ANTIPSYCHOTICS

PHARMACOLOGY
DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS
FACULTY OF MEDICINE DIPONEGORO UNIVERSITY
2018
WHAT IS PSYCHOSIS?

◼ A thought disorder characterized by disturbances of

reality and perception, impaired cognitive functioning,
and inappropriate or diminished affect (mood).
PSYCHOSIS : AN OVERVIEW

◼ The most important types of psychosis are:

◼ Schizophrenia
◼ Affective disorders (e.g. depression, mania)
◼ Organic psychoses (mental disturbances caused by
head injury, alcoholism, or other kinds of organic
disease).
SCHIZOPHRENIA (affecting 1% of the population)

Symptoms:
- Halucination / delution
- Thought disorder symptom (+)
- Ideas of reference

• Social withdrawal
• Flattening of emotional response symptom (-)
- Cognitive impairment
 DOPAMINE THEORY OF SCHIZOPHRENIA

Many lines of evidence point to the aberrant

increased activity of the dopaminergic system as
being critical in the symptomatology of
schizophrenia.

There is a greater occupancy of D2 receptors by

dopamine => greater dopaminergic stimulation
DOPAMINE THEORY OF SCHIZOPHRENIA

Dopamine Correlates:
● Antipsychotics reduce dopamine synaptic activity.
● These drugs produce Parkinson-like symptoms.
● Dopamine agonist / pro-drug (amphetamine; levodopa)
caused exacerbation of schizophrenia
● Increased DA receptor density (Post-mortem, PET).
● Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.
DOPAMINE THEORY OF SCHIZOPHRENIA

◼ Confronting evidences:
- Antipsychotics are only partialy-effective (70%
patients), while in 30% patients are resistant.
- Antipsychotic drugs bind not only to D2 receptor, but
also D4, 5-HT, α-adrenoreceptors, M-cholinoreceptor,
histamine.
- Clinical remission takes longer time compared to the
changes in receptor, because the effect of anti psychotics
need blockade to at least 80% of total D2 receptor.
DOPAMINERGIC PATHWAYS

I. Mesolimbic pathway
(motivation, pleasure, reward)
II. Mesocortical pathway
(cognitive, motivation,
emotional)
III. Nigrostriatal pathway (tremors,
rigidity, postural imbalance)
IV. Tuberoinfundibular pathway
(hiperprolactinemia)
 Tyrosine
Dopamine Synapse
Tyrosine

L-DOPA

DA
 Dopamine System
• DOPAMINE RECEPTORS
– There are at least 5 subtypes of receptors:
– D1 and D5: mostly involved in postsynaptic
inhibition.
– D2, D3, and D4: involved in both pre-and
postsynaptic inhibition.

D2: the predominant subtype in the brain:

regulates mood, emotional stability in the limbic
system and movement control in the basal
ganglia.
tremors, rigidity, and postural imbalance
Dopamine Reuptake System
THE SEROTONIN HYPOTHESIS

◼ The 5-HT2 “antagonism” might be responsible for some

beneficial actions of antipsychotic
◼ Newer generations of antipsychotic also work on 5-HT
receptor
◼ These drugs are inverse agonists.
◼ The 5-HT2 modulate the release of dopamine, NE,
glutamate, GABA & ACh. Stimulation of 5-HT2 receptors
by newer generations of antipsychotic leads to inhibition
of dopamine release.
THE GLUTAMATE HYPOTHESIS

◼ Amphetamine, LSD, ketamine, blocks NMDA-type

(n-methyl-d-aspartate) glutamate receptor, produce
schizophrenia-like symptoms.
◼ NMDA-hypofunction → excessive release of excitatory
neurotransmitter in the frontal cortex, hyperstimulation of
neurons through non-NMDA receptor → cortical neuron
damaged and deteriorated → cognitive impairment.
◼ Drugs that improve the function of NMDA maybe useful in
schizophrenia.
ANTIPSYCHOTICS

◼ Neuroleptic = major tranquilizer to control psychosis.

◼ Not curing, only decreasing psychological symptoms in
schizophrenic patients (thought disorder, emotional
withdrawal, halucinations/delutions).
◼ Chronic treatment may lead to toxicities (neurologic,
autonom, endocrine, etc).
 CLASSIFICATION

◼ Main categories are:

◼ Typical antipsychotics
Phenothiazines (chlorpromazine, perphenazine,
fluphenazine, thioridazine et al)
Thioxanthenes (flupenthixol, clopenthixol)
Butyrophenones (haloperidol, droperidol)
◼ Atypical antipsychotics (e.g. clozapine, risperidone, sulpiride,
olanzapine)
Newer drugs → ektrapiramidal effects ↓
PHARMACOKINETICS

A. Absorption & Distribution

◼ Most antipsychotics are readily but incompletely absorbed.
◼ Significant first-pass metabolism.
◼ Bioavailability is 25-65%.
◼ Most are highly lipid soluble.
◼ Most are highly protein bound (92-98%).
◼ High volumes of distribution (>7 L/Kg).
◼ Slow elimination.
**Duration of action longer than expected, metabolites are present and
relapse occurs, weeks after discontinuation of drug.**
PHARMACOKINETICS (2)

B. Metabolism
◼ Most antipsychotics are almost completely metabolized.
◼ Most have active metabolites, although not important in
therapeutic effect, with one exception. The metabolite of
thioridazine, mesoridazine, is more potent than the parent
compound and accounts for most of the therapeutic
effect.
DOPAMINERGIC PATHWAYS

I. Mesolimbic pathway
II. Mesocortical pathway
III. Nigrostriatal pathway
IV. Tuberoinfundibular
pathway
PHARMACODYNAMICS
Blockade of “dopamine-tracts” in the brain:
• Mesocortical & Mesolimbic (mental and mood regulation)
• Nigrostriatal tracts (EP)
• Tuberoinfundibular (endocrine disturbance)

Adverse Effects:
• Extra pyramidal dysfunction
• Hyperprolactinemia

Clozapine → specifically inhibit D4 and 5-HT - receptor; used for

patients who are un-responsive to standard/traditional anti psychotic
drugs.
PHARMACODYNAMICS

Obat-obat anti psikotik generasi I menunjukkan

penghambatan terhadap reseptor D2 › reseptor D1;

Obat-obat yang lebih baru (sulpiride, amisulpiride,

remoxipride) sangat selektif terhadap reseptor D2;

Clozapine relative tdk selektif terhadap reseptor D1 dan D2,

tapi mempunyai afinitas yang tinggi terhadap reseptor D4.
FIRST GENERATION ANTIPSYCHOTIC
(TYPICAL ANTIPSYCHOTIC)

◼ Alleviate “positive” symptoms

◼ Do not affect “negative” symptoms
◼ Cause extrapyramidal side effects (parkinsonian), tardive
dyskinesia (abnormal choreoathetotic movement)
◼ Other side-effects and toxicity: sedation, postural hypotension,
anticholinergic effects (dry mouth, blurry vision, constipation),
weight gain, worse lipid profile
◼ Non-psychiatric use (as anti-nausea & anti-vomitus)
◼ Haloperidol : more potent and have fewer autonomic effects
compared to Phenotiazines, but greater extrapyramidal effects.
SECOND GENERATION ANTIPSYCHOTIC
(ATYPICAL ANTIPSYCHOTIC)

A. Clozapine
• Reduce symptoms in ~30% of those who do not improve with
standard/typical treatment
• No parkinsonian or tardive dyskinesia side effects
• May reduce negative symptoms
• Action at non-dopamine receptors: drowsiness & weight gain
(histamine), dizziness & low blood pressure (alfa adrenergic),
drowsiness hypersalivation blurred vision, cognitive impairment, etc
(anticholinergic)
• Life-threatening agranulocytosis
SECOND GENERATION ANTIPSYCHOTIC
(ATYPICAL ANTIPSYCHOTIC)

◼ Risperidone
• 5-HT2 and D2 blocker (improves antipsychotic & reduce
extrapyramidal effects)
• Side effects: agitation, anxiety, insomnia, headache, nausea
• “First-line” drug, especially when negative symptoms are predominate
• Indication: schizophrenia, bipolar disorder, irritability in individual with
autism
• Available in long-acting injectable form, oral (tablet and liquid)
SECOND GENERATION ANTIPSYCHOTIC
(ATYPICAL ANTIPSYCHOTIC)

◼ Olanzapine
• Similar to Clozapine
• D2 and 5-HT2 blockade (latter is greater)
• Antimuscarinic effects
• Improves both positive and negative symptoms
• Side effects: weight gain, sedation, dizziness, orthostatic
hypotension
SECOND GENERATION ANTIPSYCHOTIC
(ATYPICAL ANTIPSYCHOTIC)

◼ Quetiapine
• 5-HT2 and D2 antipsychotic
• Comparable to Haloperidol in reducing positive symptoms, with little
extrapyramidal symptoms
• Available in XR/long acting form
• Indication: acute and maintenance treatment for schizophrenia,
bipolar disorder (manic phase), as adjunctive treatment for major
depression, adolescent mania
DOPAMINERGIC PATHWAYS

I. Mesolimbic pathway
II. Mesocortical pathway
III. Nigrostriatal pathway
IV. Tuberoinfundibular
pathway
TOXICITY

Endocrine and metabolic effects

◼ Gynecomastia, amenorea, galaktorhea, infertility (ejaculate
failure)
◼ Pregnancy → trimester III : jaundice infant, EP in the baby

Neuroleptics Malignant Syndrome

In patients who sensitive to EP effect of antipsychotics
Muscle rigidity, impaired of sweating, hyperpyrexia, autonomic
instability
ANTI DEPRESSANT
PATHOPHYSIOLOGY OF DEPRESSION

◼ Monoamine Hypothesis
Monoamine: Serotonin, Norepinephrine, Dopamine
Deficiency in the amount or function of cortical & limbic amines may lead to
depression.
Abnormal functioning gene on serotonin transporter gene may cause the
person to develop depression.
◼ Neuroendocrine Hypothesis
Elevated cortisol level, hypothyroidism, estrogen deficiency.
◼ Neurotrophic Hypothesis
Changes in brain-derived neurothropic factors (BDNF) which has critical role
on regulation of neural plasticity, resilience and neurogenesis.
MONOAMINE
HYPOTHESIS
◼ MAO = Monoamine
oxidase
◼ SERT = Serotonin
transporter
◼ NET = Norepinephrine
transporter

◼ Neurotransmitters pass
along signal
◼ Smaller amount of
neurotransmitters causes
depression
MONOAMINE OXIDASE (MAO) AND DEPRESSION
◼ MAO catalyze deamination of intracellular monoamines
◼ MAO-A oxidizes epinephrine, norepinephrine, serotonin
◼ MAO-B oxidizes phenylethylamine
◼ Both oxidize dopamine nonpreferentially
◼ MAO transporters reuptake extracellular monoamine
TYPES OF ANTIDEPRESSANT

Selective Serotonin-Norepi
Tricyclic
Serotonin nephrine
Antidepressants
Reuptake Reuptake
(TCAs)
Inhibitors (SSRIs) Inhibitors (SNRIs)

Monoamine
Atypical
Oxidase Inhibitors
Antidepressants
(MAOIs)
 TREATMENT FOR DEPRESSION

◼ Psychotherapy
◼ Electroconvulsive therapy
◼ Medication
◼ SSRIs
◼ MAOIs
◼ TCAs
◼ SNRIs
◼ NDRIs
◼ TeCAs
 SELECTIVE SEROTONIN REUPTAKE INHIBITORS

◼ Most commonly prescribed class Serotonin

◼ Current drugs
◼ Mechanism of action
◼ Side effects
 SSRIs ON THE MARKET
◼ Citalopram: Major depression
◼ Dapoxetine: Premature Ejaculation
◼ Escitalopram: Major depression and various other anxiety
disorders Fluoxetine 1:1
◼ Fluxoetine: Major depression, OCD, bulimia, etc
◼ Fluvoxamine: OCD
◼ Paroxetine: Major depression or anxiety
◼ Sertraline: Major depression or anxiety
◼ Zimelidine had neurological problems like Guillan Barre
◼ Indalpine had problems with fetal low WBC

Sertraline
SSRIs MECHANISM OF ACTION

◼ Inhibit Serotonin reuptake

◼ Ser-438 residue in the human serotonin transporter
(hSERT) appears to be a determining factor in SSRI potency
◼ Antidepressants interact directly with hSERT
SSRIs SIDE EFFECTS
• Anhedonia
• Apathy
• Nausea/vomiting
• Drowsiness or somnolence
• Headache
• Bruxism (involuntarily grinding of the teeth)
• Extremely vivid and strange dreams
• Dizziness
• Fatigue
• Changes in sexual behavior
• Suicidal thoughts
 SSRIs SIDE EFFECTS

◼ Many disappear within 4 weeks (adaption phase)

◼ Side effects more manageable compared to MAOIs
and TCAs
◼ Sexual side effects are common
◼ SSRI cessation syndrome
◼ Brain zaps
◼ Sexual dysfunction
 SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIs)

◼ Slightly greater efficacy than SSRIs

◼ Slightly fewer adverse effects than SSRIs
◼ Current drugs
◼ Venlafaxine
◼ Desvenlafaxine
◼ Duloxetine
◼ Levomilnacipran Venlafaxine 1:1
Duloxetine
◼ Mechanism of Action
◼ Very similar to SSRIs
◼ Works on both neurotransmitters
SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIs)

◼ In addition to their use in major depression, SNRIs have

application in the treatment of pain disorders, incl.
neuropathies and fibromyalgia
◼ SNRIs have effect on noradrenergic activity → increase
blood pressure and heart rate
◼ Side effects
◼ Similar to SSRIs
◼ Suicide
TRICYCLIC ANTIDEPRESSANTS (TCAs)
◼ Imipramine; used for major depression
◼ Desipramine; active metabolite of imipramine, used
for neuropathic pain
◼ Clomipramine
◼ Trimipramine; depression, insomnia, and pain
Imipramine
◼ Amitriptyline; most widely used, most effective
◼ Nortriptyline
◼ Protriptyline; depression UNIQUE BECAUSE IT IS
ENERGIZING rather than sedating
◼ Doxepin; used for depression and insomnia
 TCAs MECHANISM OF ACTION
◼ TCAs blocks serotonin,
norepinephrine, and dopamine
transporters, slowing reuptake
◼ TCAs also allow for the
downregulation of post-synaptic
receptors, such as: alpha
receptors, histamine receptors,
muscarinic receptors
◼ All TCAs and SSRIs contain an
essential amino group that
appears to interact with Asp-98
in hSERT
TCAs – Non-antidepressant usage

◼ Amitriptyline & Nortriptyline : migraine prevention,

neuropathic pain
◼ Doxepine : insomnia
 TCAs SIDE EFFECTS

◼ Muscarinic M1 receptor antagonism - anticholinergic effects

including dry mouth, blurred vision, constipation, urinary
retention and impotence
◼ Histamine H1 receptor antagonism - sedation and weight
gain
◼ Adrenergic α receptor antagonism - postural hypotension
◼ Direct membrane effects - reduced seizure threshold,
arrhythmia
◼ Serotonin 5-HT2 receptor antagonism - weight gain (and
reduced anxiety)
 TCAs SIDE EFFECTS
◼ Nonselectivity results in greater side
effects
◼ TCAs can also lead to cardiotoxicity
◼ Increased lactate dehydrogenase
(LDH) leakage
◼ Slow cardiac conduction
◼ High potency can lead to mania
◼ Contraindicated with persons
with bipolar disorder or manic
depression
 MONOAMINE OXIDASE INHIBITORS (MAOIs)

◼ MAO is a mitochondrial enzyme that degrades

monoamines, such as serotonin & norepinephrine
◼ MAO’s type: MAO-A and MAO-B → different site of
distribution
◼ MAOI inhibits the activity of MAO enzymes, preventing
breakdown of monoamines neurotransmitters, increasing
their availability.
 MONOAMINE OXIDASE INHIBITORS (MAOIs)

◼ MAO Inhibitors (nonselective)

◼ Phenelzine
◼ Tranylcypromine
◼ Isocarboxazid

◼ MAO-B Inhibitors (selective for MAO-B)

◼ Selegiline → also reducing the symptom of Parkinson disease
MONOAMINE OXIDASE INHIBITORS (MAOIs)
◼ Effective treatment, BUT they show high incidence of drugs
interaction, and also drug-food interactions → second or third line
◼ MAO enzymes are present in the gut, breaking down the monoamines
ingested in foods.
◼ The inhibited MAO enzymes can’t metabolize tyramine that is
contained in aged or fermented foods → build up tyramine →
synaptic nerve terminal, act as cathecolamine-releasing agent.
◼ The release of cathecolamine → hypertensive crisis → stroke.
◼ Patients under MAOI therapy must avoid tyramine-rich foods
◼ MAOIs interact with certain drugs
◼ Serotonin syndrome (muscle rigidity, fever, seizures)
◼ Pain medications and SSRIs must be avoided
• Drowsiness/Fatigue
• Constipation
MAOIs
• Nausea SIDE EFFECTS
• Diarrhea
• Dizziness
• Low blood pressure
• Lightheadedness,
• Decreased urine output
• Decreased sexual function
• Sleep disturbances
• Muscle twitching
• Weight gain
• Blurred vision
• Headache
• Increased appetite
ATYPICAL ANTIDEPRESSANTS

◼ Bupropion → weak NE and dopamine reuptake inhibitor, also used in

nicotine craving & withdrawal symptoms
◼ Mirtazapine → alpha-2 presynaptic receptor antagonist, increasing
noradrenergic and serotonergic neurotransmitter, antihistamine
activity → sedative
◼ Trazodone
◼ Nefazodone
→ inhibit reuptake of serotonin, and block post synaptic serotonin
receptors 2A, antagonize H1 and adrenergic alpha 1 receptor → sedative
ATYPICAL ANTIDEPRESSANTS

◼ Vilazodone
→ Serotonin partial agonist reuptake inhibitor (partially stimulate
serotonin receptor and inhibit its reuptake)
◼ Vortioxetine
→ Inhibits serotonin reuptake as well as activate and block different
subtypes of serotonin receptors involved in mood regulation
LITHIUM – Mood stabilizer

Farmakokinetik :
- diabsorbsi cepat dan lengkap
- didistribusi di seluruh cairan tubuh
- diekskresi di ginjal melalui urine
- t 1/2 : 20 jam

Mekanisme Kerja :
- belum diketahui dengan baik
- diduga : menghambat recycling membrane phospoinositides neuron
- terutama Inositol Triphospate (IP3) dan Diacylglycerol (DAG) : berperan
sebagai second - messenger α-receptor maupun M receptor →
neuroplasticity, mood stabilizing
Penggunaan Klinik

- Bipolar affective disorder (manics-depressive disease)

- Pada initial treatment → kombinasi dengan antipsychotik
- Pada kasus respon yang inadequate terhadap lithium → Carbamazepin ;
Clonazepam.

Toksisitas :
Narrow therapeutic index
- Tremor, sedasi, ataxia, aphasia
- Thyroid enlargement
- Reversible nephrogenic Diabetes Incipidus
- Edema
- Leukositosis → selalu terjadi
- Pregnancy → congenital cardiac anomaly
THANK YOU