Professional Documents
Culture Documents
1891
o Paul Ehrlich - methylene blue (antimalarial phenothiazine): psychosis and
anti-nausea
1952
o Chlorpromazine - anesthetic, antihistaminic (anti-nausea)
o Reserpine antihypertensive (alpha blockade) with NE, DA and 5-HT
1957-1958
o TCAs and MAOIs
1958
o Clozapine synthesized
1971
o Clozapine in practice
1972
o Lithium
1988
o Risperidone
Conventional
Antipsychotics
Conventional
Antipsychotics
Low Potency
o Chlorpromazine (Thorazine)
o Prochlorperazine (Compazine)
o Thioridazine* (Mellaril)
o Mesoridazine* (Serentil)
*QTc issues
Conventional
Antipsychotics
High Potency
o Haloperidol (Haldol)
o Fluphenazine (Prolixin)
o Pimozide* (Orap)
o Thiothixene (Navane)
o Perphenazine (Trilafon)
o Trifluoperazine (Stelazine)
*QTc issues
Conventional
Antipsychotics
*QTc issues
Mode of Action
Mode of Action
D2 blockade in the
mesolimbic pathway
reduces hyperactivity
and positive symptoms
Blockade needed for
antipsychotic effects
about 80%
If greater than 80% spillover into dorsal striatum
resulting in EPS; and in
the pituitary
hyperprolactinemia.
high cost of business
spillage in other
Fig. 5-3 Stahls Essential Psychopharm. 4th Ed
pathways (see Cost)
Mode of Action
blunting
o Protective against EPS (not TD) in Nigrostriatal pathway:
Dopamine usually block Ach release, so dopamine Blockade
increases Ach -> EPS; if M1 is blocked Ach cannot act -> no
or less EPS.
o Agents with weak M1 blockade -> higher EPS
Mode of Action
Histamine H1blockade
o weight gain and drowsiness
1-adrenergic blockade
o orthostatic hypotension and drowsiness
Cost
Cost
Chlorpromazine
CNS: D2 blocker
o EPS, antiemetic, anti-psychosis
o Lowers seizure threshold because Na channel block ->
anesthesia
o Impairs hypothalamic temperature control at high doses
-> poikilothermia (body temp drops when room temp
drops)
Weak diuretic
o Vasopressin inhibitor
Haloperidol
Loxapine
FGA SE Profile
https://www.uspharmacist.com/article/metabolic-effects-of-atypical-
Atypical
Antipsychotics
List
Aripiprazole (Abilify)
Asenapine (Saphris)
Clozapine (Clozaril FazaClo)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Olanzepine (Zyprexa)
Quetiapine (Seroquel)
Paliperidone (Invega)
Risperidone (Risperdal)
Zisprasidone (Geodon)
Cariprazine (Vraylar)
5-HT production
5-HT destruction
Link to
Depressio
n
5HT2A functions
Cortical neurons
(1)Serotonin is released in the
cortex and binds to
5HT2Areceptors on
glutamatergic pyramidal
neurons, causing activation of
those neurons.
(2)Activation of glutamatergic
pyramidal neurons leads to
glutamate release in the
brainstem, which in turn
stimulates GABA release.
(3)GABA binds to dopaminergic
neurons projecting from the
substantia nigra to the
striatum, inhibiting dopamine
release (indicated by the
Figure 5-15 Stahls Essential
dotted outline of the
Psychopharm. 4th ED.
5HT2A
(1) In the striatum, serotonergic
projections synapse directly with
dopaminergic neurons and indirectly
via GABAergic neurons. At GABAergic
neurons, serotonin binding to
5HT2Areceptors disinhibits GABA
release, which in turn decreases
release of dopamine (indicated by
the dotted outline of the
dopaminergic neuron). Similarly,
when serotonin binds to
5HT2Areceptors directly on dopamine
neurons, this causes a decrease in
dopamine release.
(2) Serotonin can also decrease
dopamine release in the striatum via
5HT2Abinding in the brainstem. That
is, serotonin released in the raphe
nucleus binds to 5HT2Areceptors on
GABAergic interneurons. This causes
GABA to be released onto
Understanding 5HT2A
Understanding 5HT1A
dopamine is released.
o Blocking 5HT1A -> decreases dopamine
5HT1Areceptorstimulationis functionally
analogous to cortical 5HT2Areceptorblockade
antipsychotics
Binding profiles
antidepressant benefits
o Weak - olanzapine, quetiapine, and aripiprazole
D2 partial agonism
modest affinity
D1,D2 &D3, D5
High for D4
affinity for 5HT2A&H1
M1, H1, alpha1
Few EPS, no TD and
no hyperprolactin
Decreases suicide
Therapeutic: 300-450
Max dose: 900/day
Side effects
Example Titration
Schedule
Olanzapine
oral disintegrating
tablet
acute intramuscular
injection
long-acting 4-week
intramuscular depot
Olanzapine
(Zyprexa)
5HT7and 2antagonism
Quetiapine
(Seroquel)
Atypical receptors
(weak D2) + active
metabolite,
Norquetiapine
o NE reuptake
inhibitor
o 5HT7, 5HT2C, and
2antagonism
o 5HT1Apartial
agonist
PO tab: IR and XR
No EPS or incr. PRL
Quetiapine
(Seroquel)
Asenapine
Similar to
Mirtazipine but no
antidepressant
properties
Sublingual -> oral
numbness, cannot
drink for 10min
Acute sx
Needs more
studies
Risperidone
516),
o Bipolar aggression towards
others, self-injury,
tantrums, rapid-cycle (ages
1017)
o schizophrenia (ages 1317)
Zisprasidone
(Geodon)
Potential
antidepressant
o 5HT2C, 5HT7, 5HT1B/D,
2ant., 5HT1Apartial
agonism, and weak
NE & 5HT reuptake
blockade
Iloperidone
Newer
Orthostasis
Low EPS and
weight
Potential antidepressant
Lurasidone (Latuda)
Aripriprazole (Abilify)
Cariprazine (Vraylar)
Schizophrenia
Acute mania/mixed
of Bipolar I
PO (1.5mg to 6mg)