Chapter 9 Anxiolytics and Hypnotics Drugs

1. Chapter 9Anxiolytics and Hypnotics Drugs Dr. Shereen Ayoub Faculty of Medicine Al-Azhar University

2. Causes of Anxiety 1). Medical: • Respiratory • Endocrine • Cardiovascular • Metabolic • Neurologic.

3. Causes of Anxiety 2). Drug-Induced: • Stimulants • Amphetamines, cocaine, TCAs, caffeine. • Sympathomimetics • Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine. • Anticholinergics\Antihistaminergics • Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin. • Dopaminergics • Amantadine, bromocriptine, L-Dopa, carbid/levodopa.

4. Causes of Anxiety • Miscellaneous: • Baclofen, cycloserine, hallucinogens, indomethacin. 3). Drug Withdrawal: • BDZs, narcotics, BARBs, other sedatives, alcohol.

5. Introduction Hypnotics: agent that induces sleep sleeping pills, sedative medications, sedative-hypnotics • sedative-anxiolytic (antianxiety) • sedative-hypnotic • different degree of CNS depression • pharmacologic effects are dose related • small doses: sedation • larger doses: hypnosis • larger doses: surgical anesthesia (loss of sensation) • Hypnotics are usually anxyolitic and hypnotic • Not all anxiolytics are hypnotic • “situational-stress” insomnia, best treated with hypnotics

6. I. ANTIAXIETY DRUGS/SEDATIVES Various antianxiety agents (minor tranquilizers, psychosedatives) have been used throughout the ages to alleviate feelings of stress, anxiety, discomfort, etc Currently, benzodiazepines are among the most widely prescribed antianxiety drugs because of their higher therapeutic index (severe CNS depressant doses/antianxiety doses) than older agents . Figure 22-1. Dose-response curves for two hypothetical sedative-hypnotics

9. Functional Diversity of the GABAA Receptor Subunits Studies (largely in knockout animals—with specific subunit deletions or animals with variant alleles of specific subunits) indicate (strongly suggest) functional specificity of different GABAA subunits: ● α1 subunit-containing GABAA receptors:sedation ● α2 subunit-:anxiolysis. ● α3 subunit-: processing of sensory motor information related to a schizophrenia endophenotype. ● α4 subunit-: sedative, hypnotic and anesthetic effects of some agents in the thalamus. ● α5 subunit- (extrasynaptic): associative temporal and spatial memory by inhibitory modulation of activities in the hippocampus. ● β3 subunit-: sedation, hypnosis and anesthesia by, e.g., pentobarbital, propofol and etomidate, but not by the neurosteroidal anesthetic alphaxalone).

10. Benzodiazepines-Anxiolytics • chlordiazepoxide (Librium®) • diazepam (Valium®) • clonazepam (Klonopin®) • clorazepate (Tranxene®) • lorazepam (Ativan®) • oxazepam (Serax®) • alprazolam (Xanax®) • Triazolam

11. BenzodiazepinesMechanism of Action • Binds to the benzodiazepine receptors on GABA neuron • GABA is the major inhibitory neurotransmitter in the CNS • Benzodiazepines relieve anxiety through enhancement of the inhibitory activity of GABA • No antipsycotic, No analgesic, Not affect ANS

12. Generalized Anxiety Disorder Panic Disorder (alprazolam) Insomnia Schizophrenia Muscular spasms (duiazepam) Depression Seizure Disorders, epilepsy (clonazepam , diazepam) Delirium Alcohol Withdrawal Conscious Sedation insomnia (flurazepam long acting, temazepam intermediate, triazolam short) Benzodiazepines-Indications

13. BenzodiazepinesPharmacokinetic Differences Facts and Comparison

14. BenzodiazepinesPharmacokinetic Differences Facts and Comparison

15. BenzodiazepinesParenteral Administration • Used for acute anxiety/agitation, seizures, sedation • IM lorazepam & midazolam provides rapid, reliable and complete absorption • Avoid IM administration of diazepam and chlordiazepoxide due to variability in rate and extent of absorption • IV lorazepam • onset of action 1-5 minutes • IM lorazepam • onset of action 15-30 minutes • inject undiluted, deep into muscle mass

16. BenzodiazepinesParenteral Administration • Parenteral administration may produce apnea, hypotension, bradycardia, or cardiac arrest (particularly in severely ill, geriatric, unstable cardiovascular system, limited pulmonary reserve, or if drug administered to rapidly IV) • Avoid co-administration of lorazepam IM with olanzapine IM due to reports of death related to combination • Lipophylic, rapidly absorbed after oral administration • Fate: hepatic microsomal, excreted in urine as glucoronides or oxidized metabolites • Cross placenta, secreted in milk

17. Benzodiazepines-DDI • Clozapine: severe hypotension, respiratory or cardiac arrest, loss of consciousness • Cigarette smoking may decrease the sedative effects of usual benzodiazepine doses • Alcohol increases sedation • Anti-fungals may increase plasma concentration of benzodiazepines

18. BenzodiazepinesAdverse Reactions • CNS depression: drowsiness, sedation, psychomotor impairment, ataxia • Disorientation, confusion, irritability • Impairment in memory and recall • Respiratory depression • Percaution: liver disease, glaucoma, alcohole, CNS depressant

19. Benzodiazepines • Tolerance • Decrease in response to the medication effects • Dependence • Physical Dependence: when medication is stopped, withdrawal or discontinuation symptoms occur • Addiction: complex behavioral syndrome that includes an obsession with obtaining and using the drug, excessive, prolonged and harmful use despite adverse consequences, denial, rationalization, minimization and justification

20. Benzodiazepines • Abuse • Taking prescribed medication inappropriately • Usually multiple substances involved • Multiple uses for polysubstance abuse • Enhance euphoriant effects of opioids (boost methadone doses) • Alleviate withdrawal (between heroin fixes) • Temper cocaine highs • Augment alcohol effects and modulate withdrawal state

21. Benzodiazepine Withdrawal • Symptoms: insomnia, anxiety, autonomic instability (increased heart rate and BP, tremor, diaphoresis) insomnia, muscle cramps, confusion, seizures, irritability, ataxia • Time frame for emergence of symptoms corresponds to half-life of the benzodiazepine • Example: alprazolam has high risk of withdrawal- due to short half-life • To Avoid Benzodiazepine Withdrawal …. Convert to longer acting agent to taper slowly

22. Benzodiazepine Overdose • May be intentional or secondary to accumulation of doses • Symptoms: somnolence, impaired coordination, slurred speech, diminished reflexes, confusion, respiratory depression, hypotension

23. Benzodiazepine Overdose • Treatment Options • Supportive and symptomatic care • Gastric lavage • Activated Charcoal • IV hydration and maintain adequate airway • IV Flumazenil (Romazicon®): Benzodiazepine antagonist

24. Flumazenil (Romazicon®) • Benzodiazepine antagonist that competitively binds to benzodiazepine receptors • 0.2 mg IV over 30 seconds, then 0.5 mg at 1 minute interval, up to 3 mg • Rapid response: 1-2 min, up to 10 min • Duration: 1-5 hours

25. Flumazenil (Romazicon®) • Use with caution if patient ingest TCA and benzodiazepine due to risk of seizures • Monitor patients respiratory rate and cardiac status • SE: Agitation, confusion, sweating, nausea/vomiting, blurred vision, seizure • Re-sedation can occur due to short half-life, may repeat dose at 20 minutes intervals with maximum of 1 mg/dose and 3mg/hr

26. Serotonin Agonist-Buspirone • MOA: unknown, does not interact with GABA-BZ receptor complex, has partial agonist of serotonin type 1A receptor • Act on dopamine receptors • No anticonvulsant or muscle relaxant • No potential for abuse, physical dependence or withdrawal symptoms • Delayed onset of action (2-3 weeks)

27. Serotonin Agonist-Buspirone • Slow onset of action, metabolized by CYP3A4 • Increase prolactin secretion and growth hormones, cause hypothermia • SE: nausea, dizziness, headache, insomnia, agitation • Increased risk of serotonin syndrome when co-administered with SSRI

28. Other anxiolytic & hypnotic • Zolpidem • act on GABA, No anticonvulasant, No withdrawal effect • more selective for alpha-1 subunit of benzodiazepine receptor complex • orally rapid absorbed, hepatic oxidation by Cyt-P450 • SE: nausea, dizziness, headache, insomnia, agitation, GI-upset • Zaleplon • Affect psychomotor & cognitive function • Short half life 1h • Metabolized by Cyp 3A4

29. Antihistamines • Hydroxyzine (also antemetic) • 50-400 mg/d • Diphenhydramine • 25-200 mg/d • SE: sedation, dry mouth, blurred vision, constipation, urinary retention, headache • Available as injection

30. Beta-Blockers • Propranolol (Inderal®) • Atenolol (Tenormin®) • Helpful with performance anxiety by suppressing sympathetic nervous system activity and autonomic symptoms (palpitation/tremor) • SE: bradycardia, hypotension, depression, nightmares, insomnia

31. II. HYPNOTICS Hypnotics may be indicated in insomnia, the major symptoms of which include inability to initiate asleep or stay asleep once initiated (i.e., frequent/premature awakenings). Causes of insomnia include organic and psychological disorders, life style, environmental factors) A. Physiology of sleep: The awake state: maintained largely by the arousal system (reticular formation) of the brain stem. Induction and maintenance of sleep: involves (i) active inhibition of pathways involved in wakefulness and arousal (e.g., serotonergic, muscarinic, adrenergic, histaminic and dopaminergic systems), and (ii) specific brain nuclei (e.g., median raphe nucleus of the lower brain stem). 1. Stages of sleep: • Non-rapid eye movement (NREM) sleep: accounts for 70-75% total sleep duration and progresses through 4 stages: -Stage I (~5-10 min duration), Stage II (~15 min duration), Stages III and IV (Slow wave sleep; ~ 70 min) • Rapid eye movement (REM; paradoxical) sleep: a sleep phase during which most dreams occur

32. C. Management of sleep disorders • Nonpharmacological approaches: include good “sleep hygiene” (e.g., constant bedtime, avoidance of stimulants immediately prior to bedtime, etc) • Pharmacological approaches: The “ideal” hypnotic drug should have - a rapid onset of action - minimal effect on normal sleep pattern/stages - the ability to sustain sleep of normal duration - no hangover, daytime sedative effects, or memory impairment potential - minimal addiction or tolerance potential and rebound insomnia - a high therapeutic index • Effects of most hypnotics on sleep pattern: ↓ onset latency, ↑ NREM duration, ↓ REM duration • DRUGS USED IN THE MANAGEMENT OF INSOMNIA • Benzodiazepines • a. Mechanism of action: decreaseneuronal excitability via agonist effect at the GABAA receptor. • b. Classification: by duration of action as short-acting (e.g., triazolam), intermediate-acting (e.g., temazepam) and long-acting (flurazepam).

33. Barbiturates • Phenobarbital • Pentobarbital • Amobarbital • Mephobarbital • Secobarbital • Aprobarbital

34. Barbiturates, at high concentrations, directly activate the GABAA receptor to enhance chloride permeability-- in addition to allosteric modulation of the GABAA receptor - Nonspecific neuronal depression has been reported at highly very high (toxic) doses 5. Neonatal hyperbilirubinemia and kernicterus.*

37. F. Drug Interactions • Pharmacokinetic: • - ↑ metabolism of many other drugs (including barbiturates) with resulting diminution of their efficacy, due to induction of phase I (several CYPs) and Phase II (UGT, etc) enzymes. • Pharmacodynamic: • Potentiation of CNS depressant effects of other CNS depressants (including benzodiazepines, alcohol, antihistamines, etc). • G. Adverse effects • - hangovers • - hyperalgesia • - paradoxical effects: CNS excitation, especially in the elderly • - hypersensitivity: Allergic reactions occur, especially in persons with asthma, urticaria, angioedema, or similar conditions* • - respiratory and cardiovascular effects • • sub-lethal dose intoxication : ganglionic blockade  hypotension/hypothermia   respiration. • • ≥10x hypnotic doses:  central chemoreceptor sensitivity (CO2 sensing)  hypoxic drive of respiration  respiratory failure (the major cause of barbiturate-induced deaths).

38. • Barbiturate poisoning: common in suicide attempts; commonly managed by supporting respiration and urine alkalinization (via bicarbonate administration). H. Contraindications: - barbiturates and other potent inducers of cytochrome P450 are contraindicated in acute intermittent porphyria: an inherited toxicity syndrome that results in accumulation of porphyrrin and porphyrrin precursors (due to abnormal regulation of porphyrin synthesis). In affected subjects, porphyrins and their precursors accumulate and trigger neural and other symptoms • neural lesions: widespread demyelination of peripheral and cranial nerves   paralysis and widespread CNS lesions. • skin and soft tissues lesions - Other contraindications: concomitant CNS depressants

39. Sedative Hypnotics • Benzodiazepines • Barbiturate • Antihistamines • Chloral Hydrate • Ethanol

40. Benzodiazepines- Sedative/Hypnotics • Flurazepam (Dalmane®) • Onset of action 15-45 minutes • Dose: 15-30 mg QHS • More effective as you take longer due to accumulation of active metabolite with long half-life • Temazepam (Restoril®) • 10-15 hr half-life • Dose: 15-30mg QHS • Improves sleep maintenance • Slow absorption- so delayed onset of action

41. Benzodiazepines-Sedative/Hypnotics • Triazolam (Halcion®) • Short half-life • Short term treatment (7-10 days) • Dose 0.125mg-0.5mg QHS • Benzodiazepines increase total sleep time, but may prevent transition from lighter stage 2 sleep into deep, restorative (stage 3 and 4) sleep