Immediate Acting Antianxiety Agents
Benzodiazepines, Barbiturates, Alcohol, Beta Blockers (ex. Panic attacks)
Delayed Action Antianxiety Agents
Antidepressant drugs, Buspirone (ex. Medical anxiety)
Benzodiazepine Effects
Diazepam (Valium)
Relief of Anxiety (Tame animals), Sedation, Hypnosis (Large TI 70+) > Limited REM suppression, Amnesia, Anticonvulsant (Medically induced), Muscle Relaxant, Controls gagging and vomiting, Minimal effect on heart and respiration (Lost safety margin with combination of drugs; Exception = Midazolam - Between Benzodiazepine and Barbiturate), Treatment of alcohol withdrawal - chlordiazepoxide, May contribute to mild analgesia, Adjunct treatment in psychiatry
Diazepam
(Valium); Benzodiazepine; Very Fast onset; Single dose, behavioral, 6hr, multidose, blood level up to 200; Long active metabolites; Used for antianxiety, anticonvulsant, sedation and hypnotic, muscle relaxant, amnesia; Mild respiratory depression - may be lethal when combined with other depressants, Amesia; Class D pregnancy
Triazolam
(Halcion); Benzodiazepine; Fast onset; 2-3hr duration half-life; Short active metabolites; Hypnotic, Used for antianxiety, anticonvulsant, sedation and hypnotic, muscle relaxant, amnesia; Amnesia; Class X pregnancy
Midazolam
(Versed); Benzodiazepine; Fast onset; 1-12hr duration; Short active metabolites; Pre-anesthesia and conscious sedation, given parenterally; Overdose can cause respiratory depression and result in death; Amnesia; Class D pregnancy; pH4 - water/lipid soluble, More efficacy binds to receptor than Diazepam, Possible platelet aggregation, Status epilepticus/Local anesthetic induced seizures, IV, IM, Intranasal, Intrabuccal
Flurazepam
(Dalmane); Benzodiazepine; Inter med. onset; Multidose, Up to 100hr duration; Long active metabolites; Hypnotic (Similar to diazepam); Amnesia, Class X pregnancy
Alprazolam
(Xanax); Benzodiazepine; Rapid onset; 12-15hr duration; Short active metabolites; May have antidepressant properties; Not much amnesia; Class D pregnancy
Clonazepam
(Klonopin); Benzodiazepine; Slow onset; 24hr duration; Used as anticonvulsant; Partial agonist; Class D pregnancy
Chlordiazepoxide
(Librium); Benzodiazepine; Inter med. onset; 5-30hr duration; Long active metabolites; Withdrawal; Minimal respiratory depression, Amnesia
Lorazepam
(Ativan); Benzodiazepine; Int. (2hrs) onset; 10-18hr duration; Pre-op sedation in elderly; Mild respiratory depression; Amnesia, Class D pregnancy
Oxazepam
(Serax); Benzodiazepine; Int.Slow onset; 5-13hr onset; Pre-op sedation in elderly; Mild respiratory depression; Amnesia; Class D pregnancy
Benzodiazepine Warnings and Contraindications
Sedation, Amnesia, Paradoxical excitation, Allergy, Avoid use in pregnancy class - D,X, Venous thrombosis (IV - Diazepam), Increase drug metabolizing enzymes, Altered kinetics in liver or kidney failure (Black box warning), Pulmonary disease (COPD, Myesthinia gravis, Sleep Apnea), Respiratory depression - Midazolam, Narrow angle glaucoma BB, Tolerance and dependence, Drug interactions
Benzodiazepine Drug Interactions - Physiologic Stimulants and Depressants
Stimulants: Nicotine, Caffiene, Methylphenidate, Amphetamine, Cocaine
Depressants: Sedatives, Anesthetics, Opiates, Neurologics (decrease Benzodiazepine safety)
Benzodiazepine Drug Interactions - Drugs Inhibiting Metabolism of Benzodiazepines
Erythromycins (Midazolam, Alprazolam, Triazolam), Diltiazam and Verapamil (Substrates for CYP3A4), Azole Antifungals (Diazepam + Fluconazole = 2.5XDiazepam); Grapefruit juice (Midazolam, Alprazolam, Triazolam); Cimetidine, Oral contraceptive, Fluoxetine (SSRI); Propoxyphene, Propranolol; Isoniazd, Vaproic acid
Smoking with Benzodiazepine
(Antagonizes sedation)
Flumazenil
(Romazicon); Benzodiazepine Antagonist; Reverses actions (Blocks BZ receptor) (exception - Antagonizes zolpidem, Z drugs), Reverses sedation and amnesia better than respiratory depression, Relatively short acting (t1/2 =1hrs), Some use in epilepsy; 5mg/min up to 3mg/hr; May precipitate withdrawal in BZ dependent individuals or overdosed cyclic antidepressants
Zolpidem
(Ambien); Hypnotic Drug; Act on BZ1 (Omega 1), Anticonvulsant, Amnesia like Triazolam, Issues with sleep driving, eating and sex; 10mg men/5mg women; Max effect in 1.6hrs, Half life in 2.5hrs, Ambien CR; Metabolized CYP3A4 in liver (Reduce in hepatic disease, elder, no active metabolites), Absorption reduced by meals; Side effects: Drowsiness, Dizziness, Allergy, Hallucinations (Combine with SSRI), Risk of dependence; Interaction reverse by Flumazenil
ZZZ Drugs
Zolpidem, Zaleplon (Sonata), esZopiclone (Lunesta); Behaviorally similar to BZs; Pregnancy Class C; Flumazenil reverses;
Buspirone
(Buspar); Long acting Anti-anxiety; Don’t prescribe for dental anxiety; Proposed action partial agonist at serotonin 5HT receptors, Minor antagonist action on dopaminergic receptors, Increased use in psychiatry; Min sedation, Not anticonvulsant, Little risk of dependence; Drug interaction - MAO inhibitors (hypertension), RX 5-10mg
Melatonin agonists
Natural pineal hormone, OTC, Remelteon (Rozerem) - Sleep onset insomnia, MT1, MT2, MT3 agonist; Shorten sleep latency, Hormone associated with circadian rhythm, Side effects (Tasimelteon - Hetlioz - 24hr sleep-wake disorder in blind)
Suvorexant
(Belsomra CIV); Orexin antagonist, Marginally effective, Hangover sleepiness, Expensive
Phenobarbital
Barbiturate; 3 Partition coefficient, Slow absorption from stomach, Slow entry into CNS, 30% renal excretion, Terminate liver and kidney, Long duration of action, Anticonvulsant and sedative, Soluble in oil/water
Pentobarbital
Barbiturate; 50 Partition coefficient, Rapid absorption from stomach, Rapid entry into CNS, Negligible renal excretion, Termination of action in liver; Short duration of action; Hypnotic use
Thiopental
580 Partition coefficient, Rapid absorption from stomach (Not oral); Very rapid rate of entry into CNS, Negligible renal excretion, Redistribution and liver termination of action, Ultrashort duration of action, Induction anesthetic use, Moves out of brain into mass of body down concentration gradient
Barbiturate Pharmacology
Hypnotics, Sedatives, Anesthetic, Muscle relaxants, Anticonvulsant, Not analgesic (May be hyperalgesic)
Barbiturate Side Effects and Toxicity
Hangover, Paradoxical excitement (Inhibitory neurons more, Occurs before anesthesia), Decreased REM sleep, Dependence (Related to dose and duration - Severe withdrawl), Induce drug metabolizing enzymes of liver (P450, UGT) - Metabolic intolerance (Pharmacokinetic intolerance, Some pharmacodynamic, Less and less drug effect), Drug interactions (Sedation), Porphyria (ALA synthetase increase contraindication), Respiratory and cardiac depression (High dose), Allergies, Birth defects Class D
Barbiturate Examples
Nembutal = Pentobarbital, CII, Hypnotic; Luminal = Phenobarbital, CIV, Raise seizure threshold; Pentothal = Thiopental, CIII, Through paradox excitation to anesthesia; Presate = Hexobarbital, CII, Preop Sedative that is rapid
Selected Non-Barbiturate Sedative - Hypnotics
Examples: Quaaludes (CI), Glutethimide (CII), Thalidomide - Sedative, Antiinflammatory, Immunosuppressant (Apthous ulcers, leprosy, brain malignancy, major teratogen); Similar to barbiturate and toxicity
Chloral Hydrate
Short, mild sedative; Metabolized to trichoral ethanol; Used in elder and children (Diazepam or antihistamines are safer); Eliminated by liver and kidney (ONE PURPOSE) - Induce hepatic enzymes P450; Drug interaction with alcohol (Micky finn); Irritation of GI tract and poor taste; Tolerance and dependence; Possibly carcinogenic; Active metabolite - Trichloroethanol, Inactive metabolite - Trichloroacetic acid
Date Rape Drugs
Canada - Triazolam (Halcion); Outside US - Flunitrazepam (Rhoypnol), Ketamine (Ketalar) - sedation and analgesic and Phencylidine, TX - Gamma-Hydroxbutyrate (GHB) - Release of GH - Severe withdrawl
Centrally Acting Muscle Relaxants (CAMRs)
Acts on CNS poly-snaptic reflexes, Effectiveness is proportional to sedative, Important to warn patient of drowsiness, Used with NSAID analgesic in pain, Adjunct in TMJ treatment, Large TI than barbiturates (~20) but less safe than Diazepam (~70), Similar side effect and toxicity to barbiturates, Can induce liver enzymes, Tolerance and dependence, Beers list (problem in elder)
CAMR Examples
Mephenisin like - Carisoprodol (Soma), CIV; Chlorozoxazone (Paraflex); Methocarbamol (Robaxin); Pregnancy Class C
Non-Mephenisn like - Orphenadrine (Norflex); Cyclobenzaprine (Flexeril) - Antihistamine like, Structurally dissimilar, Tricyclic antidepressant - Blocks reuptake of NE and 5HT; Pregnancy Class C and B
Agents for Relief or Spasticity
MS or spasticity
Baclofen (Lioresal), Dantrolene (Dantrium), Tizanidine (Zanaflex)
Baclofen
(Lioresal); GABA-B receptor to decrease spasticity, MS or spinal cord injury, Intrathecal (spinal) route; Side effects - CNS depression, Tolerance and dependence, Teratogenic (Pregnancy Class C), Trigeminal neuralgia, Cerebral palsy, Tardive dyskinesia, Titrated dose
Dantrolene
(Dantrium); Acts in muscle - Contractile response; Used in upper spinal cord lesions that induce spasticity - Used in malignant hyperthermia; Side effects - Serious heptatoxicity, Sedation, Weakness, Respiratory depression, Diarrhea; Titrate dose, Pregnancy Class C
Tizanidine
(Zanaflex); Alpha 2 agonist - Reduce cardiac tone and relax muscles, Treats spasticity associated with MS and spinal cord injury; Flutripine - alpha 2 agonist and NMDA inhibitor; May cause pQT; Side effects - Drowsiness, PROFOUND DRY MOUTH, Mydriasis, Asthenia, Dizziness, Hypotension (Orthostatic as well), Pregnancy Class C
Natureceutical Agents with Sedative Property
Valarian, Kava Kava, Melatonin
Agents with Sedation as Side Effect
Opiates, Anticonvulsants, Antipsychotics, Tranquilizers, Tricyclic Antidepressants, Anticholinergics, Beta receptor blockers, Diuretics, Anesthetics
Agents Antagonizing Sedation Stimulants
Caffeine, Nicotine, Amphetamines, Cocaine
CNS Depressants
Alcohol, Chloral Hydrate (CIV); Solvents and glues - General - Hydrocarbons; Barbiturates (CII - Phenobarbital=IV), Nonbarbiturate Sedatives (CII), Muscle relaxants - CIV, Benzodiazepines (CIV), Cannabis (CI)
