Clinical Pharmacology of Inhaled Anesthetics

1. Clinical Pharmacology of Inhaled Anesthetics Dr. Greg Bryson Dept of Anesthesiology The Ottawa Hospital 2012.09.27

2. Objectives I • Chemical structure • Structure - function relationships • Physiochemical properties • Definition of MAC • Factors which affect MAC • Mechanism of action • Uptake and Distribution

3. Objectives II • Fa/Fi curves, and factors which affect them • Physiological effects of inhalation anesthetics: • Cardiovascular system • Respiratory system • Central nervous system • Neuromuscular junction • Others • Metabolism/toxicity of inhalation anesthetics

4. The reality • You use these drugs every day • If you don’t know them – no one else does • None of this stuff is “new” • All of it is in the textbooks • Some of it is useful – some is “on the exam” • I can’t cover all of it in 3 hours

5. Greg’s goals for this lecture • Inflict my view of what you should know • Put this in a clinical (read: useful) context • Explain that which needs explaining • Leave the memory work to you • Take my daughter to cross country practice

6. Reference material • Miller 7th Edition • Chapter 20. Inhaled Anesthetics. Mechanisms of Action. • Chapter 21. Inhaled Anesthetics. Uptake and Distribution. • Chapter 22. Pulmonary Pharmacology. • Chapter 23. Cardiovascular Pharmacology. • Chapter 24. Inhaled Anesthetics. Metabolism and Toxicity.

7. Nitrous Oxide Diethyl Ether Halothane Chemical structure I Xe Xenon

8. Fun with chemistry • Alkanes precipitate arrythmias • Halogenationreduces flammability • Fluorination reduces solubility • Trifluorcarbon groups add stability

9. F Cl H F Enflurane Isoflurane Sevoflurane Desflurane Chemical structure II

10. Physical characteristics • Please cram the contents of table 15.1 from Barash 5th Ed the night before the exam. Take home points include: • desflurane boils at 24 OC • halothane is preserved with thymol • vapor pressures are needed for some exam questions • knowledge of blood:gas partition coefficients may actually be useful (uptake and distribution)

11. Vapor pressure and vaporizer Fig 25-17. Miller 7th Ed

12. Partition coefficients • Represent the relative affinity of a gas for 2 different substances (solubility) • Measured at equilibrium so partial pressures are equal, but... • The amounts of gas dissolved in each substance (concentration) aren’t equal. • The larger the number, the more soluble it is in the first substance

13. Key Physical Properties Tables21.1 and 24.1. Miller 7th Ed * Old textbooks on my shelf

14. Mechanism of Action Meyer-Overton Protein-interference Fig 20-2 Miller 7th Ed

15. Mechanism of action II • Protein Receptor Hypothesis • ligand-gated ion channels (GABA, glycine, NMDA-glutamate) • voltage-gated ion channels (Na, K, Ca) • G-proteins (guanine nucleotide) • Protein kinase C • Site of action • Brain v spinal cord (amnesia v immobility) • Axonal v synaptic • Pre v post synaptic

16. Minimum alveolar concentration • Alveolar concentration required to prevent movement in 50% of subjects • standard stimulus • represents brain concentration • consistent within and between species • Additive • Variants • BAR (1.7 – 2.0 MAC) • Awake (0.3 -0.5 MAC)

17. Increasing age (6% per decade) Hypothermia Hyponatremia Hypotension (MAP<50mmHg) Pregnancy Hypoxemia (<38 mmHg) O2 content (<4.3 ml O2/dl) Metabolic acidosis Narcotics Ketamine Benzodiazepines 2 agonists LiCO3 Local anesthetics ETOH (acute) And many more... Factors decreasing MAC Table 15.5. Barash 5th Edition

18. Factors increasing MAC • Hyperthermia • Chronic ETOH abuse • Hypernatremia • Increased CNS transmitters • MAOI • Amphetamine • Cocaine • Ephedrine • L-DOPA Table 15.4. Barash 5th Edition.

19. Factors with no influence on MAC • Duration of anesthesia • Sex • Alkalosis • PCO2 • Hypertension • Anemia • Potassium • Magnseium • And others

20. Uptake and distribution • Anesthesia depends upon brain partial pressure • Alveolar partial pressure (PA) = Pbrain • The faster PA approaches the desired level the faster the patient is anesthetized • PA is a balance between delivery of drug to the alveolus and uptake of that drug into the blood • Time for an analogy

21. a b To induce anesthesia the bucket (PA) must be full. Unfortunately the bucket has a leak (uptake). To fill the bucket you must either (a) pour it in faster (increase delivery) or (b) slow down the leak (decrease uptake).

22. Factors influencing uptake • Solubility (blood:gas pc) • Cardiac output • Alveolar-venous pressure gradient • For those of you who like formulae: Uptake =  • Q • (PA-Pv)/BP

23. The blood:gas pc is useful, really. • Anesthesia is related to the partial pressure of the gas in the brain. • If a drug is dissolved in blood, it isn’t available as a gas • More molecules of a soluble gas are required to saturate liquid phase before increasing partial pressure • Speed of onset/offset closely related to solubility • The lower the blood:gas pc - the faster the onset

24. FA/FI Curves

25. Factors influencing delivery • Alveolar ventilation • Breathing system • volume • fresh gas flow • Inspired partial pressure (PI) • concentration effect • second gas effect

26. Minute ventilation and uptake Figure 21-5. Miller 7th Ed

27. Cardiac Output and Uptake Fig 21-7. Miller 7th Ed

28. Concentration and 2nd gas effects 54% Fig 21.3 Miller 7th Ed

29. Concentration and 2nd Gas Effects Fig 21.4. Miller 7th Ed

30. V/Q distribution and uptake • Ventilation < perfusion (shunt) • blood leaving shunt dilutes PA from normal lung • induction with low solubility agent will be delayed • little difference with soluble agents (slow anyway) • Ventilation > perfusion (dead space) • uptake is decreased which enhances rise in FA • may speed induction for soluble agents • less difference with low solubility agents (fast anyway)

31. Endobronchial intubation Figs 21 – 11 and 12. Miller 7th Ed.

32. Break

33. Objectives II • Physiological effects of inhalation anesthetics: • Cardiovascular system • Respiratory system • Central nervous system • Neuromuscular junction • Others • Metabolism/toxicity of inhalation anesthetics

34. Effects on organ systems • Cardiovascular (Ch 23) • Pulmonary (Ch 22) • CNS (Ch 13) • Neuromuscular • Hepatic (Ch 66) • Renal (Ch 45) • Uterine (ch 69) • Miscellaneous

35. Inhaled anesthetics - CV system • Effect is hard to quantify • In vitro and in vivo effects often quite different • Sympathetic stimulation • Baroreceptor reflexes • Animal model vs human subject • Information provided in this lecture is a broad overview. • Chapter 23, Miller 7thEd for details

36. Myocardial contractility • All volatile anesthetics are direct myocardial depressants in vitro, including N2O. • Effect on circulation in vivo modified by effects on pulmonary circulation and sympathetic stimulation. • Ca++hemostasis in sarcoplasmic reticulum • As best as we can tell, at 1 MAC anesthetics depress contractility in the following order • H = E > I = D = S.

37. Heart rate • Effects variable and agent-specific • halothane decreases HR • Sevoflurane and enflurane neutral • Desflurane associated with transient tachycardia • occurs with rapid increases in MAC • associated with increases in serum catecholamines • similar effect may be seen with isoflurane

38. Blood pressure • All decrease BP, except N2O • Effect caused by a combination of • Vasodilation • Myocardial depression • Decreased CNS tone • Relative contribution of each is drug dependent

39. Cardiac output • Despite myocardial depression cardiac output is well-maintained with isoflurane and desflurane • preservation of heart rate • greater reduction in SVR • preservation of baroreceptor reflexes

40. Systemic vascular resistance • All are direct vasodilators, except N2O • relax vascular smooth muscle • cAMP - Ca++and/or nitric oxide involved • variable effects on individual vascular beds

41. Dysrhytmias • Halothane potentiates catecholamine-related dysrhythmias • ED50 of epinehrine producing dysrhythmias at 1.25 MAC • halothane 2.1 g•kg-1 • isoflurane 6.9 g•kg-1 • enflurane 10.9g•kg-1 • Sevo + Des similar to isoflurane • Lidocaine doubles ED50 of epinephrine • Children somewhat more resistant Chapter 2. Stoelting P&P. 2nd Ed Chapter 5. Barash 5th ED

42. Coronary blood flow • Isoflurane is a potent coronary vasodilator • In theory, dilation of normal coronary vessels can direct blood flow away from stenotic coronaries • Steal-prone anatomy • total occlusion of 1 major coronary vessel • collateral perfusion with 90% stenosis • In practice, doesn’t seem to be a problem

43. Myocardial protection • Ischemic preconditioning • Volatiles appear able to replicate the effect • Activation of mitochondrial KATP channels • maintain Ca++hemostasis • prevent mitochondrial Ca++ overload • Inhibition of adenosine 1 (A1) receptors and guanine inhibitory (Gi) proteins abolish protection • Free radical scavenging (ROS)

44. Respiratory system • Volatile anesthetics affect all aspects of RS • With exception of bronchodilation, none good. • For all the gory details (Chapter 22. Miller 7th Ed)

45. Bronchial musculature • Reduce vagal tone • Direct relaxation • decreased intracellular Ca++ • decreased sensitivity to Ca++ • When bronchospastic, a dose dependent reduction in Raw occurs with most agents • Exception is Xenon • Increased viscosity causes increased Raw

46. Mucociliary function + surfactant • Volatile anesthetics decrease ciliary beat • Decreased mucus clearance • Decreased production of phosphatidylcholine • PC used to make surfactant • occurs in as little as 4 hours • reversible in 2 hours

47. Pulmonary blood flow • Intrinsic vasodilators • Hypoxic pulmonary vasoconstriction • Intrinsic changes in HPV confounded by • changes in cardiac output • pulmonary artery pressure • position • Shunt and PO2 appear unchanged in studies of inhaled anesthetics during one lung ventilation

48. Control of ventilation • All decrease tidal volume • Most increase frequency • Net effect is: • decrease minute ventilation • increased PaCO2 (E>D=I>S=H) • Xenon appears to do the opposite • Decreased sensitivity and response to • Hypoxia • Hypercarbia • Inspiratory and expiratory loads

49. Lung volumes • Decreased FRC • decreased intercostal muscle activity • phasic expiratory muscle activity • Cephalad displacement of dependent diaphragm • Dependent atelectasis

50. Enclosed Air Spaces • N20 leaves blood 34x more than N2 absorbed • Sure, other agents are more soluble but we don’t give them at 70% end-tidal concentration • distension of closed air spaces • 70% N2O will double a pneumo in 10 minutes Fig 21-13 Miller 7th Ed.