4 - CNS Cases

Biostatistics and Biological Standardization of Drugs (306)
Department of Pharmacology and Toxicology

Faculty of Pharmacy Cairo University
Report Cases Showing Central

Adverse Effects
Case I: Delirium and extrapyramidal symptoms due to a lithium-
olanzapine combination therapy
A 62-yr-old woman started to experience bipolar episodes twenty
years ago and has been on lithium therapy continuously. A
significant point in her history was the deterioration in her mental
status last year after the addition of a typical antipsychotic
(chlorpromazine 200 mg/day) to her therapy in order to lessen her
abrupt insomnia. The patient was brought to emergency unit with
signs and symptoms of lethargy, confusion and hyperprexia ten
days after initiation of chlorpromazine. At the examination, she had
increased muscle tone of upper limbs and paresia (partial loss of
voluntary movement) of lower limbs. The discontinuation of all
drugs resulted in complete remission within 72 h.
Later, lithium therapy were re-initiated without recurrence of any of

the previously mentioned clinical symptoms. She did not receive any
other concomitant drugs till three weeks ago. A physician prescribed
olanzapine 5 mg/day due to her increased suspiciousness towards her
neighbors and possible appearance of auditory hallucinations. She
was referred to the emergency service with symptoms of alteration in
mental status, psychomotor slowness, difficulty in walking, and
tremor in limbs.
1. What is the mechanism of therapeutic action of chlorpromazine

and olanzapine?
2. Which nervous system receptors are antagonized by the
antipsychotic agents?
3. What are the main differences between chlorpromazine and
olanzapine?
4. What are the main adverse effects of chlorpromazine and
olanzapine?
5. What mediates the cognitive impairment induced by
chlorpromazine?
6. What are the signs of the extrapyramidal side effects?
7. What mediates the extrapyramidal side effects (EPSs) of the
8. What preclinical tests are used to screen for potential adverse
effects on the locomotor activity?
Background
Bipolar disorder is a lifetime mental disorder
that is characterized by recurrent fluctuations in
mood, energy, and behavior. Patients may switch
from dejection to excitement, from profound
despair to limitless optimism, or from paralyzing
fatigue to superhuman levels of activity and
energy.
Episodes usually last several months and recurrences every 2 years
or so are common.
Bipolar disorder
There is no cure for bipolar disorder but the goal of treatment is
to achieve remission from acute episodes (manic or depressive)
and to prevent/delay future episodes (mood stabilization).
Pharmacotherapy
Lithium Valproic acid/divalproex
• Other anticonvulsants such as lamotrigine, or carbamazepine
• Antipsychotics such as chlorpromazine, olanzapine, or quetiapine
• High potency benzodiazepines such as clonazepam and lorazepam
are alternative or adjunctive treatments for bipolar disorder.
• Antidepressants are occasionally added for the treatment of
acute depressive episodes.
Frequently, treatment with a single agent is ineffective, and
combinations are necessary.
Bipolar disorder Pharmacotherapy
Lithium is a very powerful antimanic medication; its mechanism of

action is unknown.
Lithium has a narrow therapeutic index; adverse effects include
polyuria, polydipsia, tremors, weight gain, sedation, lethargy,
cognitive impairment, motor coordination, gastrointestinal upset, hair
loss, acne, psoriasis and hypothyroidism
Antipsychotics: Typical antipsychotics such as haloperidol and

chlorpromazine exert high D2 antagonism and low 5-HT2A
antagonism, while newer atypical antipsychotics such as aripiprazole
and olanzapine show moderate to high D2 antagonism and high 5-
HT2A antagonism. Blocking D2 receptors in the mesolimbic system in
the brain is assumed to underlie the beneficial antipsychotic effect
Antipsychotics also exert anticholinergic, antiadrenergic, and/or
antihistaminic effects to various extends.
Bipolar disorder
Antipsychotics adverse effects:
Extrapyramidal effects: Blockade of dopamine receptors in the
nigrostriatal pathway probably causes these unwanted movement
symptoms. The second generation (atypical) antipsychotics exhibit a
lower incidence of EPS.
• Dystonia (sustained contraction of muscles leading to twisting,
distorted postures)
• Parkinson-like symptoms (decreased motor activity including
difficulty initiating movement, mask-like facial expression, slowed
speech, tremors that are predominant at rest and decreases with
movement, rigidity and stiffness)
• Akathisia (motor restlessness, inability to sit still)
• Tardive dyskinesia (involuntary movements, usually of the tongue,
lips, neck, trunk, and limbs)
Hyperprolactinaemia occurs with blockade of dopamine receptors in
the pituitary may result in galactorrhoea, gynecomastia, sexual
dysfunction
Bipolar disorder
Antipsychotics adverse effects:
Anticholinergic effects include blurred vision, dry mouth, confusion,
constipation and urinary retention. The anticholinergic effects may
actually assist in reducing the risk of EPS with these agents.
Antiadrenergic effects cause orthostatic hypotension and light-
headedness.
Antihistaminic effects cause sedation particularly with chlorpromazine,
olanzapine, quetiapine, and clozapine.
Poikilothermia (condition in which body temperature varies with the
environment) partially due to inhibition of sweating, a result of
anticholinergic properties of some antipsychotics.
Hypertriglyceridemia and hypercholesterolemia
Weight gain
Electrocardiogram changes include increased heart rate (anticholinergic
effects), or reflex tachycardia from (adrenergic blockade), prolongation
of the QTc, which has been associated with ventricular arrhythmias.

and olanzapine?
olanzapine?
olanzapine?
chlorpromazine?

and olanzapine?
Blocking D2 and 5-HT2A receptors in the mesolimbic system in the brain

is assumed to underlie the beneficial antipsychotic effect of
chlorpromazine and olanzapine

Chlorpromazine and olanzapine block dopaminergic, serotonergic,

muscarinic, adrenergic and histaminic receptors in the CNS

olanzapine?
Chlorpromazine is a 1st generation (typical) antipsychotic which shows
high D2 antagonism and low 5-HT2A antagonism, with higher incidence
of extrapyramidal effects, sedation, and hyperprolactinemia.
Olanzapine is a 2nd generation (atypical) antipsychotic which shows

moderate D2 antagonism and high 5-HT2A antagonism with lower
incidence of extrapyramidal effects but higher incidence of weight gain.

olanzapine?
Movement disorder (extrapyramidal effects) such as dystonia,
parkinson-like symptoms, akathisia, tardive dyskinesia
Hyperprolactinaemia galactorrhoea, gynecomastia, sexual
dysfunction
Anticholinergic effects include blurred vision, dry mouth,
confusion, constipation and urinary retention
Antiadrenergic effects cause orthostatic hypotension and light-
headedness
Antihistaminic effects cause sedation
Weight gain
Electrocardiogram changes, ventricular arrhythmias
Hypertriglyceridemia and hypercholesterolemia
Poikilothermia

chlorpromazine?
The cognitive impairment is probably induced by the
anticholinergic and antidopaminergic actions of chlorpromazine
• Dystonia (sustained contraction of muscles leading to twisting,

distorted postures)
• Parkinson-like symptoms (decreased motor activity including
difficulty initiating movement, mask-like facial expression,
slowed speech, tremors that are predominant at rest and
decreases with movement, rigidity and stiffness)
• Akathisia (motor restlessness, inability to sit still)
• Tardive dyskinesia (involuntary movements, usually of the
tongue, lips, neck, trunk, and limbs)

Blockade of dopamine receptors in the nigrostriatal pathway


Functional observational battery, spontaneous motor activity and

neuromuscular coordination test (e.g. rotarod)
Case II: Reversible cognitive impairment associated with
valproate treatment
A 6-year-old girl experienced her first generalized clonic seizure and

was prescribed phenobarbital (PB) at a dosage of 4 mg/kg/day
which was increased to 6 mg/kg/day after a second similar seizure
at the age of 7 years. Behavior was normal and school performance
was excellent. Two follow-up electroencephalogram (EEG)s at age 7
and 8 years revealed normal background activity and a marked
increase in interictal abnormalities, with diffuse discharges of
rhythmic spike and slow wave complexes without any detectable
clinical manifestations. Therefore, valproic acid (VPA) 20 mg/kg/day
was added, resulting in serum levels of 23 pg/ml for PB and 65
pg/ml for VPA. The Wechsler Intelligence Scale for Children-I11
(WICS) at age 8 years, 4 months showed a full-scale-IQ of 90 (verbal
85, performance 98). Raven’s Progressive Matrices score was 25/36
(95th age-adjusted percentile.
valproate treatment
PB was discontinued and VPA increased to 26 mg/kg/day, with
serum levels of 99 pg/ml and 84 pg/ml at age 8 years, 9 months,
and 9 years, 5 months, respectively. Moderate learning difficulties,
ascribed mainly to poor concentration and memory, were reported
by the parents and teachers. Since these symptoms were
considered as possibly related to the severe interictal EEG
abnormalities, sequential add-on therapy with clobazam and
ethosuximide was tried. These drugs produced no lasting clinical or
EEG improvement. VPA monotherapy was therefore reinstituted, at
an unchanged dosage of 26 mg/kg/day (900 mg/day).
When the patient was 10 years old, lamotrigine (LTG) at a
maintenance dosage of 6 mg/kg/day was added. Because of the
patient’s progressive learning difficulties and decreased alertness,
VPA dosage was reduced to 23 mg/kg/day (800 mg/day), resulting
in serum levels of 95 pg/ml.
valproate treatment
At the age of 10 years, 6 months, the girl showed progressive
deterioration in cognitive functions, lack of interest in
surroundings, marked decline in school performance, memory loss,
disorientation to place and time, and praxic difficulties. Neurologic
examination was normal, except for marginal unsteadiness of gait.
SerumVPA levels on two separate occasions within one month were
106 kg/ml, and ammonia levels were 67 pg/dl. At age 10 years 8
months, repeat IQ testing (WISC) showed a full-scale IQ of 72
(verbal 72, performance 75) while PM 47 score was 24/36 (50th
AAP).
Alerted by reports suggesting a possible association between VPA
and reversible pseudoatrophy of the brain, we reduced VPA dosage
to 17 mg/kg/day serum levels 64 kg/ml). Within 10 days the
decreased dosage produced dramatic cognitive and behavioral
improvement.
valproate treatment
At the age of 11 years, 3 months Repeat testing showed a full-scale
WISC IQ of 92 (verbal 92, performance 95) and a PM 47 score of
33/36 (>95th AAP).Neurological examination was normal. EEG
showed normal background activity and diffuse slow spike and
wave abnormalities, still occupying about 25% of slow wave sleep.
Case II: Reversible cognitive impairment associated with valproate
treatment
1. Why do you think the girl was prescribed valproic acid at 8 y old and
why it was stopped when she was 11 y old?
2. What are the indications of valproic acid? What is its mechanism of
action?
3. What are the main adverse effects of valproic acid?
4. What is the main adverse effect the patient was suffering from in the
case above? What is the triggering agent and mechanism?
5. Why do you think the patient developed only cognitive impairment as
an adverse for valproic acid and not the other known and more
common adverse effects reported for valproic acid?
6. What are the factors that modulate memory and learning?
7. Are there other drug classes that can cause cognitive impairment?
8. Which preclinical tests can be used to screen for potential adverse
effects on cognitive function?
9. What is the role of pharmacists in reporting a suspected adverse
reaction related to a drug?
treatment
Background
Epilepsy is the second most common neurologic disorder after stroke
affecting approximately 1% of the world population. Epilepsy is a
chronic heterogeneous neurological disorder characterized by
recurrent seizures resulting from abnormal electrical activity of
cerebral neurons that may be caused by a wide variety of etiologies
e.g. trauma, infection, or tumors
Pharmacotherapy
Antiepileptic drugs act via multiple mechanisms, the main three are:
• Enhancement of GABAergic inhibitory transmission,
• Suppression of excitatory usually glutamatergic transmission
and/or
• Modification of ionic conductance e.g. blocking sodium channels
or enhancing potassium channels conductance.
treatment
Pharmacotherapy
Benzodiazepines
Carbamazepine
Ethosuximide
Gabapentin
Lamotrigine
Phenobarbital and primidone
Phenytoin and fosphenytoin
Pregabalin
Topiramate
Valproic acid and divalproex
Others
Choice of drug treatment is based on the type of the seizures,
patient variables (age, pregnancy, nursing, comorbid medical
conditions, lifestyle, and personal preference), and characteristics
of the drug (such as cost, safety profile, drug interactions).
treatment
Pharmacotherapy
Valproic acid, is used as an anticonvulsant and mood-stabilizing
drug, primarily in the treatment of epilepsy, bipolar disorder and
prevention of migraine headaches. Valproate has a broad spectrum
of anticonvulsant activity, although it is primarily used as a first-line
treatment for tonic-clonic seizures, absence seizures and myoclonic
seizures and as a second-line treatment for partial seizures and
infantile spasms
Adverse effects include weight gain, headache, nausea, vomiting,

tremor, hair loss, GI upset, liver damage, alopecia, and sedation.
Hepatic failure, pancreatitis, and teratogenic effects have
been observed.
treatment
1- Why do you think the girl was prescribed valproic acid at 8 years
old and why it was stopped when she was 11 years old?
The girl suffered from generalized clonic seizure at age 6 and was
initiated on phenobarbital which is the drug of choice for seizures
in infants/children because of its favourable safety profile.
However, phenobarbital can cause significant sedation which may
interferes with school tasks. More importantly, the girl continued to
show marked increase in EEG abnormalities so she was shifted to
valproic acid at 8 years old. At 11 years old, valproic acid was
discontinued due to its suspected effect role in the progressive
cognitive impairment the patient was experiencing
treatment
2-What are the indications of valproic acid? What is its mechanism

of action?
Valproic acid is used as an antiepileptic, a mood stabilizer in bipolar
disorder and in migraine prophylaxis.
The mechanism of action is not fully understood but it involves
enhancing the GABAergic inhibitory transmission, blocking N-
methyl D-aspartate (NMDA) receptor mediated excitation,
increasing potassium conductance and blocking sodium and
calcium channels leading to hyperpolarization of neural membrane
potentials.
treatment
3- What are the main adverse effects of valproic acid?
Mainly gastrointestinal upset e.g. nausea, vomiting, abdominal

pain, diarrhea and indigestion. Severe hepatotoxicity may occur in
certain patients; therefore, continuous monitoring of liver function
is recommended. Thrombocytopenia can also occur. There is an
extending list of adverse effects for valproic acid including but not
limited to hair loss, increased appetite, weight gain, mood changes
anxiety, confusion, hallucinations, memory impairment,
extrapyramidal syndrome, hyperammonaemic encephalopathy
treatment
4- What is the main adverse effect the patient was suffering from in
the case above? What do you think is the triggering agent and
mechanism?
Progressive cognitive impairment manifested as lack of interest in
surroundings, marked decline in school performance, memory loss,
and disorientation to place and time.
The effect could be possibly due to a direct effect of valproic acid
on central GABAergic and glutamatergic transmission, or an indirect
central effect of valproic acid mediated by valproic acid-induced
hyperammonemia. The ammonia level was tested and found to be
within the normal range (67 pg/dl). However, the involvement of
valproic acid is supported by the remission of the signs of dementia
after discontinuation of valproic acid in addition to several other
reports documenting the association of valproic acid with cognitive
impairment.
treatment
5- Why do you think the patient developed only cognitive
impairment as an adverse for valproic acid and not the other
known and more common adverse effects reported for valproic
acid?
The genetic makeup of an individual affects his/her response to

drugs. Pharmacogenomics aims to develop rational means to
optimize drug therapy, with respect to the patients‘ genotype, to
ensure maximum efficacy with minimal adverse effects
(personalized medicine).
treatment
6- What are the factors that modulate memory and learning?
Memory and learning depend upon the coordinated action of
different brain regions but the involvement of the hippocampus
and entorhinal cortex is confirmed. The integrity of the central
cholinergic, dopaminergic (particularly D1 receptors), GABAergic
and glutamatergic (particularly inotropic NMDA receptors and
metabotropic glutamate receptor 5) transmission is crucial for the
maintenance of memory.
Memory
treatment
7- Are there other drug classes that can cause cognitive
impairment?
Yes, anticholinergics either muscarinic antagonists or nicotinic

antagonists, dopaminergic antagonist e.g. haloperidol, NMDA
receptors antagonists e.g. ketamine, benzodiazepines,
cannabinoids, ethanol, baclofen, ethanol and γ-hydroxybutyric acid.
treatment
8- What are the preclinical tests that can be used to screen for
potential adverse effects on cognitive function?
The radial arm maze task, Morris water maze task and the
autoshaping lever-press task are commonly used to assess
cognitive function in experimental animals.
treatment
9- What is the role of pharmacists in reporting a suspected adverse
reaction related to a drug?
Filling in an adverse drug reactions reporting form

http://epvc.gov.eg.allium.arvixe.com/Pagefiles/file/Drugs%20Englis
h%20web%20form.pdf
and mailing or emailing it to the respective authority. In Egypt it is

the Egyptian pharmaceutical Vigilance Center (EPVC)
www.epvc.gov.eg
Case III: Memory loss secondary to the administration of a muscarinic
blocker)
Overactive bladder (OAB) is a common condition in the elderly.
Treatments for OAB include nonpharmacological/behavioral
therapy, pharmacological therapy, and surgical therapy.
Antimuscarinic agents are the current pharmacological treatment
for OAB. A 66-year-old female presented with memory loss
secondary to the administration of oxybutynin (a muscarinic
blocker), which resulted in medication nonadherence. Upon review
of her medications, the pharmacist recommended discontinuing
the oxybutynin. At a three-week follow-up visit, the patient
reported an improvement in memory and medication adherence.
Pharmacists can play a vital role in recognizing drug-induced side
effects and educating patients in an effort to improve medication
adherence.
blocker)
1. What are the factors that modulate memory?

2. State the pharmacological classes that can cause cognitive
impairment.
3. What is the main adverse effect the patient was suffering from
in the case above? What do you think is the triggering
mechanism?
4. Name three preclinical tests that can be used to screen for
5. What is the role of pharmacists in reporting a suspected
adverse reaction related to a drug?
blocker)
1. What are the factors that modulate memory?

Memory and learning depend upon the coordinated action of
different brain regions but the involvement of the hippocampus
and the entorhinal cortex is confirmed. The integrity of the central
cholinergic, dopaminergic (particularly D1 receptors), GABAergic
and glutamatergic (particularly inotropic NMDA receptors and
metabotropic glutamate receptor 5) transmission is crucial for the
maintenance of memory.
Memory
blocker)
2. State the pharmacological classes that can cause cognitive

impairment.
1- Anticholinergic (muscarinic and nicotinic blockers)

2- dopaminergic agonists and antagonists
3- GABA modulators
4- NMDA receptor antagonists
5- miscellaneous group including opioids, cannabinoids and γ-
hydroxybutyric acid.
blocker)
3. What is the main adverse effect the patient was suffering from
in the case above? What do you think is the triggering
mechanism?
The patient suffered from memory loss which resulted in

medication non-adherence. Oxybutynin (a muscarinic blocker)
interferes with the central cholinergic transmission which is
crucial for the maintenance of memory.
blocker)
4. Name three preclinical tests that can be used to screen for

The radial arm maze task, Morris water maze task and the
autoshaping lever-press task are commonly used to assess
cognitive function in experimental animals
blocker)
5. What is the role of pharmacists in reporting a suspected

adverse reaction related to a drug?
The pharmacist has to fill in the adverse drug reaction reporting

form and file it to the responsible authorities e.g. the
pharmacovigilance department in the Egyptian Drug Authority

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Biostatistics and Biological Standardization of Drugs (306)

Department of Pharmacology and Toxicology

Report Cases Showing Central

Later, lithium therapy were re-initiated without recurrence of any of

1. What is the mechanism of therapeutic action of chlorpromazine

Lithium is a very powerful antimanic medication; its mechanism of

Antipsychotics: Typical antipsychotics such as haloperidol and

1. What is the mechanism of therapeutic action of chlorpromazine

1. What is the mechanism of therapeutic action of chlorpromazine

Blocking D2 and 5-HT2A receptors in the mesolimbic system in the brain

2. Which nervous system receptors are antagonized by the

Chlorpromazine and olanzapine block dopaminergic, serotonergic,

3. What are the main differences between chlorpromazine and

Olanzapine is a 2nd generation (atypical) antipsychotic which shows

4. What are the main adverse effects of chlorpromazine and

5. What mediates the cognitive impairment induced by

6. What are the signs of the extrapyramidal side effects?

• Dystonia (sustained contraction of muscles leading to twisting,

7. What mediates the extrapyramidal side effects (EPSs) of the

Blockade of dopamine receptors in the nigrostriatal pathway

8. What preclinical tests are used to screen for potential adverse

Functional observational battery, spontaneous motor activity and

A 6-year-old girl experienced her first generalized clonic seizure and

Adverse effects include weight gain, headache, nausea, vomiting,

2-What are the indications of valproic acid? What is its mechanism

3- What are the main adverse effects of valproic acid?

Mainly gastrointestinal upset e.g. nausea, vomiting, abdominal

The genetic makeup of an individual affects his/her response to

Yes, anticholinergics either muscarinic antagonists or nicotinic

Filling in an adverse drug reactions reporting form

and mailing or emailing it to the respective authority. In Egypt it is

1. What are the factors that modulate memory?

1. What are the factors that modulate memory?

2. State the pharmacological classes that can cause cognitive

1- Anticholinergic (muscarinic and nicotinic blockers)

The patient suffered from memory loss which resulted in

4. Name three preclinical tests that can be used to screen for

5. What is the role of pharmacists in reporting a suspected

The pharmacist has to fill in the adverse drug reaction reporting

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