ANTIPSYCHOTIC DRUGS since 1950s

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ANTI-PSYCHOTIC DRUGS (since 1950s) Mainly 15-45
age range, but increasing in kids! Stop PANIC,
HOSTILITY, FEAR
Before 1950s in the WEST Dr. Freeman (US)
popularized lobotomies for curing many mental
illnesses gt18,000 lobs US (1939-1950) Rosemary
Kennedy had one Lived to 86 but suffered as a
result
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East Extract of the Indian Snakeroot plant
(used as antidote to snake bites) RAUWOLFIA was
used
Depletes serotonin and catecholamines but many
side effects nausea, nightmares
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THE TRICYCLIC ANTIDEPRESSANTS R
CH2CH2CH2NMe2 X Cl
CHLORPROMAZINE aka Thorazine, Promactil,
Prozil, Sanopron,... Chloropromazine was a
cheap, failed anti-histamine, which was
unbelievably effective withdrawn patients
became active violent patients became
calmed 95 of those institutionalized could go
home (75-200 mg daily)
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• Chlorpromazine is a so-called dirty drug
• antagonist for many different postsynaptic
  receptors
• dopamine receptors (subtypes D1, D2, D3 and D4)
  account for antipsychotic properties
• serotonin receptors (5-HT1 and 5-HT2)
  antiaggressive properties but also leading to
  weight gain, fall in blood pressure, sedation
• histamine receptors (H1 receptors) accounts for
  sedation, antiemetic effect, vertigo, fall in
  blood pressure and weight gain
• M1 and M2 muscarinic acetylcholine receptors
  symptoms such as dry mouth, blurred vision,
  constipation, difficulty or inability to urinate,
  loss of memory
• dopamine reuptake inhibitor (mild)
  antidepressive

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Dopamine present in greater amounts in brains of
schizophrenics, so all tricyclic antidepressants
antagonize the D2 site 20 second-generation
drugs are in use and they are more specific for
the desired D2 receptor (as well as 5-HT2, see
next slide) eg. Fluphenazine (dose 2-10 mg)
Current Canadian Tricyclic Anti-Depressants
maprotiline, amitryptyline,clomipramine desipramin
e, doxepin, imipramine, nortryptyline,
trimipramine, chlorpromazine, methotrimeprazine,
fluphenazine, perphenazine, prochlorperazine,
thioproperazine, trifluoperazine, mesoridazine,
pericyazine,pipotiazine, thioridazine,flupenthixol
, thiothixene, zuclopenthixol, mirtazapine
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Additional binding to the 5-HT2 (serotonin) sites
helps to control POSITIVE (voices) and NEGATIVE
(withdrawal) symptoms egs. HALDOL (Haloperidol)
and CLOZARIL (Clozapine)
2-6 mg
25 mg initially There are many
variants of each, and all have reduced side
effects, but Clozapine gives reduced white blood
cell counts and therefore needs weekly blood tests
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ZYPREXA (olanzapine) is a more expensive version
of clozapine 8/day, but 17 US veteran hospitals
reported that haldol benztropine (10 cents per
day) is just as good
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ANOTHER STATEGY Selective Serotonin Re-uptake
Inhibitors (SSRIs) (first anti-depression drugs
by design from 1980s on)
PROZAC () ZOLOFT PAXIL
(1988, Lilly) (Pfizer)
(Glaxo) gt one million Rx/month
20-80 mg/day/once 50 mg/day/once
20 mg/day/once
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COMT catechol-O-methyl transferase MAO
Monoamine oxidase
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ACTION blocks serotonin re-uptake (binds 5-HT1A
receptors) serotonin stays around longer, nerve
impulse more likely to be transmitted overdose
does not appear to be possible however Main
side effects nausea (Paxil lt Zoloft lt Prozac),
dry mouth, dizziness, weight loss... PAXIL
(SEROXAT in UK, paroxetine) only shows side
effects early on but they diminish after a few
weeks Sales increased 5x in less than a decade
(2.7B) ALL SSRIs now have a black box
warning DO NOT GIVE TO PATIENTS ALSO USING MAO
(monoamine oxidase) INHIBITORS DO NOT GIVE TO
SUICIDAL PATIENTS, WITH EPILEPSY OR SEIZURES
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Current Canadian Drugs in this Class and
Related SSRIs citalopram, fluoxetine,
paroxetine, sertraline fluvoxamine, venlafaxine
(also SNRI) Monoamineoxidase inhibitors
phenelzine, tranylcypromine, moclobemide. Other
bupropion, trazodone, l-tryptophan
SSRI's linked to serious lung disorder in
newborns avoid during pregnancy http//www.hc-sc
.gc.ca/ahc-asc/media/advisories-avis/2006/2006_11_
e.html
Paroxetine PAXIL in First Trimester of
Pregnancy May Have Small Increased Risk of
Heart-Related Birth Defects, Compared to Other
Antidepressantshttp//www.hc-sc.gc.ca/dhp-mps/me
deff/advisories-avis/public/paxil_4_pc-cp_e.html
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RITALIN (Methylphenidate) (Novartis (CIBA)) ()
Stimulant for ADHD (attention deficit hyperactive
disorder) Unruly children behave properly
within minutes Why a stimulant for
hyperactivity? ADHD patients have decreased
brain activity in areas critical to concentration
ACTION increases dopamine levels in brain,
injected or orally, which activates motivation
and drive (like speed!) main effect is on
behaviour rather than body motor function Only
tested on kids gt 6 years age
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Side effects nervousness, insomnia, tics, loss
of appetite, stomach pain some suppression of
growth with long-term use Not tested during
pregnancy Dose Children 5-10 mg, 3 x per
day Adults 5-20 mg, 3 x per day About 5 of
US kids estimated on drug!!!
Also approved in Canada dexamphetamine,
atomoxetine
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MANIC DEPRESSION - LITHIUM Suffer mood swings
3 months up excess drink, grand plans,
impulse spending, quit job, give away
possessions then 6-9 months down rejection,
suicidal feelings FIX Li2CO3 LITHANE (Pfizer)
Lithium carbonate
Mechanism not known but has many measurable
effects decreases dopamine in brain (changes
metabolism), alters c-AMP formation, alters Na
transport in nerve muscle cells DOSE 3 x
600mg day is close to the toxic dose!