8.8 Antidepressants Flashcards
2 extremes of affective disorders
depression and mania
depression
is charactized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetie or sleep, melancholia, suicidal, homocidal thoughts and attempts, slow to react
mania
refers to elation or irritable mood racing thought,
accelerated speech,
increased activity,
reduced sleep,
reckless or violent behaviour and
may be progressivley loss of contact with reality
Amine hypothesis of depression
functional deficit of NT amines (NE and serotonin),
dec synaptic NE in forebrain neurons,
dec alpha adrenergic receptors in forebrain,
inc inhibitory 5HT2A receptors leading to dec 5HT,
abnormal HPA which produces cortisol–> dec catecholamine neurotransmission
Antidepressants act
acutely to increase the concentration of neurotransmitters NE and or serotonin in the cortical synapses.
mode of action of antidepressnats
complex with acute and chronic adaptive changes decrease in 5HT2A rec leading to inc BDNF (brain derived neurotropic factor), inc cAMP/PKA signaling and inc CREB protein
how long does full antidepressant effect take
2-6 weeks, change in cortical synaptic palsticity
Antidepressant classification
monoamine oxidase inhibitors,
tricyclic antidepressants,
selective serotonin reuptake inhibitors,
atypical antidepressants (Serotonin blockers),
other (serotonin NE reuptake inhibitors -SNRI)
what is MAO
a flavin containing mitochondrial enzyme present in never liver, and intestine
MAO-A
preferentially degrades NE and Serotonin
MAO-B
degrades dopamine preferentially
MAO inhibitors
exert aciton in presynaptic axoplasme
Non selective MAOI
tranylcypromine,
Phenelzien
MAO-A -I to treat
atypical depression – Moclobemide
MAO-B-I to treat
parkinsonism –Selegeline
MAO inhibitors
phenelzine, tranylcypromine
bind covalently to enzyme so prolonged action,
well absorbed orally,
max effect is seen after 2-4 weeks,
use-in atypical depressions
(when all other antidepressants are not useful and ECT refused)
What is safe
MAO-A I safer and more effective than nonselective.
but Moclobemide binds reversibly: safer
MAO inhibitors adverse effects (Phenelzine, Tranylocypromine)
unpredictable side effects limit the widespread use,
most common adverse effects of MAO-I is postural hypotension,
Anticholinergic side effects like dry mouth,
blurred vision,
dysuria and constipation (but less common compared to TCA),
weight gain,
sleep distrubances,
sexual dysfunction (phenelzine)
MAO-I drug interactions– inc NE
inc NE --> hypertensive crisis, durgs: NT releasers (tyramine), TCA, alpha 1 agonists (cold medications), levodopa,
Symptoms: inc BP, arrhythmias, rarely subarachnoid bleeding and stroke, excitation, hyperthermia
MAO-I drug interactions – inc 5HT
inc serotonin–> serotonin syndrome (life-threatening),
drugs: SSRIs, TCAs, Meperidine, Dextromethorphan,
Symptoms: sweating, rigidity, fever, myoclonus, hypertermia, ANS instability, seizures, coma
MAO-I drug interactions–chees rxn
MAO-I interact with indirectly acting tyramine--dangerously leading to hypertension, tachycardia, cardiac arrhythmias, and stroke --chees rxn.
Pts on MAO inhibitors must therefore be eucated to avoid tyramine containing foods
(aged chees, chicken, liver, beer, and red wines)
Tricyclic antidepressants (TCA) NE and 5HT reuptake inhibitors
tertary amines: clomipramine, Amitriptyline, Doxepin, imipramine,
Secondary amine:
desipramine,
nortriptyline
TCA therapuetic efficacy
all have similar therapuetic efficacy and choice of drug depends on the pt tolerance and duration of action,
pts who do no respond to one TCA may benefit from a different drug in this group,
these drugs are valuable alternative for pts who do not respond to SSRIs
TCA NE/5HT reuptake inhibitors
inhibition of NT uptake, Blocking of receptors
TCA - Inhibition of NT uptake
inhibit neuronal re-uptake of both serotonin and NE into presynaptic nerve terminals
- -> inc monoamines in the scynaptic cleft, positive adaptive receptor changes
- –> antidepressant effects (over several weeks),
do not block dopamine reuptake
TCA - Blocking of receptors
also block alpha 1,
muscarinic and
histamine 1 receptors
–> untowards effects
TCA Vd
lipophilic – large Vd (10-50L/kg)
TCA half life
long t1/2 so given orally once daily.
Not easily removed by dialysis in overdose
—>dangerous
TCA tertiary amines have
N desmethyl active metabolites –
amitryptiline (nortryptiline),
Imipramine (Des-methyl imipramine).
T1/2 longer (30-70hrs)
amoxapine
has a hyroxyl active metabolite extrapyramidal adverse effects
–bc metabolite blocks dopamine receptors
TCA hepatic metabolism
CYPS 2D6, 2C19,
CYP 3A4/5
what induces the metabolism of TCA
Anitconvulsants (barbiturates, carbamazepine) cigarette smoking induce the metabolism,
so decrease TCA effects
TCA adverse effects
antimuscarinic effects–drymouth, blurred vision, constipation, memory dysfucntion, tachycardia, palpitations, urinary retention,
alpha1 blockade—orthostatic hypotension, syncope and falls and reflex tachycardia (palpitations),
histamine 1 block—sedation, weight gain; tremors seizures, arrhythmia, secxual dysfunction.
Unmasking mania
Precautions of TCA
manic depressive pts, bc they unmask manic behavior,
anticholinergic effects: glaucoma, BPH,
narrow TI (fatality at > 1ug/ml),
drug toxicity: the “3Cs”
–coma, convulsions, and cardiotoxicity
TCA contraindications
acute MI, BBB (inc arrhythmia risk and cardiac depression)
Drug interactions of TCA
hypertensive crisis with MAO inhibitors –hypertension, hyperthermia, seizures and coma (when given with MAO inhibitors),
Serotonin syndrome when given with SSRI and MAO inhibitors,
toxic sedation with Ethanol and other CNS depressants,
blunted antihypertensive action of alpha2 agonists (clonidine) and guanethidine
Overdose and toxicity of TCA
overdose of TCA produces
severe anticholinergic and antiadrenergic signs,
respiratory depression, arrhythmias, shock, seizures, coma, and death
treatment of TCA overdose
supportive — NaHCO3 for cardiac toxicity
(arrhythmia: NaHCO3 increases the ratio of nonionized TCA to ionized TCA and thereby decreases the binding of the TCA to the sodium channel in cardiac membranes)
Uses of TCA
major depression,
phobic and panic disorder/anxiety states,
obsessive-compulsive disorders (OCDs) - (Clomipramine),
Neuropathic pain (amitriptyline),
enuresis (imipramine)
SSRI – selective serotonin reuptake inhibitors
fluoxetine,
paroxetine,
sertraline,
fluvoxamine,
citalopram,
escitolopram,
why are SSRIs better than TCAs
They overall produce fewer serious adverse effects than TCAs (devoid of ANS and CVS effects);
hence first line drug in the management of depression
SSRI action
block the re-uptake of serotonin
- -> increased concentration of serotonin in the synaptic clefts
- -> greater postsynaptic 5HT stimulation
SSRI cause gradual decrease in 5HT2AR causing
inc NE release,
inc BDNF,
inc intraneuronal cAMP/PKA,
inc CREB protein in cerebral cortex
how long do SSRIs take to work
usually take 2 weeks to produce improvement in mood and max benefit requires 12 weeks or more
Adverse effects of SSRIs
anxiety, agitation, bruxism, sexual dysfucntion (anorgasmia), weight loss
SSRI toxicity
serotonin syndrome (tremor, hyperthermia, muscle regidity, and cardiovascualr collapse)
with MAO inhibitors, TCAs, Meperidine, Dextromethorphan
SSRI and children
should be used cautiously in children and teenagers, as it induces suicidal tendancy.
Fluoxetine is the only SSRI shown to be effective in children
St. John’s wort
herbal medication has been considered as safe for mild or moderate depression,
active ingredient is hypercin (mild SSRI activity),
it ihibits MAO and also appears to block the reuptake of serotonin,
may cause serotonin syndrome
SSRI pharmacokinetics
all SSRIs are well absorbed after oral admin,
sertralin undergoes significant first-pass metabolism,
good distribution and metabolism by P450-dependent enzymes and glucuronide or sulfate conjugation
Fluoxetine differs from other SSRIs in 2 respects
has a much longer half life,
active metabolite compound
norfluoxetine halflife of 10 days
Fluoxetine and Paroxetine inhibit
hepatic CYP450 isoenzymes 2D6, 2C9 which metabolizes TCAs, antipsychotics, opiates, some antiarrhytmics and beta blockers,
so increased risk of toxicity.
Uses of SSRIs
major depression,
OCD (SSRIs supplanted the use of Clomipramine),
Bulimia,
Anxiety disorders (including panic disorder),
Premenstral dysphoric disorders (PMDD)
Atypical antidepressants
trazodone,
nefazodone,
venlafaxine,
desvenlafaxine,
bupropion,
mirtazapine,
amoxapine
maprotiline, ,
duloxetine
Trazodone
inc 5HT level in the brain
reduces reuptake, and by interfering with its metabolism, and metabolites are strong 5HT receptor agonist
Trazodone causes
cardiac arrhythmia,
postural hypotension,
priapism (due to alpha-blocking activity) and
sedation (due to H1-blocking activity)
Trazodone anticholinergics
has no significant anticholinergic activity and has fewer ANS and CVS effects than TCAs and is
safer than TCAs in overdose
Trazodone extra properties
due to its sedating property, it is commonly used as an adjunct to an SSRI in pts with insomnia
Nefazodone
poor oral bioavailability (F=0.2),
action like trazadone,
nefazodone also causes sedation but is not associated with priapism or sexual dysfunction,
less used bc of concerns about rare hepatotoxicity
Venlafaxine
nonselective reuptake blocker
(inhibit both NE and 5HT reuptake; SNRI devoid of ANS side effects),
does not block muscarinic, adrenergic, or histaminic receptors,
thus have fewer adverse effects than TCAs
Venlafaxine use
may be effective in treating depression in pts in which SSRIs are ineffective,
in addition depression is often accompanied by chronic painful symptoms (neuropathic pain), such as backache and muslce aches, against which SSRIs are also relatively ineffective
Venlafaxine
most common adverse effects -- nausea, dizziness, sexual distrubances, anxiety and insomnia and at higher doses, increases BP
Desvenlafaxine (SNRI)
active metabolie of Venlafaxine with
no demonstrated clinical advantage over the parent compound
Duloxetine
inhibits serotonin and NE reuptake (SNRI),
should not be administered to pts with hepatic insufficiency, as metabolites are excreted in urine,
use is restricted in pts with end stage renal diseases
Duloxetine
like venlafaxine, used in depression associated with neuropathic pains, such as backache and muslce aches, against which SSRIs are also relativley ineffectve,
Also approved for the treatment of diabetic neuropathy and fibromyalgia
Duloxetine GI side-effects are common
nausea, dry mouth, constipation
Duloxetine other adverse effects
insomnia, dizziness, somnolence, sweating, and sexual dysfunction
Bupropion
dopamine reuptake blockers,
no more in use for the treatment of depression due to its side-effects (related to overactivity of dopamine),
a formulation of bupropion developed as adjucnt therapy for cessation of smoking,
bupropion causes seizures and insomnia
Mirtazapine
enhances the Noradrenergic transmission presynaptic alpha 2 receptors antagonist and increasing NE release (like Yohimbine),
dec NE reuptake (NET),
serotonin 5HT2-receptor antagonist activity,
histamine (H1) antagonist with greater sedating effects (advantageous in depressed pts having sleep difficulty)
Mirtzapine is associated
with increased appetite and weight gain,
better tolerated,
no antimuscuranic effects like TCAs,
less likely than TCA to preceipitate mania
Amoxapine
primarily NE reuptake inhibitor,
with less effect on 5HT reuptake,
its hydroxy metabolite blocks dopamine receptors
Amoxapine sideeffects
extrapyramidal adverse effects (similar to those caused by antipsychotics),
including tardive dyskinesia,
overdose cause seizures
Maprotiline
primarily NE reuptake inhibitor with less effect on 5HT reuptake,
highly sedating,
cause seizure and in higher dose cardiotoxic
Seligiline MAO inhibitor
used to treat Parkinson’s disease,
also approved by the FDA for major depression,
used as a skin patch
enuresis
TCA imipramine
ADHD
TCA imipramine, Desipramine
Anxiety states like Panic/Phobia and Bulimia nervosa
SSRI Fluoxetine, Venlafaxine, Duloxetine
OCD
SSRI Fluvoxamine, clomipramine
Neuropathic pain
TCA Amitryptyline
Premenstraal dysphoric disorder
SSRI Fluoxetine
SSRI are safe and effective for
depressed pts with cardiovascular disorders
SSRI is first line for
treatment of OCD and other anxiety disorders
MAO inhibitors are effectve and used as the last resort for
treatment of atypical depression
Psychotic depressed pts usually requre
ECT bc effects are fast
Antimaniac classification
Lithium slats (Li+) carbonate/citrate (drug of choice for actue mania and prophylaxis),
Anticonvulsants: Sodium valproate (acute treatment and prophylaxis),
Lamotrigine (chornic prophylaxis only),
Antipsychotics: Chlorpromazine, Atypicals, Acute mania, breakthrough on Li+ treatemnt
Lithium
monvalant cation,
narrow TI,
Li and sodium valproate are used for prevention and treatment of mania (bipolar affective disorder) in combination with antidepressants/antispsychotics
Li and other drugs like_..are used for mania
Sodium valproate,
Carbamazepine (off label), and
Clonazepam
Li mechanisms of action
interferes with second messenger system,
inhibits inositol monophosphatase, thus interferes with phophatiyl inositol pathway,
decreases the concentration of inositol in the brain and thus interferes witht the re-synthesis (recyling) of phosphatidylinositol biphosphate (PIP2),
leading to relative depletion of DAG IP3 and ultimately
Ca in neuronal membranes of CNS,
also dec cAMP
Li putative mechanisms
Li/Valproate
- -> dec IP3
- -> dec cerebral PKC (alpha beta isoforms)
- -> dec MARCKS/protein, altered synaptic/neuronal plasticity, change gene expression
- -> inc AP-1DNA binding, inc B cell lymphocyte protein 2 (BCL2) decreasing neuronal apoptosis
Li other effects
no acute effects in normal individuals as well as in MDI pts,
neither sedative nor euphoriant,
but on prolonged adminsitration acts as a mood stabilizer in bipoalr disease,
takes 1-2 weeks to produce effects
Li pharmacokinetics
orally absorbed, slow onset --2-4 hrs, low Vd (0.7-0.9L/Kg) approaches ECF, T1/2 --> 20-24hrs, takes 5-6 days to achieve steady state, excretion --renal by GFR. 80% is reabsorbed in the proximal renal tubule
what enhances lithium toxicity
thiazides,
Furosemide,
NSAIDs (indomethacin, phenylbutazone)
Li is excreted in
breast milk and sweat
Li renal clearance
20% of creatinine clearance which is about
15-20ml/min
what increases renal excretion of Li
Na load increases Li excretion,
but Na deficiency as in dehydration or diarrhea leads to Li retention from inc reabsorption
Adverse effects of lithium
TI –very low (needs TDM),
Therapeutic range (0.6 - 1.25 mEq/L),
tremor,
flu-like symptoms,
life threatening seizures (dose-dependent),
Polyuria,
polydipsia (nephrogenic diabetes insipidus –manage with Amiloride),
hypothyroidsim,
ataxia confusions and weight gain,
increased leukocytes during chronic thrapy,
teratogenic
Lithium and hypothyroidsm
lithium prevents deiodination of T4 and T3 and also decreases TSH activity so you might see hypothyroidsim with goitre
in case of pregnancy don_t use Li bc very teratogenic. Used
lorazepam,
clonazepam,
gabapentin
Li > 2mmol/L
confusion (imp first sign of toxicity), drowsiness, vomiting, ataxia, dizziness, and severe tremor develop
Li >2.5 mmol/L
chronic movements of limbs,
seizures,
circulatory collapse, and
coma occur
Li toxicity treatement
includes discontinuing lithium,
hemodialysis, and then
use of anticonvulsants
Li uses
prevention and Treatment of mania
treatment of bipoalr disorder must be individualized on the basis of
symptoms,
response to drug therapy and other treatment modalities, and the
minimization of adverse effects
Li is the cornerstone of therapy bc
it aborts an acute manic episodes, and also appears to exert a mild antidepressive effect
Li usually given for
9-12 months,
then dose tapering with clinical monitoring and TDM,
pt must have no renal or CVD and available for TDM,
depression that persists after Li treatment is treated with antidepressant drugs,
carbamazepine and valproate are also used to Li
Li usually controls an acute manic episode within
1-2 weeks after initiating treatment
other drugs may be required to control acute symptoms while awaiting full effect of lithium to develop
benzodiazepines may relieve manic symptoms and promote sleep,
an antipsychotic agent (risperidone, quetiapine or Olanzapine) may be required to suppress delusions and other psychotic symptoms associated with mania,
Lamotrigine has received FDA approval for prevention of recurrent depression in bipolar disorders
What are drugs of choice for acute manic episodes and for maintenance treatment of bipolar disorder
Li,
valproate,
or a second-generation antipsychotic,
alone or in combination with eachother
Carbamazepine as Li alternative
not and FDA approved alternative
Li or Quetiapine
is preferred for treatment of depression in bipolar disorder
Lamotrigine + Li
an alternative for maintenance therapy of bipolar disorder
Lamotrigine
alos a reasonalbe alternative to Li alone or Quetiapine for depressive episodes
Long-acting IM Risperidione
can delay mood disorder relapse in pts with frequent episodes
