1. Anxiolytics and Hypnotics Drugs

2. Causes of Anxiety Respiratory Endocrine Cardiovascular Metabolic
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 3). Drug Withdrawal:
Miscellaneous:
Baclofen, cycloserine, hallucinogens, indomethacin.
3). Drug Withdrawal:
BDZs, narcotics, BARBs, other sedatives, alcohol.

5. Hypnotics: agent that induces sleep
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 Dose-response curves for two hypothetical sedative-hypnotics

8. The α and β subunits exist in the receptor complex as:
homodimers (e.g., α1α1, β2β2 ) or
heterodimers (α1α5, β1β4).

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).
● Central Benzodiazepine receptors (BZDRs) can be grouped into 2 classes: BZDR1
- BZDR2
- brain regions differ in the distribution of the 2 classes of receptors
- a majority of the brain’s GABAA receptors contain the 1 subunit (which belongs to the
BZDR1class)
● BZDR1 activation enhances affinity for α1 subunit-containing GABAA receptors but
decreases affinity for an α5 subunit-containing GABAA receptor; α5-containing BZDs belong
to the BZDR2 class.
● Pharmacological/therapeutic implications of BZDR heterogeneity
- Most BZDs in clinical use interact with both BZD1 and BZD2:
- this explains the wide spectrum of adverse effects that characterize most benzodiazepines.
- Imidazopyridine hypnotics [zaleplon (Sonata), zolpidem (Ambien), zipiclone (Lunesta)]
are 1BZDR-selective

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

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

13. Benzodiazepines Pharmacokinetic Differences
Peak Plasma Level (Hour)
Speed of onset
Alprazolam
1-2
Intermediate
Chlordiazepoxide
1-4
Clonazepam
Diazepam
0.5-2
Very Fast
Lorazepam
2-4
Oxazepam
Slow
Facts and Comparison

14. Benzodiazepines Pharmacokinetic Differences
Elimination
Half Life (Hour)
Alprazolam
7-27
Chlordiazepoxide
5-30
Clonazepam
18-50
Diazepam
20-80
Lorazepam
10-20
Oxazepam
5-20
Facts and Comparison

15. Benzodiazepines Parenteral 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 minutes
inject undiluted, deep into muscle mass

16. Benzodiazepines Parenteral 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. Benzodiazepines Adverse 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 Dependence
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) Diphenhydramine
mg/d
Diphenhydramine
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 A. Physiology of sleep:
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: decrease neuronal 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. 5. Neonatal hyperbilirubinemia and kernicterus.*
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
*Because hepatic glucuronyl transferase and the bilirubin-binding Y protein are increased by the barbiturates, phenobarbital has been used successfully to treat hyperbilirubinemia and kernicterus in the neonate. The nondepressant barbiturate phetharbital (N-phenylbarbital) works equally well. Phenobarbital may improve the hepatic transport of bilirubin in patients with hemolytic jaundice.
5. Neonatal hyperbilirubinemia and kernicterus.*

37. - paradoxical effects: CNS excitation, especially in the elderly
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).
*hypersensitivity reactions may be manifested as localized swellings, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis)

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
Because barbiturates enhance porphyrin synthesis, they are absolutely contraindicated in patients with acute intermittent porphyria or porphyria variegata

39. Sedative Hypnotics Benzodiazepines Barbiturate Antihistamines
Chloral Hydrate
Ethanol

40. Benzodiazepines- Sedative/Hypnotics
Flurazepam (Dalmane®)
Onset of action minutes
Dose: 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