ANTI-PSYCHOTIC DRUGS

DON D. CUA, MD
Department of Pharmacology
TYPES OF PSYCHOSIS
SCHIZOPHRENIA
AFFECTIVE DISORDERS
(DEPRESSION/MANIA)
ORGANIC PSYCHOSES (CAUSED BY HEAD
INJURY, ALCOHOLISM, OTHERS)
SCHIZOPHRENIA
A clinical syndrome characterized by profound
disruption in cognition and emotion, affecting
the most fundamental attributes: language,
thought, perception, affect and sense of self.
clear sensorium but marked thinking
disturbance.
THE NATURE OF SCHIZOPHRENIA
1% population, begins at an early age, with
strong hereditary factor
SEX: Equally prevalent in men and women
AGE: MEN-between 15 and 25
WOMEN-between 25 and 35
POSITIVE SYMPTOMS
Delusions
Disorganized behavior
Hallucinations
Disorganized speech/thinking
Thought disorder
Catatonic behaviors
NEGATIVE SYMPTOMS
Withdrawal from social contacts
Flattening of emotional responses
Alogia, Avolition-Apathy, Anhedonia-Asociality
Attention deficit
Diagnostic Criteria for Schizophrenia
DSM IV
A. Two or more of the following (one-month period)
delusions, hallucinations, disorganized speech, grossly
disorganized or catatonic behavior and negative
symptoms.
B. Social/occupational dysfunction: one or major areas
of functioning such as work, interpersonal relations, or
self-care, are markedly below the level achieved prior to
the onset.
C. Continuous signs of the disturbance persist for at
least SIX months.

THE DOPAMINE HYPOTHESIS

SCHIZOPHRENIA: WITH EXCESSIVE DOPAMINERGIC
ACTIVITY; NORe and GABA
ANTI-PSYCHOTIC DRUGS BLOCK POSTSYNAPTIC
D2 RECEPTORS IN CNS
DRUGS THAT INCREASE DOPA AGGRAVATE
SCHIZOPHRENIA
DOPAMINE RECEPTOR DENSITY in schizos
POSITRON EMISSION TOMOGRAPHY (PETS)
Dopamine Receptor Density
HOMAVANILLIC ACID (HAV)
CHANGE IN AMOUNT
CLASSIFICATION OF ANTIPSYCHOTIC DRUGS
1.TYPICAL ANTIPSYCHOTICS:
A. PHENOTHIAZENE DERIVATIVE
3 ring structure, 2 benzene rings are linked by
sulfur & nitrogen atom
N position 10 is replaced by carbon atom with a
double bond to the side chain
ALIPHATIC DERIVATIVE:
CHLORPROMAZINE
TRIFLUPROMAZINE
PIPERIDINE DERIVATIVE:
THIORIDAZINE
MESORIDAZINE
PIPERACETAZINE
NOTE: Decrease incidence of EPS side effects due to
antimuscarinic activity
PIPERAZINE DERIVATIVE:
FLUPHENAZINE
PERPHENAZINE
TRIFLUOPERAZINE
Most potent phenothiazene &
thioxanthene antipsychotic compound
NOTE: EPS but tendency to produce sedation or
autonomic side effects.
B. THIOXANTHENE DERIVATIVES
ALIPHATIC DERIVATIVE:
CHLORPROTHIXENE
PIPERAZINE DERIVATIVE:
CHLOPENTHIXOL
FLUPENTIXOL
THIOTHIXENE
C. BUTYROPHENONE:
HALOPERIDOL

CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

1. TYPICAL ANTI-PSYCHOTICS
A. Phenothiazine Derivatives
Aliphatic Derivative: CHLORPROMAZINE
Piperidine Derivative: THIORIDAZINE
Piperazine Derivative: FLUPHENAZINE,
PERPHENAZINE, TRIFLUOPERAZINE
B. Thioxanthene Derivative:THIOTHIXENE
C. Butyrophenone: HALOPERIDOL
2. ATYPICAL ANTI-PSYCHOTICS
CLOZAPINE
LOXAPINE
RISPERIDONE
MOLINDONE
SERTINDOLE
ZIPRASIDONE
OLANZAPINE
QUETIAPINE
PIMOZIDE
DIFFERENCES AMONG ANTI-PSYCHOTIC DRUGS
CHLORPROMAZINE alpha1=5HT2 > D2 >D1
HALOPERIDOL
D2>D1=D4>alpha1>5HT2
CLOZAPINE
D4=alpha1>5HT>D2=D1
RISPERIDONE
D2=5HT2
OLANZAPINE
5HT2> or= D1, D2, alpha2
Pimozide
D2 exclusively
DOPAMINE RECEPTORS
D1 like family
D1: CHROMOSOME 5; INCREASE cAMP
>activation of adenyl cyclase
D5 : CHROMOSOME 4; INCREASE cAMP
D2 like family
D2: CHROMOSOMES 11: DECREASE cAMP
>blocks calcium channels
> opens potassium channels
D3: CHROMOSOME 11: DECREASE cAMP
D4: DECREASE cAMP
DOPAMINERGIC SYSTEM
1. MESOLIMBIC-MESOCORTICAL
substancia nigra >limbic system
BEHAVIOR
2. NIGROSTRIATAL
substancia nigra>caudate & putamen
VOLUNTARY MOVEMENTS
3. TUBEROINFUNDIBULAR
arcuate nuclei & periventricular neurons>
hypothalamus & post pituitary
INHIBITS PROLACTIN SECRETION

4. MEDULLARY-PERIVENTRICULAR
motor nuclei of the vagus
EATING BEHAVIOR
5. INCERTOHYPOTHALAMUS
from the medial zona incerta to the
hypothalamus and the amygdala
REGULATE THE ANTICIPATORY MOTIVATIONAL
PHASE OF COPULATORY BEHAVIOR IN RATS
ANTI-PSYCHOTIC AGENTS
PSYCHOLOGICAL EFFECTS
sleepiness, restlessness, impaired performance
& judgment
NEUROPHYSIOLOGIC EFFECTS
hypersyncrony focal /unilateral
ENDOCRINE EFFECTS
amenorrhea, galactorrhea, increase libido,
false(-) pregnancy test
decrease libido in males, gynecomastia
CARDIOVASCULAR EFFECTS
orthostatic hypotension
high resting pulse rate
increase PR, decrease stroke volume,
decrease mean arterial pressure
decrease peripheral resistance
PHARMACOKINETICS
READILY BUT INCOMPLETELY ABSORBED
FIRST PASS METABOLISM
HIGHLY LIPID SOLUBLE
LARGE VOLUME OF DISTRIBUTIION
PROTEIN BOUND
COMPLETELY METABOLIZED Except
mesoridazine (major metabolites of
thioridazine)
LITTLE EXCRETED UNCHANGED
T is 10 -24 hours
CLINICAL INDICATIONS
A. PSYCHIATRY INDICATIONS
SCHIZOPHRENIA
SCHIZO-AFFECTIVE DISORDERS
MANIC EPISODES IN BIPOLAR DISORDERS
GILLES DE LA TOURETTE SYNDROME
SENILE DEMENTIA
B. NON-PSYCHIATRIC INDICATIONS
ANTI-EMETIC EFFECT
ANTI-PRURITIC EFFECT
PRE-OPERATIVE ANESTHESIA
NEUROLEPTIC ANESTHESIA

SIDE EFFECTTS OF NEUROLEPTIC DRUGS

A. NEUROLOGIC EFFECTS
1. ACUTE DYSTONIA : spasm of muscles tongue, face,
neck, back, may mimic seizures
During the first 1 -5 days of Rx
Mechanism unknown
Rx: anti-parkinsons agents
2. AKATHISIA : motor restlessness
5 -60 days
Mechanism unknown
Rx with diphenhydramine
3. PARKINSONISM
bradykinesia, rigidity, tremor, mask facies,
shuffling gait seen in 5-30 days
Mechanism: antagonism of dopamine
Rx: anti-parkinsons agents
4. NEUROLEPTIC MALIGNANT SYNDROME
catatonia, stupor, fever, unstable BP,
myoglobulinemia after weeks of treatment
Mechanism: antagonism of dopamine
Rx: Stop neuroleptic immediately; dandrolene;
bromocriptine, Anti-parkinsons- not effective
5. PERIODIC TREMOR RABBIT SYNDROME
Peri-oral tremors after months or years of
treatment
Mechanism : unknown
Rx: Anti-parkinsons Drugs
6. TARDIVE DYSKINESIA
Supersensivity of D receptors (cholinergic def)
oral-facial dyskinesia, choreoathetosis, dystonia
After months or years of RX
Worse on withdrawal
Mechanism: excess function of dopamine
Rx: prevention crucial
Rx: unsatisfactory
ADVERSE EFFECTS
B. BEHAVIORAL EFFECTS
Pseudo-depression; toxic confusional state
C. AUTONOMIC NERVOUS SYSTEM EFFECTS
urinary retention, dry mouth, loss of
accomodation, constipation (MUSCARINIC
CHOLINERGIC BLOCKADE)
orthostatic hypotension, impotence, failure to
ejaculate ( ALPHA ADRENORECEPTOR
BLOCKADE)
D. METABOLIC & ENDOCRINE EFFECTS
Weight gain, hyperglycemia,
hyperprolactinemia, amenorrhea-galactorrhea
syndrome, infertility, impotence in males
E. TOXIC OR ALLERGIC REACTIONS
Agranulocytosis (clozapine) , cholestatic
jaundice, skin eruptions

F. CARDIAC TOXICITY
Ventricular arrythmias (thioridazine)
G. OCULAR COMPLICATIONS:
browning of vision
ANTI-MANIC AGENTS
MANIA-- STATE OF ELEVATED MOOD & PSYCHOMOTOR
ACCELERATION, WITH EXCESS CATHECHOLAMINES
ACTIVITY
TREATMENT: LITHIUM CARBONATE
CATHECOLAMINE RELEASE FROM ADRENERGIC NERVE
TERMINALS
LITHIUM
INDICATIONS:
BIPOLAR DISORDERS
THYROTOXICOSIS
INAPPROPRIATE ADH SECRETION
LITHIUM PHARMACOKINETICS
ABSORPTION: virtually complete within 6 -8 hrs; peak
plasma levels in 30 min to 2 hrs
DISTRIBUTION: in total body water; slow entry into
intracellular compartment. No protein binding
METABOLISM: None
EXCRETION: virtually entirely in urine; plasma half life is
about 20 hours
LITHIUM PHARMACODYNAMICS
EFFECTS ON ELECTROLYTES & IONS TRANSPORT:
Substitute for sodium in generating action
potentials
EFFECTS ON NEUROTRANSMITTERS
Enhance effects of serotonin?
Decrease norepinephrine & dopamine turnover
Block dopamine receptor supersensitivity
Augment synthesis of acetylcholine?
EFFECTS ON SECOND MESSENGERS
effect on Inositol 1,4,5 triphospate (IP3 )/
Diacylglycerol (DAG)-needed in alpha a and
muscarinic transmission
Lithium inhibits several important enzymes in the
normal recycling of membrane phosphoinositides.
(-) IP2----IP1
(-) IP1----inositol
It will lead to a depletion of PIP2(phosphotidylinositol4,5-bis-phosphate) which is the membrane precursor of
IP3 and DAG
LITHIUM could cause a selective depression of the
overactive circuits.

LITHIUM ADVERSE EFFECTS

1. CNS EFFECTS: dizziness, mild ataxia
2. NEUROMUSCULAR EFECTS: fine tremors
3. CVS EFFECTS: ventricular arrythmias
4. GIT EFFECTS: nausea, vomiting, diarrhea
5. GUT EFFECTS: polyuria
6. ENDOCRINE EFFECTS: hypothyroidism
7. ALLERGIC REACTION: pruritus, rash
8. OVERDOSE TOXICITY: vomiting, drowsiness,
decrease consciousness and seizures
Rx: dialysis
The TWO most common side effects
UNCOUPLING OF THE VASOPRESSIN and TSH
RECEPTORS FROM THEIR G PROTEINS
LITHIUM CONTRAINDICATIONS
A. MARKED DEHYDRATION OR SODIUM DEPLETION
B. SIGNIFICANT RENAL OR CARDIAC DISEASES
C. PREGNANCY
D. RENAL CONCENTRATION ABILITY
Nephrogenic diabetes insipidus with polyuria
LITHIUM DRUG INTERACTIONS
A. THIAZIDE DIURETICS: DECREASE RENAL
CLEARANCE OF LITHIUM
B. NSAID: DECREASE LITHIUM CLEARANCE
C. ANTIPYSCHOTIC AGENTS: INCREASE
NEUROTOXICITY
DEPRESSION
I. REACTIVE OR SECONDARY DEPRESSION
Core Depression Syndrome: depression,
anxiety, tension, bodily complaints, guilt (>
60%)
II. ENDOGENOUS DEPRESSION
Core Depression Syndrome plus ABNORMAL
vital signs rhythm of sleep, motor activity,
libido, decrease appetite ( 25%)
III. DEPRESSION ASSOCIATED WITH BIPOLAR AFFECTIVE
DISORDER (10-15%)
Pathogenesis of Major Depression
DECREASED FUNCTIONAL AMINE-DEPENDENT SYNAPTIC
TRANSMISSION
ANTI-DEPRESSANTS
A.TRICYCLIC ANTI-DEPRESSANTS(TCA)
THREE-RING NUCLEUS(anti-muscarinic, anti-H and @(-)adrenergic)
IMIPRAMINE. AMITRYPTYLINE
(mixedNorE and serotonin uptake inhibitors)
DOXAPIN, NORTRIPTYLINE , DESIPRAMINE,

CLOMIPRAMINE , PROTRIPTYLINE, TRIMIPRAMINE

Note: toxicity due alpha adrenergic blocking activity
B. HETEROCYCLIC: SECOND & THIRD GENERATIONS
1. SECOND GENERATIONS
AMOXAPINE (dopamine receptor antagonist)
MAPROTILINE
TRAZODON, BUPROPION
2. THIRD GENERATIONS
MIRTAZAPINE, VENLAFAZINE,NEFAZODONE
C. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)
FLUOXETINE
PAROXETINE
SERTRALINE, CITALOPRAM, FLUVOXAMINE
D. MONOAMINE OXIDASE INHIBITORS (MAOI)
PHENELZINE, TRANYLCYPROMINE
MOCLOBEMIDE ,SELEGILINE
NOTE:
MAO-Aamine oxidase responsible for NORe,
serotonin and tyramine
MAO-B---selective for dopamine(SELEGILINE)
ANTI-DEPRESSANTS PHARMACODYNAMICS
A.ACTION OF ANTIDEPRESSANTS ON BIOGENIC AMINE
NEUROTRANSMITTERS
TCA(-) NorE and serotonin reuptake pump
OFF-SWITCHES of the amine transmission
MAO inhibitors (-) major degradation pathway resulting
to accumulation of amines in presynaptic stores for the
amino neurotransmitters and increase release
Trazodone,Nefazodone and Mirtazepine(-) 5HT2a or
5HT2c
Mirtazepine (-) alpha 2 NorE receptors
(Increase therapeutic effects)
B. RECEPTOR & POSTRECEPTOR EFFECTS
Increase in neurotransmitter in the synapse acting on
postsynaptic receptor giving ultimate effect.
by decreasing cAMP rather than increase.
and decreasing postsynaptic B adrenoreceptors as
clinical improvement is seen.
C. EFFECTS OF SPECIFIC ANTIDEPRESSANTS
PHARMACOKINETICS
A. TRICYCLICS
Incompletely reabsorbed
First pass metabolism
Large volume of distribution
Metabolized due to transformation of tricyclic
nucleus and alteration of the aliphatic side
chain
( hydroxylation and conjugation and demethylation)
B. HETEROCYCLICS
Variable bioavailability
High protein binding

 Variable and large volume of distribution

Active metabolites
C. SSRI: FLUOXETINE
Well absorbed
PPC: 4 8 hrs
Inhibits drug metabolizing enzymes
D. MAOI
Readily absorbed
CLINICAL INDICATIONS
A. DEPRESSION
B. PANIC DISORDER (Imipramine)
C. OBSESSIVE COMPULSIVE(SSRI-Fluoxetine)
D. ENURESIS (TCA)
E. CHRONIC PAIN (TCA, Phenothiazine)
F. OTHERS: Eating Disorder (Bulemia)(SSRI)
Cataplexy associated with narcolepsy, school phobia,
attention deficit syndrome
NOTE: Serotonin Syndrome-hyperthermia, muscle
rigidity and myoclonus
ADVERSE EFFECTS
A.TRICYCLICS
Sedatiion: sleepiness
Sympathomimetic: tremors, insomnia
Anti-muscarinic: blurred vision, constipation
confusion, urinary incontinence
Psychiatric: psychoses aggravated
CVS: orthostatic hypotension
Neurologic: Seizures
Metabolic-Endocrine: weight gain, sexual disturbance
Foods that interact with MAOI
High in tyramine content :
BEER
BROAD BEANS, LAVA BEANS
CHEESE
CHICKEN LIVER
SAUSAGES
RED WINE
YEAST
MAO INHIBITORS
headache, drowsiness, dry mouth, weight gain,
postural hypotension, sexual disturbance
AMOXAPIN
Tricyclic & anti-psychotic effects
MAPROTILINE
Tricyclic effects
TRAZODONE & NEFAZODONE: drowsiness, dizziness,
insomnia, nausea and agitation
BUPROPION
dizziness, dry mouth, tremor

FLUOXETINE
Anxiety, insomnia, tremors, decrease libido, GIT
effects
OVERDOSE TOXICITY
Coma with shock, metabolic acidosis,
respiratory
depression,
sudden
apnea,
agitation, delirium
Hypertensive crisis
Cardiac conduction defects such as arrhythmias
DRUG INTERACTIONS
MAO Inhibitors and sympathomimetics and
opiates
Anti-hypertensive
drugsexaggerated
hypotension
TCAincrease concentration with cimetidine
and phenothiazines
DRUGS WITH SPECIAL IMPORTANCE
Desipramineless sedating, low anti-muscarinic effects
Amitryptyline-more sedating and marked antimuscarinic effects
Maprotiline-seizures
Trazodoneprolonged penile erection
Fluoxetineminimal sedative effects, very low antimuscarinic effects
Nefazodone-less sedating, no SSRI