1. Joseph De Soto MD, PhD, FAIC
Anesthetics
Joseph De Soto MD, PhD, FAIC

2. Overview
General anesthesia is a reversible state of the central nervous system (CNS) depression, causing loss of perception of stimuli. Anesthesia is responsible for providing these benefits:
Sedation and reduced anxiety
Lack of awareness and amnesia
Skeletal muscle relaxation
Suppression of undesirable reflexes
Analgesia
Because, no single agent provides all the desirable properties needed for appropriate anesthesia several categories of drugs are combined to produce optimal anesthesia.

3. Types of Medications needed for Anesthesia
Preanesthetics: help calm patients, relieve pain, and prevent side effects of subsequently administered anesthetics.
Neuromuscular blockers: these facilitate the tracheal intubation and surgery.
General anesthetics: Can be delivered via inhalation or intravenous.

4. Considerations in the Selection of Anesthetics
Cardiovascular: anesthetics agents suppress cardiovascular function to different degrees. The state of the cardiovascular system is an important consideration in giving anesthesia especially where coronary artery disease, heart failure, dysrhythmias, valvular disease, and other cardiovascular disorders.
Hypotension may occur during anesthesia resulting in reduced perfusion pressure ischemic injury to tissues.
Treatment with vasoactive agents may be necessary.

5. Considerations in the Selection of Anesthetics
Respiratory system: asthma and ventilation or perfusion abnormalities complicate the control of inhalation anesthetics. Inhaled agents depress respiration but act as bronchodilators. IV anesthetics and opioids suppress respiration.
Liver & kidney: The liver and kidneys influence long term distribution and clearance of drugs. The release of fluoride, bromide, and other metabolites of halogenated hydrocarbons can affect and damage these organs.
Nervous system: the presence of neurological disorders such as myasthenia gravis, neuromuscular disease, etc. will affect the choice of anesthetic.

6. Considerations in the Selection of Anesthetics
Pregnancy: special precautions should be observed when anesthetics and adjunctive agents are administered during this time. Effects on fetal organogenesis are of major concern.
Nitrous oxide: can cause aplastic anemia in the newborn.
Benzodiazepines: can cause cleft palate and cause hypotonia in the newborn

7. Preanesthetics
H2 blockers: are frequently given to reduce gastric acidity.
Benzodiazepines: are used to facilitate amnesia and reduce anxiety
Opioids: are used for analgesia
Antihistamines: are used to prevent allergic reactions
Antiemetics: to prevent nausea and vomiting
Anticholinergics: to prevent bradycardia

8. Stages & Depth of Anesthesia
General anesthesia has three stages: 1) Induction, 2) maintenance, and 3) recovery.
Induction: is the time from administration of an anesthetic to development of effective anesthesia.
Maintenance: provides sustained anesthesia.
Recovery: is the reverse of induction and depends on how fast the anesthetic diffuses away from the brain

9. Induction
General anesthesia is normally induced with an IV agent like propofol producing unconsciousness in 30 to 40 seconds. Additional, inhalation and/or IV drugs may also be given to produce the desired depth anesthesia.
IV neuromuscular blockers such as rocuronium, vecuronium, or succinylcholine are also given at this time to facilitate tracheal intubation and muscle relaxation.
Children may be induced with sevoflurane via inhalation.

10. Maintenance of Anesthesia
Maintenance of anesthesia: After administering the anesthetic , vital signs and response to stimuli are monitored continuously to balance the amount of drug inhaled and the depth of infusion.
Maintenance is commonly provided with volatile anesthetics , which offer good control over the depth of anesthesia.
Opioids such as fentanyl are used for analgesia along with inhalation agents, as inhalation agents are not good analgesics.

11. Recovery
Postoperatively, the anesthetic admixture is withdrawn, and the patient is monitored for return of consciousness.
Redistribution from the site of action of anesthetics underlies recovery not metabolism of the anesthetics.
Neuromuscular blockers are generally metabolized. If they have not been at time of recovery reversal agents to the neuromuscular blockers might be used.

12. Depth of Anesthesia
The depth of anesthesia has four sequential stages characterized by increasing CNS depression as the anesthetic accumulates in the brain.
Stage I – Analgesia: loss of pain sensation results from interference with sensory transmission in the spinothalamic tract. The patient progresses from conscious and conversational to drowsy. Amnesia and reduced awareness of pain occur.
Stage II – Excitement: The patient displays delirium and possibly competitive behavior. A rise and irregularity in blood pressure and respiration occur. Rapid acting IV agents are given before inhalation anesthesia is adminsitered.

13. Depth of Anesthesia
Stage III – Surgical anesthesia: there is a gradual loss of muscle tone and reflexes as the CNS is further depressed. Regular respiration and relaxation of skeletal muscle occurs . Respiration steady and slow. This is the ideal stage for surgery.
Stage IV – Medullary Paralysis: Severe depression of the respiratory and vasomotor centers occurs. Ventilation and circulatory support must be given to prevent death. Death may be imminent.

15. Inhalation Anesthetics
Modern inhalation anesthetics are nonflammable , nonexplosive agents, and include nitrous oxide and the volatile hydrocarbons. These agents decrease cerebrovascular resistance , resulting in increased brain perfusion.
These agents also cause increased bronchodilation but decrease spontaneous ventilation.
Inhalation anesthetic agents have a very steep dose response curves and very narrow therapeutic index.
No antagonist exist.

16. Potency
Potency: is defined quantitatively as the minimum alveolar concentration , the end – tidal concentration of inhaled anesthetic needed to eliminate movement of 50% of patients stimulated by a standard incision.
Thus, MAC is the median effective dose (ED50) of the anesthetic , expressed as the percentage of gas in a mixture required to achieve that effect.
Numerically then, MAC is small for potent anesthetics and large for non-potent anesthetics.

18. Potency
The more lipid soluble an anesthetic , the lower concentration needed to produce anesthesia and the higher the potency.
Factors that can increase MAC thereby making them LESS potent are hyperthermia, increase of catecholamines, and chronic alcohol abuse.
Factors that decrease MAC make the patient more sensitive increased age, hypothermia, pregnancy, sepsis, and α2 agonists.

20. Mechanism of Action
No specific receptor has been identified as the locus of general anesthetic action. Indeed, the fact that chemically unrelated compounds produce anesthesia argues against the existence of a single receptor.
General anesthetics increase the sensitivity of λ-aminobutyric acid receptors to the inhibitory neurotransmitters. This allows hyperpolarizability. They also increase the sensitivity of glycine receptors which for the most part are inhibitory.
Nitrous oxide and ketamine seem to inhibit N-methyl-D-aspartate (NMDA) receptors, the receptor that responds to excitatory glutamate.
These actions may be due to changes in the cellular membrane with anesthetics.

23. Specific Inhalation Anesthetics
Halothane: this is the prototype drug for which other agents are compared for inhalation anesthetics. Halothane is a potent anesthetic but weak analgesic. It is usually co-administered with nitrous oxide, opioids and local anesthetics.
Halothane relaxes both skeletal and uterine muscle and hence can be used in obstetrics though most OB/GYN’s prefer sevoflurane.
Halothane is metabolized to toxic hydrocarbons and bromide ion. Women are especially, susceptible to severe halothane side effects which occur in 1/10,000 patients. These include fever, anorexia, liver failure . Half of those with this rare response will die of liver necrosis.

24. Specific Inhalation Anesthetics
Halothane is not liver toxic to children like it is adults. To avoid live toxicity in adults halothane should NOT be used on the same patient more than once in a 2-3 week interval.
Halogenated hydrocarbons are vagomimetic and may cause atropine sensitive bradycardia.
Halogenated hydrocarbons can produce concentration dependent hypotension. This can be treated with phenylephrine the α1 agonist.

25. Specific Inhalation Anesthetics
Sevoflurane: this inhalation anesthetic has low pungency without irritating the airways making it very suitable for pediatric patients.
Sevoflurane, after desflurane, it is the volatile anesthetic with the fastest onset and offset. Sevoflurane is the preferred agent for mask induction due to its lesser irritation to mucous membranes
Sevoflurane is metabolized in the liver and the metabolites may be nephrotoxic and may cause an increase in intracranial pressure if fresh gas flow is to low.

26. Specific Inhalation Anesthetics
Nitrous Oxide: is a potent analgesic but weak anesthetic. It is often used with a 30 to 50% combination with oxygen for analgesia. Nitrous oxide alone cannot produce anesthesia but it is commonly combined with other agents.
Nitrous oxide is poorly soluble in the blood and moves very rapidly in and out of the body. Nitrous oxide does not produce muscle relaxation nor depress respiration.
This drug has moderate to no effect on the cardiovascular system and on cerebral perfusion. It is also the most safe of the inhalation agents in terms of organ safety.

27. Specific Inhalation Anesthetics
Isoflurane: this agent does not undergo metabolism in the kidney or liver and hence is not toxic to these organs. It does produce however, dose-dependent hypotension. It is pungent and stimulates the respiratory apparatus causing coughing, and salivation. This is used when cost is a factor.
Desflurane: this medication provides very rapid onset of action and recovery due to low blood solubility. This makes it popular for outpatient surgeries. This medication also stimulates the respiratory apparatus – not as much as isoflurane – and does not cause kidney or liver damage.

28. Comparative Side Effects
Halothane
Isoflurane
Desflurane
Sevoflurane
Arrhythmias ++
Increased sensitivity to Catecholamines
Cardiac Output
Decreased +
Blood Pressure
Respiratory Depression _
Hepatic Toxicity
Renal Toxicity

29. Specific Intravenous Anesthetics
Propofol: is an IV sedative/hypnotic used for the induction and/or maintenance of anesthesia. It is the first choice these days for the induction of general anesthesia and sedation.
Induction with this medication occurs within 30 to 40 seconds after administration. Propofol depresses the CNS though at times it is accompanied by spontaneous movement, yawning, and hiccups.
Propofol reduces intracranial blood pressure by lowering the systemic pressure due to vasodilation.
Side effects: pain on injection, hypotension, decrease in intraocular pressure and dystonia.

30. Specific Intravenous Anesthetics
Opioids: Due to the analgesic property, opioids are commonly used in combination with other anesthetics. The choice of opioid is based primarily on the duration of action needed.
The most common opioids are fentanyl, sufentanil, remifentanil due to their ability to rapidly induce analgesia.
Opioids may be given intravenously, intrathecally or epidurally.
Opioids can cause hypotension, respiratory depression, and muscle rigidity. Naloxone is an antidote for opioid overdose.

31. Specific Intravenous Anesthetics
Barbiturates: thiopental is an ultra short acting barbiturate with high lipid solubility and is a potent anesthetic but not an analgesic. This medication may cause hypovolemia or shock and can cause apnea, coughing, chest wall spasm and bronchospasm. It is no longer used in the United States.
Benzodiazepines: Midazolam is most commonly used for its sedation effects with anesthetics though diazepam and lorazepam are also used. All three of these drugs facilitate amnesia while, causing sedation, enhancing the inhibitory effects neurotansmitters.

32. Specific Intravenous Anesthetics
Ketamine: is a short acting , non-barbiturate anesthetic which induces a dissociated state in which the patient is unconscious and does not feel pain.
This dissociative anesthesia provides sedation, amnesia, and immobility.
Ketamine is contraindicative in hypertensive and stroke patents but is beneficial in asthmatics due to its bronchodilation effects and in hypovolemic patients due to its stimulation of the sympathetic nervous system.
It is not used in children and the elderly due to the increased cerebral blood flow and its ability to induce hallucinations.

33. Specific Intravenous Anesthetics
Etomidate: this medication lacks water solubility so it is formulated in propylene glycol. This agent induces anesthesia but has no analgesic effect.
This medication has no cardiovascular effect and is used for patients with cardiovascular dysfunction or coronary artery disease.
Adverse effects: decreased plasma cortisol, and aldosterone which can last up to 8 hours past the last administration of this medication.
Involuntary muscle movement is common and benzodiazepines or opioids are generally administered with this agent to limits these muscle movements.

34. Specific Intravenous Anesthetics
Dexmedetomidine: this is a sedative used in intensive care settings and surgery. It is unique in that is provides sedation without respiratory depression.
Dexmedetomidine provides sedative, analgesic, sympatholytic, and anxiolytic effects.
Adverse effects: Hypotension, anemia, bradycardia, fever, pleural effusion, leukocytosis, and pulmonary edema

36. Neuromuscular Blockade
Neuromuscular blockers are used to abolish reflexes to facilitate tracheal intubation and to provide muscle relaxation as needed for surgery.
These act by blocking the nicotinic receptors in the neuromuscular junction.
These agents include: cisatracurium, pancuronium, rocuronium, vecuronium and the depolarizing agent: succinylcholine.

38. Local Anesthetics
Local anesthetics block nerve conduction of sensory impulses and in higher concentrations motor impulses by blocking the sodium channel.
Among the local anesthetics are bupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, and tetracaine.
Bupicaine can be cardiotoxic if accidently given to a vein.
Mepivacaine can be toxic to a fetus.

40. Actions of Local Anesthetics
Local anesthetics cause vasodilation, leading to rapid diffusion away from the site of action and a shorter duration of action. Hence, epinephrine is generally added to these medications to increase the rate of local absorption by decreasing diffusion. This also decreases systemic toxicity.
Anesthetics rarely cause allergic reactions except for ester type local anesthetics such as cocaine , procaine and tetracaine but patients often complain about them. These are called psychogenic and may cause urticaria, edema and even bronchospasms.

42. Administration to Children and the Elderly
The maximum dose based on weight should be calculated before any local anesthetic is given to a child to prevent overdose. For the elderly one should stay a good deal below the recommended doses.
The elderly also tend to have cardiovascular issues and hence, one should lower the amount of epinephrine that one adds to the local anesthetic.
Toxic symptoms of systemic effects due to local anesthetics include cardiovascular instability, CNS excitation or depression, and altered mental status.

43. Epidural
The epidural route is frequently employed by certain physicians and nurse anesthetists to administer local anesthetic agents through a catheter placed into the epidural space.
The injection can result in a loss of sensation—including the sensation of pain—by blocking the transmission of signals through nerve fibers in or near the spinal cord.
Reasons for an epidural: For analgesia alone, where surgery is not contemplated. An epidural injection or infusion for pain relief is less likely to cause loss of muscle power, but has to be augmented to be sufficient for surgery.

44. Epidural
As an adjunct to general anesthesia. The anesthetist may use epidural analgesia in addition to general anesthesia. This may reduce the patient's requirement for opioid analgesics.
As a sole technique for surgical anesthesia. Some operations, most frequently Caesarean section, may be performed allowing the patient to remain awake during the operation.
For post-operative analgesia. Analgesics are given into the epidural space typically for a few days after surgery, provided a catheter has been inserted.
For the treatment of back pain. Injection of analgesics and steroids into the epidural space may improve some forms of back pain. See below.

46. Comparing Epidural with Spinal Anesthesia
Spinal anesthesia is where a needle is placed in the subarachnoid space.
The injected dose for an epidural is larger, being about 10–20 mL in epidural anesthesia compared to 1.5–3.5 mL in a spinal.
In an epidural, an indwelling catheter may be placed that avails for additional injections later, while a spinal is almost always a one-shot only.
The onset of analgesia is approximately 25–30 minutes in an epidural, while it is approximately 5 minutes in a spinal.
An epidural often does not cause as significant neuromuscular block, while a spinal more often does.

47. Malignant Hyperthermia
In a very small number of patients exposure to halogenated hydrocarbons anesthetics or succinylcholine may produce malignant hyperthermia.
The disorder causes a large increase in skeletal muscle oxidative metabolism leading potentially to circulatory collapse and death.
Individuals with muscular dystrophy, myopathy, myotonia, and osteogenesis imperfecta are the most susceptible to malignant hyperthermia.