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?
- Loperamide
- 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?
- Codeine
- 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?
- Heroin
- 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?
- Constipation
- 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:
- Meperidine
- 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)?
- Meperidine
- 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 GABAAreceptor?
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 GABABreceptor?
Increased potassium ion efflux out of cells leading to membrane hyperpolarization and subsequent decreased neuronal firing
What medication binds specifically to the GABAB 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:
- Eszopiclone
- Zolpidem
- 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?
- Lorazepam
- Oxazepam
- 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?
- Barbiturates
- 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-HT1A 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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