The Pharmacology of Intravenous Anesthetic Induction Agents

1. The Pharmacology of Intravenous Anesthetic Induction Agents • Dr. Abdul Karim B Othman • Anesthetist. HSNZ

2. Paracelsus (1493 - 1541), the “founding father” of toxicology .....“ all things are poison and nothing is without poison ; only the dose permits something not to be poisonous”

3. - in the absence of an ideal anesthetic devoid of significant side effects ....- balanced anesthesia allows dose reductions in an effort to minimize toxicity

4. Lundy (1926) .... “balanced anesthesia” • combination of premedication, local anesthesia, and general anesthesia to reduce the dose of each agent and thereby improve safety

5. - combination of various iv drugs including hypnotics, analgesics, sedation, and muscle relaxants, often with inhaled anesthetics- with the goal of inducing anesthesia without significant side effects

6. Properties of ideal induction agent • - inducing anesthesia without significant side effects

7. General anesthesia ... a generalized depression of the CNS, includes ... • amnesia (synaptic plasticity in hippocampus) • hypnosis (disruption of thalamocortical interactions) • immobility (depression of spinal reflexes) • often associated with • analgesia • suppression of autonomic reflexes

8. No current available drug achieves these criteria.

9. Properties of the ideal iv anesthetic agent • Pharmacodynamic / pharmacokinetic properties • Physicochemical properties

10. Pharmacodynamic / pharmacokinetic properties • Causes hypnosis and amnesia • Rapid onset (time of one-arm-brain circulation) • Rapid metabolism to inactive metabolites • Minimal cardiovascular and respiratory depression • No histamine release or hypersensitivity reactions • Nontoxic, nonmutagenic, noncarcinogenic

11. Pharmacodynamic / pharmacokinetic properties • No untoward neurologic effects, such as seizures, myoclonus, antanalgesia, neurotoxicity • Other beneficial effects: analgesic, antiemetic, neuroprotection, cardioprotection • Pharmacokinetic-based models to guide accurate dosing • Ability to continuously monitor delivery

12. Physicochemical properties • Water soluble • Stable formulation, nonpyrogenic • Nonirritating, painless on iv injection • Small volume needed for induction • Inexpensive to prepare and formulate • Antimicrobial preparation

13. appropriate drugs are selected based on the anesthetic goals for each patient as dictated by the procedure to be performed • and • patient-specific pathophysiologic considerations

14. Mechanism of action • primary target of iv anesthetic agents are ionotropic (ion channel-linked) receptors for the endogenous neurotransmittersglutamate, the principle excitatory transmitter, or gamma-aminobutyric acid (GABA), the principal inhibitory transmitter

15. GABAA receptors conduct chloride and bicarbonate anions to hyperpolarize the membrane of mature neurons, and the primary targets for the anesthetic effects (sedation, anxiolysis, hypnosis, amnesia) of all iv anesthetics and sedation,except ketamine

16. Pharmacokinetic Principles

18. Barbiturates ...e.g.; thiopental thiomylal methohexital

19. Barbiturates • weak acid • poorly water soluble in neutral pH • formulated as racemic mixtures of their water-soluble sodium salt • use sodium carbonate to maintain an alkaline pH range of 10 to 11

20. alkalinity - result in severe tissue damage from extravasation or intra-arterial injections - induce precipitation of drug that are weak bases (e.g., vecuronium, rocuronium, lidocaine, labetalol, and morphine)

21. Classified broadly as • Oxybarbiturates • O2 at C2 (methohexital) • Thiobarbiturates • sulfur at C2 (thiopental, thiamylal) • ⇪ lipophilicity , ⇪ potency • more rapid onset and shorter duration of action

22. Alkylation of N-1 ⇪ lipophilicity & speed of onset, BUT⇪ excitatory side-effects e.g.: methohexital

23. Use for induction • induce anesthesia (iv) for 4 to 8 minutes • dose requirement are ⬇by • pharmacodynamic interactions • (opioid, ∝2 - adrenergic agonist, benzodiazepines premedication, or acute ethanol intoxication) • pharmacokinetic effects • (anemia, hypoproteinemia, low cardiac output, or shock) • methohexital : 3x > potent with pain on injection

24. Systemic effects .....Cardiovascular • Principal hemodynamic effect • transient ⬇ systemic arterial pressure and C.O • ⬆ HR and minimal change in SVR • hypotension (from marked venodilation) • minimal myocardial depression in usual dose • ⬇ myocardial contractility in higher dose

25. Cardiovascular • ⬆ HR (methohexital > thiopental) result from baroreceptor reflex-mediated SNS stimulation • Thiopental and thiamylal can induce histamine release • hypotension effects are more pronounced in • hypertension • hypovolemia • valvular or IHD or shock

26. Deleterious hemodynamic effects in condition that are worsened by reduced preload or tachycardia • e.g., MI, CCF, pericardial tamponade and valvular heart disease

27. Respiratory • potent central resp depressants • dose-dependent ⬇ in min volume and tidal volume ➥ apnea • depressed medullary center ventilatory responses to both hypercapnia and hypoxia • do not depress laryngeal and tracheal reflexes

28. Neurologic • potent anticonvulsant • brain protection & ⬇ ICP in intracranial hypertension • Thiopental • long-term cerebral protection in focal ischemia • ineffective in cerebral resuscitation after global ischemia (cardiac arrest) • undesirable CNS effects • paradoxical excitement • involuntary skeletal muscle movements

29. methohexital • trigger seizure foci in susceptible patients • advantage in epilepsy surgery and ECT • Others .... stimulate mitochondrial enzyme gamma-aminolevulinic acid reductase, the rate-limiting enzyme in porphyria biosynthesis • exacerbate acute intermittent porphyria

30. Propofol ...

31. Physicochemical properties • 2,6-di-isoprophyphenol • lipophilic • very weak acid • nonionized at physiologic pH • very insoluble in water

32. Formulated at • 1% (v/v) in an oil/water emulsion containing 10% soybean oil, 1.2% egg lechitin, and 2.25% glycerol • pH range of 6.0 to 8.5 • excellent medium for microbial growth

33. Use for induction • rapid redistribution and hepatic elimination • rapid return to consciousness with minimal residual effect • rapid clearance and short context-sensitive halftime • maintenance of anesthesia by continuous infusion without significant cumulative effects • exhibit pharmacodynamic synergism with benzodiazepines and opioid • pain on injection

34. Systemic effects ... Cardiovascular • ⬇ BP by 15 to 40% (propofol > thiopental) • significant ⬇ in SVR and cardiac filling • little or no direct effect on myocardial contractility • effect on HR is variable BUT bradycardia > tachycardia • resets baroreceptor reflex control of HR • unchanged HR despite ⬇ in BP

35. Cardiovascular • hemodynamic effect is magnified in • hypovolemic, elderly, and impaired L vent function • enhance relaxation of intrinsic muscle • pressor response to tracheal intubation is less marked • minimal ⬆ in plasma histamine release • not arrhythmogenic • does not sensitize heart to catecholamines

36. Respiratory • potent respiratory depression • apneic period : 30 to 60 seconds • greater depression of laryngeal reflexes • cause bronchodilation

37. Neurologic • anticonvulsant ➠ treating refractory epilepsy • excitatory phenomena can occur with induction or at emergence • tremor, hypertonus, opishotonus, & spontaneous or dystonic movement • not likely to induce EEG seizure activity • epileptogenic in seizure disorder • shorten the duration of convulsion after ECT

38. Other • antiemetic activity • antipruritic • more effective in reducing IOP • not trigger malignant hyperthermia • no direct effect on neuromuscular transmission or neuromuscular blocking agents

39. Etomidate

40. Physicochemical properties • carboxylated imidazole derrivative • weak base • poorly water soluble • formulated as an hyperosmotic solution in 35% propylene glycol • prepared as pharmacologically active R(+) stereoisomer

41. Use for induction • fewer CVS and resp depression • useful in • impaired LV function, cardiac tamponade and hypovolemia • minimal effect in • HR, SV, C.O, and vent filling pressure • minimal effect in BP except in • valvular heart disease (up to 40%) • pain on injection

42. Systemic effects ... Cardiovascular • hemodynamic stability resulted from reduced effect on • SNS • baroreceptor reflex responses • smaller change in supply and demand of myocardium oxygen • has a negative inotropic effect • not evoke histamine release • low incidence of hypersensitivity reactions

43. Respiratory • less respiratory depression than barbiturates • ⬇ MV, TV but ⬆ RR • transient apnea in geriatric patients • depress sensitivity of medullary respiratory center to CO2

44. Neurology • ⬇ CMRO2 & cerebral blood flow • ⬇ elevated ICP without ⬇ arterial BP and CPP • ⇪ supply-demand ratio for cerebral oxygen • inhibition of nitric oxide limits its neuroprotective potential in animal models of stroke • used to control status epilepticus, also can activate seizure foci

45. Neurology • precipitate generalized seizure activity (epilepsy) • does not inhibit evoked seizures in ECT • induction is accompanied by a high incidence (> 80% of unpremedicated patients) of excitatory phenomena • spinal muscle movement • hypertonus, and • myoclonus

46. Other • directly suppresses adrenal cortical function • reversibly inhibit 11 beta-hydroxylase, a key enzyme in steroid biosynthesis which persist 6 to 8 hours after an induction dose and is unresponsive to adrenocorticotropic hormone • nausea & vomiting • potentially porphyrinogenic (avoided in porphyria)

47. inhibitor of plasma cholinesterase➥ prolong the action of succinylcholinesterase in cholinesterase deficiency

48. Ketamine

50. Physicochemical properties • weak base • partially water soluble, arylcyclohexylamine derrivative • formulated as a racemic mixture of 2 enentiomers • S(+)-enantiomer is 3x > potent in producing anesthesia with fewer side effects with higher therapeutic index