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) popularizedlobotomies for curing many mental illnesses

>18,000 lobs US (1939-1950)

Rosemary Kennedy had oneLived to 86 but suffered as a result

East: Extract of the Indian Snakeroot plant (used as antidote to snakebites) RAUWOLFIA was used

NH

N

OOC

OCH3

OCH3

OCH3CH3OOC OCH3H

H

HCH3O NH

NH2HO

Rauwolfia Serotonin [5-HT]

Depletes serotonin and catecholamines

but many side effects: nausea, nightmares

THE TRICYCLIC ANTIDEPRESSANTS

R = CH2CH2CH2NMe2

X = Cl

S

N XR

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withdrawn patients became active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 5-HT2, see next slide)

eg. Fluphenazine (dose 2-10 mg):

S

N

NN

OH

CF3

Current Canadian Tricyclic Anti-Depressants: maprotiline, amitryptyline,clomipraminedesipramine, doxepin, imipramine, nortryptyline, trimipramine, chlorpromazine, methotrimeprazine, fluphenazine, perphenazine, prochlorperazine, thioproperazine, trifluoperazine, mesoridazine, pericyazine,pipotiazine, thioridazine,flupenthixol,thiothixene, zuclopenthixol, mirtazapine

Additional binding to the 5-HT2 (serotonin) sites helps to control POSITIVE (voices) and NEGATIVE (withdrawal) symptoms

egs. HALDOL (Haloperidol) and CLOZARIL (Clozapine)

F COCH2CH2CH2 NOH

Cl

O

NClN

N

Haloperidol (Janssen(McNeil)) Clozapine (Novartis)

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

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

NH

NN

N

S

Olanzapine

N

O

H

.MeSO3H

Benztropine

ANOTHER STATEGY: Selective Serotonin Re-uptake Inhibitors (SSRI’s)(first anti-depression drugs by design from 1980’s on)

F3C OCH2CH2NHCH3

CH3NH

Cl

Cl

Fluoxetine Sertaline

NH

O

O

O

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-O-methyl 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) INHIBITORSDO NOT GIVE TO SUICIDAL PATIENTS, WITH EPILEPSY OR SEIZURES

Current Canadian Drugs in this Class and Related

SSRI’s: citalopram, fluoxetine, paroxetine, sertralinefluvoxamine, venlafaxine (also SNRI)

Monoamineoxidase inhibitors: phenelzine, tranylcypromine, moclobemide.

Other: bupropion, trazodone, l-tryptophan

SSRI's linked to serious lung disorder in newborns – avoid during pregnancyhttp://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)) (±)

NHCO2Me

.HCl

Methylphenidate

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 functionOnly 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 dayAdults 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!