Lecture 4 spring

2024
 NARS: National Academic Reference Standards
‫المعايير القومية المرجعية االكاديمية‬

It is the minimum level of knowledge and skills that a graduate must possess to ensure good practice
of his profession. These standards have been set by the National Authority for Quality Assurance of
Education and Accreditation agency (NAQAAE(

NARS Programme Course LOs

LOs

Learning outcomes (Knowledge and skills ): measurable achievements that the learner
will be able to understand after learning processes is completed
 NAQAAE issued two versions of these standards in 2009 (outcome based) and
2017 (competency based) consecutively, as a result of upgrading and updating
the attributes of pharmacy graduates globally.
Competency: the capability of applying the acquired skills and knowledge that enable the student
to successfully perform in professional and educational contexts.

NARS 2009 (Outcome based) NARS 2017 (Competency based)

It depends on make use of all the information the

Depends on gaining a huge amount of information with
minor applications
student acquired during the study period to solve
professional problems that he encounters through
his/her work, whether in private pharmacies, hospitals
or research centers through integrating the knowledge
and skills the student gain to solve such problems
References

• ACCP Updates in Therapeutics® 2022:

Pharmacotherapy Preparatory Review and
Recertification Course

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 interactive teaching

•Case study
•Open discussion
•On campus quiz
SCHIZOPHRENIA
Symptoms of Schizophrenia
Positive-Psychotic Dimension
• Hallucinations .(Visual &auditory hallucinations)
• Delusions .(These are erroneous beliefs)
• Disorganized speech (Loose associations, Tangential” speech, “Word salad
• Disorganized behavior(clothing ,appearance , repetitive action)
Negative symptoms
• Alogia(aphasia)
• Flat affect
• Poor attention
• Lack of motivation
Cognitive
• Memory disturbance
• Attention impairment
• Poor executive function
Conceptual disorganization, according to the Brief Psychiatric Rating Scale (BPRS), is
the “degree to which speech is confused, disconnected, vague or disorganized

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Diagnosis
The Diagnostic and Statistical Manual for Mental Disorders
(DSM-5) identifies five symptoms for diagnosis. At least two of
the following symptoms must be present for at least 1 month,
and at least one of the symptoms should be delusions,
hallucinations, or disorganized speech.
• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behavior
• Negative symptoms

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 There are four phases of schizophrenia:

A. Prodromal phase: This phase is characterized by gradual development of

symptoms that may go unnoticed until a major symptom occurs. It may include isolation,
deterioration of hygiene, loss of interest in work or school.

B. Acute phase: Clinically significant positive symptoms are present. People may be
unable to care for themselves during this phase.

C. Stabilization phase: The acute symptoms begin to decrease, and this phase
may last for several months.

D. Stable phase: During this phase, symptoms have markedly declined and may not
be present. Non-psychotic symptoms such as anxiety and depression may be present.

NB:
Complete remissions without symptoms are uncommon
Cause :
The causes of schizophrenia are unknown.

Pathophysiology:
The primary neurotransmitters believed to be
involved in the cause are dopamine and
serotonin
Management :
Antipsychotic Agents
A- First-generation antipsychotics (FGAs; also called typical
or conventional antipsychotics;. These include all the older
antipsychotics. Chlorpromazine, a phenothiazine, was the
first to be used clinically.

B- Second-generation antipsychotics (SGAs; also called

atypical antipsychotics: These include the newer agents,
beginning with clozapine. The adverse effect profile of
SGAs is more heterogeneous and differs from that of
FGAs.
Nigrostriatal pathway
Substantia Nigra to Striatum
. Motor control
this pathway can result in
Parkinson's Disease Tuberoinfundibular
pathway
Hypothalamus to Pituitary
Mesolimbic and Mesocortical pathways
gland . Hormonal
. Memory
regulation . Maternal
. Motivation and emotional response
behavior (nurturing)
. Reward and desire
. Pregnancy
. Addiction
. Sensory processes
. Can cause hallucinations and
schizophrenia if not functioning
properly
Management :
Antipsychotic Agents
A- First-generation antipsychotics

These agents can be categorized according to potency as

antagonists at the dopamine D2 receptors, which are
thought to be the mechanism of pharmacologic activity,
particularly in the mesolimbic areas of the brain for
treating psychotic symptoms.

Blockade in the mesocortical areas may worsen

negative and cognitive symptoms.

Potency at the D2 receptors can be split into low,

intermediate, and high. FGAs can be interconverted
using chlorpromazine dose equivalents.
Management :
Antipsychotic Agents
A- First-generation antipsychotics
ii. Adverse effect profiles also differ by potency and are
relatively uniform for agents with similar dopamine
potency.

(a)Low potency: Concomitant anticholinergic,

antihistaminic, and α-adrenergic blocking properties
are also present.

(b) High potency: Less potency at the other receptors;

dopamine-related adverse effects, including
extrapyramidal symptoms (EPS) and
hyperprolactinemia, tend to be the main adverse effects
and are more prevalent than with low-potency agents.
Management :
Antipsychotic Agents
A- First-generation antipsychotics

(c) Sedation: More common with low-potency agents.

Sedation is usually worse initially and then better
tolerated with time. Sedation tends to be dose related.

(d) Anticholinergic effects: More common with low-

potency agents. Dry mouth, constipation, blurred vision,
and urinary hesitancy can occur. Dose-dependent.

(e) Orthostatic hypotension (OH): More common

with low-potency agents because of blockade of the α-
adrenergic receptor.
Management :
Antipsychotic Agents
B- Second-generation antipsychotics
SGAs were developed to reduce EPS adverse effects, including
tardive dyskinesia, and to improve efficacy. The characteristics
that define “atypicality” are not all agreed on, but in general, they
all share at least three characteristics:
(a) The risk of EPS is lower than with typical
antipsychotics at usual clinical doses

(b) The risk of tardive dyskinesia is reduced.

(c) The ability to block serotonin-2A receptors is present.

This third property may improve the negative symptoms
of schizophrenia and reduce the risk of EPS. This may
also be related to SGA efficacy in mood disorders
Antipsychotic Agents
“first generation”, “typical Atypical “second generation”(
Block postsynaptic D2 (PK,PRL) Same but more meso limbic selective(D4+
α1__ortho.hypo and 5HT2
M1__anti ch
H1___sedation
CTZ__dec.vomiting

positive symptoms positive and negative

A-phenothiazine :Fluphenazine Clozapine

Trifluoperazine Risperidone
Perphenazine Olanzapine
Mesoridazine Quetiapine
Thioridazine Ziprasidone
Chlorpromazine Aripiprazole
B-non-phenothiazine Haloperidol Paliperidone
Thiothixene Iloperidone
Loxapine Asenapine
Molindone Lurasidone
 Management
Treatment Goals
1. Acute
•a. Reduce acute symptoms.
•b. Return patient to baseline level of function.
2. Maintenance
•a. Prevent recurrence of symptoms.
•b. Maximize functioning and quality of life

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Management
• Choosing an antipsychotic: In practice, SGAs are preferred
as first-line treatment. However, most guidelines recommend
either an FGA or an SGA.

• The 2020 APA guidelines recommend individualizing

treatment to the specific patient. This includes
gathering information
- on previous treatment experiences and
responses
- the patient’s treatment preferences
- discussing the potential risk-benefit of potential
medications, as well as other treatment options

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Management
Therapy initiation
a. First episode: Younger or treatment-naive patients
may be more sensitive to adverse effects and may
respond more quickly to treatment. Hence, it is
recommended to start with a lower dose. This may
also improve chances of adherence by avoiding
adverse effects.

b. In patients with a history of treatment with

antipsychotics, higher doses and more aggressive
titrations may be appropriate.

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Management
Therapy initiation
c. Older individuals with concomitant physical health issues
and medications may need starting doses that are as small as
one-fourth to one-half the usual adult starting dose.

d. Once medication is initiated, escalation to a therapeutic

dose can be achieved relatively rapidly, though this will vary
depending on the individual drug.

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Management
•Dose optimization:
a. Can be difficult to determine during the
acute phase because it may take patients
2–4 weeks to show an initial response with
conservative titration; often, more
aggressive titration is used for inpatients to
hasten response. This must be weighed
against the increased risk of adverse
effects.
b. Therapy duration: Maintaining the antipsychotic for
life time at the minimal effective dose continuously
may be the best approach for most patients.
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Management
• Long-term therapy should include monitoring
•for metabolic complications such as
diabetes, weight gain, and lipid
abnormalities (watch BMI, lipid profile and
HbA1C)
•Abnormal movements.(watch???
It may lead to patient cessation of
therapy.

• Any changes in antipsychotics (other than

between FGAs) or discontinuations should be
performed gradually to avoid withdrawal
symptoms.
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Management
Treatment-resistant schizophrenia(defined as lack of
response to two or more adequate trials of antipsychotics,
usually of different classes): Clozapine is the agent of
choice.
Complications with clozapine includes:
• Severe neutropenia (agranulocytosis): This is the
most limiting adverse effect. Severe neutropenia can
lead to a dramatic decrease in neutrophils, which
increases the risk of serious or fatal infections.

• In January 2020, the FDA strengthened an existing

warning regarding clozapine-associated
constipation. It can progress to serious
complications, including necrotizing colitis and
intestinal ischemia, hospitalization, and death.
Consider prophylactic laxatives in high-risk patients.
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 Pharmacological
agents side effects
and corresponding
management

26
Extrapyramidal symptoms (EPS): Can occur with all antipsychotics, but are
most common among the FGAs, particularly the high-potency agents. EPS
are thought to result from blockade of D2 receptors in the nigrostriatal
pathway. There are four main manifestations:

27
EPS
Side effect Management

Dystonia (These episodes are Acute dystonia is treated with

often acute. The risk is greatest in intramuscular anticholinergics.
young men and with high doses
of parenteral antipsychotics.
Examples include torticollis,
laryngospasm, and oculogyric
Oral anticholinergics are often used
crisis to prevent dystonias in high-risk
patients.
EPS
Side effect
Pseudo- Parkinsonism
This is manifested by symptoms
such as bradykinesia, rigidity,
tremor, or akinesia.
Management
the dose of the antipsychotic should be lowered
or the patient changed to another antipsychotic
with less possibility of causing parkinsonism.
If neither is possible, parkinsonism is usually
responsive to oral anticholinergic agents such
as diphenhydramine, trihexyphenidyl, and
benztropine.
 EPS side effect
Side effect Management

Akathisia Reducing the antipsychotic dose and changing to an

agent with a lower incidence of akathisia are the best
This is a somatic
options, but these are not always feasible.
restlessness and
inability to stay still or
Akathisia responds poorly to anticholinergics.
calm.
Lipophilic (fat soluble) β-blockers such as propranolol are
typically used.

Benzodiazepines can also be used to treat akathisia but are

considered second line behind β-blockers.

Agents with serotonin-2 activity, including mirtazapine (which

has the most evidence), trazodone may also be helpful.
EPS
Side effect Management

Tardive dyskinesia Symptoms may decrease over time with lowering the
usually involves the antipsychotic dose (after an initial symptom increase).
orofacial muscles and is However, this dose reduction must be weighed against
often insidious. worsening symptoms of schizophrenia.
With continued drug Changing to an agent that is associated with less tardive
exposure, particularly at dyskinesia is also an option.
high doses, tardive
dyskinesia is often The risk is higher with FGAs than with SGAs.
irreversible. Clozapine has not been associated. The other
Risks are likely related SGAs also appear to have a low potential to cause tardive
to Those taking high dyskinesia
antipsychotic
doses, those older Patients taking antipsychotics should be monitored at least
than 54 years, women. annually using a rating scale, such as AIMS (Abnormal
Involuntary Movement Scale) or DISCUS (Dyskinesia
Identification System Condensed User Scale).
https://www.mdcalc.com/calc/10435/abnormal-involuntary-
movement-scale-aims
EPS
Side effect Management

Tardive dyskinesia Valbenazine (Ingrezza) and deutetrabenazine (Austedo) are both

U.S. Food and Drug Administration (FDA) approved as the first
drugs to carry an indication for tardive dyskinesia. The exact
mechanism of action is unknown.

Anticholinergic agents should not be given to treat tardive

dyskinesia and may in fact worsen the symptoms.

a pursed lips (pulled inwards from all directions); b puckered lips

(protruded into a kiss formation); c tongue protrusion, d twisted
tongue
Other side effects
Side effect Management

Neuroleptic malignant syndrome Discontinue the offending agent and give

(NMS) supportive therapy, including fluids and
Occurs with all agents but is more cooling.
common with high potency
Bromocriptine and dantrolene have been
FGAs.
used with varying success.
This syndrome is manifested by
agitation, confusion, changing Do not reinitiate antipsychotics until at
levels of consciousness, least 14 days after resolution of NMS
muscle rigidity, fever, symptoms.
tachycardia, autonomic
instability, and diaphoresis
Other Side effects
Side effect Management

Hyperprolactinemia Antipsychotics, particularly FGAs and Among the SGAs,

risperidone

Thermoregulation: Thermoregulatory problems are more common with low-potency

FGAs, but they are also possible with SGAs having more
anticholinergic properties, such as clozapine, olanzapine, and
quetiapine.
Sexual Loss of libido and anorgasmia may occur in men and women.
dysfunction:
Weight gain and Among the SGAs, the risk is highest with clozapine
diabetes and olanzapine, followed by quetiapine and risperidone.
Among the FGAs, low-potency agents have a higher risk than
high-potency agents. Important interventions include keeping the
dose as low as possible and implementing dietary management to
minimize weight gain.

Seizures Antipsychotic medications lower the seizure threshold. The risk is

highest with predisposing factors. Chlorpromazine and
clozapine carry the highest risk.
Side effects Management
Dystonia
Acute IM anticholinergic
prevention Oral anticholinergic
Pseudo PK change/ reduce dose
Or oral anticholinergics
Akathisia B Blocker ( propranolol)

Tardive dyskinesis change/ reduce dose

Valbenazine or deutetrabenazine

NMS Stop + supportive + Bromocriptine and

dantrolene
Metabolic side effects Keep dose to the lowest effective +
dietary management / or Change to an
agent with lower risk
Comorbidity Drug of choice Drug to avoid
PD Quietapine,
Pimavanserin
Metabolic abnormalities Clozapine and
or obesity olanzapine

Bipolar I or mixed Most of SGA

Seizures Chlorpromazine and
clozapine
Constipation clozapine
Low WBCs Clozapine
Patient Case
• L.M. is a 25-year-old man recently given a diagnosis of
schizophrenia. He frequently hears voices telling him that he is “stupid
and worthless” and that he should “just jump off his apartment
building.” His parents became very concerned over his isolative
behavior and brought him to the hospital. The patient was given
haloperidol in the psychiatry unit and now presents with neck
stiffness and in oculogyric crisis. Until now, they have not taken
medications because they thought they could control their symptoms
on their own with vitamins, though they have difficulty remembering to
take these. The patient has an additional history of marijuana and
alcohol use disorders. A blood alcohol concentration is 0, and a urine
drug screen is negative.

• Which one of the following is the most appropriate treatment of L.M.’s

symptoms at this time?
A. Benztropine.
B. Haloperidol.
C. Olanzapine.
D. propanolol..
Which is the best example of an adverse effect of aripiprazole that
would be of concern when initiated in this patient?
A. Sedation.
B. Anticholinergic effects.
C. Akathisia.
D. Corrected QT (QTc) prolongation.
One year later, they no longer respond to aripiprazole, and you
decide to change their medication. They are only interested in
oral medications. Given this patient’s history, which agent is
most appropriate at this time?
• A. Clozapine.
• B. Fluphenazine.
• C. Olanzapine.
• D. Ziprasidone.
 Overview of Anxiety Disorders
Compulsion

Repetitive
behavior
obsessio

6 M of the
following

Easily GAD
fatigue Poor
Restlessness
& irritability Conc
Sleep Muscle
disturbance tension
Management
Disease Management
1-Generalized anxiety Benzodiazepines rapid effect ( short period discontinue
disorder in 3-4 weeks )
Buspirone,( second line )
SSRI, Venlafaxine,duloxetine. (first line )
Pergabline ( second line or adjunctive )
Cognitive-behavior or another psychotheray(CBT)
2-Panic disorder: Benzodiazepines
SSRI,(drug of choice )
Cognitive-behavior or another psychotherapy
3-Obsessive‐compulsive SSRIs (Alone, SSRIs often fail to control OCD
disorder: completely. Not many other drugs help.
Augmentation with haloperidol or an SGA may help.)
clomipramine(2nd line)
CBT
Management
Disease Management

4-Posttraumatic stress Psychotherapy is considered the cornerstone of

disorder: treatment ( first line therapy)
Medications are considered adjuncts to
psychotherapy. They are preferred if
psychotherapists are not readily available or if a
patient declines psychotherapy.
- SSRIs first line pharmacological
- Augment +/- SSRI with other agents to treat
specific symptoms.
i. Prazosin is commonly used for PTSD-associated
nightmares,
ii. Anticonvulsants can be used for aggression,
anger (carbamazepine, lamotrigine,topiramate).
iii. SGAs can be used for psychotic symptoms
iv. Benzodiazepines are sometimes used acutely for
sleep disturbances, but use should be very
limited.
 Managemant
Disease Management

5-Social anxiety disorder a. CBT is the most important modality.

b. Antidepressants: First-line medication for

treatment; SSRIs Response to antidepressants
tends to be slow (up to 12 weeks)

c. Benzodiazepines (alprazolam and

clonazepam) are considered second-line
agents, but use should be minimized.

d. Anticonvulsants: Pregabalin is considered a

first-line agent, and gabapentin is a second-line
agent
6-Specific phobias No medications Systematic desensitization
Drug Use
SSRI All first line except PTSD they are 2 nd line after/ or in the absence
of psychotherapy
Venlafaxine GAD ( first line )
Duloxetine GAD ( first line )
Buspirone GAD ( second line )
BZ Panic &early GAD,SAD with SSRI ( as rapid action) and may be in
very limited cases as adjuvant for sleep disturbance in PTSD +/-
SSRI
SGA PTSD for psychotic features if present +/- SSRI
OCPD with SSRI as a augmentation if no remission with SSRI alone
Anticonvulsant Pergabline ( 2nd line GAD ) and 1 st line for SAD
Gapabentine ( 2nd line SAD)
carbamazepine, lamotrigine,topiramate (+/- SSRI for agression in
PTSD)
Prazosine +/- SSRI for nightmares of PTSD
C.P. is a recent Iraq war veteran who has been treated successfully with
paroxetine for his major depression for the past 3 weeks. He presents to the
clinic with nightmares, “feeling on edge all the time,” and flashbacks of his
time in the war. He is evaluated for and given a diagnosis of posttraumatic
stress disorder (PTSD). He has no history of substance dependence and has
no significant medical history.
12. Which one of the following recommendations is most appropriate at this
time?
A. Continue paroxetine because it treats both PTSD and major depression.
B. Discontinue paroxetine and start sertraline, which treats both PTSD and
major depression.
C. Continue paroxetine and add lorazepam for the anxiety symptoms.
D. Discontinue paroxetine and start buspirone for the anxiety symptoms.
• A 27-year-old with panic disorder is having difficulty
functioning at work. The first panic attack occurred while
getting a cup of coffee. It felt like a heart attack and was
evaluated at the local emergency department, where
physical causes were ruled out. There have been several
subsequent episodes. Place and time of repeat episodes
are unpredictable. Absenteeism from work is high, and job
security is thus a concern. The medical history is otherwise
unremarkable. Which medication would most quickly allow
the patient to return to work?
• A. Alprazolam.
• B. Buspirone.
• C. Paroxetine.
• D. Venlafaxine.
• A 21-year-old has newly diagnosed OCD. They cannot
hold a job because they are consumed by their
obsessions and compulsions. They are convinced that
their obsessions are reality. Which medication is most
appropriate to initiate?
• A. Bupropion.
• B. Desipramine.
• C. Fluoxetine.
• D. Mirtazapine.
Assoc. Prof. Dr. Iman Gomaa 48