Transcript 7 Psychotics

ANTI-PSYCHOTIC DRUGS (since 1950’s)
Mainly 15-45 age range, but increasing in kids!
Stop PANIC, HOSTILITY, FEAR
Before 1950’s in the WEST:
Dr. Freeman (US) popularized
lobotomies for curing many
mental illnesses
>18,000 lobs US (1939-1950)
Rosemary Kennedy had one
Lived to 86 but suffered as a
result
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
N
CH3O
NH H
H
CH3OOC
Rauwolfia
OCH3
H
OOC
OCH3
OCH3
HO
NH2
NH
OCH3
Serotonin [5-HT]
THE TRICYCLIC ANTIDEPRESSANTS
R = CH2CH2CH2NMe2
R
N
X
X = Cl
S
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withdrawn patients became active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)
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
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 5HT2, see next slide)
eg. Fluphenazine (dose 2-10 mg):
Current Canadian Tricyclic Anti-Depressants:
maprotiline, amitryptyline,clomipramine
desipramine, doxepin, imipramine,
nortryptyline, trimipramine, chlorpromazine,
methotrimeprazine, fluphenazine,
perphenazine, prochlorperazine,
thioproperazine, trifluoperazine,
mesoridazine, pericyazine,pipotiazine,
thioridazine,flupenthixol,
thiothixene, zuclopenthixol, mirtazapine
N
N
N
S
CF3
OH
Additional binding to the 5-HT2 (serotonin) sites helps to control
POSITIVE (voices) and NEGATIVE (withdrawal) symptoms
egs. HALDOL (Haloperidol) and CLOZARIL (Clozapine)
N
F
COCH2CH2CH2 N
OH
Cl
N
N
O
Haloperidol (Janssen(McNeil))
2-6 mg
Cl
Clozapine (Novartis)
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
ZYPREXA (olanzapine) is a more expensive version of
clozapine $8/day, but 17 US veteran hospitals reported that
haldol + benztropine (10 cents per day) is just as good
N
N
N
.MeSO3H
N
H
NH
Olanzapine
S
O
Benztropine
ANOTHER STATEGY:
Selective Serotonin Re-uptake Inhibitors (SSRI’s)
(first anti-depression drugs by design from 1980’s on)
NH
Cl
O
CH3NH
Cl
O
CH2CH2NHCH3
F3C
O
O
Fluoxetine
Sertaline
F
Paroxetine
PROZAC (±)
ZOLOFT
PAXIL
(1988, Lilly)
(Pfizer)
(Glaxo)
> one million Rx/month
20-80 mg/day/once
50 mg/day/once
20 mg/day/once
COMT =
catechol-Omethyl
transferase
MAO =
Monoamine
oxidase
ACTION: blocks serotonin re-uptake (binds 5-HT1A receptors):
serotonin stays around longer, nerve impulse more likely to be
transmitted – overdose does not appear to be possible however
Main side effects: nausea (Paxil < Zoloft < Prozac), dry mouth,
dizziness, weight loss...
PAXIL (SEROXAT in UK, paroxetine): only shows side effects
early on but they diminish after a few weeks
Sales increased 5x in less than a decade (2.7B$)
ALL SSRI’s 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
Current Canadian Drugs in this Class and Related
SSRI’s: 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 Antidepressants
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/paxil_4_pc-cp_e.html
RITALIN (Methylphenidate) (Novartis (CIBA)) (±)
Stimulant for ADHD (attention deficit
hyperactive disorder)
NH
CO2Me
.HCl
Methylphenidate
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 > 6 years age
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
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!