antidepressants Flashcards Preview

Pharmacology > antidepressants > Flashcards

Flashcards in antidepressants Deck (26)
Loading flashcards...

what does norepinephrine do?

Neurotransmission is involved in:

the reticular activating system: basic arousal, alertness, wakefulness, insomnia
the limbic system: anxiety, depression, appropriateness
central responses to stress
Both NE and E in the pons-medulla affect cardiovascular control
the hypothalamus: feeding, thermoregulation

More recently

NE shown to provide a modulatory role in focus, attention and performance


What does serotonin do?

Neurotransmission is involved in:

the limbic system: psychosis, anxiety, depression
the hypothalamus: thermoregulation, pituitary secretion
Helps shape cortical circuits


what does dopamine do?

Neurotransmission is involved in:

the extrapyramidal motor system: Parkinson’s disease (PD)
the limbic system: psychosis, anxiety, depression
the hypothalamus: reward/pleasure, pituitary secretion, thermoregulation
the chemoreceptive trigger zone: emesis


What is major depressive disorder?


is a heterogeneous genetic disorder(s) with onset at anytime of life

is typically recurring

affects about 10% of the population, i.e., population norm is about 10%

the WHO predicts by 2030 MDD will be the #1 health issue world-wide


what are the symptoms of major depressive disorder?


sad, frustrated, hopeless


inappropriate negative thoughts and ideas
impaired concentration, confusion, pseudo-dementia


what is the neurovegetative (affect function)?

loss of appetite

loss of libido

loss of energy, lack of motivation

loss of interest in almost everything

neuroendocrine abnormalities, no diurnal rhythm

sleep disorder, REM advance and early morning awakening

can’t experience or anticipate pleasure


what are some of the highest symptoms in depressed patients?

insomnia, sadness of mood, tearfulness, poor concentration


what are antidepressant interventions?


Insulin-induced hypoglycemic convulsions
historic only

Electro-convulsive therapy
historical problems
currently safe and effective

Monoamine oxidase inhibitors

Neurotransmitter reuptake inhibitors

Atypical antidepressants


what do MAOs A and B do? and what does MOA do?

Monoamine oxidase inhibitors

monoamine oxidase (MAO)
is a mitochondrial enzyme that helps prevent the buildup of excessive intracellular levels of neuroactive amines
is the chemical part of the blood-brain barrier
2 isoforms: MAO-A and MAO-B

is found in neurons, the liver, and the GI tract
highest affinity for serotonin
less affinity for noradrenaline, dopamine and trace amines like tyramine

is found in neurons, the liver, and platelets
highest affinity for dopamine
less affinity for noradrenaline and tyramine


what is tranylcypromine?

T1/2 = 2 hours but binds ‘irreversibly’ to MAO, so 1 dose lasts about 7 days
inhibits both MAO-A and MAO-B. This increases levels of 5-HT, NE and DA in neurons in the brain
increases the absorption of dietary tyramine from the gut into the blood stream


what is moclobemide?

T1/2 = 2 hours but is ‘reversible’, competitive binding
is a selective inhibitor of MAO-A
Increases levels of serotonin and noradrenaline in brain without affecting blood tyramine
The ‘wine-cheese’ reaction is usually not a problem because moclobemide has a short half life, is taken after meals, is reversible, and does not alter MAO-B in the liver.

Moclobemide is better because it doesn’t effect dopamine as much and it leaves MAO-B available.


what are side effects of MAOIs?

Side effect of MAOIs
CNS excitation
Suppression of REM sleep
Serotonin syndrome
Tyramine cheese effect


what are Non-selective or norepinephrine serotonin reuptake inhibitors?

Neurotransmitter reuptake inhibitors

Non-selective reuptake inhibitors (NSRIs)

inhibit both noradrenaline and serotonin reuptake
“broad spectrum”
older drugs, tricyclic antidepressants, TCAs
Imipramine, T1/2  17 hours
Amitriptyline, T1/2  38 hours
also block muscarinic and alpha1 adrenergic receptors producing impaired memory, etc., and postural hypotension, respectively

Some like the imipramine and amitriptyline could be used to suppress pain transmission back to the brain.

 newer drugs
Venlafaxine (Effexor), T1/2  7 hours
Duloxetine (Cymbalta), T1/2  12 hours
no affinity for any neurotransmitter receptors


what are selective serotonin reuptake inhibitors (SSRIs)?

Selective serotonin reuptake inhibitors (SSRIs)

inhibit only serotonin reuptake
Fluoxetine (Prozac) T1/2  3 days, has an active metabolite norfluoxetine, total biological half-life about 7 days
 lacks affinity for neurotransmitter receptors
 inhibits cytochrome p450 2D6 (and others) causing potentially fatal drug interactions with narcotics, beta blockers, etc.
Fluvoxamine (Luvox) T1/2  15 hours
Paroxetine (Paxil) T1/2  24 hours (discontinuation syndrome)
lack active metabolites
have less serious p450 related drug interactions than fluoxetine
Sertraline (Zoloft) T1/2  26 hours
Citalopram (Celexa) T1/2  35 hours


what are the Selectrive noradrenaline reuptake inhibitor?

Selective noradrenaline reuptake inhibitors

desipramine T1/2  38 hours
is the active metabolite of imipramine (T1/2  17 hrs)
has less affinity for muscarinic and alpha 1-receptors than imipramine

nortriptyline T1/2  55 hours
is the active metabolite of amitriptyline (T1/2  38 hrs)
has less affinity for muscarinic and alpha 1-receptors than amitriptyline

maprotiline T1/2  36 hours
Tetracyclic antidepressant
side effects comparable to tricyclic antidepressants


what are atypical antidepressants?

Very heterogeneous group of drugs
Amoxapine: T1/2  8 hours
Moderate and strong reuptake inhibitor of 5-HT and NE, respectively
Antagonist of select 5HT, NE and DA receptors (antagonist/inverse agonist)

Nefazodone: T1/2  3-4 hours
selective inhibitor of NE uptake
block 5HT2A,high potency
Can be hepatotoxic (contraindicated in patients with liver disease)

Trazodone: T1/2  4-8 hours
weak inhibitor of 5-HT uptake and antagonizes 5-HT and alpha adrenergic receptors

Bupropion: T1/2  4-8 hours
weak inhibitor of DA uptake (NE re-uptake as well)
Nicotinic acetylcholine receptor antagonist (helps people to stop smoking)
Effective alone, but often added to cases of incomplete response with SSRIs

Mirtazapine: T1/2  30 hours
blocks pre-synaptic alpha 2-receptors that inhibit release of noradrenaline and serotonin
increase both noradrenaline and serotonin release
also blocks several types of post-synaptic serotonin receptors
generally mild side effects
(increased appetite and weight gain)

not a good drug for if they have pain.


what is the antidepressant mechanism?


Drug effects are maximal within a few hours

clinical improvement not seen for 2 to 6 weeks
therefore the direct, acute drug action is not the therapeutic action of antidepressants

down regulation of beta-adrenergic receptors is common to all anti-depressant interventions

how (or even if) beta-receptor down-regulation participates in mood normalization is currently unknown

likely to be other, currently undiscovered, common factors

maybe brain-derived neurotrophic factor (???)


what are some other uses for antidepressants?

Panic disorder :
symptoms look like anxiety, drug response like depression
most anti-depressants given chronically reduce or prevent panic attacks
dose and time course same as for depression

Obsessive-compulsive disorder:
predominant symptom is anxiety
chronic SSRIs reduce or prevent the anxiety, obsessive thoughts and compulsive behaviors
dose and time course same as for depression

Generalized anxiety disorder:
is classic anxiety
chronic NSRIs, SSRIs, TCAs reduce anxiety better than benzodiazepines
dose and time course same as for depression
90% comorbidity of GAD and MDD


what are some drugs for bipolar disorders?

Valproic acid
Atypical antipsychotics


what is mania?

Mania: It is a state of neurological abnormality, where there is an elevated or irritable mood, arousal, and/or energy levels.
It is opposite to depression.


what are the characteristics of bipolar disorder?

affects 1% to 2% of the general population
much higher in professionals and entertainers.
mood swings that cycle between depression and mania.
cycle length varies from hours to years in different patients.
several different genes have been identified
onset at any time of life (typically younger).


what are some typical symptoms of individuals with mania?

distractibility, pressured speech, euphoria, lability, flight of ideas.


what is lithium and cabamazepine used for in bipolar disorder?

Lithium: T1/2  8-30 hours
Cornerstone treatment option as it can abort an acute manic episode, prevent future manic episodes, and exerts a mild antidepressive effect
Long-term patient compliance is often poor due to side-effects (nausea, diarrhea, drowsiness, weight gain, fine hand tremor, polyuria)

Low therapeutic index - (0.6-1.2 meq/L vs. 1.4 meq/L for toxicity) Nausea and vomiting are early signs of overdose
Very dangerous to use in conjunction with other meds (diuretics – Na+)
Interferes with receptor-activated Phosphatidylinositol turnover
Antagonizes 5-HT1A and 5-HT1B autoreceptors, preventing feedback inhibition of 5-HT release
Enhances glutamate reuptake, clearing glutamate from synapse

Carbamazepine: T1/2  15-30 hours
Decreases voltage-gated Na channels
Potentiates GABA receptor currents
Exhibits antimanic, antidepressant, and prophylactic effects equivalent to lithium with fewer adverse effects in many patients
Adverse effects include: dizziness, ataxia, double vision


what is valproic acid and lamotrigine used for in bipolar disorder?

Valproic acid: T1/2  13-21 hours
Decreases voltage-gated Na channels
Potentiates GABA receptor currents
additional effects as an histone deacetylase inhibitor (epigenetic effects)
Especially useful in patients with rapid cycling of manic and depressive episodes
Adverse effects include: nausea, vomiting, diarrhea, headache, tremor, double vision, drowsiness, dizziness

Lamotrigine: T1/2  13 hours
Decreases voltage-gated Na channels
It also blocks L-, N-, and P-type calcium channels and has weak 5-HT3 receptor inhibition. These actions thought to inhibit glutamate release in cortex and striatum/limbic areas -- these neuroprotective and antiglutamatergic effects are promising contributors to its mood stabilizing activity.
is effective in the treatment of the depressed phase of bipolar disorder, where as other sodium channel blocking antiepileptic drugs are not.
Adverse effects include: dizziness, ataxia, double vision


what about atypical antipsychotics and combination therapy for bipolar disorder?

Atypical antipsychotics: (olanzapine risperidone, aripiprazole)
Atypical antipsychotics are approved for treatment of acute mania or mixed episodes
Antipsychotics may be required to suppress delusions and other psychotic symptoms accompanying mania

Combination therapy: Olanzapine and fluoxetine
Antidepressant monotherapy may precipitate mania, and thus the combination of olanzapine with fluoxetine (symbyax) can be used


what is the treatment guideline for bipolar disorder?

20 -40 % of patients do not response to lithium or tolerate its adverse effect.
Therefore --> Anticonvulsants: valproate, Carbamazepine, or lamotrigine.
Atypical antipsychotics may be used for treatment of acute mania or mixed episodes.
Antidepressents may precipitate mania, and thus combination therapy of Olanzapine with fluoxetine can be used for the treatment of depression associated with bipolar disorder.