in this lecture we are going to cover
pharmacology of antipsychotics
so antipsychotics are a class of drugs
used primarily to treat psychotic
disorders such as schizophrenia mania
due to bipolar disorder and severe
depression now in order to gain better
understanding of mechanism of action of
antipsychotic drugs first we need to
discuss the role of dopamine in the
development of psychosis so the
monoamine neurotransmitter dopamine
plays a key role in the so called
dopamine hypothesis which argues that
the unusual behavior and experiences
associated with psychosis
can be largely explained by changes in
dopamine function in the brain now
dopamine has four major pathways by
which it affects the brain
number one the mesolimbic pathway which
is thought to be hyperactive in
schizophrenia and to mediate positive
symptoms of psychosis such as delusions
and hallucinations
number two mesocortical pathway which is
thought to be under active in
schizophrenia and thus mediate negative
psychotic symptoms such as loss of
motivation and social withdrawal
number three the nigrostriatal pathway
which is part of the extrapyramidal
nervous system and controls motor
function and movement deficiency of
dopamine in this pathway can lead to
dystonia and parkinsonian symptoms while
axis of dopamine can lead to
hyperkinetic movements such as sticks
and dyskinesias the last major pathway
number four is the tube arrow
infundibular pathway which controls
prolactin secretion specifically
dopamine in this pathway inhibits
prolactin release and as a reminder
collectin is a hormone that enables
north production and is also involved in
the control sexual desire and regulation
of immune system now within those
different pathways dopamine interacts
with specific receptors that mediate
functional effects of dopamine there are
five primary types of dopamine receptors
known as d1 d2 d3 d4 and d5 out of the
five d1 and d2
receptors are found in the highest
density in nearly all the pathways
involved in psychotic disorders however
the two receptors are the most
clinically relevant because they are the
main targets of antipsychotic drugs now
antipsychotics can be grouped into older
first generation agents known as
typicals and the newer second-generation
agents known as atypicals the first
generation typical antipsychotics all
share the same main therapeutic goal
that is to block d2 receptors
furthermore typical antipsychotics are
not selected for any of the four
dopamine pathways and thus will block d2
receptors in almost all areas of the
brain this has positive as well as
negative consequences so blockade of
dopamine receptors in the mesolimbic
pathway reduces positive symptoms such
as delusions and hallucinations which is
beneficial
however blockade of dopamine receptors
in them as a cortical pathway that is
already under active in schizophrenia
may cause worsening of negative symptoms
and does lead to diminished
energy lack of motivation restrictions
in emotional and verbal expressiveness
and social disengagement furthermore
blockage of dopamine receptors in the
negros traído pathway may lead to
extrapyramidal disorders
tardive dyskinesia and parkinson's-like
symptoms such as tremors muscle rigidity
and difficulty in starting and stopping
movements lastly blockade of dopamine
receptors in the tubero infundibular
pathway may cause increasing blood
prolactin levels which then may lead to
Galacta RIA gynecomastia and sexual
dysfunction now based on their affinity
for d2 receptors typical antipsychotics
are often sub classified as high potency
or low potency the examples of high
potency antipsychotics are haloperidol
flu phenazine prochlorperazine and tri
flow pairs in the example of low potency
antipsychotic
is chlorpromazine
so generally speaking the high potency
agents produce stronger antipsychotic
effect at relatively low doses however
they also tend to cause more
extrapyramidal side effects and greater
increase in prolactin levels on the
other hand the less selective low
potency agents do not bind to d2
receptor as tightly as the high potency
agents and generally affect a range of
other receptors including alpha to
energic cholinergic and histamine
receptors this can result in a variety
of side effects for example blockage of
alpha adrenergic receptors can lead to
orthostatic hypotension blockade of
muscarinic receptors can lead to
anticholinergic symptoms such as dry
mouth blurred vision difficulty
urinating and constipation and block it
up h1 histamine receptors can lead to
sedation and some weight gain now let's
move on to the second generation
atypical antipsychotics in contrast to
typical antipsychotics that primarily
block only d2 receptors atypical agents
appear to block both d2 receptors as
well as serotonin receptors subtype 2a
because serotonin inhibits dopamine
release agents that block serotonin
receptors may increase dopamine levels
in brain areas that need it furthermore
a typical occupied d2 receptors
transiently and dissociate quickly
allowing for relatively normal dopamine
neurotransmission
this modest d2 receptor blockade in
combination with serotonin receptor
blocking is thought to significantly
lower the incidence of extrapyramidal
side effects as well as decrease
negative symptoms and improve cognition
compared to typical agents the examples
of atypical antipsychotics are
re-proposal clozapine Loris adone
olanzapine quetiapine
risperidone and ziprasidone now in
addition to dopamine and serotonin 2a
receptor block ii atypical
antipsychotics also bind to many other
targets including other subtypes
certain receptors as was histamine alpha
adrenergic and muscarinic receptors as a
result the side-effects of
second-generation agents can vary
depending on the drugs receptor binding
profile so for example atypical
antipsychotics that have strong affinity
for certain receptors subtype to C such
as clozapine and olanzapine may cause
metabolic side effects including weight
gain hyperglycemia and dyslipidemia
agents that have strong affinity for h1
receptors such as clozapine on Lanza
beam and quetiapine may cause sedation
and make also contribute to weight gain
agents that have significant affinity
for alpha one adrenergic receptors such
as clozapine and risperidone may cause
orthostatic hypotension in addition to
that out of all second-generation
agents risperidone seems to have the
strongest affinity for d2 receptors and
because of that it has the highest
potential to induce extrapyramidal side
effects and hyperprolactinemia lastly
clozapine is the only antipsychotic that
can cause serious condition called a
granule psychosis that occurs when the
bone marrow does not produce enough
white blood cells called granulocytes
because this condition can be fatal
periodic blood cell counts must be
performed to ensure patient safety and
with that I wanted to thank you for
watching I hope you enjoyed this video
and as always stay tuned for more