Download Blockade of D2 receptor increases prolactin release and causes

Antipsychotics
Psychosis

a state in which a person’s mental capacity
to recognize reality, communicate, and relate
to others is impaired

delusions, hallucinations (auditory, visual,
tactile, olfactory), grossly disorganized
thinking in a sensible manner

thus interfering with the capacity to deal with
life’s normal everyday demands
Psychotic Disorders
 Schizophrenia
 Manic
phase of bipolar (manicdepressive) illness
 Senile Psychosis
 Drug induced psychosis
 Post surgical delirium
 Amphetamine intoxication
 Acute idiopathic psychotic illness
Schizophrenia






Characterized by delusions, hallucinations
(hearing voices), thinking and speech
disturbances
Often affected during adolescence
Strong genetic component
Characterized by 2 components;
 breakdown of personality
 loss of contact with reality
Considered neurodevelopmental disorder
possibly overactivity of mesolimbic
dopaminergic neurons
Schizophrenia Etiology

Dopamine Hypothesis
 no longer considered to cover all aspects of
schizophrenia
 Important in understanding pos./neg. symptoms

Serotonin Hypothesis
 5-HT stimulation responsible for hallucinations
 Atypical antipsychotics – MOA

Glutamate Hypothesis
 Hypofunction of NMDAr - decreased GABAergic
inhibitory activity
Manic Phase of Bipolar Disorder

two phases that cycle back and forth -mania and depression.

cyclic attacks of mania induce paranoid
schizophrenia (grandiosity, bellicosity,
paranoia, and overactivity)
Mechanism of Action of
Antipsychotics
○5
DA receptors (D1-D5)
 D1 like – D1 and D5 activate adenyl cyclase
 D2 like – D2, D3 and D4 inhibit adenyl cyclase
 involved in psychotic disorders
 Blockade of D2 receptor is antipsychotic action
 Efficacy
of the typical neuroleptic drugs correlate
to their ability to block D2 receptors in the
mesolimbic system. (high EPS)
 Antagonized by levodopa and amphetamine
 The Atypical antipsychotics, Clozapine has a high
affinity for the D4 receptor (low EPS)
Dopaminergic Systems

Until 1959, DA was not recognized as a NT
in CNS, but a precursor to NE.

Neurons that secrete dopamine are primarily
located in three discreet regions of the brain
Dopamine Pathways

Nigrostriatal

Mesocortical / Mesolimbic

Tuberoinfundibular

Medullary-Periventricular

Incertohypothalamic
Douglas L. Geenens, D.O. 2000
Major Dopamine Pathways
Mesolimbic pathway
•Hyperactivity on this pathway is
associated with positive symptoms of
schizophrenia
Mesocortical pathway
•Deficit in dopamine in this pathway is
associated with negative and cognitive
symptoms of schizophrenia
Major Dopamine Pathways
Nigrostriatal pathway
•Part of extrapyramidal system,controls motor movement
•Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement
disorder such as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
•Increased neuronal activity of this pathway inhibits prolactin
release
•Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea
Antipsychotic Actions

positive symptoms reduced by typical
neuroleptics

Negative symptoms not as responsive to
typical, but respond to atypical.

All have a calming effect, reduce spontaneous
physical movement.

Onset of action of Antipsychotic – 2 weeks
Positive and Negative
Symptoms of Schizophrenia

Positive symptoms - symptoms that most
individuals do not normally experience but
are “added” in schizophrenia.

Negative symptoms - symptoms that reflect
the loss or absence of normal traits or
abilities (motivation). feelings that are "taken
away" such as motivation
Antipsychotics

Referred to as antischizophrenic, antipsychotic or
major tranquilizers

Typical (neurolelptics) properties due to dopamine
receptor antagonism
 first generation, 1950’s, D2
 High EPS

Atypical properties due to Serotonin and DA receptor
antagonism
 Second generation

Not curative, does not eliminate thinking disorder, but
allow patient to function in supportive environment
Antipsychotics
Reserpine and chlorpromazine were first drugs used for
schizophrenia/psychosis
 Typical antipsychotics are divided into 5 major classifications based on
structure. Side chains have significant effect on potencies


Typical (neuroleptics)
Phenothiazines - Chlorpromazine (Thorazine)
 2. Butyrophenones – Haloperidol (Haldol)
 3. Thioxanthenes – Thiothixene (Navane)
 4. Dibenzoxazepines – Loxapine (Loxapac)
 1.

Atypical
○ Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seroquel),
Olanzapine (Zyprexa), Ziprasidone (Geodon)
○ Aripiprazole (Abilify)

Proper management of psychotic disorder can be determined by
familiarity of side effects of drugs in each class
Phenothiazine
( Typical Antipsychotics)

1. Aliphatic – least potent, intermediate, EPS,
intermediate anticholinergic action, high sedative action
 Chlorpromazine (Thorazine)

2. Piperidine – least potent, lower incidence of EPS, high
incidence of anticholinergic action
 Thioridazine (Mellaril)

3. Piperazine – most potent, selective and effective,
increased incidence of Tardive dyskinesia
 Fluphenazine (Prolixin)
 Perphenazine (Trilafon)
 Trifluperazine (Stelazine)
Pharmacological Action of
Phenothiazine
 Basal Ganglia – blockade of D1 or D2 results in EPS
 Cardiovascular – depressed by antipsychotics –
hypotension
 Chemoreceptor trigger zone (CTZ) - These
receptors are blocked by phenothiazines (antiemetic action).
 Hypothalmus - stimulate release of prolactin
 Misc. – no physical dependence, decrease seizure
threshold
 Autonomic effects – anticholinergic action
(piperidines – strongest, piperizines – weakest)
 α – adrenergic antagonist - hypotension
Side Effects of Phenothiazines
 Orthostatic hypotension – due to α- blockade, dose/effect
response
 Extrapyramidal Syndrome – increased cholinergic activity
(Piperazine – highest, Piperidines – lowest)
 Parkinson-like Syndrome
 Akathesia – uncontrollable restlessness, distress, anxiety
 Tardive Dyskinesia – develops late in antipsychotic therapy,
usually at high doses x 6 months, rhythmic motions of head,
face and shoulders, may be irreversible
 Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl),
benztropine (Cogentin) or trihexephenidyl (Artane)
Therapeutic use of Phenothiazines

Tx psychotic disorders
 Schizophrenia, senile dementia, extreme paranoia,
manic phase of manic depressive syndrome

Anti-emetics – radiation toxicity, anticancer
meds, opioids, gastroenteritis

Phenothiazines
○ Control positive symptoms – Hallucinations,
delusions, hostility, hyperactivity
○ Not negative symptoms – social withdrawal,
lack of expression, decrease in speech
patterns
Butyrophenone

Haloperidol (Haldol)
 alleviates positive symptoms
 manic phase of bipolar disorder
 severe EPS, < α - adrenergic blockade
 < sedation than phenothiazines
 Used in Huntington’s Chorea, Tourette’s
Syndrome
Thioxanthenes
•
very specific for D2 receptor
•
very low affinity for 5-HT receptor
•
very potent
•
intermediate EPS
•
sedative action and hypotension
Atypical Antipsychotics

In the last decade new "atypical" antipsychotics
have been introduced

More effective, less side effects

appear to be equally effective for helping reduce
the positive symptoms like hallucinations and
delusions
 but may be better than the older medications at relieving
the negative symptoms of the illness, such as withdrawal,
thinking problems, and lack of energy.
Mechanism of Action of
Atypical Antipsychotics

Blockade of DA2 (weak) and / or 5-HT receptors. Many also
block cholinergic, adrenergic, and histamine receptors –
variety of side effects (low D2)

DA receptor antagonism in brain (typical and atypical
antipsychotics)
 Neuroleptics are antagonized by agents that increase DA
concentration (L-dopa and amphetamines)

Serotonin receptor antagonism in brain (atypical)
NEUROBIOLOGY OF
CLOZAPINE
Here you can see that Clozapine will not bind to any Dopamine receptor, it
is selective, it has an affinity for the D4 receptor subtype.
Atypical Antipsychotics

Clozapine (Clozaril)

Risperidone (Risperdal

, Quetiapine (Seroquel)

Olanzapine (Zyprexa)



Ziprasidone (Geodon)
Aripiprazole (Abilify)
Atypical Antipsychotics

Admin PO QD or BID

Low or no EPS

5-HTr antagonist
 5-HT2A receptor

No effect on prolactin
 Exception (Compared to clozapine and quetiapine)
Increase prolactin release, low risk of tardive dyskinesia

Control both positive and neg. symptoms
Atypical Antipsychotics

Low or no EPS

5-HT2A antagonist

Control both positive and neg. symptoms
Atypical Antipsychotics
(second generation)

Clozapine (prototype)
 little to no EPS, high incidence of agranulocytosis
(regular CBC’s), high incidence of siezures, blood
dyscrasia, weight gain

Olanzapine (Zyprexa)
 sedation, weight gain, no agranulocytosis, low
incidence of siezures

Quetiapine (Seroquel)
 sedation, low incidence of all side effects
Summary of Antipsychotics
Atypical antipsychotics can be distinguished
from the classsic neuroleptics by three main
characteristics;
 Less likely to induce EPS
 More effective against negative symptoms of
schizophrenia
 Able to effectively treat patients unresponsive
to classic neuroleptics.

Treatment of Bipolar Disorder

Manic Phase
 many symptoms of paranoid schizophrenia (grandiosity,
excitement, impulsivity, disinhibition, aggression, diminished
need for sleep, paranoid thoughts and overactivity)
 Decrease in activity of DA and NE relieve mania

Depressive Phase
 Similar to major depression, depressed mood, sleep
disturbance, anxiety, and sometimes psychotic symptoms

Mixed manic and depressive symptoms are sometimes seen,
high risk of suicide

Strong genetic component, no effect on normal individuals
Treatment of Mania

Lithium - Closely related to Na+ and K+ in
generating AP

MOA involves interference of
 second messengers inositol triphosphatase (IP3)
and diacylglycerol (DAG)
 neurotransission mechanisms.
○ Important in α-adrenergic and muscarinic
transmission
Lithium Drug Interactions

Diuretics - renal clearance is reduced by
25%, dose may need to be reduced.
 Same w/ some anti-inflammatory drugs that
block prostaglandin synthesis.

Neuroleptics (typical) – produce more
EPS when combined w/ Lithium
Adverse Effects of Lithium

Tremors
 Propranolol and atenolol alleviate lithium induced
tremors


Decreased thryoid function (reversible)
Nephrogenic Diabetes Insipidus
 Resistant to vasopressin – treated w/ Amiloride
 pts. should avoid dehydration

Edema
 Related to Na+ retention

Pregnancy
 Increased renal clearance during, and lowered
postpartum
Other Antimanic Mood-Stabilizing
agents

Valproic Acid
 Shows efficacy equivalent to Lithium
 Effective in pts not responding to Lithium
 May be used in combination
 S/E – GI distress weight gain and alopecia

Carbamazepine
 Oxcarbazepine not effective
 May be used prophylactic therapy
 May be used w/ Lithium but not Valproic Acid