P.
01L HUNTINGTON, WILSON, ANTI-PSYCHOTICS
and ANTI-DEPRESSANTS
OUTLINE
I. HUNTINGTON’S DISEASE
II. WILSON’S DISEASE
III. ANTI-PSYCHOTICS
IV. ANTI-DEPRESSANTS
I. HUNTINGTON’S DISEASE
• Huntington’s disease is an autosomal dominant inherited
disorder caused by an abnormality (expansion of a CAG
trinucleotide repeat that codes for a polyglutamine
tract) of the huntingtin gene on chromosome 4. An
autosomal recessive form may also occur.
• Huntington disease–like (HDL) disorders are not associated with
an abnormal CAG trinucleotide repeat number of the huntingtin
gene. Autosomal dominant (HDL1, 20pter-p12; HDL2, 16q24.3)
and recessive forms (HDL3, 4p15.3) occur.
• Huntington’s disease is characterized by progressive chorea and
dementia that usually begin in adulthood. The development of
chorea seems to be related to an imbalance of dopamine,
acetylcholine, GABA, and perhaps other neurotransmitters in the
basal ganglia (Figure 28–6). Pharmacologic studies indicate that
chorea results from functional overactivity in dopaminergic
nigrostriatal pathways, perhaps because of increased
responsiveness of post-synaptic dopamine receptors or
deficiency of a neurotransmitter that normally antagonizes
dopamine. Drugs that impair dopaminergic neurotransmission,
either by depleting central monoamines (eg, reserpine,
tetrabenazine) or by blocking dopamine receptors (eg,
phenothiazines, butyrophenones), often alleviate chorea,
whereas dopamine-like drugs such as levodopa tend to
exacerbate it.
• Both GABA and the enzyme (glutamic acid decarboxylase)
concerned with its synthesis are markedly reduced in the basal
ganglia of patients with Huntington’s disease, and GABA
receptors are usually implicated in inhibitory pathways. There is
also a significant decline in concentration
of choline acetyltransferase, the enzyme responsible for
synthesizing acetylcholine, in the basal ganglia of these patients.
PHARMA | 1 of 9
These findings may be of pathophysiologic significance and have
led to attempts to alleviate chorea by enhancing central GABA
or acetylcholine activity, but with disappointing results. As a
consequence, the most commonly used drugs for controlling
dyskinesia in patients with Huntington’s disease are still those
that interfere with dopamine activity. With all the latter drugs,
however, reduction of abnormal movements may be associated
with iatrogenic parkinsonism.
• Tetrabenazine (12.5–50 mg orally three times daily) depletes
cerebral dopamine and reduces the severity of chorea. It has
less troublesome adverse effects than reserpine, which has also
been used for this purpose. Tetrabenazine is metabolized by
cytochrome P450 (CYP2D6), and genotyping has therefore been
recommended to determine metabolizer status (CYP2D6
expression) in patients needing doses exceeding 50 mg/d. For
poor metabolizers, the maximum recommended dose is 50 mg
daily (25 mg/dose); otherwise, a maximum dose of 100 mg daily
can be used. Treatment with postsynaptic dopamine receptor
blockers such as phenothiazines and butyrophenones may also
be helpful. Haloperidol is started in a small dose, eg, 1 mg
twice daily, and increased every 4 days depending on the
response. If haloperidol is not helpful, treatment with increasing
doses of fluphenazine in a similar dose, eg, 1 mg twice daily,
sometimes helps. Several recent reports suggest that
olanzapine may also be useful; the dose varies with the
patient, but 10 mg daily is often sufficient, although doses as
high as 30 mg daily are sometimes required. The
pharmacokinetics and clinical properties of these drugs are
considered in greater detail elsewhere in this book. Selective
serotonin reuptake inhibitors may reduce depression,
aggression, and agitation. However, strong CYP2D6 inhibitors
should be used with caution, as it may be necessary to decrease
the dose of tetrabenazine taken concurrently.
• Other important aspects of management include genetic
counseling, speech therapy, physical and occupational therapy,
dysphagia precautions, and provision of social services.
II. WILSON’S DISEASE
• A recessively inherited (13q14.3–q21.1) disorder of copper
metabolism, Wilson’s disease is characterized biochemically by
reduced serum copper and ceruloplasmin concentrations,
pathologically by markedly increased concentration of copper in
the brain and viscera, and clinically by signs of hepatic and
neurologic dysfunction. Neurologic signs include tremor,
choreiform movements, rigidity, hypokinesia, and dysarthria and
dysphagia. Siblings of affected patients should be screened for
asymptomatic Wilson’s disease.
• Treatment involves the removal of excess copper, followed by
maintenance of copper balance. Dietary copper should also be
kept below 2 mg daily. Penicillamine (dimethylcysteine) has
been used for many years as the primary agent to remove
copper. It is a chelating agent that forms a ring complex with
copper. It is readily absorbed from the gastrointestinal tract and
rapidly excreted in the urine. A common starting dose in adults
is 500 mg three or four times daily. After remission occurs, it
may be possible to lower the maintenance dose, generally to not
less than 1 g daily, which must thereafter be continued
indefinitely. Adverse effects include nausea and vomiting,
nephrotic syndrome, a lupus-like syndrome, pemphigus,
myasthenia, arthropathy, optic neuropathy, and various blood
dyscrasias. In about 10% of instances, neurologic worsening
Lea MARTIN
 occurs with penicillamine. Treatment should be monitored by
frequent urinalysis and complete blood counts.
• Trientine hydrochloride, another chelating agent, is
preferred by many over penicillamine because of the lesser
likelihood of drug reactions or neurologic worsening. It may be
used in a daily dose of 1–1.5 g. Trientine appears to have few
adverse effects other than mild anemia due to iron deficiency in
a few patients. Tetrathiomolybdate may be better than
trientine for preserving neurologic function in patients with
neurologic involvement and is taken both with and between
meals. It is not yet commercially available.
• Zinc acetate administered orally increases the fecal excretion of
copper and can be used in combination with these other agents.
The dose is 50 mg three times a day. Zinc sulfate (200 mg/d
orally) has also been used to decrease copper absorption. Zinc
blocks copper absorption from the gastrointestinal tract by
induction of intestinal cell metallothionein. Its main advantage
is its low toxicity compared with that of other anticopper agents,
although it may cause gastric irritation when introduced.
• Liver transplantation is sometimes necessary. The role of
hepatocyte transplantation and gene therapy is currently under
investigation.
III. ANTIPSYCHOTICS
INDICATIONS
A. PSYCHIATRIC INDICATIONS
• Schizophrenia is the primary indication for antipsychotic
agents. However, in the last decade, the use of antipsychotics
in the treatment of mood disorders such as bipolar disorder
(BP1), psychotic depression, and treatment-resistant depression
has eclipsed their use in the treatment of schizophrenia.
• Catatonic forms of schizophrenia are best managed by
intravenous benzodiazepines. Antipsychotic drugs may be
needed to treat psychotic components of that form of the illness
after catatonia has ended, and they remain the mainstay of
treatment for this condition. Unfortunately, many patients show
little response, and virtually none show a complete response.
• Antipsychotic drugs are also indicated for schizoaffective
disorders, which share characteristics of both schizophrenia
and affective disorders. No fundamental difference between
these two diagnoses has been reliably demonstrated. It is most
likely that they are part of a continuum with bipolar psychotic
disorder. The psychotic aspects of the illness require treatment
with antipsychotic drugs, which may be used with other drugs
such as antidepressants, lithium, or valproic acid.
• The manic phase in bipolar affective disorder often requires
treatment with antipsychotic agents, although lithium or valproic
acid supplemented with high-potency benzodiazepines (eg,
lorazepam or clonazepam) may suffice in milder cases. Recent
controlled trials support the efficacy of monotherapy with
atypical antipsychotics in the acute phase (up to 4 weeks) of
mania. In addition, several second generation antipsychotics are
approved in the maintenance treatment of bipolar disorder.
They appear more effective in preventing mania than in
preventing depression. As mania subsides, the antipsychotic
drug may be withdrawn,
although maintenance treatment with atypical antipsychotic
agents has become more common. Nonmanic excited states
may also be managed by antipsychotics, often in combination
with benzodiazepines.
• An increasingly common use of antipsychotics is in the
monotherapy of acute bipolar depression and the adjunctive
PHARMA | 2 of 9
use of antipsychotics with antidepressants in the treatment of
unipolar depression. Several antipsychotics are now FDA
approved in the management of bipolar depression including
quetiapine, lurasidone, and olanzapine (in a combination
formulation with fluoxetine). The antipsychotics appear more
consistently effective than antidepressants in the treatment of
bipolar depression and also do not increase the risk of inducing
mania or increasing the frequency of bipolar cycling. Likewise,
several antipsychotics, including aripiprazole, quetiapine, and
olanzapine, are now approved in the adjunctive treatment of
unipolar depression. Although many drugs are combined with
antidepressants in the adjunctive treatment of major
depression, antipsychotic agents are the only class of agents
that have been formally evaluated for possible approval for this
purpose. Residual symptoms and partial remission are common,
with antidepressants showing consistent benefit in improving
overall antidepressant response.
• Some of the intramuscular antipsychotics have been approved
for the control of agitation associated with bipolar disorder and
schizophrenia. Antipsychotics such as haloperidol have long
been used in the ICU setting to manage agitation in delirious
and postsurgical patients. The intramuscular forms of
ziprasidone and aripiprazole have been shown to improve
agitation within 1–2 hours, with fewer extrapyramidal symptoms
than typical agents such as haloperidol.
• Other indications for the use of antipsychotics include
Tourette’s syndrome and possibly disturbed behavior in
patients with Alzheimer’s disease. However, controlled trials
of antipsychotics in the management of behavioral symptoms in
dementia patients have generally not demonstrated efficacy.
Furthermore, second-generation as well as some first-
generation antipsychotics have been associated with increased
mortality in these patients. Antipsychotics are not indicated for
the treatment of various withdrawal syndromes, eg, opioid
withdrawal. In small doses, antipsychotic drugs have been
promoted (wrongly) for the relief of anxiety associated with
minor emotional disorders. The antianxiety sedatives (see
Chapter 22) are preferred in terms of both safety and
acceptability to patients.
B. NONPSYCHIATRIC INDICATIONS
• Most older typical antipsychotic drugs, with the exception of
thioridazine, have a strong antiemetic effect. This action is due
to dopamine-receptor blockade, both centrally (in the
chemoreceptor trigger zone of the medulla) and peripherally (on
receptors in the stomach). Some drugs, such as
prochlorperazine and benzquinamide, are promoted solely
as antiemetics.
• Phenothiazines with shorter side chains have considerable H1-
receptor-blocking action and have been used for relief of
pruritus or, in the case of promethazine, as preoperative
sedatives. The butyrophenone droperidol is used in
combination with an opioid, fentanyl, in neuroleptanesthesia.
The use of these drugs in anesthesia practice is described in
Chapter 25.
DRUG CHOICE
• Choice among antipsychotic drugs is based mainly on
differences in adverse effects and possible differences in
efficacy. In addition, cost and the availability of a given agent
on drug formularies also influence the choice of a specific
antipsychotic. Because use of the older drugs is still widespread,
Lea MARTIN
 especially for patients treated in the public sector, knowledge of or less and the lower risk of tardive dyskinesia have contributed
such agents as chlorpromazine and haloperidol remains to its widespread use. Olanzapine and quetiapine may have even
relevant. Thus, one should be familiar with one member of each lower risk and have also achieved widespread use.
of the three subfamilies of phenothiazines, a member of the
thioxanthene and butyrophenone group, and all of the newer DOSAGE
compounds— clozapine, risperidone, olanzapine, quetiapine,
ziprasidone, and aripiprazole. Each may have special
advantages for selected patients. A representative group of
antipsychotic drugs is presented in Table 29–3.
• For approximately 70% of patients with schizophrenia, and
probably for a similar proportion of patients with bipolar disorder
with psychotic features, typical and atypical antipsychotic drugs
are of equal efficacy for treating positive symptoms. However,
the evidence favors atypical drugs for benefit for negative
symptoms and cognition, for diminished risk of tardive
dyskinesia and other forms of EPS, and for lesser increases in
prolactin levels.
• Some of the atypical antipsychotic drugs produce more weight
gain and increases in lipids than some typical antipsychotic
drugs. A small percentage of patients develop diabetes mellitus,
most often seen with clozapine and olanzapine. Ziprasidone is
the atypical drug causing the least weight gain. Risperidone,
paliperidone, and aripiprazole usually produce small increases in
weight and lipids. Asenapine and quetiapine have an
intermediate effect. Clozapine and olanzapine frequently result
in large increases in weight and lipids. Thus, these drugs should
be considered as second- line drugs unless there is a specific
indication. That is the case with clozapine, which at high doses
(300–900 mg/d) is effective in the majority of patients with
schizophrenia refractory to other drugs, provided that treatment
is continued for up to 6 months. Case reports and several clinical
trials suggest that high-dose olanzapine, ie, doses of 30–45
mg/d, may also be efficacious in refractory schizophrenia when • The range of effective dosages among various antipsychotic
given over a 6-month period. agents is broad. Therapeutic margins are substantial. At
• Clozapine is the only atypical antipsychotic drug indicated to appropriate dosages, antipsychotics—with the exception of
reduce the risk of suicide. All patients with schizophrenia who clozapine and perhaps olanzapine—are of equal efficacy in
have made life-threatening suicide attempts should be seriously broadly selected groups of patients. However, some patients
evaluated for switching to clozapine. who fail to respond to one drug may respond to another; for this
• New antipsychotic drugs have been shown in some trials to be reason, several drugs may have to be tried to find the one most
more effective than older ones for treating negative symptoms. effective for an individual patient. Patients who have become
The floridly psychotic form of the illness accompanied by refractory to two or three antipsychotic agents given in
uncontrollable behavior probably responds equally well to all substantial doses become candidates for treatment with
potent antipsychotics but is still frequently treated with older clozapine or high-dose olanzapine. Thirty to fifty percent of
drugs that offer intramuscular formulations for acute and patients previously refractory to standard doses of other
chronic treatment. Moreover, the low cost of the older drugs antipsychotic drugs respond to these drugs. In such cases, the
contributes to their widespread use despite their risk of adverse increased risk of clozapine can well be justified.
EPS effects. Several of the newer antipsychotics, including • Some dosage relationships between various antipsychotic drugs,
clozapine, risperidone, and olanzapine, show superiority over as well as possible therapeutic ranges, are shown in Table 29–
haloperidol in terms of overall response in some controlled trials. 4.
More comparative studies with aripiprazole are needed to
evaluate its relative efficacy. Moreover, the superior adverse-
effect profile of the newer agents and low to absent risk of
tardive dyskinesia suggest that these should provide the first
line of treatment.
IV. ANTIDEPRESSANTS
• The best guide for selecting a drug for an individual patient is CLINICAL INDICATIONS
the patient’s past responses to drugs. At present, clozapine is A. DEPRESSION
limited to those patients who have failed to respond to • The FDA indication for the use of the antidepressants in the
substantial doses of conventional antipsychotic drugs. The treatment of major depression is fairly broad. Most
agranulocytosis and seizures associated with this drug prevent antidepressants are approved for both acute and long-term
more widespread use. Risperidone’s superior adverse-effect treatment of major depression. Acute episodes of MDD tend to
profile (compared with that of haloperidol) at dosages of 6 mg/d

PHARMA | 3 of 9 Lea MARTIN

 last about 6–14 months untreated, but at least 20% of episodes
last 2 years or longer.
• The goal of acute treatment of MDD is remission of all
symptoms. Since antidepressants may not achieve their
maximum benefit for 1–2 months or longer, it is not unusual for
a trial of therapy to last 8–12 weeks at therapeutic doses. The
antidepressants are successful in achieving remission in about
30–40% of patients within a single trial of 8–12 weeks. If an
inadequate response is obtained, therapy is often switched to
another agent or augmented by addition of another drug. For
example, bupropion, an atypical antipsychotic, or mirtazapine
might be added to an SSRI or SNRI to augment antidepressant
benefit if monotherapy is unsuccessful. Seventy to eighty
percent of patients are able to achieve remission with sequenced
augmentation or switching strategies. Once an adequate
response is achieved, continuation therapy is recommended for
a minimum of 6–12 months to reduce the substantial risk of
relapse.
• Approximately 85% of patients who have a single episode of
MDD will have at least one recurrence in a lifetime. Many
patients have multiple recurrences, and these recurrences may
progress to more serious, chronic, and treatment-resistant
episodes. Thus, it is not unusual for patients to require
maintenance treatment to prevent recurrences. Although
maintenance treatment studies of more than 5 years are
uncommon, long-term studies with TCAs, SNRIs, and SSRIs
suggest a significant protective benefit when given chronically.
Thus, it is commonly recommended that patients be considered
for long-term maintenance treatment if they have had two or
more serious MDD episodes in the previous 5 years or three or
more serious episodes in a lifetime.
• It is not clear whether antidepressants are useful for all subtypes
of depression. For example, patients with bipolar depression
may not benefit much from antidepressants even when added
to mood stabilizers. In fact, the antidepressants are sometimes
associated with switches into mania or more rapid cycling. There
has also been some debate about the overall efficacy of
antidepressants in unipolar depression, with some meta-
analyses showing large effects and others showing more modest
effects. Although this debate is not likely to be settled
immediately, there is little debate that antidepressants have
important benefits for most patients.
• Psychotherapeutic interventions such as cognitive behavioral
therapy appear to be as effective as antidepressant treatment
for mild to moderate forms of depression. However, cognitive
behavioral therapy tends to take longer to be effective and is
generally more expensive than antidepressant treatment.
Psychotherapy is often combined with antidepressant
treatment, and the combination appears more effective than
either strategy alone.
B. ANXIETY DISORDERS
• After major depression, anxiety disorders represent the most
common application of antidepressants. A number of SSRIs and
SNRIs have been approved for all the major anxiety disorders,
including PTSD, OCD, social anxiety disorder, GAD, and panic
disorder. Panic disorder is characterized by recurrent episodes
of brief overwhelming anxiety, which often occur without
PHARMA | 4 of 9
precipitant. Patients may begin to fear having an attack, or they
avoid situations in which they might have an attack. In contrast,
GAD is characterized by a chronic, free-floating anxiety and
undue worry that tends to be chronic in nature. Although older
antidepressants and drugs of the sedative-hypnotic class are still
occasionally used for the treatment of anxiety disorders, SSRIs
and SNRIs have largely replaced them.
• The benzodiazepines (see Chapter 22) provide much more rapid
relief of both generalized anxiety and panic than do any of the
antidepressants. However, the antidepressants appear to be at
least as effective as, and perhaps more effective than,
benzodiazepines in the long-term treatment of these anxiety
disorders. Furthermore, antidepressants do not carry the risks
of dependence and tolerance that may occur with the
benzodiazepines.
• OCD is known to respond to serotonergic antidepressants. It is
characterized by repetitive anxiety-provoking thoughts
(obsessions) or repetitive behaviors aimed at reducing anxiety
(compulsions). Clomipramine and several of the SSRIs are
approved for the treatment of OCD, and they are moderately
effective. Behavior therapy is usually combined with the
antidepressant for additional benefits.
• Social anxiety disorder is an uncommonly diagnosed but a fairly
common condition in which patients experience severe anxiety
in social interactions. This anxiety may limit their ability to
function adequately in their jobs or interpersonal relationships.
Several SSRIs and venlafaxine are approved for the treatment
of social anxiety. The efficacy of the SSRIs in the treatment of
social anxiety is greater in some studies than their efficacy in
the treatment of MDD.
• PTSD is manifested when a traumatic or life-threatening event
results in intrusive anxiety-provoking thoughts or imagery,
hypervigilance, nightmares, and avoidance of situations that
remind the patient of the trauma. SSRIs are considered first-line
treatment for PTSD and can benefit a number of symptoms
including anxious thoughts and hypervigilance. Other
treatments, including psychotherapeutic interventions, are
usually required in addition to antidepressants.
C. PAIN DISORDERS
• It has been known for over 40 years that antidepressants
possess analgesic properties independent of their mood effects.
TCAs have been used in the treatment of neuropathic and other
pain conditions since the 1960s. Medications that possess both
norepinephrine and 5-HT reuptake blocking properties are often
useful in treating pain disorders. Ascending corticospinal
monoamine pathways appear to be important in the
endogenous analgesic system. In addition, chronic pain
conditions are commonly associated with major depression.
TCAs continue to be commonly used for some of these
conditions, and SNRIs are increasingly used. In 2010, duloxetine
was approved for the treatment of chronic joint and muscle pain.
As mentioned earlier, milnacipran is approved for the treatment
of fibromyalgia in the USA and for MDD in other countries. Other
SNRIs, eg, desvenlafaxine, are being investigated for a variety
of pain conditions from postherpetic neuralgia to chronic back
pain.
D. PREMENSTRUAL DYSPHORIC DISORDER
• Approximately 5% of women in the child-bearing years will have
prominent mood and physical symptoms during the late luteal
phase of almost every cycle; these may include anxiety,
Lea MARTIN
 depressed mood, irritability, insomnia, fatigue, and a variety of
other physical symptoms. These symptoms are more severe
than those typically seen in premenstrual syndrome (PMS) and
can be quite disruptive to vocational and interpersonal activities.
The SSRIs are known to be beneficial to many women with
PMDD, and fluoxetine and sertraline are approved for this
indication. Treating for 2 weeks out of the month in the luteal
phase may be as effective as continuous treatment. The rapid
effects of SSRIs in PMDD may be associated with rapid increases
in pregnenolone levels.
E. SMOKING CESSATION
• Bupropion was approved in 1997 as a treatment for smoking
cessation. Approximately twice as many people treated with
bupropion as with placebo have a reduced urge to smoke. In
addition, patients taking bupropion appear to experience fewer
mood symptoms and possibly less weight gain while
withdrawing from nicotine dependence. Bupropion appears to
be about as effective as nicotine patches in smoking cessation.
The mechanism by which bupropion is helpful in this application
is unknown, but the drug may mimic nicotine’s effects on
dopamine and norepinephrine and may antagonize nicotinic
receptors. Nicotine is also known to have antidepressant effects
in some people, and bupropion may substitute for this effect.
• Other antidepressants may also have a role in the treatment of
smoking cessation. Nortriptyline has been shown to be helpful
in smoking cessation, but the effects have not been as
consistent as those seen with bupropion.
F. EATING DISORDERS
• Bulimia nervosa and anorexia nervosa are potentially
devastating disorders. Bulimia is characterized by episodic
intake of large amounts of food (binges) followed by ritualistic
purging through emesis, the use of laxatives, or other methods.
Medical complications of the purging, such as hypokalemia, are
common and dangerous. Anorexia is a disorder in which reduced
food intake results in a loss of weight of 15% or more of ideal
body weight, and the person has a morbid fear of gaining weight
and a highly distorted body image. Anorexia is often chronic and
may be fatal in 10% or more of cases.
• Antidepressants appear to be helpful in the treatment of bulimia
but not anorexia. Fluoxetine was approved for the treatment of
bulimia in 1996, and other antidepressants have shown benefit
in reducing the binge-purge cycle. The primary treatment for
anorexia at this time is refeeding, family therapy, and cognitive
behavioral therapy.
• Bupropion may have some benefits in treating obesity.
Nondepressed, obese patients treated with bupropion were able
to lose somewhat more weight and maintain the loss relative to
a similar population treated with placebo. However, the weight
loss was not robust, and there appear to be more effective
options for weight loss.
G. OTHER USES FOR ANTIDEPRESSANTS
• Antidepressants are used for many other on- and off-label
applications. Enuresis in children is an older labeled use for some
TCAs, but they are less commonly used now because of their
side effects. The SNRI duloxetine is approved in Europe for the
treatment of urinary stress incontinence. Many of the
serotonergic antidepressants appear to be helpful for treating
vasomotor symptoms in perimenopause. Desvenlafaxine is
under consideration for FDA approval for the treatment of these
vasomotor symptoms, and studies have suggested that SSRIs,
PHARMA | 5 of 9
venlafaxine, and nefazodone may also provide benefit. Although
serotonergic antidepressants are commonly associated with
inducing sexual adverse effects, some of these effects might
prove useful for some sexual disorders. For example, SSRIs are
known to delay orgasm in some patients. For this reason, SSRIs
are sometimes used to treat premature ejaculation. In addition,
bupropion has been used to treat sexual adverse effects
associated with SSRI use, although its efficacy for this use has
not been consistently demonstrated in controlled trials.
CHOOSING AN ANTIDEPRESSANT
• The choice of an antidepressant depends first on the indication.
Not all conditions are equally responsive to all antidepressants.
However, in the treatment of MDD, it is difficult to demonstrate
that one antidepressant is consistently more effective than
another. Thus, the choice of an antidepressant for the treatment
of depression rests primarily on practical considerations such as
cost, availability, adverse effects, potential drug interactions, the
patient’s history of response or lack thereof, and patient
preference. Other factors such as the patient’s age, gender, and
medical status may also guide antidepressant selection. For
example, older patients are particularly sensitive to the
anticholinergic effects of the TCAs.
• On the other hand, the CYP3A4-inhibiting effects of the SSRI
fluvoxamine may make this a problematic choice in some older
patients because fluvoxamine may interact with many other
medications that an older patient may require. There is some
suggestion that female patients may respond to and tolerate
serotonergic better than noradrenergic or TCA antidepressants,
but the data supporting this gender difference have not been
consistent. Patients with narrow-angle glaucoma may have an
exacerbation with noradrenergic antidepressants, whereas
bupropion and other antidepressants are known to lower the
seizure threshold in epilepsy patients.
• At present, SSRIs are the most commonly prescribed first-line
agents in the treatment of both MDD and anxiety disorders.
Their popularity comes from their ease of use, tolerability, and
safety in overdose. The starting dose of the SSRIs is usually the
same as the therapeutic dose for most patients, and so titration
may not be required. In addition, most SSRIs are now
generically available and inexpensive. Other agents, including
the SNRIs, bupropion, and mirtazapine, are also reasonable
first-line agents for the treatment of MDD. Bupropion,
mirtazapine, and nefazodone are the antidepressants with the
least association with sexual side effects and are often
prescribed for this reason. However, bupropion is not thought
to be effective in the treatment of the anxiety disorders and may
be poorly tolerated in anxious patients. The primary indication
for bupropion is in the treatment of major depression, including
seasonal (winter) depression. Off-label uses of bupropion
include the treatment of attention deficit hyperkinetic disorder
(ADHD), and bupropion is commonly combined with other
antidepressants to augment therapeutic response. The primary
indication for mirtazapine is in the treatment of major
depression. However, its strong antihistamine properties have
contributed to its occasional use as a hypnotic and as an
adjunctive treatment to more activating antidepressants.
• The TCAs and MAOIs are now relegated to second- or thirdline
treatments for MDD. Both the TCAs and the MAOIs are
potentially lethal in overdose, require titration to achieve a
therapeutic dose, have serious drug interactions, and have
many troublesome adverse effects. As a consequence, their use
Lea MARTIN
 in the treatment of MDD or anxiety is now reserved for patients
who have been unresponsive to other agents. Clearly, there are
patients whose depression responds only to MAOIs or TCAs.
Thus, TCAs and MAOIs are probably underused in treatment-
resistant depressed patients.
• The use of antidepressants outside the treatment of MDD tends
to require specific agents. For example, the TCAs and SNRIs
appear to be useful in the treatment of pain conditions, but
other antidepressant classes appear to be far less effective.
SSRIs and the highly serotonergic TCA, clomipramine, are
effective in the treatment of OCD, but noradrenergic
antidepressants have not proved to be as helpful for this
condition. Bupropion and nortriptyline have usefulness in the
treatment of smoking cessation, but SSRIs have not been
proven useful. Thus, outside the treatment of depression, the
choice of antidepressant is primarily dependent on the known
benefit of a particular antidepressant or class for a particular
indication.

DOSING
• The optimal dose of an antidepressant depends on the indication
and on the patient. For SSRIs, SNRIs, and a number of newer
agents, the starting dose for the treatment of depression is
usually a therapeutic dose (Table 30–3). Patients who show little
or no benefit after at least 4 weeks of treatment may benefit
from a higher dose even though it has been difficult to show a
clear advantage for higher doses with SSRIs, SNRIs, and other
newer antidepressants. The dose is generally titrated to the
maximum dosage recommended or to the highest dosage
tolerated if the patient is not responsive to lower doses. Some
patients may benefit from doses lower than the usual minimum
recommended therapeutic dose. TCAs and MAOIs typically
require titration to a therapeutic dosage over several weeks.
Dosing of the TCAs may be guided by monitoring TCA serum
levels.
• Some anxiety disorders may require higher doses of
antidepressants than are used in the treatment of major
depression. For example, patients treated for OCD often require
maximum or somewhat higher than maximum recommended
MDD doses to achieve optimal benefits. Likewise, the minimum
dose of paroxetine for the effective treatment of panic disorder
is higher than the minimum dose required for the effective
treatment of depression.
• In the treatment of pain disorders, modest doses of TCAs are
often sufficient. For example, 25–50 mg/d of imipramine might
be beneficial in the treatment of pain associated with a
neuropathy, but this would be a subtherapeutic dose in the
treatment of MDD. In contrast, SNRIs are usually
prescribed in pain disorders at the same doses used in the
treatment of depression.

ADDITIONAL TABLES

PHARMA | 6 of 9 Lea MARTIN

 ANTIDEPRESSANT

PHARMA | 7 of 9 Lea MARTIN

 ANTIPSYCHOTICS

PHARMA | 8 of 9 Lea MARTIN

PHARMA | 9 of 9 Lea MARTIN
 M.01L DOH APPROVED MEDICINAL PLANTS
Dr. Buñag, Dr. Yasay | Midterm 2019

DOH-APPROVED ACTIVE PREPARATION INDICATION/S MODE OF ADVERSE EFFECTS & DRUG-DRUG

MEDICINAL PLANT CONSTITUENTS ACTION CONTRAINDICATIONS INTERACTION
AKAPULKO Chrysophanic acid  Soaps  Tinea infection  Unknown No sufficient studies  Anticoagulant
(fungicidal activity)  Creams  Eczema done to investigate the therapy:
 Shampoo  scabies adverse or side effects ANTAGONISTIC
 Lotion during pregnancy and effect due to vitamin
 Ointment breast feeding. It is K content
recommended to avoid  Treatment for
its use. autoimmune
disease:
SN: Cassia alata CANAVININE
EN: Ringworm content may worsen
bush/shrub, wild senna symptoms of SLE
Distribution:  Medications for
Abundant throughout DM, HTN, etc.: May
the Philippines in counteract or
settled areas at low and aggravate the
medium altitudes effectiveness
AMPALAYA Momordicin  Ampalaya tops: Alternative  Increase insulin No known toxicity/side Caution in patients
Steam (upper 4 treatment for secretion effects/adverse effects using:
leaves) and eat half a Diabetes Mellitus  Decrease intestinal  Oral hypoglycemic
cup 2x daily. Type 2 glucose drugs: May
 Decoction: Boil 6  Increase peripheral aggravate
tbsp of finely chopped uptake and hypoglycemia
leaves in 2 glasses of utilization of glucose  Drugs that impairs
water over low fire (15 hepatic function
mins). Drink 1/3 cup,
3x times a day, 30
SN: Momordica mins ac. Don't use
charantia aluminum pots (clay or
EN: Bitter melon, Bitter enamel only)
gourd, Climbing vine  Marketed as food
Distribution: Asia, supplements
South Africa and South
America. In the
Philippines, the
commercial cultivation
of the crop is
concentrated to Region
II and IV
BAWANG Organosulfur  Wound cleaning:  Helps lower LDL,  Endothelium-  Nausea: 6% Bleeding tendencies:
compounds: ALLICIN Crush and juice the blood pressure dependent  Hypotension: 1.3%  Anticoagulants
(unusual odor) bulb then apply. You  Remedy for vasodilation  Allergy: 1.1% (warfarin)
Precursor: ALLIIN may cover the afflicted arteriosclerosis  BP lowering effect  Bleeding: rare

PHARMA | 1 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON

 area with a gauze and  Boosts immune  HMG-CoA o Causes bleeding  Antiplatelet drugs
bandage. system reductase tendency (aspirin)
 Sore throat: Peel the  Antioxidant, inhibitor o For patients taking
skin and chew for antibacterial, o Cholesterol- anticoagulants and
several minutes. anticoagulant lowering effect antiplatelet drugs
Swallow the juice. properties (like statins for (Warfarin, ASA)
 Toothaches: Crush  Cough and cold hypercholesterol Strict monitoring of BP
then bite garlic. remedy emia) and bleeding episodes
SN: Allium sativum  Athlete’s foot: Soak  Relives sore  Significant reduction
EN: Garlic feet in salty water then throat in cholesterol and TG
Distribution: Ilocos, apply garlic juice. Do  Aids in TB but its effect in LDL
Southern Tagalog and this 3X day for a week. treatment and HDL is not
central Luzon regions  Pain (arthritis,  Relieves significant
toothache, headache, rheumatism pain,  Inhibit TXA2
and rheumatism): toothaches synthesis
Cloves of may be  Kills skin fungus
crushed and applied
to affected areas
 Fever: Decoction of
the bulbs and leaves.
 Nasal congestion:
Steam and inhale
(vinegar + chopped
garlic + water)
BAYABAS  Alkaloids  Toothache and  Antibacterial  Microbicidal/  Consumed  nuclear medicine
 Flavonoids wound cleaning  Antifungal Antidiarrheal: excessively: procedures: Affect
(antioxidant) (prevent infection,  Antioxidant Treatment option for Frequent headaches membrane
 Glycosides facilitate healing):  Antihypertensive diarrhea caused by may occur structures in ion
 Polyphenols, phenols Decoction or infusion  Antidiarrheal E. coli or S. aureus-  Overeating the fruit transport causing
 Reducing of fresh leaves  Hypoglycemic produced toxins,  rapid increase in alteration in
compounds  Diarrhea:Decoction  Antitumor Shigella spp., Vibrio fiber leading to radiolabelling of
 Saponins of bark and leaves  Trypanocidal spp., B-strep, P digestion-related side blood constituents
 Tannins o Boil 4 to 6 tbsp of  Antiproliferative aeruginosa and B issues (gas, bloating, with Tc99m
 Anthocyanins chopped leaves in  Antispasmodic subtilis diarrhea)
 Carotenoids 18 oz of water for  Hypocholesterole  Antioxidant  Hyperglycemic
SN: Psidium guajava  Essential oils 15minutes. Strain mic action: Radical effect: Diabetic
EN: Guava,  Fatty acids and cool. Drink 1/4  Hypoglycemic scavenging (hydroxyl patients should peel
Round/Tropical guava  Lectins of the decoction  Anti-solar radicals) and off the fruit before
Distribution: Widely  Triterpenes every 3-4hrs.  Analgesic inhibiting lipid consumption.
distributed throughout  Vitamin C o Bark (chronic  Antipyretic peroxidation.  Fruit peel: Useful for
the Philippines in all diarrhea): ½ oz of  Hematopoietic  Antidiabetic effect hypoglycemia induced
islands and provinces. the bark or root  Anti-plaque (type 2 diabetic by excess insulin or
bark in 6 oz of  Protective: mice model): In other hypoglycemic
water is boiled nephro, hepato, part, mediated via drugs
down to 3 oz, and gastro the inhibition of
given in teaspoon  Immunomodulat PTP1B (protein
doses. Also used for ory properties

PHARMA | 2 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON

 prolapsus ani of tyrosine
children. phosphatase 1B)
 Toothache: Chew 2-3  Trypanocidal
young leaves and put (flavonoids,
into the tooth cavity tannins): Broad
 Swollen gums: antimicrobial and
Decoction of rootbark iron chelating activity
as mouthwash 3x daily (effective way of
 Skin ulcers, pruritic killing
or infected wounds: trypanosomes).
Apply decoction of  Antihypertensive/
leaves or unripe fruit Antidiarrheal:
as wash or the leaf Inhibition of
poultice on the wound intracellular calcium
 Vaginal wash or release from the
douche: Warm sarcoplasmic
decoction of leaves reticulum of skeletal
(after childbirth) muscle
 Hyperactive Gut
Disorders
(diarrhea and gut
spasm): Ca++
antagonist-like
constituent/s
possess wound
healing inhibitory
effect on gut motility
 Quercetin:
Spasmolytic and
antidiarrheal
 Antitumor/Antica
ncer: Depressing Tr
cells (regulatory);
Inhibit growth of B16
melanoma cells.
 Potential
Cytotoxic Effects:
Decrease in cell
viability and growth
compared to control
and corticosteroids;
Acceleration of
wound healing
LAGUNDI  n-hexadecanoic  Wash and clean the  Skin disease  Inhibits  Special precautions for  Paracetamol: May
acid (potent wound with decoction (dermititis, phosphodiesteras patients with allergy have decreased
bronchodilator)  Crush leaves and apply scabies ulcer and e  increase in to the plant and for plasma
on forehead eczema) intracellular cAMP use in pregnancy concentration

PHARMA | 3 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON

  Chrysoplenol D  Pound leaves and  Headache and cGMP, and lactation: Safety
(anti-histamine and apply on affected area  Rheumatism promoting smooth among pregnant and
muscle relaxant  Boil the chopped  Sprain muscle relaxation lactating women has
properties) leaves in 2 glasses of  Contusions and reduced not been studied.
water for 10-15 mins  Insect bites inflammation
then drink ½ cup TID  Asthma or cough  Calcium blocking
 Boil leaves and drink  Fever effect induces
concoction  Dysentery smooth muscle
 OTC: syrup, tablet  Colds relaxation leading to
SN: Vitex negundo vasodilation
 Pain
EN: Five-leaved chaste
tree, cut leaf vitex
Distribution: Native
to tropical Eastern and
Southern Africa and
Asia. It is widely
cultivated and
distributed in the
Philippines.
NIYOG-NIYOGAN  Polyphenols (Anti-  Seeds  Anti-Diarrheal  Prevention of  Diarrhea No known drug-drug
inflammatory) (anthelmintic):  Anti- glucose uptake  Abdominal pain interactions
 Alkaloids o Eaten raw 2hrs Helminthic and tubulin  Abdominal distention
 Carbohydrates before the patient’s (Ascariasis): polymerization   Hiccups
 Proteins (amino last meal of the day Cure rate 85% Vs damage to the  Allergic reactions
acids) o Adults: 10 seeds pyrantel mucopolysaccharide when applied to the
 Saponins o 4-7y/o: 4 seeds pamoate: 90% membrane of the skin (rare)
 Glycosides only  Anti- worms  paralysis
SN: Quisqualis indica
 Steroids o 8-9y/o: 6 seeds Inflammatory and death.
EN: Yesterday, Today,
 Tannins o 10-12y/o: 7 seeds (Nephritis)  Anti-AChase
Tomorrow; Burma or
 Flavonoids  Decoctions  Antimicrobial inhibitor
Rangoon Creeper, Liane
 Phenolic compounds o Roots: Remedy for  Analgesic o Methanolic
Vermifuge and Chinese
rheumatism  Antioxidant extract of the
honeysuckle
o Fruits: Relief of flower dose-
Distribution: Endemic
toothaches dependently
in the Philippines
inhibits
acetylcholinestera
se activity
SAMBONG  Volatile oil (leaves):  Leaves as tea: Fresh  Diuretic Chemolysis of  Special precaution and Antagonistic effect:
o Camphor leaves are gathered (hypertension Calcium-containing warnings: Not enough  Warfarin
o Limonene and chopped into small and fluid stones are known about the  Chemotherapeutic
o Traces of borneol, pieces, and then retention) use during drugs
saponin, washed under running  Dissolution of pregnancy and  Immunosuppressant
sesquiterpene, water thoroughly. kidney stones: breast-feeding s
and tannin. Chopped leaves are Avert or delay the  Allergic reaction for
 L-borneol: Most tossed into a liter of need for dialysis sensitive individual
abundant and active boiling water. Leaves or organ (itching and skin
SN: Blumea constituent are steeped for 10 transplantation irritation)
balsamifera
PHARMA | 4 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON
EN: Aromatic shrub,  Terpenoids minutes then the tea is
Ngai camphor, Blumea  Fatty acids allowed to cool. The
camphor, Ragweed  Phenols tea may be taken 4x a
plant  Alcohols day.
Distribution:  Aldehydes  Commercial
Grassland and waste  Ethers preparations:
places in the Philippines  Ketones Capsules, tablets and
 Pyridines tea
 Furans
 Alkanes
 Flavonoids
 Sterols
TSAANG-GUBAT  Rosmarinic acid  Decoction  Stomach ache  Rosmarinic acid and  In rare cases, it causes  Not known to be
(antispasmodic)  Tea preparation  Allergic skin microphyllone that allergic reactions harmful when taken
 Microphyllone  Herbal wash reactions counter the when applied to the in recommended
(analgesic)  Herbal gargle histamine release skin dosages
 Fluoride from mast cells  Synergism with
(mouthwash) that cause type-1 sambong and
reactions (mast cell lagundi  anti-
stabilizer) allergic effects
SN: Carmona retusa  Intestinal muscle potentiated
EN: Philippine tea tree, relaxant
wild tea
Distribution: Grows
wild in the tropical
climate of India, Sri
Lanka and Philippines.
ULASIMANG-BATO  Alkaloids  Rheumatic pains  Asthma  Anti-inflammatory  No reported side  There are still no
(pancit-pancitan)  Flavonoids and gout:  Wound activity: effects for most documented drug-
 Saponins o Fresh salad  Fever Interference with PG people. to-drug interactions
 Terpenoids o Infusion or  Hemorrhoid pain synthesis  Allergic reactions: in the medical
 Steroids decoction: Boil 1  Hypertension  Patuloside A Strong mustard-like literature
 Glycosides cup of leaves/stem  Diarrhea (xanthone odor  asthma-like  Avoid using with
 Compounds in 2 cups of water  Snake bite glycoside): Broad symptoms in patients anti-inflammatory
identified  Skin disorders:  Measles spectrum with known and diuretics
o dill apiole Pound the leaves  Rheumatism and antibacterial  hypersensitivity
o phytol and/or the stalks and arthritis growth inhibition
SN: Peperomia
o stigmasterol make a poultice (boil in  Hyperuricemia  Alternative to
pellucida
o sitosterol water for a minute or  Skin disorders: allopurinol to
EN: Pepper elder,
o secolignans two then pounded) abscesses, control uric acid
Shining bush,
o tetrahydrofuran then applied directly to pimples and boils levels in the blood
Peperomia
lignans the afflicted area.  Headaches  Dose-dependent
Distribution: Endemic
o highly  Headaches: Heat a  Abdominal pain depressant
in the Philippines
methoxylated couple of leaves in hot  Kidney problems activity: Beneficial
dihydronaphthale water, bruise the for excessive mental
none surface and apply on excitement disorder
o peperomins the forehead.

PHARMA | 5 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON

 o sesamin  Abdominal pains
o isoswertisin and kidney
problems: Decoction
of leaves and stalks
YERBA BUENA  Volatile oil (0.22%)  Toothaches: (1) Wet  Tops and Peppermint oil and its  Allergic reactions  No known severe
containing pulegone, a small piece of cotton leaves: main constituent (-)-  Burning interactions with
menthol, menthene, with juice expressed Carminative menthol (responsible  Mouth sensation other drugs
menthenone and from crushed leaves;  Oil: Rubefacient for rather half of the  Flushing  Caution when taking
limonene. apply this impregnated and stimulant effect of the oil)  Ulcers o Hypoglycemic
 Shoot leaf gave the cotton bud to the  Stimulant inhibit the cationic  Rash drugs: Lowers
highest yield of oil, tooth. (2) Boil 6 tbsp.  Stomachic influx through 5-  Skin irritations blood glucose
0.62%; while the of leaves in two  Aromatic HT3 receptor  Avoid among o Anti-
SN: Mentha arvensis, stems had negligible glasses of water for 15  Antiseptic channels in a o Pediatrics who hypertensive
Mentha spicata yield. minutes; strain and  Antispasmodic concentration- cannot tolerate drugs: Lowers
EN: Peppermint, wild  Menthol: major cool. Divide the  Sudorific dependent manner. ADRs blood pressure
mint, marsh mint component of all the decoction into 2 parts  Emmenagogue.  Both do not compete o Patients with
Distribution: Widely oils. and take every 3 to 4 with the radioligand GERD: worsens
cultivated to some  Other oils identified: hours. [3H]GR65630 for the symptoms
extent in all parts of the o B-caryophyllene  Flatulence: Boil 4 5-HT3 binding site
Philippines. oxide tbsp of chopped leaves (not act directly).
o a-phellandrene in 1 cup water for five  Action: mediated by
o Terpinolene minutes; strain. Drink binding to a
o Limonene the decoction while modulatory site
o Menthone lukewarm. Facilitates distinct from that of
o Pulegone. expulsion of flatus. serotonin, an
 Cough: Boil 6 tbsp of allosteric binding site
chopped leaves in 2 not yet identified
glasses of water for 15 (might represent a
mins; cool and strain. valuable future
Divide the decoction target for the
into three parts; take 1 development of a
part 3 times a day. new class of anti-
 Mouthwash: Soak 2 emetics lacking the
tbsp chopped leaves in typical side effects
1 glass of hot water for caused by setrones
30 minutes; strain. Use due to their direct
the infusion as action on 5-HT5
mouthwash. receptors).
 Peppermint oil and
menthol oil

END

PHARMA | 6 of 6 BLOCK A, PERALTA-RIPARIP, SAMSON

 PROBLEM-BASED LEARNING ACTIVITY
Dr. YasayApril 29, 2019
OUTLINE
I. Case 1
II. Case 2
III. Case 3
IV. Case 4
CASE 1
A 55-year-old man presents to the emergency department
with a 2-week history of expanding ulcer on his lower leg. He has
a history of chronic neutropenia and transfusion-dependent
anemia secondary to myelodysplastic syndrome requiring chronic
therapy and deferoximine for hepatic iron overload. He first noticed
a red bump on his leg while fishing at his cabin in the woods and
thought it was a bug bite. It rapidly enlarged, first as a red swollen
area and then began to ulcerate. He was given dicloxacillin orally,
but with no improvement. In the emergency department, he is
febrile to 39 degrees Celsius and looks unwell. On his left leg, he
has a 6x12 cm black ulcer with surrounding swelling and erythema
that is tender. An immediate operative debridement yields
pathologic specimens demonstrating broad, club-like non-septate
hyphae and extensive tissue necrosis.
• Consist of fever, chills, muscle spasms, vomiting, headache,
and hypotension
• Premedication with antipyretics, antihistamines,
meperidine, or corticosteroids can be helpful
B. Cumulative toxicity
• Renal damage is the most significant toxic reaction
o Manifestations:
▪ renal tubular acidosis
▪ severe potassium and magnesium wasting
• Degree of azotemia is variable and often stabilizes during
therapy
• Reversible adverse effects
o decreased renal perfusion (a form of prerenal renal
failure)
• Irreversible adverse effects
o Renal tubular injury and subsequent dysfunction
o In prolonged administration (>4g), irreversible
amphotericin nephrotoxicity usually occurs
o Abnormalities of liver function tests are occasionally
seen
o Varying degree of anemia due to reduced erythropoietin
production by damaged renal tubular cells
o Seizures and a chemical arachnoiditis
▪ often with serious neurologic sequelae.
▪ After intrathecal therapy with amphotericin

1. What is the diagnosis? What initial medical therapy CASE 2

would be most appropriate? A 5-year-old girl presents with a 1-week history of
MUCORMYCOSIS intermittent chills, fever and sweats. She had returned home 2
• treated with an initial, prolonged therapy of liposomal weeks earlier to spend 3 weeks with her grandparents in Palawan.
ampothericin B She received all childhood immunizations, but no additional
treatment before travel. Three days ago, the child was seen in an
2. What is liposomal amphotericin B? How is it different outpatient clinic and diagnosed with a viral syndrome. Examination
from ampothericin? reveals a lethargic child, with a temperature of 39.8 degrees
LIPOSOMAL AMPHOTERICIN B Celsius and splenomegaly. She has no skin rash or
• lipid-packaged formulation that binds to mammalian lymphadenopathy. Initial lab studies are remarkable for hematocrit
membrane less readily (vs. Amphotericin: COLLOIDAL) 29.8%, platelets 45,000/mm3, creatinine 2.5 mg/dL and mildly
• allows the use of effective doses of with lower toxicity elevated bilirubin and transaminases. A blood smear shows ring
• Lipid vehicle serves as a reservoir, reducing non-specific forms of Plasmodium vivax at 1.5% parasitemia.
binding to human cell membranes
o Allows for the reduction of toxicity without sacrificing 1. What treatment should be started? Explain. Give the
efficacy and permits use of larger doses mechanism of action of the drugs and their
• Use is usually limited to patients restricted to, or not pharmacokinetics.
responding to, conventional ampothericin treatment • Chloroquine
• Much more expensive o DOC in the treatment of uncomplicated nonfalciparum
malaria
3. Give the adverse effects and other clinical uses of the o It rapidly terminates fever (in 24-48 hours) and clears
drugs that you plan to give the patient. parasitemia (in 48-72 hours) caused by sensitive parasites.
AMPHOTERICIN B • Primaquine
• Mainly used as the initial induction regimen to rapidly o DOC for the eradication of dormant liver forms of P.vivax
reduce fungal burden in immunosuppressed patients and those and P.ovale
with severe fungal pneumonia, severe cryptococcal meningitis, o used for chemoprophylaxis against ALL malarial species
or disseminated infections with endemic mycoses such as
histoplasmosis or coccidioidomycosis DRUG MOA PHARMACOKINETICS
• After which, it would be replaced by one of the newer azole Chloroquine Acts by • It is rapidly and
drugs for chronic therapy or prevention of relapse concentrating in almost completely
• Topical drops or direct subconjunctival injection can be parasite food absorbed from the
used in mycotic corneal ulcers, keratitis, and fungal arthritis. vacuoles, gastrointestinal tract,
• Bladder irrigation is also done to treat candiduria preventing the reaches maximum
biocrystallization of plasma
2 BROAD CATEGORIES FOR AMPHOTERICIN B ADVERSE the hemoglobin concentrations in
EFFECTS: breakdown about 3 hours, and is
A. Infusion-related toxicity product, heme, rapidly distributed to
into hemozoin, and the tissues

PHARMA | 1 of 5 GRP 4C
 thus eliciting • It has a very large
parasite toxicity apparent volume of
due to the buildup distribution of 100–
of free heme. 1000 L/kg and is
slowly released from
tissues and
metabolized
• Chloroquine is
principally excreted in
the urine with an
initial half-life of 3–5
days but a much
longer terminal
elimination half-life of
1–2 months.
Primaquine Unknown • The drug is well Katzung’s Basic & Clinical Pharmacology 13th ed
mechanism of absorbed orally,
action reaching peak plasma • Non-falciparum infections and falciparum malaria from
levels in 1–2 hours areas with no known resistance should be treated with
• The plasma half-life is chloroquine
3–8 hours • P. vivax and P. ovale malaria should be subsequently treated
• widely distributed to with primaquine to eradicate liver forms
the tissues, but only a • Uncomplicated falciparum malaria is most often treated with
small amount is Malarone or new artemisinin-based combination
bound there • Severe falciparum malaria is treated with intravenous
• Rapidly metabolized artesunate, quinidine or quinine
and excreted in the
urine CASE 3
• 3 major A 35 year old white woman who recently tested seropositive
metabolites appear for both HIV and Hepatitis B virus surface antigen is referred for
to have less evaluation. She is feeling well overall but reports a 25 pack year
antimalarial activity smoking history. She drinks 3-4 beers/week and has no known
but more potential for medication allergies. She has a history of heroin use and is
inducing hemolysis currently receiving methadone. PE reveals normal vital signs and
than the parent no abnormalities. Cell count is 5800 cells/mm 3 with a normal
compound differential. Hemoglobin is 11.8 g/dL. All liver function tests are
within normal limits, CD4 cell count is 278 cells/ mm3 and viral load
2. What chemoprophylaxis and treatment can be given to is 110, 000 copies/mL.
patients and when is it indicated
1. What other laboratory tests should be ordered? Which
Antiretroviral medications would you begin? Explain.
• Prior to initiation of this regimen, Pregnancy should be
ruled out
• Patient should be counseled that efavirenz, should not be taken
during pregnancy

LABORATORY TESTS:
Table 52-2 is lifted from Katzung’s Basic & Clinical Pharmacology 13th ed
CDC RECOMMENDATIONS FOR CHEMOPROPHYLAXIS:
• Chloroquine for areas infested by only chloroquine-sensitive
malaria parasites
• Malarone, Mefloquine for chloroquine-resistant P.
falciparum
• Doxycycline for areas with high pevalence of multi-drug
resistant falciparum malaria
A. Renal function
• Emcitritabine is contraindicated in patients with renal
failure
• Tenofovir increases risk of new onset or worsening renal
impairment
• Tenofovir alone or in combination causes reduction of
renal function over time as well as cases of Fanconi’s
syndrome and acute renal failure
B. Bone mineral density test
• Tenofovir-associated proximal renal tubulopathy
causes excessive renal phosphate and calcium losses and
1-hydroxylation defects of vitamin D, and preclinical studies
in several animal species have demonstrated bone toxicity
• Monitoring of bone mineral density should be considered
with long-term use of tenofovir in those with risk factors for
or with known osteoporosis
C. Lactose tolerance test (or Hydrogen breath test)

PHARMA | 2 of 5 GRP 4C
 • Since tenofovir is formulated with lactose, these may
occur more frequently in patients with lactose intolerance.
D. Total Cholesterol levels
• For the use of efavirenz, total cholesterol and triglyceride
elevations may occur
• monitor before therapy and periodically thereafter
Combination antiviral therapy against both HIV and
hepatitis B virus (HBV) is indicated in this patient, given the
high viral load and low CD4 cell count (but not low enough to be
considered as AIDS).
A. Emcitritabine
• The oral solution is contraindicated in pregnant women,
patients with renal (elimination is by both glomerular
filtration and active tubular secretion) or hepatic failure
• Because of its activity against HBV, patients co-infected
with HIV and HBV should be closely monitored if treatment
with emtricitabine is interrupted or discontinued, owing to
the likelihood of hepatitis flare
• Often co-administered with tenofovir, and a once-daily,
fixed-dose combination formulation is available, both alone
and in combination with efavirenz
B. Tenofovir
• Treatment of patients with HBV infection
• Cause lactic acidosis
• Associated with decreased fetal growth and reduction in
fetal bone porosity in monkeys
• There is significant placental passage in humans.
C. Lamivudine
• has activity against HBV
• Short-term safety of lamivudine has been demonstrated for
both mother and infant
• Because of the similar mechanisms of action and resistance
profiles of lamivudine and emtricitabine, the
combination of both is not recommended
D. Efavirenz
• Other potential adverse reactions are nausea, vomiting,
diarrhea, crystalluria, elevated liver enzymes, and an
increase in total serum cholesterol by 10–20%
• High rates of fetal abnormalities occurred in pregnant
monkeys exposed to efavirenz in doses roughly equivalent
to the human dosage
• Several cases of congenital anomalies have been reported
in humans
• Therefore, efavirenz should be avoided in pregnant
women, particularly in the first trimester
• Efavirenz may lower methadone levels, patients
receiving these two agents concurrently should be
monitored for signs of opioid withdrawal and may require
an increased dose of methadone
TENOFOVIR AND EMTRICITABINE
• two nucleoside/nucleotide reverse transcriptase inhibitors
• a potentially excellent choice as components of an initial
regimen:
o both are active against HIV-1 and HBV
o do not interact with methadone
o available in a once-daily, fixed-dose combination
• Efavirenz: (nonnucleoside reverse transcriptase inhibitor)
could be added and still maintain a once-daily regimen
2. Give the mechanism of action and pharmacokinetics of
the drugs that you plan to give.
PHARMA | 3 of 5
EFAVIRENZ
• Nonnucleoside reverse transcriptase inhibitor
(NNRTIs)
o NNRTI bind directly to HIV-1 reverse transcriptase,
resulting to allosteric inhibition of RNA- and DNA-
dependent DNA polymerase activity
• it does not compete with nucleoside triphosphates and does
not require phosphorylation to be activated
• can be given once daily, long half-life (40-55 hours),
moderately well-absorbed from oral administration, should be
taken with an empty stomach due to increasing toxicity when
taken with high-fat meal; elimination is through feces
• known to be an inducer and inhibitor of CYP3A4, it induces its
own metabolism and interacts with the metabolism of other
drugs such as Methadone. It lowers methadone levels in
patients who take these 2 drugs and they should be monitored
for signs of opioid withdrawal and may require an increase in
dosage of methadone
TENOFOVIR AND EMTRICITABINE
• Nucleoside Reverse Transcriptase Inhibitors (NRTIs
o NRTIs act by competitive inhibition of HIV-1 reverse
transcriptase; incorporation into the growing viral DNA
chain causes premature chain termination due to inhibition
of binding with the incoming nucleotide
• Requires intracytoplasmic activation via phosphorylation by
cellular enzymes to the triphosphate form
• Emtricitabine can be given once daily, with a long
intracellular half-life (>24 hours), oral bioavailability is 93%
and it is unaffected by food and CSF penetration is low
• Tenofovir is a water-soluble prodrug of active tenofovir, can
be given once daily, it has a prolonged serum half-life (12-17
hours) and intracellular half-life, oral bioavailability increases
when taken after high-fat meal; elimination occurs by both
glomerular filtration and active tubular secretion
CASE 4
A 62-year-old woman with a history of depression is found
in her apartment in a lethargic state. An empty bottle of bupropion
is on the bedside table. In the emergency department, she is
unresponsive to verbal and painful stimuli. She has a brief
generalized seizure, followed by a respiratory arrest. The
emergency physician performs endotracheal intubation and
administers a drug intravenously, followed by another substance
via a nasogastric tube. The patient is admitted to the intensive care
unit for continued supportive care and recovers the next morning.
1. What drug might be used intravenously to prevent
further seizures? What substance is commonly used to
adsorb drugs still present in the GIT? Describe their
mechanism of action.
DRUGS THAT CAN BE USED IV TO PREVENT SEIZURES:
A. BENZODIAZEPINES
a. Diazepam
• MOA: Modulates postsynaptic effect of GABA-A
transmission, resulting in an increase in presynaptic
inhibition. Acts on part of limbic system, thalamus and
hypothalamus to induce a calming effect.
b. Lorazepam
• MOA: Increases the action of GABA; It may depress all
levels of the CNS, including limbic and reticular
formation
GRP 4C
B. VALPROIC ACID:
• MOA: Acts on sodium and calcium channels by inhibiting
them. It increases the activity of inhibitory neurotransmitter
GABA.
Our patient is going into respiratory arrest
• Diazepam and lorazepam can cause respiratory depression. So,
if these drugs are given, the patient has to be monitored
closely.
“GUT DIALYSIS”
• The primary substance used to adsorb drugs in the GIT is
activated charcoal
• In our case, a slurry of activated charcoal is given orally or by
nasogastric tube
• Owing to its large surface area, activated charcoal can adsorb
many drugs and poisons
• Repeated doses of oral activated charcoal may enhance
systemic elimination of some drugs by a mechanism referred
to as “gut dialysis”
Other methods that can be used are the following:
A. Emesis – induced by/with ipecac syrup.
B. Gastric lavage – with the patient awake and protected
airway, gastric lavage may be performed using an orogastric
or nasogastric tube.
C. Cathartics – may hasten the removal of toxins and reduce
absorption in the GIT.
2. What are the other methods of enhancing elimination
of toxins. Describe each.
DECONTAMINATION
• a procedure involving removal of induced toxins from the
gastrointestinal tract
• If ingestion of the toxic substance is within an hour, gastric
emptying by induced emesis or gastric lavage can be still
efficient
• But for most ingestions, it is much recommended to administer
activated charcoal
A. EMESIS
• Emesis is induced by administering Ipecac syrup to treat
some childhood ingestion at home under the telephone
supervision of physician or poison control personnel,
• Rarely used in the home or hospital due to risk involved
with inappropriate use over unproven benefit
• Not be used in patients intoxicated with corrosive agents
like petroleum distillate or a rapid acting convulsant
• manual usage of fingertip to stimulate the pharynx,
use of salt water, and apomorphine are ineffective and
not advisable to be used or done
B. GASTRIC LAVAGE
• Done thru an orogastric or nasogastric tube
• More advisable in patients in endotracheal tube for airway
protection
• Lavage solutions such as 0.9 % saline are preferred to
be given at body temperature to prevent hypothermia
C. ACTIVATED CHARCOAL
• Given in poison toxicity due to its absorptive properties to
many drugs and poisons
• Does not bind to iron, lithium or potassium and it binds to
alcohol and cyanide only poorly
• Not advisable in poisoning from corrosive mineral acids and
alkali
PHARMA | 4 of 5
• Repeated doses of oral activated charcoal, although
unproved clinical benefit, may enhance systemic
elimination of some drugs like carbamazepine, dapsone,
and theophylline by a mechanism called GUT dialysis
D. CATHARTICS
• Said to be helpful in faster removal of toxins from the GIT
and reduce absorption
• Balanced polyethylene glycolelectrolyte (GoLYTELY,
CoLyte) can enhance gut decontaminated after ingestion of
iron tablets, enteric coated medicines illicit drug-filled
packets, and foreign bodies
o Given orally, 1-2 liters per hour or 500ml per hour for
several hours until rectal effluent is clear
E. DIALYSIS PROCEDURES
• 2 types:
o Peritoneal dialysis is a relatively simple and available
technique, but is inefficient in removing most drugs
o Hemodialysis on the other hand, is more efficient than
peritoneal dialysis and has been well studied
▪ It assists in correction of fluid and electrolyte
imbalance and may also enhance removal of toxic
metabolites (eg, formic acid in methanol poisoning;
oxalic and glycolic acids in ethylene glycol poisoning)
▪ Especially useful in overdose cases in which the
precipitating drug can be removed and fluid and
electrolyte imbalances are present and can be
corrected (eg, salicylate intoxication)
F. FORCED DIURESIS AND URINARY PH MANIPULATION.
• Previously popular but of unproved value
• May cause volume overload and electrolyte abnormalities and
is not recommended
• Renal elimination of a few toxins can be enhanced by
alteration of urinary pH:
o urinary alkalinization is useful in cases of salicylate
overdose
o Acidification may increase the urine concentration of
drugs such as phencyclidine and amphetamines but is not
advised because it may worsen renal complications from
rhabdomyolysis, which often accompanies the
intoxication
3. Give a short description of the following agents that
cause intoxication as to: signs and symptoms and
management:
CYANIDE
• MOA: Cyanide binds readily to cytochrome oxidase, inhibiting
oxygen utilization within the cell and leading to cellular hypoxia
and lactic acidosis.
• Signs and symptom: shortness of breath, agitation, and
tachycardia followed by seizures, coma, hypotension, and
death. Severe metabolic acidosis is characteristic. The venous
oxygen content may be elevated because oxygen is not being
taken up by cells.
• Management: rapid administration of activated charcoal
(binds cyanide poorly BUT it can reduce absorption) and
general supportive care
o The conventional antidote kit: includes
▪ Nitrites (amyl nitrite and sodium nitrite) induce
methemoglobinemia, which binds CN−, creating the
less toxic cyanomethemoglobin
▪ Na Thiosulfate is a cofactor in the enzymatic
conversion of CN− to the much less toxic thiocyanate
(SCN−)
GRP 4C
 ▪ Hydroxocobalamin (Cyanokit) is a new cyanide shock, and systemic coagulopathy with prolonged clotting
antidote, a concentrated form, combines rapidly with time and reduced platelet count
CN− to form nontoxic cyanocobalamin (another form of • Management
vitamin B12) o emergency field remedies such as incision and suction,
tourniquets, and ice packs are far more damaging than
DIGOXIN useful
• Signs and symptoms o Avoidance of unnecessary motion, on the other hand, does
o Vomiting is common in patients with digitalis overdose. help to limit the spread of the venom
o Hyperkalemia may be caused by acute digitalis overdose or o Definitive therapy relies on intravenous antivenom (also
severe poisoning known as antivenin) and this should be started as soon as
o Hypokalemia may be present in patients as a result of long- possible.
term diuretic treatment. (Digitalis does not cause
hypokalemia.) ETHYLENE GLYCOL AND METHANOL
o A variety of cardiac rhythm disturbances may occur, • Signs and symptoms
including sinus bradycardia, AV block, atrial tachycardia o CNS depression and a drunken state similar to ethanol
with block, accelerated junctional rhythm, premature overdose
ventricular beats, bidirectional ventricular tachycardia, and o Formic acid (from methanol) or hippuric, oxalic, and
other ventricular arrhythmias glycolic acids (from ethylene glycol) cause a severe
• Management metabolic acidosis and can lead to coma and blindness (in
o General supportive care should be provided the case of formic acid) or renal failure (from oxalic acid
o Atropine is often effective for bradycardia or AV block and glycolic acid)
o Digoxin antibodies has revolutionized the treatment of o Initially, the patient appears drunk, but after a delay of up
digoxin toxicity to several hours, a severe anion gap metabolic acidosis
▪ Administered IV in the dosage indicated in the package becomes apparent, accompanied by hyperventilation and
insert altered mental status
▪ Symptoms usually improve within 30–60 minutes after o Patients with methanol poisoning may have visual
antibody administration disturbances ranging from blurred vision to blindness
▪ May also be tried in cases of poisoning by other cardiac • Management
glycosides (eg, digitoxin, oleander), although larger o fomepizole (4-methylpyrazole) inhibit the enzyme alcohol
doses may be needed due to incomplete cross-reactivity dehydrogenase
o Ethanol is also an effective antidote, but it can be difficult
THEOPHYLLINE to achieve a safe and effective blood level
• Signs and symptoms
o Sinus tachycardia and tremor
o Vomiting
o Hypotension, tachycardia, hypokalemia, and hyperglycemia
may occur, probably owing to β2-adrenergic activation
o Cardiac arrhythmias include atrial tachycardia, premature
ventricular contractions, and ventricular tachycardia
o In severe poisoning (eg, acute overdose with serum level
> 100 mg/L), seizures often occur and are usually
resistant to common anticonvulsants
o Toxicity may be delayed in onset for many hours after
ingestion of sustained release tablet formulations.
• Management
o General supportive care
o Aggressive gut decontamination should be carried out using
repeated doses of activated charcoal and whole bowel
irrigation
o Propranolol or other β blockers (eg, esmolol) are useful
antidotes for β-mediated hypotension and tachycardia
o Phenobarbital is preferred over phenytoin for convulsions;
most anticonvulsants are ineffective
o Hemodialysis is indicated for serum concentrations greater
than 100 mg/L and for intractable seizures in patients with
lower levels

RATTLESNAKE ENVENOMATION
• Signs and symptoms
o severe pain, swelling, bruising, hemorrhagic bleb
formation, and obvious fang marks
o Systemic effects include nausea, vomiting, muscle
fasciculation, tingling and metallic taste in the mouth,

PHARMA | 5 of 5 GRP 4C