Antidepressants Flashcards
Symptoms Associated With Depression
Sadness, Despair, Guilt, Pessimism Decrease in energy Decrease in sex drive Insomnia and fatigue Thoughts of death and suicide Mental slowing, lack of concentration
Treatment of Depression
Antidepressant Pharmacology
First introduced 40 years ago
Also used for treatment of other disorders including:
Anxiety disorders, dysthymia, chronic pain and behavioral problems
Evolution of drug therapy
Antidepressants discovered accidentally while investigating antipsychotic efficacy of modifications of phenothiazines
Imipramine - first antidepressant discovered
Around the same time, monoamine oxidase inhibitors were identified
Second generation antidepressants identified to address problems with first generation antidepressants
Late 1980’s- SSRI’s were developed
Now working on other antidepressant treatments
Tricyclic Antidepressants
Effectively relieve depression with anxiolytic and analgesic action
First choice for treatment of depression
Pharmacological properties
Block presynaptic NE reuptake transporter
Block presynaptic 5-HT reuptake transporter
Block postsynaptic histamine receptors
Block postsynaptic ACh receptors
Imipramine and Amitriptyline
Prototypical TCAs
Desipramine (Norpramin) – pharmacologically active intermediate metabolite of imipramine (Tofranil)
Nortriptyline (Pamelor) – an active intermediate metabolite of amitriptyline (Elavil)
Clinical Limitations of TCA’s
Slow onset of action
Wide variety of effects on CNS (adverse side effects):
Can directly impair attention, motor speed, dexterity, and memory
Cardiotoxic and potentially fatal in overdoses
Pharmacokinetics
Well absorbed upon oral administration Relatively long half-lives Metabolized in the liver Converted into intermediates that are later detoxified Readily cross the placenta
Pharmacological Effects of TCA’s
In CNS: blocks presynaptic 5-HT, DA and NE receptors
Blocking of ACh receptors leads to dry mouth, confusion, blurry vision and mental confusion
Blocking of histamine receptors leads to drowsiness and sedation
Effects on the PNS include: cardiac depression, increased electrical irritability, can be life threatening with OD
Monoamine Oxidase Inhibitors (MAOI’s)
Long acting, irreversible inhibitors of monoamine oxidase
Have been used since the 1950’s but have a controversial past
Has potential for serious side effects and potentially fatal interactions with other drugs and food
Avoid with tyramine containing products => hypertensive crisis
MAO is one of two enzymes that break down neurotransmitters 5-HT and NE
Two types
MAO-A: inhibition causes antidepressant activity
MAO-B: inhibition causes side effects
Irreversible MAOI’s
Nonselective: block both A and B types
Form a permanent chemical bond with part of the MAO enzyme (enzyme function returns only as new enzyme is biosynthesized)
Have a rapid rate of elimination, excess drug is rapidly metabolized
Inhibition occurs slowly
Ex: phenelzine (Nardil), tranylcypomine (Parnate), isocarboxazid (Marplan)
Second Generation (Atypical) Antidepressants
Developed in the late 1970’s and 1980’s
Maprotiline – one of the first clinically available antidepressants, has a long half life and blocks NE reuptake
Amoxapine – primarily a NE reuptake inhibitor
Trazodone – not a potent blocker of NE or 5-HT, its active metabolite blocks a subclass of 5-HT receptors
Bupropion – selectively inhibits DA reuptake, used for ADHD, side effects include: anxiety, restlessness, tremors, and insomnia
Second Generation (Atypical) Antidepressants Continued
Clomipramine – structurally a TCA but exerts inhibitory effects on 5-HT reuptake
Desmethyclomipramine – active metabolite; classified as a mixed 5-HT and NE reuptake inhibitor
Used to treat OCD, depression, panic disorder and phobic disorders
Venlafaxine – also a mixed 5-HT and NE reuptake inhibitor
Also inhibits the reuptake of DA
Produces improvements in psychomotor and cognitive function
Serotonin - Specific Reuptake Inhibitors (SSRI’s)
Available for the past 15 years
Allows for more serotonin to be available to stimulate postsynaptic receptors
Available to treat depression, anxiety disorders, ADHD, obesity, alcohol abuse, childhood anxiety, etc.
SSRI’s
Fluoxetine (Prozac) – first SSRI available, long half life, slow onset of action, can cause sexual dysfunction, anxiety, insomnia and agitation
Sertraline (Zoloft) – second SSRI approved, low risk of toxicity, few interactions, more selective and potent than Prozac
Paroxetine (Paxil) – third SSRI available, more selective than Prozac, highly effective in reducing anxiety and posttraumatic stress disorder (PTSD) as well as OCD, panic disorder, social phobia, premenstrual dysphoric disorder, and chronic headache
SSRI’s continued
Fluvoxamine (Luvox) – structural derivative of Prozac, became available for OCD, also treats PTSD, dysphoria, panic disorder, and social phobia
Citalopram (Celexa) – well absorbed orally, few drug interactions, treats major depression, social phobia, panic disorder and OCD
SSRI’s Syndrome
Serotonin syndrome
At high doses or combined with other drugs an exaggerated response can occur
This is due to increased amounts of serotonin
Alters cognitive function, autonomic function and neuromuscular function
Potentially fatal
Serotonin withdrawal syndrome
With discontinuation of any SSRI onset of withdrawal symptoms occur within a few days and can persist 3-4 weeks
Symptoms: disequilibrium, gastrointestinal problems, flu-like symptoms, sensory disturbances, sleep disturbances
