PHARMACOLOGY - CASE 1A

Dr. C. Laic N.D.

January 23, 2007

Taryn Deering
David Denis
Ivona Guzik
Sarah Hawthorn
Christa Reed
CASE 1A

A.J., a 42 yr old male has finally taken your advice and stopped smoking. He comments
on how he felt better when he was smoking. He not only feels flu-ish (transient fever,
sore throat, and fatigue), but ever since quitting smoking, he has had transient: chest pain,
rapid heartbeats, and shortness of breath. The dizziness when getting out of bed peaked
last night, and the next morning after breakfast he experience his first seizure.

Current medications include:

Aspirin 84 mg/d
Clozapine 150 mg 3 x/d
Niacin 300 mg/d

Dietary Habits:
2 coffees in the morning
heavy carbohydrate meals
red meats 4 x/week
1 can of coke in the afternoon
snacks on chips in the evening

1. What differential diagnosis are you considering and why?

DDx Supporting Sx’s

Nicotine withdrawal Dizziness
Clozapine toxicity (neuroleptic malignant Dizziness (orthostatic hypotension),
syndrome) Seizures/Convulsions, Tachycardia, Chest
pain, Shortness of breath, Flu-like
symptoms: fever, sore throat, fatigue
Neuroleptic malignant syndrome Fever, unstable vitals, muscle fatigue
Niacin toxicity Hypotension, Cardiac Arrhythmia
(Recommended dose of niacin is 16 mg/d,
AJ is taking a dose of 300 mg/d)
Cardiovascular pathology Tachycardia, Chest pain, Shortness of
(ex: Angina pectoris) breath
Respiratory pathology Shortness of breath, Tachycardia, Chest
(ex: Pulmonary embolism) pain, Dizziness, Fever
Neurological pathology (ex: Epilepsy) Seizures
Infection Flu-like symptoms: fever, sore throat,
fatigue

Based on the above list of differential diagnoses and their supporting symptoms, we
suspect that A.J. is suffering primarily from Clozapine toxicity in conjunction with
nicotine withdrawal.

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2. What laboratory monitoring/physical exams should be considered with his
current medications, and current symptoms?

Lab/Physical exam Rationale

 CVS Cardiovascular exam To assess cardiovascular status and rule out
cardiac pathology
ECG To monitor cardiac function (ex: ST
depression seen in Angina pectoris). To
ensure that A.J.’s symptoms do not progress
to serious cardiac pathologies such as a
Myocardial infarction (Clozapine increases
risk of myocarditis, blood pressure
complications, and arrhythmias)
CRP C-Reactive Protein is a highly sensitive
marker for predicting coronary events
 BLOOD CBC Increased WBC count may indicate
infection, while a decreased WBC count
may indicate Clozapine toxicity
ANC Absolute neutrophil count to monitor
Clozapine-induced agranulocytosis
LDH Lactic Dehydrogenase to assess organ
injury, especially injury to the heart or liver
 LIVER AST & ALT Specific markers to monitor liver function
and Clozapine-induced hepatocellular
toxicity
 RESP. Lung exam To assess respiratory status and rule out
lung pathology
PFTs Pulmonary function tests to detect any
abnormalities in respiratory function
 CNS EEG Electroencephalogram to rule out Epilepsy
 KIDNEY CPK plasma To rule out neuroleptic malignant syndrome

3. Based on pharmacokinetic properties, what is the most likely cause of his

symptoms?

Clozapine is a psychotropic drug which, like many other pharmacological agents,

requires the P450 system in order to be metabolized by the body. CYP 1A2, 2D6, and
3A4 are the specific isoenzymes that are responsible for these processes in the liver. CYP
1A2 in particular is a major determinant of the rate of Clozapine elimination and
therefore causes variability in responsiveness and optimal dosing for individual patients.
CYP 1A2 is induced by many other substances, for example polycyclic aromatic
hydrocarbons (PAHs), nicotine and caffeine. PAHs are present in cigarettes and cause an
increase in CYP 1A2. Consequently, more of this isoenzyme is available to detoxify
drugs like Clozapine, which leads to a faster rate of metabolism and less bioavailability
within blood plasma. As a result, increased amounts of the drug are needed in order to
achieve desired effects within the body.

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Clozapine and Cigarette Smoking
The same phenomenon occurs with nicotine whereby there is induction of CYP 1A2
which leads to faster elimination of Clozapine. A study conducted by Meyer in 2001
found that there was 20-40% lower mean serum clozapine concentrations in smokers
compared with nonsmokers due to enzyme induction. Likewise, case reports conducted
by Skogh et al. showed similar effects in a patient who had successfully taken Clozapine
for seven years but upon smoking cessation developed seizures. The side effects
diminished and schizophrenia was managed by making a 40% reduction in the dosage
that he had been taking while he was smoking cigarettes.

In the case of A.J., it is likely that intake of PAHs and nicotine through cigarette smoking
increased the speed at which he was able to metabolize this drug. When A.J. quit
smoking CYP 1A2 induction was depressed and the rate of Clozapine metabolism
declined. Therefore, more of the drug was available to exert its effects than previously in
his system when he was smoking. Consequently, this resulted in the toxicity symptoms
A.J. is presenting with. In addition, A.J. is a frequent user of caffeine, a drug which
competes for CYP 1A2 and ultimately increases the duration of action of Clozapine in the
body. Furthermore, caffeine overdose can lead to seizures and cardiac arrhythmia, which
would serve to exacerbate his condition. Therefore, cigarette smoking is an important
feature of a patient’s case history which must not be overlooked since it alters the
pharmacodynamics and pharmacokinetics of other drugs within the body.

4) What naturopathic recommendations would you consider?

First of all, there is an immediate need for interdisciplinary communication between the
patient’s M.D., Psychiatrist, and N.D. in order to establish a cooperative relationship to
better care for the patient. A.J.’s current side-effects could have been avoided or at least
minimized by implementing a plan where the dose of Clozapine was slowly reduced to
compensate for the increased availability of the drug in his system. There are also other
antipsychotic medications that could be considered for the patient at this time which have
fewer side-effects. In consult with the prescribing doctor, it may be necessary to
recommend nicotine patches to the patient to increase the metabolism of Clozapine until
a more optimal level can be achieved. Also, A.J.’s use of Aspirin and Niacin should be
explored as these agents may be unnecessary. At this point, it would be beneficial for the
patient to decrease his caffeine intake because it is amplifying the longevity of the drug in
his system. Altering his diet to reduce the load on the liver would also enable this patient
to better detoxify Clozapine. Naturopathically, there are many things that can be done for
this patient. For instance, Homeopathy and Traditional Chinese Medicine both report
success in dealing with psychiatric patients and can in some cases negate the use of
pharmacological agents altogether. Drug efficacy and toxicity can also be affected
through the use of various botanical remedies and nutritional supplements. Therefore,
this case should be managed at an interdisciplinary level in order to provide more
comprehensive care for this patient.

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 RESEARCH

1. Describe physiologic effects of nicotine and caffeine and methamphetamines on

the body.

Nicotine, caffeine, and methamphetamines are drugs classified as central nervous system
stimulants, acting to promote a sympathetic response in the body by increasing levels of
epinephrine and/or norepinephrine. As such, these drugs work to increase heart rate,
blood pressure, and respiration rate while inducing hyperglycemia and bronchodilaton.
While these drugs are all similar in their effects, they differ in their mechanism of action.

Nicotine activates the Nicotinic Acetylcholine Receptors, which are abundant in

dopamine-releasing neurons. Nicotine works via the hypothalamic-pituitary-adrenal
pathway where it stimulates the release of adrenocorticotropic hormone, cortisol, and
catecholamines (epinephrine, norepinephrine, dopamine).

Caffeine has a number if interactions in the brain, most notably by acting as an antagonist
of adenosine receptors, promoting the release of dopamine and acetylcholine. This
results in CNS stimulation, increased gastric acid secretion, and induction of diuresis.
Caffeine also has the ability to increase levels of epinephrine and serotonin in the body.

Methamphetamine increases the stimulation of post-synaptic receptors and blocks the

reuptake of norepinephrine and serotonin; thus, resulting in higher levels of both
neurotransmitters within the synaptic space. Methamphetamine is also believed to release
dopamine, and at high levels is responsible for serotonin release.

Due to their collective effect on brain dopamine levels, nicotine, caffeine and
methamphetamine are also classified as psychostimulants. Psychostimulants increase
mental alertness and focus, decreasing fatigue, and induce a feeling of euphoria. It is this
feeling of euphoria or pleasure that makes this class of drugs highly addictive. Finally,
while the interactions are complex, it is important to note that when combined, stimulants
such as nicotine, caffeine, and methamphetamine can also have a synergistic effect.

2. Describe the 3 main treatment approaches for dealing with nicotine dependence.
List naturopathic supportive therapies.

Conventional therapeutic approaches to smoking cessation include Nicotine Replacement

Therapy (NRT), Bupropion, and Behavioural modification. NRT can reduce the severity
of withdrawal symptoms and cravings in patients abstaining from tobacco and has been
shown to double quit rates compared to placebo. NRT can potentially reduce exposure to
carbon monoxide, carcinogens, and the more than 4000 other compounds found in
tobacco.

Bupropion was originally marketed as an antidepressant drug with dopaminergic and

noradrenergic activity. In clinical trials some of the test subjects treated for depression

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noted a decrease in their desire to smoke, leading investigators to explore the usefulness
of the drug in the treatment of tobacco addiction. Studies show that patients taking NRT
combined with bupropion significantly achieved higher short-term and long-term quit
rates when compared to placebo.

The effectiveness of behavioural modification therapy on smoking cessation remains

inconclusive. Several studies using group or individual counseling have shown increased
rates of smoking discontinuation. However, other studies using behavioural modification
techniques such as: relaxation, visualization, reward/punishment, and aversion therapy
reported an efficacy of only 2%. Thus, it is difficult to quantify and determine how much
counseling is required to obtain the desired effect. Overall, a combination of all three
therapies is likely to be most effective in achieving the highest smoking cessation rates.

From lifestyle counseling to acupuncture, naturopathic treatment relies on aspects from

all modalities to treat the whole person. Some smoking cessation strategies currently in
practice at the RSNC include:

 Botanical Tinctures – Avena sativa (Oats), Eleuthrococcus senticosus (Siberian

ginseng), Lobelia inflate (Indian tobacco), Passiflora incarnate (Passion flower),
Bupleureum-D Formula, Lily Preserve the Metal Formula
 Homeopathic Remedies – Tabacum, Fumes cigaratum, R77 Nicotine addiction
 Supplementation – Antioxidants (A, C, E, and Se), Legend for Men/Women, Ester
ACES, Ester-C
 Acupuncture – General addiction points: PC 6, HT 7, LI 4, LU 7, LI 20 (all
bilaterally)
 Counseling – Encouragement, positive affirmations, support therapy, behaviour
modifications

3. Describe symptomology of caffeine withdrawal and naturopathic treatment

options for treatment of caffeine dependence.

The most common withdrawal symptom of caffeine is a headache. As mentioned earlier,

caffeine is an antagonist for the neurotransmitter adenosine. When someone has gained
tolerance for caffeine their body adapts by up-regulating its adenosine receptors. When
caffeine use is stopped adenosine now binds in greater numbers than usual causing
headaches due to adenosine acting as a vasodilator in the brain.

Caffeine also stimulates the stress response by increasing production of epinephrine and
norepinephrine. When caffeine use is stopped there is an adrenal crash that occurs
because caffeine is no longer artificially keeping the body in a sympathetic state. This
adrenal crash contributes to the symptoms of headaches, fatigue, decreased energy and
alertness, depressed mood, and others.

Supporting someone as they come off of caffeine is vital. This can be done in a number
of ways. Nutritionally the individual should be eating a complete and nutritious diet full
of fruits, vegetables, and adequate protein intake. Ideally the individual is already aware

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of any food intolerances they may have and is avoiding them. It may also help to
supplement magnesium as it has been shown to aid in the prevention and treatment of
headaches.

The most important support is to make sure that the individual is coming off of caffeine
slowly. Stopping caffeine cold turkey is much more likely to produce symptoms than
slowly reducing intake over the course of a week or two. Emotional support and
encouragement will also help ensure compliancy when experiencing withdrawal
symptoms.

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