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ANTIPSYCHOTICS: Traditional Drugs (p.1)
1. Introduction
antipsychotic drugs = “major tranquilizers”, “neuroleptics”
these drugs have revolutionized the tx of schizophrenia since 1950s
do not cure schizophrenia (or mania or Tourettes), but do significantly
reduce their symptoms
allow clearer thought, less agitation
without marked sedation, dependence, addition, or tolerance (to the
beneficial effects)
there are two broad categories of antipsychotic drugs:
a. 1st generation or traditional (phenothiazines & butyrophenomes)
b. 2nd generation or atypicals (dual action drugs)

history of their development:
French surgeon (Henri Laborit), 1950, searching for a drug to reduce
surgical shock (fear, anxiety, high ANS arousal, high muscle
started with a phenothiazine molecule (which was like histamine)
--- no effect on ANS, but did calm pts while they were still awake
French chemist (Paul Carpentier) experimented with phenothiazine,
added Cl- atom --- chlor promazine (Thorazine)!
Laborit persuaded MD colleague to try it on his patients (1952)
significantly improved manic, agitated, hallucinating pts., enabled
them to live as out-pts, without physical restraints
in 1955 Thorazine was approved for use in USA --- immediate
reduction in #s of hospitalized pts.
and for the first time interest in the neural basis of “mental”
illness began, suggested a biological cause (vs. learned)
ANTIPSYCHOTICS: Traditional Drugs (p.2)
2. Neural Basis of Schizophrenia (summary)
. Sxs significantly worsen in early 20s (as frontal lobes become fully
active – damaged)
. large overlap with depression (limbic system damaged)
. sources of neural damage: pathological genetic expression,
acquired damage (viral, CNS stimulant abuse, prenatal fever)
. damage to DA, glutamate, 5HT, & GABA systems
. widespread damage (multi NT systems, many symptoms):
perceptual distortions (esp. auditory), language (disorganized speech),
poor inferential thinking (delusions), poor social skills (blunted affect,
distorted emotions), poor motor skills, anhedonia, poor cognitive/
executive function skills (poor focus, concentration, memory)
. implies widespread, basic damage (in synaptogenesis, synaptic
“pruning”, apoptosis, neural migration, muelination, neural meitosis)
. Sxs associated with both “soft” and “hard” neurological signs
3. So-called “positive” and “negative” Sxs of schizophrenia
+ Sxs: delusions, hallucinations, bizarre behaviors/postures
dissociated/fragmented thoughts, illogical thinking
incoherent speech, impaired executive functioning
most likely due to overly active DA system
- Sxs: blunted affect, odd/reduced emotional reactions, apathy
no initiative, no motivation, no interests, no goals
social withdrawal
lack of spontaneous speech
likely due to underactive glutamate/NMDA system, perhaps
secondary to abnormalities in 5HT system
drugs used to treat psychosis affect many RSs:
DA2, AChMuscarinic, 5HT1A, 5HT2, H1, NE alpha#1&2, & more
ANTIPSYCHOTICS: Traditional Drugs (p.3)
4. Traditional Antipsychotics
are especially good at reducing the + Sxs (do not reduce – Sxs)
major SEs – EPSEs (extrapyramidal side effects), TD (tardive
major affect on NS is to block DA2 postsynaptic RSs --- up-regulation?
DA2 RSs are found in 4 systems in the CNS:
mesocortical hypothalamic-pituitary
mesolimbic nigrostriatal-basal ganglia
also block several other NTs: ACh, NE, 5HT, H (are “dirty drugs”)
as + Sxs decrease, S becomes more aware of improvement
all neuroleptics are about equal in decreasing the + Sxs
but different pts. respond better to different drugs…implies that there
are individual differences in exact underlying NTs/neural systems
must also combine pharmacotherapy with supportive environment and
cog.-behavioral therapy
S can live as out-pt now…but increases stress of needing to cope with
“real world” and increased risk for medication non-compliance
general approach:
treat S initially with higher doses, enough to reduce + Sxs
when S stabilizes, the begin to reduce dose to lowest possible dose
to still block + Sxs & yet has fewest SEs possible
use only one drug at a time if possible
use no/minimal other drugs to control SEs
do not recommend “drug holidays”, may actually worsen SEs
ANTIPSYCHOTICS: Traditional Drugs (p4)
4. Traditional Antipsychotics (cont.)
there are high and low potency neuroleptics:
high potency drugs - strongly block DA2 RS, weak antiACh effects
lots of EPSEs, higher risk for TD
fewer antiACh effects, but greater risk for NMS (neuroleptic
malignant syndrome)
less sedation, less orthostatic hypotension
e.g. haloperidol (Haldol) fluphenazine (Prolixin,Permitil)
trifluoperazine (Stelazine) thiothixene (Navane)
molindone (Moban) perphenazine (Trilafon)
pimozide (Orap) loxapine (Loxitane)
low potency drugs – weakly block DA2 RSs, strong antiACh effects
fewer EPSEs, less risk for TD
severe antiACh effects (constipation, poor memory/concentration,
dry mouth, urinary retention, worsened glaucoma, orthostatic
hypotension; at higher doses --- delirium, tachycardia,
bradycardia, blurred vision)
more sedation, more orthostatic hypotension
esp. in elderly Ss
e.g. thioridazine (Mellaril) chlorpromazine (Thorazine)
mesoridazine (Serentil)
which drug is given to which pt. is mostly a matter of which set of
will tolerate better
like the antidepressants, may have to do trial&error approach
fortunately, there is a large therapeutic index for all these meds
ANTIPSYCHOTICS: Traditional Drugs (p. 5)
5. SE: Motor Disturbances
found in 70-85% of all pts. on neuroleptics
blockage of DA2 RSs in basal ganglia
note: NC pts. develop Parkinson’s Disease when >80% of DA
neurons have died
these motor disturbances are often called EPSEs or “Parkinson-like”
a. Parkinsonian effects (40% of all pts.)
rigidity & tremors (resting)
poverty of movement
difficulty initiating a movement/ending a movement
no (emotional) facial movements or gestures, stiff
slowness of movement (bradykinesia)
jerky handwriting
short, rotating head movements
become rigid & immobile as Sxs worsen (“frozen”) except for stiff,
shaking limbs
secondary to imbalance in DA & ACh (DA < ACh)
. give pt.an antiACh drug as well (Artane, Cogentin, Symmetrel)
. use an antipsychotic that blocks both DA & ACh
e.g. thioridazine (Mellaril)
. use a DA agonist(e.g.amantadine/Symmetrel,selegiline/Deprenyl)
esp. a problem in elderly pts. who have already lost some DA neurons
b. Akathesia (20% of all pts.)
compulsive restlessness, repetitive & purposeless movements
can look like anxiety but isn’t
esp. in younger Ss
tx. w/ DA agonists or w/ ACh antagonists…why?
sometimes tx. with propranolol/Inderol (beta-blocker)
very unpleasant SE
ANTIPSYCHOTICS: Traditional (p.6)
5. SEs: Motor Disturbances (cont.)
c. Dystonias (67% of all pts.)
sudden, jerky movements
usually seen shortly after start use of drug (w/i 4 days) or shortly
after drug’s dose is increased
continuous, involuntary writhings caused by widespread and
sustained muscle contractions, spasms
e.g. “oculogyric crisis”
e.g. mouth puckers, tongue protrusion, inability to swallow, disrupted
breathing movements (spasms in diaphragm), profuse sweating
also tx. with DA agonists or antiACh drugs
esp. in young males
d. Akinesia
reduced movements
tremors, shuffling gait/steps, stiff posture
muscle rigidity --- “catatonic” posture, “waxy flexibility”
socially withdrawn, appear “depressed” – makes difficult to Dx pt.
truly depressed psychotic or “iatrogenic” effects from meds?
esp. w/ potent, low antiACh neuroleptics
e.g. haloperidol (Haldol), thiothixene (Navane)
is a reversible effect (when increase DA or decrease ACh or D/C
antipsychotic…but psychotic Sxs return…
e. Tardive Dyskinesia (25% of adults, 12.5% of adolescents)
“late-appearing” Dyskinesia (>6 months after start of meds)
poorly coordinated movements
insidious onset of Sxs
ANTIPSYCHOTICS: Traditional (p. 7)
5. SEs: Motor Disturbances (cont.)
e. Tardive Dyskinesia (cont.)
“worm-like” movements of tongue, tongue thrusting/protrusion
darting tongue movements
puffing out of cheeks
eyelids flutter, upper lip trembles (“rabbiting”)
head arches backward or turns to side
rocking, pelvic thrusting
fling or flail arms
esp. in older (> 50 – 70 years), and female pts.
more severe in pts. w/ - Sxs of schizophrenia
gets worse after antipsychotic drug is D/Cd, at least initially…why?
gets better if drug dose is increased…why?
what is underlying mechanism?. “denervation supersensitivity
How to help with TD?
use lower doses to traditional antipsychotics
do not use these drugs, esp. in elderly females
use newer antipsychotics
D/C traditional antipsychotics at the very first sign of TD Sxs
may still be reversible early on
7. SEs: Autonomic NS & Hormonal Imbalances
occur because of blockage of DA2 RSs in hypothalamus
e.g. weight gain, constipation
e.g. faulty temperature regulation (including NMS)
e.g. sexual disturbances (esp. thioridazine/Mellaril)
ANTIPSYCHOTICS: Traditional (p.8)
7. SEs: Autonomic NS & Hormonal Imbalances (cont.)
NMS = neuroleptic malignant syndrome
1 – 2.4% of pts. on neuroleptics, 14-30% of these die (renal failure)
high fever (108 degrees F.), sweating
confusion, muscle rigidity, tremors, depressed respiration, ANS
hyper-reactivity, stupor, hypertension, increased heart rate
esp. w/ high potency neuroleptics (e.g. Prolixin)
esp. young adult males & non-schizophrenics
8. SEs: AntiACh Effects
typical anticholinergic syndrome
dry mouth, blurred vision (dilated pupils), constipation
decreased memory
increased intraocular pressure (worsens glaucoma)
urinary retention
esp. chlorpromazine/Thorazine
9. SEs: AntiNE Effects
typical antiadrenergic effects
lowered blood pressure, orthostatic hypotension (esp. in elderly)
10. SEs: AntiH Effects
antihistaminergic effects
sedation, weight gain, antiemetic effects
11. Other SEs
agranulocytosis (35% of these pts. die)
hepatitis and liver damage (esp. chlorpromazine/Thorazine)
photosensitivity (skin “sunburn”, “night blindness”)
note: patient non-compliance with medication is almost entirely due to
inability to tolerate the negative SEs of traditional antipsychotics

ANTIPSYCOTICS: Traditional (p.9)
12. Other Uses of Traditional Antipsychotics
to reduce Sxs of Tourette’s Syndrome
to reduce nausea & vomiting (e.g. in pt. on chemotherapy for cancer)
to reduce severe, continuous hiccups
to sedate pt. before surgery, or in an agitated pt.
to delay ejaculation (premature ejaculator)
to relieve severe itching
to reduce severe manic symptoms (while waiting for Li effects to start)
to reduce withdrawal effects (esp. hallucinations) & delirium tremens
to reduce psychedelic hallucinations
all of the above have been successfully treated by use of traditional

Source: http://psych.fullerton.edu/mwhite/475pdf/475Antipsychotics-TraditionalDrugs.pdf

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