M5: Sedatives & Hypnotic Drugs Flashcards
Sedatives & Hypnotic Drugs
Sedatives (anxiolytics):
- Reduce anxiety
- Exert a calming effect without inducing sleep
Hypnotics:
- Produce drowsiness
- Encourage onset & maintenance of sleep
CNS Depression
Hypnotics > sedatives
Dose-response relationship:
+ → sedation
++ → hypnosis
+++ → anaesthesia
++++ → coma
+++++ → death
Treatment of Sleep Disorders
- Nonpharmacologic therapy:
- Proper diet
- Exercise
- Avoid stimulants
- Comfortable sleep environment
- Sleep at regular time - Pharmacotherapy:
- Sedative-hypnotic drugs
General Indicators of Sedative-Hypnotics
- for relief or anxiety
- for insomnia
- for sedation and amnesia before and during surgical procedures
- as a component of balanced anesthesia
- for control of ethanol or other sedative-hypnotic withdrawal states
- muscle relaxation
- aids for treatment in psychiatry
Classes of Sedative-Hypnotic Drugs
- Benzodiazepines
DRUG = Diazepam - New Hypnotics: Nonbenzodiazepiens, Z-drugs)
DRUG = Zolpidem - Barbiturates
DRUG = Phenobarbital
OTHERS:
4. Melatonin Receptor Agonists
DRUG = Ramelteon
- Orexin Antagonist
DRUG = Suvorexant - 5-HT Receptor Agonist
DRUG = Buspirone - Antihistaminics
DRUG = Diphenhydramine
GABAA Receptor
- Ligand: GABA
- Mediates inhibitory synaptic transmission in the CNS
- Target of barbiturates, benzodiazepines, and newer hypnotics
BENZODIAZEPINES
- Properties
- Mechanism of Action
- Classification
- Pharmacokinetics
- Pharmacological Effects
- Adverse Effects
- Tolerance & Dependence
- Drug Interactions
PROPERTIES:
1. Widely used sedative-hypnotics
2. Commonly used: 1990s
3. Chemical structure:
Heterocyclic 1,4-benzodiazepine ring system
Chemical Structure: Triazole ring
4. Available: 1960
MECHANISM OF ACTION:
1. Act allosterically
2. Bind specific site on GABAA receptor (distinct from GABA binding site) →
Increase receptor affinity to GABA →
Facilitate GABA-mediated Cl– channel opening frequency
Increase membrane hyperpolarization →
CNS depression
CLASSIFICATION:
1. Short Acting = triazolam
2. Intermediate Acting = alprazolam
3. Long Acting = diazepam
PHARMACOKINETICS:
1. Absorption through GIT:
- Variable rate – e.g., triazolam is extremely rapid
- Gastric HCl converts clorazepate (prodrug) nordiazepam (active form)
- Metabolism:
In the liver:
- Phase 1: oxidation by P450 isozymes specially CYP3A4
- Phase 2: conjugation glucuronides
Excretion:
- In urine
Administration:
- oral, IM, IV, rectal
Metabolism and Excretion:
**Active metabolites
Desmethyldiazepam = nordiazepam
PHARMACOLOGICAL EFFECTS:
1. Sedation
2. Hypnosis
3. Anesthesia
- Decline when taken regularly for 1-2 weeks
4. Anticonvulsant effect
5. Muscle relaxation
6. Respiratory depression
7. Cardiovascular depression (dangerous)
ADVERSE EFFECTS:
1. Common:
- Drowsiness, dizziness, alertness & concentration
- Impaired coordination
- Decrease in libido & ED
- Impaired memory – anterograde amnesia
- Paradoxical reactions – e.g., seizures, aggression
- Overdose & Acute Toxicity:
- CNS: drowsiness, slurred speech, nystagmus, ataxia, coma
- Respiratory depression
- CVS: hypotension, cardiac arrest
TOLERANCE:
- Develops with long-term use
- Shown mainly with sedative-hypnotic, muscle relaxant & anticonvulsant effects
- Partial cross tolerance
- Mechanism:
- Not well understood
- In animals:
downregulation of
receptors
DEPENDENCE:
- Arises from perceived relief of anxiety, euphoria, disinhibition & promotion of sleep
- Psychological Dependence:
Simple neurotic behaviour - Physiologic Dependence:
Altered physiological state
Requires continuous administration to avoid withdrawal (abstinence) syndrome - Withdrawal Syndrome :
Symptoms range from rebound anxiety to seizures
To prevent: avoid abrupt drug cessation
Withdrawal Symptoms:
1. Psychological:
- Anxiety
- Restlessness
- Irritability
- Insomnia
- Headaches
- Poor concentration
- Depression
- Social Isolation
- Physical:
- Sweating
- Heart Palpitations
- Muscle tension
- Tightness in the chest
- Difficulty breathing
- Tremors
- Nausea
- Vomiting or diarrhea
DRUG INTERACTIONS:
Additive CNS depression with:
INCREASE IN:
- Other CNS depressants
- Alcohol
- Opioids
- Anticonvulsants
- Antidepressants
- Antihistamines
Antagonist - Flumazenil
- 1,4-benzodiazepine derivative
- Competitive antagonist with high affinity to benzodiazepine binding site on GABAA receptor
- Blocks many actions of benzodiazepines & Z-drugs
- Used in the treatment of overdose (antidote)
- Administration: IV – dose should be repeated (short t1/2)
NEWER HYPNOTICS (Z-DRUGS)
- Mechanism of Action
- Pharmacological Effect
- Pharmacokinetics
- Administration
DRUGS = Zolpidem, Zaleplon, and Eszopiclone
MECHANISM OF ACTION: similar to benzodiazepines
PHARMACOLOGICAL EFFECT:
similar to benzodiazepines
Strong hypnotics but weak sedatives
PHARMACOKINETICS:
1. Zaleplon:
- Tmax (hours) = <1
- t1/2 = 1-2
- Metabolized via aldehyde dehydrogenase
- Zolpidem
- Tmax (hours) = 1-3
- t1/2 hours = 1.5 - 3.5
- No active metabolites
BARBITURATES:
- Properties
- Chemical Structure
- Mechanism of Action
- Medical Uses, Adverse Effects, Drug Interactions
PROPERTIES:
- Available: 1903
- Dependence potential recognized: 1950s
- Mostly replaced by benzodiazepines:
- Significant higher risk of overdose
- Lack of antidote
CHEMICAL STRUCTURE:
- Derived from barbituric acid
MECHANISM OF ACTION:
1. Act allosterically
2. Bind specific site on GABAA receptor (distinct from GABA & benzodiazepines binding sites) →
Increase receptor affinity to GABA →
Increase duration of GABA-mediated Cl– channel opening →
Increase membrane hyperpolarization → CNS decrease +
GABA agonist effect (high dose)
Excitatory AMPA (Glutamate) receptor inhibition
MEDICAL USES, ADVERSE EFFECTS & DRUG INTERACTIONS:
- Medical Uses:
- General anesthetics – e.g., thiopental – IV
- Anticonvulsants
- Insomnia (replaced by benzodiazepines)
e.g., phenobarbital – oral - Adverse Effects & Drug Interactions:
- Similar to benzodiazepines
- Dependence > benzodiazepines
- Hepatic microsomal enzyme induction → increase in metabolism of drugs
- More linear dose-response → increase in toxicity
SEDATIVE-HYPNOTICS: General Consideration
- Lipophilic drugs
- Pregnancy:
Avoid in:
- 1st trimester – teratogenic effect
- 3rd trimester – may induce premature labour
- Z-drugs are safer than benzodiazepines (lack of data)
- Antihistamines might be a reasonable choice in early pregnancy - Dependence & withdrawal symptoms:
- Barbiturates > benzodiazepines > Z-drugs
- Short-acting > long-acting drugs
- Cross dependence can help prevent withdrawal symptoms – e.g., longer-acting drugs alleviate withdrawal symptoms by shorter-acting drugs
