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what are the 3 classes of drugs used to treat depression, mania?

Tricyclic antidepressants TCAs
monoamine oxidase inhibitors MOAIs
specific serotonin reuptake inhibitors SSRIs

1

what are examples of TCAs?

imipramine and amitriptyline
more recent ones- clomipramine, dothiepin and lofepramine= fewer side effects

2

what is a benefit of TCAs?

they are the most efficacious at treating all forms of depression- mild to very severe

3

what is the mechanism of action of TCAs?

block reuptake of amines- NA and 5-HT
not very selective
their metabolites are active but sometimes have different selectivity
they cause increased functional availability of monoamines - in the synapse
this is the direct mode of action becaues other drugs can do the same but they are not antidepressants

4

what is the therapeutic delay of TCAs?

2-4 weeks
often get worse before getting better

5

what are TCAs thought to do ?

down regulate of receptors for various CNS neurotransmitters such as NA and 5-HT
beta receptors down regulated by most TCAs but this is unlikely to be the real MOA because beta blockers are not antidepressants

6

what are the effects of TCAs in man?

MOOD EFFECTS - only affect depressed patients, mood returns to normal after about 2-4 week delay
AUTONOMIC EFFECTS - these may cause a decrease in mood, fall in BP due to blocking alpha receptors, atropinic effects- blurred vision an dry mouth
SEDATION, HYPNOSIS- may be a benefit as depressed patients often suffer from a lack of sleep
CARDIOTOXICITY- tachycardia, dysrhythmia, important in overdose, nt just related to increased NA release

7

what are the CNS effects in acute overdose?

excitement
delirium
convulsions
later coma, respiratory depression
may take days to recover

8

what drugs do TCAs interact with ?

antihypertensives - need uptake system - alpha methyldopa
thryoid hormones potentiate TCAs
summation of MAOIs - none of these antidepressants can be taken together, especially not the TCAs with MAOIs and MAOIs with SSRIs

9

what are some examples of SSRIs ?

fluoxetine (prozac)
citalopram
paroxetine
sertraline
these are the most commonly prescribed antidepressants

10

what are the benefits of SSRIs compared to TCAs?

lower autonomic effects - atropinic
lower cardiovascular effects
lower acute toxicity
less sedation

11

what is delay caused by SSRIs?

2-4 week delat
they are all very similar and have some NA reuptake inhibtion

12

what are the side effects of SSRIs ?

nausea, anorexia
insomnia , rather than sedation
aggression and violence
sexual dysfunction
loss of libido
failure to orgasm
lower acute toxicity

13

what happens if you take an SSRI and a MAOI together ?

"serotonin syndrome"- excessive serotonin in CNS and PNS
causes tremors, CVS collapse, decrease in BP, hyperthermia and can be fatal
caused mainly by over stimulation of 5HT1A

14

where is MAO found?

they are intracellular found in mitochondria

15

what are the 2 isoforms of MAO?

A and B
distinguished by substrate specificity
A is more important for serotonin
B prefers NA and DA - B inhbits the breakdown of DA so its involved in parkinsons disease but it is not involved in antidepressant effects

16

what does MAO-A deficit humans have ?

seem to show violent behaviour, mental retardation - strong aggressive behaviour

17

what were MAOIs originally used for ?

used as anti-TB dugs
wasnt useful for TB but seemed to make the patients feel happier

18

what is the main purpose of MAOIs ?

increases the amount of monoamine neurotransmitters

19

what is the result of the antidepressant effects caused by when using MAOIs?

due to MAO-A inhibition
these have a link to 5-HT because they increase 5HT levels
also increases NA
levels are increased in both the CNS and PNS and plasma

20

what effect does having increased intracellular levels of 5HT by MAOIs?

causes reversal of transporter to release serotonin into cleft

21

describe phenylzine:

non selective between A and B
long lasting covalent bonding

22

describe tranylcypramine:

not as stable binding so recovery is quicker

23

describe clorgyline:

MAO-A selective

24

what are the effects of MAOIs?

mood elevation- delay 2 weeks, occurs in both depressed and normal ptients
mood swings- agitation, hypomania
atropinic effects- central action causing reduced parasympathetic outflow
hepatotoxicity- uncommon, monitor liver function
hypertensive crisis
severe headache and hypertensive crisis- occur with interactions with TCAs, precursor of amines(L-DOPA), tyramine in food
abnormal syndrome with pethidine- causes fever, restlessness, coma, hypotension

25

why are MAOIs usually used in hospitals ?

due to its hepatoxcity
it cannot be used in patients with liver disease

26

what is the cheese effect ?

increased tyramine caused by MAOIs
tyramine is normally degraded by MAO in the gut and liver

foods high in tyramine include: red wine and marmite

27

what is the abnormal syndrome with pethidine caused by MAOIs?

result of the formation of abnormal metabolite - norpethidine demethylated form after inhbition of MAO
could possibly effect other enzymes

28

what causes depression ?

many different subtypes so likely there are many reasons
50% depressive show high ACTH levels- there circadian rhythms for release are lost
sleep disturbances - changes in REM
- evidence is this is that there are 12 hours phase shifts
- evidence of sleep deprivation/changes has relieved depression in some cases
HOWEVER too much cortisol is not actually causing depression

29

what is the biogenic amine hypothesis ?

original simplistic theory that depression is caused by decreased amine levels in the brain - NA particularly but also serotonin and dopamine

30

what evidence of there to support the biogenic amine hypothesis ?

poor evidence for the differences but there is good supporting evidence from drugs such as reserpine inducing depression and TCAs and MAOIs relieving it

31

what do SSRIs do ?

they block reuptake pump which increaases serotonin in the somatodendritic area
this causes the desensitisation of the 5HT-1a autoreceptors
this reduces the inhibition of serotonin release- it stops the -ve feedback loop
this increases serotonin from the axonal terminal
the post synaptic receptor desensitise so this increases the chance of serotonin binding to a serotonin receptor