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
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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
-
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
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
29
Q
Tricyclic Antidepressants
Drugs
A
- Amitriptyline
- Nortriptyline
- Imipramine
- Desipramine
- Clomipramine
30
Q
TCAs
Mechanism of Action
A
⊗ 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
33
Q
TCAs
Adverse Effects
A
- 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
Q
TCA
Toxicity
A
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
-
Quinidine-like effect ⇒ conduction delays
-
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
37
Q
Trazodone
MOA
A
- 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
42
Q
Mirtazapine
Mechanism of Action
A
-
⊗ 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
46
Q
Bupropion
Therapeutic Uses & Pharmacokinetics
A
Atypical depression and smoking cessation
Extensive first pass metabolism ⇒ short T ½
More than once a day dosing may be required
48
Q
Monoamine Oxidase Inhibitors (MAOIs)
Drugs and MOA
A
Phenelzine, Tranylcypromine, Isocarboxazid, Selegiline
Mechanism of Action:
⊗ MOA ⇒ ↓ monoamine metabolism ⇒ ↑ transmission
-
Phenelzine and tranylcypromine are currently in the US
-
Irreversible non-selective MAOi (MAOA and MAOB)
- MAO-A preferentially catabolizes NE and 5-HT
-
Irreversible non-selective MAOi (MAOA and MAOB)
-
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)
51
Q
Monoamine Oxidase Inhibitors
Adverse Effects
A
-
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
- ⊗ of both isozymes ⇒ ⊗ tyramine metabolism
-
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
53
Q
Antidepressants
Table
A
