A simplified crash course on Intravenous Anesthetics and Muscle Relaxants 1. Intravenous anesthetics
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1 A simplified crash course on Intravenous Anesthetics and Muscle Relaxants 1. Intravenous anesthetics Mechanism of action: Usually by inhibiting activating, or activating inhibitory signaling pathways in the brain. Facilitatory actions on GABAA receptors seem most important, although undoubtedly modulation of other receptors and channels plays a role as well. Primary: to induce general anesthesia. To supplement general anesthetics, particularly at the end of a case To maintain general anesthesia To provide sedation To control blood pressure To protect the brain To prevent nausea 1.1. Propofol Most recent intravenous anesthetic. An alkylphenol formulated as a 1% solution in intralipid (explaining the color). Site of action: probably the GABAA receptor. Induction of anesthesia Maintenance of anesthesia Sedation Nausea reduction Hypnosis Not antalgesic like the barbiturates Respiratory effects similar to thiopental (but a better bronchodilator) Cardiovascular depression slightly more profound than with thiopental Antiemetic Pain on injection (mix or precede with lidocaine) Myoclonus file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (1 de 10) [18/09/ :24:30]
2 Cardiovascular instability Formulation: 10 mg/ml Dose: for induction; /min for sedation; /min for maintenance Onset: 30 sec Duration: 5 min Cost: $ 9.05/200 mg 1.2. Barbiturates Derivatives of barbituric acid. Sulphur substitution leads to more lipophilic compounds with a rapid onset and shorter duration of action (cf. thiopental and pentobarbital). Site of action: Primarily enhancement of inhibitory GABAA signaling in the CNS. They are hypnotics and have no analgesic action, or even some antalgesic action. Thiopental (pentothal) Intravenous induction. Block acute blood pressure increases (e.g. head pinning). Seizure control Provide a degree of brain protection. Thiopental reversibly reduces cerebral electrical activity to the level of EEG silence, with a significant reduction in cerebral metabolism. Modest decrease in blood pressure, which can be more pronounced in hypovolemic patients or those with cardiovascular disease. Temporary depression of ventilation, with little change in airway reflexes. Hypovolemia Poor cardiac status Formulation: 25 mg/ml Induction dose: 3-5 Onset: 30 seconds Duration of action: 5-10 minutes file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (2 de 10) [18/09/ :24:30]
3 Cost: $2.76/500 mg Methohexital (Brevital) Rectal anesthesia induction in children up to 5 yr Anesthesia induction for ECT (because of seizure enhancement) and occasional types of epilepsy surgery CNS effects similar to thiopental, with the the exception of: Activation of epileptic foci Blood pressure effects similar to those of thiopental Respiratory effects similar to thiopental (generally not noted with rectal administration) Myoclonus Pain on injection (in smaller veins) Similar to thiopental Formulation: 500 mg dry powder Dose: 1.5 IV, 30 PR Onset: 30 sec IV, 5-20 min PR Duration of action: 5-10 min IV; when administered PR, drowsiness will be noted up to 1-2 h Cost: $8.77/500 mg 1.3. Etomidate Etomidate is an imidazole, supplied as a highly hyperosmotic solution (>4500 mosm/l) in propylene glycol. Site of action: Presumably activation of GABA signaling. Induction of anesthesia in hemodynamically unstable patients. Cerebral effects very similar to those of thiopental: hypnosis, no analgesia In contrast to thiopental, etomidate has minimal effects on the cardiovascular system. Minimal respiratory effects Inhibits 11-b-hydroxylase, a key enzyme in steroid production. This led to increased morbidity and mortality in ICU patients sedated for prolonged periods with etomidate, but has not been shown to file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (3 de 10) [18/09/ :24:30]
4 result in morbidity after a single induction dose. Myoclonus Pain on injection and thrombophlebitis Post-op nausea and vomiting Formulation: 2 mg/ml Dose: 0.3 Onset: < 1 min Duration of action: 3-10 min Cost: $17.21/200 mg 1.4. Ketamine Ketamine is a phencyclidine derivative (similar to PCP). Site of action: Inhibition of signaling at the NMDA receptor, although multiple secondary sites (s opioid receptors, muscarinic acetylcholine receptors) exist. Induction of anesthesia in children, by almost any imaginable route Induction of anesthesia in severely hypovolemic patients Supplementation of sedation during painful procedures Cerebral protection Potent analgesic "Dissociative" anesthesia Adrenergic activation Minimal respiratory effect Amnesia Nystagmus Salivation Dreaming and emergence reactions (less in children) Increased ICP Open-eye injury Ischemic heart disease Psychological disease file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (4 de 10) [18/09/ :24:30]
5 Formulation: Two concentrations: 10 mg/ml and 100 mg/ml. Careful! Dose: IV, 4-6 IM for induction. Onset: 1 min IV, 5 min IM Duration of action: 15 min Cost: 10 mg/ml: $ 5.70 for 200 mg; 100 mg/ml: $11.40 for 500 mg 1.5. Benzodiazepines A large family, of which only midazolam tends to get used in the OR. Potent sedative and amnestic actions. Site of action: GABAA receptor. Midazolam (Versed) Occasionally for induction of anesthesia (cardiac surgery, not covered here) Usually for sedation or premedication Amnesia in patients who do not tolerate any anesthetic (trauma) Sedation Amnesia Modest respiratory depression Modest hemodynamic effects Elderly patients can exhibit paradoxical reactions Patients with marginal respiratory function Formulation: 1 mg/ml Dose: mg for sedation Onset: 5 min Duration of action: 45 min Cost: $3.47/2 mg file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (5 de 10) [18/09/ :24:30]
6 2. Opiates Derivatives of morphine, act at opiate receptors present in multiple forms at multiple sites. Potent analgesics. Issues applicable to all compounds: supplementation of general anesthesia pain relief induction of anesthesia in cardiac patients (not covered here) premedication (blunting of hemodynamic response to intubation). Narcotics should not be given long before induction to painfree patients because of dysphoric reactions. Side effects: respiratory depression nausea and vomiting muscle rigidity others with primarily nuisance value: urinary retention, pruritus, dysphoria Respiratory depression Morphine Use: As above. Post-op pain relief, because of its long duration of action As above Histamine release (not seen with the other compounds), leading to: Decreases in blood pressure As above Formulation: 10 mg/ml Dose: Onset: 10 min Duration of action: 2 h file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (6 de 10) [18/09/ :24:30]
7 Cost: $ 0.49/10 mg Synthetic narcotics: fentanyl, alfentanil, sufentanil Fentanyl is the "standard" narcotic for perioperative use. Alfentanil is used primarily for relief of brief, intense pain (e.g. head pinning), or for supplementation of anesthesia close to the end of a case. It is approximately 5x less potent than fentanyl. Sufentanil is approximately 10x as potent as fentanyl, which is not reflected in the formulation! Remifentanil is ester-metabolized, and therefore so short-acting that it is administered by infusion. Name Formulation Dose Onset Duration Cost fentanyl 50 mg/ml min 1.5 h $ 0.34/250 mg alfentanil 500 mg/ml min 30 min $ 5.40/1000 mg sufentanil 50 mg/ml min 1 h $18.40/100 mg remifentanil powder 0.5-1, then 4 min 8-10 min? /min 3. Muscle relaxants Muscle relaxants block the nicotinic acetylcholine receptors at the muscle endplate, thereby inhibiting neuromuscular transmission and inducing muscle flacidity. Inactivation of the receptor can be attained in two ways: by depolarizing the receptor continuously, which leads to a complex form of desensitization (depolarizing muscle relaxants); or by competitively antagonizing the receptor (non-depolarizing muscle relaxants). Degree of relaxation can be assessed using a twitch monitor. The two standard modes of testing are the train-of-four (four pulses at 0.5 sec intervals) and tetanus (usually at 50 Hz). 3.1 Depolarizing muscle relaxants The only one of these in clinical use is succinylcholine ("sux"). It is still the relaxant with the briefest duration of action, a result of its rapid metabolism by butyrylcholinesterase ("pseudocholinesterase") in plasma. The rapid onset (30 sec) minimizes unprotected airway time, the rapid degradation allows patients to manage their own airway quickly again after an unsuccessful intubation. Succinylcholine administration results in a parallel decrease in height of all twitches on the train-of-four (no "fade"). After administration of high doses a pattern similar to that seen with non-depolarizing drugs is occasionally observed, the so-called and confusing Phase II block. Side effects: The initial depolarization of muscles causes fasciculations. These are associated with muscle pain postoperatively, and can largely be prevented by administration of a small dose of non-depolarizing relaxant (curare 3 mg) one minute prior to succinylcholine. In that case the dose of succinylcholine should be increased by 1.5 to compensate for the antagonism of succinylcholine file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (7 de 10) [18/09/ :24:30]
8 by the non-depolarizing drug. Lidocaine also appears to prevent this muscle soreness. The muscle depolarization also results in release of K+ from myocytes. In patients with upregulated nicotinic receptors (burns, major trauma, paralyzed limbs, head trauma, neuromuscular disease) this can lead to cardiac arrest. The drug should not be used between 1 day after and 1 year after such events. In case of persisting paresis, it remains contraindicated. Succinylcholine can induce malignant hyperthermia in susceptible patients. Prolonged paralysis occurs in case of butyrylcholinesterase abnormalities Increases in intra-ocular pressure Increases in intracranial pressure (modest) Bradycardia, particularly in children after a second dose (pretreat with atropine) The difficult airway Documented or suspected susceptibility to malignant hyperthermia Upregulated nicotinic receptors Children <5 yrs. This is a heavily debated issue. Patients with open eye injury Patients with increased ICP (a relative contraindication) Formulation: 20 mg/ml Dose: 1 ; in children 2 Onset: 30 sec Duration of action: 5 min Cost: $0.36/200 mg 3.2. Non-depolarizing muscle relaxants Because of the side effects of succinylcholine, a rapidly acting non-depolarizing drug would be very welcome. Although improvements are being made, nothing is quite as fast in onset, and in brevity of action nothing comes even close. Administration of non-depolarizing drugs leads to a "fade" on train-of-four (i.e. each subsequent twitch is smaller) and to post-tetanic potentiation: an increase in train-of-four response after a brief tetanic stimulus. Side effects (see table for details): Histamine release Vagolytic effect (muscarinic inhibition) Sympathomimetic effect (autonomic ganglia stimulation) file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (8 de 10) [18/09/ :24:30]
9 Few. Non-depolarizing drugs are incredibly safe, as long as the airway is adequately taken care of. Name Hist Vago Gangl Formulation Dose Onset Duration Cost Succinylcho +/- stim stim 20 mg/ml 1 30 s 5-10 min $0.36/200 d-tubocurarine +/- - blocks 3 mg/ml min min $4.51/60 m Metocurine +/-- - +/- block 2 mg/ml min min $20.27/40 Pancuronium - +/- block - 1 mg/ml min min $1.31/10 m Doxacurium mg/ml min min $13.49/5 m Vecuronium mg powder min min $18.11/10 Cisatracurium mg/ml min min $39.47/100 Rocuronium - +/- block - 10 mg/ml 1 1 min min $14.62/50 Mivacurium +/ mg/ml min min $8.05/100 Hist=histamine release; Vago=vagolytic; Gangl=ganglionic stimulation. Succinylcholine is included for comparison Reversal Reversal of longer-acting muscle relaxants is at times indicated. This is accomplished by inhibitors of cholinesterase, resulting in increased availability of acetylcholine which competitively reverses the neuromuscular blockade. Side effects: Bradycardia from cardiac muscarinic stimulation Bronchoconstriction Potentially: increased intestinal tone, leading to rupture of just-placed intestinal sutures, which annoys surgeons. These side effects can be (partially) prevented by administration of a muscarinic antagonist, which is usually given at the same time as the reversal drug. Two cholinesterase inhibitors are available: neostigmine and edrophonium. file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (9 de 10) [18/09/ :24:30]
10 Neostigmine Neostigmine is slower in onset than edrophonium, but has a longer duration of action and can reverse a greater degree of neuromuscular blockade. The muscarinic antagonist glycopyrrolate (7-15 ), which has a longer duration of action and a longer time to onset than atropine, is often used with neostigmine to minimize cardiovascular changes. Formulation: 1 mg/ml Dose: Onset: full reversal is attained in approximately 10 min Duration of action: 1.5 h Cost: $0.71/10 mg (glycopyrrolate: $0.24/0.2 mg) Edrophonium Atropine (7-10 ) is often given with edrophonium, as its somewhat more rapid onset and shorter duration of action match the pharmacokinetics of edrophonium. Formulation: 10 Dose: Onset: full reversal is attained in approximately 5 min Duration of action: 1 h. This means that long-acting relaxants may outlast edrophonium! Cost: $5.98/100 mg (atropine: $0.41/0.4 mg) Back to the Anesthesiology Residency page Copyright Dept. of Anesthesiology, University of Virginia 09/29/97 file:///d /X. SOLER/BIBLIO2/Intravenous Anesthetics and Muscle Relaxants.htm (10 de 10) [18/09/ :24:30]
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