Nonvolatile anesthetics

1. Nonvolatileanesthetics Presented by jacobhummel, m.d. Tulane anesthesiology

2. objectives • An overview of the nonvolatile anesthetics • - Kinetics/Dynamics • - Organ system effects • -Effects of Propofol on the cardiovascular system • -Pharmacological differences between fospropofol& • propofol • -Effects of Barbiturates on CBF and CMRO2 • -How Benzodiazepines affect ventilation • -Ketamine effects on CBF and CMRO2 • -Dexmedetomidine, effects of bolus vs. infusion

3. GOALS • -It is my desire to have you walking away from this lecture feeling well versed in all topics related to nonvolatile anesthetics • -It is also my desire for everyone to find this lecture enjoyable and entertaining and serve as a catalyst to our collective PLD session this afternoon

4. Disclosures • All opinions expressed today are those of a licensed physician, however, some CRNAs still claim that CA-1s, like myself, are still only students

5. General overview • Nonvolatile anesthetics have several uses, but primarily are used for • INDUCTION • MAC/ICU SEDATION • Several of these drugs can be administered via various routes, but their use in anesthesiology is primarily via the intravenous route • Most of the anesthetics described are lipophilic in nature which means RAPID ONSET and RAPID TERMINATION of their anesthetic effects

6. Pharmacokinetics • What the body does to the drug… • -The drugs in this class are primarily administered intravenously and therefore bypass absorption • -The initial termination of their effects leading to waking up from anesthesia is the result of re-distribution into less perfused tissues • -Biotransformation is primarily completed by the liver • Phase I: oxidation (P450), reduction, hydrolysis • Phase II: conjugation with glucuronides

7. Kinetics (cont.) • -Kidneys are the prinicipal organ of excretion • -The kinetics for most drugs can be described by a two-comparment model, central and peripheral • -The kinetics for some drugs are better explained by a three-compartment model, central and 2 peripherals

8. Pharmacodynamics • What the drug does to the body… • -The mechanism of action of most drugs depends on the interaction with a receptor • -The receptors are likely tied to either the function of ion channel or the production of a second messenger • -Most of our anesthetics act at the synapse of neurons and affect GABAa chloride channels or NMDA cation channels

9. Propofol • Most frequently administered drug for induction of anesthesia and also used for ICU sedation, procedure sedation, rapid sequence induction and PONV • Formulations support bacterial growth and there are cases of SEPSIS and DEATH related to propofol contamination • Egg allergy not necessarily a contraindication to its use

10. Propofol-kinetics • Initial distribution half-life of 2-8 minutes, typically 8-10 minute wake-up from induction dose • Clearance of propofol exceeds hepatic blood flow, suggesting extrahepatic metabolism • Moderate cirrhosis and chronic renal failure do not affect clearance • …however, being a pop icon does affect how your body clears the drug…

11. Propofol (cont.) • Decrease in arterial blood pressure due to drop in SVR • Hypotension is more pronounced than thiopental and more likely to occur with: • Large doses!, Rapid Injection!, Old Age! • Also impairs normal baroreflex response (no inc. HR)

12. Propofol (Cont.) • Profound respiratory depressant as many patients will become apneic after induction dose • Inhibits response to hypoxia and hypercarbia • Positives include depression of upper airway reflexes and less incidence of wheezing According to the 2009 autopsy report, "the cause of death is acute propofol intoxication," which caused the singer to stop breathing

13. Propofol (Cont.) • Decreases cerebral blood flow and intracranial pressure • Provides neuroprotection against focal ischemia (not global) • Induction accompanied by twitching/spontaneous movement easy to be confused as seizure activity but appears to have anticonvulsant properties • And when it comes to antiemetic effects, you can’t BEAT IT!

14. Fospropofol • The water-based prodrug of propofol and was approved by the FDA for use as a sedation agent for MAC procedures • Metabolized by alkphos in a reaction that produces propofol, phosphate and formaldehyde • Kinetics have been difficult to establish • Dynamics similar to propofol but onset and recovery are prolonged

15. Fospropofol-Safety • ASPF newsletter: • http://www.apsf.org/newsletters/html/2010/summer/07_Fospropofol.htm • Fospropofol has the advantage of less pain on injection, less risk of hyperlipidemia and less bacterial contamination • High incidence of perinealparesthesias and pruritus…awkward • Frustrating pharmacokinetics but serves as an alternative during propofol shortages

16. Barbiturates Derived from barbituric acid, this class has varying degrees of hypnotic, sedative and anticonvulsive effects • Substitutions at Carbon #5 determines hypnotic potency and anticonvulsant effect • Substitutions at Carbon #2 alter the lipid solubility

17. Barbiturates (cont.) • Even though they are derived from acid, the ultimate formulations are alkaline with a pH of 10 therefore they cannot mix with acids (NMBDs) or it will precipitate • Precipitates will block IV lines and cause tissue necrosis if accidentally injected into an artery • The formulations are also racemic mixtures and the potencies reflect the ratio of the different isomers

18. Barbiturates-kinetics • Duration of action determined by re-distribution, not metabolism • All of the barbiturates, except for phenobarbital are metabolized by oxidation in the liver and excreted into the urine after conjugation • Chronic administration of barbiturates or other drugs that induce oxidative enzymes (P450) enhance its metabolism

19. Barbiturates (Cont.) • Thiopental is highly protein bound (80%), but its great lipid solubility and high nonionized fraction (60%) account for maximal brain uptake within 30 sec. • Induction dose affected by: • AGE, SERUM ALBUMIN, BLOOD ACIDITY and VOLUME STATUS • Methohexital and thiopental have similar distribution patterns, but methohexital is cleared quicker than thiopental which accounts for the slightly faster recovery after anesthesia

20. Question • Which of the patients described below will require the smallest induction dose of thiopental? • 45 year-old hyperventilating and anxious with questionable drug abuse history • 65 year-old with hx of liver disease who was involved in a trauma with lots of blood loss • 65 year-old with hx of CAD currently on a high protein diet • 22 year-old sickle cell patient who has crackles on exam after transfusion of 2 units of PRBCs

21. ANSWER • A. 45 year-old hyperventilating and anxious with questionable drug abuse history • B. 65 year-old with hx of liver disease who was involved in a trauma with lots of blood loss • C. 65 year-old with hx of CAD currently on a high protein diet • D. 22 year-old sickle cell patient who has crackles on exam after transfusion of 2 units of PRBCs • Increased age, Decreased albumin, Hypovolemic and Acidotic

22. Barbiturates -Pharmacodynamics • The sedation for anesthesia is achieved through the action at the reticular activating system • Suppress transmission of excitatory neurotransmitters and enhance transmission of inhibitory transmitters • They work at the synapse by either limiting neurotransmitter release or stereoselectively interacting with postsynaptic receptors

23. Barbiturates (Cont.) • CARDIAC – smaller depressant effects than propofol, depress the medullary vasomotor center and decrease sympathetic outflow • Negative ionotropic effects are usually masked by baroreceptor-mediated reflexes like increased heart rate • RESP – decrease tidal volumes and decrease rate • Blunt response to hypercarbia and hypoxia • Induction doses will cause apnea • Not as good as propofol for facilitating airway instrumentation

24. Barbiturates (cont.) • CEREBRAL – A good choice for neurosurgical cases because they are potent cerebral vasoconstrictors and decrease CBF, CMRO2 and ICP • Provide neuroprotection from focal cerebral ischemia (not global) • Increasing doses decrease CMRO2 to a point where there is a flat line on the EEG • Methohexital does not have this isoelectric effect, in fact, it activates epileptic foci and is used in surgery aimed to ablate epileptic foci • NO ANALGESIC PROPERTIES! In fact, it may lower the pain threshold

25. question • In which scenario would a barbiturate not offer neuroprotection for the patient? • Cerebral Ischemia resulting from… • Acute cerebellar stroke • Clips used during aneurysmal surgery • Cardiac arrest • Surgical retraction

26. Answer • Cerebral Ischemia resulting from… • Acute cerebellar stroke • Clips used during aneurysmal surgery • Cardiac arrest • Surgical retraction • This is an example of global ischemia

27. Thiopental vsPropofol • “(Propofol)… resulted in a significantly quicker recovery and an earlier return of psychomotor function as compared with thiopentoneand midazolam irrespective of the agent used for maintenance of anaesthesia.”

28. benzodiazepines • Benzodiazepines are used for premedication, IV sedation, induction of anesthesia and suppression of seizure activity • The structures of commonly used benzodiazepines and their antagonist flumazenil share a seven-member diazepine ring • The benzene ring adds to the lipophilicity

29. BenzoDiazepines-kinetics • Diazepam is quite lipid soluble and rapidly penetrates the blood-brain barrier • Midazolam is water-soluble, but its imidazole ring closes at a physiological pH making it highly lipophilic • Lorazepam is only moderately lipophilic, why it has slower onset and recovery • Collectively they are slower in onset and recovery than thiopental

30. Benzodiazepines-kinetics • Benzodiazepines are metabolized in the liver into water-soluble glucuronides that are excreted by the kidneys • Midazolam and diazepam have similar distribution patterns, but midazolam has a significantly shorter half-life (2 hrs) than diazepam (30 hrs) because of its high hepatic extraction ratio • But the same holds true for the benzodiazepines as with the other anesthetics, the termination of their action is dependent on re-distribution and not metabolism

31. Benzodiazepines-dynamics • Like barbiturates, benzodiazepines also activate GABAa receptor complexes and enhance Cl- current to hyperpolarize neurons and effectively reduce their excitability • Benzodiazepines have their own specific binding site on GABA receptors and midazolam has a twice greater affinity for these receptors than diazepam • GABA receptors responsive to benzodiazepines are almost exclusively located on post-synaptic nerve endings in the cerebral cortex minimal depressant effects on ventilation and blood pressure

32. Benzodiazepines (CONt.) • CARDIAC – minimal depressant effects, HR occasionally rises • RESP – usually minimal depressant, but can cause apnea but usually in the presence of opiates • Produces decreased response to carbon dioxide • CEREBRAL – like barbiturates, they decrease CBF and CMRO2, but to a smaller extent • Midazolam unable to produce isoelectric EEG, suggesting a ceiling effect to their decreases in CMRO2 • Minimal effect on ICP, no neuroprotective qualities

33. As an induction agent? • Rarely used for induction, but you can use a dose of 0.1-0.3 mg/kg • Onset of induction is slower than other induction agents • Appears on paper to have a better organ system profile with less cardiac and respiratory affects, but it is unlikely it offers any advantage over the other induction agents

34. opiods • Class of drugs known for their analgesic effects • Classified as anesthetics because of their sedative qualities

35. Opiods - kinetics • Fentanyl and Sufentanil have the highest lipid solubility leading to quick onsets and quick recoveries (5-20 minutes) • Even though it has less lipid solubility, alfentanil is quicker in onset than fentanyl and sufentanil • Redistribution terminates the action of all opiods, however large doses must depend on biotransformation to adequately lower plasma levels • Biotransformation takes place in the liver and since they all have a high extraction ratio, clearance depends on hepatic blood flow

36. Opiods (Cont.) • Remifentanil has a unique ester structure makes it susceptible to ester hydrolysis in the blood • This extrahepatic metabolism is so rapid and complete that the duration of remifentanil infusion infusion has little effect on wake-up times • Its context sensitive half time (time required for the plasma concentration to decline by 50% after termination of infusion) is 3 minutes regardless of the duration of infusion • Remifentanil is therefore an excellent choice as a continuous infusion

37. OPiods • CARDIAC – minimal direct effects, but the release of histamine leads to decreses in SVR and blood pressures • Meperidine is similar in structure to atropine and can cause increased heart rate • RESP – decrease ventilation, particularly respiratory rate • Elevated apneic threshold (CO2 level at which they breathe) • Fentanyl, sufentanil and alfentanil increase chest wall rigidity that is responsive to neuromuscular blocking agents • Histamine can also cause bronchospasm

38. Opiods • CEREBRAL – variable effects on ICP and CPP, reduce CMRO2 and ICP in general, but to a lesser extent than barbiturates or benzodiazepines • Stimulation of the CTZ is responsible for the high incidence of nausea/vomitting • G.I. – slows gastric emptying and sounds a lot like an internal medicine problem • ENDOCRINE – block the hormones associated with the stress response, may be beneficial to patients with heart disease

39. question • Propofol: • a.Has a faster onset-time for hypnosis than thiopental. • b.Has a longer context-sensitive half-time than fentanyl after a 1 h infusion. • c.Has a higher clearance than alfentanil. • d.Is suitable for infusions of long duration because it has a large volume of distribution at steady state. • e.Has a clearance that is greater than hepatic plasma flow.

40. question • . Alfentanil: • a.Reaches steady-state more rapidly than fentanyl using a constant infusion rate. • b.Is less lipid soluble than fentanyl. • c.Has a faster onset-time than propofol because it has a lower pKa. • d.Has the same context-sensitive half-time after an infusion of 2 h as after an infusion of 6 h. • e.Administration can be through a commercially available target-controlled delivery device.

41. ketamine • A derivative of PCP and 10 times less potent, it differs from other anesthetics in it stimulating effects on the organ systems and the analgesia it provides • The R-(-) isomer is the most potent stereoisomer and all formulations in the U.S. are only available as racemic mixtures

42. Ketamine-kinetics • High lipid solubility ensures rapid onset • Termination of effects occur first as the result of redistribution to other inactive tissues and then metabolized in the liver by P450 • Ketamine has very low protein binding (12%)

43. Ketamine-dynamics • Major effect of ketamine is through the inhibition of the NMDA receptor complex • After induction of ketamine, patients go into a cataleptic state where their eyes are open and a slow, nystagmic gaze is present • Frequently increases lacrimation and salivation, should pre-treat with an anticholinergic like glycopyrrolate • No amnestic qualities, will need to supplement with midazolam if used as sole anesthetic

44. Ketamine-dynamics • Significant analgesic properties • Emergence from ketamine may include vivid dreams, hallucinations, out of body experiences along with an array of distorted senses (visual, auditory, tactile) • Patients can either experience fear or euphoria • Children have a decreased incidence of these emergent reactions

45. Ketamine (cont.) • CARDIAC – produces transient increases in systemic blood pressure and heart rate through sympathetic stimulation • However, it also is a direct myocardial depressant…only shows in a critically ill patient • RESP – does not produce respiratory depression • Response to hypercarbia remains intact • Protective airway reflexes remain intact • Relaxes bronchial smooth muscle • Beware, kids can still get laryngospasm on ketamine

46. Ketamine (cont.) • CEREBRAL – Ketamine is not to be used for someone with intracranial pathology as it increases CBF, increases CMRO2 and increases ICP • However, it can be used as an anticonvulsant • …Ultimately, ketamine is an important alternative because of its desirable cardio and respiratory effects while also providing analgesia by different routes, but its regular use is prohibited by emergence reactions

47. etomidate • Etomidate is a hypnotic with no analgesic properties and minimal hemodynamic effects • Structurally unrelated to other anesthetics, but behaves very similar to barbiturates • Etomidate contains a carboxylated imidazole ring • Prepared in propylene glycol, causes pain on injection

48. Etomidate-kinetics • Only available as IV, bypasses absorption • Highly protein-bound, but still characterized as a very rapid onset of action due to its high lipid solubilityand large nonionized fraction at physiological pH • Redistribution is responsible for decreasing the plasma concentration to awakening levels • Shorter half-life than thiopental because of its clearance

49. Etomidate-dynamics • Depresses the reticular activating system and mimics the inhibitory effects of GABA • Unlike barbiturates, it has disinhibitory effects in the extrapyramidal motor area leading to myoclonus at a rate of 30-60% • PONV more than common than seen with a barbiturate induction

50. Etomidate(cont.) • CARDIAC – Produces minimal, if any, changes in heart rate and cardiac output with a slight decrease in systemic blood pressure • Contractility remains the same • No histamine release