Lecture 7 local and general anesthetics

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 7:

Pain, Local and General Anesthetics Marc Imhotep Cray, M.D.

Learning Objectives:

CNS Pharmacology Lecture 7

LOCAL ANESTHETICS 1. The mechanisms by which local anesthetics block nerve conduction.

2. An understanding of how the physiochemical properties of local anesthetics influence the pharmacodynamics and pharmacokinetics of these drugs.

3. What undesirable side effects may occur with the use of local anesthetics and why these side effects happen.

4. The unique characteristics and the common clinical use for each prototypical local anesthetic.

5. The most commonly caused severe complications of local anesthetics when they are systemically absorbed or injected intravenously.

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Learning Objectives cont.

CNS Pharmacology Lecture 7

GENERAL ANESTHETICS 1. The definition of general anesthesia and how it can be achieved.

2. A working understanding of the pharmacokinetics for inhalational anesthetics.

3. The various stages of anesthesia.

4. How the blood: gas coefficient influences the onset of action (and termination of anesthesia) for inhaled anesthetics.

6. How blood flow to a tissue influences the tension of an anesthetics gas in that tissue.

7. The definition of minimum alveolar concentration (MAC) and what information it provides about a volatile anesthetic.

8. The pharmacokinetic properties of the ultrashort-acting hypnotics and how these properties make this class of drugs popular general anesthetic agents.

9. The advantages and disadvantages for clinically used inhaled and intravenously administered general anesthetics. When they should be used and when they are contraindicated.

10. The concept that inhalational and intravenous anesthetics cause varying degrees of respiratory depression with an exception being ketamine.

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Classification Schema: Local and General Anesthetics Local Anesthetics A. Esters: Procaine Cocaine Tetracaine Benzocaine B. Amides: Lidocaine Mepivacaine Bupivacaine L-Bupivacaine Ropivacaine Marc Imhotep Cray, M.D.

General Anesthetics A. Halogenated Hydrocarbons: Isoflurane Sevoflurane Desflurane B. Inert Gas Nitrous Oxide C. Ultrashort-Acting Barbiturates Thiopental Methohexital

CNS Pharmacology Lecture 7

General Anesthetics cont.

D. Sedative-Hypnotics Ketamine Etomidate Propofol E. Opioids Morphine Fentanyl F. Benzodiazepines Midazolam

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A “Functional” Classification Schema of Anesthetics: PREANESTHETIC MEDICATIONS Antacids Anticholinergics Antiemetics Antihistamines Benzodiazepines Opioids GENERAL ANESTHETICS: INHALED Desflurane SUPRANE Halothane FLUOTHANE Isoflurane FORANE Nitrous oxide NITROUS OXIDE Sevoflurane ULTANE

GENERAL ANESTHETICS: INTRAVENOUS Barbiturates Benzodiazepines Dexmedetomidine PRECEDEX Etomidate AMIDATE Ketamine KETALAR Opioids Propofol DIPRIVAN NEUROMUSCULAR BLOCKERS (An ANS Lecture) Cisatracurium, pancuronium, rocuronium, succinylcholine, vecuronium

LOCAL ANESTHETICS: AMIDES Bupivacaine MARCAINE Lidocaine XYLOCAINE Mepivacaine CARBOCAINE Ropivacaine NAROPIN LOCAL ANESTHETICS: ESTERS Chloroprocaine NESACAINE Procaine NOVOCAINE Tetracaine PONTOCAINE Cocaine

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CNS Pharmacology Lecture 7

Pain Pathways:  Tissue injury can lead to cellular changes involving release of chemicals (e.g., histamine) that start or quicken neuronal impulses that are interpreted as pain  Many neuronal pathways transmit pain sensation  For example, pain from peripheral injury reaches CNS via primary afferent neurons, whose cell bodies form the dorsal root ganglia (DRG)  Disorders such as phantom limb pain may involve abnormal DRG structure or function

 Primary afferents end mainly in the dorsal horn of the spinal cord Secondary neurons cross spinal cord and ascend in pathways to the thalamus, the cerebral cortex, and other sites

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CNS Pharmacology Lecture 7

Pain Pathways(2) A descending system of opioid (endorphins, enkephalins), 5-HT (e.g., from raphe nuclei), and noradrenergic (e.g., from locus ceruleus) pathways can lessen afferent signals Drugs that act at pathways mediating pain sensation or perception are:  local (e.g., lidocaine) and  general (e.g., halothane) agents,  opioids (e.g., morphine), and  nonopioids (e.g., aspirin and acetaminophen)

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Pain Pathways

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 7

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CNS Pharmacology Lecture 7

Local Anesthetics

Modified from: Trevor and Katzung. Pharmacology Examination & Board Review 10th ed. 2013

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Local Anesthetics: Spinal Afferents and Mechanisms of Action

CNS Pharmacology Lecture 7

 Local anesthetics cause temporary loss of pain sensation without loss of consciousness by blocking conduction along sensory nerve fibers  Some selectivity for pain afferents is achieved partly by using agent close to target neurons (local administration)  All currently used drugs block voltage-dependent Na+ channels in excitable cells, which decreases likelihood of an action potential  Target site of drugs is on cytoplasmic side of neuron membrane, so drug molecules must pass through membrane ( must have lipophilicity)

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CNS Pharmacology Lecture 7

Local Anesthetics (2)  Local anesthetics are both lipophilic and hydrophilic and are weak bases (amides or esters) that exist in equilibrium between ionized (hydrophilic) and nonionized (lipophilic) forms  nonionized (lipophilic) forms diffuse more readily through membrane  ionized (hydrophilic) form diffuse more readily through cytoplasm  Esters are metabolized by plasma cholinesterases (butyrylcholinesterases)  Amides are hydrolyzed in liver (amidases)  Because local anesthetics act on all excitable cells, they can cause toxicity, including fatal cardiovascular effects or seizures

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Local Anesthetics (3)

CNS Pharmacology Lecture 7

A. REDUCTION OF SODIUM AND POTASSIUM ION PERMEABILITY (PNa AND PK) in activated nerve membranes leads to local anesthesia 1. There are no effects on resting membranes 2. Effects on nerve action potential of both sensory and motor nerve fibers include: o Reduction in amplitude o Reduction in rate of rise o Reduction in conduction velocity o Blockade of axonal conduction 3. Sensory neurons are blocked before motor neurons because sensory axons are usually smaller and have less myelin

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Local Anesthetics (4)

CNS Pharmacology Lecture 7

B. Local anesthetics, except for benzocaine, have three common structural components: 1. The aromatic residue is lipophilic, which is important for good membrane penetration 2. The amino group is hydrophilic a. It can become charged by picking up a proton b. pH and pKa determine whether the local anesthetic is present predominantly in the charged or uncharged forms Lidocaine

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Local Anesthetics (5)

CNS Pharmacology Lecture 7

i. ii.

Only uncharged form crosses nerve cell membrane It is converted to charged form inside axon, which then interacts with binding sites within ion channels iii. Stock solutions of local anesthetics are acidic (local anesthetic is ionized)  Acidity must be neutralized before anesthesia can occur iv. Local anesthetics will be less effective for inducing anesthesia in areas of inflammation because: a. pH is low b. Most of anesthetic will be charged and unable to penetrate nerve cell membrane

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CNS Pharmacology Lecture 7

Local Anesthetic Mechanism of Action

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CNS Pharmacology Lecture 7

Local Anesthetics (6) v. Mucous membranes have a low buffering capacity and cannot readily neutralize acidity of local anesthetic solution  As a result, mucous membranes are relatively difficult to anesthetize

c. The pKa must be between 7 and 9 so that some of local anesthetic is in the charged form and some is in uncharged form at physiological pH

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Local Anesthetics (7)

CNS Pharmacology Lecture 7

3. The intermediate chain determines how a local anesthetic is metabolized and can be either an ester or an amide a. Esters are broken down by butyrylcholinesterases in blood i. Cocaine is only used for topical anesthesia ii. Procaine (Novocain) is metabolized to para-aminobenzoic acid (PABA)ďƒ It can induce an allergic reaction iii. Chloroprocaine (Nesacaine) is metabolized most rapidly, has the shortest duration of action, and theoretically has the lowest risk of systemic toxicity iv. Tetracaine (Pontocaine) is 10 times as potent as procaine and Lidocaine 10 times as toxic

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CNS Pharmacology Lecture 7

Local Anesthetics (8) b. Amides, which are metabolized by amidases in liver, include: i. Lidocaine (Xylocaine) ii. Mepivacaine (Carbocaine) iii. Bupivacaine (Marcaine), which is cardiotoxic

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CNS Pharmacology Lecture 7

Local Anesthetics (9) C. TOXIC EFFECTS are very uncommon but can be serious if systemic absorption of local anesthetic is excessive: 1. Myocardial depression is due to sodium channel blockade in myocardial muscle 2. Vasodilation leads to a fall in blood pressure 3. Anxiety, depression, and convulsions can occur due to CNS neurotoxicity 4. Hypersensitivity reactions are rare and occur primarily with esters, which contain PABA derivatives

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CNS Pharmacology Lecture 7

Local Anesthetics (10) D. EPINEPHRINE (EPI) IS FREQUENTLY COMBINED WITH LOCAL ANESTHETICS 1. EPI reduces blood flow in anesthetized area which a. Reduces bleeding, making it useful during some types of surgeries b. Prolongs anesthesia by slowing the loss of anesthetic from area of injection c. Reduces systemic concentration of the anesthetic, thereby lowering the incidence of toxicity 2. EPI is not used with cocaine because cocaine by itself has vasoconstrictor activity, and it is not used on end-appendages where ischemia can be induced Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 7

Local Anesthetics (11) E. Symptoms of local anesthetic toxicity must be treated aggressively 1. Oxygen reduces hypoxia 2. Vasopressors or intravenous fluids increase blood pressure 3. Diazepam reduces convulsions F. During spinal anesthesia, blood pressure may fall due to blockade of sympathetic pathways in spinal cord

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General Anesthetics:

CNS Pharmacology Lecture 7

Modified from: Trevor and Katzung. Pharmacology Examination & Board Review 10th ed. 2013

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CNS Pharmacology Lecture 7

General Anesthetics: Properties  General anesthetics (inhalational and intravenous agents) have a rapid, smooth onset of action and clinically desirable rapid reversal of effect  Concentrations of inhalational agents in body and pharmacokinetics depend on drugs’ partial pressure in lungs and solubility in blood and brain tissue  Induction of anesthesia is more rapid for drugs with high partial pressure in lungs and high solubility in blood (e.g., nitrous oxide, desflurane, sevoflurane)  Onset of anesthesia is slowed when pulmonary blood flow is reduce Marc Imhotep Cray, M.D.

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General Anesthetics Properties (2)

CNS Pharmacology Lecture 7

 Site of drug action is brain; exact mechanism is unknown but may be related to lipid solubility and activation of GABAA receptors (enhanced Cl− influx, hyperpolarization of neurons) (recent theories vs classic theories)  Elimination from brain and exhalation from lungs stop effect of drug  Redistribution to other tissues delays elimination and may increase occurrence of adverse effects  Intravenous agents include barbiturates, benzodiazepines, ketamine, opioids, and propofol Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 7

Principles of General Anesthesia: A. THE PRIMARY OBJECTIVES of general anesthesia are: 1. Amnesia 2. Analgesia 3. Unconsciousness 4. Suppression of autonomic reflexes 5. Muscle relaxation B. Due to blood–brain barrier, all CNS drugs including general anesthetics must either be lipid soluble or carried across barrier by active transport (e.g., P-glycoproteins) in order to be effective

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CNS Pharmacology Lecture 7

Principles of General Anesthesia (2) C. Mechanism of action of general anesthetics has been difficult to determine 1. Classical theories involve a physical association of anesthetics with cell membranesďƒ leads to several implications a. Potency of inhaled anesthetics is defined in terms of minimal alveolar concentration (MAC) i.

MAC is anesthetic alveolar partial pressure required to prevent movement in 50% of patients in response to a skin incision ii. It is inversely related to oil–water partition coefficient for that anesthetic

b. Association of anesthetic with cell membranes reduces excitability of membranes c. Important receptors for inhalation anesthetics are not known d. There are no specific antagonists for inhalation anesthetics Marc Imhotep Cray, M.D.

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Principles of General Anesthesia (3) 2. Recent theories involve an enhancement of effects of inhibitory neurotransmitters (e.g., gammaaminobutyric acid, GABA) 3. At low concentrations of a general anesthetic, CNS is depressed more than other tissues  as concentration is increased, all excitable cells are eventually depressed

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CNS Pharmacology Lecture 7

Principles of General Anesthesia (4) D. Factors to considered when selecting anesthetics: 1. Patient’s kidney and liver function 2. Patient’s respiratory function, since anesthetics are respiratory depressants 3. Cardiac or CNS abnormalities 4. Family or personal history of malignant hyperthermia 5. Pregnancy status of patient, to avoid harm to the fetus 6. Other drugs being taken by patient, both legal and illegal

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Principles of General Anesthesia (5)

CNS Pharmacology Lecture 7

E. Anesthetics induce characteristic stages of anesthesia:  Stage 1 involves analgesia patient is conscious  Stage 2 involves excitement, due to blockade of inhibitory pathways in brain can be a dangerous phase due to vomiting, restlessness, delirium, and other hyperexcitable effects that may occurpatient is unconscious  Stage 3 is stage at which surgery is usually performed patient is unconscious, and skeletal muscles are relaxed  Stage 4 involves respiratory and cardiovascular depression, which, if pronounced, can lead to death Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 7

Principles of General Anesthesia (6)  Loss of eyelash reflex and a pattern of respiration that is regular and deep are most reliable indications of stage III (surgical anesthesia)  Analgesia and amnesia are characteristics of stage I anesthesia, whereas  Loss of consciousness is associated with stage II anesthesia  Maximum papillary dilation also occurs during stage III anesthesia, but closer to progression to stage IV anesthesia  stage IV anesthesia is an undesirable stage associated with respiratory and cardiovascular failure Marc Imhotep Cray, M.D.

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Principles of General Anesthesia (7)

CNS Pharmacology Lecture 7

F. The three steps of anesthesia are induction, maintenance, and recovery: 1. Induction describes period from beginning of anesthetic administration until effective surgical anesthesia is achieved 2. Maintenance involves sustained surgical anesthesia, which is often performed with inhalation anesthetics because they provide a high degree of control 3. Recovery describes period from discontinuation of anesthesia until patient has regained consciousnessďƒ anesthesiologist continues to monitor patient during this period Marc Imhotep Cray, M.D.

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Principles of General Anesthesia (8)

CNS Pharmacology Lecture 7

G. Rate of induction of inhaled anesthesia is dependent on blood solubility of an anesthetic, assuming that anesthetic is being administered as only agent Note that this is generally not the case in most surgeries 1. Blood solubility can be determined by measuring blood–gas partition coefficient λ 2. High blood solubility leads to a slow rise in partial pressure of anesthetic in body and a slow induction a. undesirable because it prolongs Stage 2 of anesthesia b. Halothane has high blood solubility slow induction, whereas nitrous oxide (N2O) has low blood solubility rapid induction 3. Induction of highly blood soluble anesthetics is most readily hastened by “overpressuring” (using a high concentration of anesthetic)

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Principles of General Anesthesia (9)

CNS Pharmacology Lecture 7

F. Factors affecting distribution vary with the phase: 1. Initial distribution of an anesthetic will depend on relative tissue blood flow; more anesthetic will go to areas with higher blood flow (e.g., heart, brain, endocrine organs) 2. Final distribution will be dependent on tissue–blood partition coefficients, although tissue–blood partition coefficient for most anesthetics in most tissues is approximately 1 a. An exception is fat–blood partition coefficient, which is usually high b. Movement of an anesthetic into fat will be slow due to low blood supply to fat only after long anesthesias will significant amounts of anesthetic be sequestered in fat c. Recovery from long anesthesias may be slower than anticipated due to slow elimination of anesthetic from fat Marc Imhotep Cray, M.D.

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Inhalation Anesthetics:

CNS Pharmacology Lecture 7

A. Inhalation anesthetics act as gases in body and follow gas laws: 1. Dalton’s Law. An anesthetic exerts a partial pressure that is proportional to percent of anesthetic in mixture.

2. Fick’s Law. The anesthetic diffuses down its concentration gradient.

3. Henry’s Law. The amount of anesthetic dissolved in a liquid is proportional to partial pressure of anesthetic in the gaseous mixture

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CNS Pharmacology Lecture 7

Inhalation Anesthetics (2) B. DIETHYL ETHER was the first useful anesthetic 1. It has several major disadvantages, including: a. Very slow induction (位 =16) b. Flammability c. Respiratory irritation, which frequently leads to enhanced secretions, nausea, and vomiting 2. It is, however, a complete anesthetic, meaning that it a. Induces muscle relaxation, due to actions on the spinal cord and neuromuscular junction b. Induces analgesia c. Induces unconsciousness

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Inhalation Anesthetics (3) Halogenated Hydrocarbons

CNS Pharmacology Lecture 7

C. As compared to diethyl ether, newer inhalation anesthetics, which are halogenated hydrocarbons, are 1.

2.

3.

Less soluble in blood, resulting in faster rates of induction and recovery Nonflammable Less irritating to the respiratory tract

D. Common disadvantages of newer inhalation anesthetics are that they 1.

2.

3.

4.

5.

6.

Depress respiration Decrease blood pressure in a dose-related fashion Dilate cerebral blood vessels, which can increase intracranial pressure Relax the uterus during pregnancy Induce a low incidence of malignant hyperthermia, which can be treated with dantrolene Have weaker analgesic actions

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Inhalation Anesthetics (4) Halogenated Hydrocarbons

CNS Pharmacology Lecture 7

1. Halothane (Fluothane) was first anesthetic in group (Prototype) a. It is a poor skeletal muscle relaxant and a poor analgesic; thus usually combined with other drugs (e.g., muscle relaxants and analgesics)ďƒ combination is called balanced anesthesia b. Halothane sensitizes myocardium to catecholaminesďƒ arrhythmias may occur when catecholamines are administered c. Metabolism of halothane to halogenated products is high, which may account for infrequent hepatotoxicity d. For these reasons, it is not commonly used in the United States any longer

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Inhalation Anesthetics (5) Halogenated Hydrocarbons

CNS Pharmacology Lecture 7

2. Enflurane (Ethrane) can induce seizure patterns during anesthesia and is also no longer used in United States 3. Isoflurane (Forane) has respiratory irritant effects 4. Sevoflurane (Ultane) is partially metabolized by liver and may be hepatotoxic 5. Desflurane (Suprane) has fastest onset of and recovery from anesthesiaďƒ It also has respiratory irritant effects

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Inhalation Anesthetics (6) Halogenated Hydrocarbons

CNS Pharmacology Lecture 7

F. NITROUS OXIDE is a gas with 1. Rapid onset and recovery (Îť =0.4) 2. Excellent analgesic activity 3. No effect on the function of most vital systems 4. Inadequate potency, leading to a. Unconsciousness only when used with other anesthetics b. A second gas effect during induction, which accelerates onset of anesthesia by other inhalation anesthetics c. Diffusion hypoxia during recovery, due to filling of lungs with nitrous oxide so that inadequate oxygen is inhaledďƒ This can be avoided by administering 100% oxygen for a short time at conclusion of nitrous oxide anesthesia Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 7

Inhalation Anesthetics (7) G. Miscellaneous anesthetics are of historical interest 1. Methoxyflurane is a. most potent anesthetic available for clinical use b. best analgesic anesthetic c. Nephrotoxic and thus seldom used 2. Cyclopropane is an explosive gas.

3. Chloroform is a. A complete anesthetic b. Hepatotoxic

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Intravenous General Anesthetics:

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 7

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (2) A. BARBITURATES, such as thiopental (Pentothal), have a rapid onset of anesthesia due to high lipid solubility 1. When administered they go primarily to areas of high blood flow, such as brain 2. Short duration of anesthesia is due to redistribution from brain to more soluble peripheral tissues with less blood flow, such as skeletal muscle and fat 3. Clearance from body by metabolism is very slow

4. Duration of anesthesia becomes longer with repeated administrations because less redistribution can occurďƒ As a result, primary uses of thiopental are for a. Induction of anesthesia b. Procedures of short duration

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Intravenous General Anesthetics (3)

CNS Pharmacology Lecture 7

5. Thiopental has the following properties: a. Marked respiratory and cardiovascular depression, especially with a rapid bolus injection b. Weak skeletal muscle relaxant activity c. Antianalgesic activity (increases sensitivity to pain) d. Pharyngeal stimulation e. Very alkaline solution, which causes severe tissue injury if given through an infiltrated IV

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (4) B. PROPOFOL (Diprivan) also has a rapid onset of action and recovery.

1. Although the anesthesia is terminated by redistribution, there are fewer cumulative effects compared with barbiturates, and it can be used for long anesthesias.

2. The postoperative complications (e.g., nausea, vomiting, residual drowsiness) are less than with other IV anesthetics.

3. It can markedly reduce blood pressure.

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (5) C. OPIOIDS, such as fentanyl (Duragesic), sufentanil (Sufenta), and alfentanil (Alfenta), are narcotic analgesics. They are often used with other anesthetics.

1. Following anesthetic properties: a. Good analgesia b. Euphoria c. Respiratory depression, which can be reversed by naloxone d. Muscle rigidity e. Nausea and vomiting 2. Anesthesia is very safe with little cardiovascular depression 3. Droperidol (Inapsine), an antipsychotic (neuroleptic), can be combined with fentanyl (Innovar) to induce neuroleptanalgesia a. Patient is sometimes conscious and can respond b. It can be supplemented with nitrous oxide to induce unconsciousness (neuroleptanesthesia)

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (6) D. MIDAZOLAM (Versed) is a water-soluble benzodiazepine with a rapid onset of action and a shorter duration than other benzodiazepinesďƒ It is used for sedation 1. Pt. remains conscious at low doses, but experiences amnesia during anesthesia 2. At high doses, some LOC is induced 3. Can induce respiratory depression that is reversible by administration of benzodiazepine antagonists, such as flumazenil (Romazicon)

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (7) E. KETAMINE (Ketalar) is an analog of phencyclidine, a hallucinogen 1. It induces a dissociative anesthesia a. Pt. may look awake but is unresponsive b. Analgesic effects are excellent c. Muscle tone is either unchanged or increased d. Respiration is not affected 2. Ketamine can be administered intravenously or intramuscularly 3. Side effects are related to hallucinogenic activity, which leads to a. Vivid dreams b. Hallucinations, which can be reduced by diazepam

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CNS Pharmacology Lecture 7

Intravenous General Anesthetics (8) F. ETOMIDATE (Amidate) is a hypnotic that lacks analgesic activity 1. It is used in patients with coronary artery disease (CAD) and other cardiac diseases 2. Etomidate inhibits enzyme 11β-hydroxylase, ďƒ leads to decreased synthesis of glucocorticoids and mineralocorticoids

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THE END

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CNS Pharmacology Lecture 7

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Further study (SDL):

CNS Pharmacology Lecture 7

MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Eilers H & Yost S. Ch. 25. General Anesthetics, 429-47, Kenneth Drasner K. Ch. 26 Local Anesthetics,449-62 In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed.

Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 8. Analgesics 9. Drugs of Abuse

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