DRUGS USED IN PSYCHIATRIC

DISORDERS
dr. IGA Artini, M.Sc
Department of Pharmacology
Faculty of Medicine
Udayana University
Able to describe the pharmacokinetic and
pharmacodynamic of sedative-hypnotic drugs
Learning outcomes
Able to describe the pharmacokinetic and
pharmacodynamic of antipsychotic drugs
Able to describe the pharmacokinetic and
pharmacodynamic of drugs used in mood disorders
1. SEDATIVE-HYPNOTIC AND
ANXYOLITIC DRUGS
2. ANTIPSYCHOTIC DRUGS
3. DRUGS USED IN MOOD DISORDERS
(ANTIDEPRESSANT DRUGS AND
LITHIUM)
DRUGS USED IN PSYCHIATRIC
DISORDERS
Types of ion channels and neurotransmitter receptors in the CNS
GPCR which interact directly with ion channel

(1) Action potential in presynaptic
(2) synthesis of transmitter;
(3) storage;
(4) metabolism;
(5) release;
(6) reuptake;
(7) degradation;
(8) receptor for the transmitter;
(9) receptor-induced
increase or decrease in ionic
conductance.
Site of action for drugs act on neurotransmitter
SEDATIVE-HYPNOTIC AND
ANXYOLITIC DRUGS

Diazepam, chlordiazepoxide, clorazepate, oxazepam,
lorazepam, prazepam, temazepam, flurazepam,
alprazolam, triazolam, estazolam
Benzodiazepines
Phenobarbital, thiopental, pentobarbital, secobarbital
Barbiturates
Buspirone, chloral hydrate, zaleplon, zolpidem
Miscellaneous agents
Class of sedative-hypnotic drugs
Triazolam : fast absorption ( diazepam, chlorazepate)
Diazepam, triazolam rapid onset (chlordiazepoxide, lorazepam)
Form active metabolite long T1/2, cumulative effect
Estazolam, oxazepam, lorazepam directly converted to inactive
metabolite
Pharmacokinetic of benzodiazepines and barbiturates
- Chlordiazepoxide : 24 hrs
- Diazepam : 72 hrs
- Flurazepam : 75 hrs
- Lorazepam : 12 hrs
- Nitrazepam : 24 hrs
- Oxazepam : 12 hrs

Barbiturates : well absorbed
Thiopental : very rapid onset
Slow metabolized but inactive
metabolite T1/2 long
Enzyme inducer (>< BDZ)

Biotransformation of benzodiazepines
Boldface, drugs available for clinical use; *, active metabolite
GABAA receptor-
chloride ion channel
macromolecular
complex
Antagonized by flumazenil
Binding of BDZ into BDZ
binding site (between alpha 1
and gamma 2) facilitates the
inhibitory actions of GABA
increase the frequency of
GABA-mediated chloride ion
channel opening.
5/27/2014 Ngatidjan, ANTIPSIKOTICS
r-GABA
r-BDZ
BDZ not substitute GABA, only facilitate GABA activity but not directly interact.
BDZ binding to r-BDZ increase probability of chloride channel opening
Increase frequency of channel opening hyperpolarization reducce
nerve cell activity
Barbiturates Mechanism of Action
Bind to GABAA receptor (different sites from BDZ)
Not antagonized by flumazenil
Increase the duration of GABA-mediated chloride
ion channel opening
Facilitate the inhibitory effect of GABA
Also depress glutamic acid action
Pharmacodynamic of sedative-hypnotic drugs
Sedation (relief of anxiety)
Hypnosis (promote sleep onset and increase
the duration of the sleep state)
Anesthesia (loss of consciousness, amnesia
and suppression of reflexes)
Anticonvulsant
Muscle relaxation
Medullary depression (respiratory arrest,
hypotension, cardiovascular collapse, death)
NREM phase 1, 2, 3 and 4 intercepted by REM 90'
* sleeping onset
* phase 2 NREM
* phase 3 and 4 NREM
* REM
NREM : 70 - 75%
- phase 1 : begin to sleep
- phase 2 : superficial sleeping
- phase 3 : more deep sleeping
- phase 4 : deep sleeping
REM : 25 - 30%
For drug A, an increase in dose above that needed for hypnosis may lead to a state
of general anesthesia. At still higher doses, sedative-hypnotics may depress
respiratory and vasomotor centers in the medulla, leading to coma and death.
Drug B, has greater safety margin (safer for clinical use)
A : Older sedative
hypnotics including
barbiturates and
alcohols
B : Newer sedative
hypnotics including
benzodiazepines
CNS effect depend on dose
Adverse effect of sedative-hypnotic drugs
Psychomotor dysfunction (cognitive impairment, decreased
psychomotor skill, daytime sedation, amnesia), rebound
insomnia, dependence, tolerance, CNS depression, allergy,
abuse, CV and respiratory depression (if OD)
Additive CNS depression (severe respiratory and
cardiovascular depression) alcohol, antihistamine,
antipsychotic, opioid, TCA, anticonvulsant
Barbiturates induce formation of liver microsomal enzymes
Barbiturates contraindicated in porrphyria disease
Other sedative-hypnotic drugs
Buspirone not interact directly to GABA system, partial
agonist for 5HT1A receptor, slow onset
Zolpidem : bind BZ1 receptor selectively; antagonized
by flumazenil; minimal tolerance and dependence;
minimal psychomotor depression and amnesia; rapid
onset; short duration
ANTIPSYCHOTIC DRUGS
Anti
psychotics
Older
(classic)
drugs
Pheno
thiazines
Chlorpromazi
ne, Thio
ridazine,
Fluphenazine
Thio
xanthenes
Thiothixene
Butyro
phenones
Haloperidol
Newer
drugs
(atypical)
Clozapine,
Loxapine
Olanzapine,
Risperidone,
Quetiapine,Zipra
sidone,
Aripiprazole
Pharmacokinetic : Long half life, highly lipid soluble, bind
protein, long duration
Site of action of neuroleptics
Older drugs have high affinity for D2 receptor in brain
Most of newer drugs not a potent antagonist of D2 receptor
Mesocortical mesolimbic
(behavior) antipsychotic
effect
Nigrostriatal (coordinating
voluntary movement)
Tuberoinfundibular (inhibit
prolactin secretion)
Medullary periventricular
(eating behavior)
Incertohypotalamic
(copullatory behavior in
rats)
Butyrophenones
Phenothiazines
Atypical neuroleptics
(Clozapine, Olanzapine, Risperidone)
Pharmacodynamics : Autonomic effect, performance disorders, psychomotor
disorder, sedation, endocrine effect, neurologic effect, cardiovascular effect
Clinical uses : Treatment of schizophrenia, schizoaffective, mania, bipolar
disorders, non psychiatric indication (antiemetic)
Receptor affinity profile of neuroleptics
The receptor affinities of each drug are compared in relation to its D2-
receptor affinity, arbitrarily set at (++); antagonistic effects, except for
ziprasidone (5-HT1A agonism)
Common side effects of antipsychotics and the
mechanisms
Toxicity of antipsychotics
Dose dependent EPS include Parkinson-like syndrome with
bradykinesia, rigidity and tremor
Reversed by decrease in dose, muscarinic blocking agent
(trihexyphenydyl)
Reversible neurologic effects
Choreoathetoid movement of muscles of lip and buccal cavity
No effective drug
Tardive dyskinesia
Blockade of peripheral muscarinic receptors and alpha adrenoceptor
Cause atropine-like effects (dry mouth, constipation, urinary retention,
visual problem), postural hypotension
Autonomic effects
Phenothiazine more sedating; fluphenazine, haloperidol least sedating
Sedation
Toxicity of antipsychotics (contd)
Hyperprolactinemia, gynecomastia, amenorrhea-galactorrhea
syndrome, infertility, weight gain, hyperglycemia
Endocrine and metabolic effect
Muscle rigidity, impairment of sweating, hyperpyrexia, autonomic
instability, leucocytosis
May be life threatening
Neuroleptic malignant syndrome
Visual impairment, fatal ventricular arrhythmia (thioridazine),
agranulocytosis (clozapine)
Miscelaneous toxicity
Drug interaction involving antipsychotics
Anticholinergic : additive of atropine-like effects
CNS depressant (alcohol, barbiturates,
benzodiazepines, antihstamines, TCA, opioid) : additive
CNS depression
Alpha adrenoceptor blocker : additive of alpha blocker
effect
ANTIDEPRESSANT DRUGS
Monoamine-deficiency hypothesis of depressive disorders
Anti
depressants
Tricyclic
Antidepressants
Imipramine
Amitriptyline
Heterocyclic
Antidepressants
Bupropion
Amoxapine
Maprotiline
Trazodone
Mirtazapine
Nefazodone
Venlafaxine
Selective
Serotonin
Reuptake
inhibitors
Fluoxetine
Sertraline
Citalopram
Fluvoxamine
Paroxetne
Monoamine
Oxidase
Inhibitors
Phenelzine
Tranylcypromine
Isocarboxazid
Antidepressant Profile
TCA well absorbed, large Vd, T1/2 8-36 h,
structure related to phenothiazine
SSRI require hepatic metabolism, other than
fluoxetine not form long acting metabolite
MAOI structure resemble amphetamine,inhibit both MAO
A and B ireversibly, enzyme inhibitor, prolong duration
Mechanism of action
of antidepressant
TCA and heterocyclics
inhibit reuptake of NE and 5-
HT in brain (inhibit
transporter);
SSRI selectively inhibit
reuptake of 5-HT in brain
(inhibit transporter);
MAOI inhibit metabolism of
amine amine accumulation
Other effects of antidepressant include
amine (NE) uptake blockade in ANS,
sedation, CNS stimulation, muscarinic
receptor blockade, cardiovascular
effects, seizure
Targets of Antidepressant Action on Noradrenergic
and Serotonergic Neurons
Clinical Uses
Major depressive disorders
SSRI is preferred (more tolerable SE and safety,
even though not more effective)
TCA for psychomotor retardation, sleep disturbances,
poor appetite, weight loss
Bipolar disorders, acute panic attacks, phobic disorders,
ADHD, enuresis
SSRI cause lose weight, for OCD, generalized anxiety
disorders, panic attacks, social phobia, bulimia
MAOI anxiety, phobia

Common side effect of antidepressant
Anticholinergic manifest as atropine-like effects (dry mouth, blurred
vision, urinary retenton, reduce sweating, constipation)
Orthostatic hypotension due to alpha adrenoceptor blockade
Overdosage of TCA lethal, 3Cs (coma, convulsion,
cardiotoxicity), respiratory depression, circulatory collapse,
hyperpyrexia, severe arrhythmia
Overdosage of Heterocyclics seizure and cardiotoxicity
Amoxapine dopamine receptor blocker akathisia, parkinsonism,
amenorrhea-galactorrhea syndrome
Overdosage of SSRI seizure
Serotonin syndrome interaction fluoxetine and MAOI, life
threatening, severe muscle rigidity, hyperthermia, myoclonus,
cardiovascular instability, CNS stimulation (seizure)
Overdosage of MAOI hyperthermia, seizure
Drug Interactions involving Antidepressants
Antidepressant Interact with Effect
Fluoxetine
Fluvoxamine

MAOI

Nefazodone
Paroxetine

Sertraline
TCA
Lithium, TCA, warfarin
Alprazolam, theophylline, TCA,
warfarin
Sympathomimetics, tyramine,
SSRI
Alprazolam, triazolam
Procyclidine, theophylline, TCA,
warfarin
TCA, warfarin
CNS Depressant (ethanol,
sedative), clonidine, metyldopa

Increase other drug level
Increase other drug level

Hypertension crisis, serotonin
syndrome
Increase other drug level
Increase other drug level

Increase its effect
Additive CNS depressant,
decrease antihypertensive effect
Serotonin
biosynthesis and
metabolism
Spectrum of Clinical Findings
LITHIUM
LITHIUM PROFILE
Absorbed rapidly, half life 20 h, slow onset,
therapeutic plasma concentration 0.6 1.4 mEq/L
Diuretic may increase lithium blood level
Theophylline increase renal clearance of lithium
Treatment of bipolar disorder
Neurologic effect (tremor, sedation, aphasia,
ataxia), thyroid enlargement, reversible
nephrogenic DI, edema, leukocytosis, congenital
cardiac anomalies
Effect of lithium on the IP3 and DAG second-messenger
PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C;
G, coupling protein; EFFECTS, activation of protein kinase C,
mobilization of intracellular Ca2+, etc
The actions of Li+ on postsynaptic receptor-mediated second-
messenger signaling systems