Antipsychotic

Drugs

Russell Crowe in “A Beautiful Mind”

 Psychotic Disorders
Definition: Psychotic disorders are defined
as mental disorders in which the
personality is severely altered and a
person’s contact with reality is impaired.

Characteristics: delusions, hallucinations, odd

behavior, and incoherent or disorganized
speech

Causes: Traumatic Experience,

Stressful Event, and Drug Use
Major Psychotic Disorders
 Brief Psychotic Disorder
 Delusional Disorder
 Schizoaffective Disorder
 Schizophreniform
 Shared Psychotic Disorder
 Schizophrenia
 x D1 x D2 D3 D4

Frontal x X x x

Caudat/ X x
Putamen

Amigdala x

Accumbens X x x

Pallidus x x x

Hippocamp X

Hipotalamus x

Subst neagra x

Bulb Punte x
 Psychosis:

Schizophrenia – split between thought and emotion.

Diagnostic criteria for Schizophrenia

A. Characteristic symptoms: Two (or more) of the following, each present

for a significant portion of time during a 1-month period (or less if
successfully treated):

(1) delusions

(2) hallucinations

(3) disorganized speech (e.g., frequent derailment or incoherence)

(4) grossly disorganized or catatonic behavior

(5) negative symptoms, i.e., affective flattening, alogia, or avolition

Note: Only one Criterion A symptom is required if delusions are bizarre or

hallucinations consist of a voice keeping up a running commentary on the
person's behavior or thoughts, or two or more voices conversing with
each other.
Criteria for Manic Episode DSM – IV

A. A distinct period of abnormally and persistently elevated,

expansive, or irritable mood, lasting at least 1 week (or any duration if
hospitalization is necessary).
B. During the period of mood disturbance, three (or more) of the
following symptoms have persisted (four if the mood is only irritable) and
have been present to a significant degree:
(1) inflated self-esteem or grandiosity
(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
(3) more talkative than usual or pressure to keep talking
(4) flight of ideas or subjective experience that thoughts are racing
(5) distractibility (i.e., attention too easily drawn to unimportant or
irrelevant external stimuli)
(6) increase in goal-directed activity (either socially, at work or school, or
sexually) or psychomotor agitation
(7) excessive involvement in pleasurable activities that have a high potential
for painful consequences (e.g., engaging in unrestrained buying sprees,
sexual indiscretions, or foolish business investments)
Names - Antipsychotic

Antipsychotic drugs were initially called

neuroleptics because they were found to cause
neurolepsy, which is an extreme slowness or
absence movement

Major tranquilizer – as opposed to minor

tranquilizer (benzodiazepines). Refers to sedating
property, but is not a “stronger” version of minor
tranquilizer. Antipsychotic effect is not achieved
through sedation.
Traditional
Antipsychotics
 Phenothiazines
 chlorpromazine (Chlorpromazine Mixture,
Chlorpromazine Mixture Forte, Largactil)
 fluphenazine (Anatensol, Modecate)
 flupenthixol (Fluanxol)
 pericyazine (Neulactil)
 pimozide (Orap)
 thioridazine (Aldazine)
 trifluoperazine (Stelazine)
 zuclopenthixol (Clopixol)
 Butyrophenones
 droperidol (Droleptan Injection)
 haloperidol (Haldol, Serenace)
Newer Antipsychotics
 Atypical agents
 aripiprazole (Abilify)
 clozapine (CloSyn, Clopine, Clozaril)
 risperidone (Risperdal)
 quetiapine (Seroquel)
 amisulpride (Solian)
 olanzapine (Zyprexa)
 ziprazidone (Zeldoxx)
Typical
antipsychotics were
developed before 1975,
they have Parkinsonian
side effects and are
only effective against
positive symptoms.
Atypical
antipsychotics were
developed after 1990.
They have minimal
parkinsonian effects
and are effective
against both positive
and negative
symptoms.
 Neurophysiology
Dopamine hypothesis: schizophrenia is caused by an
excess of dopamine activity in the brain.

In the 1970s it was noted

that the clinical potency
of a drug was correlated
with its affinity for D2
receptors

Philip Seeman
Dopamine pathways
 Mentation & Mood
 Mesocortical
 Mesolimbic
 Extrapyramidal
Function
 Nigrostriatal
 Prolactin release
 Tuberoinfundibular
 Emesis
 Chemoreceptor trigger
zone
3
3
Dopamine systems in the brain

Mesolimbic DA system from the VTA to the Nucleus

Accumbens and frontal cortex - Reward system and
schizophrenia
Nigrostriatal system from the Substantia Nigra to the
basal ganglia. - extrapyramidal motor system.

Antipsychotic drugs
block DA receptors in
both systems and
therefore Parkinsonian
symptoms are side
effects.
 Dopamine Hypothesis today:

Drugs like amphetamine and cocaine cause psychotic

behavior, but so do other drugs like PCP and LSD suggesting
that serotonin and NMDA receptors for glutamate are involved
as well.
Drugs that block DA receptors block psychotic behavior, but
there is a delay in effectiveness of antipsychotic drugs
suggesting an adaptation in a brain mechanism
 Typical and Atypical Antipsychotics

Typical antipsychotics have a high affinity for D2

receptors.
Atypical antipsychotic drugs have high affinity for D3 and
D4 receptors and low affinity for D2 receptors. D3 receptors
are found in the n. acc. and D4 receptors in the cortex
amygdala and hippocampus. There are few D3 and D4
receptors in the motor system.
Atypicals also have a higher affinity for the 5HT2A receptor
than the D2 receptor while typicals have a lower affinity for
the 5HT2A receptor than the D2 receptor. This has the effect
of counteracting the D2 blockade in the motor system
Mechanism of Action

2
Blockade of serotonin receptors also causes
diminished response of glutamanergic neurons in the
cortex. (oppostie effect of LSD). This may reduce
hallucinations
Atypical antipsychotic drugs are also more effective in
treating the negative symptoms of schizophrenia like
alogia and avoilition.

Other neurotransmitters known to be involved are

acetylcholine, histamine, GABA, and NE. Different
drugs have different profiles if relative activity of
different transmitters.
New Era in Psychiatric Medicine
• Chlorpromazine was the
first anti-psychotic drug developed
• Initially this drug was
administered to patients before
a surgery because it produced
anti- anxiety effects.
• It was then tried on patients
with mental illnesses and it
was discovered that it relieved
psychotic episode symptoms.
Phenothiazines
 Chlorpromazine belongs to this class of
drugs.
 Other examples include:

Perphenazine
Fluphenazine

Trifluoperazine
Mechanism of Action of Phenothiazines

 The drugs found in this class are

antagonists.
 They work by blocking the D2 receptors in
the dopamine pathways of the brain; thus,
decreasing the normal effect of dopamine
release.
 Blocking the D2 receptors in the
mesolimbic pathway results in the
antipsychotic effect.
Side Effects Associated with
Phenothiazines
• Pharmacological  Serious Side Effects
Side Effects • Parkinsonian-like

• Constipation syndrome
• Dystonia
• Retention of urine
• Diskinesia
• Increased heart
• Neuroleptic
rate
Malignant
• Dry mouth
Syndrome (NMS)
• Dilated pupils
Butyrophenones

 Butyrophenones are high-potency antipsychotics

(potency refers not to effectiveness but rather to
the ability to bind to dopamine receptors)
 Haloperidol (Haldol) is the most common of the
butyrophenones:
Other Butyrophenones
 Droperidol

 Benperidol
Mechanism of Action
 All the butyrophenones work in the same
manner as the phenothiazines.

 They block the D2 receptors in the

dopamine pathways, thus, thwarting any
possible over excitation of the dopamine
receptors.
Side Effects of
Butyrophenones
Pharmacological effects include:
 Dry mouth
 Urinary retention
 Dimmed sight

 More Serious Side effects

include:
-Dystonia
-Tardive Dyskinesia
- Akathisia
Comparisons Between
the Two Classes of Drugs
 Phenothiazines  Butyrophenones
 Low potency
 High potency
 Are sedative
 Block D2 receptors  Non-sedative
 metabolism and removal  Block D2
of phenothiazines is
complex and among the receptors
slowest of any group of  Metabolism and
drugs
 cause extra pyramidal
removal is quicker
symptoms  Cause extra
pyramidal
symptoms
Typical Antipsychotics
 Phenothiazines and Butyrophenones are typical antipsychotics
 These drugs are no longer regarded as the best practice for
treating psychotic disorders, even though they are still commonly
utilized in emergency treatments.
 The reason for this is that they are not very selective. They do not
only block the D2 receptors of the mesolimbic pathway but also
block the D2 receptors in the nigrostriatal pathway,
mesocortical zone, and tuberoinfundibular pathway.
 The fact that they are not very selective causes the extra
pyramidal symptoms such as tardive diskinesia
clozapine
Atypical Anti-psychotics
 Were developed in an attempt to minimize the
side effects of typical anti-psychotics
 They have proven to cause fewer extra
pyramidal symptoms (EPS) when compared
to typical anti-psychotics.
 They produce fewer EPS because they are
more selective.
Common Atypical
Antipsychotics
 Clozapine

 Risperidone

 Olanzapine
Other Atypical
Antipsychotics
 Quetiapine:

 Ziprasidone:
 Mode of Action
 Antagonists
 Atypical antipsychotic drugs have a similar
blocking effect on D2 receptors but appear to be
more selective in targeting the intended pathway
to a larger degree than typical antipsychotics.
 They also interact with other neurotransmission
systems, particularly with the serotonergic and
noradrenergic pathways.
Side Effects Associated with
Atypical
Antipsychotics
 Glucose Metabolism Disorders such as hyperglycemia, onset of
diabetes type 2, and worsening of pre-existing diabetes ( This
was particularly seen with patients treated with olanzapine and
clozapine)
 Weight Gain has been seen with patients taking Olanzapine; the
increase of weight gain can result in other heart diseases such as
hypertension and coronary heart disease.
 QTc prolongation which occurs when there is an abnormally long
delay between the electrical excitation and relaxation of the
ventricles of the heart which can cause death
Differences among
Antipsychotic Drugs
 All effective antipsychotic drugs block D2
receptors
 Chlorpromazine and thioridazine
 block α1 adrenoceptors more potently than D2
receptors
 block serotonin 5-HT2 receptors relatively strongly
 affinity for D1 receptors is relatively weak
 Haloperidol
 acts mainly on D2 receptors
 some effect on 5-HT2 and α1 receptors
 negligible effects on D1 receptors
 Pimozide and amisulpride
 act almost exclusively on D2 receptors
Differences among
Antipsychotic Drugs
 Clozapine
 binds more to D4, 5-HT2, α1, and histamine H1
receptors than to either D2 or D1 receptors
 Risperidone
 about equally potent in blocking D2 and 5-HT2
receptors
 Olanzapine
 more potent as an antagonist of 5-HT2 receptors
 lesser potency at D1, D2, and α1 receptors
 Quetiapine
 lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors
Differences among
Antipsychotic Drugs
 Clozapine, olanzapine and quetiapine
 potent inhibitors of H1 histamine receptors
 consistent with their sedative properties
 Aripiprazole
 partial agonist effects at D2 and 5-HT1A
receptors
Differences among
Antipsychotic Drugs
 Chlorpromazine: α1 = 5-HT2 > D2 > D1

 Haloperidol: D2 > D1 = D4 > α1 > 5-HT2

 Clozapine: D4 = α1 > 5-HT2 > D2 = D1

 Metabolic effects
Weight gain over 1 year (kg)
aripiprazole 1
amisulpride 1.5
quetiapine 2–3
risperidone 2–3
olanzapine >6
clozapine >6
Most Common Problems
Associated with
Antipsychotic Treatment
• The slow onset of antipsychotic efficacy
• The development of antipsychotic-induced
side effects
• Patients’ vulnerability to relapse following
antipsychotic drug discontinuation.
 Current and Future Work in
Antipsychotic Treatment
• Synthesis of compounds acting on N-Methyl-D-
Aspartate (NMDA) sub-group of glutamate
receptors, which are believed to be involved in
the pathogenesis of psychotic symptomatology.
• Aripiprazole is a new atypical antipsychotic drug
that shows both partial agonist activity at the D2
and 5HT1A receptors and potent antagonism
activity at the 5HT2A receptors.
• Individualized treatment based on genetic profile
in attempts to eliminate side effects
• Antidepressants
 Definitions
 Affective disorders - mental illnesses
characterized by pathological changes in mood
(not thought – compare with schizophrenia)
1. Unipolar disorders
 Depression – pathologically depressed mood (life time
prevalence up to 17%)
 Mania – excessive elation and accelerated psychomotoric
activity (rare)

2. Bipolar disorder (manic-depressive illness) – „cycling

mood“
 = severe highs (mania, event. hypomania) and lows
(major depressive episodes)
 prevalence 1-5%, life-time illness, stronger genetic
background
 Depression
 common mental disorder that presents with depressed mood,
loss of interest or pleasure, feelings of guilt or low self-worth,
disturbed sleep or appetite, low energy, and poor concentration
(WHO def.)
 Major Depressive Episode Criteria/Core symptoms
 Five (or more) of the following symptoms have been present during
the same 2-week period and represent a change from previous
functioning; at least one of the symptoms is either (1) depressed
mood or (2) loss of interest or pleasure.
 depressed mood most of the day…
 markedly diminished interest or pleasure
 significant weight loss /gain
 insomnia or hypersomnia
 psychomotor agitation or retardation, fatigue or loss of energy
 feelings of worthlessness or excessive or inappropriate guilt
 diminished ability to think or concentrate, or indecisiveness
 recurrent thoughts of death or suicidal ideation without a specific
plan or a suicide attempt (!)
 Neurobiological theory of
depression
 Monoamine (catecholamine) theory (1965) = the underlying
biological or neuroanatomical basis for depression is a deficiency
of central noradrenergic and/or serotonergic transmission
in the CNS
Supported by:
 pharmacological effect of antidepressants (TCA, MAOI)
 In the past, medication of hypertension with reserpine
induced depression
Contradiction:
 several drugs (e.g. cocaine) increase the amount of these
neurotransmitters in the CNS but are unable to treat
depression
 the effect of antidepressants on neurotransmitter levels is
relatively quick but onset of antidepressant action is
significantly delayed
 „Receptor theory“ = the problem is in up-regulation of post-
synaptic receptors and alterations in their sensitivity
The antidepressant treatment increases the amount of
monoamines in CNS and thereby gradually normalize the
density/sensitivity of their receptors
 The precise pathophysiology of depression remains unsolved
Traditional Antidepressants
 Tricyclic antidepressants
 amitriptylline (Endep, Tryptanol)
 clomipramine (Anafranil, Chem mart Clomipramine, GenRx
Clomipramine, Placil, Terry White Chemists Clomipramine)
 doxepin (Deptran, Sinequan)
 dothiepin (Dothep, Prothiaden)
 imipramine (Tofranil)
 nortriptylline (Allegron)
 trimipramine (Surmontil)
 Tetracyclic antidepressants
 Mianserin (Lumin, Tolvon)
 MAOIs (monoamine oxidase inhibitors)
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
Newer antidepressants
 SSRIs (specific serotonin reuptake inhibitors)
 citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil,
GenRx Citalopram, Talam, Talohexal, Terry White Chemists
Citalopram)
 escitalopram (Lexapro)
 fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine,
Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan,
Prozac, Terry White Chemists Fluoxetine, Zactin)
 fluvoxamine (Faverin, Luvox, Movox, Voxam)
 paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine,
Oxetine, Paxtine, Terry White Chemists Paroxetine)
 sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx
Sertraline, Sertraline-DP, Terry White Chemists Sertraline,
Xydep, Zoloft)
 RIMA (reversible inhibitor of monoamine oxidase A)
 moclobemide (Arima, Aurorix, Chem mart Moclobemide,
Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry
White Chemists Moclobemide)
 Tricyclic Antidepressants
(TCAs)
 Chemical structure with characteristic
three-ring nucleus – lipophilic nature
 Originally developed as antipsychotics
(1949), but were found to have no effect in
this indication.
imipramine
 Principal mechanism of action:
 blockade of re-uptake of monoamine neurotransmitters
noradrenaline (NA) and serotonin (5-HT) by competition
for binding site of the carrier protein. 5HT and NA
neurotransmission is similarly affected but the effect on
the dopamine system is much less important (compare
with cocaine)
 in most TCA, other receptors (incl. those outside the CNS)
are also affected: blockade of H1-receptor, α -receptors,
M-receptors
 Pharmacokinetics
 Administered orally – rapid absorption, however
extensive first pass effect ⇒ low and inconsistent BAV
 Strong binding to plasma proteins (90-95% bound).
They are also bound in tissues + wide distribution (high
lipophilicity) = large distribution volumes (ineffectiveness
of dialysis in acute intoxications).
 Biotransformation – in the liver (CYP450, N-
demethylation and tricyclic ring hydroxylation) – most of
these metabolites are active! CYP450 polymorphisms !
Glucuronidation → inactive metabolites excreted in the urine.
 Elimination half-lives - generally LONG (T1/2 =10-80h).
Elderly patients – even longer T1/2, risk of accumulation.
 Adverse effects
 TCA are effective antidepressants but their use is
complicated by numerous troublesome adverse
effects
 Anticholinergic (atropine-like) due to M-blockade
Dry mouth, blurred vision, constipation, urinary retention
(more in amitriptyline, less in imipramine) Palpitations,
tachycardia
 Postural (orthostatic) hypotension + reflex
tachycardia - α -blockade of adrenergic transmission in the
vasomotor center (frequent in elderly)
 Sedation, drowsiness, difficulty in concentration
(amitriptyline, H1-blockade)
 Sexual dysfunction (loss of libido, impaired erection)
 Acute intoxication
 low therapeutic index
 Target systems – the CNS and heart
 excitement, hallucinations, delirium, convulsions,
coma and respiratory depression - Pronounced
atropine-like effects.
 Cardiac dysrrhythmias – tachycardia (antimuscarine
action), atrial or ventricular extrasystoles, QRS
complex widening, QT interval elongation.
Ventricular fibrillation and sudden death may occur.
 Hypotension
 Treatment- diazepam (seizures), physostigmine
 No effect of haemodialysis and hemoperfusion is
practically ineffective
Newest antidepressants
SNRI (serotonin noradrenergic reuptake inhibitors)
venlafaxine (Efexor-XR)
NaSSA (noradrenergic and specific serotonergic
antidepressant)
mirtazapine (Avanza, Avanza SolTab, Axit, Mirtazon,
Remeron)
SaSRI (serotonine antagonist and serotonine
reuptake inhibitor)
 trazodone (Trittico, Desyrel)
NaRI (selective noradrenaline reuptake inhibitor )
reboxetine (Edronax)
Serotonin receptors
 5–HT1
 subtypes
 5–HT1A , 5–HT1B , 5–HT1D , 5–
HT1E , 5–HT1F
 primarily responsible for the
therapeutic
(antidepressant) effects of
increased intrasynaptic
serotonin
 5–HT2
 subtypes
 5–HT2A , 5–HT2B , 5–HT2C
 primarily responsible for the
toxic effects of increased
intrasynaptic serotonin
Serotonin receptors
 5–HT1

 subtypes

5–HT , 5–HT1B , 5–HT1D , 5–HT1E , 5–

1A
HT1F
 5–HT2

 subtypes

5–HT , 5–HT2B , 5–HT2C

2A
Serotonin receptors
 5–HT3

 5–HT4 (rat)
 5–HT5 (rat)
5–HT , 5–HT5
5A

 5–HT6 (rat)
 5–HT7 (rat and human)
 Selective Serotonin Re-uptake
Inhibitos (SSRI)
 More modern (1st drug fluoxetine available in 1988) and
safe antidepressants

 Principal mechanism of action:

 selective inhibition of 5-HT (serotonin) reuptake →
gradual complex changes in the density and/or
sensitivity both autoreceptors (5-HT1A) and
postsynaptic receptors (important subtype 5-HT2A )
 Other indications of SSRI - anxiety disorders: generalized
anxiety, panic disorder, social anxiety disorder,
obsessive-compulsive disorder
+ bulimia nervosa, gambling
Most important SSRI
 Fluoxetine
 Fluvoxamine
 Paroxetine Enantioselective forms e.g.
escitalopram (S-enantiomer)
 Sertraline
 Citalopram
Selectivity of antidepressants

1000 Nisoxetine

Nomifensine
Maprotiline (approx)
100
Ratio NA: 5-HT uptake inhibition
NA-
selective
10 Desipramine
Imipramine
Nortriptyline
Non- 1
Amitriptyline
selective

Clomipramine
0.1 Trazodone
Zimelidine
5-HT-
selective
0.01
Fluoxetine

0.001 Citalopram (approx)

NaSSA NaRI
SSRI

NaSSA
 Pharmacokinetics
 Good absorption after oral administration
 Important biotransformation in the liver
 CYP450 - 2D6 and 2C19 isoforms (polymorphism →
interindividual variability in the clinical effect) and active
metabolites (e.g. fluoxetine)
 Long half-lives of elimination(s)
 fluoxetine (T1/2=50h) + active metabolite (T1/2 =240h)
 Drug interaction: based on plasma protein binding and
CYP blockade
 increased effect of co-administered TCA but also β -
blockers, benzodiazepines etc.
 Adverse effects
 Relative improvement to other antidepressants
(mostly mild)

 GIT – nausea, vomiting, diarrhea

 Headache
 Sexual dysfunctions
 Restlessness (akathisia)
 Insomnia and fatigue
 Few patients experience an increase in anxiety or
agitation during early treatment
 Serotonin syndrome upon intoxication or drug
interactions
Serotonin excess
 Primary neuroexcitation (5–HT2A)
 mental status
 agitation/delirium
 motor system
 clonus/myoclonus
 inducible/spontaneous/ocular
 tremor/shivering

 hyperreflexia/hypertonia

 autonomic system
 diaphoresis/tachycardia/mydriasis
 Other responses to neuroexcitation
 fever
 rhabdomyolysis
Severe serotonin toxicity
 Combination therapy
 multiple different mechanisms of serotonin
elevation
 Rapidly rising temperature
 Respiratory failure
 hypertonia/rigidity
 Spontaneous clonus
Treatment options
 Supportive care
 symptom control
 control of fever
 ventilation
 5–HT2A antagonists
 ideal
 safe
 effective

 available
Cyproheptadine
 blockade of brain 5–HT2 receptors

Chlorpromazine
 5–HT2 antagonist
Therapy
 Oral therapy
 cyproheptadine 12 mg stat then 4–8 mg q 4–6h
 Oral therapy unsuitable or fails
 chlorpromazine 25–50 mg IVI stat then up to 50
mg orally or IVI q6h
 Ventilation impaired and/or fever >
39oC
 anaesthesia, muscle relaxation ± active cooling
 chlorpromazine 100–400 mg IMI/IVI over first
two hours
 Other and atypical
antidepressants
 Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)
 trazodone (sedative effects)
 nefazodone (newer and improved) decreased some SSRI
adverse reactions
 Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
 venlafaxine - pharmacodynamic like in TCA however improved
profile of adverse reactions
 Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)
 bupropion – rather CNS activating effects (low sedation),
usage: severe depression + smoking cessation treatment.
Adverse reactions: insomnia, excitation, restlessness, lowers
epilepsy threshold
 Noradrenaline Reuptake Inhibitors (NaRI)
 reboxetine – also rather activating
 maprotiline
 Noradrenergic/Specific Serotonergic Antidepressants
(NaSSA)
 mirtazapine – increased NA and 5-HT neurotransmission
through blockade of their autoreceptors (low 5-HT adverse
effects – blocks also postsynaptic 5-HT receptors)
 MonoAmine Oxidase Inhibitors
(MAOI)
 Principal mechanism of action:
 Inhibition of intracellular enzyme MAO in CNS neurons
(= decrease in degradation of catecholamines and
serotonin).
 In contrast to other antidepressants, when given to
normal non-depressed subjects they increase a motor
activity and cause euphoria + excitements (while TCA
would cause only sedation and/or confusion).
⇒ risk of abuse!
 MAOI drugs

 Irreversible non-selective inhibitors (hydrazides)

 phenelzine
 tranylcypromine

 Reversible Inhibitors of MAO-A (RIMA)

 moclobemide

Great difference in adverse reactions between these

groups

Note: Reversible inhibitors of MAO-B (e.g. selegiline) are used in

the treatment of Parkinson's disease.
 Interaction with foods
 Tyramine „cheese and wine“ reaction
 some kind of foods contain high amounts of tyramine
(natural indirect sympathomimetic produced during
fermentation), which is however normally metabolized by
MAO in the gut and liver.
 In depressed patients treated with MAOI, these enzymes
are also inhibited → bioavailability of tyramine is
significantly higher which together with pharmacodynamic
synergism → strikingly increased noradrenaline
transmission results in hypertensive crisis, severe headache
and potentially fatal intracranial hemorrhage or other organ
damage.
 Dietary precautions: restriction in the consumption of
some maturing cheeses, wine, beer, yogurts, bananas
etc.
 Adverse reactions and toxicity
 Hypertension
 Postural hypotension (in up to 1/3 patients)
 CNS stimulation – tremor, excitement, insomnia,
convulsions in overdose.
 Weight gain (increased appetite)
 Atropine-like adverse effects – like in TCA but less
common
 Rare severe hepatotoxicity (hydrazine MAOI)
 Therapy of bipolar disorder
 Main aim: to eliminate mood episodes, maximize
adherence to therapy, improve functioning of the
patients and eliminate adverse effects

„MOOD STABILIZERS“
 Lithium
 Valproate

 Carbamazepine

 Lamotrigine

 Adjunctive agents (antidepressants and

benzodiazepines)
 Lithium
 Since 1949 - indication as a prophylactic treatment in bipolar
disorder. Effective also in 60-80% patients with mania or
hypomania.
 Principle mechanism of action
 remains elusive though profound effects on second
messenger systems (mainly IP3) is supposed.
 Lithium

 Pharmacokinetics
 administered orally (readily and almost completely
absorbed)
 distribution - extracellular, then gradually accumulates

in various tissues
 elimination – 95% in urine (T = 20-24h; when the
1/2
treatment is abruptly stopped - slow 2nd phase of
excretion /1-2 weeks/ representing Li+ taken up by cells
occurs)
 only 20% of Li+ filtered by GF is excreted (80%

reabsorbed)
 Lithium – toxicity and adverse
reactions
 Acute intoxication, symptoms:
 GIT: vomiting, profuse diarrhea
 CNS: confusion, tremor, ataxia, convulsions, coma.
 Heart: arrhythmias, hypotension

Unfortunately there is no specific antidote → supportive treatment

 Toxicity of long-term therapy

 Renal toxicity – the kidney's ability to concentrate the urine
is decreased
 Lithium – toxicity and adverse
reactions
 Adverse reactions: polyuria and polydipsia, weight gain, GIT
disturbances (vomiting, nausea, dyspepsia), alopecia

 Drug interactions: thiazides – increased Li reabsorption →

intoxication

Critical importance of TDM to reach desirable effects without risk of

toxicity!
The effects as well as toxicity correlates much more better with plasma
concentrations than with dose. The range of plasma concentrations is
narrow:
0.5-1.0 mmol/L (above 1.5 mmol/L toxic effects appear)