Anesthetic agents

1. Anesthetic agents JehnMihill

2. Objectives • To review some commonly used anesthestic agents • To discuss briefly some definitions related to the pharmacology of these medications • To discuss some common applications of these drugs in the context of your everyday work

3. Some definitions • Half life (T1/2) The time taken for the plasma concentration of a drug to fall by 50% when first order kinetics are observed • Volume of distribution (Vd) The volume into which a drug appears to be uniformly distributed at the concentration in plasma • Influenced by lipid solubility, binding to plasma proteins and molecular size. • - A low Vd indicates drug mainly restricted to intravascular space. High Vd indicates significant tissue uptake

4. Redistribution -the process by which a drug is moved from the vessel rich group to the vessel poor group • This is the primary method responsible for the termination of effect of the majority of anesthestic drugs • Pharmacokinetics • Commonly explained as what the body does to the drug • Pharmacodynamics • - what the drug does to the body

5. Pharmacokinetics (simplified) • Absorption : the process of a substance entering the blood circulation

6. Metabolism (biotransformation) • Role of metabolism is to convert active lipid soluble drug into water soluble and often inactive drug • Phase 1 reaction: • Redox reaction (addition of a polar group), that prepares the drug for phase 2 reaction, and sometimes inactivates the drug • Phase 2 reaction: - Glucoronidation (addition of an ionized group to the drug) that prepares the drug for excretion, and often inactivates the drug

7. Excretion: The elimination of substances from the body. (often done by the kidneys- but can be lungs etc) • Plasma concentration curves • Drugs injected intravenously are removed from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic pattern

9. Types of induction agents • Propofol • Barbiturates: Thiopental, Methohexital • Benzodiazepines: Midazolam, Diazepam • Phenylcyclidines: Ketamine • Etomidate • Dexmedetomidine

10. The ideal IV anesthestic • Physicochemical • water soluble • long shelf life • stable on exposure to light • Pharmacokinetics • small volumes required • short duration of effect; rapidly inactivated

11. The “ideal” IV anesthetic • Physicochemical-water soluble - long shelf life; stable on exposure to light • Pharmacokinetics - small volumes required - short duration of effect; rapidly inactivated

12. Year of introduction of different IV anesthetics • 1935 – Thiopental • 1957 – Methohexital • 1960 – Droperidol • 1965 – Ketamine • 1965 – Diazepam • 1972 – Etomidate • 1977 – Propofol • 1978 – Midazolam • 2000 – Dexmedetomidine

13. Propofol • History • Physicochemical properties • Pharmacokinetics • Effects on organ-systems • Clinical uses

14. History • 1st clinical trial reported by Kay and Rolly in 1977 • Initial formulation with Cremophor resulted in anaphylactoid reactions • Reformulated as a lipid emulsion • Today is the most frequently used IV anesthetic

15. Physiochemical properties • Alkylphenol • Oil at room temperature, insoluble in aqueous solution, highly lipid soluble • Present formulation: 1% propofol + 10% soybean oil + 2.25% glycerol + 1.2% egg phosphatide + 0.005% disodium edetate • Stable at room temperature • Not light sensitive

18. Pharmacokinetics • Two-compartment model • Redistribution half-life 2-8 minutes • Elimination half-life around 4 hours • - rapid liver metabolism • extrahepatic metabolism (lungs) • excreted by the kidneys • Context-sensitive half-time < 40 minutes (for infusions up to 8 hours)

20. Pharmacology • Primarily a hypnotic agent • Mechanism NOT fully understood – evidence points to binding to the beta subunit of the GABAA receptors in the hippocampus and prefrontal cortex • Produces a sense of well-being by increasing dopamine levels in the nucleus accumbens • Antiemetic effect by decreasing serotonin levels in the area postrema

21. Pharmacology • Anticonvulsant at induction doses • Decreases ICP and reduces CMRO2 while maintaining autoregulation • Dose-dependent duration of apnea after induction • During infusions TV is preferentially decreased, while RR is maintained

22. Pharmacology • Most prominent CVS effect – decrease in SBP by 25-40%, mostly by reducing SVR • Atenuates the tachycardic response to hypotension (resets the baroreflex) • Preserves the global myocardial oxygen supply-demand ratio • Effective in treating pruritus induced by spinal opiates

23. Clinical Uses • Induction and Maintenance of anesthesia • Sedation for countless procedures • OK for Neuro (ECTs) and Cardiac cases • ED95unpremedicated patients 2.5mg/kg • Earlier return of psychomotor function than thiopental or methohexital • Lower incidence of PONV than any other hypnotic agent

24. Side Effects • Pain on injection • Myoclonus < than etomidate, but > than thiopental • Propofol Infusion Syndrome -lethal, first described in children • subsequently in critically ill adults • with infusions 5mg/kg/hr for > 48 hours; includes cardiomyopathy, skeletal myopathy, hyperkalemia, lipemia, metabolic acidosis

26. Barbiturates • History • Thiopental, Methohexital • Physicochemical properties • Pharmacokinetics • Effects on organ-systems • Clinical uses

27. History • Barbital – 1st barbiturate with sedative properties described in 1903 • Hexobarbital – 1st short acting barbiturate introduced clinically in 1932 in Europe • Thiopental – introduced clinically in North America by R. Waters and J. Lundy in 1935 was characterized after Pearl Harbor as “the ideal form of euthanasia in war surgery”

28. Physicochemical • Water soluble salts in alkaline solutions; if alkalinity is reduced barbiturates precipitate as free acids • Thiopental is stable for 1 week if refrigerated after reconstitution • Methohexital remains stable for 6 weeks • The groups (aryl or alkyl) attached to the C atom in position 5 are responsible for the hypnotic activity

30. Pharmacology • Mechanisms of action remain largely unknown • evidence shows that binding of a barbiturate to the GABAA receptor both enhances (at low barbiturate concentrations) and mimics (at high concentrations) the action of GABA on the GABAA receptor, thus enhancing the actions of this inhibitory neurotransmitter

31. Pharmacology • Dose-related decrease in CMRO2 until isoelectric point is reached; after that, cerebral metabolic rate remains at 50% of baseline • Parallel reductions in CBF (the ratio of CBF to CMRO2 is unchanged) and ICP • CPP is preserved because ICP decreases to a greater extent than MAP • Protection from incomplete cerebral ischemia

32. Pharmacology • Cardiovascular depression from both cardiac and vascular effects. • Peripheral vasodilation is accompanied by a decrease in contractility secondary to reduced availability of Ca to myofibrils. In addition HR is increased. • Patients without adequate compensatory mechanisms may therefore display serious hemodynamic depression

33. Clinical Uses • Excellent hypnotic – onset 15 seconds • No analgesia • Thiopetal – analgesic at low doses • Methohexital is cleared more rapidly than thiopental – recovery profile similar to propofol

34. Contraindications • Porphyria may be precipitated by the administration of thiopental • Garlic and onion taste in 40% of patients • Allergic reactions such as facial edema, bronchospasm and anaphylaxis have been reported • Local tissue irritation at the site of injection leading in rare cases to tissue necrosis

35. Benzodiazepines • History • Midazolam, Diazepam, Lorazepam • Physicochemical properties • Pharmacokinetics • Effects on organ-systems • Clinical uses

36. History • Chlordiazepoxide(Librium) was discovered accidentally to have sedative, hypnotic and amnestic effects in the early 1960’s when a patient who was taking it fell, fractured her sacrum, yet did not remember the trauma, nor did she complain of pain • Diazepam(Valium) was first used in 1965 • Lorazepam(Ativan) was synthesized in 1971 • Midazolam(Versed) was introduced in 1978 • 1977 specific benzodiazepine receptors were described

38. Physicochemical • Highly lipid soluble at physiologic pH, water soluble when formulated in a buffered acidic medium (pH 3.5) • Midazolam solution contains 0.8% NaCl, 0.01% disodium edetate and 1% benzyl alcohol • pH is adjusted to 3 with HCl

39. Pharmacokinetics • Biotransformation occurs in the liver, the metabolites have activity and over time can accumulate • Termination of action is the result of redistribution from the CNS to other tissues • Midazolam has greater hepatic clearance than diazepam and lorazepam • All 3 are affected by obesity

41. Pharmacology • Hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle relaxant activities • Mechanism of action is well understood: occupation of the BDZ receptor modulates GABA • BDZ receptors are found in the olfactory bulb, cortex, cerebellum, hippocampus, substantia nigra and inferior colliculus

43. Pharmacology • Log-term exposure to benzodiazepines produces tolerance • Reduce CMRO2 and CBF in a dose-related manner, while maintaining their normal ratio • Increase the seizure threshold • Produce dose-related ventilatory depression and act synergistically with opioids even though they act at different receptors

44. Pharmacology • Only slight reduction in MAP • HR and CO are maintained – safe for use in aortic stenosis • Act synergistically with opioids in decreasing systemic BP – probably due to reduced sympathetic tone when the drugs are given together

45. Clinical Uses • Preoperatively for sedation and anxiolysis • Intraoperatively during local or RA • Induction of GA: 0.2mg/kg • No analgesia • Recent reports focused on the potential role of IT midazolam as an adjunct to IT opioids

46. Phencyclidines (Ketamine) • History • Physicochemical properties • Pharmacokinetics • Effects on organ-systems • Clinical uses

47. History • Phencyclidine was introduced in clinical use in 1958, but produced an unacceptably high rate of postanesthetic hallucinations and delirium. Still used illicitly today for recreational purposes. • Ketamine, one of 200 derivatives of phencyclidine was released for clinical use in 1970

48. Physicochemical • Partially water soluble • Prepared as an acidic solution – pH 3.5 to 5.5 containing the preservative benzethonium chloride • Racemic mixture of 2 enantiomers in equal amounts • The isomer S(+) is also available commercially

49. Pharmacokinetics • Metabolized by the liver to a compound (norketamine) with significantly less activity (20%) • Two-compartment model • Distribution half-life: 11-16 minutes • Elimination half-life: 2-3 hours