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Antipsychotic Drugs

LEARNING OBJECTIVES Suggested Reading:


Each student will be able to explain the *CH 29: Antipsychotic Agents
dopamine hypothesis of schizophrenia and Katzung 12th edition (online)
compare it to the more recent modifications of
this hypothesis.
Each student will be able to differentiate
between older (typical, conventional) and newer
(atypical) antipsychotics in regards to symptom
relief, receptor selectivities, mechanisms of
action, adverse effects and toxicities.
Each student will be able to identify additional
psychiatric, neurologic, and therapeutic
indications for antipsychotic drugs.
Each student will be able to explain why typical
antipsychotic drugs can produce extrapyramidal
side effects, neuroleptic malignant syndrome,
and hyperprolactinemia.
Each student will be able to explain the
mechanisms responsible for the anti-emetic and
anti-pruritic effects of some antipsychotic drugs.
Antipsychotic Drugs List
Chlorpromazine
Thioridazine
Antipsychotic Drugs Phenothiazines Fluphenazine
Perphenazine
Prochlorperazine
Promethazine
Trifluoperazine

Thiothixene
Typical (Conventional) Chlorprothixene
Thioxanthines Clopenthixol
Antipsychotics Flupenthixol

Haloperidol
Butyrophenones Droperidol

Clozapine
Loxapine
Olanzapine
Quetiapine
Atypical Miscellaneous Risperidone
Antipsychotics Structures Ziprasidone
Aripiprazole
Pimozide
Sertindole
Therapeutic Indications
Psychosis/
Schizophrenia

Agitation/Disruptive Behavior
(e.g. anxiety associated with
chronic pain)

Antipsychotic Autism Spectrum Disorder


Drugs
Tourette Disorder
Emesis/nausea

Pruritis (itch)
Receptor Mechanisms of
Action of Antipsychotic Drugs

Dopamine Hypothesis of
Schizophrenia!
Antipsychotic Drugs Affect Multiple Receptors
Dopamine Receptor Take-home Points:

Antipscychotic
Block Antipsychotic drugs affect multiple
receptor subtypes responsible for

Effects
Serotonergic (5HT2A) therapeutic effects and for a broad
Receptor array of unwanted effects.
Block D2 receptor binding predictive of
efficacy for typical antipsychotics.
D1 receptor binding is least predictive
of clinical efficacy for typical
antipsychotics.
Antipsychotic 5HT2A receptor block underlies clinical
efficacy of atypical antipsychotics
Drugs (e.g. risperidone, aripiprazole).

Muscarinic
Adverse
Effects

Receptor Block

Alpha-adrenoceptor
Block

Histamine (H1)
Receptor Block
Dopamine D2 and Serotonin 5HT2A
Receptor Antagonism Primarily
Responsible for Antipsychotic
Mechanism of Action
Dopamine Pathways and Antipsychotics
(See next page for summary)

MESOLIMBIC

NIGROSTRIATAL

MESOCORTICAL

Mechanism of TUBEROINFUNDIBULAR Mechanism Underlying


Antipsychotic Action
Other Therapeutic Indications
and
Adverse Effects
Dopamine Pathways and Antipsychotics
Dopamine Pathway Origin Projection Function Disorders

Mesolimbic Ventral Ventral Reward Schizophrenia


Tegmental Striatum Arousal Addiction
Area (Nucleus
(midbrain) Accumbens)
Mesocortical Ventral Frontal Emotion, Schizophrenia
Tegmental Cortex motivation
Area
(midbrain)
Nigrostriatal Substantia Dorsal Voluntary Parkinsons Disease
Nigra striatum movement
(midbrain)
Tuberoinfundibular Hypothalamus Anterior Prolactin Hyperprolactinemia
(arcuate pituitary secretion
nucleus) (dopamine
inhibits
prolactin
secretion)
Antipsychotic Mechanisms
Potency: D2 > 5HT2A (Little to no affinity for D1)
D2 receptor block in the mesolimbic pathway
underlies therapeutic (antipsychotic) efficacy and
Conventional adverse effects (see next slides).
Antipsychotics Agents reduce positive symptoms of schizophrenia
(D2 block) but ineffective against negative symptoms.
Clinical potency: Butyrophenones >
Phenothiazines > Thioxanthines
Potency: 5HT2A > D2 (Little to no affinity for D1)
5-HT2A receptor block in the mesocortical pathway
and D2 receptor block in the mesolimbic pathway
reduce positive symptoms of schizophrenia.
Atypical 5HT2A receptor block in the mesocortical pathway
Antipsychotics originally thought to provide greater reduction of
negative symptoms of schizophrenia. However, with
the exception of clozapine, it now thought that
atypicals are not much better than typicals in
reducing negative symptoms.
5HT2A Receptor Activation and
Dopamine Hyperactivity Contribute to Positive
Symptoms of Schizophrenia
PREFRONTAL
CORTEX
NUCLEUS
ACCUMBENS
+ 5HT2A
DOPAMINE

5HT2A receptors are Positive symptoms


located on neurons in of schizophrenia
the prefrontal cortex MESOLIMBIC due to hyperactivity
that project into the PATHWAY in mesolimbic
VTA. Activation of dopaminergic
+
these 5HT2A receptors pathway that
enhances mesolimbic VENTRAL increases
dopamine activity TEGMENTAL dopamine release
leading to increased AREA into accumbens.
dopamine release in (VTA)
accumbens.
Antagonism of 5HT2A Receptors Decreases
Mesolimbic Dopamine Activity and Decreases
Positive Symptoms of Schizophrenia
PREFRONTAL 5HT2A receptor
CORTEX antagonism in
NUCLEUS
prefrontal cortex
ACCUMBENS
decreases activity of
+ 5HT2A
neuronal projections
DOPAMINE into VTA. This ultimately
decreases mesolimbic
activity and reduces
5HT2A Receptor dopamine release into
Antagonist accumbens. Thus,
MESOLIMBIC antagonism of either
(Atypicals) PATHWAY serotonin (5HT2A) and
+ dopamine (D2) systems
can reduce dopamine
VENTRAL hyperactivity in
TEGMENTAL accumbens and reduces
AREA positive symptoms.
(VTA)
Interactions of antipsychotic drugs
with multiple receptor systems
results in a broad array of
pharmacological effects that are
useful against other disease states
but also cause adverse effects.
Pharmacologic Effects of Antipsychotic Drugs
Antipsychotic effects (Typicals)
Dopamine Receptor Antiemetic effects
Block Extrapyramidal effects (Dystonias,
akathisias, Parkinson-like
symptoms, tardive dyskinesias)
Hyperprolactinemia

Serotonergic (5HT2A)
Receptor Antipsychotic effects (Atypicals)
Block
Drug
Muscarinic Dry mouth, blurred vision, loss of
Receptor Block accommodation, constipation, difficulty
urinating, toxic-confusional state

Alpha-adrenoceptor Orthostatic hypotension, failure to ejaculate


Block

Histamine (H1)
Sedation
Receptor Block
Additional Therapeutic Indications
Autism Spectrum
Disorder

Tourette Disorder
Antipsychotic
Drugs
Pruritis (itch)

Emesis/nausea
Antiemetic Effects

D2
Typical Antipsychotic
D2 Drugs
Motion Sickness
Chemotherapy/Radiation Therapy
Antiemetic effects
Typical antipsychotics are effective anti-emetics.
Atypical antipsychotics not effective anti-emetics.

Emesis (vomiting) controlled by two brainstem sites.


Chemoreceptor trigger zone (caudal portion of 4th ventricle
outside of the blood-brain barrier) can respond directly to
chemical stimuli in the blood or cerebrospinal fluid.
Vomiting center in the medulla coordinates motor
mechanisms of vomiting.

Dopamine D2 receptor activation in both sites


promotes emesis. Antagonism of D2 receptors can
inhibit nausea and vomiting.
Phenothiazines (prochlorperazine) and butyrophenones
(haloperidol, droperidol) used to inhibit vomiting associated
with chemotherapy and radiation treatment.
Adverse Effects of Typical
Antipsychotics
Adverse Effects of Antipsychotics
Antipsychotic drugs produce significant side effects
in 80% of patients but therapeutic index is high.

Typical antipsychotics produce more severe adverse


effects than atypical antipsychotics (due to a more
pronounced D2 block).

Adverse Effects produced by typical antipsychotics


can be divided into two broad categories:
antagonist action at D2 receptors located
outside of the mesolimbic and mesocortical
systems (most important are the extrapyramidal
effects exerted via nigrostriatal pathway).
nonspecific antagonist action at other receptors
(alpha-adrenoceptors, histamine, muscarinic).
Extrapyramidal Side Effects
(Typical Antipsychotics)
Direct
DA D1 + Pathway
+
Typical Antipsychotic Drug Voluntary Movement
_
+
_
_
Indirect
DA D2
Pathway

Nigrostriatal Normal: Dopamine from nigrostriatal pathway stimulates neurons of direct


Pathway pathway (D1) and inhibits neurons (D2) of the indirect pathway. Both of
these effects work together to promote voluntary movement.
Antipsychotic Drugs (Typical): D2 receptor antagonism removes
Substantia inhibitory brake of dopamine on indirect pathway causing the indirect
Nigra pathway to inhibit, and oppose, activity in the direct pathway. This results in
movement dysfunction (dystonias, akathisias and Parkinsonian symptoms).
Solution: Symptoms often treated with antiparkinsonian drugs
Levodopa
Anticholinergic drugs (e.g. benztropine, amantadine)
Extrapyramidal Side Effects
(Time Course)
Appearance of movement disorders due to effects on
extrapyramidal system is time-dependent.

Time post-administration of antipsychotic drug


Dystonias Akathisias Parkinsonian Tardive
Symptoms Dyskinesias

Abnormal postures,
twitching, and
*Involuntary, repetitive movements that
repetitive movements
are belated in onset.
caused by sustained
*Slow onset (develops 6 months to years
muscle contractions.
following initiation of therapy).
Syndrome characterized *Limited pharmacological treatments
by inability to sit still or *May be caused by dopamine receptor
remain motionless. sensitization (i.e. long-term dopamine
receptor block may cause body to
Bradykinesia, produce more dopamine receptors)
tremor, and rigidity increasing antipsychotic doses
temporarily relieves symptoms.
Neuroendocrine Adverse Effects
(Hyperprolactinemia)
Hypothalamus
D2 receptor antagonism by typical antipsychotics
(Dopamine) can cause excessive release of prolactin from the
anterior pituitary and produce hyperprolactinemia.
Typical Normal (absence of drug): prolactin (hormone
Antipsychotic that stimulates mammary gland development and
_
Drug milk production) secretion from anterior pituitary
D2 is tonically inhibited by dopaminergic activation of
D2 receptors.
Antipsychotic Drug: inhibits D2 receptors,
Anterior Pituitary leading to increased prolactin secretion.
(Prolactin)
Hyperprolactinemia: high blood prolactin
concentration. Symptoms are:
Galactorrhoea (unexplained milk secretion)
Infertility
Prolactin Irregular menstrual cycles and amenorrhea
(Blood) (absence of menstrual bleeding)
Gynecomastia (breast enlargement in males)
Neuroleptic Malignant Syndrome
(Adverse Effect)
Definition:
Rare side effect of antipsychotic therapy that can be lethal.
Mechanism:
Due to rapid blockade of postsynaptic dopamine D2 receptors
located in thermoregulatory center of hypothalamus.
Symptoms:
Hyperthermia, muscle rigidity, tachycardia, tachypnea
Diagnostics:
Creatine kinase isozymes elevated reflecting muscle damage.
Clinical intervention:
Discontinuation of antipsychotic therapy followed by
administration of dopamine agonists (bromocriptine) or a
muscle relaxant (dantrolene).
Adverse Effects at
Non-dopaminergic Targets
Antipsychotic
Drug

_ _ _

Muscarinic Alpha-adrenoceptor Histamine (H1)


Receptor Block Block Receptor Block

Dry mouth, blurred Orthostatic Sedation


vision, loss of hypotension, failure *More marked with
accommodation, to ejaculate phenothiazines and
constipation, difficulty *Hypotension responds to atypicals
urinating, toxic- fluid replacement *All atypicals block
confusional state histamine H1
receptors except
sertindole
Atypical Antipsychotics
All atypicals block histamine H1
receptors except sertindole.
Atypical Antipsychotics: Diabetes
mellitus and diabetic ketoacidosis

Studies of weight gain, hyperglycemia,


diabetes mellitus and diabetic ketoacidosis
are associated with clozapine, olanzapine
and quetiapine.

Letter to the Editor, JAMA, Nov. 28, 2001:


adolescent patients on clozapine or olanzapine
10 times more likely to become diabetic.
Baltimore Sun, March 20, 2003: Studies Link
Zyprexa to Diabetes Deaths.
Am J Psy, April 2002: Association of Diabetes
Mellitus with Use of Atypical Neuroleptics in the
Treatment of Schizophrenia.
See next page
Percentage of patients with schizophrenia who
also had a diagnosis of diabetes (by age group)
Potential Atypicals > Typicals
Reason
_
Histamine AMPK Appetite
Younger patients on atypicals have greater prevalence of diabetes
mellitus than younger patients on typical antipsychotics.

30
Conventionals (Typicals)
25 Atypicals

20
Diagnosed
with diabetes 15
(%)

10

0
All Ages <40 y 40-49 y 50-59 y 60-69 y >70 y
Sernyak MJ et al. Am J Psychiatry. 2002;159:561-566.
Side Effects of Atypical Antipsychotics

CLOZAPINE RISPERIDONE OLANZAPINE QUETIAPINE ZIPRASIDONE ARIPIPRAZOLE


-DRENOCEOPTOR BLOCK
Low Blood Pressure +++ + +/0 ++ 0/+ 0/+
MUSCARNIC BLOCK
Dry mouth,
constipation +++ 0 +/++ 0 0 0
DOPAMINE D2 BLOCK
Tremors, stiffness, 0 +/++ 0/+ 0 +/0 0
endocrine problems
HISTAMINE H1 BLOCK
Sedation +++ +/- ++ +++ 0 0
HISTAMINE H1 BLOCK
Weight gain ++++ + ++++ ++ -/+ -/+
HISTAMINE H1 BLOCK
Lipids +++ + +++ ++ 0 0
Blood sugar +++ + +++ ++ 0 0
Legend: + or - indicates an effect was present ( and how great the effect was)
0 indicates effect not seen
+/- indicates that studies have reported both increases and decreases
Adapted from: Nasrallah HA, Mulvihill T. Ann Clin Psychiatry. 2001(Dec);13(4):215-227
Miscellaneous Adverse Effects

Miscellaneous toxicities
Thioridazine retinal deposits cause visual
impairments, high doses leads to fatal ventricular
arrhythmias.
Sertindole prolonged QT segment leading to
arrhythmias.
Clozapine 1-2% incidence of agranulocytosis
that lowers white blood cell count.
Summary
ATYPICALS
TYPICALS

MESOLIMBIC NIGROSTRIATAL CORTICAL


(Dopamine) (Dopamine) (5-HT)

EXTRAPYRAMIDAL
SIDE EFFECTS

POSITIVE
SYMPTOMS