CNS Agents

GENERAL AND LOCAL ANESTHETICS

State which stage of anesthesia each of the following descriptions refers to?

Delirium; violent behavior; increased blood pressure; increased respiratory rate; irregular breathing rate and volume; amnesia; retching and vomiting with stimulation; disconjugate gaze

Stage II (excitement)

Depression of vasomotor center; depression of respiratory center; death may occur

Stage IV (medullary depression)

Eye movements cease; fixed pupils; regular respiration; relaxation of skeletal muscles

Stage III (surgical anesthesia)

Loss of pain sensation; patient is conscious; no amnesia in early part of this stage

Stage I (analgesia)

Give examples of inhaled anesthetics:

Halothane; nitrous oxide; isoflurane; enflurane; sevoflurane; desflurane; methoxyflurane

With regard to inhaled anesthetics, what does MAC stand for?

Minimum alveolar concentration. Note: this is not to be confused with monitored anesthesia care also commonly referred to as MAC, which is a combination of regional anesthesia, sedation, and analgesia.

What is MAC in regard to inhaled anesthetics?

The concentration of inhaled anesthetic required to stop movement in 50% of patients given a standardized skin incision; a measure of potency for inhaled anesthetics

For potent inhaled anesthetics, is the MAC small or large?

Small (inverse of the MAC is used as an index of potency for inhaled anesthetics)

Which inhaled anesthetic has the largest MAC?

Nitrous oxide (>100%)

Which inhaled anesthetic has the smallest MAC?

Halothane (0.75%)

As lipid solubility of an inhaled anesthetic increases, what happens to the concentration of inhaled anesthetic needed to produce anesthesia, that is, does it increase or decrease?

It decreases.

What is the blood/gas partition coefficient?

The ratio of the total amount of gas in the blood relative to the gas equilibrium phase. It refers to an inhaled anesthetic’s solubility in the blood.

If an inhaled anesthetic has a high blood/gas partition coefficient, will times of induction and recovery be increased or decreased?

It will be increased because the time to increase arterial tension is longer.

Give an example of an inhaled anesthetic with a low blood/gas partition coefficient (low blood solubility):

Nitrous oxide (0.5); desflurane (0.4)

Give an example of an inhaled anesthetic with a high blood/gas partition coefficient (high blood solubility):

Halothane (2.3); enflurane (1.8)

Which inhaled anesthetic, halothane or nitrous oxide, will take longer to change the depth of anesthesia when the concentration of the inhaled anesthetic has been changed?

Halothane

Are MAC values additive?

Yes

Are MAC values higher or lower in elderly patients?

They are lower, thus elderly patients generally require lower concentrations of inhaled anesthetics.

Are MAC values higher or lower when opioid analgesics and/or sedative hypnotics are used concomitantly?

They are lower.

Do inhaled anesthetics increase or decrease the response to Pco₂ levels?

Decrease

Do inhaled anesthetics increase or decrease cerebral vascular flow?

Increase

Do inhaled anesthetics increase or decrease intracranial pressure?

Increase

Do inhaled anesthetics relax or strengthen uterine smooth muscle contractions?

Relax (except methoxyflurane when briefly inhaled, therefore, can be used during childbirth)

Which of the inhaled anesthetics is not a halogenated hydrocarbon?

Nitrous oxide

Are the inhaled halogenated hydrocarbon anesthetics volatile or nonvolatile gases?

Volatile gases

Which inhaled anesthetic is associated with malignant hyperthermia?

Halothane

What characterizes malignant hyperthermia?

Hyperthermia; muscle rigidity; acidosis; hypertension; hyperkalemia

Should a patient with a family history positive for malignant hyperthermia be concerned?

Yes, because a genetic defect in ryanodine receptors may be inherited.

What drug is given to treat malignant hyperthermia?

Dantrolene

Which inhaled anesthetic is associated with increased bronchiolar secretions?

Isoflurane

Which inhaled anesthetic is associated with hepatitis?

Halothane

Halothane is not hepatotoxic in what patient population?

Pediatric patients

Which inhaled anesthetic is the least hepatotoxic?

Nitrous oxide

Which inhaled anesthetic is associated with increased bronchiolar spasms?

Isoflurane

Which inhaled anesthetic relaxes bronchial smooth muscle?

Halothane

Which inhaled anesthetic is associated with cardiac arrhythmias?

Halothane

Which inhaled anesthetics increase heart rate (via reflex secondary to vasodilation)?

Isoflurane; desflurane

Which inhaled anesthetics decrease heart rate?

Halothane; enflurane; sevoflurane

Which inhaled anesthetic decreases renal and hepatic blood flow?

Halothane

Give examples of intravenous (IV) anesthetics:

Propofol; fentanyl; ketamine; midazolam; thiopental; etomidate

Which of the previously mentioned IV anesthetics is a barbiturate?

Thiopental

Which of the previously mentioned IV anesthetics is a benzodiazepine?

Midazolam

Which of the previously mentioned IV anesthetics is an opioid?

Fentanyl

Is thiopental used for induction, maintenance, or both?

Induction

Pharmacodynamically, how does recovery occur with the rapid-acting barbiturates?

Rapid redistribution from the central nervous system (CNS) to peripheral tissues

State whether thiopental increases, decreases, or does not change each of the following physiologic effects:

Cerebral blood flow

No change

Respiratory function

Decreases

Blood pressure

Decreases

Why should caution be taken when administering thiopental to asthmatic patients?

May cause laryngospasm

Midazolam offers which type of amnesia making it useful for monitored anesthesia care?

Anterograde amnesia

What is the antidote for midazolam-induced respiratory depression?

Flumazenil, which is also the antidote for any benzodiazepine overdose

What adverse drug reaction may be caused by fentanyl when given intravenously?

Chest wall rigidity

Does propofol have good analgesic properties?

No

About which allergies should a patient be questioned before administration of propofol?

Egg and soybeans. Propofol is prepared as a lipid emulsion using egg and soybean lecithin. This gives propofol its white color and can cause allergic reactions in patients with sensitivities to these substances.

Does propofol increase or decrease blood pressure?

It decreases blood pressure.

Is propofol used for induction, maintenance, or both?

It is used for both.

Which IV anesthetic causes dissociative anesthesia?

Ketamine

What is dissociative anesthesia?

The patient is unconscious and feels no pain, yet appears awake. Eyes may open and the swallowing reflex is present, but the patient is sedated, immobile, and usually amnestic. Hallucinations and delirium are common.

Which anesthetic has antiemetic properties?

Propofol

Which IV anesthetic is a cardiovascular stimulant (increases blood pressure and cardiac output)?

Ketamine

Which IV anesthetic causes vivid dreams and hallucinations?

Ketamine

Does ketamine increase or decrease cerebral blood flow?

Increase

What is the most cardiac-stable IV anesthetic agent?

Etomidate

Are local anesthetics weak acids or weak bases?

Weak bases

Give examples of amide local anesthetics:

Lidocaine; prilocaine; articaine; mepivacaine; bupivacaine (all have >1 “i” in their generic name)

Give examples of ester local anesthetics:

Cocaine; benzocaine; procaine (all have only one “i” in their generic name)

Which medication, when used in combination, reduces systemic toxicity and increases the duration of action of local anesthetics?

Epinephrine, by inducing a local vasoconstriction

Epinephrine should not be combined with local anesthetics when injecting near which anatomic sites?

Digits; nose; ears; penis; and any end-artery circulation

Which type of enzymes metabolize amide local anesthetics and where are they located?

Amidases located in the liver

Which type of enzymes metabolize ester local anesthetics and where are they located?

Esterases located in tissues and blood

What is the mechanism of action of local anesthetics?

Inhibition of sodium channels in axonal membranes via binding to the channels in their inactivated state and preventing a structural change to the resting state

Do local anesthetics need to be in the ionized or nonionized form to bind to the sodium channel?

Ionized form

Do local anesthetics need to be in the ionized or nonionized form to gain access to the sodium channel, which is located on the inner side of the axonal membrane?

Nonionized form (must be able to cross lipophilic axonal membrane)

All local anesthetics cause vasodilation with the exception of which drug?

Cocaine (causes vasoconstriction)

Nerve fibers most sensitive to blockade are of smaller or larger diameter?

Smaller diameter

Nerve fibers most sensitive to blockade have low or high firing rates?

High firing rates

Which nerve fibers are most sensitive to local anesthetics?

Type B fibers; type C fibers

Which nerve fibers are least sensitive to local anesthetics?

Type A α-fibers

What are the adverse effects of local anesthetics?

Hypotension (except cocaine); nystagmus; seizures; dizziness; allergic reactions (rare)

Allergic reactions are more associated with ester or amide local anesthetics?

Esters (via para-aminobenzoic acid [PABA] formation)

OPIOID ANALGESICS AND ANTAGONISTS

Which neurotransmitter binds to the δ-opioid receptor?

Enkephalin

Which neurotransmitter binds to the δ-opioid receptor?

Dynorphin

Which neurotransmitter binds to the β-opioid receptor?

β-Endorphin

What is the mechanism of action of medications that activate presynaptic opioid receptors?

Inhibits calcium influx through voltage-gated ion channels, thereby inhibiting neurotransmitter release

What is the mechanism of action of medications that activate postsynaptic opioid receptors?

Increases potassium efflux from cells leading to membrane hyperpolarization and thereby inhibition of neurotransmitter release

Opioid receptors are coupled to what type of proteins?

Inhibitory G-proteins (inhibits adenylyl cyclase)

What is the prototype opioid analgesic?

Morphine

Why must caution be taken when using opioids in patients with head injuries?

Opioids may increase intracranial pressure

Where in the midbrain are opioid receptors located?

Periaqueductal gray region (binding to these receptors leads to activation of descending pathways to the raphe nuclei, thereby decreasing transmission throughout pain pathways)

Where in the dorsal horn of the spinal cord are opioid receptors located?

Primary afferent fibers (binding to these receptors leads to inhibition of substance P release)

Are opioid analgesics better at relieving intermittent or persistent pain?

Persistent pain

What is the mechanism of morphine-induced hypotension and pruritus?

Increased histamine release from mast cells

Do opioid analgesics increase or decrease gastrointestinal (GI) peristalsis?

Decrease (they cause constipation)

Which two opioids are used specifically to treat diarrhea?

1. Loperamide
2. Diphenoxylate

Which opioid analgesic does not increase the tone of the biliary tract, bladder, and ureter?

Meperidine (antagonizes muscarinic receptors)

Do opioid analgesics increase or decrease uterine contractions during pregnancy?

They decrease uterine contractions, thus a good contraction pattern should be achieved before placement of an epidural catheter during labor.

Do opioid analgesics cause miosis or mydriasis of the pupils?

Miosis (common sign of opioid overdose is pinpoint pupils)

What is the mechanism of opioid-induced miosis?

Increased parasympathetic (cholinergic) activity in the pupilary constrictor muscles

Which opioid analgesic does not cause miosis?

Meperidine (antagonizes muscarinic receptors)

Which two opioids are used specifically to treat cough?

1. Codeine
2. Dextromethorphan

Opioids suppress the cough reflex.

Synthetic

Is dextromethorphan a natural or synthetic opioid?

Synthetic

What is the mechanism of opioid-induced urinary retention?

Increases antidiuretic hormone (ADH)

Do opioid analgesics promote emesis or act as antiemetics?

Promote emesis

What is the mechanism of opioid-induced emesis?

Activation of the chemoreceptor trigger zone (CTZ)

Where is the CTZ located?

Area postrema

What is the mechanism of opioid-induced respiratory depression?

Reduced sensitivity of respiratory center to carbon dioxide levels

What is the most common cause of death in opioid overdose?

Respiratory depression

What are the two most lipophilic opioids?

1. Heroin
2. Fentanyl

These two medications rapidly cross the blood-brain barrier (BBB) to produce euphoric effects.

Which opioid is the least lipophilic?

Morphine

Is morphine metabolized via phase I or phase II reactions?

Phase II metabolism (glucuronidation)

Does morphine-3-glucuronide have analgesic activity?

No

Does morphine-6-glucuronide have analgesic activity?

Yes

Which two opioid-induced effects do patients not develop tolerance to?

1. Constipation
2. Miosis

What are the signs and symptoms of opioid withdrawal?

Lacrimation; rhinorrhea; diaphoresis; yawning; goose bumps; anxiety; muscle spasms; diarrhea; increased pain sensation

Which medication is used to counteract the respiratory depression seen in opioid overdose?

IV naloxone (may need to give multiple doses as naloxone has a shorter half-life than morphine)

What is the mechanism of action of naloxone?

(μ,-Receptor antagonist

Which opioid antagonist is given orally to decrease cravings in alcoholism?

Naltrexone

Which opioid analgesic is used to prevent withdrawal symptoms in patients discontinuing heroin use?

Methadone

Which central-acting α₂-agonist is used to prevent withdrawal symptoms in patients discontinuing heroin use?

Clonidine

Give examples of strong opioid agonists:

Morphine; fentanyl; heroin; methadone; meperidine; hydrocodone; hydromorphone

Give examples of weak opioid agonists:

Codeine; propoxyphene

Give examples of partial opioid agonists:

Buprenorphine; pentazocine

Propoxyphene is a derivative of which opioid analgesic?

Methadone

Name two synthetic opioid analgesics:

1. Meperidine
2. Methadone

Fentanyl is chemically related to which synthetic opioid analgesic?

Meperidine

Does morphine have a high or low oral bioavailability?

Low

Which two opioids should not be given in combination with monoamine oxidase inhibitors (MAOIs)?

1. Meperidine
2. Dextromethorphan

These combinations may produce serotonin syndrome.

What drug do you get by acetylating morphine?

Heroin

Is codeine itself an active opioid analgesic?

No (must be metabolized via cytochrome β-450 2D6 to active morphine)

Which medication is commonly given in combination with codeine for the treatment of pain?

Acetaminophen

ANXIOLYTIC AND SEDATIVE-HYPNOTIC AGENTS

For each of the following sedative-hypnotic-induced CNS effects, place in order from effect caused by lowest to highest dose of drug: coma; anesthesia; hypnosis; sedation/anxiolysis; medullary depression.

Sedation/anxiolysis; hypnosis; anesthesia; medullary depression; coma

What is the first step in ethanol metabolism?

Alcohol dehydrogenase converts ethanol to acetaldehyde.

What is the second step in ethanol metabolism?

Acetaldehyde dehydrogenase converts acetaldehyde to acetate.

What enzyme does disulfiram inhibit?

Acetaldehyde dehydrogenase, leading to a build up of acetaldehyde

Which metabolite of ethanol is responsible for causing headache, hypotension, nausea, and vomiting (“hangover”)?

Acetaldehyde

What does GABA stand for?

Gamma-aminobutyric acid

How many subunits make up the GABA receptor?

Five subunits

Which subunit does GABA bind to?

α-Subunit

Which subunit on the GABA receptor do benzodiazepines bind to?

γ-Subunit (binding potentiates the affinity of the GABA receptor for GABA; does not activate the receptor alone without GABA)

Which subunit on the GABA receptor do barbiturates bind to?

β-Subunit (binding potentiates the affinity of the GABA receptor for GABA; does not activate the receptor alone without GABA)

What physiologic process takes place when GABA binds to the GABA_Areceptor?

Increased chloride ion influx into cells leading to membrane hyperpolarization and subsequent decreased neuronal firing

What physiologic process takes place when GABA binds to the GABA_Breceptor?

Increased potassium ion efflux out of cells leading to membrane hyperpolarization and subsequent decreased neuronal firing

What medication binds specifically to the GABA_B receptor?

Baclofen

What is baclofen used for?

Muscle relaxation

Do benzodiazepines potentiate GABA by increasing the duration or frequency of chloride ion channel opening?

Frequency

Do barbiturates potentiate GABA by increasing the duration or frequency of chloride ion channel opening?

Duration

Name three nonbenzodiazepine sleep aids that specifically bind to the BZ₁-receptor subtype:

1. Eszopiclone
2. Zolpidem
3. Zaleplon

Does zolpidem display anticonvulsant, antianxiety, or muscle relaxant properties?

No, it is a selective hypnotic along with zaleplon and eszopiclone.

Do benzodiazepines have good analgesic properties?

No

What types of actions do benzodiazepines display?

Muscle relaxant; anticonvulsant; antianxiety; sedative-hypnotic; anterograde amnesia (midazolam); alcohol withdrawal

Give examples of benzodiazepines:

Diazepam; lorazepam; alprazolam; chlordiazepoxide; clonazepam; clorazepate; midazolam; flurazepam; flunitrazepam; temazepam; triazolam; oxazepam

What is the name of the prototype benzodiazepine?

Chlordiazepoxide

What benzodiazepine is colloquially referred to as the “date rape” drug and is illegal in the United States?

Flunitrazepam (trade name: Rohypnol; slang: “roofies”)

Which benzodiazepine is the longest acting?

Diazepam

Which benzodiazepine is the shortest acting?

Midazolam

What three benzodiazepines undergo phase II metabolism?

1. Lorazepam
2. Oxazepam
3. Temazepam

Which benzodiazepines are commonly used as anticonvulsants?

Diazepam; clonazepam

Which benzodiazepines are commonly used to treat alcohol withdrawal?

Oxazepam; lorazepam; diazepam; chlordiazepoxide

Which benzodiazepines are commonly used as sleep aids?

Temazepam; triazolam; flurazepam

Which benzodiazepines are commonly used as anxiolytics?

Diazepam; lorazepam; alprazolam

Why is alprazolam not the drug of choice when treating patients with chronic anxiety?

It has a short half-life, and therefore may cause withdrawal symptoms, such as anxiety, which subsequently worsens the condition and leads to higher addiction rates.

Give examples of long-acting benzodiazepines (duration of action of 1-3 d):

Diazepam; chlordiazepoxide; flurazepam; clorazepate

Give examples of intermediate-acting benzodiazepines (duration of action of 10-20 h):

Lorazepam; temazepam; alprazolam

Give examples of short-acting benzodiazepines (duration of action of 3-8 h):

Midazolam; oxazepam; triazolam

Give examples of benzodiazepine withdrawal signs and symptoms:

Insomnia; anxiety; agitation; seizures; restlessness; confusion

What are the adverse effects of benzodiazepines?

Confusion; drowsiness; ataxia; cognitive impairment; amnesia; respiratory depression

Is withdrawal more likely to occur with long-acting or short-acting benzodiazepines?

Short-acting benzodiazepines (abrupt withdrawal may ensue as drug levels are rapidly decreased versus long-acting benzodiazepines which offer a “self-tapering” mechanism which decreases the chance of withdrawal)

What is the antidote for benzodiazepine-induced CNS depression?

Flumazenil (short half-life; therefore, multiple administrations may be necessary)

What is the mechanism of action of flumazenil?

Benzodiazepine receptor antagonist

Will flumazenil decrease the effects of barbiturates?

No (barbiturates act at a different GABA receptor subtype than benzodiazepines)

Which two sedative-hypnotic drug classes are potentially fatal with overdose and/or withdrawal?

1. Barbiturates
2. Alcohols

Benzodiazepines may be potentially fatal but to a lesser extent than barbiturates and alcohols.

Give examples of long-acting barbiturates (duration of action of 1-2 d):

Phenobarbital; pentobarbital

Give examples of short-acting barbiturates (duration of action of 3-8 h):

Amobarbital; secobarbital

Give an example of an ultra-short-acting barbiturate (duration of action of 30 min):

Thiopental

What is phenobarbital commonly used to treat?

Seizures (generalized tonic-clonic and partial seizures)

What is thiopental commonly used for?

Induction of anesthesia

What are short-acting barbiturates commonly used for?

Sedation; hypnosis

What kind of drug interactions can barbiturates produce?

Induction of cytochrome β-450 enzymes

What are the adverse effects of barbiturates?

Drowsiness; impair cognitive function (especially in pediatric patients); “hangover” effect; nausea; dizziness; increase heme synthesis (contraindicated in patients with acute intermittent porphyria); coma; respiratory depression; cardiovascular depression; addiction

Give examples of barbiturate withdrawal signs and symptoms:

Insomnia; tremors; anxiety; restlessness; nausea; vomiting; seizures; cardiac arrest; delirium; hyperreflexia; agitation

What drug class is used to prevent barbiturate withdrawal?

Long-acting benzodiazepines

Over-the-counter (OTC) sleep aids have what types of medications in them?

Sedating antihistamines

Give examples of sedating antihistamines:

Diphenhydramine; doxylamine; hydroxyzine (prescription only)

Give examples of antidepressants that have been used for sedation and hypnosis:

Trazodone; amitriptyline

Which medication is a partial agonist at 5-HT_1A receptors and is effective in treating generalized anxiety disorder?

Buspirone

Does buspirone have anticonvulsant and muscle relaxant properties?

No

Is buspirone sedating?

No

How long does it take for buspirone to exert its anxiolytic effects?

1 to 2 weeks (therefore, not useful in treating an acute anxiety attack)

What types of withdrawal signs and symptoms does buspirone cause?

None

ANTIDEPRESSANT AGENTS

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