Term
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Definition
Chlordiazepoxide
Diazepam
Lorazepam
Trazolam
Flurazepam
Temazepam
Alprazolam
Clonazepam
Midazolam |
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Term
| Selective Benzodiazepine R Agonists |
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Definition
Zolpidem
Zaleplon
Eszopiclone |
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Term
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Definition
Phenobarbital
Pentobarbital
Thiopental |
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Term
| Other Non-Benzodiazepine, Non-Barbiturate Sedative-Hypnotic:OBSOLETE |
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Definition
| Chloral hydrate, Mephobamate |
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Term
| Nonsedating Anxiolytic Drugs |
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Definition
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Term
| Characteristics of ALL sedative hypnotics |
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Definition
With increasing dose, all sedative-hypnotics can produce:
RElief of anxiety
Sedation "stages of Anesthesia
Euphoria-Disinhibition
HYPNOSIS
Anesthesia
Death
All sedative-hypnotics also have a potential for dependence and abuse--"abuse liability" |
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Term
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Definition
Benzodiazepines(BZ) have a much flatter dose-response curve than barbiturates-"Ceiling Effect"-precludes severe CNS depression--Large therapeutic index
It is very difficult to produce True Anesthesia and Death with BZ alone--(easey in comb. with other CNS depressants) |
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Term
Benzodiazepines
Absorption and Distribution |
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Definition
Oral: All BZ are lipophilic, rapidly and completely absorbed after oral use & distribute throughout the body.
I.M.: Chlordiazepoxide & diazepam are not well absorbed; lorazepam & midazolam are well absorbed I.M.
I.V. : Diazepam & Lorazepam for STATUS EPILEPTICUS |
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Term
Benzodiazepines
Biotransformation |
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Definition
All BSz undergo hepatic metabolism
Many benzodiazepines (e.g. diazepam,
chlordiazepoxide, flurazepam, etc) are oxidized in the liver to active metabolites with longer half- lives than the parent drug.
Some benzodiazepines (e.g. alprazolam, triazolam, and midazolam) are oxidized to short-acting or inactive metabolites.
Oxazepam, lorazepam, and temazepam are all directly conjugated with glucuronate to inactive metabolites which are eliminated in urine-- may be safer to use IN ELDERLY |
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Term
| Long acting Benzodiazepines |
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Definition
| Chlordiazepoxide, Diazepam, flurazepam |
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Term
| Intermediate acting Benzodiazepines |
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Definition
Alprazolam
lorazepam
temazepam
clonazepam |
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Term
| Short acting Benzodiazepines |
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Definition
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Term
Benzodiazepines
Pharmacodynamics
Site and MOA |
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Definition
BZs act on polysynaptic pathways throughout the CNS eg cortex, limbic system etc. They appear to selectively increase the inhibitory effects of GABA
BZs bind to specific binding sites on the GABAaR which functions as a chloride ion cheannel activated by GABA. The BAGAaR-chloride ion channel complex consists of 5 membrane-spanning subunits. Multiple forms of alpha, Beta and gamma subunitis are arranged in different pentameric combinations to form multiple isoforms of GABAaR in many regions of the brain.
A major isoform of the GABAaR consists of two alpha 1, two beta2, and one gamma 2 subunits.
GABA binds to 2 sites between alpha and beta subunits which leads to Cl- channel opening and hyper-poarization.
BZ binds to an allosteric site between alpha and gamma subunits
Barbiturates binds adjacent to alpha and beta subunits both in presence and absence of GABA
Ethanol binds to a distinct site on the inophore and increases Cl- influx. It also contains binding sites for steroids and inhalational anesthestics. |
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Term
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Definition
Relief of Anxiety (Anxiolytic): Low doses can relieve anxiety that produce very little sedation and drowsiness
Sedationa nd Hypnosis: BZ will induce SLEEP
↓ latency of sleep onset**-- induce sleep
↑ duration of stage 2 sleep (NREM)**
↓ duration of REM sleep
↓ duration of slow-wave sleep (stage 3 & 4)
-- Tolerance develops with continued use.
“REM Rebound”--↑ REM sleep and/or insomnia can occur following discontinuation of chronic drug use.--WITHDRAWAL |
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Term
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Definition
Anesthesia: A general “anesthetic-like” stage can be produced with IV midazolam (Versed), lorazepam (Ativan), or diazepam (Valium) w/ good anterograde amnesia.
-- NOT capable of producing surgical anesthesia alone.
Anticonvulsant effects. SEIZURE
All BD have varying degrees of anticonvulsant activity.
Clonazepam (Klonopin)-- very selective.
Diazepam,Lorazepam-- Tolerance ↑ readily.
e. Central Muscle relaxant effects:
MOA:
↓ Transmission at skeletal NMJ |
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Term
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Definition
Relief of anxiety: Major use
Situational anxiety
Generalized anxiety disorder
Panic disorders - - high potency BZ
e.g. alprazolam (Xanax)
clonazepam (Klonopin)
Phobias
Obsessive – compulsive disorder (OCD)– Ineffective; SSRI’s--PROZAC
Drug of choice: A longer-acting agent is more reliable in relief of anxiety, e.g. diazepam; lorazepam & oxazepam prefer for elderly.
Treatment of sleep disorders: ↓ latency to sleep onset & ↑ stage 2 of NREM sleep. a. Only 5 are approved by FDA for Insomnia: triazolam (Halcion; generic) – short-acting temazepam (Restoril; generic) - intermediate estazolam (ProSom; generic) – intermediate flurazepam (Dalmane; generic) – long-acting quazepam (Doral) – long acting Symptomatic treatment only; long-term use is irrational and dangerous: Tolerance ↑; REBOUND INSOMNIA during withdrawal, esp. triazolam– amnesia, confusion in elderly. |
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Term
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Definition
Preanesthetic medication-- ↑ sedation & amnesia
Alcohol withdrawal: Cross-dependence
e.g. Chlordiazepoxide (Librium)
Diazepam (Valium)
e Skeletal muscle spasm and spasticity from degenerative diseases e.g. multiple sclerosis & cerebral palsy:
Diazepam (Valium)
b. I.V. anesthesia, e.g. endoscopic examinations, cardioversion : Diazepam, Midazolam
c. Anticonvulsant:
Acute, status epilepticus :
Diazepam, Lorazepam
Chronic: Diazepam, Clonazepam |
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Term
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Definition
CNS side-effects: a. Most common: Drowsiness, sedation, ataxia, impaired motor coordination, driving & judgment; anterograde amnesia. b. Start with lower dose and gradually ↑ dose; some tolerance will develop. Elderly patients are more susceptible: Confusion; anterograde amnesia; ↑ incidence of falls & hip fractures; cumulative effects - - CAUTION
“Paradoxical” psychological effects - -
excitement, anxiety, mild euphoria and even hallucinations -- ‘Disinhibitory’ effect.
3. Allergic reactions: rash, anaphylaxis-rare.
4. Teratogenic effects: Diazepam (Valium) - cleft lip and palate: It is now assumed that all BZ are potentially teratogenic. (Debated!) |
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Term
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Definition
When ingested alone, Rarely life threatening.
In combination with other sedative-hypnotics (alcohol, barbiturates, etc.), serious CNS depression and death can occur. |
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Term
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Definition
Flumazenil (Romazicon) – A competitive BZ receptor antagonist.--ANTIDOTE
Rapid reversal of sedation and improvement of psychomotor performance following IV injection of 0.2 mg.
The drug can cause confusion, agitation, anxiety and convulsions in pts that are physically dependent on BZ.
b. Β-carboline derivatives act as inverse agonists & allosteric modulators of GABA-R function → bind to BZ sites & ↓ Cl- conductance
. → anxiety & seizures. |
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Term
| Drug dependence and abuse:Tolerance |
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Definition
Psychological dependence: Relief of anxiety and euphoria can lead to craving and compulsive drug-seeking behavior.
Physical dependence: An altered physiological state which necessitates continued administration of the drug to prevent appearance of withdrawal symptoms.
c. All S-H have potential for PSYCHOLOGICAL AND PHYSICAL DEPENDENCE –and therefore, ABUSE.
Therefore, BZ have an “abuse potential” & are Controlled Substances (Schedule IV).
Rapid-onset agents (e.g. diazepam) appear to have higher abuse potential due to more intense effect and greater reinforcement of drug-taking behavior
Dependence is relatively frequent in individuals with a history of alcohol and drug abuse. |
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Term
BZ
Withdrawal Symptoms:Occur after abrupt discontinuation of BZ |
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Definition
Confusion, anxiety, agitation, restlessness, insomnia, tremor, tachycardia, convulsions -- potentially life-threatening.
Symptoms are more intense with the short-to-intermediate acting BZ, e.g. triazolam, than with long-acting drugs e.g. flurazepam
Do not ABRUPTLY discontinue.
↓ DOSE BY 10-15%/wk over 4-8 wks.
Treatment of withdrawal: substitute with diazepam or chlordiazepoxide |
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Term
BZ
Contraindications and Cautions: |
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Definition
Known hypersensitivity
History of alcoholism/drug abuse
Pregnancy
Respiratory disease
Liver impairment
Elderly: Lower the dose
Driving, operating machinery
Monitor duration of therapy - - educate patient |
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Term
BZ (Cont)
Drug interactions |
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Definition
Alcohol: ↑ CNS depressant effects
Other CNS depressants
Cimetidine (Tagament): METABOLISM |
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Term
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Definition
Structurally unrelated to the BZ; Selective BZ-R agonists.
Selectively bind to BZ sites on GABAА R
→
Possesses minimal anticonvulsant and muscle relaxant activity.
Used as hypnotic agents for insomnia; Schedule IV – Replaced older BZ.
α1 subunits – mediate sedation, amnesia
α2 & α3– mediate anxiolytic, muscle relaxation |
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Term
Zolpidem
Pharmacokinetics |
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Definition
Rapid onset of 30 minutes; half-life is 1 hr for zaleplon, 2.5 hrs for zolpidem and 6 hrs for eszopiclone.
Undergo hepatic oxidation to inactive metabolites; eszopiclone is extensively metabolized by CYP3A4 |
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Term
Benzosiazepine R agonists
Pharmacological Effects |
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Definition
Zolpidem and Zaleplon
↓ sleep latency and has little effect on total sleep time.
Minimal rebound insomnia and no withdrawal symptoms
Little or no tolerance. |
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Term
Zolpidem
Adverse Effects and drug interaction |
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Definition
Headache, somnolence, dizziness, malaise, lethargy-- less w/ Zaleplon.
Impaired coordination and memory--mild
Cautions with other CNS depressants.
Potent CYP3A4 inhibitors, such as itraconazole, clarithromycin, ritonavir: ↑ [ESZ]
Rifampin: ↓ [ESZ] |
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Term
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Definition
A melatonin receptor agonist; approved for treatment of sleep-onset insomnia.
A highly effective agonist for melatonin type 1 (MT1) and melatonin type 2 (MT2) receptors located in the hypothalamus
→
MT1 R regulates sleepiness while MT2 R may mediate the phase shifting effects of melatonin on 24-hr biological clock.– Day-shift to Night–shift. |
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Term
Ramelteon
Pharmacokinetics |
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Definition
Orally active; undergoes extensive first- pass metabolism in the liver by CYP1A2.
Plasma half-life is 1-3 hrs.
. Effects:
↓ latency to sleep by 8-15 min and ↑ total sleep time by 12-19 min. |
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Term
Ramelteon
Adverse effects: |
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Definition
Somnolence, dizziness & fatigue; hallucination & bizarre behavior.
↑ serum prolactin can result in infertility & ↓ libido.
Angioedema & anaphylaxis-- dyspnea, nausea.
NOT a controlled substance and has no abuse potential.
NO Rebound insomnia and withdrawal symptoms; teratogenic in rats. E. Drug interactions:
CYP1A2 inhibitors e.g. ciprofloxacin: ↑ level
Rifampin: ↓ Level |
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Term
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Definition
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Term
| Short-To-Intermediate-Acting Barbiturates |
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Definition
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Term
| Ultrashort-Acting Barbiturates |
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Definition
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Term
Barbiturates (Cont.)
Pharmacokinetics: |
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Definition
1. Barbiturates are well absorbed orally and
distributed widely throughout the body.
2. All barbiturates redistribute from the brain to splanchnic areas, to skeletal muscle and finally, to adipose tissue. Redistribution is important for short duration of action of thiopental and other short-acting drugs.
3. They cross the placenta & can depress the fetus.
4. Barbiturates, except phenobarbital, are metabolized in the liver and inactive metabolites are excreted in the urine. |
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Term
Barbiturates
Pharmacodynamics |
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Definition
Barbiturates bind to an allosteric site on the GABAA R-Cl- Channel →
Also act to Directly Cl- influx in the absence of GABA→ do NOT exhibit a “Ceiling Effect” |
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Term
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Definition
| General CNS depressants - - with ↑ in dose, can elicit all stages of anesthesia from mild sedation to disinhibition, anesthesia and finally respiratory depression with CV collapse and death.– Small T.I. |
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Term
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Definition
| 3. Tolerance: e.g. PB • Drug-disposition tolerance (“pharmacokinetic tolerance”) CYTOCHROME P-450 enzymes • Pharmacodynamic tolerance (“functional tolerance”) • Cross-tolerance among CNS depressant drugs |
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Term
Barbituarates
Clinical uses and Adverse Reactions |
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Definition
Anxiety: largely replaced by BZ. Anticonvulsant -- PB Anesthesia– IV Thiopental
Adverse Reactions: Similar to BZ, but more pronounced. 1. Acute: a. Side-effects: pronounced drowsiness, rebound insomnia, confusion, ataxia, paradoxical excitement. b. Overdose toxicity: Barbiturate Poisoning - - was the leading causes of death in the past. c. Allergic reactions: Skin rash, fever. |
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Term
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Definition
| a. Barbiturates have a high potential for dependence and abuse, Esp. SHORT-ACTING barbiturates. b. Physical dependence - - Withdrawal Syndrome: 1) Rebound hyperexcitability of CNS can result in convulsions followed by CV collapse and death. 2) Treatment (“detoxification”) • Re-introduced a sedative-hypnotic— preferably a long-acting agent: e.g. Diazepam • Gradually decrease dose by 10-15% /week over 4-8 weeks. |
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Term
Barbiturates (Cont)
Drug Interactions: |
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Definition
• Other CNS depressants - - additive.
• Enzyme induction:↑ metabolism:
oral anticoagulants
oral contraceptives, etc.
↑ porphyria synthesis: contraindicate in pts with acute intermittent porphyria. |
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Term
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Definition
Short-acting, lipid-soluble sedative-hypnotic
with unpleasant taste; primarily used as a
hypnotic.
Acts as a prodrug - - converted to trichloroethanol in liver.
Irritating to the GI & causes epigastric distress |
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Term
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Definition
May also interact with dopamine D2 R.
- Lacks hypnotic muscle relaxant and anticonvulsant properties of the other sedative-hypnotic drugs. • Does not potentiate the depressant effects of alcohol & other CNS depressants • Does not have abuse potential or physical dependence liability. - No rebound anxiety or withdrawal symptoms. |
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Term
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Definition
| Anxiolytic effect may require up to 7 to10 days and optimal effects may take 3 to 4 weeks.– DELAYED onset. b. May be the DOC in chronic anxiety, esp. in elderly pts and in anxious pts with a history of substance abuse. 4. Adverse Reactions: a. Less sedating than sedative-hypnotics: Minimal impairment of cognitive and psychomotor function. b. Most common: dizziness, nausea, headache and nervousness. |
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