Pharm of Antidepressant-Antimanic Agents Flashcards
Depressed mood
amygdala (A) and ventromedial prefrontal cortex (VMPFC) – innervated by NE-5HT-DA projections from brainstem nuclei
Apathy
NE and DA
-PFC, hypothal, nuc accumb
Sleep disturbances
Hypothal, thal, basal forebrain, diffuse areas of prefrontal cortex
-NE-5HT-DA
fatigue
-deficient NE and DA
Guilt
5HT
Changes in weight/appetite
5HT
Suicidal ideation
“emotional” brain regions such as amygdala, ventromedial prefrontal cortex, and orbitofrontal cortex (OFC)
Monoamine (biogenic amine) theory
-Initial observation that reserpine depleted brain NE / 5HT and induced depression
- drugs effective in treating depression shared the common
feature of enhancing availability of NE / 5HT at post syn receptor
-doesn’t totally explain etiology of depression
-LIKELY downstream effects rather than NT themselves (synaptic changes from antidep therapy can lead to alterations of gene expression that improve mood)
Neurodegenerative hypothesis
-major depression is associated with neuronal loss in prefrontal cortex and hippocampus and
antidepressant therapies act by inhibiting-reversing this loss by stimulating neurogenesis
-Prodepressive pathways: stress induced activation of HPA axis that promotes neural apoptosis and also enhances excitotoxic actions of glutamate via NMDA receptors
-antidepressive pathways involve monoamines NE and 5HTacting on GPCR and BDNF acting on TrkB to switch on genes that promote neurogenesis as well as protecting against apoptosis
Inhibition of NT reuptake
TCADs SSRIs SNRIs NDRI Mixed postsynaptic antag/serototin reuptake inhibitor
Amitryptiline
TCAD
- block of serotonin and NE reuptake
- sedative action
- antimuscarinic action
SSRI drugs
fluoxetine
Paroxetine
Escitalopram
Venlafaxine
SNRI
Buproprion
NE and DA reuptake inhibitor: NDRI
Trazodone
Mixed postsynaptic antagonist-serotonin reuptake blocker
-Sedative action
Phenelzine
MAOI
-block enzyme of major degradation pathway for NE and 5HT in neuron (allowing more presynaptic ccumulation and release) leading to chronic compensatory changes at synapse
ECT
increases the amount and activity of rate limiting enzymes for synthesis of NE (tyrosine hyroxylase) and serotonin (typtophan hydroxylase)
CNS stimulants
block reuptake pump and or increase release of NE, but also block DA reuptake or increase DA release
-cause mood elev in normals, NOT effective antidepressant as tolerance develops rapidly to mood elevating effects
SE of SSRIs
acute: nausea, diarrhea, activation insomnia, restlessness, dry mouth
delayed onset: weight gain, sexual dysfunction, cognitive blunting
Very LOW likelihood of fatalities in overdose
Withdrawal: flu like–>severity related to t1/2 (shorter>longer; paroxetine>fluoxetine)
SNRI SE
htn, anxiety
-more rapid appearance of withdrawal sx than SSRIs
NDRI SE
(bupropion)
- anxiety
- potential for sz @ high doses
Trazodone SE
drowsiness
Overdose: minor problems only
TCAD SE
- poor SE profile leading to declining use
- sedation
- Antimuscarinic (blurred vision, constip, dry mouth, urinary hesitancy, fuzzy thinking)
- CV (orthostatic hypotension: alpha1 blockade), arrhythmias and sudden death in overdose
- Neuro: tremor, paresthesias, can see sz in overdose
- Metabolic: weight gain, sexual disturbances
DDI for most agents
additive CNS depressant effects when used with other sedatives
MAOIs DDI
hypertensive crisis with certain drugs and foods high in TYRAMINE (beer/wine/cheese)
SSRIs + MAOIs
serotonin syndrome ([hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia)]
SSRI DDI
Inhibition of P450 drug metabolizing enzymes by fluoxetine / paroxetine (CYP2D6)
Pharmacokinetics TCADs/SSRIs/heterocyclic agents
Incomplete absorption, significant 1st pass effect, high protein
binding/lipid solubility (high Vd)
–>wide interpatient variations in plasma levels for a given dose
Pharmacokinetics MAOIs
Inhibition is irreversible and occurs after drug no longer detectable in plasma (2 weeks)
Bipolar storm
- excessive activity in neuron A
(2) widespread input from its dendrites triggers too much axonal flow, mediated by voltage-sensitive
sodium channels (VSSC)
(3) this in turn overly activates voltage-sensitive calcium channels (VSCC) linked to glutamate release
(4) triggering excessive, chaotic, unpredictable neurotransmission from neuron A to neuron B
(5) this “bipolar storm” is then by detected by postsynaptic NMDA receptors on neuron B
(6) with subsequent excitation of its own VSSC and so on
Lithium
-mech of antimanic action unclear
- Requires 10-21 days for onset (effects greatest on cells with highest activity—use dependence)
-eliminated via kidney
-maintenance tx for manic and depressive episodes,
commonly used in combination with other agents.
adverse effects:
- narrow therapeutic index
- tremor, weakness, GI, decreased thyroid func, polyuria, polydipsia, confusion/sed/lethargy with mod toxicity
- severe toxcity: sz, stupor coma
- diuretics can decrease renal clearance by 25%–> increased Li levels (also with NSAIDs)
