NEUROPHARMACOLOGY OF ANESTHETIC AGENTS

Robert H. Sirait. dr., SpAn Dept. Anesthesiology FK UKI

NEUROPHARMACOLOGY OF ANESTHETIC AGENTS

I. BASIC UNDERSTANDING : NEUROPHYSIOLOGY
1.CEREBRAL BLOOD FLOW (CBF) 2.CEREBRAL METABOLIC RATE (CMR) 3.CEREBROSPINAL FLUID (CSF) 4.INTRACRANIAL PRESSURE (ICP)

5.BLOOD BRAIN BARRIER (BBB)

1. CEREBRAL BLOOD FLOW (CBF)

Total CBF in adults 750 ml/min (15-20% CO) - Gray matter 80 ml/100gr/min - White matter 20 ml/100gr/min - Averages 50ml/100gr/min - < 20-25 ml/100gr/min slowing electroencephalogram (EEG) - 15-20 ml/100gr/min flat (isoelectric) EEG - < 10 ml/100gr/min irreversible brain damage
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Regulation Cerebral Blood Flow

1.1. Cerebral perfusion pressure (CPP) - Normal : 80 - 100 mmHg - CPP = MAP ICP - Normal ICP 5-15 mmHg - CPP < 50 mmHg slowing EEG - CPP 25-40 mmHg flat EEG - < 25 mmHg : irreversible brain damage - Decreases CPP: Cerebral vasodilatation - Increases CPP: Cerebral vasoconstriction
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1.2. Autoregulation - CBF constant between MAPs 60-160 mmHg - MAPs > 160 mmHg disrupt BBB - MAPs shift to the right in patient with chronic arterial hipertension - Cerebral autoregulation: miogenic and metabolic mechanism arterial tone tissue metabolitest ( H+, NO, adenosine, prostaglandins,and ionic concentration gradients) vasodilatation and increases flow

1.3. Extrinsic mechanism a. PaCO2 (particularly) - CBF directly proportionate to PaCO2 20-80 mmHg - CBF changes 1-2 ml/100g/min per mmHg change PaCO2 - Hyperventilation (PaCO2 < 20 mmHg ): shift to the left the oxygen Hb dissociation curve. - Cerebral blood volume (CBV) 0.05ml/100gr/min of brain per 1 mmHg in PaCO2
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b. PaO2 - Hiperoxia : associated minimal CBF (-10%) - Severe hipoxemia PaO2 < 50 mmHg : CBF
c. Temperature - CBF changes 5 - 7% per 1C change temperature - Hypothermia CMR and CBF - If the temperature the brain falls 10C the CMR 50% - If the temperature the brain increases 10C the CMR doubles
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d. Viscosity - The most important determinant blood viscosity is hematocrit - The optimal cerebral oxygen delivery occur at hematocrit 30%

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e. Autonomic Influences - Intracranial vessels are innervated by sympathetic (vasoconstrictive) , parasympathetic (vasodilatory), and non-cholinergic non adrenergic fiber, serotonin and vasoactiv intestinal peptide

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2. CEREBRAL METABOLIC RATE (CMR)

- 20% of total body oxygen - 60% cerebral oxygen used to generating ATP to -

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support neuronal electrical activity CMR for oxygen consumption (CMR 02) 3 - 3,8 ml/100gr/min CMR for glucose consumption is 5 mg/100gr/min, > 90% is metabolized aerobically During starvation : ketone bodies become major energy substrates Acute hypoglicemia hypoxia Hyperglycemia global and focal hypoxic cerebral acidosis & cellular injury

3. CEREBROSPINAL FLUID (CSF)

- Production 21 ml/h (500 ml/d), total volume

150ml, formed : a. >> choroid plexuses of the cerebral lateral ventricles active secretion of Na+ b. smaller by the ventricle ependymal cell linings - isotonic fluid, lower : K+, HCO3-, glucose concentration - Decreases production: acetazolamide, corticosteroids, spironolactone, furosemide, isoflurane, and vasoconstrictors - Absorption: translocation fluid from arachnoid 14 granulations cerebral venous sinuses

4. INTRACRANIAL PRESSURE (ICP)

The cranial : rigid structure. fixed total volume : brain 80%, blood 12%,

and CSF 8% Normal pressure 10 mmHg Major compensatory mechanism to rises ICP : a. Displacement CSF from cranial to the spinal compartment b. CSF absorpstion c. CSF production d. Cerebral blood volume (CBV)

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4. INTRACRANIAL PRESSURE (ICP)

Elevation ICP can lead to catastrophic herniation: a. Gyrus falx cerebri b. Tentorium cerebelli c. Foramen magnum d. Defect in the skull (transcarvarial)

The initial management increases ICP. Maintaining cerebral O2 delivery with : a. Supplemental O2 b. Elevation of head c. Intubation d. Hyperventilation e. Limitation excees free water and vol resusc. 16

5. BLOOD BRAIN BARRIER (BBB)

Tight junctions vascular endhotelial cells

Freely enter : CO2, O2 and Lipid soluble

substances (such as most anesthetics) Penetrates poorly: most ions, proteins, and large substances such as mannitol Disrupted by : severe-hypertension, tumors, trauma, strokes, infections, marked hypercapnia, hypoxia, and sustained seizure activity
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II. EFFECT OF ANESTHETIC AGENTS

Effect on CNS reducing electrical activity : - Decreases carbohydrate metabolism - Increases energy stores (ATP, ADP, and Phosphocreatine)
A.VOLATILE/INHALATION AGENTS
- Decreases CMR

- Dilate cerebral vessels

- Impaired autoregulation
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dose dependent

B. INTRAVENOUS AGENTS
- Reduce CMR and CBF (ex. of ketamine)

a. Barbiturates Major actions on CNS : - Hypnosis - Depression of CMR - Reduction of CBF : cerebral vascular resistance - Anticonvulsant activity
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Comparative effects of anaesthetic agents on cerebral physiology

Agent
Halothane Isoflurane Desflurane Sevoflurane Nitrous oxide Barbiturates Etomidate Proprofol Benzodiazepines Ketamine Opioids ? ? ? ?

CMR

CBF

CSF Production

CSF Absorption

CBV

ICP

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Lidocaine

Electroencephalographic Changes during Anesthesia. Activation Inhalational agents (subanesthetic) Barbiturates (small doses) Benzodiazepines (small doses) Etomidate (small doses) Nitrous oxide Depression Inhalation agents (12 MAC) Barbiturates Opioids Propofol Etomidate

Ketamine
Mild hypercapnia Sensory stimulation Hypoxia (early)

Hypocapnia
Marked hypercapnia Hypothermia Hypoxia (late)

b. Propofol - Similar to barbiturates :

CBF and CMR

c. Benzodiazepin - CBF and CMR but lesser extent than barbiturates and propofol
d. Ketamine - Dilates the cerebral vasculature and

CBF

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e. Neuromuscular blocking agents (NMBAs) - Lack direct action secondary effect (histamin released cerebral vasodilatation ICP) f. Opioids - Minimal effect on CBF, CMR and ICP, unless PCO2 (respiratory depression)

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C. ANESTHETIC ADJUNCTS - Lidocaine ( CMR, CBF and ICP ) - Vasopressors ( CBF : normal autoregulation and intact BBB) - Vasodilators ( Cerebral vasodilatation and CBF) - Mannitol (osmotic diuretic)

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