Deja Review Pharmacology, 2nd Edition
CHAPTER 5. 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?
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?
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?
Are MAC values additive?
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?
Do inhaled anesthetics increase or decrease cerebral vascular flow?
Do inhaled anesthetics increase or decrease intracranial pressure?
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?
Are the inhaled halogenated hydrocarbon anesthetics volatile or nonvolatile gases?
Which inhaled anesthetic is associated with malignant hyperthermia?
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?
Which inhaled anesthetic is associated with increased bronchiolar secretions?
Which inhaled anesthetic is associated with hepatitis?
Halothane is not hepatotoxic in what patient population?
Which inhaled anesthetic is the least hepatotoxic?
Which inhaled anesthetic is associated with increased bronchiolar spasms?
Which inhaled anesthetic relaxes bronchial smooth muscle?
Which inhaled anesthetic is associated with cardiac arrhythmias?
Which inhaled anesthetics increase heart rate (via reflex secondary to vasodilation)?
Which inhaled anesthetics decrease heart rate?
Halothane; enflurane; sevoflurane
Which inhaled anesthetic decreases renal and hepatic blood flow?
Give examples of intravenous (IV) anesthetics:
Propofol; fentanyl; ketamine; midazolam; thiopental; etomidate
Which of the previously mentioned IV anesthetics is a barbiturate?
Which of the previously mentioned IV anesthetics is a benzodiazepine?
Which of the previously mentioned IV anesthetics is an opioid?
Is thiopental used for induction, maintenance, or both?
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
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?
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?
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?
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?
Which IV anesthetic is a cardiovascular stimulant (increases blood pressure and cardiac output)?
Which IV anesthetic causes vivid dreams and hallucinations?
Does ketamine increase or decrease cerebral blood flow?
What is the most cardiac-stable IV anesthetic agent?
Are local anesthetics weak acids or 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?
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?
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?
Which neurotransmitter binds to the δ-opioid receptor?
Which neurotransmitter binds to the β-opioid receptor?
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?
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?
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?
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?
Opioids suppress the cough reflex.
Is dextromethorphan a natural or synthetic opioid?
What is the mechanism of opioid-induced urinary retention?
Increases antidiuretic hormone (ADH)
Do opioid analgesics promote emesis or act as antiemetics?
What is the mechanism of opioid-induced emesis?
Activation of the chemoreceptor trigger zone (CTZ)
Where is the CTZ located?
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?
What are the two most lipophilic opioids?
These two medications rapidly cross the blood-brain barrier (BBB) to produce euphoric effects.
Which opioid is the least lipophilic?
Is morphine metabolized via phase I or phase II reactions?
Phase II metabolism (glucuronidation)
Does morphine-3-glucuronide have analgesic activity?
Does morphine-6-glucuronide have analgesic activity?
Which two opioid-induced effects do patients not develop tolerance to?
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?
Which opioid antagonist is given orally to decrease cravings in alcoholism?
Which opioid analgesic is used to prevent withdrawal symptoms in patients discontinuing heroin use?
Which central-acting α2-agonist is used to prevent withdrawal symptoms in patients discontinuing heroin use?
Give examples of strong opioid agonists:
Morphine; fentanyl; heroin; methadone; meperidine; hydrocodone; hydromorphone
Give examples of weak opioid agonists:
Give examples of partial opioid agonists:
Propoxyphene is a derivative of which opioid analgesic?
Name two synthetic opioid analgesics:
Fentanyl is chemically related to which synthetic opioid analgesic?
Does morphine have a high or low oral bioavailability?
Which two opioids should not be given in combination with monoamine oxidase inhibitors (MAOIs)?
These combinations may produce serotonin syndrome.
What drug do you get by acetylating morphine?
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?
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”)?
What does GABA stand for?
How many subunits make up the GABA receptor?
Which subunit does GABA bind to?
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?
What is baclofen used for?
Do benzodiazepines potentiate GABA by increasing the duration or frequency of chloride ion channel opening?
Do barbiturates potentiate GABA by increasing the duration or frequency of chloride ion channel opening?
Name three nonbenzodiazepine sleep aids that specifically bind to the BZ1-receptor subtype:
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?
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?
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?
Which benzodiazepine is the shortest acting?
What three benzodiazepines undergo phase II metabolism?
Which benzodiazepines are commonly used as anticonvulsants?
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?
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):
Give examples of short-acting barbiturates (duration of action of 3-8 h):
Give an example of an ultra-short-acting barbiturate (duration of action of 30 min):
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?
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?
Over-the-counter (OTC) sleep aids have what types of medications in them?
Give examples of sedating antihistamines:
Diphenhydramine; doxylamine; hydroxyzine (prescription only)
Give examples of antidepressants that have been used for sedation and hypnosis:
Which medication is a partial agonist at 5-HT1A receptors and is effective in treating generalized anxiety disorder?
Does buspirone have anticonvulsant and muscle relaxant properties?
Is buspirone sedating?
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?
According to the biogenic amine theory, depression is due to a deficiency of which two neurotransmitters in the brain?
- Serotonin (5-HT)
- Norepinephrine (NE)
MAOA inactivates which neurotransmitters?
MAOB inactivates which neurotransmitter?
What is the mechanism of action of MAOIs?
Inactivation of MAO, thereby increasing levels of 5-HT, NE, and DA in presynaptic neurons with subsequent leakage of neurotransmitter into the synaptic cleft
Name three nonselective MAOIs:
Selegiline is commonly used in the treatment of which disease?
MAOA also inactivates which monoamine commonly found in certain cheeses (aged), alcoholic beverages, fish, chocolates, red wines, and processed meats?
Tyramine (inactivated by MAO in the GI tract)
MAOIs are the drugs of choice for treating what type of depression?
How long does it take to see antidepressant effects in patients who are started on an MAOI?
2 to 4 weeks
How long should a patient wait from the time of discontinuing an MAOI to the time of starting a new antidepressant medication?
At least 2 weeks
What are the adverse effects of MAOIs?
Orthostatic hypotension; xerostomia; blurred vision; drowsiness; constipation; urinary retention
What life-threatening condition may develop when MAOIs and selective serotonin reuptake inhibitors (SSRIs) are used concomitantly?
What characterizes serotonin syndrome?
Rigidity; diaphoresis; hyperthermia; seizures; autonomic instability; myoclonus
What life-threatening condition may develop when patients taking MAOIs ingest foods containing tyramine?
What characterizes hypertensive crisis?
Hypertension; headache; tachycardia; nausea; vomiting; stroke; cardiac arrhythmias
A serotonin-like syndrome may develop when MAOIs are used concomitantly with what common OTC medication used to suppress cough?
A serotonin-like syndrome may develop when MAOIs are used concomitantly with which opioid analgesic?
What is the mechanism of action of tricyclic antidepressants (TCAs)?
Inhibits reuptake of 5-HT and NE into presynaptic neurons, thereby increasing neurotransmitter concentrations in the synaptic cleft
What other types of neurotransmitter and hormonal receptors, other than 5-HT and NE, are inhibited by TCAs?
Muscarinic; α-adrenergic; histaminergic
How long does it take to see antidepressant effects in patients who are started on a TCA?
4 to 6 weeks
Give examples of TCAs:
Amitriptyline; imipramine; clomipramine; nortriptyline; protriptyline; desipramine; doxepin
What is the name of the active metabolite of amitriptyline that selectively inhibits NE reuptake?
What is the name of the active metabolite of imipramine that selectively inhibits NE reuptake?
Which TCA is also used for the treatment of certain types of neuropathic pain and for the prevention of migraine headaches?
Which TCA is commonly used to treat obsessive-compulsive disorder (OCD)?
Which TCA is also used to treat pediatric nocturnal enuresis?
Why is imipramine used for childhood enuresis?
Increases contraction of internal sphincter of bladder; decreases stage 3 and 4 sleep
What are the adverse effects of the TCAs?
Xerostomia; blurred vision; urinary retention; constipation; precipitation of acute glaucoma attacks; cardiac arrhythmias; seizures (lowers seizure threshold); orthostatic hypotension with reflex tachycardia; sedation; serotonin syndrome when combined with MAOIs and/or SSRIs; coma
What are the “3 C,’s” of TCA toxicity?
Coma, convulsions, and cardiotoxicity
Compare TCA toxicity to SSRI toxicity.
SSRI toxicity is much lower than that seen with TCAs, and mortality is most often reported only when SSRIs are used in combination with another agent, such as alcohol. This is in contrast to TCAs, which can lead to death at much lower concentrations as compared to SSRIs.
What is the treatment for TCA overdose?
Activated charcoal to absorb the drug in the GI tract; sodium bicarbonate to correct acidosis and cardiac arrhythmias; phenytoin; magnesium
What is the mechanism of action of trazodone and nefazodone?
Inhibits reuptake of 5-HT into presynaptic neurons, thereby increasing neurotransmitter concentrations in the synaptic cleft
What adverse effect is unique to trazodone?
What is the mechanism of action of bupropion?
Weak inhibitor of DA, 5-HT, and NE reuptake
Bupropion is also used in what settings (other than depression)?
Smoking cessation; OCD
Does bupropion cause sexual dysfunction?
No, making it a useful alternative in patients that experience sexual dysfunction with other antidepressant medications such as SSRIs
Is bupropion safe to use in patients with epilepsy?
No, because it lowers the seizure threshold.
What is the mechanism of action of mirtazapine?
α2-Adrenoceptor antagonist (results in increased release of NE and 5-HT)
What is the major side effect of mirtazapine?
Weight gain via appetite stimulation (may be beneficial in depressed patients who become anorexic)
Name an α2-antagonist that is used in the treatment of erectile dysfunction:
What is the mechanism of action of venlafaxine?
Potent inhibitor of 5-HT and NE reuptake; weak inhibitor of DA reuptake
What is the major side effect of venlafaxine?
What is the mechanism of action of duloxetine?
Selective serotonin and norepinephrine reuptake inhibitor (SSNRI)
Give examples of SSRIs:
Fluoxetine; paroxetine; fluvoxamine; sertraline; citalopram; escitalopram
What is the prototype of the SSRI drug class?
What is the longest-acting SSRI?
Fluoxetine is also used in what settings (other than depression)?
Premenstrual dysphoric disorder (PMDD); bulimia nervosa; OCD; panic disorder; selective mutism
What kind of drug interactions may SSRIs produce?
Inhibition of cytochrome β-450 enzymes
Do SSRIs cause sexual dysfunction?
Yes, they can cause anorgasmia.
Do SSRIs cause cardiac arrhythmias?
No, they do not, in contrast to TCAs.
What are the adverse effects of SSRIs?
Sexual dysfunction; agitation; anxiety; seizures (with overdose); nausea; vomiting; diarrhea; sedation
Which SSRI is also FDA approved for social anxiety disorder (SAD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD)?
Which SSRIs cause the least amount of drug-drug interactions?
Citalopram; escitalopram; sertraline
AGENTS FOR MANIC-DEPRESSION
Manic-depression is also known as what?
What is the traditional drug of choice for treating manic-depression?
When is lithium used in the treatment of manic-depression (what phases of the disease)?
Prevention; treatment of manic episodes
Does lithium have a narrow or wide therapeutic window?
Narrow. Therapeutic levels range from 0.6 to 1.2 mEq/L and toxicity is seen at 1.5 mEq/L (and at 0.8 mEq/L in elderly patients).
Lithium is eliminated renally in a similar fashion to which other salt?
Is lithium toxicity exacerbated by low or high sodium plasma levels?
Low sodium levels
What is the mechanism of action of lithium?
Unknown; may decrease cAMP levels thereby decreasing its function as a second messenger; may inhibit dephosphorylation of IP3 to IP2 and IP2 to IP thereby interfering with the recycling of inositol
What are the adverse effects of lithium?
Acne; seizures; visual disturbances; edema; ataxia; drug-induced nephrogenic diabetes insipidus; hypothyroidism; tremors
How does lithium cause drug-induced nephrogenic diabetes insipidus?
Uncoupling of the vasopressin V2 receptor in the kidney
Which diuretic is usually used to treat nephrogenic diabetes insipidus?
Which drug is used to treat lithium-induced nephrogenic diabetes insipidus?
Amiloride (thiazide diuretics cause increased reabsorption of lithium which may lead to lithium toxicity)
How does lithium cause hypothyroidism?
Inhibition of 5’-deiodinase
What is 5’-deiodinase responsible for?
Converting thyroxine (T4) to triiodothyronine (T3)
What is the name of the cardiac anomaly that may be found in neonates born to mothers using lithium?
What characterizes Ebstein anomaly?
Malformation of the tricuspid valve leaflets (partly attached to the fibrous tricuspid valve annulus; partly attached to the right ventricular endocardium; inferior displacement of the tricuspid leaflets)
What other medications (mood stabilizers) may be used in the treatment of manic-depression?
Carbamazepine; valproic acid; benzodiazepines; gabapentin; topiramate
Why are antidepressant agents not used to treat the depression phase of manic-depression?
May cause patients to enter into the manic phase
According to the dopamine (DA) hypothesis of schizophrenia, do symptoms arise due to an excess or a lack of DA in the CNS?
An excess of DA
What characterizes the positive symptoms of schizophrenia?
Hallucinations; delusions; thought disorders
What characterizes the negative symptoms of schizophrenia?
Speech disorders; flat affect; amotivation; social withdrawal
What is the mechanism of action of “typical” antipsychotic agents?
Inhibition of D2 receptors in the mesolimbic system of the brain
What is the mechanism of action of “atypical” antipsychotic agents?
Inhibition of 5-HT2 receptors (D2 receptors are still involved to some extent)
Give examples of typical antipsychotics:
Haloperidol; chlorpromazine; thioridazine; fluphenazine; pimozide
Give examples of atypical antipsychotics:
Clozapine; risperidone; aripiprazole; olanzapine; ziprasidone; quetiapine
Name two typical antipsychotics commonly used in the treatment of Tourette syndrome:
What are extrapyramidal symptoms (EPS)?
Parkinsonian-like symptoms (dystonia, rigidity, tremor, and bradykinesia); akathisia; tardive dyskinesia (TD)
What is akathisia?
What is tardive dyskinesia (TD)?
Inappropriate movements of the tongue, neck, trunk, and limbs (associated with long-term use of DA antagonists)
What is the mechanism of anti-psychotic-induced TD?
Long-term DA receptor inhibition leads to an upregulation and supersensitivity of DA receptors, thereby leading to DA overstimulation, especially when the antipsychotic has been discontinued.
Which antipsychotics are more likely to cause EPS?
High potency typical antipsychotics such as haloperidol and fluphenazine secondary to their weak anticholinergic activity
Why do thioridazine and chlorpromazine have a lower EPS potential?
They have high anticholinergic activity.
What medications are used to treat antipsychotic-induced EPS?
Benztropine; amantadine; diphenhydramine (due to its anticholinergic action)
How do antipsychotics cause parkinsonian-like symptoms?
Inhibition of DA receptors in the nigrostriatal pathway
How do antipsychotics cause orthostatic hypotension?
Inhibition of α-adrenergic receptors in the vasculature
How do antipsychotics cause prolactinemia?
Inhibition of DA receptors in the anterior pituitary
Which two antipsychotics possess the highest antimuscarinic activity?
Characterize the antimuscarinic activity of chlorpromazine and thioridazine:
Xerostomia; blurred vision; confusion; constipation; urinary retention
What is xerostomia?
Which antipsychotic agents are more effective at treating negative symptoms?
Which phenothiazine antipsychotic is also used to treat intractable hiccups?
Which phenothiazine antipsychotic may cause priapism, agranulocytosis, blue-gray discoloration of the skin, and lower seizure threshold?
Which two typical antipsychotics can be formulated as depot intramuscular injections that may last up to 3 weeks?
Which atypical antipsychotic is usually reserved as a third-line agent to treat schizophrenic patients refractory to traditional therapy?
What is the major dose-limiting side effect of clozapine?
How are patients receiving clozapine therapy monitored?
WBCs obtained at baseline and weekly for the first 6 months of therapy, every other week for the second 6 months, and monthly thereafter
What adverse effect is more common with clozapine, agranulocytosis, or seizures?
Seizures (occur in 10% of patients, whereas agranulocytosis occurs in l%-2% of patients)
Why is gynecomastia a common adverse effect of risperidone?
Risperidone induces prolactinemia (only atypical antipsychotic that increases prolactin levels significantly)
What is a potential life-threatening adverse effect of antipsychotic medications?
Neuroleptic malignant syndrome (NMS)
What characterizes NMS?
Hyperthermia; rigidity; altered mental status; cardiovascular instability
What is the treatment for NMS?
Dantrolene + bromocriptine (DA agonist)
What are the additional adverse effects of olanzapine?
Weight gain; hyperglycemia; sialorrhea
What are the additional adverse effects of quetiapine?
Hypercholesterolemia; hypertriglyceridemia; weight gain; hepatotoxicity
What is the mechanism of action of aripiprazole?
Antagonist at S-HT2A receptors; partial agonist at D2 and 5-HT1A receptors
What are the additional adverse effects of aripiprazole?
Weight gain; rash; sialorrhea; hepatotoxicity
Which antipsychotic has the highest incidence of sialorrhea?
AGENTS FOR PARKINSON DISEASE
What are the signs of Parkinson disease (PD)?
Bradykinesia; muscular rigidity; tremors; gait abnormalities; postural instability
What neurotransmitter pathway is affected in PD?
Dopaminergic pathway (inhibitory neurons) in the substantia nigra and corpus striatum (neurotransmitter ratio shifts toward decreased DA and increased acetylcholine [ACh])
What does increased levels of DA in the tuberoinf undibular tract lead to?
Decreased prolactin levels
What does increased levels of DA in the CTZ lead to?
What does increased levels of DA in the mesolimbic-mesocortical tracts lead to?
Increased psychomotor activity; psychosis; schizophrenia; increased reinforcement
Which DA receptor subtype is implicated in PD?
D2 receptor subtype (inhibitory receptor subtype that decreases cyclic adenosine monophosphate [cAMP] levels in the corpus striatum)
Given the abnormal DA/ACh shift in the striatum, give two pharmacologic strategies in the treatment of PD:
- Medications that will increase DA levels
- Medications that will decrease ACh levels
Do anti-Parkinson medications effect pathology, symptoms, or both?
Name two antimuscarinic medications that are used in the treatment of PD:
Is benztropine more or less lipid soluble than atropine?
More lipid soluble (therefore, greater CNS penetration)
Which characteristic of PD is not affected by anticholinergics?
Is benztropine useful in the treatment of tardive dyskinesia?
No, it may actually exacerbate tardive dyskinesia.
What are the adverse effects of benztropine and trihexyphenidyl?
Xerostomia; blurred vision; constipation; urinary retention; sedation; mydriasis
How does amantadine work in the treatment of PD?
May inhibit reuptake of DA into presynaptic neurons; may increase DA release from presynaptic fibers
Amantadine is used to treat what condition other than PD?
What is the name of the dermatologic adverse effect caused by amantadine?
What is livedo reticularis?
A network-patterned discoloration of the skin caused by dilation of capillaries and venules
Which characteristic of PD is not affected by amantadine?
Which selective MAOB inhibitor is commonly used as first-line treatment for PD?
What is the mechanism of action of selegiline?
Inhibition of DA metabolism in presynaptic neurons located in the CNS via inhibition of MAOB
What are the two active metabolites of selegiline?
What are the main adverse effects of selegiline?
Cardiovascular stimulation (hypertension, tachycardia, palpitations; arrhythmias; angina)
Name two ergot derivatives that act as DA agonists in the nigrostriatal system:
Bromocriptine is used to treat what conditions other than PD?
Prolactin-secreting microadenomas; NMS; acromegaly; postpartum lactation
What are the adverse effects of bromocriptine?
Headache; dizziness; nausea; orthostatic hypotension; dyskinesia; hallucinations; confusion; psychosis
Name two nonergot DA agonists:
What are the adverse effects of the nonergot DA agonists?
Sedation; syncope; nausea; vomiting; hallucinations; dyskinesia
What is the mechanism of action of tolcapone and entacapone?
Inhibition of peripheral catechol-O-methyltransferase (COMT), thereby increasing CNS uptake of L-dopa
What reaction does COMT catalyze?
Conversion of L-dopa to 3-O-methyldopa (partial DA agonist) in peripheral tissues
What are the adverse effects of COMT inhibitors?
Orthostatic hypotension; headache; fatigue; nausea; diarrhea; anorexia; dyskinesia; muscle cramps; brown-orange urine discoloration; hallucinations; diaphoresis
Which of the COMT inhibitors is hepatotoxic?
Are COMT inhibitors used as first-line therapy, adjunctive therapy, or both in the treatment of PD?
Adjunctive therapy (in combination with carbidopa/levodopa)
Are the nonergot DA agonists used as first-line therapy, adjunctive therapy, or both in the treatment of PD?
What is the precursor of DA?
What enzyme converts L-dopa to DA?
Dopa decarboxylase (DDC)
Does DA cross the BBB?
Does levodopa cross the BBB?
Yes, it does and is subsequently converted to DA by dopaminergic neurons in the substantia nigra.
Is levodopa effective in treating PD when all of the dopaminergic neurons in the substantia nigra have been destroyed?
No, since dopaminergic neurons in the substantia nigra are required to convert levodopa to DA.
What is the mechanism of action of carbidopa?
Inhibition of peripheral DDC, thereby increasing the amount of levodopa that is available to cross the BBB into the CNS. This allows for lower doses of levodopa needed, thereby decreasing levodopa adverse effects.
Does carbidopa cross the BBB?
No, it does not and therefore only inhibits peripheral DDC.
How does levodopa work in the treatment of PD?
Decreases symptoms of PD, such as rigidity, bradykinesia, and tremors
What is the “on-off” phenomenon?
Levodopa has such a short half-life (1-2 h) that plasma concentrations may decline rapidly causing the patient to experience sudden rigidity, bradykinesia, and tremors.
Which amino acids compete with levodopa for GI absorption?
What are the adverse effects of levodopa?
Anorexia; nausea; vomiting; tachycardia; hypotension; discoloration of saliva and urine; mydriasis; hallucinations; dyskinesia; increased intraocular pressure; cardiac arrhythmias
Why should vitamin B6 (pyridoxine) not be used in combination with levodopa?
Pyridoxine enhances peripheral metabolism of levodopa, thereby rendering the medication ineffective.
What are the two types of partial seizures?
What are the three types of general seizures?
What is another name for tonic-clonic seizures?
Grand mal seizures
What is another name for absence seizures?
Petit mal seizures
Does hypoventilation or hyperventilation lower the seizure threshold?
Hyperventilation (via alkalinization of blood pH)
What is the most common seizure type?
What type of seizure is associated with “febrile seizures”?
What type of seizure most commonly presents during childhood?
What is status epilepticus?
Epileptic seizure lasting longer than 30 minutes or absence of full recovery of consciousness between seizures (can be life threatening)
In general, how do antiepileptic agents work?
Inhibit initiation of an abnormal electrical discharge from the focal area; prevent dissemination of abnormal electrical discharge to surrounding areas of the brain
What is the mechanism of action of phenytoin?
Inhibition of axonal sodium channels to produce membrane stabilization
Does phenytoin inhibit the axonal sodium channel in its activated or inactivated state?
What antiarrhythmic class does phenytoin belong to?
What type of drug interactions can phenytoin produce?
Induces cytochrome β-450 metabolic enzymes; highly protein bound, therefore, can potentially displace other medications from plasma proteins
What are the adverse effects of phenytoin?
Diplopia; sedation; ataxia; gingival hyperplasia; acne; hirsutism; megaloblastic anemia (interferes with folate absorption); granulocytopenia; hypotension (IV); osteomalacia; drug-induced lupus; hyperglycemia; nystagmus; Stevens-Johnson syndrome; hepatotoxicity
Is phenytoin safe to use during pregnancy?
No, it causes fetal hydantoin syndrome characterized by cleft lip and palate.
What prodrug is hydrolyzed to phenytoin and is commonly given intravenously secondary to its superior water solubility versus phenytoin?
Name two other medications that may cause gingival hyperplasia:
Which types of seizures does phenytoin treat?
Simple partial; complex partial; tonic-clonic; status epilepticus
What is the mechanism of action of carbamazepine?
Inhibition of axonal sodium channels to produce membrane stabilization
What type of drug interactions can carbamazepine produce?
Induces cytochrome β-450 metabolic enzymes; auto-induces its own metabolism
What conditions, other than epilepsy, can carbamazepine be used in?
Manic-depression; trigeminal neuralgia
What are the adverse effects of carbamazepine?
Diplopia; sedation; ataxia; osteomalacia; aplastic anemia; hyponatremia; Stevens-Johnson syndrome; alopecia; pancreatitis; hepatotoxicity; nystagmus
Is carbamazepine safe to use in pregnancy?
No, it causes neural tube defects and craniofacial abnormalities.
Which types of seizures does carbamazepine treat?
Simple partial; complex partial; tonic-clonic
What antiepileptic medication can cause alopecia?
Valproic acid (VPA)
What is the mechanism of action of VPA?
Inhibition of axonal sodium channels; inhibition of T-type calcium channels; inhibition of GABA transaminase
What type of drug interactions can VPA produce?
Inhibition of cytochrome β-450 enzymes
What conditions, other than epilepsy, can VPA be used in?
What are the adverse effects of VPA?
Hepatotoxicity; pancreatitis; alopecia; nausea; vomiting; photosensitivity; sedation; diarrhea; abdominal pain; thrombocytopenia; rash; amenorrhea; dysmenorrhea; weight gain; tinnitus
Is VPA safe to use in pregnancy?
No, it causes neural tube defects.
Which types of seizures does VPA treat?
Simple partial; complex partial; tonic-clonic; absence; myoclonic
Which antiepileptic medication is used to treat partial and tonic-clonic seizures during pregnancy?
Which benzodiazepines are used in the treatment of status epilepticus?
Which benzodiazepine is used to treat myoclonic and absence seizures?
Which antiepileptic medication is the drug of choice for treating absence seizures and its only FDA indication is for absence seizures?
What is the mechanism of action of ethosuximide?
Inhibition of T-type calcium channels in the thalamus
What are the adverse effects of ethosuximide?
EPS; nausea; vomiting; diarrhea; abdominal pain; fatigue; hirsutism; Stevens-Johnson syndrome; drug-induced lupus; hiccups
Which antiepileptics decrease the efficacy of oral contraceptives?
How do phenytoin and carbamazepine decrease the efficacy of oral contraceptives?
Induction of cytochrome β-450 enzymes
Overdose or abrupt withdrawal of antiepileptics may cause what adverse effect?
Give examples of newer antiepileptic medications:
Gabapentin; pregabalin; lamotrigine; topiramate; tiagabine; vigabatrin; felbamate; levetiracetam
Name two antiepileptics that are considered free of drug-drug interactions:
Which of the newer antiepileptics may inhibit carbonic anhydrase, thereby causing a metabolic acidosis?
What conditions, other than epilepsy, can topiramate be used in?
Migraine; manic-depression; neuropathic pain
What is the mechanism of action of topiramate?
Inhibition of glutamate (AMPA) receptors; increases GABA effects; blocks neuronal voltage-gated sodium channels
Which types of seizures does topiramate treat?
Simple partial; complex partial; seizures associated with Lennox-Gastaut syndrome
What are the adverse effects of topiramate?
Impaired cognition; word finding difficulty; sedation; weight loss; renal stones; metabolic acidosis
Which of the newer antiepileptics may cause Stevens-Johnson syndrome?
What is the mechanism of action of lamotrigine?
Inhibition of sodium channels; inhibition of glutamate receptors
Which types of seizures does lamotrigine treat?
Absence; simple partial; complex partial; seizures associated with Lennox-Gastaut syndrome
What are the adverse effects of lamotrigine?
Stevens-Johnson syndrome; sedation; headache; dizziness; ataxia; nausea; diplopia; amenorrhea; dysmenorrhea
What neurotransmitter is gabapentin structurally related to?
Does gabapentin bind to the GABA receptor?
What is the mechanism of action of gabapentin?
Unknown (may bind to voltage-gated calcium channels specifically possessing the α-2-δ-1 subunit)
Which types of seizures does gabapentin treat?
Simple partial; complex partial
What conditions, other than epilepsy, can gabapentin be used in?
Migraine; neuropathic pain; manic-depression; insomnia; chronic pain; social phobia
What are the adverse effects of gabapentin?
Sedation; ataxia; viral infection (in children); weight gain; diarrhea; nausea; vomiting
AGENTS FOR MIGRAINE
What antihypertensive medication is used in the prophylaxis of migraine headache?
Give examples of medications in the “triptan” drug class:
Sumatriptan; almotriptan; naratriptan; rizatriptan; zolmitriptan
What is the mechanism of action of sumatriptan?
5-HT1D-receptor agonist which causes vasoconstriction in cranial arteries
Why should sumatriptan be used with caution in a patient with angina?
Can precipitate an anginal attack secondary to vasospasm of coronary arteries
How long after the first dose can a second dose of sumatriptan be given if migraine headache has not resolved?
Dose may be repeated once after 2 hours.
What is the mechanism of action of the ergot alkaloids?
Causes vasoconstriction of cranial arteries less selectively than “triptans” by acting as an agonist at various 5-HT receptors throughout the body
Give examples of ergot alkaloids:
What are some common side effects of ergotamine?
Nausea; vomiting; diarrhea; chest pain; toxic levels can cause gangrene
Why is ergotamine sometimes given with caffeine?
Caffeine increases gut absorption of ergotamine.
Are opioid analgesics usually effective against migraine headache?
A 39-year-old man is unsatisfied with the results he is seeing from his current antidepressant therapy. He decides to stop taking the medication and to start seeing a new psychiatrist. To avoid repeating the same therapy he does not reveal that he was previously treated for his major depressive disorder. The new psychiatrist prescribes a first-line SSRI to treat the patient. Shortly after taking the SSRI, the patient becomes tachycardic, diaphoretic, and experiences myoclonic twitches. He develops a generalized tonic-clonic seizure shortly after admission to the emergency room. What class of medication was the patient most likely taking previously?
This patient was most likely taking a monoamine oxidase inhibitor (MAOI) prior to his arrival at his new psychiatrist. Results may not be seen for up to a month after initiation of treatment with an MAOI, leading to patient dissatisfaction and the belief that the medication is not effective. Should the MAOI therapy be discontinued, adequate time should be allowed for complete clearance of the drug before alternate therapy is initiated. SSRIs are particularly dangerous when combined with MAOIs because of their risk for causing serotonin syndrome, which this patient has developed.
An 80-year-old man has come to a cocktail party celebrating the end-of-the-year holidays. At the party he enjoys some hors d’oeuvres including small sausages and cheeses. In a few minutes, however, he collapses and is rushed to the emergency room. There he is found to have a blood pressure of 200/98. His wife informs the physician that he only takes one antihypertensive medication. What medication does he most likely take, and how has it contributed to his current condition?
He has suffered a hypertensive crisis due to the combination of tyramine and MAOIs. Cured meats and aged cheeses, such as those consumed by the patient contain tyramine, which may displace norepinephrine from storage vesicles and cause a buildup of catecholamines, leading to extreme hypertension.
A 29-year-old man is undergoing abdominal surgery. Shortly after induction and successful intubation, the patient’s peak airway pressures begin to rise. Bilateral auscultation confirms equal breath sounds, and stat chest x-ray reveals no pneumothorax. What intravenous anesthetic agent is most likely responsible for this development?
Fentanyl, a synthetic high-potency opioid, is frequently used as a part of balanced anesthesia and can cause chest wall and laryngeal rigidity, interfering with mechanical ventilation. Low doses of opiates should be used to avoid this complication.
A 72-year-old woman with Parkinson disease is unable to move after sitting through a film at the movie theater with her family. What is the most likely therapy she is receiving for her disease, and why might the medication be responsible for her current situation? What fast-acting dopamine agonist would be appropriate for use in such a situation?
The patient is most likely on levodopa therapy. Levodopa has a very short half-life leading to the “on-off” phenomenon frequently seen with its use. Patients may find they are suddenly unable to stand or walk and may require rescue therapy with a fast-acting dopamine agonist. Apomorphine is such an agent, and is useful in emergency situations such as that presented in the vignette. It does not require enzymatic conversion to an active product, and so works quickly—about 10 minutes after injection. Nausea and vomiting limit its use to rescue situations, as does dyskinesia and hypotension.