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Pharmacology 2 > 8.8 Antidepressants > Flashcards

8.8 Antidepressants Flashcards

1
Q

2 extremes of affective disorders

A

depression and mania

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2
Q

depression

A 
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
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3
Q

mania

A

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

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4
Q

Amine hypothesis of depression

A

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

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5
Q

Antidepressants act

A

acutely to increase the concentration of neurotransmitters NE and or serotonin in the cortical synapses.

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6
Q

mode of action of antidepressnats

A 
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
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7
Q

how long does full antidepressant effect take

A

2-6 weeks, change in cortical synaptic palsticity

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8
Q

Antidepressant classification

A

monoamine oxidase inhibitors,
tricyclic antidepressants,
selective serotonin reuptake inhibitors,
atypical antidepressants (Serotonin blockers),
other (serotonin NE reuptake inhibitors -SNRI)

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9
Q

what is MAO

A

a flavin containing mitochondrial enzyme present in never liver, and intestine

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10
Q

MAO-A

A

preferentially degrades NE and Serotonin

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11
Q

MAO-B

A

degrades dopamine preferentially

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12
Q

MAO inhibitors

A

exert aciton in presynaptic axoplasme

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13
Q

Non selective MAOI

A

tranylcypromine,

Phenelzien

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14
Q

MAO-A -I to treat

A

atypical depression – Moclobemide

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15
Q

MAO-B-I to treat

A

parkinsonism –Selegeline

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16
Q

MAO inhibitors

A

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)

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17
Q

What is safe

A

MAO-A I safer and more effective than nonselective.

but Moclobemide binds reversibly: safer

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18
Q

MAO inhibitors adverse effects (Phenelzine, Tranylocypromine)

A

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)

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19
Q

MAO-I drug interactions– inc NE

A 
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
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20
Q

MAO-I drug interactions – inc 5HT

A

inc serotonin–> serotonin syndrome (life-threatening),

drugs: 
SSRIs, 
TCAs, 
Meperidine, 
Dextromethorphan, 
Symptoms: 
sweating, 
rigidity, 
fever, 
myoclonus, 
hypertermia, 
ANS instability, 
seizures, 
coma
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21
Q

MAO-I drug interactions–chees rxn

A 
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)

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22
Q

Tricyclic antidepressants (TCA) NE and 5HT reuptake inhibitors

A 
tertary amines:  
clomipramine, 
Amitriptyline, 
Doxepin, 
imipramine,

Secondary amine:
desipramine,
nortriptyline

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23
Q

TCA therapuetic efficacy

A

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

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24
Q

TCA NE/5HT reuptake inhibitors

A

inhibition of NT uptake, Blocking of receptors

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25
Q

TCA - Inhibition of NT uptake

A

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

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26
Q

TCA - Blocking of receptors

A

also block alpha 1,
muscarinic and
histamine 1 receptors

–> untowards effects

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27
Q

TCA Vd

A

lipophilic – large Vd (10-50L/kg)

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28
Q

TCA half life

A

long t1/2 so given orally once daily.
Not easily removed by dialysis in overdose
—>dangerous

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29
Q

TCA tertiary amines have

A

N desmethyl active metabolites –
amitryptiline (nortryptiline),

Imipramine (Des-methyl imipramine).

T1/2 longer (30-70hrs)

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30
Q

amoxapine

A

has a hyroxyl active metabolite extrapyramidal adverse effects

–bc metabolite blocks dopamine receptors

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31
Q

TCA hepatic metabolism

A

CYPS 2D6, 2C19,

CYP 3A4/5

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32
Q

what induces the metabolism of TCA

A

Anitconvulsants (barbiturates, carbamazepine) cigarette smoking induce the metabolism,
so decrease TCA effects

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33
Q

TCA adverse effects

A

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

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34
Q

Precautions of TCA

A

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

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35
Q

TCA contraindications

A

acute MI, BBB (inc arrhythmia risk and cardiac depression)

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36
Q

Drug interactions of TCA

A

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

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37
Q

Overdose and toxicity of TCA

A

overdose of TCA produces
severe anticholinergic and antiadrenergic signs,

respiratory depression, arrhythmias, shock, seizures, coma, and death

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38
Q

treatment of TCA overdose

A

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)

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39
Q

Uses of TCA

A

major depression,
phobic and panic disorder/anxiety states,
obsessive-compulsive disorders (OCDs) - (Clomipramine),
Neuropathic pain (amitriptyline),
enuresis (imipramine)

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40
Q

SSRI – selective serotonin reuptake inhibitors

A

fluoxetine,
paroxetine,

sertraline,

fluvoxamine,

citalopram,
escitolopram,

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41
Q

why are SSRIs better than TCAs

A

They overall produce fewer serious adverse effects than TCAs (devoid of ANS and CVS effects);

hence first line drug in the management of depression

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42
Q

SSRI action

A

block the re-uptake of serotonin

  • -> increased concentration of serotonin in the synaptic clefts
  • -> greater postsynaptic 5HT stimulation
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43
Q

SSRI cause gradual decrease in 5HT2AR causing

A

inc NE release,
inc BDNF,
inc intraneuronal cAMP/PKA,
inc CREB protein in cerebral cortex

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44
Q

how long do SSRIs take to work

A

usually take 2 weeks to produce improvement in mood and max benefit requires 12 weeks or more

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45
Q

Adverse effects of SSRIs

A 
anxiety, 
agitation, 
bruxism, 
sexual dysfucntion (anorgasmia), 
weight loss
46
Q

SSRI toxicity

A

serotonin syndrome (tremor, hyperthermia, muscle regidity, and cardiovascualr collapse)

with
MAO inhibitors, 
TCAs, 
Meperidine, 
Dextromethorphan
47
Q

SSRI and children

A

should be used cautiously in children and teenagers, as it induces suicidal tendancy.

Fluoxetine is the only SSRI shown to be effective in children

48
Q

St. John’s wort

A

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

49
Q

SSRI pharmacokinetics

A

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

50
Q

Fluoxetine differs from other SSRIs in 2 respects

A

has a much longer half life,

active metabolite compound
norfluoxetine halflife of 10 days

51
Q

Fluoxetine and Paroxetine inhibit

A 
hepatic CYP450 isoenzymes 2D6, 2C9 which metabolizes 
TCAs, 
antipsychotics, 
opiates, 
some antiarrhytmics and beta blockers,

so increased risk of toxicity.

52
Q

Uses of SSRIs

A

major depression,
OCD (SSRIs supplanted the use of Clomipramine),
Bulimia,
Anxiety disorders (including panic disorder),
Premenstral dysphoric disorders (PMDD)

53
Q

Atypical antidepressants

A

trazodone,
nefazodone,

venlafaxine,
desvenlafaxine,

bupropion,

mirtazapine,
amoxapine

maprotiline, ,

duloxetine

54
Q

Trazodone

A

inc 5HT level in the brain

reduces reuptake, and by interfering with its metabolism, and metabolites are strong 5HT receptor agonist

55
Q

Trazodone causes

A

cardiac arrhythmia,
postural hypotension,
priapism (due to alpha-blocking activity) and
sedation (due to H1-blocking activity)

56
Q

Trazodone anticholinergics

A

has no significant anticholinergic activity and has fewer ANS and CVS effects than TCAs and is

safer than TCAs in overdose

57
Q

Trazodone extra properties

A

due to its sedating property, it is commonly used as an adjunct to an SSRI in pts with insomnia

58
Q

Nefazodone

A

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

59
Q

Venlafaxine

A

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

60
Q

Venlafaxine use

A

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

61
Q

Venlafaxine

A 
most common adverse effects -- 
nausea, 
dizziness, 
sexual distrubances, 
anxiety and 
insomnia and 
at higher doses, increases BP
62
Q

Desvenlafaxine (SNRI)

A

active metabolie of Venlafaxine with

no demonstrated clinical advantage over the parent compound

63
Q

Duloxetine

A

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

64
Q

Duloxetine

A

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

65
Q

Duloxetine GI side-effects are common

A

nausea, dry mouth, constipation

66
Q

Duloxetine other adverse effects

A 
insomnia, 
dizziness,
 somnolence, 
sweating, and 
sexual dysfunction
67
Q

Bupropion

A

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

68
Q

Mirtazapine

A

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)

69
Q

Mirtzapine is associated

A

with increased appetite and weight gain,
better tolerated,
no antimuscuranic effects like TCAs,
less likely than TCA to preceipitate mania

70
Q

Amoxapine

A

primarily NE reuptake inhibitor,
with less effect on 5HT reuptake,
its hydroxy metabolite blocks dopamine receptors

71
Q

Amoxapine sideeffects

A

extrapyramidal adverse effects (similar to those caused by antipsychotics),
including tardive dyskinesia,
overdose cause seizures

72
Q

Maprotiline

A

primarily NE reuptake inhibitor with less effect on 5HT reuptake,
highly sedating,
cause seizure and in higher dose cardiotoxic

73
Q

Seligiline MAO inhibitor

A

used to treat Parkinson’s disease,
also approved by the FDA for major depression,
used as a skin patch

74
Q

enuresis

A

TCA imipramine

75
Q

ADHD

A

TCA imipramine, Desipramine

76
Q

Anxiety states like Panic/Phobia and Bulimia nervosa

A

SSRI Fluoxetine, Venlafaxine, Duloxetine

77
Q

OCD

A

SSRI Fluvoxamine, clomipramine

78
Q

Neuropathic pain

A

TCA Amitryptyline

79
Q

Premenstraal dysphoric disorder

A

SSRI Fluoxetine

80
Q

SSRI are safe and effective for

A

depressed pts with cardiovascular disorders

81
Q

SSRI is first line for

A

treatment of OCD and other anxiety disorders

82
Q

MAO inhibitors are effectve and used as the last resort for

A

treatment of atypical depression

83
Q

Psychotic depressed pts usually requre

A

ECT bc effects are fast

84
Q

Antimaniac classification

A 
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

85
Q

Lithium

A

monvalant cation,
narrow TI,
Li and sodium valproate are used for prevention and treatment of mania (bipolar affective disorder) in combination with antidepressants/antispsychotics

86
Q

Li and other drugs like_..are used for mania

A

Sodium valproate,
Carbamazepine (off label), and
Clonazepam

87
Q

Li mechanisms of action

A

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

88
Q

Li putative mechanisms

A

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
89
Q

Li other effects

A

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

90
Q

Li pharmacokinetics

A 
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
91
Q

what enhances lithium toxicity

A

thiazides,
Furosemide,
NSAIDs (indomethacin, phenylbutazone)

92
Q

Li is excreted in

A

breast milk and sweat

93
Q

Li renal clearance

A

20% of creatinine clearance which is about

15-20ml/min

94
Q

what increases renal excretion of Li

A

Na load increases Li excretion,

but Na deficiency as in dehydration or diarrhea leads to Li retention from inc reabsorption

95
Q

Adverse effects of lithium

A

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

96
Q

Lithium and hypothyroidsm

A

lithium prevents deiodination of T4 and T3 and also decreases TSH activity so you might see hypothyroidsim with goitre

97
Q

in case of pregnancy don_t use Li bc very teratogenic. Used

A

lorazepam,
clonazepam,
gabapentin

98
Q

Li > 2mmol/L

A 
confusion (imp first sign of toxicity), 
drowsiness, 
vomiting, 
ataxia, 
dizziness, and 
severe tremor develop
99
Q

Li >2.5 mmol/L

A

chronic movements of limbs,
seizures,
circulatory collapse, and
coma occur

100
Q

Li toxicity treatement

A

includes discontinuing lithium,
hemodialysis, and then
use of anticonvulsants

101
Q

Li uses

A

prevention and Treatment of mania

102
Q

treatment of bipoalr disorder must be individualized on the basis of

A

symptoms,
response to drug therapy and other treatment modalities, and the
minimization of adverse effects

103
Q

Li is the cornerstone of therapy bc

A

it aborts an acute manic episodes, and also appears to exert a mild antidepressive effect

104
Q

Li usually given for

A

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

105
Q

Li usually controls an acute manic episode within

A

1-2 weeks after initiating treatment

106
Q

other drugs may be required to control acute symptoms while awaiting full effect of lithium to develop

A

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

107
Q

What are drugs of choice for acute manic episodes and for maintenance treatment of bipolar disorder

A

Li,
valproate,
or a second-generation antipsychotic,

alone or in combination with eachother

108
Q

Carbamazepine as Li alternative

A

not and FDA approved alternative

109
Q

Li or Quetiapine

A

is preferred for treatment of depression in bipolar disorder

110
Q

Lamotrigine + Li

A

an alternative for maintenance therapy of bipolar disorder

111
Q

Lamotrigine

A

alos a reasonalbe alternative to Li alone or Quetiapine for depressive episodes

112
Q

Long-acting IM Risperidione

A

can delay mood disorder relapse in pts with frequent episodes

Pharmacology 2 (12 decks)

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