Download ANTI-PSYCHOTIC DRUGS

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
MAJOR AFFECTIVE /MANIC
DEPRESSIVE DISORDERS
Abnormal emotion or mood
 Disorders of affect & depression,
dysphoria, elation or mania
 Bipolar or non-bipolar
 Can occur as a mild disorder or can be
associated with other psychiatric or medical
illnesses
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NEUROSES:
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Less pervasive psychiatric disorders
Comprehend reality, suffering & disability are
sometimes severe
Acute or transient, persistent or recurrent
Mood changes- anxiety , panic, depression
Limited abnormalities of thought- obsessions,
irrational fears
Behavior – rituals, compulsions, hysterical
conversions
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.
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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

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ALIPHATIC DERIVATIVE:
CHLORPROMAZINE
TRIFLUPROMAZINE
PIPERIDINE DERIVATIVE:
THIORIDAZINE
 MESORIDAZINE
 PIPERACETAZINE
 Decrease incidence of EPS side effects
due to  antimuscarinic activity

PIPERAZINE DERIVATIVE:
FLUPHENAZINE
 PERPHENAZINE
 TRIFLUOPERAZINE
 Most potent phenothiazene &
thioxanthene antipsychotic
compound
  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
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A. Phenothiazine Derivatives
Aliphatic Derivative: CHLORPROMAZINE
Piperidine Derivative: THIORIDAZINE
Piperazine Derivative: FLUPHENAZINE,
PERPHENAZINE, TRIFLUOPERAZINE
B. Thioxanthene Derivative:
THIOTHIXENE
C. Butyrophenone: HALOPERIDOL
CLASSIFICATION OF ANTI-PSYCHOTIC
DRUGS
2. ATYPICAL ANTI-PSYCHOTICS
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CLOZAPINE
LOXAPINE
RISPERIDONE
MOLINDONE
SERTINDOLE
ZIPRASIDONE
OLANZAPINE
QUETIAPINE
PIMOZIDE
DOPAMINE RECEPTORS
D1 like family

D1: CHROMOSOME 5; INCREASE cAMP…>
activation of adenyl cyclase
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D5 : CHROMOSOME 4; INCREASE cAMP
D2 like family
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D2: CHROMOSOMES 11: DECREASE
cAMP …>blocks calcium channels
……> opens potassium channels
D3: CHROMOSOME 11: DECREASE cAMP
D4: DECREASE cAMP
DIFFERENCES AMONG
ANTI-PSYCHOTIC DRUGS
CHLORPROMAZINE alpha1=5HT2 > D2 >D1
HALOPERIDOL D2>D1=D4>alpha1>5HT2
CLOZAPINE
RISPERIDONE
OLANZAPINE
D4=alpha1>5HT>D2=D1
D2=5HT2
5HT2> or= D1, D2, alpha2
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
DOPAMINERGIC SYSTEM
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
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NEUROPHYSIOLOGIC EFFECTS
> hypersyncrony focal /unilateral
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ENDOCRINE EFFECTS
> amenorrhea, galactorrhea, increase libido, false(-)
pregnancy test
>decrease libido in males, gynecomastia
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ANTI-PSYCHOTIC AGENTS
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CARDIOVASCULAR EFFECTS
 orthostatic
hypotension
 high resting pulse rate
 increase PR, decrease stroke volume,
decrease mean arterial pressure
 decrease peripheral resistance
PHARMACOKINETICS
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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 ½ is 10 -24 hours
CLINICAL INDICATIONS
A. PSYCHIATRY INDICATIONS
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SCHIZOPHRENIA
SCHIZO-AFFECTIVE DISORDERS
MANIC EPISODES IN BIPOLAR DISORDERS
GILLES DE LA TOURETTE SYNDROME
SENILE DEMENTIA
B. NON-PSYCHIATRIC INDICATIONS
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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-parkinson’s 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
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Mechanism: antagonism of dopamine
Rx: anti-parkinson’s agents
4. NEUROLEPTIC MALIGNANT SYNDROME
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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-parkinson’s 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)
ADVERSE EFFECTS
D. METABOLIC & ENDOCRINE EFFECTS
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Weight gain, hyperglycemia, hyperprolactinemia,
amenorrhea-galactorrhea syndrome, infertility, impotence in
males
E. TOXIC OR ALLERGIC REACTIONS
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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
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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
andmuscarinic 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(phosphotidylinositol-4,5-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
3.
4.
5.
6.
7.
8.
tremors
CVS EFFECTS: ventricular arrythmias
GIT EFFECTS: nausea, vomiting, diarrhea
GUT EFFECTS: polyuria
ENDOCRINE EFFECTS: hypothyroidism
ALLERGIC REACTION: pruritus, rash
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.
B.
C.
THIAZIDE DIURETICS: DECREASE
RENAL CLEARANCE OF LITHIUM
NSAID: DECREASE LITHIUM
CLEARANCE
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
ANTI-DEPRESSANTS
C. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRI)
 FLUOXETINE
 PAROXETINE
 SERTRALINE, CITALOPRAM, FLUVOXAMINE
D. MONOAMINE OXIDASE INHIBITORS (MAOI)
 PHENELZINE, TRANYLCYPROMINE
 MOCLOBEMIDE ,SELEGILINE
 NOTE: MAO-A—amine oxidase responsible for NORe,
serotonin and tyramine
MAO-B---selective for dopamine(SELEGILINE)
ANTI-DEPRESSANTS
PHARMACODYNAMICS
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
A.
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
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PHARMACOKINETICS
C. SSRI : FLUOXETINE
 Well absorbed
 PPC: 4 – 8 hrs
 Inhibits drug metabolizing enzymes
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D. MAOI
 Readily absorbed
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CLINICAL INDICATIONS
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
A.
ADVERSE EFFECTS
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TRICYCLICS
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
Sedation:
Foods that interact with MAOI
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High in tyramine content :
BEER
 BROAD BEANS, LAVA BEANS
 CHEESE
 CHICKEN LIVER
 SAUSAGES
 RED WINE
 YEAST
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 MAO INHIBITORS
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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 drugs—exaggerated hypotension
TCA—increase concentration with cimetidine and
phenothiazines
DRUGS WITH SPECIAL
IMPORTANCE
Desipramine—less sedating, low anti-muscarinic
effects
Amitryptyline-more sedating and marked antimuscarinic effects
Maprotiline-seizures
Trazodone—prolonged penile erection
Fluoxetine—minimal sedative effects, very low
anti-muscarinic effects
Nefazodone-less sedating, no SSRI
Drugs that Interact with MAOI
A. INDIRECTLY ACTING
SYMPATHOMIMETICS: amphetamines, ephedrine,
metaraminol, phenylpropanolamine
B. OTHER ADRENORECEPTOR AGENTS &
RELATED AGENTS: levodopa, methyldopa,
guanethidine, reserpine
C. OPIOID ANALGESICS & DERIVATIVES:
morphine, codeine, meperidine, dextromethorphan
D. MISCELLANEOUS DRUGS: buspirone, fluoxetine,
LSD
Who is wise and understanding
among you? Let him show it by his
good life, by deeds done in humility
that comes from wisdom.
James 3: 13