Oct 26 Antidepressants: Efficacy and Side Effects

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Oct 26 Antidepressants Efficacy and Side
Effects
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• Drugs Used to Treat Depressive Disorders
• MAO inhibitors (last week)
• 2. Tricyclic antidepressants
• 3. Selective Serotonin Reuptake Inhibitors

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• B. Tricyclic Antidepressants (and tetracyclic)
• main treatment for depression from 1960-1980
• still among best treatments for the moderately
  to severely depressed (non-delusional) person
  80 response
• many side effects and poor safety margin
• oldest is Imipramine (Tofranil)
• 10 are on US market

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B. Tricyclic Antidepressants (and
tetracyclic) Imipramine (Tofranil) Desipramine
(Norpramin) Amitriptyline (Elavil) Nortriptyline
(Aventyl Pamelor) Clomipramine
(Anafranil) Trimipramine (Surmontil) Doxepin
(Sinequan Adapin) Protriptyline
(Vivactil) Amoxapine (Asendin) Maprotiline
(Ludiomil)
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• Pharmacokinetics
• Well absorbed orally
• Peak in 2-6 hours
• Individual differences in metabolism slow
  metabolizers and fast metabolizers (lt 40X)
• Liver metabolism by CYP2D6
• Renal clearance
• Most TCAs have half-life around 24 hours
• Allows once/day dosing for all
• Elderly may need lower doses
• Very narrow therapeutic index (6-10) with fatal
  cardiac arrhythmias as cause of death (can
  overdose on a 1 week supply)
• Plasma concentrations are monitored

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• Pharmacodynamics
• vary in ratio of blocking NE and SE reuptake
  all block NE
• also block muscarinic cholinergic receptors,
  alpha receptors for NE in PNS, and histamine
  receptors
• Actions on NE (and SE) occur within hours, but
  depression reduction takes 1-2 weeks Why?
• 1. Receptor Sensitivity Hypothesis correlates
  of depressive symptom reduction
• With repeated increase in the NE supply due to
  tricyclic action, beta adrenergic receptors for
  NE in brain down regulate by reducing in number
• Also enhanced serotonergic transmission at 5HT1A
  receptors alongside down regulation of 5HT2
  receptors

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1. Receptor Sensitivity Hypothesis correlates
of depressive symptom reduction With repeated
increase in the NE supply due to tricyclic
action, beta adrenergic receptors for NE in brain
down regulate by reducing in number Also enhanced
serotonergic transmission at 5HT1A receptors 2.
May stimulate neuronal proliferation and increase
number of neurons in limbic areas (fits with idea
that stress ultimately destroys hippocampal
neurons as part of how chronic stress may cause
depression)
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Tricyclic Action Side effects

• Reuptake blockade of NE heart arrhythmias
• Blockade of Muscarinic Receptors Dry mouth and
  eyes
• (anticholinergic effects) Urinary retention
• Constipation
• Blurred vision
• Confusion-gt Delirium
• Blockade of alpha-NE Postural hypotension
• receptors in the PNS Dizziness
• (anti-adrenergic effects) Drowsiness
• Blockade of histamine receptors Sedation
• Weight gain
• (15 lbs in 6mo)

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• Tricyclic Antidepressants Drug Interactions
• based on liver enzyme competition or induction
• Prozac and TCAs TCA levels build up to
  dangerous level
• MAOIs also dangerous stroke seizures
• Haloperidol and Phenothiazines (antipsychotics)
  can block metabolism of TCAs they build up
• Barbiturates induce metabolism - need higher
  dose of TCAs
• Phenytoin (Dilantin) Phenytoin may be elevated
  into toxic range

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• C. Selective Serotonin Reuptake Inhibitors
  SSRIs
• first one, Prozac, entered US market in 1987
• in 1988, sales of Prozac matched that for all
  antidepressants combined in 1986
• strong promotion as equal efficacy (70) but
  with fewer side effects, easier standardized
  dosing, no need for blood monitoring, and greater
  safety
• equal efficacy plus can treat people who could
  not take alternative meds due to side effects and
  personal health characteristics (70 respond) or
  who did not respond to other meds (50-60
  respond)
• also used for certain anxiety disorders, eating
  disorders, and post-addiction therapies

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SSRIs Fluoxetine (Prozac) Depression, Bulemia,
OCD Fluvoxamine (Luvox) - OCD Citalopram (Celexa)
- Depression Sertraline (Zoloft) Depression,
OCD, Panic Disorder, Paroxetine (Paxil)
Depression, OCD, Panic, Social Anxiety
Disorder All SSRIs share similar pharmacodynamic
action, efficacy, ease of dosing, and somewhat
similar side effect profiles in large group
studies (but individual differences lead some to
prefer one over another)
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• Pharmacokinetics
• oral dosing with little variability in needs
  across people
• Prozac standardized dose is 20-40 mg/day orally
  (may be elevated to 60-80 if no response)
• one Prozac death recorded at overdose of 7000 mg
  wide safety margin TI much above 100 (one
  attempted overdose of 12000, but threw up)
• does bind with blood proteins (94 of dose),
  must saturate first then efficacy in about 1 week
  (not 2 as for tricyclics)
• metabolized by liver CYP2D6 so some drug
  interactions and variability across slow vs fast
  metabolizers

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• Pharmacodynamic Action
• inhibit the serotonin reuptake transportor more
  potently than NE or DA
• far less potent binding to muscarinic receptors
  for ACh than tricyclics, hence fewer
  anticholinergic side effects
• far less potent binding to histamine receptors
  than tricyclics, hence fewer side effects of
  sedation
• need to taper dose to reduce withdrawal signs

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Side Effects ( are for Prozac) Anxiety,
nervousness, insomnia 10-15 Appetite
suppression 9 of people (not weight gain, but
loss of 5 of bodyweight) Nausea, dizziness,
headache 5 Allergic skin rash 4 Mania 1
rate (about same as for Tricyclics) Seizures -
lt1 - but not used in seizure-disordered patients
due to interactions with Phenytoin and
Tegretol Hypoglycemia during use and
hyperglycemia on withdrawal careful monitoring
or exclusion of use in diabetic patients Sexual
dysfunction impotence, ejaculatory disturbance
(perhaps less for Prozac and Luvox)
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Drug Interactions Tricyclics - enzyme
competition Carbamazepine(Tegretol)and Phenytoin
(Dilantin) Dextromethorphan MAOI can experience
fatal effects serotonin syndrome
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Exam 1. Explain the nature of action of NE and
how that explains the side effects experienced by
patients on TCAs slide 8 2. Choose an SSRI, get
the physicians insert, list the top 8 side
effects, and explain 3 based on what you know
about how serotonin or another relevant
neurotransmitter works. Your local pharmacy will
give you the physicians insert. Fluoxetine
(Prozac) Depression, Bulemia, OCD Fluvoxamine
(Luvox) - OCD Citalopram (Celexa) -
Depression Sertraline (Zoloft) Depression,
OCD, Panic Disorder Paroxetine (Paxil)
Depression, OCD, Panic, Social Anxiety Disorder