Medical Expert Witness Forensic Toxicologist | Medical Expert Witness Services & More | Dr. Nachman Brautbar

Drug Interactions

Medications, Food Supplements,
Industrial Chemicals, and Alcohol

By Nachman Brautbar, M.D.

Definition
A drug interaction refers to the possibility that one drug may alter the pharmacological effects of another drug given concurrently. The net result may be enhanced or diminished effects of one or both of the drugs or a new effect that is not seen with either drug alone.

Commonly Described Drug Interaction

  • Alcohol
  • Cimetidine
  • Metoprolol
  • Molindone
  • Medicines for anxiety or sleeping problems, such as diazepam or alprazolam
  • Medicines for mental depression
  • Medicines for mental problems or psychotic disturbances
  • Phenytoin
  • Pimozide
  • Warfarin

How Common is it?
Estimates of the incidence of drug-drug interactions, prescription drug interactions and over the counter medications have been reported as high as 20% of patients, who are on more than 5 medications at a time (polypharmacy).

Factors Affecting Drug Metabolism
Prescription drug interactions involving drug metabolism can increase or decrease the amount of drug available for action by inhibition or induction of metabolism Interactions may occur among administered drugs, or between drugs, dietary substances, and industrial chemical exposures such as solvents used in degreasing, painting, and metal processing.

What Drugs Are Most Likely to be Involved in Drug Interaction?

  1. P450 Inhibitors (Location - Liver) HIV Protease inhibitors Macrolide antibiotics Azole antifungals Non-nucleoside reverse transcriptase inhibitors H2Antogonists
  2. P450 Inducers (Location - Liver) Rifamycin antibiotics HIV Protease inhibitors Non-nucleoside reverse transcriptase inhibitors Anticonvulsants (that are P450 inducers)
  3. Metabolized Drugs with Narrow Therapeutic Indices Non-sedating antihistamines Long-acting opiate analgesics Antiarrhythmics Long-acting benzodiazepines Ergotamines and dihydroergotamine Illicit drugs Coumarin anticoagulants Oral Contraceptives

Case Study - 1
Halogenated hydrocarbons, including many general anesthetics can sensitize the heart to the arrhythmogenic actions of catecholamines.

A painter is exposed to a chlorinated compound in a paint booth, no protective devices and poor ventilation, and has been using over-the-counter ephedrine containing products prescribed by the company doctor for an industrial sinusitis. After an 8 hour shift of heavy exposure to solvents he develops cardiac arrhythmia and collapses.

Paramedics on the scene determined "some type of cardiac arrhythmia". In the hospital all the studies showed no evidence of coronary artery disease. It was determined that the ephedrine increased the sensitivity of the heart to the arrhythmia causing effects of the solvents (paint thinners).

Since the ephedrine was given to cure from sinusitis on an industrial basis, the patient's hospitalization and future monitoring are industrial. Furthermore, due to the patient's increased cardiac sensitivity to painting solvents a work restriction of no exposure to concentration of chemical vapors and fumes is appropriate.

Here the interaction is between the solvents and ephedrine.


Case Study - 2
G.W. worked for G.B.B. for 4 years. He injured his neck on the job and developed a chronic pain syndrome, as well as psychiatric problems. He was prescribed the following medications by 4 different physicians:

  1. Inderal and Lasix for high blood pressure. (Internal)
  2. Tricyclic antidepressants, for depression. (Psychiatrist)
  3. Xanax for sleep. (Family Doctor)
  4. Propoxyphene for chronic pain. (Orthopedist)
  5. Prilosec for stomach irritation. (Internal)
  6. Over-the-counter Benadryl and Tylenol from time to time. (Self)

Recently he was prescribed Ultram (analgesic for moderate pain) by a second opinion orthopedist. He improved and returned to work to an accommodated position of light duty requiring, among others, driving a light vehicle.

The following week he was involved in a car collision on the job due to some type of "seizure-like" activity. In the Emergency room he was found to have elevated blood levels of Ultram, Amitriptyline, and minimal levels of alcohol and opiates (negligible levels).

The insurance carrier was arguing the defense of "intoxication". The toxicologist explained 1) that the drug interactions, specifically that Amitriptyline inhibits the metabolism of Ultram and therefore increases its level of Ultram in the blood, 2) that elevated levels of Ultram in the blood can cause seizures, 3) and relied on the laboratory studies demonstrating high levels of Ultram and the known generic capability of Ultram at high doses to cause seizures, and 4) alcohol levels were irrelevant since they were very low (0.0178).

Analysis:

  1. The patient was given Ultram and at the same time he was taking Amitriptyline. Amitriptyline elevates the blood levels of Ultram, by inhibiting the enzyme in the liver responsible for the breakdown of Ultram.
  2. His Ultram levels were therefore elevated due to the interaction with Amitriptyline, and resulted with a seizure, which would not have occurred absent the concomitant administration of Ultram and Amitriptyline. High blood levels of Ultram can cause new onset seizures. By itself, Ultram is a good medication, as is Amitriptyline. As a result of the car collision the patient developed post-concussion syndrome and fibromyalgia, on an industrial basis (job-related).


Case Study - 3
Sudden Death in a 36-Year-Old Man
(This case is an example of how knowledge of drug interaction and the pharmacology plays a key role in the final analysis.)

A patient presented to his clinician with depression. He was otherwise physically healthy. There was harassment and discrimination on the job going on for several months, Human Resource office was involved to resolve the problem but nothing worked.

His doctor prescribed Amitriptyline (Elavil), 150 mg/day, and Fluoxetine (Prozac), 40 mg/day. The patient responded quickly. However, several weeks later, the patient is found dead at home.

An autopsy found no other cause of death. The results of the blood samples showed toxic levels of Amitriptyline and its active metabolite, Nortriptyline. The coroner signed this case out initially as a suicide. The insurance carrier argued suicide, and therefore the death is not the result of the emotional problems on the job and is not industrial.

The high levels of amitriptyline and its metabolites indicate a drug overdose. The patient had severe clinical depression which may lead to suicide.

On the other hand, there were several factors against suicide: 1) absence of suicide note, 2) no missing pills from his Amitriptyline prescription bottle, and 3) no pill fragments in his stomach.

The key here was the toxicologist's findings that no pills were missing and the autopsy did not find pill fragments in the stomach, which is against an acute intoxication from ingesting a large amount of pills.

The final answer about the cause of death came by examining the relative ratios of Amitriptyline to Nortriptyline in the gastric contents, blood, and tissue samples taken at autopsy. Amitriptyline is converted into Nortriptyline. After taking Amitriptyline on a regular basis (for a week or more), an equilibrium (steady-state) is reached between the blood and deep compartments in the tissue. Once steady-state is reached, the ratio of Amitriptyline to Nortriptyline is the same in the tissue compartment as it is in the blood.

In an acute Amitriptyline overdose we would expect that the highest ratio of Amitriptyline to Nortriptyline would be in the stomach fluid, next highest in the blood, and lowest in the deep compartments. In this case, the ratios in stomach fluid were the same, proving that this patient did not die from an acute overdose. Meaning that the ratio of Amitriptyline to Nortriptyline in the stomach and blood were not high, meaning that much time went by (at least 1 week) to reach this ratio, which is against an acute intoxication.

A month later, the death certificate was corrected to show death occurred as a result of a unintentional overdose of Amitriptyline consistent with Prozac-induced inhibition of Amitriptyline metabolism. The metabolism of Amitriptyline was inhibited by Prozac and therefore Amitriptyline levels kept rising in the blood. Here the Prozac inhibited the enzyme which metabolizes Amitriptyline.

The death of this injured worker is industrial


Herbal and Food Supplements
Many of our patients use over-the-counter herbal and non-herbal food supplements, without discussion with their physicians. These can add to drug interaction problems, and at times can be very significant.


Ginkgo

Use: For memory enhancement as well as a painful condition stemming from poor circulation in the legs.

Caution: Because it interferes with blood platelets' clot-forming ability, medical caution when using concurrently anti-clotting drugs such as Coumadin or blood thinners such as aspirin, Plavix and Ticlid.

For related reasons, many experts recommend that ginkgo not be combined with nonsteroidal anti-inflammatory drugs such as Advil, Motrin and Aleve.

The American Herbal Products Assn cautions that ginkgo may interact with antidepressants called MAO inhibitors that include Eldepryl, Nardil, and Parnate.


Ginseng

Use: To increase energy and stamina.

Caution: May increase blood pressure and heart rate. May interfere with the action of the anti-clotting drug Coumadin.


Ma Huang

Use: To treat colds and nasal congestion; contains ephedrine, a powerful stimulant.

Caution: This Chinese herb should not be taken with a class of antidepressants called MAO inhibitors, such as Marplan, Nardil and Parnate, because the combination could dangerously elevate blood pressure.

Also should not be taken with some heart medications such as Lanoxin because of risk of irregular heart rhythms or fast heartbeat.


Alcohol (Ethanol) and Drug Interactions

  1. Alcohol is a brain (CNS) depressant, and therefore additive with other CNS depressants such as antihistamines, narcotics, Xanax, Valium, opiates.
  2. Impairment can occur at significantly lower levels of blood alcohol levels due to this additive effect on the brain. For example: alcohol usage and concomitant ingestion of opiates.
  3. Effects of alcohol on the liver via P450 enzyme causes reduced metabolism of other medications and therefore may increase the concentration of a given drug which is metabolized by this enzyme.


For Additional Reading

  1. Goodman & Gilman's The Pharmacological Basis of Therapeutics - 9th Edition, McGraw-Hill Publishers, 1996
  2. Physician's Desk Reference, 53rd Edition, Medical Economics Company, 1999
  3. LG Miller, Herbal Medicinals: Selected Clinical Considerations Focusing on Known or Potential Drug-Herb Interactions, Archives of Internal Medicine, Volume 158(20):2200-2211, 9 November 1998
  4. E Richelson, Pharmokinetic Drug Interactions of New Antidepressants: A Review of the Effects on the Metabolism of Other Drugs, May Clinic Proceedings, Volume 72(9):835-847, September 1997


Dr. Brautbar is a board-certified internist and nephrologist, and certified in forensic medicine. If you are interested in retaining Dr. Brautbar for forensic and expert witness testimony services, please submit the Contact Form.


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