHANISM OF ACTION Possible mechanisms GABA facilitatory action The interaction of thiopentone with specific membrane component of GABA A receptors decreases the rate of dissociation of GABA from these receptors, hence increasing the duration of opening of chloride channels Uniquely depress the Reticular Activating System which is important in maintaining the wakefulness.

11. They also mimic action of GABA by directly activating GABA A receptors – GABA mimetic action. They also target a) glutamate receptors b) adenosine receptors c) neuronal nicotinic acetlycholine receptors. 12

12. PHARMACOKINETICS Effect site equilibration time: 30 secs Context sensitive half life: prolonged because drug is stored in fat and skeletal muscle re-enters the circulation to maintain plasma concentration.

13. PROTIEN BINDING Thiopentone , as a highly lipid soluble barbiturate, is most avidly bound to plasma protein ( i.e. 72 – 86 %). Higher binding occurs at lower plasma concentration. Changes in pH from 7.35 – 7.5 do not alter degree of protein binding.

14. Decreased protien binding of thiopentone leads to increased free portion of the drug. Conditions with decreased protien binding - Drugs which displace thiopentone from their binding sites eg . Aspirin , Phenylbutazone - Uraemia - Cirrhosis of liver - Neonates

15. DISTRIBUTION Depends on : Lipid solubility Protein binding Degree of ionisation Tissue blood flow Volume of distribution ( Vd ) of thiopentone is 2.5 L/kg 16

16. Brain: Max. brain uptake occurs within 30 sec. ( rapid effect site equilibration ) Brain receives about 10% of total dose in first 30-40 sec. Over next 5 min conc. decreases to half the initial peak conc. d/t redistribution. Redistribution is the principal mechanism for early awakening. After 30 min, drug is further redistributed and only 10% remains in brain. 17

17. Skeletal muscles: Skeletal muscles are the most prominent sites of initial redistribution Equilibrium with skeletal muscles is reached in about 15 min. after iv injection Dose of thiopentone is reduced when skeletal muscle perfusion is reduced ( shock) or when skeletal muscle mass is reduced ( elderly). 18

18. Fat: Drug content continues to increase 30min. after injection Fat : blood partition coefficient is about 11. Thiopentone will move from blood to fat as long as conc. in fat is less than 11 times that of blood. Max. deposition in fat is present after 2.5 hrs and this tissue becomes potential reservoir for maintaining plasma conc. 19

19. Large or repeated doses of thiopentone produces a cumulative effect because of storage capacity of fat. When this occurs , usual quick awakening characteristic of these drugs is absent. For this reason, dose of thiopentone is best calculated according to the lean body mass to avoid an overdose. 20

20. IONISATION Thiopentone is a weak acid with a pka of 7.6 Acidosis favours non- ionised fraction of drug and alkalosis has opposite effect. The non- ionised form has greater access to CNS than ionised form Acidosis will thus increase and alkalosis decrease the intensity of effect. 21

21. METABOLISM Metabolism occurs at a slow rate, 10 – 24 % of the drug being metabolized by the liver each hour ( low hepatic extraction ratio of 0.15 ) After several hours , most of the drug stores are in the fat and the fraction of the drug delivered to the liver is far less than in first few min after injection Metabolised in liver to hydroxythiopental & carboxylic acid derivatives. 22

22. The metabolites are more water soluble and have less CNS activity. Principal sites of metabolism being: Oxidation at C5 Desulfuration at C2 Hydrolytic opening of barbituric acid ring 23

23. EXCRETION Thiopentone is filtered by the kidneys but High protein binding limits the magnitude of filtration High lipid solubility favours reabsorption <1% is excreted unchanged in urine. Alkalinization of urine hastens renal excretion because of shift towards ionised state caused by pH change. Clearance Adults 3 mL /kg/min Children 6 mL /kg/min 24

24. Elimination half life : High d/t low hepatic clearance. Thiopentone - 11.6hrs Methihexitone - 3.6 hrs. More in obese patients. Increase with age- intercompatmental shift is slow. Greater effect in old with same amount of drug. Pediatric patients –opposite effect i.e. rapid hepatic clearance 25

25. SYSTEMIC EFFECTS Effects on CNS : Depression directly proportional to plasma level . 3 - 4 mg/kg produces sleep Dose related reduction in CMR progressive slowing of the EEG, a reduction in the rate of ATP consumption, and protection from focal cerebral ischemia 26

26. With the reduction in CMRO 2 comes a parallel reduction in cerebral perfusion, which is seen as Decreased cerebral blood flow (CBF) and ICP. With reduced CMRO 2 cerebral vascular resistance increases and CBF decreases. Potent anticonvulsant activity 27

27. Effects on CVS: Cardiovascular depression from barbiturates is a result of both central and peripheral effects. There is peripheral vasodilation resulting in pooling of blood in the venous system. A decrease in contractility is another effect and is related to reduced availability of calcium to myofibrils. 28

28. Mechanisms for the decrease in cardiac output include (1) direct negative inotropic action, (2) decreased ventricular filling because of increased capacitance, and (3) transiently decreased sympathetic outflow from the CNS. The increase in heart rate (10% to 36%) results from baroreceptor -mediated sympathetic reflex stimulation of the heart in response to the drop in output and pressure. 29

29. The cardiac index is unchanged or reduced. Mean arterial pressure is maintained or slightly reduced. When thiopental is given to hypovolemic patients, there is a significant reduction in cardiac output, as well as a decrease in blood pressure . 30

30. Effects on respiratory system Dose related central respiratory depression respiratory acidosis Transient apnea Minute ventilation is diminished Patients with chronic lung disease are slightly more susceptible to the respiratory depression associated with thiopental 31

31. The initial apnea that occurs during drug administration lasts a few seconds and is succeeded by a few breaths of reasonably adequate tidal volume, followed by a more lengthy apneic period. During induction of anesthesia with thiopental, ventilation must be assisted . 32

32. Effects on hepatic system: Modest decrease in blood flow. Stimulate increase in liver microsomal enzyme induction after 2 – 7 days of sustained drug administration. Effects on renal system: Decreased renal blood flow Decrease GFR oliguria 33

33. Immunological effects Anaphylactic reactions may occurs in 1:30,000. This may be due to sulfur, which may evoke mast cell histamine release. Majority of reported cases are in patients with the history of chronic atopy , who often have received thiopentone previously without adverse responses. Long term administration of thiopentone is associated with increased incidence of nosocomial infection due to bone marrow suppression and leucopenia. 34

34. Other actions : Pupillary response is lost with surgical anaesthesia . Loss of eyelash reflex commonly used as a clinical endpoint for an adequate induction dose. Skeletal muscle tone fall more than smooth muscle tone. Uterine tone is unaffected. 35

35. Placental transfer Readily cross placenta but fetal plasma concentration is less than those of maternal plasma concentration Clearance by fetal liver Dilution by blood from fetal viscera & extremities. 36

36. THERAPEUTIC USES Induction of anesthesia Treatment of increased intracranial tension Anticonvulsant As a sole agent for short surgical procedures As a supplement during regional block 37

37. Induction of anaesthesia : 3-5 mg/kg iv of 2.5% solution until loss of eyelash reflex Rectal dose for induction is 20-30 mg/kg Thiopentone infusion is not used because of long context sensitive half time and prolonged recovery period.

38. Treatment of raised ICT : thiopentone causes cerebral vasoconstriction leading to decrease in CBF and CBV. Dose: 35-40mg/kg Cerebral protection with barbiturates is seen only after focal ischaemia and not after global ischaemia .

39. Anticonvulsant agent : used in treatment of - convulsions due to local anaesthetic toxicity - status epilepticus - eclamptic convulsions

40. CONTRAINDICATIONS Absolute Acute intermittent porphyria Hypersensitivity to barbiturates/ sulpha drugs Relative Respiratory obstruction,inadequte airway, status asthamaticus Previous immune reaction Fixed and low cardiac output states ( tight MS) Severe cardiovascular instability & shock Without proper i.v line and airway equipment 41

41. DRUG INTERACTIONS Ethanol, Opioids , Antihistaminics potentiate the sedative effect of thiopentone . Contrast media, sulphonamides occupy same protein binding sites thus increases the free drug available and potentiate the sedative effect of the drug. 42

42. COMPLICATIONS Vascular injury due to chemical nature of drug venous 5% of patients thickening of vein wall resolves after several weeks arterial severe pain and thrombosis ischaemic injury 43

43. Mechanism : Precipitation of thiopentone microcrystals in arterial vessels → inflammatory response and arteritis Endothelial damage → Platelet aggregation →Aseptic thrombosis Clinical features : Immediate , intense vasoconstriction & excruciating pain that radiates along the course of the artery. Blanching of extremity followed by cyanosis Gangrene & permanent nerve damage may occur. 44

44. Treatment: Dilution of drug By injection of saline through the needle which still remains in the artery. Prevention of arterial spasm Injection of lidocaine , papaverine or phenoxybenzamine may be administered to produce vasodilatation General measures to sustain adequate blood flow 45

45. If needle is removed- inject vasodilator drug in proximal artery Direct injection of heparin in the artery may be considered. Sympathectomy - stellate ganglion block or brachial plexus block. Urokinase 46

46. Side-effects Involuntary movements Immunosuppression Cough, laryngeal spasm, bronchospasm , apnea Allergic reactions (1:30,000) Hypotension, tachycardia Loss of vasomotor control 47

47. Effects on gravid uterus: Readily crosses the placenta When used in doses below 5mg/kg concentration in fetal brain tissue is minimal.

48. THANK YOU !