Induction Agents 2013/05/28 1

Transcription

1 Induction Agents 2013/05/28 1

2 Basic concepts One arm-brain circulation time Compartments Protein binding Redistribution vs. Metabolism Receptor binding 2013/05/28 2

3 One arm-brain circulation time From introduction into circulation Pharmacological effect on target organ 2013/05/28 3

4 One arm-brain circulation time Prolonged by Decreased cardiac output Old age Hypothermia Clinical implication: Inject slowly wait for effect 2013/05/28 4

5 Compartments 2013/05/28 5

6 Compartments Blood supply distribution IV induction agent Vessel rich group (brain, heart, kidney, liver) Muscle Fat Bone 2013/05/28 6

7 Protein binding All induction agents - high protein binding (>75% except ketamine -12%) Active drug = free fraction Low protein/albumin = increased free fraction Overdose!!!! Clinical implication: Half the calculated dose, inject slowly 2013/05/28 7

8 Redistribution 2013/05/28 8

9 Redistribution vs. Metabolism Redistribution From one compartment to another Decreased [] in vessel rich group Arousal hang over effect Metabolism Inactivation, breakdown in organ systems Elimination via renal, GIT 2013/05/28 9

10 Receptor binding GABA A agonists Cl - channel openers Inhibitory effect on exitation NMDA antagonists (Ketamine) Ca 2+ channel blocker 2013/05/28 10

11 Ideal induction agent Safe Easy to use Cheap No / minimal cardiovascular effects Rapid distribution and metabolism No active metabolites Analgesia 2013/05/28 11

12 Ideal induction agent (cont d) No allergic reactions No pain upon administration No involuntary movements No nausea and vomiting 2013/05/28 12

13 Classification Barbiturates - Sodium thiopentone - Methohexital Non-barbiturates - Etomidate - Propofol - Ketamine - Benzodiazepines 2013/05/28 13

14 STP Pentothal 2013/05/28 14

15 STP Pentothal Synthesized by Lundy in 1932 / 1934 Pearl Harbour as sole agent killed many Ultra-short acting thiobarbiturate Sulphur analogue of pentobarbitone Yellow powder, garlic smell, bitter taste Preparation: 2,5% = 25mg/ml (500mg/20ml) 85% plasma protein binding (albumin) 10-15% per hour metabolised by liver 2013/05/28 15

16 STP Pentothal Free (unionised) fraction crosses BBB Barbiturates are inherently acidic Dissolved STP ph = 10,5 due to added 6% Sodium Carbonate Acidosis excess H+ 2013/05/28 16

17 STP Pentothal Acidosis excess H+ Acidic drugs will ionize less Unionized fraction Fraction to cross BBB 2013/05/28 17

18 STP Pentothal Induction agents = lipid soluble lipid solubility plasma protein binding eg. STP / Methohexitone = 85% Propofol 95% plasma proteins free fraction fraction available to cross BBB 2013/05/28 18

19 STP Pentothal (cont d) CNS Induction in one arm-brain circulation time Anticonvulsant Anti-analgesic in small dose Decreases intracranial pressure - CBF - CSF production - CMRO /05/28 19

20 CNS STP Pentothal (cont d) Degree of cerebral protection in area of focal ischaemia if administered before the ischaemic insult Does not protect against global ischaemia intraocular pressure 2013/05/28 20

21 STP Pentothal (cont d) RESPIRATORY Sensitizes the upper airway (compared with Propofol) Apnoea 2-3 min 2013/05/28 21

22 STP Pentothal (cont d) CVS BP vasodilation + myocardial depression Be careful in FIXED CARDIAC OUTPUT! Intra-arterial injection Extravenous injection never use stronger than 2,5% STP 2013/05/28 22

23 STP Pentothal (cont d) INTRA-ARTERIAL INJECTION: BURNS / DELAYED OR ABSENT INDUCTION Stop injecting! Don t remove the canula! Flush with IV fluids Dilute STP Lignocaine Burning Heparin Prevent thrombosis Brachial plexus block Vasodilation Papaverine Vasodilation 2013/05/28 23

24 STP Pentothal (cont d) EXTRAVENOUS INJECTION: BURNS!! Stop injecting! Not as harmful as intra-arterial injection May cause local ulceration if > 2,5% 2013/05/28 24

25 STP Pentothal (cont d) Absolute contraindications Porhyria variegata Airway obstruction Fixed cardiac output Severe shock Relative contraindications Atopic asthma Severe liver disease, anaemia Myxoedema 2013/05/28 25

26 PROPOFOL MILK OF AMNESIA 2013/05/28 26

27 PROPOFOL 2,6 di-isopropylphenol Highly lipid soluble Emulsion: - soybean oil - egg phosphatide - glycerol Excellent medium for Candida Feeling of well-being (addiction) Erotic feelings! 2013/05/28 27

28 PROPOFOL (cont d) CVS BP by 30-40% No tachycardia! RESPIRATORY Apnoea if injected fast Sensitivity of upper airway 2013/05/28 28

29 PROPOFOL (cont d) BURNING large vein fast running drip Lignocaine 10mg in 20ml Propofol 1mg IV before Propofol Opioid Lipuro medium chain fatty acids 2013/05/28 29

30 PROPOFOL (cont d) Too good to be true? No hangover / accumulation Anti-emetic Anxiolytic Amnesia Anti-pruritus VIAGRA-IN-A-VIAL! 2013/05/28 30

31 PROPOFOL (cont d) Ideal agent for TIVA Ideal agent for Conscious Sedation Ideal agent for placement of LMA Excitatory phenomena - myoclonus - opisthotonus 2013/05/28 31

32 PROPOFOL (cont d) PROPOFOL INFUSION SYNDROME (PRIS) CLINICAL FEATURES OF PRIS 1. Sudden onset of marked bradycardia / complete heart block that is resistant to treatment 2. Lipaemic plasma 3. Hepatomegaly 4. Metabolic acidosis (base deficit > 10 mmol/l) 5. Rhabdomyolysis & Myoglobinuria 6. Multi-organ failure 2013/05/28 32

33 PROPOFOL INFUSION SYNDROME (PRIS) PATHOGENESIS: Blockade of L-CAT - FFA transfer mitochondrial O 2 utilization fatty acid β oxidation APT production FFA in blood 2013/05/28 33

34 PROPOFOL (cont d) TREATMENT: Prevention keep Propofol infusion rate < 4mg/kg/h and for not more than 24 hour Dialysis / plasmapheresis Pacemaker 2013/05/28 34

35 PROPOFOL Side effects Burns on injection Drops BP by 30-40% Myoclonus Apnoea for 30 sec PRIS 2013/05/28 35

36 ETOMIDATE 2013/05/28 36

37 ETOMIDATE Carboxylated imidazole Protein binding = 75% EEG grand mal epilepsy Cough and hiccoughing Burns Thrombophlebitis PONV Myoclonus 2013/05/28 37

38 ETOMIDATE UNWANTED EFFECTS OF ETOMIDATE BRAND / BURNS BEWE / MYOCLONUS BRAAK / NAUSEA BYNIER / ADRENALS BAIE DUUR / VERY EXPENSIVE 2013/05/28 38

39 ETOMIDATE (cont d) Adrenal cortex inhibition 2013/05/28 39

40 ETOMIDATE (cont d) Adrenal cortex inhibition - 11β-hydroxilase inhibition (and 17α-) - Lasts for 8 h after single bolus - Vitamin C restores cortisol to normal levels NB: Problem with TIVA and single shot induction! Hypnotic [ ] = 200nM/ml Adrenal suppression [ ] = 10nM/ml 2013/05/28 40

41 ETOMIDATE (cont d) Remarkable : - CARDIOVASCULAR STABILITY! (Alteration in BP, pulse rate negligible) Indicated for: IHD, hypertensive disease Valvular disease Cardiac surgery 2013/05/28 41

42 KETAMINE Phencyclidine derivative Related to LSD (lysergic acid diethylamide) 2013/05/28 42

43 KETAMINE (cont d) What makes KETAMINE different? Analgesic Cataleptic state Dissociation Nystagmus Protects airway reflexes to certain extend? Increased lacrimation, salivation, skeletal muscle tone 2013/05/28 43

44 KETAMINE (cont d) What makes KETAMINE different? Acts on NMDA receptors (antagonist) protective CMRO 2, ICP, IOP Petit mal activity on EEG Hallucinations, delirium, dreams Bronchodilator Apnoea in very large doses Ideal sole anaesthetic agent 2013/05/28 44

45 KETAMINE (cont d) What makes KETAMINE different? Catecholamine release & re-uptake: BP Pulse rate BUT Direct myocardial suppression 2013/05/28 45

46 KETAMINE (cont d) What makes KETAMINE different? Catecholamines Direct Myocardium BP Pulse rate CO 2013/05/28 46

47 KETAMINE (cont d) What makes KETAMINE different? Myocardial suppression No release of Catecholamines BP Pulse rate CO 2013/05/28 47

48 KETAMINE (cont d) What makes KETAMINE different? Very large therapeutic index! IV = 1-2mg/kg IM = 3-5 mg/kg PO/rectal = 5-10mg/kg 2013/05/28 48

49 KETAMINE (cont d) Contraindications for Ketamine: - Hypertension - Ischaemic heart disease - ICP - Open eye injury - Psychiatric problems - Epileptics - Aneurisms - Decompensated shock (NA depleted) 2013/05/28 49

50 Dexmedetomidine Highly selective α2 agonist Long T½ = to reach Css Used as infusion Bolus 1μg/kg for 10 min Constant infusion 0,2-0,7μg/kg Registered only for: Post cardiac surgery sedation for 24h 2013/05/28 50

51 Dexmedetomidine Advantages Sedation Analgesia No respiratory depression Anti-shivering agent Disadvantages Biphasic blood pressure response Followed by severe hypotension 2013/05/28 51

52 BY THE WAY. ONE ABSOLUTE CONTRAINDICATION FOR THE ADMINISTRATION OF ALL THE INDUCTION AGENTS AND ALL THE MUSCLE RELAXANTS IS 2013/05/28 52

53 BY THE WAY. A COMPROMISED AIRWAY! ( and that includes Ketamine) 2013/05/28 53

54 BY THE WAY. ETOMIDATE + PROPOFOL 2013/05/28 54