Anesthesia Pharmacology:  General Anesthesia

Comparative Pharmacology and Physiology

Seizure activity and inhalational anesthetics:

• Overview: seizures

  • Seizure Types

  • Anticonvulsant medication:

    • These drugs should be continued using the patient's normal medication regimen, until surgery.

    • Following surgery, anticonvulsant medication should be administered parenterally until the oral route of administration is available

    • Anesthetic approaches should not be used which might increase seizure probability. 

    • Anticonvulsant drugs, because they affect liver metabolizing enzyme systems and neuromuscular systems, may interact with anesthetics:

      • For example, phenobarbital (Luminal) may promote metabolism of anesthetic agents.  This effect occurs because phenobarbital (Luminal) increases the activity of the hepatic drug metabolizing system (P450 system).  Specifically, phenobarbital (Luminal) and many other drugs increase the genetic expression of certain P450 enzymes.

      • Increased metabolism of volatile, halogenated anesthetics may increase organ toxicity risk

  • Anesthetics and seizures:

    • Most inhaled anesthetics (including nitrous oxide) may produce seizure activity.

      • The likelihood of seizure appears extremely rare with halothane (Fluothane) or isoflurane (Forane)

•  Enflurane (Ethrane)

  • Enflurane (Ethrane) has been shown to induce fast frequency/high voltage (EEG) which may progress to spike wave activity closely resembling EEG changes associated with seizure

  • Furthermore, tonic-clonic seizure manifestation may occur.

  • Factors that increase the likelihood of enflurane (Ethrane)-induced seizure activity include:

    • Enflurane (Ethrane) administration at concentration greater than 2 MAC

    • Hyperventilation which causes a decrease in PaCO₂ to less than 30 mm Hg

    • The patient being exposed to repetitive auditory stimuli during anesthetic administration

  •   Children are probably particularly susceptible to enflurane (Ethrane)-induced seizure activity.

• Isoflurane (Forane), Desflurane (Suprane), Sevoflurane (Sevorane, Ultane)

  • Desflurane (Suprane) and isoflurane (Forane) exhibit dose-dependent EEG depression.

  • Accordingly, these agents do not cause seizure activity on the EEG

    • Furthermore, sevoflurane (Sevorane, Ultane) suppresses lidocaine (Xylocaine)-induced convulsions.

    • There is a report that two epileptic, pediatric patients developed EEG evidence of seizure activity during sevoflurane (Sevorane, Ultane) anesthesia.

• Nitrous oxide

  • Increased motor activity (with opisthotonus and conus) at clinical concentrations

  • Tonic-clonic seizures following nitrous oxide administration to a healthy child is very rare.

• Ketamine (Ketalar) use and its possible relationship to seizure induction is a controversial area.

  • It is probably reasonable to avoid ketamine (Ketalar) administration in patients with known seizure disorders since alternative drugs, e.g. benzodiazepines, propofol (Diprivan), barbiturates are available.

• Propofol (Diprivan)

  • Propofol (Diprivan) has been shown to most likely increase seizure threshold, exhibiting greater EEG depression than thiopental (Pentothal).

• Methohexital (Brevital), a very short-acting barbiturate, may produce seizures in pediatric patients.  

  • Although methohexital (Brevital) is not explicitly contraindicated in seizure-prone patients, the similarly rapidly-acting and short-acting thiopental (Pentothal) would be preferable.

• Fentanyl (Sublimaze), sufentanil (Sufenta), alfentanil (Alfenta)

  • These agents are unlikely to provoke seizure at the normal clinical  dose range.

  • However, high-dose fentanyl (Sublimaze) (200-400 ug/kg) or sufentanil (Sufenta) (40-160 ug/kg) should be used cautiously in patients with known seizure disorders

  • Note: patients receiving anticonvulsants often require increased fentanyl (Sublimaze) during surgery: (probably because of anticonvulsant-mediated induction of hepatic microsomal metabolizing system

•  Drug-drug interaction

  • Patients receiving phenytoin (Dilantin) and carbamazepine (Tegretol) may have increased resistance to nondepolarizing muscle relaxants

• Volatile anesthetics when administered at concentrations > 0.6 MAC are typically associated with cerebrovascular consequences

  • A common vascular manifestation is cerebral vasodilation

  • Furthermore, dose-dependent increases in CBF (cerebral blood flow) would be expected along with concurrent decreases in cerebral metabolic requirements

  • Greatest CBF increase  would be observed following halothane (Fluothane) administration.

    •  200% CBF (two-fold) increase could occur at 1.1 MAC

  •  Increases in CBF are particularly important to consider in patients have intracranial space-filling lesions.

    •   In this patient group, serious consideration should be given to using approaches that minimize CBF increases.

  • Anesthesia using halothane (Fluothane) in combination with nitrous oxide (1.5 MAC) causes a significant increase in regional cerebral blood flow (166%).

  • A relatively reduced degree of CBF increase is seen with enflurane (Ethrane), which exhibits about a 30%-50% CBF increase at 1.1 MAC

  • Isoflurane (Forane) is associated with the least CBF increase, causing no apparent change in CBF at 1.1 MAC. 

    • On this basis, at least, isoflurane (Forane) might be preferred agent in  patients who are sensitive to consequences of increased CBF.

• Time course for CBF changes following anesthetic administration

  • Increases in CBF occur within minutes following anesthetic administration.  

    • The change in cerebral blood flow appears independent of changes in BP

  • CBF remains elevated compared to cerebral metabolic oxygen requirements for as long as 4 hours, during surgical anesthesia with halothane (Fluothane), isoflurane (Forane), or sevoflurane (Sevorane, Ultane)

  • Halothane (Fluothane) may cause loss of CBF regulation which contributes to brain swelling

  • Other inhaled anesthetics, e.g. desflurane (Suprane) and sevoflurane (Sevorane, Ultane), do not change CBF autoregulation (as measured by cerebral circulation responsiveness to changes in PaCO₂.)

• Dose-dependent decreases in CMR with inhaled anesthetics

  • Greater decreases with isoflurane (Forane) than with halothane (Fluothane) at equivalent MAC

  • At concentrations < 1 MAC, isoflurane (Forane) does not consistently increase CBF-- possibly due to decreased CMR.

    • As CMR decreases, less CO₂ is produced -- opposing a CBF increase

• Inhaled anesthetics increase in ICP with parallel increase in CBF

  • Patients at greatest danger: those with intracranial space-filling lesions

  • Protection against increases in ICP:

    •  Hypocapnia

      •  In hypocapnic patients with intracranial masses:

        •  Desflurane (Suprane) < 0.8 MAC: no increase in ICP:

        •  Desflurane (Suprane) > 1.1 MAC: increases ICP (about 7 mm Hg)

      • Hyperventilation decreases the likelihood that inhaled anesthetics will increase ICP (PaCO₂ decreased to about 30 mm Hg)

        • Halothane (Fluothane): Hyperventilation should be started before halothane (Fluothane) introduction

        • Isoflurane (Forane): Hyperventilation should proceed concurrent with anesthetic administration

        • Enflurane (Ethrane): Hyperventilation: increases seizure activity (greater seizure activity leads to increased CMR and CO₂ production)

• Volatile Anesthetics

  • Many volatile anesthetics directly dilate the cerebral vasculature, causing an increase in cerebral blood flow (CBF).-- including:

    • Halothane (Fluothane), enflurane (Ethrane), sevoflurane (Sevorane, Ultane), desflurane (Suprane), isoflurane (Forane).

    • Halothane (Fluothane) in combination with nitrous oxide (1.5 MAC) ­increase CBF by about 65%

      • At equal anesthetic potency, enflurane (Ethrane) and isoflurane (Forane) have a reduced effect.

      • Enflurane (Ethrane) increase blood flow about 35%; isoflurane (Forane) less than that. (sevoflurane (Sevorane, Ultane) and desflurane (Suprane): similar to isoflurane (Forane) in terms of cerebral blood flow effects (CBF)

• Clinical Correlation: Volatile agents

  • Increased CBF influences intracranial pressure (ICP)

    • Increased cerebral blood flow (tends to increase the amount of intracranial blood) can cause increased ICP under conditions of abnormal intracranial elasticity

    • Volatile anesthetics reduce the cerebral metabolic rate (CMR)

      • Isoflurane (Forane) reduces the CMR to a greater the degree than halothane (Fluothane) (Sevoflurane (Sevorane, Ultane) and desflurane (Suprane): similar to isoflurane (Forane))

      • Isoflurane (Forane): reduces CMR which itself causes reduced CBF; direct isoflurane (Forane)-mediated CBF increases are offset by indirect isoflurane (Forane)-mediated decreases (cause by decreased CMR)

  • Enflurane (Ethrane): induces seizure-type discharges -- a phenomenon enhanced by hypocapnia

    • Seizures due to: 1.5 MAC enflurane (Ethrane) + hypocapnia + auditory stimulus: resulted in CMR increases and a 50% CBF increase.

  • Desflurane (Suprane):

    •  Faster anesthesia onset and recovery compared to isoflurane (Forane)

    •  Greater ICP increases compared isoflurane (Forane)

      •  Desflurane (Suprane): not recommended for patients with CNS space-filling lesions

    •  Desflurane (Suprane):

      • Sympathetic hyperactivity in healthy volunteers

      • Laryngospasm (and other upper respiratory difficulties): may occur in pediatric patients

  • Sevoflurane (Sevorane, Ultane)

    •  Possible toxicity: metabolic products -- inorganic fluoride ion; substance P.

    •  Effective alternative in combination with nitrous oxide for pediatric induction

    •  May, like enflurane (Ethrane), induce seizures

  • Nitrous oxide:

    •  May increase CBF and ICP -- barbiturates and hypocapnia may prevent these changes

    •   Nitrous oxide in combination with volatile anesthetics may cause greater increases in CBF than with nitrous oxide alone

    •  Nitrous oxide, administered alone, may significantly increase CMR

    •  Commonly used in neuroanesthesia -- nitrous oxide effects on CBF, CMR, and ICP should be carefully evaluated

  •  Conclusion:

    • Volatile agent of choice for patients with cerebral ischemia or patients who may develop cerebral ischemia: isoflurane (Forane)

• Intravenous anesthetics

  • Barbiturates

    •  Decrease CMR and CBF

    •  May substantially decrease mean arterial pressure (MAP) which can reduce cerebral perfusion pressure (CPP)

    •  Thiopental (Pentothal) (high-dose: 10-55 mg/kg):

      • Isoelectric EEG

      • CMR reduction-- 50%

      • CMR reduction cerebrovascular constriction ® CBF reduction

      •  Barbiturates:

        •  Effective in reducing elevated ICP

        •  Effective in controlling epileptiform CNS activity (methohexital (Brevital) -- exception; may activate seizure foci in patients with temporal lobe epilepsy.

  • Etomidate (Amidate)

    • CMR reduction

    • CBF reduction

    • Direct-acting vasoconstrictor

    • No significant cardiovascular depression (by contrast to barbiturate)

    • Reduced adrenocortical response to stress with prolonged use

  • Propofol (Diprivan)

    • CMR reduction

    • CBF reduction

    • ICP reduction

    • Cerebral perfusion pressure (CPP): must be carefully followed since propofol (Diprivan) reduces mean arterial pressure (MAP).

    • Longer-lasting ventilatory depression (compared to barbiturates)

  • Benzodiazepines

    • CMR reduction is less than with barbiturates

    • CBF reduction is less than with barbiturates

    • ICP reduction (secondary to CBF effect)

    • Flumazenil (Romazicon) (dibenzodiazepine antagonist)

      •  Reduces CMR, CBF, and ICP reducing effects of midazolam (Versed)

      •   Cautious or no use of flumazenil (Romazicon) in patients with high ICP or abnormal intracranial elasticity

  • Opioids

    •  Morphine and fentanyl (Sublimaze): minor reduction/no effect on CBF and CMR

    •  Uncertain effects of sufentanil (Sufenta) on CBF and CMR

    •  In brain tumor patients: alfentanil (Alfenta) increases CSF pressure;

  • Ketamine (Ketalar)

    •  Dissociative anesthetic

    •  Increases CBF and CMR; activates certain brain regions

    •  Not commonly used in neuroanesthesia.

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