Term
|
Definition
| reduces anxiety and causes a calming effect |
|
|
Term
|
Definition
| produce drowsiness and encourage onset and maintenance of a state of sleep |
|
|
Term
|
KEY CONCEPTS on SEDATIVE-HYPNOTICS
|
|
Definition
- Dose-related inhibition of activity in the central nervous system.
- Enhance the actions of the inhibitory neurotransmitter, GABA
|
|
|
Term
| THE BOTTOM LINE ON BARBITURATES |
|
Definition
|
• With the exception of the iv anesthetics and some very specialized uses, barbiturates are NOT considered drugs of choice as hypnotics (H), preoperative sedatives (PS), anticonvulsant drugs (AC) or for ER management of seizures (ER).
|
|
|
Term
Barbiturates on the UUHSC Drug List
Phenobarbital
(Luminal) |
|
Definition
|
|
Term
Barbiturates on the UUHSC Drug List
Pentobarbital |
|
Definition
|
|
Term
Barbiturates on the UUHSC Drug List
Thiopental
(Pentothal) |
|
Definition
|
|
Term
| Wilcox Abbreviations On Barbiturates |
|
Definition
- H = hypnotic sleep induction, (not drugs of choice)
- PS = Preoperative sedation (not drugs of choice)
- ER = Emergency room management of seizures (not drugs of choice)
- AC = Anticonvulsant, Management of epilepsy
- second line agent
- third line agent
- Intravenous anesthetic: thiopental and methohexital
|
|
|
Term
PHARMACOLOGICAL ACTIONS OF BARBITURATES
DEPRESSION OF CNS ACTIVITY
(5)
|
|
Definition
|
–Ranges from sedation to coma, death; not selectively anxiolytic
–Action in reticular activating system
–May enhance perception of pain
–May produce paradoxical excitation in children, elderly
–CNS toxicity in overdose: hypothermia, hypotension, circulatory collapse (potentially lethal), respiratory depression (potentially lethal)
|
|
|
Term
PHARMACOLOGICAL ACTIONS OF BARBITURATES
(continued)
(5) |
|
Definition
|
•Inhibition of ganglionic transmission; decreased blood pressure
•Decreased tone and contractions of GI and urinary tract smooth muscle
•Metabolized via oxidation of hepatic enzymes and excreted as glucuronide conjugates
•With chronic use: induction of cytochrome P-450 drug metabolizing enzyme systems; potential for adverse drug interactions and therapeutic failures
•Potential for addiction and physical dependence
|
|
|
Term
| Chronic administration of barbiturates |
|
Definition
- markedly increases the protein and lipid content of the hepatic smooth endoplasmic reticulum, as well as the activities of glucuronyltransferase and CYPs 1A2, 2C9, 2C19, and 3A4.
- The induction of these enzymes increases the metabolism of a number of drugs and endogenous substances, including steroid hormones, cholesterol, bile salts, and vitamins K and D.
- This also results in an increased rate of barbiturate metabolism, which partly accounts for tolerance to barbiturates.
|
|
|
Term
BENZODIAZEPINES ON THE UUHSC DRUG LIST TO BE DISCUSSED
Anxiolytics
(3)
|
|
Definition
- Diazepam (valium)
- Alprazolam (xanax)
- Lorazepam (ativan)
|
|
|
Term
BENZODIAZEPINES ON THE UUHSC DRUG LIST TO BE DISCUSSED
Hypnotics
(4) |
|
Definition
- Temazepam (Restoril)
- Zolpidem (Ambien)
- Zaleplon (Sonata)
- Eszopliclone (Lunesta)
|
|
|
Term
BENZODIAZEPINES ON THE UUHSC DRUG LIST TO BE DISCUSSED
Preop Sedation |
|
Definition
|
|
Term
BENZODIAZEPINES ON THE UUHSC DRUG LIST TO BE DISCUSSED
Antagonist |
|
Definition
|
|
Term
KEY CONCEPT:
All benzodiazepines exert the same pharmacological actions.
(6)
|
|
Definition
|
•Antianxiety ( low doses)
•Conscious sedation (moderate doses)
•Skeletal muscle relaxation (centrally based) (moderate doses)
•Anticonvulsant (moderate doses)
•Sleep induction (high doses)
•Anterograde memory impairment
–Dose-related
|
|
|
Term
|
Definition
| loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long term memories from before the event remain intact |
|
|
Term
ADVANTAGES OF BENZODIAZEPINES vs. OTHER (OLDER) SEDATIVE-HYPNOTICS
*
(5)
|
|
Definition
|
•Clearly anxiolytic in low doses
•Skeletal muscle relaxation effect
•High therapeutic index; much safer in overdose
•No induction of drug metabolizing enzymes
•KEY CONCEPT: Benzodiazepines are more limited in their CNS depressant action than older sedative-hypnotics.
|
|
|
Term
PHARMACOKINETICS OF BENZODIAZEPINES
*
(3)
|
|
Definition
|
•KEY CONCEPT: The duration of action of benzodiazepines is largely determined by the presence or absence of biologically active metabolites.
–LONG ACTING BZD’S have active metabolites w/ long t1/2’s.
–SHORT ACTING BZD’S have inactive or no metabolites.
|
|
|
Term
|
METABOLISM OF BENZODIAZEPINES
(3)
|
|
Definition
|
•Hepatic clearance
–Water soluble metabolites for clearance
–Phase I via microsomal oxidation
•CYP3A4
•Many phase I metabolites are active
–Phase II
•Glucuronide formation and excretion
|
|
|
Term
METABOLISM OF BZs
(slide #15 diagram)
|
|
Definition
|
Hepatic metabolism accounts for the clearance of all benzodiazepines.
- The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N-dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4.
- The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, some with long half-lives (Figure 22–5).
- For example, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. Alprazolam and triazolam undergo -hydroxylation, and the resulting metabolites appear to exert short-lived pharmacologic effects because they are rapidly conjugated to form inactive glucuronides.
- The short elimination half-life of triazolam (2–3 hours) favors its use as a hypnotic rather than as a sedative drug.
|
|
|
Term
Metabolism of BZs
diagram |
|
Definition
|
|
Term
| MECHANISM OF ACTION OF BENZODIAZEPINES |
|
Definition
|
•KEY CONCEPT: Benzodiazepines enhance the actions of the inhibitory neurotransmitter, g-amino-butyric acid (GABA).
- BZD’s facilitate the opening of the Cl- ion channel in response to GABA; enhance neuronal hyperpolarization
|
|
|
Term
|
BZs BIND AT THE JUNCTION BETWEEN THE a AND g SUBUNITS
|
|
Definition
|
|
Term
|
Definition
|
|
Term
|
PATCH CLAMP STUDIES REVEAL MECHANISM OF ACTION OF DIAZEPAM AND PHENOBARBITAL
|
|
Definition
|
|
Term
BZ BINDING TO GABAA RECEPTORS WITH DIFFERENT a SUBUNITS CONTRIBUTES TO FUNCTION
|
|
Definition
|
•a1: mediates sedation, amnesia, ataxia
•a2 & a3: mediates anxiolytic actions and muscle relaxation
•
•a5: memory impairment
[image]
|
|
|
Term
EFFECTS OF SEDATIVE-HYPNOTICS ON SLEEP
Short term
(5)
*
|
|
Definition
|
•SHORT TERM EFFECTS (< one week):
–Decrease sleep latency
–Increase total sleep time
–Decrease nocturnal awakenings
–Increase time in stage 2
–Decrease time in stages 3,4, REM
|
|
|
Term
EFFECTS OF SEDATIVE-HYPNOTICS ON SLEEP
Long term
(6)
*
|
|
Definition
|
•LONG TERM (7-10 nights)
–Drug dependency insomnia:
•Decreased sleep time
•Increased nocturnal awakenings
•Early morning awakenings and next-day anxiety (esp. BZDs)
•Further increase stage 2
•Further decrease in 3,4, REM
|
|
|
Term
|
EFFECTS OF SEDATIVE-HYPNOTICS ON SLEEP
(3)
|
|
Definition
|
•KEY CONCEPT: Most sedative-hypnotics alter sleep architecture to increase lighter stages and decrease deeper stages.
- Most lose effectiveness and worsen sleep within 1-2 weeks.
- This may reflect rapid development of physical dependence.
- Zolpidem, zaleplon and eszopiclone (BZD agonists) are exceptions
|
|
|
Term
Effects of sedatives-hypnotics on sleep
diagram |
|
Definition
|
|
Term
EFFECTS OF TEMAZEPAM (RESTORIL ®)
(5)
|
|
Definition
|
•Rapid onset
•Classic effects on sleep architecture
•short duration of action; no active metabolites; no next-day sedation BUT
•Next-day amnesia (traveler’s amnesia)
•Rapid development of early morning awakening and next-day anxiety when used 5+ nights
|
|
|
Term
EFFECTS OF ZOLPIDEM (AMBIEN ®)
ON SLEEP
(4)
*
|
|
Definition
|
•A partial agonist at BZD receptors
–Effective hypnotic and sedative but no skeletal muscle relaxant or anticonvulsant effects
•Rapid onset and short duration of hypnotic action(however, new CR prep is longer duration);
no active metabolites
•Reduces latency and increases sleep time without affecting sleep stages in doses up to 20 mg
|
|
|
Term
EFFECTS OF ZOLPIDEM (AMBIEN ®) ON SLEEP
(Continued)
(7)
*
|
|
Definition
|
•Little or no next-day sedation; some next-day amnesic effect
–Recent concerns on sleep-driving and sleep-eating
•Some early morning awakening may develop but maintains hypnotic effectiveness for several weeks
•Well tolerated in elderly
•Adverse effects include: dizziness, headache, GI upset
•Abuse potential seems low
•Zaleplon and eszopiclone are similar; but perhaps less amnesia or day-after somnolence
|
|
|
Term
ADVERSE EFFECTS OF BENZODIAZEPINE HYPNOTICS
(8)
*
|
|
Definition
|
•*NEXT-DAY (RESIDUAL) SEDATION, DROWSINESS (hangover)
–more pronounced with long-acting agents
–Can be additive with ethanol
–Concern with elderly
•*DEVELOPMENT OF REBOUND INSOMNIA
–Early morning awakening, next-day anxiety
–More pronounced with short-acting agents
•*ANTEROGRADE AMNESIA
|
|
|
Term
OTHER DRUGS FOR SLEEP
(6)
*
|
|
Definition
|
•OTC antihistamines
•Chloral hydrate
•Alcohol
•Valerian
•Melatonin
•Ramelteon (Rozerem ®) (a melatonin agonist)
|
|
|
Term
|
Definition
- Valerian has been used as a medicinal herb since at least the time of ancient Greece and Rome. Its therapeutic uses were described by Hippocrates, and in the 2nd century, Galen prescribed valerian for insomnia [5,7].
- In the 16th century, it was used to treat nervousness, trembling, headaches, and heart palpitations [8].
- In the mid-19th century, valerian was considered a stimulant that caused some of the same complaints it is thought to treat and was generally held in low esteem as a medicinal herb [2].
- During World War II, it was used in England to relieve the stress of air raids [9].
- In the United States, valerian is sold as a nutritional supplement.
|
|
|
Term
|
GENERAL THERAPEUTUC PRINCIPLES FOR USE OF SEDATIVE-HYPNOTICS IN INSOMNIA
(3)
|
|
Definition
|
•Part of an integrated treatment plan
•Benzodiazepines are preferred, esp. zolpidem and related
•Treatment is individualized, i.e., frequency and duration of use
|
|
|
Term
SEDATIVE-HYPNOTIC
“CLUB” DRUGS
Rohypnol ®: flunitrazepam
(3)
|
|
Definition
|
–Long acting, hypnotic BZD
–Strong anterograde amnesia, esp. w/ alcohol
–Potentially lethal respiratory depression when combined w/ alcohol
|
|
|
Term
SEDATIVE-HYPNOTIC
“CLUB” DRUGS
Gamma-hydroxybutyrate (GHB)
(3)
|
|
Definition
|
–CNS depressant; GABA agonist?
–Sedation, sleep, amnesia, respiratory depression (potentially lethal, esp. with alcohol)
–Precursor, gamma-butyrolactone, assoc with physical dependence
|
|
|
Term
|
GHB (AKA sodium oxybate)as Xyrem ® for Narcolepsy
(4)
|
|
Definition
|
•FDA-approved in 2002
•Taken at night, improves nighttime sleep
•Decreases daytime sleepiness
•Decreases incidence of cataplexy, sleep paralysis and hypnogogic hallucinations
|
|
|
Term
ANXIOLYTICS
KEY CONCEPTS:
(5)
*
|
|
Definition
|
• Selective reduction in anxiety, without markedly impairing mental or motor performance.
–Sedation connotes overall calming, associated with decreased alertness and motor coordination
•The “classic” anxiolytics are benzodiazepines and buspirone (BuSpar®).
•SSRI and SNRI antidepressants are now used more frequently for long term Rx of formal anxiety disorders.
–Effective; therapy for co-morbid depression
|
|
|
Term
THE ANXIETY PHARMACY
(7)
*
|
|
Definition
|
Disorder Effective Rx
–Short term stress = BZDs; antihistamines
–GAD = BZDs; buspirone, SSRI and SNRI antidepressants
–Panic = alprazolam; SSRI and SNRI antidepressants
–Social anxiety = antidepressants
–Performance anxiety = ß-blockers, antidepressants
–Post Traumatic Stress = antidepressants
–Obsessive-Compulsive = clomipramine, SSRI antidepressantss
|
|
|
Term
|
Definition
- Generalized anxiety disorder (GAD)
- is an anxiety disorder that is characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry.
- This excessive worry often interferes with daily functioning, as individuals suffering GAD typically anticipate disaster, and are overly concerned about everyday matters such as health issues, money, death, family problems, friend problems, relationship problems or work difficulties.
- They often exhibit a variety of physical symptoms, including fatigue, fidgeting, headaches, nausea, numbness in hands and feet, muscle tension, muscle aches, difficulty swallowing, bouts of difficulty breathing, difficulty concentrating, trembling, twitching, irritability, agitation, sweating, restlessness, insomnia, hot flashes, and rashes.
- These symptoms must be consistent and on-going, persisting at least 6 months, for a formal diagnosis of GAD to be introduced
- Approximately 6.8 million American adults experience GAD.
|
|
|
Term
|
BENZODIAZEPINES IN ANXIETY DISORDERS
Indications
(3)
|
|
Definition
|
•INDICATIONS:
–Rx of anxiety in acute stress situations
–Rx of GAD
–Rx of Panic Disorder (alprazolam)
|
|
|
Term
BENZODIAZEPINES IN ANXIETY DISORDERS
Efficacy
(4)
|
|
Definition
|
•EFFICACY:
–Relieve psychological and somatic symptoms w/ fast onset of action
–Approx 65-75% will respond
–Short acting agents, I.e. alprazolam, lorazepam, preferred for acute, short term stresses; in elderly; w/ hepatic disease
Tolerance not usually a problem in this setting |
|
|
Term
|
ANXIOLYTIC BENZODIAZEPINES
ON UUHSC DRUG LIST
(3)
|
|
Definition
|
•alprazolam (Xanax ®)
•lorazepam (Ativan ®)
•diazepam (Valium ®)
|
|
|
Term
|
Definition
|
•Prescribed for panic attacks, generalized anxiety disorder (GAD), and societal anxiety disorder (SAD).
•Has specific anti-panic effects; as needed basis
•Rapidly absorbed
•Shorter half-life than diazepam
•Tolerance to sedation develops; less so for anxiolytic activity
|
|
|
Term
|
Definition
|
•Prescribed for:
– management of anxiety disorders or short-term (≤4 months) relief of the symptoms of anxiety or anxiety associated with depressive symptoms
–I.V.: Status epilepticus, amnesia, sedation
–Management of alcohol withdrawal
|
|
|
Term
|
Definition
|
•Prescribed for:
–anxiety, insomnia, seizures including status epilepticus, muscle spasms (such as in cases of tetanus), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, amnesia, preop sedation
•Long half life of active metabolites
|
|
|
Term
|
BENZODIAZEPINES IN ANXIETY DISORDERS
(2)
|
|
Definition
|
•TYPICAL Rx REGIMENS
–Single event (single dose) or short term stressors (one week Rx) w/ short-acting BZD
–GAD or Panic: Rx for 9 - 12 month +; d/c by slow taper, esp. with short-acting
|
|
|
Term
BENZODIAZEPINES IN ANXIETY DISORDERS
Common Adverse Effects
(9)
*
|
|
Definition
|
•COMMON ADVERSE EFFECTS:
–CNS depression
•Sedation, drowsiness
•Impaired psychomotor coordination
•Memory impairment; amnesia
•Disinhibition (esp. in children)
–Potentially teratogenic in pregnancy
–Transferred via milk to infants
–Physical dependence w/ long term Rx
|
|
|
Term
| DRUG INTERACTIONS WITH BENZODIAZEPINES |
|
Definition
|
•CAUTION WITH INHIBITORS OF CYTOCHROME P450
Why would you need to be careful with other drugs that inhibit cyp 450??? Because metabolized with cyps
|
|
|
Term
|
ALTERNATIVES FOR SHORT AND LONG TERM ANXIETY
(2)
|
|
Definition
|
•BUSPIRONE (BuSpar ® )
–Key concept: Buspirone is an anxiolytic but is not a sedative-hypnotic.
–No effects on GABA system; serotonin and dopamine agonist
|
|
|
Term
|
Definition
|
•Weakly sedating; no hypnotic, muscle relaxant or anticonvulsant effects
•No abuse, addiction or physical dependence liability; alternative for anxiety with history of drug abuse
•Well tolerated: some dizziness, headache, nausea
•Few drug interactions
•However, it may take several weeks before its anxiolytic effects become noticeable
|
|
|
Term
|
BUSPIRONE (continued)
(7)
|
|
Definition
|
•Buspirone is reported effective in Rx of:
–Generalized Anxiety Disorder
–Premenstrual Syndrome/Dysphoric Disorder
–Obsessive-Compulsive Disorder
–Post-Traumatic Stress Disorder
•Buspirone is ineffective in Rx of panic
•Anxiolytic action is delayed; fully effective in 1-4 weeks
•Efficacy is less than BZDs
|
|
|
Term
ALTERNATIVES FOR ANXIETY
Sedating Anti-histamines
(3)
|
|
Definition
|
–e.g., hydroxyzine (Vistaril ®, Atarax ® on UUHSC Drug List) or diphenhydramine (Benadryl ® )
–Not selectively anxiolytic, but they work in the real world
–FDA-approved for short term Rx of anxiety; ineffective in GAD or other formal anxiety disorders
|
|
|
Term
ALTERNATIVES FOR ANXIETY
ß-adrenergic blockers for performance anxiety
(5)
*
|
|
Definition
|
•ß-adrenergic blockers for performance anxiety
–Not classically anxiolytic, but blunt catecholamine-mediated somatic signs of anxiety, esp. tremor, dry mouth, GI distress
•i.e., increase comfort level, tolerability
•Not FDA- approved, but well known and widely used, esp. in performing arts
–e.g., propranolol 10 mg one hr before event
|
|
|
Term
|
DRUGS FOR
PANIC DISORDER
(5)
|
|
Definition
|
•Alprazolam
•SSRIs
•SNRI: venlafaxine
•Tricyclics; MAO inhibitors
•Buspirone and atypical antidepressants (e.g., bupropion) are generally ineffective in panic disorder
|
|
|
Term
PREOP SEDATION
MIDAZOLAM (VERSED ®)
*
|
|
Definition
|
•CLINICAL USES:
–Conscious sedation
–Skeletal muscle relaxation
–Premedication for minor surgery, diagnostic procedures
–Adjunctive agent in anesthesia, component of balanced anesthesia
|
|
|
Term
ACTIONS OF MIDAZOLAM
Characteristics
(3)
|
|
Definition
|
•CHARACTERISTICS:
–Improved water solubility vs. diazepam
–Fast onset, short duration of action
–very marked anxiolytic and amnesic effects
|
|
|
Term
ACTIONS OF MIDAZOLAM
Effective routes
(2)
|
|
Definition
|
–IV; given slowly, to avoid cardio-respiratory depression; or if bolus, with respiration
–Homemade oral prep w/ Kool-Aid effective in children
|
|
|
Term
ACTIONS OF MIDAZOLAM
Adverse effects
(3)
|
|
Definition
|
•Adverse effects
–*Respiratory depression (esp in iv bolus w/o respiration)
–Hypotension
–Headache
|
|
|
Term
|
ACTIONS OF FLUMAZENIL (ROMAZICON ® )
(3)
|
|
Definition
|
•ACTION: competitive antagonist at BZD receptors; specific benzodiazepine antagonist
•CLINICAL USES: reversal of benzodiazepine sedation; Rx of overdose
•ROUTE: only effective IV
[image]
|
|
|
Term
ACTIONS OF FLUMAZENIL (ROMAZICON ® )
Limitations
(3)
|
|
Definition
|
•LIMITATIONS:
–Very short duration of action, 20-30 min
–May precipitate withdrawal in dependent individuals
–Not clearly effective against hypoventilation
|
|
|
Term
ABUSE POTENTIAL OF BENZODIAZEPINES
*
|
|
Definition
|
•KEY CONCEPTS: Behavioral and psychological features of intoxication with BZDs are very similar to those seen with ethanol and other sedative-hypnotics.
The physical dependence that may develop is also the same as other sedative-hypnotics and ethanol.
|
|
|
Term
KEY CONCEPTS INADDICTION AND DEPENDENCE
*
|
|
Definition
|
•Addiction: compulsive drug use associated with strong craving and preoccupation with obtaining and using the drug for its rewarding effects, without regard to adverse effects
–APS/ASAM/AAPM: “.. Characterized by… impaired control over drug use, compulsive use, continued use despite harm, and craving.
|
|
|
Term
KEY CONCEPTS INADDICTION AND DEPENDENCE
(contd)
*
|
|
Definition
|
•Physical dependence: altered physiological state produced by long term administration in which target tissues adapt and require drug for normal functioning. Discontinuation produces withdrawal or abstinence.
•APS/ASAM/AAPM: “ a state of adaptation…manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, …administration of antagonist”
|
|
|
Term
ABUSE POTENTIAL OF BENZODIAZEPINES
(3)
*
|
|
Definition
|
•BZD’s have potential for abuse, but abuse and addiction are not common w/anxiolytic regimens in pnts w/ no history of drug abuse.
•BZD abuse mainly occurs in alcohol abusers.
•Physical dependence can develop w/i 6-8 months (i.e., during Rx for GAD and panic); withdrawal signs are usually mild, but can be severe with abrupt discontinuation.
|
|
|
Term
GENERAL DEPRESSANT WITHDRAWAL SYNDROME
(4)
*
|
|
Definition
|
•Acute phase of 8-10 days; prolonged phase of 1-3 months
•In mild form: anxiety, insomnia, nausea, weakness
•In severe form: between 12 hr and 72 hr: strong anxiety, weakness, nausea, abdominal cramps, orthostatic hypotension, headache
–48-72 hr: tonic-clonic seizures, delirium, disorientation; Potentially lethal hyperthermia, cardiac arrhythmias
|
|
|
