PHAR 752 Antidepressant Drugs Flashcards
Symptoms of Depression
Thoughts:
- Gloomy, hopeless, helpless
- Worry, dread, doom
- Worthlessness and guilt
- Inability to concentrate and slowed thinking
- Suicidal ideation (10-15% will attempt suicide)
Emotions and Pain (pain, sadness, anxiety, irritability, anger and anhedonia apathy)
Behaviors (loss of appetite and libido, disturbanecs in diurnal rhythm, insomnia, inability to act, social withdrawal)
Unipolar vs Bipolar depression
Bipolar characterized by manic phase (antidepressants can precipitate this phase)
Mood stabilizers often used for bipolar phase
Unipolar/Major Depression
5-15% of US adult population impacted
Major economic burden
2-3 times more common in women
Episodes can last 4-12 months with an average onset age of 30 years | usually recurrent
40% have a genetic disposition and 80% respond to treatment
Depression subcategories
Mild, moderate and severe (medication works best for moderate to severe)
Reactive depression (normal response to circumstances)
Agitated or atypical depression (fear, insomnia, extreme irritability, and restlessness)
Dysthymia (low level, long term melancholy - usually over 2 years)
Premenstrual dysphoric disorder (hormone driven?)
Post-partum depression (can occur up to 6 months following delivery)
Psychotic depression (perception of reality becomes altered)
Seasonal affective disorder
Treatment options for depression
Talk therapy Light therapy Antidepressants Exercise (reduces relapse) Electroconvulsive Therapy (ECT)
Electroconvulsive Therapy Pros/Cons
Effective in resistant depression
Rapidly effective
Disadvantage is confusion and memory loss
Antidepressant Effects
2-6 weeks latency
Improve mood, affect, appetite and sleep
Effective in 70-80% of patients
Taken prophylactically
Also used to treat neuropathic pain
Natural herbal remedy for depression
St. John’s Wort
Antidepressants biogenic amine hypothesis
Antidepressants work by extending duration of action of biogenic amines (norepinephrine, serotonin and dopamine) through blockade of reuptake or inhibition of metabolism.
This leads to an elevation in mood.
Norepinephrine deficit depression symptoms
Attention deficit, poor working memory, reduced alertness, low energy and social withdrawal
5-HT deficit depression symptoms
Agitation, appetite disturbance, sleep disturbance, anxiety
Describe antidepressant affects on biogenic amine synthesis
NE or 5HT levels increase within 2-3 hours but effects do not manifest for 2-3 weeks due to receptor and transporter modification in the brain
The integrated hypothesis of antidepressant action
Increases in 5HT or NE transmission will decrease some presynaptic receptors, increasing neurotransmitter release.
Transporter levels also decrease long-term, increasing levels of neurotransmitter in synaptic cleft.
Long-term increases in NE or 5HT transmission will cause changes in the brain (neurogenesis, increased number of synapses, glutamate signaling and improved mood)
Drugs that only target ________ reuptake are not good antidepressants. There must be some inhibition of _________ reuptake.
Norepinephrine | Serotonin
Inhibition of degradation in antidepressants (as opposed to block of reuptake) differs in that..
The transporter is not lost
Potential ultimate effects of antidepressants
Increase brain derived neurotropic factor (BDNF) and neuronal sprouting, primarily in the hippocampus
Cocaine and ketamine
Cocaine is a terrible antidepressant
Ketamine (via infusion) has a lasting antidepressant effect but often causes hallucinations
Tricyclic antidepressants
Block NE and 5HT transporters
Was the standard therapy prior to 1990
Drugs include Imipramine (Tofranil), Amitriptyline (Elavil), Desipramine (Norpramin), Doxepin (Sinequan) and Maprotiline (Ludiomil)
Used for neuropathic pain
MANY SIDE EFFECTS
Side effects of TCAs
CV effects:
- a1 adrenergic receptor antagonism (increased HR)
- Antagonism of muscarinic cholinergic receptors (increased HR) –> least with doxepin, most with amitriptyline
- NE activation of cardiac b-adrenergic receptors
Other side effects:
- histamine H1 receptor antagonism (sleepiness; worst with amitriptyline and doxepin)
- weight gain
- decreased seizure threshold
- sexual side effects related to 5HT alterations including loss of libido and impotence
TCAs and overdose
Lethal in overdose
Toxic sedative effects when combined with alcohol, benzos and barbiturates
Toxic cardiac effects
CNS anticholinergic psychosis (similar to scopolamine)
MAOIs
Block NE and 5HT breakdown
Irreversible and very long lasting
Includes Phenelzine (Nardil), Tranylcypromine (Parnate) and Isocarboxazid (Marplan)
Used only in cases of treatment resistant or atypical depression (e.g. high anxiety, phobias, hypersomnia, hyperphagia)
Useful in narcolepsy
Watch tyramine intake (wine and cheese)
MAOIs adverse effects
Insomnia followed by daytime sleepiness
Dry mouth
Impotence and loss of libido
Hepatotoxicity associated with phenelzine
Long washout period
Overdose toxicities include hyperthermia (too much serotonin) as well as hypertension, tachycardia and muscular agitation (all from too much NE)
_________ is given in hyperthermia as a result of MAOI
Dantrolene (as seen in co-administration of succinyl-choline with inhaled anasthetic)
MAOI toxic drug interactions
Can dangerously prolong half-lives of oxidatively deaminated drugs
Sympathetic crisis with sympathetic amines
Serotonin syndrome (similar to neuroleptic malignant syndrome): hyperthermia, muscle rigidity, myoclonus, mental disorientation, dose dependent and treated with dantrolene -->problematic with any drugs increasing serotonergic transmission, including triptans, SSRIs, meperidine (opioid) or dextromethorphan
