Neuropharmacology

Anesthetic Drugs and Sedatives

Anesthetic drugs cause their cerebral effects by producing metabolic and functional changes in the central nervous system (CNS). Broadly, intravenous agents tend to reduce both CBF and CMR in a parallel manner and maintain their coupling, while inhalational agents decrease the CMR and increase the CBF and appear not to maintain coupling. However, anesthesia-related CBF–CMR coupling may vary under different brain conditions as the effects of anesthetics on CBF is influenced by both a direct effect on the cerebral vascular tone (vasoconstriction or vasodilatation) and indirect changes in the CMR. Furthermore, this dual mechanism of action makes it difficult to predict whether anesthetics can cause an “intracerebral steal” or the beneficial “reverse intracerebral steal” phenomenon in the pathological brain in which CO ₂ reactivity and autoregulation may be lost. Anesthetics also produce changes in the ICP by changing the CBF and thereby the CBV, and by their influence on cerebrospinal fluid (CSF) dynamics, i.e., the rate of production and reabsorption of CSF. The cerebral effects of anesthetics are also governed by their systemic effects, primarily on the blood pressure, arterial CO ₂ , and body temperature.

A promising attribute of anesthetic drugs that has been identified lately is that some of them have the potential for neuroprotective effects and may even be able to reduce neuronal damage from ischemic insults. These effects are attributed to their ability to reduce neuronal activity and metabolic rates. Lidocaine, thiopental, and sevoflurane have shown to be protective against ischemia in animal studies, particularly when given at the beginning of an ischemic insult due to their proposed “preconditioning effect.” However, the clinical utility of anesthetics in preventing and ameliorating ischemic damage needs further investigation. The neuroprotective effects of various anesthetic drugs are discussed in a separate chapter.

Recent suggestions that anesthetic drugs can cause neurotoxicity and postoperative cognitive dysfunction (POCD) is an area of great concern for the anesthetists. Detailed discussion on this important subject can be found elsewhere in this book.

Intravenous Anesthetic Agents

Intravenous anesthetic agents are small hydrophobic compounds that when injected, enter the highly perfused and lipophilic tissues in the brain and spinal cord where they produce anesthesia in a single circulation time. Termination of anesthesia with these drugs does not reflect metabolism but their redistribution out of the CNS into the blood and then into the lesser perfused tissues like muscles and viscera. Drug redistribution can cause accumulation and slower recovery from its effects.

Barbiturates

Barbiturates are CNS depressant drugs commonly used in neurological practice for providing mild sedation to total anesthesia, and also as anticonvulsants, hypnotics, anxiolytics and analgesics. While sodium thiopental (thiobarbiturates), thiamylal (thiobarbiturates), and methohexital (oxybarbiturates) are used for induction of anesthesia, amobarbital is mainly used for performing “the Wada test,” also known as the “intracarotidsodium amobarbital procedure” used for testing cerebral language and memory representation of the cerebral hemispheres. Barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine) ( Fig. 6.1 ) and act primarily as γ-aminobutyric acid (GABA) receptor agonists ( http://en.wikipedia.org/wiki/Barbiturate ). They also act on the glutamate, adenosine, and nicotinic acetylcholine receptors. The clinically recommended dosages and pharmacokinetics of barbiturates are summarized in Table 6.1 .

Table 6.1

Physical Properties of Intravenous Anesthetic Agents

Anesthetic Agents	Thiopentone Sodium	Propofol	Etomidate	Ketamine
Induction dose (mg/kg)	3–5	2.0–2.5	0.2–0.4	0.5–1.5
Induction duration (mins)	5–8	4–8	4–8	10–15
t 1/2 (h)	12.1	1.8	2.9–5.3	3
Clearance (mL/kg/min)	3.4	23–50	18–25	19.1
Protein binding(%)	85	95–99	76	12

t _1/2 , half-life.

Cerebral Effects of Barbiturates ( Table 6.2 )

Barbiturates produce cerebral function depression and cause a dose-dependent decrease in cerebral metabolic rate for oxygen consumption (CMRO ₂ ) and CBF till the electroencephalograph (EEG) becomes isoelectric. The induction dose of thiopental causes a 25–30% decrease in CMRO ₂ with a maximum 55% decrease occurring at 2–5 times that dose. They cause a reduction in ICP due to decreases in CBF and CBV, and also maintain cerebral autoregulation and CO ₂ reactivity. In low doses, thiopental sodium causes no change in the rate of CSF formation, and either no change or an increase in the resistance to reabsorption of CSF, but in higher doses, it causes decrease in CSF formation rate with either no change or a decrease in the resistance to resorption resulting in a raised ICP. As autoregulation is similar in both brain and spinal cord, high-dose barbiturate therapy causes a significant decrease in spinal cord blood flow (SCBF) suggestive of a protective effect of barbiturates on spinal cord injury, although spinal cord metabolism seems to be less sensitive to depression by barbiturates.

Table 6.2

Cerebral Effects of Anesthetic Agents and Muscle Relaxants

Anesthetic Agents/Muscle Relaxants	ICP	CPP	CBF	CMRO 2	CSF Dynamics		BBB	Epileptogenic
					Resistance to Resorption	CSF Formation
Xenon	↓	↓/−	↓	↓↓	?	?	+	No
Isoflurane	↑/−	↓/−	↑	↓↓	↓/−/↑	−	+	No
Sevoflurane	↑/−	↓/−	↑	↓↓	↑	↓	+	Yes
Desflurane	↑/−−	↓/−	↑	↓↓	−	−/↑	+	No
Nitrous oxide	↑↑	↓↓	↑	↑	−	−	+	Yes
Thiopentone sodium	↓↓	↑↑	↓↓↓	↓↓↓	−/↓	↑/−/↓	+	No
Propofol	↓↓	↑↑	↓↓	↓↓	−	−	+	No
Etomidate	↓↓	↑↑	↓↓	↓↓	−/↓	−/↓	+	Yes
Ketamine	↑↑	↓↓	↑↑	↑	−	↑	+	Yes
Midazolam	↓/−	↑/−	↓	↓	−/↓	−/↑	+	No
Fentanyl	↑/−/↓	↓/−	↓/−/↑	↓/−	−/↓	↑/−/↓	+	Yes
Sufentanil	↑/−/↓	↓/−	↓/−/↑	↓/−	−	↑/−/↓	+	Yes
Remifentanil	↑/−/↓	−	↓/−/↑	↓/−	−	−	+	Yes
Vecuronium	−	−	−	−	−	−	/	No
Rocuronium	−	−	−	−	−	−	/	No
Succinylcholine	↑/−	↓/−	↑/−	↑/−	−	−	/	No
Dexmedetomidine	↓	↑	↓↓	↓↓	−	−	+	Yes

BBB , blood–brain barrier; CBF , cerebral blood flow; CMRO ₂ , cerebral metabolic rate of oxygen consumption; CPP , cerebral perfusion pressure; CSF , cerebrospinal fluid; ICP , intracranial pressure; ↑, increase; ↓, decrease; −, no effect; +, cross; /, does not cross; ?, unknown.

Other Effects of Barbiturates

Barbiturates cross the blood–brain barrier (BBB) very rapidly. Methohexital has been shown to reduce the seizure threshold, and hence seizure activity may be a concern on emergence from barbiturate anesthesia. Cognitive impairment on chronic use of barbiturates is well known; both propofol and barbiturates were shown to cause severe cognitive side effects, but the result was confounded by the differences in age distribution in the two study groups. Curcumin, a substance in turmeric, is being considered as a safe and effective adjuvant to barbiturates in preventing cognitive impairment due to its antioxidant, antiinflammatory, and neuroprotective properties. Recent literature has demonstrated that drugs that antagonize N -methyl- d -aspartate (NMDA) receptors and agonize GABA receptors produce widespread neurodegeneration in the developing brain. Fredriksson et al. observed a reduction in cognitive function in rodents, after a combination of thiopental or propofol and ketamine at postnatal day 10 and at 8–10 weeks of age. Significant systemic effects of barbiturates include hypotension and respiratory depression.

Current Status

Due to its ICP-reducing and possibly neuroprotective effects, barbiturates continue to be used widely in neurosurgical anesthesia, especially in patients with raised ICP. However, barbiturates may require vasopressor support to maintain cerebral perfusion pressure (CPP) and may cause delayed recovery due to accumulated effects.

Recent Research

At present, there is no evidence to prove that the administration of barbiturates in patients with acute severe head injury improves the overall outcome. A systematic review in 2012 has also found inefficient evidence in favor of its effectiveness as an anxiolytic drug.

Propofol

The chemical formulation of propofol is 2,6-diisopropylphenol ( Fig. 6.2 ). It is used for induction and maintenance of general anesthesia as well as for sedation. Propofol is also known as “milk of amnesia,” because of its milklike appearance. The presently available preparation of propofol is 1% (10 mg/mL), which contains 2.25% of glycerol as a tonicity-stabilizing agent, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with sodium hydroxide to adjust the pH. The mechanism of action of propofol is either though activation of GABA receptors or blocking action on sodium channels. A 2004 research also suggests that the endocannabinoid system may also contribute significantly to the anesthetic action of propofol. The recommended clinical dosage and pharmacokinetics of propofol is summarized in Table 6.1 .

Cerebral Effects of Propofol ( Table 6.2 )

Propofol causes decreases in CMRO ₂ and CBF similar to barbiturates, the reduction in CMRO ₂ being less than decreases in CBF. It also causes decreases in ICP by decreasing the CBF; the ICP is lowered while maintaining the CPP, unlike with barbiturates and inhalational anesthetic agents like sevoflurane and isoflurane. In clinical dosages, it does not affect cerebral autoregulation. The CO ₂ vasoreactivity is preserved, and hence, hyperventilation will decrease the ICP under propofol anesthesia. Propofol has no effect on the production and resorption of CSF. The SCBF autoregulation is maintained with low- and high-dose propofol infusion. It induces depression of metabolic activity in spinal cord gray matter also. Propofol may also have direct cerebral vasoconstrictive activity.

Other Effects of Propofol

Propofol as a highly lipophilic drug crosses BBB and placenta and distributes into the breast milk too. The anticonvulsant effect of propofol is not clear as some data suggest a proconvulsant effect when used with other drugs. A measurable postoperative memory impairment has been observed in patients who have received 1–2 h of anesthesia with propofol and remifentanil. No differences in the incidence of POCD has been demonstrated in patients anesthetized with xenon, propofol, desflurane, or sevoflurane. Propofol anesthesia for prolonged period (5 h) can cause death of neurons and oligodendrocytes in both the fetal and neonatal brain. Hence prolonged infusion in small children is best avoided as it can cause acidosis, heart failure, and even death.

Current Status

It is useful anesthetic for neurosurgery due to favorable cerebral effects, rapid onset and recovery, and minimal interference with neurophysiological monitoring. Cerebral vasoconstriction makes it a suitable drug for vascular neurosurgeries. It is useful in patients with intracranial hypertension, but caution is required as it can decrease CPP due to associated hypotension.

Recent Research

Propofol is widely used in pediatric and adult populations its safety in neonates has not been defined and at present, there is no evidence supporting its use in neonates. Both thiopental sodium and propofol are used for the treatment of refractory status epilepticus, but there is no clear evidence supporting the efficacy of either of the two drugs in terms of clinical outcome.

Etomidate

Etomidate is a short-acting anesthetic agent used for induction of general anesthesia and for sedation. The chemical formulation of etomidate is ethyl 3-[(1R)-1-phenylethyl] imidazo 5-carboxylate ( Fig. 6.3 ). Etomidate has limited suppression of ventilation and lack of histamine release and protects from myocardial and cerebral ischemia. The “etomidate speech and memory test” is used to determine speech lateralization in patients prior to performing lobectomies to remove epileptogenic centers in the brain. The drug acts primarily on GABA receptors and is highly protein bound. It is metabolized by hepatic and plasma esterases to inactive products. The pharmacological characteristics of etomidate are described in Table 6.1 .

Cerebral Effects of Etomidate ( Table 6.2 )

Etomidate reduces CMRO ₂ and CBF in a parallel manner to produce an isoelectric EEG. The maximal fall in CMRO ₂ is achieved after a fall in CBF, and this effect is possibly due to a direct effect causing cerebral vasoconstriction. It also causes a dose-dependent fall in ICP following reduction in CBF. In pediatric patients with severe traumatic brain injury, single-dose etomidate administration results in significant reductions in ICP and improvement in CPP. The reactivity to CO ₂ is maintained well under etomidate anesthesia. Its effect on cerebral autoregulation has not been evaluated. Etomidate in low dose causes no change in the rate of CSF formation and resistance to CSF resorption. However, in higher doses etomidate causes reduction in rate of CSF formation with either decrease or no change in resistance to CSF resorption.

Other Effects of Etomidate

It is a hydrophobic drug and crosses BBB very rapidly like barbiturates; the CNS effect lasts only for few minutes. Etomidate has been used to protect against cerebral ischemia in high risk patients, however no human trials are available to support the evidence. Also its role in seizure control has not been proven. Etomidate can cause POCD in elderly patients. Prolonged infusion of etomidate can cause propylene glycol toxicity that can clinically present as hyperosmolality with an increased osmolal gap, hemolysis, hemoglobinuria, and metabolic acidosis. It can cause adrenocortical suppression and involuntary muscle activity.

Current Status

Lack of cardiovascular side effects makes etomidate a useful neuroanesthetic. It can also be used safely for neurophysiological monitoring as it maintains both somatosensory evoked potential (EP) and motor EP threshold. It should be avoided or used cautiously in patients with seizure history.

Recent Research

Etomidate provides more stable hemodynamic parameters as compared to propofol. It can be used safely without serious cortisol suppression lasting more than 24 h. In comparison with ketamine for rapid sequence induction, etomidate does not provide superior intubating conditions and more favorable hemodynamic response to laryngoscopy and tracheal intubation.

Ketamine

Ketamine is a phencyclidine derivative, and its chemical formulation is arylcyclohexylamine ( Fig. 6.4 ). It produces a state called “dissociated anesthesia,” which is characterized by the presence of dissociation between thalamocortical and limbic system. It also provides intense analgesia as well as amnesia. Because of the possibility of increased airway secretions and emergence delirium, it is advised to give an antisialagogue (glycopyrrolate) and midazolam as premedication in patients receiving ketamine. Ketamine mainly binds to NMDA receptors. It acts on other receptors like opioid receptors, GABA receptors, muscarinic receptors, voltage-sensitive sodium channels, and calcium channels. The pharmacological characteristics of ketamine are described in Table 6.1 .

Cerebral Effects of Ketamine ( Table 6.2 )

Unlike other intravenous anesthetic agents, ketamine increases the CBF and CMRO ₂ . At subanesthetic doses, ketamine acts as a potent cerebral vasodilator and increases the CBF by 60% in normal situations. In patients with brain tumor and aneurysmal resection, 1 mg/kg ketamine administration does not cause increase in middle cerebral artery velocity. It was believed earlier that an induction dose of ketamine significantly increases the ICP and hence was considered contraindicated in patients with a raised ICP. However, some studies have found its use safe when accompanied with hyperventilation. Cerebral autoregulation and CO ₂ reactivity are well maintained with ketamine. It increases the rate of CSF formation but either decreases or causes no change in resistance to CSF resorption. Ketamine has protective effects on the spinal cord. It prevents loss of antioxidant activity in spinal cord tissue in cord injury cases.

Other Effects of Ketamine

Ketamine is highly lipid soluble and rapidly crosses the BBB producing quick onset of action and rapid recovery from anesthesia. Ketamine would be unlikely to have proconvulsant action; however, myoclonic and seizure like activities may occur in normal patients. It is known to cause emergence delirium, which occurs more frequently within an hour and is less frequent in children. Ketamine increases the amplitude of somatosensory EPs but decreases the auditory and visual evoked response in humans.

Current Status

It is not the first choice in neuroanesthesia, and is avoided in patients with raised ICP or decreased intracranial compliance.

Recent Research

According to Schreiberova et al., sedation by dexmedetomidine–ketamine–midazolam combination is a safe and suitable method for endovascular neurointerventions. It provides hemodynamic stability without respiratory depression.