Flashcards in Anti-Depressants Deck (67):
Pathogenesis of Depression: What is the monoamine hypothesis of mood that is the basis of all anti-depression medication therapy?
DECREASED MONOAMINE (Serotonin [5-HT] and(or) NE) results in DEPRESSED MOOD
What are the major steps of serotonin (5-hydroxytryptamine) synthesis?
1) Trp enters serotonergic neuron via Trp receptor
2) Trp gets hydroxylated into 5-HTP via Trp hydroxylase
3) 5-HTP gets decarboxylated into 5-HT (serotonin) via 5-HTP decarboxylase
What are the 3 fates of serotonin post-synthesis?
1) Can enter pre-synaptic vesicles via VAT for vesicular transport and release onto the post-synaptic membrane
2) Can enter pre-synaptic vesicles via VAT -> Exit -> REUPTAKE by 5-HT receptors of the serotonergic neuron
3) Stays in the serotonergic neuron -> Gets metabolized into 5-HIAA by cytoplasmic MAO
What are the major steps of NE synthesis?
1) Tyr enters the adrenergic pre-synaptic neuron by Tyr transporter
2) Tyr gets HYDROXYLATED into DOPA by tyrosine-3-monooxygenase
3) DOPA gets DECARBOXYLATED into DOPAMINE by aromatic L-AA decarboxylase
4) DOPAMINE gets HYDROXYLATED into NE by dopamine beta hydroxylase
What are the 4 fates of NE post-synthesis?
1) Enters into the pre-synaptic vesicle by VAT -> Exits -> Acts on post-synaptic tissue
2) Enters into pre-synaptic vesicle by VAT -> Exits -> Gets re-uptaken by adrenergic neuron by NE reuptake transporter
3) Enters into pre-synaptic vesicle by VAT -> Exits -> Post-synaptic COMT acts on NE and degrades it
4) Stays in the adrenergic neuron -> Pre-synaptic Cytoplasmic MAO degrades NE into de-aminated derivatives
What are the two targets of major classes of anti-depressants?
1) Block re-uptake of NT by the pre-synaptic neuron
2) Block CYTOPLASMIC MOA's metabolic breakdown of NT in the pre-synaptic neuron
What are the 6 major classes of anti-depressants?
5) 5-HT2-R antagonists (Serotonin antagonists)
What are the 2 main limitations of the monoamine hypothesis?
1) Anti-depressants may have a RAPID ONSET, BUT clinical effects require 3 or more weeks to present
2) Reserpine has RAPID ONSET of effect of depleting NT, BUT several weeks are required to induce depression
What can explain the discrepancy between the pharmacological action and delayed clinical effect of anti-depressants?
PRE-SYNAPTIC AUTORECEPTORS - Cell surface receptors on the pre-synaptic neuron that binds to NT released by that cell or neighboring cell
**(DIFFERENT from re-uptake transporters)
What is the potential model explanation of the delayed clinical effect of anti-depressants (i.e. explain the autoregulatory mechanism of pre-synaptic autoreceptors)?
PRE-TREATMENT: Pre-synaptic autoreceptors bind released NT -> Ligand (NT)-bound autoreceptors exert inhibitory effect on NT synthesis and release = LOW level of signaling
ACUTE TREATMENT (SSRI or TCA): Blocked re-uptake of NT -> INCREASED NT levels in the synaptic cleft -> INCREASED levels of ligand (NT)-bound autoreceptors -> ENHANCED Inhibitory effect on NT synthesis and release = LOW level of signaling
CHRONIC TREATMENT (SSRI or TCA): CONTINUOUS exposure of NT in the synaptic cleft -> DOWNREGULATION of pre-synaptic receptors -> DISINHIBITION of NT synthesis and release -> INCREASED NT release to post-synaptic cell = THERAPEUTIC level of signaling
Name the 3 classes of MA-reuptake transporter inhibitors.
CLASS 1 SSRI) Name the 6 SSRIs with their brand names.
1) **FLUOXETINE (Prozac)
3) **PAROXETINE (Paxil)
4) **SERTRALINE (Zoloft)
6) ESCITALOPRAM - S-enantiomer of citalopram (LEXAPRO)
CLASS 1 SSRI) Name the 6 clinical usages of SSRIs.
1) Major Depression
2) Anxiety Disorder
3) OCD - obsessive compulsive disorder
4) PTSD - post-traumatic stress disorder
5) PMDD - post-menstrual dysphoric disorder
CLASS 1 SSRI) What is the mechanism of action of SSRIs?
SELECTIVELY inhibits 5-HT (Serotonin) re-uptake, compared to NE re-uptake -> INCREASES 5-HT (Serotonin) level in the synaptic cleft
CLASS 1 SSRI) Side effects of SSRI are due to an elevation of what neurotransmission?
Side effects limited to ELEVATED SEROTONIN transmission in various tissues + CNS since SSRIs selectively act on 5-HT reuptake channels
CLASS 1 SSRI) What are the adverse side effects of SSRIs?
N/H/I - nausea/headache/insomnia
AA - anxiety/agitation
E - extrapyramidal effects (early in treatment
SSS - sexual dysfunction, seizures with gross overdose, serotonin syndrome if combined with MAOI
CLASS 2 SNRIs) Name the 2 SNRIs
1) **VENLAFAXINE (Effexor)
2) DULOXETINE (Cymbalta)
CLASS 2 SNRI) Name the 4 clinical uses.
1) Major Depression
2) Menopausal symptoms
3) Chronic pain
CLASS 2 SNRI) What is the mechanism of action of SNRIs?
Inhibits the re-uptake of BOTH 5-HT (Serotonin) and NE
CLASS 2 SNRI) Side effects of SNRIs are due to the elevation of which neurotransmission?
Inhibiting re-uptake of BOTH 5-HT and NE = ELEVATED neurotransmission of 5-HT and NE in various tissues + CNS
CLASS 2 SNRI) Name the adverse side effects of SNRIs.
Overlapping SSRI side effects:
N/H/I - Nausea/headache/insomnia
AA - anxiety/agitation
E - extrapyramidal effect (early treatment)
SSS - sexual dysfunction + seizures (gross overdose) + serotonin syndrome if taken with MAOI
NE-mediated side effects ("ASH")
3) Hypertension (particularly with Venlafaxine)
CLASS 3 TCA) Name the 5 TCAs.
I/C/D - A/N
CLASS 3 TCA) Name the 3 clinical uses of TCAs.
1) Major Depression
2) Chronic Pain
3) OCD (particularly CLOMIPRAMINE)
CLASS 3 TCA) What is the mechanism of TCAs? (2)
1) PRE-SYNAPTIC LEVEL: Blocks re-uptake of BOTH 5-HT (serotonin) and NE
2) POST-SYNAPTIC LEVEL: Blocks post-synaptic alpha-adrenergic receptors + muscarinic receptors + histamine receptors
CLASS 3 TCA) Do TCAs have a narrow or wide range of side effects? Why?
BROAD range of side effects because they act on a variety of other receptors (e.g. the post-synaptic alpha-adrenergic receptors)
CLASS 3 TCA) How are DESPIRAMINE and IMIPRAMINE related to each other?
They are SEPARATE TCA drugs, but DESPIRAMINE is a metabolite of IMIPRAMINE
CLASS 3 TCA) IMIPRAMINE and DESPIRAMINE each have a greater affinity (i.e. selectivity) for a particular receptor. Which ones?
IMIPRAMINE - More selective for the serotonin reuptake transporter
("I Scream ...[for ice cream]" lol)
DESPIRAMINE - More selective for the NE reuptake transporter
CLASS 3 TCA) What are the side effects of TCAs?
Overlapping side effects of SSRIs:
N/I/H, A/A, E, S/S/S - Nausea/Insomnia/Headache, Anxiety/Agitation, Sexual Dysfunction/Stroke with Gross amounts/Serotonin Syndrome when taken with MAOI
Separate, non-overlapping TCA Side Effects
"AMSA, W - AMSA War?...."
1) Alpha-block (orthostatic hypotension)
2) Muscarinic block
4) Arrhythmia + Seizures with Overdose
5) Weight Gain
How was evidence attained for the monoamine hypothesis explaining the pathogenesis of depression? What was the mechanism?
RESERPINE (introduced as an anti-hypertensive) was found to INDUCE depression
Mech: Inhibits VAT (vesicular monoamine transporter) -> Nerve endings can not concentrate and store MA in vesicles -> MA accumulate in the cytoplasm -> Get degraded by MAO -> Little/no active MA released from nerve endings
CONCLUSION: LITTLE MA = INDUCTION of DEPRESSION
CLASS 3 TCA: Which is the best MONOTHERAPY for treating severe MDD or BAD with psychosis?
CLASS 4 MAOI) Name the 2 MAOIs.
CLASS 4 MAOI) Name the main use of MAOI.
Major Depression Disorder that was UNRESPONSIVE to other drugs
CLASS 4 MAOI) What is the binding affinity of PHENELZINE to the MAO and how does it explain its duration of action?
PHENELZINE = IRREVERSIBLE MAO inhibitor = LONG-LASTING inhibition
CLASS 4 MAOI) Name the binding affinity of TRANYLCYPROMINE and its duration of action
TRANYLCYPROMINE = REVERSIBLE MAO inhibitor but still has PROLONGED effect
CLASS 4 MAOI) What are the adverse effects of MAOIs?
"3H's + COSBY w/o the BY"
1) Hypertensive reactions (MAOIs sensitize pts to indirect sympathomimetics [e.g. tyramine/epherine])
2) Hypertensive CRISES when taken with Tyramine-containing foods
4) CNS Stimulation (agitation, convulsions)
5) Orthostatic hypotension
6) Serotonin syndrome if taken with SSRI
CLASS 5: 5-HT2-R-Ant) Name the 2 serotonin receptor antagonists.
CLASS 5: 5-HT2-R-Ant) Name the 2 clinical uses of these drugs.
1) Major Depression
2) Hypnosis (particularly TRAZODONE)
CLASS 5: 5-HT2-R-Ant) What is the mechanism of these drugs?
Antagonize specifically the 5-HT2A-receptors residing in the CEREBRAL CORTEX
Inhibition of 5-HT2A-R associated with anti-anxiety, anti-depression, and anti-psychosis
CLASS 5: 5-HT2-R-Ant) Is TRAZODONE the active form blocking serotonin receptors?
NO, it is a prodrug that gets converted to the active metabolite 5-HT2A antagonist
CLASS 5: 5-HT2-R-Ant) How safe is NEFAZODONE?
"N for NOT safe"
NOT SAFE - "BLACK BOX WARNING" due to severe risk of HEPATOTOXICITY
CLASS 5: 5-HT2-R-Ant) What are the 2 adverse effects of NEFAZODONE and TRAZODONE?
1) Sedation (due to histamine H1 blockade)
2) Orthostatic hypotension (due to alpha blockade)
CLASS 6 HETEROCYCLICS) Name the 2 heterocyclic anti-depressants.
"Cycle, a type can be mountain bike (MB)"
CLASS 6 HETEROCYCLICS) What are 3 mechanisms of action of MIRTAZAPINE?
1) PRE-SYNAPTIC LEVEL: Blocks pre-synaptic alpha2receptors at BOTH adrenergic + serotonergic neurons -> Disinhibition of alpha-2-mediated inhibition of NT release -> ELEVATED NE and 5-HT RELEASE from pre-synaptic neurons
2) POST-SYNAPTIC LEVEL: Blocks several serotonin receptor isoforms
3) POST-SYNAPTIC LEVEL: Blocks histamine receptors
CLASS 6 HETEROCYCLICS) What is the mechanism of action of BUPROPION?
Mechanism of action is unclear, but it is thought to ENHANCE NE and 5-HT neurotransmission
CLASS 6 HETEROCYCLICS) What are the 3 main clinical uses of BUPROPION + MIRTAZAPINE?
1) Major Depression
2) Smoking Cessation (particularly BUPROPIONE)
3) Sedation (particularly MIRTAZAPINE)
CLASS 6 HETEROCYCLICS) What clinical condition is MIRTAZAPINE highly used for?
Insomnia/Anxiety - used to induce sedation
CLASS 6 HETEROCYCLICS) What clinical condition is BUPROPION highly used for?
CLASS 6 HETEROCYCLICS) What is the 1 adverse effect of BUPROPION?
Lowers SEIZURE threshold
CLASS 6 HETEROCYCLICS) What is the 1 major adverse effect of MIRTAZAPINE?
Sedation - Due to histamine blockade action in the post-synaptic level
PHARMACOKINETICS) List ADME of anti-depressants
A - Rapid ORAL absorption
D - Reach peak plasma levels at 2-3hrs, half-life 0.5-1day, tightly bound to plasma proteins
M - Metabolized by liver
E - Eliminated by kidney
PHARMACOKINETICS) Which is the 1 SSRI that has a particularly LONG half-life (7-9 days)?
FLUOXETINE (Prozac) is metabolized to its active form NORFLUOXETINE (half-life = 7-9d)
PHARMACOKINETICS) What is one precautionary factor when transitioning a pt from FLUOXETINE (SSRI) to a MAOI?
Even after fluoxetine is discontinued, it may remain in pt's system for a while due to its long half-life (7-9d) -> Can result in SEROTONIN SYNDROME
PHARMACOKINETICS) Which anti-depressant is extensively metabolized by CYP2D6? (*Hint SNRIs)
Thus need to be very careful if pt is taking another substance that is a CYP2D6 inducer or inhibitor
PHARMACOKINETIC INTERACTIONS) Which is a potent CYP3A4 inhibitor?
PHARMACOKINETIC INTERACTIONS) Which 2 drugs are CYP2D6 inhibitors? Which drug intakes are thus affected?
FLUOXETINE + PAROXETINE
Drugs that are CYP2D6 substrates - VENLAFAXINE (SNRI) + TCAs + anti-psychotics (HALOPERIDOL/RISPERIDONE) + codeine/oxycodone + beta-blockers
PHARMACODYNAMIC INTERACTIONS) Which side effect is additive with other substances such as ethanol and BZs?
Additive with other sedation-inducing anti-depressants:
Classes 2,3,5,6 (SNRIS - V,D + TCAs - I,C,D,A,N + 5-HT2A antagonists - N,T + heterocyclic - mirtazapine)
PHARMACODYNAMIC INTERACTIONS) How can MAOIs (P,T) cause hypertensive episodes INDIRECTLY?
MAOIs sensitize pts to indirect sympathomimetics (e.g. tyramine + ephedrine)
PHARMACODYNAMIC INTERACTIONS) What drug interactions can result in serotonin syndrome? (4)
1) SSRI + MAOI
2) SSRI + drug with MAOI activity (e.g. LINEZOLID)
3) SSRI + SEROTONERGIC drug (e.g. dextromethorphan, sumitriptan, tramodol, St John's wort)
4) SNRI + MAOI
PHARMACODYNAMIC INTERACTIONS) What is serotonin syndrome?
CNS Symptoms (2A's)- Altered mental status + Agitation
SYMPATHETIC responses - Fever + tachycardia + HTN + Diaphoresis + shivering
MOTOR - Hyper-reflexia + Myoclonus + Tremor + Ataxia + Incoordination
CLINICAL TOXICOLOGY) Are the toxic effects of TCA overdose serious?
YES, very dangerous!
Prescribed on "no refill basis" + Small quantities
CLINICAL TOXICOLOGY) Are the toxic effects of SSRIs and MAOIs overdoses severe/common?
Intoxication and OD fatalities are RARE
Would require supportive treatment
CLINICAL TOXICOLOGY) What is the toxic effect of BUPROPION overdose?
CLINICAL TOXICOLOGY) What is the toxic effect of MIRTAZAPINE overdose?
Disorientation ("think extreme sedation")
Tachycardia ("think serotonin syndrome")
CLINICAL TOXICOLOGY) What other substances are usually involved with newer anti-depressant agent overdoses?
ALCOHOL + Other drugs (not specified in podcast)
LITHIUM) What clinical diagnosis is lithium most commonly used for?
BIPOLAR AFFECTIVE DISORDER (manic type OR depressed type) - Used to stabilize mood states
LITHIUM) What is the supposed mechanism of the switch from mania to depression in BIPOLAR AFFECTIVE disorder?
Drugs that INCREASE NE/E/DA (catecholamine) activity - Exacerbates mania
Drugs that DECREASE NE/DA activity - Reduces mania