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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 Nicotine withdrawal Clozapine toxicity (neuroleptic malignant syndrome) Neuroleptic malignant syndrome Niacin toxicity Cardiovascular pathology (ex: Angina pectoris) Respiratory pathology (ex: Pulmonary embolism) Neurological pathology (ex: Epilepsy) Infection Supporting Sx’s Dizziness Dizziness (orthostatic hypotension), Seizures/Convulsions, Tachycardia, Chest pain, Shortness of breath, Flu-like symptoms: fever, sore throat, fatigue Fever, unstable vitals, muscle fatigue Hypotension, Cardiac Arrhythmia (Recommended dose of niacin is 16 mg/d, AJ is taking a dose of 300 mg/d) Tachycardia, Chest pain, Shortness of breath Shortness of breath, Tachycardia, Chest pain, Dizziness, Fever Seizures 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.
2. What laboratory monitoring/physical exams should be considered with his current medications, and current symptoms? Lab/Physical exam Cardiovascular exam ECG Rationale To assess cardiovascular status and rule out cardiac pathology 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) C-Reactive Protein is a highly sensitive marker for predicting coronary events Increased WBC count may indicate infection, while a decreased WBC count may indicate Clozapine toxicity Absolute neutrophil count to monitor Clozapine-induced agranulocytosis Lactic Dehydrogenase to assess organ injury, especially injury to the heart or liver Specific markers to monitor liver function and Clozapine-induced hepatocellular toxicity To assess respiratory status and rule out lung pathology Pulmonary function tests to detect any abnormalities in respiratory function Electroencephalogram to rule out Epilepsy To rule out neuroleptic malignant syndrome
CRP BLOOD CBC ANC LDH LIVER RESP. AST & ALT Lung exam PFTs EEG CNS KIDNEY CPK plasma
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. 3
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.
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
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 6
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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