Drug -- Alcohol Interaction: Medical Myth or Fact

           Drug -- Alcohol Interaction: Medical Myth or Fact

                   

                                             Dr. KS Dhillon

The mythconception that alcohol should never be taken with antibiotics dates back to the 1950’s. According to Karl S. Kruszelnicki [1], the venereal disease (VD) clinics of the 1950s and 1960s gave advice that alcohol should absolutely not be consumed while a patient was taking penicillin although there was no chemical interaction between penicillin and alcohol. Apparently, the advice was given for moral reasons. The doctors of the day were concerned about alcohol reducing the inhibitions of those having VD, while under the influence of alcohol, and they getting "frisky" and passing on the infection to other people before the penicillin could cure the sexually transmitted disease.

Alcohol and drug interaction

Some medications can interact with alcohol and alter the metabolism or effects of alcohol and/or the medication. There are two types of medication--alcohol interactions:
Pharmacokinetic interactions where the alcohol interferes
with the metabolism of the medication. 
Pharmacodynamic interactions where the alcohol enhances the effects of the medication, particularly in the central nervous system (e.g., sedation).

1.Pharmacokinetic interactions

Pharmacokinetics studies of the movement of the drug into, within and out of the body which essentially means what the body does to the drug.
About 10% of the alcohol consumed undergoes first-pass metabolism in the stomach, intestines, and liver. The major enzyme involved in alcohol metabolism is alcohol dehydrogenase (ADH), which converts the alcohol into acetaldehyde (a toxic compound) which is subsequently metabolized by aldehyde dehydrogenase (ALDH) to acetate. After the first-pass metabolism, alcohol goes to various parts of the body where it exerts its effect. Alcohol then goes back to the liver for metabolism and elimination. Beside ADH, CYP450 enzymes, mainly CYP2E1 are also involved in the metabolization of alcohol in the liver [2,3,4]. Alcohol consumption can alter the pharmacokinetics of certain medications by altering gastric emptying, affecting their absorption and metabolism. Similarly, certain medications can alter the pharmacokinetics of alcohol by altering gastric emptying and inhibiting gastric alcohol dehydrogenase. 

2.Pharmacodynamic interactions

Pharmacodynamics studies the effect and mechanism of action of drugs on the body which essentially means what the drug does to the body. Besides the effect of the alcohol on the central nervous system which produces impairment of performance and behavior, alcohol may contribute to the disease state which is being treated. An example would be impairment of gluconeogenesis which can lead to hypoglycemia in diabetic patients who are on treatment with oral hypoglycemic agents. A combination of nonsteroidal anti-inflammatory drugs and alcohol consumption can increase the risk of gastrointestinal hemorrhage.
Pharmacodynamic interactions involving alcohol and medications can increase the risk of adverse drug events and also increase susceptibility to the medications’ effect.

Therapeutic drug classes and drug-alcohol interactions 

There is a dearth of reliable studies on drug-interaction. Most of the evidence for drug-alcohol interactions is based on case reports and not on clinical trials [5].
There are three common therapeutic classes of drugs which interact with alcohol and these include antibiotics, cardiovascular drugs, and analgesics.

Antibiotics

Concomitant use of alcohol and certain type of antibiotics can cause or exacerbate the adverse effects. Disulfiram-like reactions have been reported in patients who consume alcohol while on the following antibiotics [6]:

• Cefamandole (Mandol)
• Cefoperazone (Cefobid)
• Cefotetan (Cefotan)
• Ceftriaxone (extremely rare)
• Chloramphenicol 
• Griseofulvin 
• Isoniazid 
• Metronidazole (Flagyl)
• Nitrofurantoin 
• Sulfamethoxazole (Bactrim)
• Sulfisoxazole

The disulfiram-like effect with cephalosporins is mediated by the inhibition of ADH, which in turn irreversibly inhibits the oxidation of acetaldehyde. The elevated concentrations of acetaldehyde produces facial flushing, nausea, vomiting, headache, tachycardia, hypotension, or a combination of all these effects. 
Metronidazole is also a known cause of disulfiram-like reactions when coadministered with alcohol. This reaction may involve ADH inhibition in the gastrointestinal (GI) tract, instead of in the liver as previously believed [7].  Disulfiram-like reaction has also been reported with the combined use of sulfamethoxazole/trimethoprim and alcohol [8].
Antitubercular drug, Isoniazid, is metabolized more quickly in chronic heavy alcohol users, and this can reduce the effectiveness of the drug [9]. Furthermore, the alcohol-isoniazid combination has been associated with an increased risk of hepatotoxicity and of disulfiram-like reactions [10]. Rifampin (Rifadin) and pyrazinamide which are also used in the treatment of tuberculosis are also known to increase liver toxicity when consumed with alcohol.
Ketoconazole (Nizoral), when combined with alcohol, may increase the risk of liver toxicity and disulfiram-like reaction.
Combination of cyclosporine and alcohol may increase the risk of central nervous system toxicity with possible seizures.
It is therefore imperative to advise patients to avoid alcohol intake for several days after consumption of antibiotic regimens known to interact with alcohol.
There is no scientific evidence to show that moderate alcohol consumption interferes with antibiotic effectiveness.

Cardiovascular Medications

Some medications for hypertension and angina are known to interact with alcohol. Nitrates such as hydralazine and nitroglycerin when taken with alcohol can increase the risk of orthostatic hypotension which may put the patient at risk of falls [3,4]. The metabolism of propranolol can be increased with chronic alcohol consumption, thereby decreasing the effectiveness of this beta-adrenergic blocking agent. Verapamil delays the elimination of alcohol and this can prolong alcohol intoxication [3,11]. Alcohol intake can also aggravate hypertension or heart failure [12,13].

Anticoagulants

Alcohol can interact with warfarin leading to an increase or decrease in its anticoagulation effect. Acute alcohol consumption can decrease the metabolism of warfarin leading to increased risk of hemorrhage. Chronic alcohol consumption increases the metabolism of warfarin leading to a decrease in the drug’s effect which can increase the risk of clot formation [3,4]. The exact mechanism of this alcohol and warfarin interaction is not known. History of alcohol consumption must be obtained from patients who are taking warfarin so that a close monitoring of the international normalized ratio (INR) can be carried out [14,15].

Antidiabetics

Diabetic patients who consume alcohol run the risk of hypoglycemia because alcohol suppresses gluconeogenesis. The risk of hypoglycemia is further increased if the patient is taking insulin or oral hypoglycemics [3,4].
Sulfonylureas such as tolbutamide and chlorpropamide when taken with alcohol are known to increase the risk of hypoglycemia. Excessive consumption of alcohol also increases the risk of diabetic complications such as diabetic neuropathy and retinopathy [3]. Heavy consumption of alcohol along with metformin intake can increase the risk of lactic acidosis [4]. Chlorpropamide, when taken with alcohol, can produce disulfiram-like reactions.

Non-Narcotic Analgesics

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Aspirin

Case-control studies show that the use of NSAID or aspirin along with alcohol can increase the risk for an upper GI bleed. There is a three to fivefold increase in the risk of GI ulceration or major GI bleed when NSAIDs are used along with alcohol [16]. Alcohol consumption can cause gastritis by increasing gastric secretion and irritating the gastric mucosa.

Acetaminophen

Acetaminophen is an over the counter drug which is often used for pain relief. It is also found in combination with several narcotic medications. There have been several case reports which have reported severe liver injury in patients who use therapeutic doses of acetaminophen in conjunction with chronic alcohol use. Well-designed clinical studies to verify the validity of this interaction are, however lacking [11].
Acetaminophen is mainly metabolized through glucuronidation or sulfation (90%-96%) and also via CYP2E1 (4%-10%). CYP2E1 is the same enzyme involved in alcohol metabolism. Metabolization of acetaminophen through CYP2E1 produces a hepatotoxic metabolite called  N-acetyl-para-benzoquinoneimine (NAPQI). NAPQI is rapidly deactivated through hepatic stores of glutathione. When acute overdoses of acetaminophen are consumed, the stores of glutathione become exhausted and NAPQI accumulation can lead to fulminant liver failure [11].
In patients taking therapeutic doses of acetaminophen (<4 g/day) there is no increased risk of hepatotoxicity in alcoholic patients unless there are other risk factors [17].
The FDA advises patients that they should consult their doctor before taking over the counter pain medication if they take more 3 alcoholic drinks a day [18].

Narcotic Analgesics 

Opioid analgesics such as methadone and codeine derivatives can act on the central nervous system (CNS) to produce sedation and respiratory depression [19]. Alcohol also acts on the brain and can increase the risk of sedation and CNS depression in patients taking opioid analgesics [19]. There is a lack of studies on the interaction of alcohol and narcotic analgesics.

Besides these three common therapeutic classes of drugs which can interact with alcohol, there are other classes of drugs which can also interact with alcohol.

Antidepressants

Tricyclic antidepressants (TCAs) such as amitriptyline, doxepin, maprotiline, and trimipramine cause sedation and alcohol can increase the sedation caused by TCAs’ through pharmacodynamic interaction. Alcohol also interferes with the metabolism of amitriptyline in the liver thereby increasing the levels of amitriptyline in the blood. Furthermore, alcohol induced liver disease also impairs amitriptyline breakdown leading to significantly increased levels of active medication in the body. These high levels of amitriptyline lead to convulsions and disturbances in heart rhythm.
Selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine, fluoxetine, paroxetine, and sertraline which are now widely used as antidepressants, however, have much less sedating effect and no serious interactions occur when these are consumed with moderate amounts of alcohol [20].
Monoamine oxidase (MAO) inhibitors such as phenelzine and tranylcypromine can induce severe high blood pressure if consumed with tyramine, a substance which is present in red wine. Hence people taking MAO inhibitors should be warned against consuming red wine.

Antihistamines

Antihistamines, which are often used for the treatment of allergies and colds, are known to cause drowsiness, sedation, and hypotension, especially in elderly patients [21]. Alcohol through pharmacodynamic interactions, can enhance the sedating effects of these antihistamines and increase the patients risk of falling and affect one's ability to drive and operate machinery. Patients taking antihistamines should be warned against
consuming alcohol.

Barbiturates and Benzodiazepines

Sedative-hypnotic agents such as barbiturates (phenobarbital) and benzodiazepines (Valium, Xanax, Ativan) have a sedative effect and when consumed with moderate amounts of alcohol, synergistic sedative effects occurs leading to substantial CNS impairment.
These sedative-hypnotic agents can impair memory, just as alcohol can. Combination of these drugs with alcohol can exacerbate this memory-impairing effect.
Alcohol can inhibit the breakdown of barbiturates in the liver thereby increasing the blood of phenobarbital.

Conclusion

Though the alcohol and medication interaction has been reasonably well studied in chronic heavy alcohol consumers, the effect of moderate alcohol consumption has not been studied as thoroughly. Risks of oversedation in patients combining benzodiazepines and alcohol and the effects of warfarin and alcohol combination can be clinically very significant. The commonly held belief that patients taking antibiotic should not take alcohol is a myth since only a small number of antibiotics produce disulfiram-like side effect. Generally, alcohol does not reduce the efficacy of antibiotics. It is imperative that people taking either prescription or OTC medications, read product warning labels to determine whether possible interactions exist. Similarly, doctors prescribing medications should be alert to the possible interaction between alcohol and the medications been prescribed.

References

1. Kruszelnicki KS. Alcohol and Antibiotics. News in Science, 2 June 2005 at http://www.abc.net.au/science/articles/2005/06/02/1380836.htm accessed on 12/11/18.
2. Jang GR, Harris RZ. Drug interactions involving ethanol and alcoholic beverages. Expert Opin Drug Metab Toxicol. 2007;3:719-731.
3. Moore AA, Whiteman EJ, Ward KT. Risks of combined alcohol/medication use in older adults. Am J Geriatr Pharmacother. 2007;5:64-74. 
4. Fraser AG. Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet.
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7. Tillonen J, Vakevainen S, Salaspuro V, et al. Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats. Alcohol Clin Exp Res. 2000;24:570-575. 
8. Heelon MW, White M. Disulfiram-cotrimoxazole reaction. Pharmacotherapy. 1998;869-870.
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10. Isoniazid package insert. Eatontown, NJ: West-Ward Pharmaceutical Corp; March 2008.
11. Jang GR, Harris RZ. Drug interactions involving ethanol and alcoholic beverages. Expert Opin Drug Metab Toxicol. 2007;3:719-731.
12. Zilkens RR, Burke V, Hodgson JM, et al. Red wine and beer elevate blood pressure in normotensive men. Hypertension. 2005;45:874-879. 
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14. Hylek EM, Heiman H, Skates SJ, et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279:657-662. 
15. Havrda DE, Mai T, Chonlahan J. Enhanced antithrombotic effect of warfarin associated with low-dose alcohol consumption. Pharmacotherapy. 2005;25:303-307.
16. Pfau PR, Lichtenstein GR. NSAIDS and alcohol: never the twain shall mix? Am J Gastroenterol.
17. Kuffner EK, Green JL, Bogdan GM, et al. The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients—a multicenter randomized study. BMC Med.
18. FDA proposes alcohol warning for all OTC pain relievers. U.S. Department of Health and Human Services. November 14, 1997. http://archive.hhs.gov/news/. 
19. Drug interactions. Thomson Micromedex. Greenwood Village, CO. www.thomsonhc.com. 
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21. Dufour MC, Archer L and Gordis E. Alcohol and the elderly. Clinical Geriatric Medicine 8:127–141, 1992.