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Lectures > Anti-depressant drugs > Flashcards

Anti-depressant drugs Flashcards

1
Q

Principles of central amine neurotransmission

A

5HT and NE are diffusely projecting systems

  • serotonin –> produced in raphe nucleus
  • NE –> produced in locus coeruleus
  • primarily released from varicosities –> facilitates the release of large amounts of NTs from vesicles into the extracellular space
  • modulate neuronal activity in a global manner

Diffusely projecting systems can provide two types of information

  1. rapid and discrete akin to more traditional neurotransmission
  2. slower tonic firing that allows for integration of information over longer periods of time `
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2
Q

5HT synthesis and regulation

A

5HT is synthesized from the amino acid tryptophan

  • tryptophan hydroxylase is rate limiting step
  • transported into vesicles by Vesicular Monoamine Transporters (VMAT) = Non-specific transporter
  • Selective re-uptake transporters recycle 5HT from the synaptic cleft –> high selectivity
  • In cytoplasm, under go reuptake into the vesicles or degradation by the monoamine oxidase (MAO) system.
  • Auto-receptors inhibit 5HT release
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3
Q

NE synthesis and regulation

A

NE is synthesized from tyrosine

  • tyrosine hydroxylase is rate limiting step
  • Dopamine-beta-hydroxylase hydrolyzes dopamine to NE –> transported into vesicles by Vesicular - Monoamine Transporters (VMAT) = Non-specific transporter
  • Selective re-uptake transporters recycle NE from the synaptic cleft –> high selectivity
  • In cytoplasm, under go reuptake into the vesicles or degradation by the MAO system
  • Autoreceptors inhibit NE release
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4
Q

Monoamine hypothesis of depression

A

States that depression results from the pathologically decreased or depleted levels of 5HT and/or NE
- thus based on this theory, it can be assumed that altering 5HT and/or NE levels could reverse depression

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5
Q

5HT deficiency syndrome

A
  • depressed mood
  • anxiety
  • panic
  • phobia
  • anxiety
  • obsessions and compulsions
  • food cravings, bulimia
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6
Q

Physiological actions of serotonin

A
  • frontal cortex –> mood
  • basal ganglia –> akathisia/agitation + OCD
  • limbic system –> anxiety
  • hypothalamus –> appetite/bulimia

when there is too much…

  • sleep centers –> insomnia
  • spinal cord –> sexual dysfunction
  • brainstem vomiting center –> nausea/vomiting
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7
Q

5HT receptor subtypes

A

G protein linked receptors –> except for 5HT3

  • inhibit 5HT release –>
  • –> 5HT1D = autoreceptor (located on cell body vs. axon terminal)
  • –> 5HT1A = pre-synaptic receptor (located on axon terminal)
  • post-synaptic receptors with several phsyiologic actions
  • –> 5HT2A, 5HT2C + 5HT3
  • implicated in clinical depression
  • –> 5HT1a, 5HT1d, 5HT2a, 5HT2c
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8
Q

NE deficiency syndrome

A
  • impaired attention
  • problems concentrating
  • deficiencies in working memory
  • slowness of information processing
  • depressed mood
  • psychomotor retardation
  • fatigue
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9
Q

Physiological actions of NE

A
  • beta 1 receptors in frontal cortex –> depression
  • alpha 2 receptors in frontal cortex –> attention
  • limbic system –> energy level, agitation, emotions
  • cerebellum –> tremor
  • brainstem –> blood pressure
  • heart –> tachycardia
  • bladder –> urinary retention
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10
Q

NE receptor suptypes

A

alpha 1 and 2 + beta 1 and 2 associated with depression

  • alpha 2 –> expressed presynaptically = critical for auto-inhibitory actions of NE neurotransmission
  • beta 1 –> post-synaptic receptors are primarily localized to the frontal cortex, may play a role in regulating the action of NE on mood

Autoreceptors located on both cell body/dendrites + nerve terminal

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11
Q

5ht-NE interactions

A

The anatomical sites of NE control of 5HT release include a brake in the frontal cortex and an accelerator in the brain stem

  • NE can facilitate 5 HT release via activation of alpha1 receptors on 5HT neurons
  • NE can facilitate decreased secretion by acting on alpha 2 autoreceptors on 5HT nerve terminals
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12
Q

Pharmacological classes and agents

A
  1. tricyclic anti-depressants
    - amitryptaline
    - desipramine
    - imipramine
    - nortriptyline
  2. MAO inhibitors
    - isocarboxazid
    - phenelzine
    - tranylcypromine
  3. SSRIs
    - fluoxetine
    - sertraline
    - paroxetine
    - citalopram
    - fluvoxamine
  4. Atypical anti-depressants
    - bupropion
    - mirtazapine
    - trazodone
    - venlafaxine
    - duloxetine
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13
Q

TCAs

A

Named for their common chemical structure consisting of 3 rings

  • block reuprtake pumps for 5HT and NE
  • share pharmacological properties depending on the structure of their amines
  • varying affinities for the 5HT and NE reuptake transporters, the TCAs are markedly similar in their clinical efficacy and side effects
  • have at least 3 other actions which are believed to contribute to the numerous side effects of TCAs
  • –> block of muscarinic cholinergic receptors
  • –> block of H1 histamine receptors
  • –> block of alpha 1 adrenergic receptors
  • –> block Na channels
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14
Q

TCAs - common side effects

A

Antihistaminergic

  • sedation
  • weight gain

Anti-cholinergic –> nausea, vomiting, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, urinary retention

Antiadrenergic

  • orthostatic hypertension
  • reflex tachycardia
  • drowsiness
  • dizziness

Na channels in the heart –> slows depolarization, could lead to cardiac arrhythmia
= most serious

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15
Q

TCAs - Pharmacokinetics

A

TCAs are lipophilic molecules that bind readily to plasma proteins and tissue –> They cross the blood-brain barrier.

Well-absorbed via the GI tract but undergo highly variable first-pass metabolism

Many of the metabolites are pharmacologically active

P450 enzyme system (primarily CYP2D6) are responsible for the metabolism. The active products are a result of demethylation or hydroxylation of the primary drugs.

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16
Q

MAO inhibitors

A

One of the first clinically effective antidepressants to be discovered

2 subtypes of MAO

  • MAO-A –> metabolizes 5HT and NE selectively, as well as tyramine; linked to blood pressure
  • MAO-B –> metabolizes dopamine; inhibition is linked to prevention of neurodegenerative processes such as parkinsons

Not widely used today –> small number of patients appear to do better on MAOIs than TCAs or the newer drugs

Classic MAOIs –> irreversible and non-selective

  • Isocarboxazid, Phenelzine sulfate, Tranylcypromine
  • MAO A + B
  • enzyme activity cannot be restored unless new enzyme is synthesized
  • can cause dangerous elevations of BP –> hypertensive crisis

Reversible and selective inhibitors of MAO-A

  • moclobemide (anti-depressant action
  • befloxatone
17
Q

MAOI - hypertensive crisis

A

Fatal interaction with tyramine containing foods

  • if MAO A is inhibited and there is increase in circulating tyramine (e.g. after eating cheese) –> there will be an increase in NE in circulation with no way of breaking it down
  • hypertensive crisis that can lead to intracranial bleeding and other organ damage ensues
  • with reversible MAOIs, if NE levels are high enough they can displace the inhibitor from MAO, allowing for normal destruction of the extra NE
18
Q

Pharmacokinetics of MAOIs

A
  • MAOIs are lipophilic and cross the blood-brain barrier.
  • They are well absorbed orally and metabolized in the liver –> inactivated by acetylation in the liver.
  • Excretion is primarily via renal clearance
  • The older generations (irreversibly bound to MAO) are cleared as a complex with the MAO.
19
Q

MAOI common side effects

A
  • Blurred vision, dizziness, sleep disturbances, fatigue, weakness and increased sweating
  • Sexual dysfunction
  • Orthostatic hypotension
  • Side effects are generally immediate and the immediate side effects often disappear in time
20
Q

SSRIs

  • drugs
  • side effects
A

Revolutionized the treatment of depression –> most widely prescribed drugs for depression tx

  • fluoxetine (prozac)
  • sertraline (zoloft)
  • paroxetine (paxil)
  • fluvoxamine (luvox)
  • citalopram (celexa)

Have few side effects and seem to be rather safe

  • better patient compliance
  • low threat for overdose
  • suicide may be considered in severe depression

Side effects

  • nausea
  • decreased libido
  • decreased sexual function
21
Q

SSRIs - mechanism of action

A
  • more selective and more potent inhibitors of serotonin uptake than TCAs
  • no block of alpha1, histamine, muscarinic cholinergic receptors or Na pumps
  • enhances 5HT action

delayed onset of action

  • during depressed state = low 5ht –> all receptors are upregulated (including autoreceptors) –> SSRI immediately blocks 5HT reuptake pump, but this results in an initial increase in 5HT only in the somatodendritic area of the 5HT neuron, not in the axon terminal where it is needed –> causes increased activity of 5HT on autoreceptors, which decreases 5HT release at nerve terminal
  • the consequence of 5HT increasing only in the somatodendritic area is a desensitization of the 5HT1a autoreceptors –> eventually they down regulate
  • downregulation of the atuoreceptors results in increased impulses –> neurons are turned on and ready to fire –> results in increased release of 5HT from terminals
  • the final step is a desensitization of the post synaptic 5HT receptors –> the receptors were up regulated bc of low 5HT levels; this downregulation is believed to mediate the reduction of side effects to the SSRIs as tolerance develops
22
Q

Serotonin syndrome

A

Drug interaction that occurs with MAOIs –> rare but serious side effects

  • dangerously high levels of 5HT can occur when both SSRIs and MAOIs are administered together
  • clinical manifestations = hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs

important to wait up to 6 weeks after medication is stopped, before starting with another drug

23
Q

Atypical/heterocyclics

A

Newer generations of antidepressants are sometimes referred to as “atypical antidepressants” because they do not fit conveniently into other categories.
- These drugs typically have multiple modes of actions but few adverse side effects.

2nd generation heterocyclics:

  • trazodone –> Serotonin2a antagonist/serotonin reuptake inhibitor
  • bupropion –> NE/DA reuptake inhibitor

3rd generation heterocyclics

  • mirtazapine –> noradrenergic and specific serotonergic antidepressant
  • venlafaxine –> serotonin-NE reuptake inhibitor
24
Q

Trazodone

A

Serotonin2a antagonist/serotonin reuptake inhibitor

  • major distinction between SARIs and other antidepressants is that SARIs are predominantly 5ht2a antagonists
  • a lesser but important action is 5HT reuptake inhibition
  • 5HT2a stimulation has undesirable affects –> agitation, anxiety, sexual dysfunction
  • trazodone has the beneficial effects of the 5HT reuptake inhibition while blocking the unwanted side effects of 5HT2a stimulation

Other actions

  • antihistamine –> sedation
  • alpha 1 inhibition –> hypotension, dizziness, sedation
25
Q

Bupropion

A

NE/DA reuptake inhibitor

  • lacks a significant serotonergic component –> may be a useful antidepressant for patients who cannot tolerate the serotonergic side effects
  • not associated with sexual dysfunction
  • a weak DA and NE reuptake blocker
  • has potent action on DA and NE transmission
  • may be a vague adrenergic modulator
26
Q

Mirtazapine

A

Noradrenergic and specific serotonergic antidepressant

  • alpha2 receptor antagonist
  • increase NE and 5HT levels
  • blocks 5HT2a, 5HT3 and thus reduces side effects of anxiety and sexual dysfunction
  • but by blocking 5HT2C and H1 receptors, cause side effects = sedation and weight gaine
27
Q

Venlafaxine

A

Serotonin-NE reuptake inhibitor

  • combines the actions of both selective serotonin reuptake inhibitors and selective NE reuptake inhibitors
  • unique in that it shares the NE and 5HT and to a lesser extent dopamine reuptake inhibitory properties of the classical TCAs, but with out the alpha1, cholinergic or histamine receptor blocking properties
  • thus, they are selective in their actions
28
Q

Basic strategies for managing MDD

A
  1. Start with SSRI and/or therapy or both
  2. be sure to wait 4-6 weeks to see effect of medication
  3. If patient still has symptoms, start to increase the medication and or therapy
  4. Do not switch or add a new medication until you have maximized the first one
  5. If SSRI doesn’t work, consider another SSRI
  6. If second SSRI doesn’t work try bupropion, mirtazapine, venlafaxine
  7. Remember it takes 4-6 weeks for a new medication or even a dose change to take effect
  8. If above meds do not work, consider TCA
  9. You can also supplement treatment with Lithium
  10. Consider MAOI or ECT

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