Psychopharmacology in
Psychiatry
Santun Bhekti Rahimah., dr., M.Kes
Definition
Drugs that
affect to behaviour.
Large scope from antidepresant alcohol
Drugs acting in the central nervous system
(CNS)
Mechanism not always been clearly
understood
it is a primary goal of neuropharmacologists
to identify the transmitters in CNS pathways
Basis for several major developments in
studies of the CNS
First, it is clear that nearly all drugs with
CNS effects act on specific receptors
modulate synaptic transmission
Second, drugs are among the most
important tools for studying all aspects of
CNS physiology,
agonists that mimic natural transmitters (and in many cases are
more selective than the endogenous substances)
antagonists are extremely useful in such studies.
Clasification
Antidepressants I
Mood stabilizers
Antipsychotics
Anxiolytic
Hypnotic - sedative
General Pharmacology strategies
Indication: Establish a diagnosis and identify
the target symptoms.
Choice of agent and dosage: Select an agent
with an acceptable side effect profile and
use the lowest effective dose.
Remember the delayed response for many
psych meds and drug-drug interactions.
Cont
Establish informed consent: The patient should
understand the benefits and risks of the
medication.
Management: Adjust dosage for optimum
benefit, safety and compliance.
Implement a monitoring program: Track and
document compliance, side effects, target
symptom response, blood levels and blood tests
as appropriate.
Basic Mechanism
Exicitatory and inhibitory post
synaps
Site of action
Neurotransmitter Pharmacology
in the Central Nervous System.
Cont
Antidepressants
Antidepressant Classifications
Tricyclics (TCAs)
Heterocyclic antidepresant
Monoamine Oxidase Inhibitors (MAOIs)
Selective Serotonin Reuptake Inhibitors
(SSRIs)
Antidepressants
Indications: Unipolar and bipolar
depression, organic mood disorders,
schizoaffective disorder, anxiety disorders
including OCD, panic, social phobia,
PTSD, premenstrual dysphoric disorder
and impulsivity associated with personality
disorders.
General guidelines for
antidepressant use
Antidepressant efficacy is similar so selection is
based on past history of a response, side effect
profile and coexisting medical conditions.
There is a delay typically of 3-6 weeks after a
therapeutic dose is achieved before symptoms
improve.
If no improvement is seen after a trial of
adequate length (at least 2 months) and
adequate dose, either switch to another
antidepressant or augment with another agent.
TCAs
Very effective but potentially
unacceptable side effect
profile i.e. antihistaminic,
anticholinergic,
antiadrenergic
Lethal in overdose (even a
one week supply can be
lethal!)
Can cause QT lengthening
even at a therapeutic serum
level
TCas
First generation: imipramine, amitriptyline,
doxepin, clomipramine
Have active metabolites including
desipramine and nortriptyline
Second generation: Amoxapine ,
maprotiline, trazodone and bupropion
Third generation: mirtazapine,
nefazodone. venlafaxine
First TCAs
Have tertiary amine side chains
Side chains are prone to cross react with other
types of receptors which leads to more side
effects including antihistaminic (sedation and
weight gain), anticholinergic (dry mouth, dry
eyes, constipation, memory deficits and
potentially delirium), antiadrenergic (orthostatic
hypotension, sedation, sexual dysfunction)
Act predominantly on serotonin receptors
Secondary TCAs/ Heterocyclics
Are often metabolites of tertiary amines
Primarily block norepinephrine
Side effects are the same as tertiary TCAs
but generally are less severe
Examples: Desipramine, notrtriptyline
PK similar wirh first gen., only nefazodone
and trazodone T1/2 short
TCas
Well absorbed orally
first pass
metabolism
High volume distribution
Hepatic metabolism
T1/2 8 36 h, once daily doses
Monoamine Oxidase Inhibitors
(MAOIs)
Bind irreversibly to monoamine oxidase thereby
preventing inactivation of biogenic amines such
as norepinephrine, dopamine and serotonin
leading to increased synaptic levels.
Are very effective for depression
Side effects include orthostatic hypotension,
weight gain, dry mouth, sedation, sexual
dysfunction and sleep disturbance
Hypertensive crisis can develop when MAOIs
are taken with tyramine-rich foods or
sympathomimetics.
MAOI Drugs
Phenelzine
isocarboxacid
Tranylcypromine
Structure related
amphetamine
MAOIs
Inhibitots of hepatic drug metabolizing enzyme
Drugs interaction
Trannytcypromine is the fastest one shorter
duratio
SSRIs
Selective Serotonin Reuptake
Inhibitors (SSRIs)
Block the presynaptic serotonin reuptake
Treat both anxiety and depressive sx
Most common side effects include GI upset,
sexual dysfunction (30%+!), anxiety,
restlessness, nervousness, insomnia, fatigue or
sedation, dizziness
Very little risk of cardiotoxicity in overdose
SSRI
Fluxetin (first SSRI)
Paroxetin
Xentraline
Escitalopram
citalopram
Fluoxetine
the SSRIs have not been shown to be more effective ,
they lack many of the toxicities of the tricyclic and
heterocyclic antidepressants.
Thus, patient acceptance has been high despite adverse
effects such as nausea, decreased libido, and even
decreased sexual function.
A dangerous pharmacodynamic interaction :may occur
when fluoxetine or one of the n
a serotonin syndrome. This sometimes fatal syndrome
includes hyperthermia, muscle rigidity, myoclonus,
and rapid changes in mental status and vital signs.
Mood Stabilizers
Bipolar Drugs/ Mood Stabilize
Classic
Lithium
Newer
Carbamazepin
Clonazepam
Olanzapine
Valproic acid
Mood stabilizers
Indications: Bipolar,
schizoaffective,
impulse control and intermittent explosive
disorders.
Classes: Lithium, anticonvulsants,
antipsychotics
Which you select depends on what you
are treating and again the side effect
profile.
Lithium
Mechanism
Not well defined.
Inhibitit inositol monophosphatase IP3
and DAG
Lithium
Only medication to reduce suicide rate.
Rate of completed suicide in BAD ~15%
Effective in long-term prophylaxis of both mania
and depressive episodes in 70+% of BAD I pts
Factors predicting positive response to lithium
Prior long-term response or family member with good
response
Classic pure mania
Mania is followed by depression
Lithium side effects
Most common are GI distress including reduced
appetite, nausea/vomiting, diarrhea
Thyroid abnormalities
Nonsignificant leukocytosis
Polyuria/polydypsia secondary to ADH
antagonism. In a small number of patients can
cause interstitial renal fibrosis.
Hair loss, acne
Reduces seizure threshold, cognitive slowing,
intention tremor
Lithium toxicity
Mild- levels 1.5-2.0 see vomiting, diarrhea,
ataxia, dizziness, slurred speech,
nystagmus.
Moderate-2.0-2.5 nausea, vomiting,
anorexia, blurred vision, clonic limb
movements, convulsions, delirium,
syncope
Severe- >2.5 generalized convulsions,
oliguria and renal failure
Antipsychotics as mood
stabilizers
FDA approved indications in Bipolar disorder
Generic name
Trade name
Manic
Mixed
Maintenance
Aripiprazole
Abilify
Ziprasidone
Geodon
X*
Risperdone
Risperdal
Asenapine
Saphris
Quetiapine
Seroquel
X*
Quetiapine XR
Seroquel XR
X*
Chlorpromazine
Thorazine
Olanzapine
Zyprexa
Olanzapine
fluoxetine comb
Symbyax
Depressed
*denotes FDA approval for adjunct therapy not
mono-therapy
Antipsychotics
Indications for use: schizophrenia,
schizoaffective disorder, bipolar disorderfor mood stabilization and/or when
psychotic features are present, delirium,
psychotic depression, dementia,
trichotillomania, augmenting agent in
treatment resistant anxiety disorders.
Key pathways affected by
dopamine in the Brain
MESOCORTICAL- projects from the
ventral tegmentum (brain stem) to the
cerebral cortex. This pathway is felt to
be where the negative symptoms and
cognitive disorders (lack of executive
function) arise. Problem here for a
psychotic patient, is too little dopamine.
MESOLIMBIC-projects from the
dopaminergic cell bodies in the ventral
tegmentum to the limbic system. This
pathway is where the positive symptoms
come from (hallucinations, delusions,
and thought disorders). Problem here in
a psychotic patient is there is too much
dopamine.
NIGROSTRIATAL- projects from the
dopaminergic cell bodies in the
substantia nigra to the basal ganglia.
This pathway is involved in movement
regulation. Remember that dopamine
suppresses acetylcholine activity.
Dopamine hypoactivity can cause
Parkinsonian movements i.e. rigidity,
bradykinesia, tremors), akathisia and
dystonia.
TUBEROINFUNDIBULAR-projects from
the hypothalamus to the anterior
pituitary. Remember that dopamine
release inhibits/regulates prolactin
release. Blocking dopamine in this
pathway will predispose your patient to
hyperprolactinemia
(gynecomastia/galactorrhea/decreased
libido/menstrual dysfunction).
Antipsychotics
Classic drugs (D2)
Chlorpomazine
Fluphenqazine
Haloperidol
Thioridazone
Trifluoperazine
Newer agents (5HT2)
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Class. By chemical structure
Phenothiazines: chlorpomazine,
thioridazone, fluphenazone
Thioxanthenes: Thiothiene
Butyrophenones: haloperidol
Heterocyclics: newer agents
Antipsychotics: Typicals
Are D2 dopamine receptor antagonists
High potency typical antipsychotics bind to
the D2 receptor with high affinity. As a
result they have higher risk of
extrapyramidal side effects. Examples
include Fluphenazine, Haloperidol,
Pimozide.
Low potency typical antipsychotics have
less affinity for the D2 receptors but tend
to interact with nondopaminergic receptors
resulting in more cardiotoxic and
anticholinergic adverse effects including
sedation, hypotension. Examples include
chlorpromazine and Thioridazine.
Antipsychotics: Atypicals
The Atypical Antipsychotics -
atypical
agents are serotonin-dopamine 2
antagonists (SDAs)
They are considered atypical in the way
they affect dopamine and serotonin
neurotransmission in the four key
dopamine pathways in the brain.
Risperidone
Available in regular tabs, IM depot forms and
rapidly dissolving tablet
Functions more like a typical antipsychotic at
doses greater than 6mg
Increased extrapyramidal side effects (dose
dependent)
Most likely atypical to induce hyperprolactinemia
Weight gain and sedation (dosage dependent)
Clozapine
Available in 1 form- a regular tablet
Is reserved for treatment resistant patients because of side
effect profile but this stuff works!
Associated with agranulocytosis (0.5-2%) and therefore
requires weekly blood draws x 6 months, then Q- 2weeks
x 6 months)
Increased risk of seizures (especially if lithium is also on
board)
Associated with the most sedation, weight gain and
transaminitis
Increased risk of hypertriglyceridemia,
hypercholesterolemia, hyperglycemia, including nonketotic
hyperosmolar coma and death with and/or without weight
gain
Haloperidone
Comes in regular tabs
Needs BID dosing
Titrate over 4 days to 12mg/day in order to minimize
risk of orthostatic hypotension
Low EPS, akathisia, wt gain and metabolic disturbances
Inhibitors of 3A4 (ketoconazole) or 2D6 (fluoxetine,
paroxetine)-Can increase blood levels two-fold!
QT Prolongation- mean increase of 19msec at 12mg BID
Not recommended for patients with hepatic impairment
Citrome L, Postgraduate Medicine
2011
Antipsychotic adverse effects
Tardive Dyskinesia (TD)-involuntary muscle movements
that may not resolve with drug discontinuation- risk
approx. 5% per year
Neuroleptic Malignant Syndrome (NMS): Characterized
by severe muscle rigidity, fever, altered mental status,
autonomic instability, elevated WBC, CPK and lfts.
Potentially fatal.
Extrapyramidal side effects (EPS): Acute dystonia,
Parkinson syndrome, Akathisia
Autonomics effect: atropin like effect
Endocrin effect
Anxiolytics
Used to treat many diagnoses including
panic disorder, generalized Anxiety
disorder, substance-related disorders and
their withdrawal, insomnias and
parasomnias. In anxiety disorders often
use anxiolytics in combination with SSRIS
or SNRIs for treatment.
Introduction
Anxiety is a state characterized by psychological
symptoms, often accompanied by physical symptoms of
autonomic arousal (palpitations, light headedness,
perspirations, butterflies, restlessness)
Benzodiazepines and/or selective serotonin reuptake
inhibitor (SSRI) antidepressant used for generalized anxiety
disorders (GAD) and panic disorders
Trycyclic antidepressant (TCAs) & Monoamine Oxidase
(MAO) Inhibitors for long term management of anxiety
Introduction (contd)
SSRI have receive FDA approval for the
treatment of GAD, panic disorders, Obsessive
Compulsive Disorders (OCD), Post traumatic
stress disorders (PTSD) & Social phobia
SSRI most be used start low, go slow
For acute relief of anxiety or panic attacks,
benzodiazepines are useful
Introduction (contd)
All Benzodiazepines currently available & are
qualitatively similar in terms of their efficacy & safety
profiles
Clonazepam & Alprazolam are most commonly to treat
anxiety disorders
The benefit of Buspirone (for GAD) are virtual absence
of dependence & abuse liability
Buspirone indicated for patients with a history of alcohol
abuse
Benzodiazepines
Prototypic agent Diazepam (D)
Other agents :
Clonazepam (C)
Alprazolam (A)
Lorazepam (L)
MOA:
Bind to components of GABA A Receptors facilitate
inhibitory actions of GABA in CNS
Indications:
Anxiety disorders (especially A & C for panic & phobic disorders)
Sedation, seizures, muscle relaxants (D)
Management of alcohol withdrawal
Benzodiazepines (contd)
Pharmacokinetics:
-
Potency C > A > L > D
T L=A< C < D
Hepatic metabolism
ADRS:
-
Cognitive impairments
Sedation, amnesia
Diminished motor skill
Warnings/Precautions:
- Additive sedative effects with other CNS depressant
(ethanol)
- Tolerance & Dependence (prolonged use)
SSRI
Prototypic agent : Fluoxetine (F)
Other agents :
Paroxetine (P)
Sertraline (S)
Citalopram (C)
MOA: Inhibit reuptake of Serotonin
Indications:
Depression
Anxiety disorders (OCD, pannic attacks, social phobias, etc)
Pharmacokinetics:
per oral only
hepatic metabolism
SSRI (contd)
ADRS:
-
Sedations or insomnia
Headache, nausea, appetite & weight changes
Sexual dysfunctions
Warning/Precautions:
-
Serotonin syndrome may occur with other
serotoninergic drugs (i.e. MAO inhibitors)
SSRI inhibit Cy-P450 liver enzymes
Buspirone
MOA:
Partial agonist AT 5 HT1A brain receptors
Anxyolitic action unknown
Indications:
Generalized anxiety disorders (GAD)
Pharmacokinetics:
Per oral only
Hepatic metabolism
ADRS:
Diziness
Headache
Nausea
Sedative- hypnotics
Bbenzodiazepins:
Short action, intermediate, long
Barbiturats:
Ultra short, short, long
Miscelaneous agent: buspirones, choral
hydrate, eszopiclone, ramelteon, zaleplon,
zolpidem
Benzodiazapines
Used to treat insomnia, parasomnias and
anxiety disorders.
Often useepressant withdrawal protocols
Side effects/cons
Somnolence
Cognitive deficits
Amnesia
Disinhibition
Tolerance
Dependence
Drug
Alprazolam
(Xanax)
Dose
Equiva
lency
(mg)
0.5
Peak Blood
Level
(hours)
Elimination
HalfLife1
(hours)
1-2
12-15
Rapid oral absorption
2-4
15-40
Active metabolites;
erratic
bioavailability
from IM
injection
1-4
18-50
Can have layering
effect
1-2
20-80
Active metabolites;
erratic
bioavailability
from IM
injection
1-2
40-100
Active metabolites
with long halflives
1-6
10-20
No active metabolites
2-4
10-20
No active metabolites
2-3
10-40
Slow oral absorption
2-3
Rapid onset; short
duration of action
10.0
Chlordiaze
poxide
(Librium)
Clonazepam
(Klonopin)
0.25
5.0
Diazepam
(Valium)
Flurazepam
(Dalmane)
30.0
Lorazepam
(Ativan)
1.0
Oxazepam
(Serax)
15.0
Temazepam
(Restoril)
30.0
Triazolam
(Halcion)
0.25
1
Comments
AGENTS USED FOR
SLEEP DISORDERS
(SEDATIVE-HYPTONIC)
Hypnotic -sedative
Sedative agent
GRADED DOSE DEPENDENT
INTRODUCTION
Insomnia is a common & non specific
disorder at 40-50% peoples
Causes of insomnia are medical illness,
alcohol/drugs, periodic limb movement
disorders, sleep apnea, psychiatric illness
Without an obvious underlying cause, it is
known as primary or psycho-physiological
Hypnotic are drug used to treat psycho-
physiological (primary) insomnia
Sedatif Hipnotic agent
Benzodiazepin
Barbiturat
Glutethimide (a piperidinedione) and
meprobamate (a carbamate)
Etanol
chloral hydrate
Trichloroethanol
paraldehyde
BARBITURATES:
- Currently not recommended, due to abuse potential & lethal
potential
- Pentobarbital, Secobarbital, Amobarbital
NON-BARBITURATES:
- Similar mechanism with barbiturates
- Chloralhydrate is still commonly used to day, due to its
efficacy as a shortterm sedative hypnotic & low cost
BENZODIAZEPINES:
- Widely used as sedative hypnotics
- Quick onset: Triazolam, Flurazepam, Quazepam
- Longer acting: Temazepam, Flurazepam
NEWLY AGENTS:
- Zaleplon (Pyrazolopyridine), Zolpidem (Imidaropyridine)
BENZODIAZEPIN
Most widely uses for hipnotic sedatif
Mechanism of action
No single mechanism
has been idendified.
Facilitate neuronal membrane inhibition by
actions at specific receptors
Facilitating and prolonging the inhibitory
effefs of GABA and gycine
Brief Pharmacology of Newer Agents
ZOLPIDEM:
-
Drugs Of Choice for insomnia
Act on benzodiazepine-Omega-1-receptor,
selectively (sedation)
Rapid onset & short duration of action
Less potential for abuse, fatal overdose,
withdrawal reactions
ZALEPLON:
- Short acting, faster onset than zolpidem
DRUG
ADVANTAGES
DISADVANTAGES
Chlorpromazine
inexpensive
ADR >> (esp. autonomic)
Thioridazine
Extrapyr. Synd. <<
Cardiotoxic
Thiothixene
Decreased tardive
dyskinesia
Haloperidol
Potent; p.e (+)
Extrapyr. Synd severe
Clozapine
May benefit: resistant
patient
Extrapyr. Synd. <<
Agranulocytosis
Risperidone
Broad efficacy
Extrapyr. Synd. << (low
dose)
Higher dose: extrapyr.
dysfunc. & hypotension
Olanzapine
Quentiapine
Neg. & pos. symptoms
Extrapyr. Synd. <<
Weight gain (less for
quentiapine)
Quentiapine: short T
Efficacy as antipsychotic are similar; SE differ
significantly
