Anti-depressants Flashcards
1
Q
Trimonoaminergic System
A
Neurotransmitters in pathophysiology and tx of mood disorders:
-
Serotonin, norepinephrine > dopamine
- Many areas receive input from all 3 systems
- All known treatments for mood disorders act on one or more of these neurotransmitter systems
-
Serotonin neurons in CNS originate in the raphe nucleus
- Projections to spinal cord
- Pain perception, visceral regulation, and motor control
- Projections to the Forebrain
- Mood, cognition, and neuroendocrine function
- Projections to spinal cord
-
Noradrenergic neurons originate in the locus coeruleus
- Projections to spinal cord
- Regulate pain pathways
- Projections to the forebrain
- Mood, arousal, and cognition
- Projections to spinal cord
-
Serotonin and NE released 1° from varicosities
- Large amounts of neurotransmitter into the projection area
- Feedback inhibition ⇒ fairly constant amount released & concentrations stays in a narrow range
- Maintains a baseline tone for the target areas
- Specific stimuli elicit rapid bursts ⇒ superimposed on baseline
- Dopamine system projections much more discrete
2
Q
Catecholamines
Synthesis, Storage, and Release
A
-
Tyrosine → L-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (rate limiting)
-
Feedback inhibition by NE via pre-synaptic α2 -adrenergic receptors
- ⊕ α2 Ad-R (GPCR) ⇒ ↓ cAMP ⇒ ↓ cAMP activated protein kinase ⇒ normally ℗ and ⊕ this enzyme
-
Feedback inhibition by NE via pre-synaptic α2 -adrenergic receptors
-
L-DOPA → Dopamine by aromatic L-amino acid decarboxylase (AAADC) (aka L-DOPA decarboxylase)
- Found in neuronal and non-neuronal cells in CNS and peripheral tissues
- Exogenous L-DOPA ⇒ ↑ catecholamines in catecholamine neurons and serotonergic neurons
-
DA → synaptic vesicles → norepinephrine by dopamine-β-hydroxylase
- NE concentrated within vesicles and ready for release
- DA and NE transport into vesicles by vesicular monoamine transporter (VMAT)
- Inhibited by reserpine
- Degradation of DA & NE by cytoplasmic monoamine oxidase
- In the adrenal medulla, NE → epinephrine by phenylethanolamine N-methyltransferase (PNMT)
3
Q
Catecholamines
Reuptake
A
- NE released into the synaptic cleft
-
Taken back up into synaptic terminal by norepinephrine reuptake transporter (NET)
- Specific for norepinephrine
- Inhibited by cocaine
- Stored in the vesicles for reuse
4
Q
Catecholamines
Metabolism
A
-
Norepinephrine → aldehyde (DOPGAL) by monoamine oxidase (MAO)
- Two forms ⇒ MAO-A and MAO-B
- On outer membranes of MΦ within neurons, glia, liver and GI tract
- Distribution of isozymes differs among cells and tissues
- Intestines ⇒ 75% MAO-A
- Liver ⇒ 50/50 split b/t MAO-A and MAO-B
- 1° metabolic barriers vs dietary tyramine and other circulating substrates
- Tyramine is metabolized by both isozymes
- MAO-A catabolizes 5-HT, NE, and dopamine
- MAO-B preferentially catabolizes dopamine
- Two forms ⇒ MAO-A and MAO-B
- Aldehyde → acidic metabolites by aldehyde dehydrogenase
-
Norepinephrine further metabolized by catechol-O-methyltransferase (COMT)
- Methylation can occur on parent compound or acid metabolite
5
Q
Catecholamine
Receptors
A
6
Q
Serotonin
Synthesis, Storage and Release
A
- Dietary L-tryptophan → 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (rate limiting)
- Only in cells that synthesize 5-HT in the brain and periphery
-
Feedback inhibition via serotonin receptors located pre-synaptically (5HT1B/D) and somatodendritic receptors (5HT1A)
- ⊕ GPCR ⇒ ↓ cAMP ⇒ ↓ cAMP activated protein kinase ⇒ normally ℗ and ⊕ this enzyme
- 5-HTP → serotonin (5-HT) by aromatic L-amino acid decarboxylase (AAADC)
- Transported into synaptic vesicles by non-specific vesicle monoamine transporter (VMAT)
- Stored, protected from monoamine oxidase, and ready for release on demand
7
Q
Serotonin
Reuptake and Metabolism
A
-
Reuptake back into the synaptic terminal by the selective serotonin reuptake transporter
- Specific transporter for serotonin
- Transporters also exist on platelets and in enterochromaffin cells in the GI tract
- Non-neuronal transporters responsible for some side effects of SSRIs/SNRIs
- 5-HT → aldehyde of 5-HT by monoamine oxidase (MAO)
- Aldehyde → 5-hydroxyindoleacetic acid (5-HIAA) by aldehyde dehydrogenase
8
Q
Serotonin Receptors
A
9
Q
Monoamine and Serotonin
Interaction
A
Reciprocal relationship:
NE ⇒ ⊗ serotonin release via α2 adrenergic heteroreceptors on serotonergic terminals
Serotonin ⇒ ⊗ norepinephrine release via 5HT2A receptors on noradrenergic neurons
10
Q
Monoamine Hypothesis of Depression
A
Depression results from a decrease in serotonin and norepinephrine transmission.
- Drugs to tx other diseases found to have a strong antidepressant effect via serotonergic and noradrenergic neurotransmitter systems
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Imipramine (tx schizophrenia) ⇒ ⊗ serotonin reuptake
- Its active metabolite ⇒ ⊗ reuptake of norepinephrine
-
Iproniazid (tx tuberculosis) ⇒ ⊗ monoamine oxidase ⇒ responsible for degradation of monoamines
- Has antidepressant effects
-
Reserpine (antihypertensive) ⇒ ⊗ VMAT ⇒ caused depression in some pts
- VMAT responsible for uptake of monoamines into storage vesicles
- Allows monoamines to be degraded by monoamine oxidase
- Subsequent ↓ in monoamine release thought to lead to depression
-
Imipramine (tx schizophrenia) ⇒ ⊗ serotonin reuptake
- Pts responsive to a serotonin reuptake inhibitor will relapse w/ low tryptophan diet (precursor for serotonin)
- Most available antidepressants ∆ monoamine neurotransmission in some way
- Hypothesis still incomplete b/c little e/o actual ∆ in monoamine levels during depression
11
Q
Neurotrophic Hypothesis of Depression
A
Depression is associated w/ a loss of neurotrophic support
&
Antidepressants will increase neurogenesis and synaptic connectivity in areas such as the hippocampus.
Brain derived neurotrophic factor (BDNF) ⇒ most important factor
- Pain and stress ⇒ ↓ BDNF ⇒ atrophic changes in areas of the brain relevant to depression
- Direct injection of BDNF in animals ⇒ antidepressant effects
- Chronic treatment w/ antidepressants ⇒ ↑ BDNF ⇒ correlates w/ onset of therapeutic effect
12
Q
Neuroendocrine Factors
A
Depression associated w/ a number of hormonal abnormalities including:
- Elevated cortisol, suggesting a disruption of the HPA
- Thyroid dysregulation
- Sex hormone deficiency
13
Q
Antidepressants
Basic Pharmacology
A
14
Q
Ketamine
A
- Has been used to tx severe resistant depression
- No therapeutic lag
- Thought to work by ↑ synaptogenesis
15
Q
Selective Serotonin Reuptake Inhibitors (SSRI)
Drugs
A
- Fluoxetine (Prozac)
- Sertraline (Zoloft)
- Citalopram (Celexa)
- Fluvoxamine (Luvox)
- Paroxetine (Paxil)
16
Q
SSRIs
Mechanism of Action
A
⊗ reuptake of serotonin into the presynaptic terminal
- Pharmacological effect occurs shortly after dosing
- Therapeutic effect occurs over 2 to 4 weeks
17
Q
SSRIs
“Therapeutic lag”
A
“Therapeutic lag” ⇒ correlates w/ desensitization of presynaptic receptors, ↑5-HT release, ↑ ⊕ of postsynaptic 5HT1A receptors
- Initial admin of SSRI ⇒ modest ↑ in 5HT at the
- Synapse
- Somatodendritic 5HT1A receptors in the raphe nucleus
- Presynaptic receptor
- Over time, somatodendritic receptors and presynaptic receptors desensitize
- Removes feedback inhibition on serotonergic neuron ⇒ large ↑ in neuronal activity ⇒ ↑↑↑ release of serotonin
-
Post-synaptic:
- 5HT1A receptors DO NOT desensitize
-
5HT2 receptors DO desensitize
- Desensitization of 5HT2A ⇒ some degree of side effect tolerance and may play a role therapeutically
18
Q
SSRIs
Therapeutic Uses
A
- Major depression (typical)
- Generalized anxiety disorder
- Post-traumatic stress disorder
- Obsessive compulsive disorder
- Panic disorder
- Premenstrual dysphoric disorder
19
Q
SSRIs
Pharmacokinetics
A
-
Fluoxetine ⇒ longest half-life
-
Norfluoxetine (active metabolite) ⇒ half-life of almost 8 days
- Needs to be discontinued 4 weeks before switching to an MAO inhibitor
- Avoid the potential for serotonin syndrome
- Needs to be discontinued 4 weeks before switching to an MAO inhibitor
-
Norfluoxetine (active metabolite) ⇒ half-life of almost 8 days
- Some of these drugs are potent inhibitors of cytochrome p450 ⇒ potential for drug interactions
20
Q
SSRIs
Common Adverse Effects
A
-
Nausea
- ⊕ of 5HT3 receptors in area postrema and on vagal afferent to the CNS
-
Diarrhea
- ⊕ of 5HT4 receptors in GI tract
-
Sexual dysfunction
- ⊕ of 5HT2A and 5HT2C receptors in spinal cord ⇒ ⊗ spinal reflexes of orgasm and ejaculation
- ⊕ of 5HT2A receptors in mesocortical tract ⇒ ↓ dopamine release ⇒ apathy and ↓ libido
-
Anxiety, agitation, insomnia
- ⊕ of 5HT2A receptors in the various areas of brain and spinal cord
-
Discontinuation syndrome
- Sudden discontinuation of short half-life SSRI’s (ex. paroxitine and sertraline) can lead to this syndrome
- Dizziness, and tingling or numbing in the skin
- Starts 1-2 days after stopping and may persist for a week
-
Serotonin syndrome
- Can occur w/ any drug that ↑ serotonin (incl. opioids)
- More likely to occur when drugs used in combo (ex. MAOi & SSRI)
- Wash out period is necessary when switching meds
- Hyperthermia, muscle rigidity, cardiovascular collapse, flushing and diarrhea
-
Reduced platelet aggregation
- ⊗ of 5-HT uptake by platelets ⇒ inadequate availability 5-HT for hemostatic mechanisms
- SSRI’s ↓ risk of clotting and repeat MI in cardiac pts for post-MI depression
- SSRI’s ↑ risk of bleeding, esp. when combined w/ ASA or other NSAID’s (benefits in pts at risk for thrombosis)
- Sweating
- Suicide
21
Q
Neuroleptic Malignant Syndrome
vs
Serotonin Syndrome
A
22
Q
Serotonin Syndrome
Treatment
A
Tx depends on severity:
- Discontinue SSRI
- Treat w/ a benzodiazepine
- 5HT2 blocker (cyproheptadine)
23
Q
SSRIs
Drug Interactions
A
Most common interactions are pharmacokinetic
- Paroxetine and fluoxetine are potent inhibitors of cytochrome p450 CYP2D6 that metabolizes the tricyclics ⇒ sign. ↑ and toxicity
- Fluvoxamine inhibits cytochrome p450 CYP3A4 that metabolizes other drugs such as diltiazem
- Citalopram is relatively free of interactions
- The most serious interaction is w/ MAOI’s to produce serotonin syndrome
24
Q
Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Drugs and MOA
A
Duloxetine ⇒ ⊗ serotonin and norepinephrine transporter
Venlafaxine ⇒ ⊗ serotonin transporter @ low doses and also ⊗ norepinephrine transporter @ higher doses
Do not bind histamine, α__-adrenergic, and muscarinic receptors ⇒ better tolerated than TCAs
25
SNRIs
Therapeutic Uses
* Major depression
* Atypical depression (**venlafaxine**)
* Generalized anxiety
* Stress urinary incontinence
* Vasomotor symptoms of menopause
* Pain of diabetic peripheral neuropathy (**duloxetine**)
26
SNRIs
Pharmacokinetics
* **Venlafaxine** → **desvenlafaxine** (active metabolite) by **cytochrome p450 enzyme**
* Both have a **T****½****of 11 hours**
* Desvenlafaxine is marketed separately ⇒ does not undergo additional oxidative metabolism
* **Duloxetine** is _extensively metabolized_ in liver by **cytochrome p450 CYP2D6**
* Contraindicated w/ hepatic insufficiency
* Also **highly protein bound**
27
SNRIs
Adverse Effects
* Relatively mild compared to TCAs
* Some overlap w/ SSRIs (Nausea)
* _Noradrenergic effects:_
* **↑ BP / HR**
* CNS activation such **insomnia, anxiety, and agitation**
* **High doses of venlafaxine** more likely to have **adverse cardiac effects**
* **Discontinuation** **syndrome**
* **Serotonin syndrome**
28
SNRIs
Drug Interactions
* Compared to SSRIs, _interactions w/ cytochrome p450 are mild_
* **Venlafaxine** is a **substrate** but not an inhibitor
* **Duloxetine** is a **moderate inhibitor** of CYP2D6 ⇒ ↑ TCAs
* The most serious interaction is w/ **MAOI’s** to produce **serotonin syndrome**
29
Tricyclic Antidepressants
Drugs
* Amitriptyline
* Nortriptyline
* Imipramine
* Desipramine
* Clomipramine
30
TCAs
Mechanism of Action
**⊗ norepinephrine and serotonin reuptake**
Considerable variation
* **_Tertiary amines_**: Amitriptyline, Imipramine, Clomipramine (CIA)
* Proportionally more effect in boosting 5-HT \> NE
* Produces more sedation, anticholinergic effects, and orthostatic hypotension
* **Clomipramine** ⊕ primarily _serotonin reuptake_
* **_Secondary amines_**: Nortriptyline, Desipramine
* More effect on NE levels
* Produces more irritability, overstimulation, and sleep disturbance
* **Desipramine** more selective for _norepinephrine_
31
TCAs
Therapeutic Uses
* **Not commonly used** d/t adverse effects and toxicity
* Used for **refractory** **depression**
* _At lower doses_, may be used to **treat pain**
* **Imipramine** has been used for **enuresis** (bed wetting)
* **clomipramine** has been used for **OCD**
* No longer preferred treatments
32
TCAs
Pharmacokinetics
* Most are dosed **once a day** and **at night** d/t sedating effects
* _Extensively metabolized_ by the **CYP2D6**
* Can interact w/ other drugs that inhibit this system such as **fluoxetine**
33
TCAs
Adverse Effects
* **Sedation**
* **Anticholinergic:** dry mouth, tachycardia, urinary retention etc
* More common w/ tertiary amines such as amitriptyline and imipramine
* **α****-Adrenergic Blockade:** postural hypotension
* **Antihistamine H1 Receptors:** weight gain and sedation
* **Sexual Side Effects**
* H1 & sexual side effects more common w/ clomipramine which is fairly specific for serotonin reuptake transporter
* **Discontinuation Syndrome**
* Because of cholinergic rebound
* **Serotonin Syndrome** if combined w/ SSRI’s or MAOi
34
TCA
Toxicity
_Remember the 3 C’s_: **coma, convulsions and cardiotoxicity**
* **Cardiotoxicity**
* **Quinidine-like effect** ⇒ conduction delays
* #1 cause of mortality in TCA toxicity
* ⊗ Fast sodium-channel in His-Purkinje system
* Impairs Na+ entry into myocardial cells
* Slows depolarization (phase 0)
* **Sodium bicarbonate** ⇒ _antidote to reverse the cardiac toxicity_
* ↑ # of open Na+ channels ⇒ ↑ Na+ gradient across poisoned channels ⇒ partially reversing fast sodium channel blockade
* Also pH dependent effects
* **Convulsions**
* ⊗ GABA-A receptor
* Major cause of seizure in TCA toxicity
* **Confusion and hallucinations** can occur in the elderly that are very susceptible to anticholinergic effects
35
TCAs
Drug Interaction
* ↑ [TCA] when administered w/ **CYP2D6 inhibitors** or in pts w/ **polymorphism** for the enzyme (~7% of Caucasians)
* **Anticholinergic or antihistamine effects** may be additive w/ other OTC meds
* **Antihypertensive medications** may exacerbate the **postural hypotension**
36
Serotonin 5-HT2 Receptor Antagonists
Drugs
**Trazodone** and **Mirtazapine**
37
Trazodone
MOA
* The _major metabolite_ ⇒ **5-HT2A antagonist &** **⊗** **serotonin reuptake**
* _Enhances 5-HT transmission_ at **postsynaptic 5-HT1A receptors** and **5-HT2 receptors** _other than 5-HT2a_
* Effects only occur at high doses
* _At much lower doses,_ acts as an **antagonist at histamine and** **α****-adrenergic receptors**
38
Trazodone
Therapeutic Uses
Most common use in current practice is as a **hypnotic**
**Treating insomnia** w/ _low doses of trazodone_ may augment effects of other antidepressants
39
Trazodone
Pharmacokinetics
* Rapidly metabolized ⇒ **low** **bioavailability**
* Requires BID dosing if used as an antidepressant
* Most often, it is administered **once a day at a low dose at night** for its _sedative properties_
40
Trazodone
Adverse Effects
* **Sedation**
* **GI upset** (less pronounced than SSRIs and SNRIs)
* Sexual side effects are uncommon
* **α****-adrenergic****blockade** ⇒ hypotension and priapism (rare)
* **Nefazodone** (analogue) ⇒ no longer commonly used because of **severe liver toxicity**
41
Trazodone
Drug Interactions
Trazodone is a **substrate for CYP3A4**
_C__ombo w/ potent inhibitors of cytochrome such as ritonavir or ketoconozole_ ⇒ ↑↑↑ levels of trazodone
42
Mirtazapine
Mechanism of Action
* **⊗** **5HT2A/2C and 5HT3 receptors** and **⊗** **presynaptic alpha-2 receptors**
* _⊗ of_ _presynaptic receptors_ ⇒ **↑** **release of norepinephrine and serotonin**
* **↑** **serotonergic transmission** @ _5HT receptors OTHER than 5HT2 receptors_, primarily the **5HT1A receptor**
* _⊗_ _of 5HT2A/2C and 5HT3 receptors_ ⇒ **eliminates side effects** ass. w/ stimulating these receptors
* Also **⊗** **histamine receptors**
43
Mirtazapine
Pharmacokinetics & Therapeutic Uses
* _harmacokinetics_:
* **T** **½** **is 20-40 hours**
* It is usually dosed **once a day in the evening** because of the sedating properties
* _Indications:_
* Could be used in **melancholic depression**
* _Antihistamine properties_ so _sedating_ ⇒ used in **depressed pts that have trouble sleeping**
* Also, mirtazapine will **enhance appetite**
44
Mirtazapine
Adverse Effects & Drug Interactions
* _Adverse Effects:_
* **Increased appetite** and **weight gain**
* **Sedating**
* Does not interfere w/ sexual function which is mediated by 5HT2A/2C receptors
* _Drug Interactions:_
* **Some cytochrome p450 type interactions**
* **Sedating properties may be additive w/ other CNS depressants** such ethanol or benzodiazepines
45
Bupropion
Mechanism of Action
**Unicyclic Antidepressant**
* Drug **resembles amphetamine** in chemical structure ⇒ **CNS activating properties**
* **↑** **norepinephrine release \>** **↑** **dopamine release**
* **Modest** **⊗** **of norepinephrine and dopamine reuptake**
* Unique structure leads to a different side effect profile
46
Bupropion
Therapeutic Uses & Pharmacokinetics
**Atypical depression** and **smoking cessation**
_Extensive first pass metabolism_ ⇒ **short** **T** **½**
More than once a day dosing may be required
47
Bupropion
Adverse Effects & Drug Interaction
* Side effects may include **agitation, insomnia and anorexia**
* Not associated w/ sexual side effects
* **Some cytochrome p450 type interactions**
* Bupropion **should not be combined w/ MAOIs**
48
Monoamine Oxidase Inhibitors (MAOIs)
Drugs and MOA
**Phenelzine, Tranylcypromine, Isocarboxazid, Selegiline**
_Mechanism of Action:_
⊗ MOA ⇒ ↓ monoamine metabolism ⇒ ↑ transmission
* **Phenelzine** and **tranylcypromine** are currently in the US
* **I****rreversible non-selective MAOi** (MAOA and MAOB)
* MAO-A preferentially catabolizes NE and 5-HT
* **Selegiline** ⇒ **selective MAO-B inhibitor**
* Used in treating Parkinson's disease
* _At usual therapeutic dose_, selegiline **primarily protects dopamine (DA) from catabolism by MAO-B**
* _At higher doses that may have antidepressant properties_, selegiline **loses isozyme-selectivity**
* ⊗ of MAO-A appears to be more important in antidepressant benefit from MAO inhibitors
* Other agents in this class referred to as the **RIMA class** (Reversible Inhibitors of Monoamine Oxidase Type A)
49
Monoamine Oxidase Inhibitors
Therapeutic Uses
**Now rarely used** because of _toxicity_ and the _potential for food interactions_
* Used for treatment of **depression unresponsive to other agents**
* Effective against **atypical depression**
* Have been used to treat **anxiety, social anxiety, and panic disorder**
* **Selegiline** is used as an **adjunct in Parkinson’s**, at higher concentrations it used for **depression**
50
Monoamine Oxidase Inhibitors
Pharmacokinetics
**Extensive first pass effect**
**Transdermal selegiline** avoids this first pass and mitigates some of the food interactions
51
Monoamine Oxidase Inhibitors
Adverse Effects
* **Tyramine effects**
* ⊗ of both isozymes ⇒ **⊗** **tyramine metabolism**
* Constituent of many foods including aged cheese, some red wines, and beer
* Tyramine escapes normal enzymatic defenses in the gut, plasma and liver ⇒ _reaches sympathetic neurons_ where it **releases NE**
* **NE is not degraded** because _MAO is inhibited_
* Can produce **dramatic hypertension**
* **Competitive, reversible MAO-A selective drugs** are much less likely to produce this type of drug interaction
* **Serotonin syndrome** via interactions w/ _drugs cause 5-HT release_
* Includes meperidine and other opiates, TCA's, L-DOPA and SSRI's
* **Hypertension** through interactions w/ _sympathomimetics_
* **CNS stimulation in overdose**
* Tranylcypromine resembles amphetamine
* Selegiline has an amphetamine like metabolite
* **Postural hypotension**
* May be due to elevated levels of dopamine in the periphery or to formation of a "false transmitter" called **octopamine**
* **Weight gain**
* Might involve desensitization of serotonergic satiety mechanisms but this is highly speculative
* Weight gain can be substantial in some pts
* Can lead to noncompliance, treatment cessation or a search for an alternative drug
52
Monoamine Oxidase Inhibitors
Drug Interactions
* _Pharmacodynamic interactions_ w/ SSRIs, SNRIs, TCAs, meperidine, others to cause the **serotonin syndrome**
* _Cognitive_: **delirium, coma**
* _Autonomic_: **hypertension, tachycardia, sweating**
* _Somatic_: **myoclonus, hyperreflexia, and tremor**
* Allow two weeks after most serotonergic drugs but 4-5 weeks w/ fluoxetine before switching to MAOIs
* MAOIs must be discontinued 2 weeks before giving another serotonergic agent
* Second major interaction is w/ **tyramine**
* **Other sympathetic drugs such as pseudoephedrine** are also _contraindicated w/ MAOIs_
53
Antidepressants
Table
