Antipsychotics

1
Antipsychotics

• Chris Pelic M.D.
• Associate Dean for Students
• Assistant Professor of Psychiatry
• Medical University of South Carolina

2
Objectives

• Learn the dopamine hypothesis of schizophrenia
• Learn basic proposed mechanism of antipsychotics
• Understand the difference between first
  generation and second generation antipsychotics
• Learn common side effects of antipsychotics

3
History of Antipsychotics

• Early 1950s accidental discovery
• Found antihistamine chlorpromazine
  (phenothiazine) exerted antipsychotic effects.
  Was used as anxiolytic before surgery
• Through side chain substitutions, more drugs
  developed
• ?13 first generation antipsychotics are still
  available
• Atypical second generation drugs - 1989

4
History Continued...

• 1959 serendipitous discovery of Clozaril
• Used in 1972 in Europe but withdrawn 3 years
  later after several cases of agranulocytosis and
  death
• Re-introduced in 1988 after trial demonstrated
  its clinical superiority but required monitoring
• Other atypical agents soon followed
• Most consider atypical agents first line tx

5
Antipsychotic therapyHistorical perspective in
theUnited States
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Dopamine Hypothesis of Schizophrenia

• from Michael D. Jibson, M.D., Ph.D.
• Ira D. Glick, M.D ASCP CURRICULUM edition 4

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Major Dopamine Pathways

• 1. Nigrostriatal tract- (extrapyramidal pathway)
  begins in the substantianigra and ends in the
  caudate nucleus and putamen
• 2. Mesolimbic tract - originates in the midbrain
  tegmentum and innervates the nucleus accumbens
  and adjacent limbic structures
• 3. Mesocortical tract - originates in the
  midbrain tegmentum and innervates anterior
  cortical areas
• 4. Tuberoinfundibular tract - projects from the
  arcuate and periventricular nuclei of the
  hypothalamus to the pituitary

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Major Dopamine Pathways

• Nigrostriatal tract- extrapyramidal pathway
• Mesolimbic tract positive symptoms
• Mesocortical tract positive symptoms/cognition
• Tuberoinfundibular tract - prolactin

9
Dopamine Hypothesis

• Clinical efficacy of antipsychotics correlates
  with dopamine D2 blockade
• Psychotic symptoms can be induced by dopamine
  agonists
• from Michael D. Jibson, M.D., Ph.D., Ira D.
  Glick, M.D ASCP CURRICULUM edition 4

Carlsson A, Am J Psychiatry 1978135164 Seeman
P, Synapse 19871133
10
Dopamine Hypothesis

• Normal subjects have 10 of dopamine receptors
  occupied at baseline
• Schizophrenic subjects have 20 of dopamine
  receptors occupied at baseline
• from Michael D. Jibson, M.D., Ph.D., Ira D.
  Glick, M.D ASCP CURRICULUM edition 4

Laruelle M, Quart J Nuc Med 199842211
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Dopamine and Antipsychotics

• 65 D2 receptor occupancy is required for
  efficacy
• 80 D2 receptor occupancy is correlated with EPS
• Shorter time of D2 receptor occupancy is
  correlated with lower EPS
• from Michael D. Jibson, M.D., Ph.D., Ira D.
  Glick, M.D ASCP CURRICULUM edition 4

Kapur S Remington G, Biol Psychiatry 200150873
12
Serotonin

• Atypical antipsychotics are high in serotonin
  activity
• Serotonin agonists (e.g., LSD) produce psychotic
  symptoms
• Dopaminergic activity is modulated by serotonin

13
Target Symptoms

• Active psychosis
• most common reason for hospitalization
• most responsive to medications
• Hallucinations, delusions, paranoid,
  disorganization
• Negative symptoms
• poor response to medication
• progress most rapidly during early acute phases
  of illness
• alogia, poor grooming, flat affect, poor
  motivation

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Pharmacologic Treatment of Psychosis
15
Who Gets An Antipsychotic?

• FDA indications schizophrenia, schizoaffective
  d/o, bipolar disorder, irritability associated
  with autism, tourettes
• OFF LABEL PTSD, MR, ODD, ADHD, Personality
  disorders
• Hiccups, motion sickness, pruritus
• Delirium, aggression, agitation, anxiety
• Many of the above uses are off label but
  accepted. Inform pt and family

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How Do They Work?

• Dopamine receptor blocking in the brain
• (5 receptor subtypes with D1, D2, D3, D4
  playing most significant role)
• 1. Full antagonist most agents
• 2. Partial agonist aripiprazole
• Serotonin receptor blocking in the brain
• (5HT2a, 1a, or 5HT2c appears to play a role)
• 1. Full antagonist most atypical agents
  with
• different ratios
• 2. Partial agonist - aripiprazole
• Other receptors acetylcholine, histamine, NE,
• alpha receptors, and glutamate

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How Do They Work? continued

• Different meds work on a different combination of
  receptors
• In general, atypical agents work at D1, D2, D4,
  5HT2a or 5HT2c, receptors as an antagonist or
  partial agonist (aripiprazole)
• Typical agents mostly work as D2 antagonists
  non-selectively

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What Do Antipsychotics Do Clinically?

• Reduce hallucinations
• Reduce delusions?? Probably not much.
• Reduce paranoia
• Calm patient and reduce agitation
• PRODUCE SIDE EFFECTS (e.g. sedation, weight gain,
  orthostatic hypotension, EPS, etc)

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• THE MEDS

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Typical Agents

• Typical agents1st generation
• 1. Older
• 2. Cheaper
• 3. Work more on positive symptoms
• 4. Primarily D2 blockade and anticholinergic
• activity
• 5. High potency vs Medium vs Low potency

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Dopamine D2 Effects

• Possible Benefit
• Antipsychotic effect

• Possible Side Effects
• EPS
• dystonia
• parkinsonism
• akathisia
• tardivedyskinesia
• Endocrine changes
• prolactin elevation
• galactorrhea
• gynecomastia
• menstrual changes
• sexual dysfunction

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What Side Effects Can They Produce?

• Parkinsonian effects changes balance between
  cholinergic and dopaminergic neurons (dopamine
  blockade leads to excess of cholinergic
  influence)
• Tardivedyskinesia
• Akathisia/akinesia
• Orthostatic hypotension
• Constipation/Urinary retention
• Weight gain
• Confusion
• Sexual dysfunction
• Seizures
• NMS
• Metabolic problems (glucose, lipids)

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Reversible Extrapyramidal signs (EPS)

• Akinesia (lack of movement, Parkinson-like)
• Dystonic Reaction (muscle spasms of face, neck,
  back)
• Dyskinesia (Blinking or twitches)
• Akathisia (Inability to sit still)

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Irreversible EPS

• TardiveDyskinesia
• Hyperkinesia (lingual or facial)
• Blinking
• Lip smacking
• Sucking or chewing
• Rolls or protrudes tongue
• Grimaces
• Choreathetoid extremity movement
• Clonic jerking fingers, ankles, toes
• Tonic contractions of neck or back

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How Do You Treat Side Effects?

• Anticholinergic meds - benztropine,
  diphenhydramine for EPS
• Dopamine agonists amantadine for EPS
• Beta-blockers - propranolol for akathisia
• Reduce the dose
• Change meds
• Stop the neuroleptic (NMS, ?TD)
• You dont use them to the patients benefit
  (e.g. sedation, weight gain)

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Neuroleptic Malignant Syndrome

• Medical emergency
• ¼ cases culminate in coma, stupor, and death
• Unexplained hyperthermia with an increase in
  muscle tone
• Usually after med increase or initiation
• Elevated CK, elevated WBC, stiffness, fever,
  autonomic instability, confusion
• Treat with dantrolene, bromocryptine fluids,
  benzos, and maybe ECT
• Dont rechallenge before 2 weeks

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Typical Agents

• Phenothiazines
• 1. Aliphatic, e.g. chlorpromazine (thorazine) and
  trifluopromazine (vesprin).
• 2. Piperazine, e.g. perphenazine (trilafon),
• trifluoperazine(stelazine), fluphenazine
• (prolixin), acetophenazine (tindal)
• 3. Piperidine, e.g. thioridazine (mellaril),
  
• mesoridazine(serentil)

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Typical Agentscontinued...

• Thiothixenes
• 1. Thiothixene (Navane)
• 2. Chlorprothixene (Taractan)

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Typical Agentscontinued...

• Butyrophenones
• 1. Haloperidol (Haldol)
• Dihydroindolines
• 1. Molindone (Moban)
• Diphenylbutylpiperidines
• 1. Pimozide (Orap)

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Reclassified By Potency

• High Potency
• 1. Haldol (Haloperidol)
• 2. Prolixin (Fluphenazine)
• 3. Stelazine (Trifluoperazine)
• 4. Orap (Pimozide)
• 5. Navane (Thiothixene)

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Reclassified By Potency

• Medium Potency
• 1. Inapsine (Droperidol)
• 2. Loxitane (Loxapine)
• 3. Moban (Molindone)
• 4. Trilifon (Perphenazine)

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Reclassified By Potency

• Low Potency
• 1. Thorazine (Chlorpromazine)
• 2. Mellaril (Thioridazine)
• 3. Serentil (Mesoridizine)

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Facts about antipsychotics

• MOST antipsychotics can prolong the Qtc interval
  of the heart (avoid if gt500msec)
• MOST antipsychotics lower seizure threshold
• Typical antipsychotics more problems with EPS,
  anticholinergic effect
• Atypical antipsychotics more problems with
  metabolic side effects

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4 Typical prototypes

• Haloperidol High potency (high D2 blockade,
  lower anticholinergic effects)
• Fluphenazine - High potency
• Thorazine low potency (lower D2 blockade,
  higher anticholinergic effects)
• Thioridazine low potency

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Haloperidol- HALDOL

• Butyrophenone
• EPS common but sedation, hypotension not
• Comes in tabs, elixir, shot (IM or IV)
• Has depot form q4weeks
• High potency
• Most commonly used 1st generation antipsychotic

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Fluphenazine- PROLIXIN

• Piperazine
• Most potent
• High potential for EPS
• Has IM and IM 2 week depot shot
• Low potential for sedation

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Chlorpromazine -THORAZINE

• Sedating/low EPS risk
• Potential for severe hypotension (be very careful
  with IV use)
• Low potency
• Very anticholinergic
• Used for intractible hiccups

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Thioridazine- MELLARIL

• Piperidine
• Low potency high anticholinergic activity
• High likelihood of QTc prolongation
• Associated with retinitis pigmentosa
• Not used clinically much

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Atypical Agents (2nd generation)

• Atypical agents
• 1. Newer
• 2. More expensive
• 3. May work on both positive and negative
• symptoms
• 4. Lower incidence of EPS, TD, NMS
• 5. Act on D1, D2, D4, serotonin receptors (as
• well as NE, glutamate, histamine)

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Potential clinical implications of receptor
activities of antipsychotics
41
Relative receptor binding affinities of atypical
antipsychotics

• ZiprasidoneRisperidoneOlanzapineQuetiapineClozapin
  e
• D2
• 5-HT2A
• 5-HT2C
• 5-HT1A
• 5-HT1D
• ?1-adrenergic
• M1-muscarinic
• H1-histaminergic
• 5-HT/NE reuptake (-5-HT)(NE) (-5-HT)(NE)
  
• Affinity represented as very high,
  high, moderate, low, negligible.
• Bovine binding affinity rat synaptosomes all
  other affinities human.

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3Atypical Prototypes

• Clozapine
• Risperidone
• Aripiperazole

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Clozapine(CLOZARIL) 1989

• Dibenzodiazepine class (CAT B)
• (D1, D2, D4, 5HT2 activity)
• Gold standard - more selective D blockade
  serotonin activity
• Reserved for more refractory cases
• High metabolic risk
• Low EPS, may help TD
• Risk for seizures (dose dep), hypotension, weight
  gain, sialorrhea
• Risk of agranulocytosis is 1
• Requires weekly WBC count looking at WBC/ANC

44
Risperidone - RISPERDAL1994

• D2 blocker, 5 HT2a blocker
• Above 6mg - EPS more likely (acts more like
  haldol)
• Potential for weight gain, sedation, orthostatic
  hypotension, sexual dysfunction
• Comes in tabs, dissolvable tabs (mtab), elixir,
  LONG ACTING (Consta)
• Known to increase prolactin levels
• Metabolic risk

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Aripiperazole-Abilify 2002

• Partial agonist of dopamine and serotonin
• Usual effective dose is starting dose of 15mg
• High potential for akathisia
• Dosed in am with food
• Has IM form for acute agitation
• Little metabolic risk
• ? About efficacy or speed of action

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Paliperidone INVEGA 2006

• Major active metabolite of risperidone
• FDA approved for schizophrenia
• OROS delivery system (like concerta)
• Works similarly to risperdal. Marketed as having
  less side effects?

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Olanzapine- ZYPREXA 1996

• Thienobenzodiazepine class (similar to clozaril)
• Very sedating and high likelihood of significant
  weight gain 10-100lbs
• Monitor lipids, glucose
• Comes in tab, dissolvable Zydis form, IM
• Very effective

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Quetiapine- SEROQUEL 1997

• Sedating, potential for orthostatic hypotension,
  and weight gain
• Very low EPS/TD risk
• Often used off label

49
Ziprasidone- GEODON 2001

• Benzothiazolyl - piperazine class
• ?Potential for QTc prolongation but not necessary
  to do EKG if no h/o cardiac disease
• Low side effects/Take with food (will lower blood
  levels if you dont). Food400calories
• Low doses you see activation, high doses you get
  dopamine blockade

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Depot Antipsychotics

• Haloperidol (Haldol) decanoate
• Fluphenazine (Prolixin) decanoate
• Risperidone depot (RisperdalConsta)

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Depot Antipsychotics

• Advantages
• Ensured compliance
• Lower total doses compared with oral medication
  may reduce side effects
• Disadvantages
• Poor patient acceptance
• Minimal flexibility in dosing

52
Anxiolytic and Sleep Medications(Sedative
hypnotics)

• Christopher Pelic M.D.
• Associate Dean for Students
• Medical University of South Carolina

53
Special thanks/credit

• Some slides adapted from
• David N. Osser, M.D.
• Harvard Medical School
• ASCP Model Curriculum
• December, 2007 Version

54
Objectives

• Introduction to anxiety
• Understand mechanism, effect, and side effects of
  barbiturates, benzodiazepines, buspirone,
  propranolol, hydroxyzine, and other antianxiety
  agents
• Learn basic agents for sleep disorders (e.g.
  zolpidem)

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The problem of anxiety

• Anxiety feeling of apprehension and fear
• 25 lifetime prevalence of any anxiety disorder
  (Nat. Co-morbidity Survey 1994)
• Many more have situational anxiety related to
  normal fears and use of medication for short
  term relief can be appealing. (Pomerantz JM, 2007)

56
History

• Alcohol, bromide, and paraldehye preparations
  were initially used
• 1903 barbital was first barbiturate used but
  toxicity and dependency issues developed
• 1950 meprobamate was developed (non-barbiturate)
  but highly addicting

57
History continued

• Late 1950s Librium (chlordiazepoxide) first
  benzodiazepine
• Few years later Valium (diazepam) was developed
  with 3-10 X potency
• Early 1960s Imipramine (TCA) was found to be
  useful for panic disorder
• MAOIs began being looked at for anxiety
• SSRI and Buspirone used in late 80s and 90s

58
Role of Medication in Anxiety

• Due to stigmatization, patients often seek a
  quick, private remedy.
• Self-medication with alcohol and drugs of abuse
  is common, and reinforced by social acceptance
  and even by psychiatric clinicians

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Barbiturates

• Used early in 20th century for anxiety and
  sedative hypnotic
• Now rarely used as anticonvulsant and anesthetic
• Steep drug response curve dangerous
• Induces liver enzymes (e.g. other drugs)
• Potential for dependence/withdrawal
• Withdrawal can be life threatening
• Work on GABAa receptor Increases Cl-
• Phenobarbital, thiopental

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Barbiturates continued

• Contraindicated in porphyria

61
Phenobarbital

• Long acting
• Rarely but used as anticonvulsant
• Slow onset
• One of most used barbiturates
• Notorious inducer of other medications

62
Pentobarbital

• Intermediate acting

63
Thiopental

• Highly lipid soluble
• Rapid onset
• Short duration of action
• IV general anesthetic

64
Benzodiazepines

• Work on GABA a specific benzo. site on this
  receptor
• Leads to hyper-polarization
• BZ1 receptor (w1) sedation and hypnosis
• BZ1 receptor (w2) cognition, motor functioning
• -
• Replaced barbiturates
• CLINICAL USES anxiety, muscle relaxation,
  hypnosis, anticonvulsant, catatonia, preop, sleep

65
Benzodiazepines

• Long Acting Benzodiazepines
• Chlordiazepoxide (Librium)
• Diazepam (Valium,)
• Flurazepam (Dalmane)
• Chlorazepate (Tranxene)
• Clonazepam (Klonopin)
• Quazepam (Doral)
• Halezapam (Paxipam)
• Medium Acting Benzodiazepines
• Lorazepam (Ativan)
• Temazepam (Restoril)
• Short acting Benzodiazepines
• Oxazepam (Serax)
• Alprazolom (Xanax)
• Triazolam (Halcion)
• Estazolam (Prosom)
• Midazolam (Versed)

66

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Benzos anxiolytic action

• Action within limbic system
• Mainly used for short term
• Abuse/dependence potential
• Tolerance/withdrawal potential

68
Benzos hypnotic action

• Decreases sleep latency
• Use in caution with pts with COPD, OSA

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Benzos muscle relaxation

• Inhibition of polysynaptic transmission at spinal
  and suprasinal locations
• Diazepam used most often in this capacity for
  back spasms

70
Benzos anticonvulsant action

• Used in preventing or abolishing seizures
• Often used for status
• IM (lorazepam) or IV (diazepam) preferred

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Benzos - sedation

• Used before procedures
• Facilitates anesthesia
• Conscious sedation
• Can produce anterograde amnesia

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Factors that effect selection

• Lipid solubility
• Half life
• Short half life/High Lipid solubilityGood PRN
  but more addicting
• Long half life/Less Lipid solubilityless
  addicting and worse PRN

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Diazepam - VALIUM

• Long half life/highly lipid solubility
• Used for withdrawal
• Used for PRN anxiety
• Can accumulate secondary to redistribution
• Used IV for seizures
• Used for back/muscle spasms

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Lorazepam - ATIVAN

• Drug of choice for status epilepticus (IM)
• Highly lipid solubility but short half life
• Used PRN anxiety
• Used a lot for alcohol withdrawal

75
Alprazolam - XANAX

• High potential for addiction
• High lipid solubility/short acting
• Requires frequent dosing
• Used mainly for PRN uses (e.g. panic attacks)

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Clonazepam - KLONOPIN

• More selective anticonvulsant activity
• Used for longer term management of anxiety,
  mania, restless leg syndrome

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Temazepam - RESTORIL

• Quick onset
• Mid acting benzodiazepine
• Used most for sleep

78
Midazolam - VERSED

• Used most perioperatively
• More rapid elimination
• Quick onset and more potent than diazepam

79
Flumazenil

• Benzodiazepine antagonist
• Used to reverse overdose or anesthesia
• Can precipitate seizures/acute withdrawal
• Rarely used

80
Benzodiazepines Metabolism

• Glucuronidation
• lorazepam oxazepam, temazepam, alprazolam,
  triazolam (used in pts with liver disease)
• Nitroreduction
• clonazepam
• Demethylation and oxidation diazepam,
  chlordiazepoxide, chlorazepate

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Some Drug Interactions with Benzodiazepines

• Cytochrome inhibitors metoprolol, propranolol,
  disulfiram, omeprazole, erythromycin, fluoxetine.
  
• Anticholinergics additive cognitive impairment
  especially in the elderly
• Additive CNS depression with other sedatives
• Clozapine added to ongoing BZ may rarely give
  severe sedation, delirium, respiratory
  depression/death

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Benzodiazepine Dose Equivalencies

• oxazepam (Serax) 15 mg
• diazepam (Valium) 5 mg
• lorazepam (Ativan) 1 mg
• alprazolam (Xanax) 0.5 mg
• clonazepam (Klonopin) 0.25 mg

83
Benzodiazepine Withdrawal Syndrome

• Anxiety
• Agitation
• Tremulousness
• Insomnia
• Dizziness
• Headaches
• Seizures
• Exacerbation of psychosis

84
Benzodiazepine Side Effects

• Dependence, addiction, abuse by far most common
  in alcoholics and other drug abusers
• Elderly watch for increased fall risk with long
  half-life drugs
• Memory impairment
• Impaired motor coordination, auto driving in
  simulated driving tests
• Disinhibition/violence more uncommon than
  presumed
• Depression

85
Pregnancy Risk with Benzodiazepines

• Pregnancy risk D level due to oral cleft,
  except clonazepam C
• Most recent studies show they are fairly safe but
  old studies suggested cleft palate

86
Buspirone - Properties

• 5HT1a partial agonist
• No sedating, muscle-relaxant, sexual, or
  anticonvulsant effects
• No abuse potential
• Used mainly for generalized anxiety disorder
• Does not suppress respiration so is useful for
  anxiety in COPD patients
• No impairment of cognition or motor coordination

87
Buspirone - prescribing

• Has some efficacy in depression at 40 mg/d
  (STARD)
• Side effects headache, insomnia, jitteriness,
  and nausea.

88
Propranolol for performance anxiety(off label
use)

• Propranolol 30 minutes prior to the event. Try
  test doses before
• Side effects hypotension, bradycardia,
  dizziness, asthma, fatigue. Evidence contradicts
  idea that betablockers mask hypoglycemia
  symptoms. (Chalon, 1999)
• Half-life 3-6 hours
• Lipophilic so crosses into brain
• Not useful for social phobia, generalized type

89
Other Unlabeled Drugs used for Anxiety

• Anticonvulsants e.g. gabapentin, valproate,
  lamotrigine, topiramate
• Pregabalin (Lyrica) got non-approvable letter
  from FDA in 2004 for GAD but approved in Europe
  in 2006.
• Tiagabine (Gabatril) didnt separate from
  placebo in unpublished studies.
• MAOIs
• Antihistamines e.g. hydroxyzine, diphenhydramine
• Prazosin and terazosin (Alpha-1 antagonists)

90
Sleep Aids

• Benzos
• Non-benzo benzos
• Ramelteon
• Antihistamines

91
Non-benzo, benzos

• Chemically unrelated to benzodiazepines
• Zolpidem - Works on BZ1 receptor
• Eszopiclone works on GABA a receptor
• Used for insomnia
• Intended for short term use or PRN

92
Ramelteon

• Works as melatonin for sleep
• Does not work immediately