10/12 Antidepressants - Walworth Flashcards
monoamine neurotransmission
action of reserpine
relationship between reserpine and depression →
monoamine hypothesis
neurotransmitters (norepi, DA, serotonin) are synthesized from a.a. precursors in specific neurons, packaged into vesicles, released in response to stimuli
- bind to postsyn cell receptors
- can also be re-uptaken by presyn cell transporter
reserpine binds to vesicles and inhibits VMAT (vesicular monoamine transporter) → prevents nerve endings from storing/concentrating monoamines in vesicles
- combined with monoamine degradation by MAO in the cytoplasm…little to no active nt released by presyn
depletion of nt by reserpine can lead to depression
→→→ hypothesis for pathegenesis of depression!
Monoamine Hypothesis: depressed mood results from decreased monoamine neurotransmission
monoamine neurotransmitters related to depression
serotonin and central adrenergic neurotransmission modulate mood
→ depression represents decr availability of either 5-HT (serotonin) or NE or both
synthesis and catabolism of serotonin, norepi
serotonergic neurons:
- pick up L-tryptophan → 5HTP → 5HT → released/reuptaken
- 5HT can be degraded in cytoplasm by MAO
noradrenergic neurons:
- pick up tyrosine → DOPA → DA → NE → released/reuptaken
- NE can be degraded in cytoplasm by MAO
- NE can be degraded in synapse by COMT
sites of action of major classes of antidepressants
1. block breakdown of nts
- MAOIs (cytoplasm)
2. block reuptake of nts
- SSRIs (membrane transporter)
- SNRIs (membrane transporter)
- TCAs (membrane transporter)
3. antagonize receptors for serotonin on postsynaptic cells
limitations to monoamine hypothesis of depression
possible explanation
TIME LAG/delay in clinical effect
- clinically useful antidepressants act rapidly at pharmacologic sites of action…
but clinical effects require 3 or more weeks of tx
- reserpine rapidly depletes nt…
but several weeks of tx are required to induce depression
possible role of presynaptic autoreceptors
autoreceptors bind nt released by a cell or neighboring cells
- NOT reuptake transporter!
autoreceptor autoregulatory mechanisms
pretreatment
acute treatment
long-term treatment
pre-treatment
- autoreceptors bind to nt (serotonin or NE) released by presynaptic cell
- ligand-bound autoreceptors exert inhibitory effect on synthesis and release of nt
→→→ low level of signaling at postsyn cell
acute treatment
- acute treatment blocks reuptake transporter proteins (TCA or SSRI) → increased binding to presyn autoreceptors → increased inhibitory effect on synthesis and release of nt
→→→ low level of signaling at postsyn cell continues
long-term treatment
- long term tx with reuptake inhibitor → continuous exposure of autoreceptors to nt → downregulation of autoreceptors!!!
- disinhibition of synthesis and release of nt
→→→ more nt made/released → therapeutic level of signaling achieved
model to explain why the time lag for tx → effect might exist
- may or may not hold up under scrutiny
sites of action of major classes of antidepressants
reuptake inhibition
- noradrenergic neurons: NET targeted by
- TCAs
- SNRIs
- serotonergic neurons: SERT targeted by
- SSRIs
- TCAs
- SNRIs
inhibition of degradation
- degradation of NE/5HT by MAO targeted by
- MAOIs
SSRIs
drugs
clinical uses
selective serotonin reuptake inhibitors
- bc relatively selective for 5HT transporter, side effects are limited to effect on 5HT-mediated responses
fluoxetine (Prozac)
paroxetine (Paxil)
sertraline (Zoloft)
citalopram
escitalopram (Lexapro)
fluvoxamine
SSRI clinical uses
- major depression
- anxiety disorder
- OCD
- PTS
- PMDD
- bulimia
SSRI adverse effects
resulting from elevation of serotonin in various tissues
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfx
- extrapyramidal effects (early on)
- seizures with gross overdose
- serotonin syndrome with MAOI
SNRI
drugs
clinical uses
serotonin and norepi reuptake inhibitor
- inhibit both NE reuptake transporter (NET) and 5HT reuptake transporter (SERT)
venlafaxine (Effexor)
duloxetine (Cymbalta)
clinical uses
- major depression
- chronic pain
- fibromyalgia
- menopausal sx
SNRI adverse effects
lots of overlap with SSRI side effects (bc still blocking SERT)
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfx
- extrapyramidal effects (early on)
- seizures with gross overdose
- serotonin syndrome with MAOI
also effects from blocking NET
- anticholinergic
- sedation
- hypertension (venlafaxine)
TCAs
drugs
clinical uses
tricyclic antidepressant
- inhibit reuptake transporters for both NE and 5HT (like SNRIs)
- also interact with variety of other receptors → broad range of side effects
imipramine (more selective for SERT)
amitriptyline
clomipramine (more selective for NET)
desipramine
nortriptyline
clinical uses
- major depression
- chronic pain
- OCD (clomipramine)
TCA adverse effects
lots of overlap with SSRI side effects (bc still blocking SERT)
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfx
- extrapyramidal effects (early on)
- seizures with gross overdose
- serotonin syndrome with MAOI
also other effects
- alpha-block (orthostatic hypotension)
- muscarinic block
- sedation
- weight gain
- arrhythmias and seizures with OD
MAOIs
drugs
clinical uses
monoamine oxidase inhibitors
- inhibit MAO
phenelzine → combines irrev with MAO (long lasting inhibition)
tranylcypromine → does not bind irrev, but has prolonged effect
clinical uses:
- major depression unresponsive to other drugs
MAOI adverse effects
- hypertensive rxn in response to indirectly acting sympathomimetics
- hypterthermia
- CNS stimulation (agitation, convulsions)
- HTN crisis with tyramine-containing food
- serotonin syndrome with SSRI
- orthostatic HTN
5HT2 antagonists
drugs
clinical uses
serotonin receptor (2) antagonists
- anti-anxiety, anti-psychotic, anti-depressive effects
nefazodone → black box warning due to hepatotox
trazodone → prodrug, converted to 5HT2A antagonist
clinical uses
- major depression
- hypnosis (trazodone)
5HT2 antagonist adverse effects
- sedation
- alpha-block (orthostatic hypotension)
heterocyclic agents
drugs
clinical uses
bupropion → mech unclear
- enhances both NE and DA neurotransmission
mirtazapine → blocks presyn alpha2 receptors (typically inhibit release of nt…action of mirtazapine disinhibits this release)
- antagonist at 5HT2A/2C and 5HT3 receptors
- antagonist of presyn alpha2 autoreceptor → enhances release of NE and 5HT
clinical uses
- major depression
- smoking cessation (bupropion)
- sedation (mirtazapine)
heterocyclics adverse effects
bupropion
- lowers seizure threshold
mirtazapine
- sedation
summary table highlighting differences of antidepressants
SSRIs block 5HT reuptake, not a whole lot of other action
SNRIs block 5HT and NE reuptake, not a whole lot of other action
TCAs block 5HT and NE reuptake, also block other receptors (ACh M, alpha adrenergic, histamine)
others…
- trazodone: antagonist at 5HT2 receptors
- bupropion: mech unclear
- mirtazapine: antagonist at 5HT2 receptors but also blockade of H1 receptors (sedative props)
PK features of antidepressant drugs
general features
special notes for SSRI, SNRI
in general, most
- rapid oral absorption
- peak pl concentration in 2-3hr
- half-life approx 0.5-1 day
- tightly bound to plasma proteins
- metabolized by liver
- eliminated by kidney
SSRIs
- norfluoxetine (metabolite of fluoxetine) has loooong halflife (7-9days)
- imp to know if transitioning to diff drug! bc it prob wont all be cleared at time of transition
SNRIs
-
venlafaxine extensively metabolized via CYP2D6
- keep an eye out for inducers
major drug interactions with antidepressants
PK interactions
- paroxetine and fluoxetine are inhibitors of CYP2D6
- many drugs are 2D6 substrates (TCAs, haloperidol/risperidone, codeine/oxycodone, betablockers)
- fluvoxamine and others are inhibitors of CYP3A4
PD interactions
- sedative effect drugs are ADDITIVE with other sedatives (esp alc and benzodiazepines)
- MAOIs sensitize pt to indirect sympathomimetics (tyramine) and to sympathomimetics (ephedrine)
- SSRI/SNRI + MAOI → serotonin syndrome
serotonin syndrome
most frequently from drug interactions from drugs acting on diff mechs to increase serotonin signaling
- SSRI + MAOI
- SSRI + drug with MAOI activity (ex. linezolid)
- SSRI + serotonergic drug (ex. dextromethorphan, sumatriptan, tramadol, St. John’s word)
- SNRI + MAOI
AMS, fever, tachycardia, HTN, agitation, tremor, myoclonus, hyperreflexia, ataxia, incoordination, diaphoresis, shivering, GI sx
overdoses of antidepressants
TCAs : extremely dangerous (no refill, small quant rx)
MAOIs : intoxication is rare, req supportive tx
SSRIs : OD fatalities rare, intoxication req supportive tx
bupropion : seizures
mirtazapine : disorientation, tachycardia
OD with newer agents often involves other drugs, incl alcohol
lithium
indicated for bipolar affective disorder
- efficacy as monotherapy for manic phase
Li mechanism: unclear
- enters cells via Na channels
- substitutes for Na in generating APs, Na exchange across membranes
PK
- completely absorbed in 6-8hr
- distributed in total body water → slow entry to intracellular compartments, no protein binding
- excreted entirely in urine
- pl halflife 20hr
- target pl conc approx 0.6-1.4 mEq/L
- TOX seen at 2 mEq/L
drug interactions
- diuretics decr renal clearance by 25%
- some NSAIDs decrease clearance by incr Li reabs in proximal tubules
Li toxicity and adverse effects
tremor common at therapeutic dose
- controlled with propranolol or atenolol
reversibly decreases thyroid rx
reversible polydipsia, polyuria
inhibits K entry to myocytes
- abnormal repol
- extracellular hyperK
- intracellular hypoK
Li contraindications
- severe deydration or Na depletion
- signficant CVD
- signficant renal impairment
- during lactation
overal drug list
