Summary by Timothy Koehler Brennan, MD, MPH
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Based on “Principles of Addiction Medicine” Chapter by Jason J. Heavner, MD, Jussi J. Saukkonen, MD, and Kathleen M. Akgün, MD
The respiratory tract is a unique interface between the body and the environment as the lungs contain the largest surface area of the body that is exposed to the external environment. A variety of addictive drugs present acute and chronic insults to the respiratory system and can overwhelm the capacity for recovery. Inhalation, injection, or ingestion of addictive drugs can have adverse effects within the airways, lung parenchyma, and pulmonary vascular bed. Respiratory complications also may arise indirectly from the effects of drugs on the central nervous system (CNS), cardiovascular system, and immune system.
RESPIRATORY FUNCTION
The respiratory tract contains and excludes foreign materials and provides an interface for immune sampling of antigens and provides a large surface area for absorption of inhaled substances and drugs. The respiratory tract also detoxifies and metabolizes proteins, drugs, and other potentially injurious substances. Drugs of abuse can derange these critical, interrelated functions of the respiratory tract and lungs. As respiration is under extensive neural control in the CNS, it is susceptible to the effects of CNS depressants and stimulants. Addictive drugs may affect the lung through direct local inflammation, increased susceptibility to infections, airway reactivity, impairment of pulmonary vascular integrity, acute lung injury, structural injury, and derangements of gas exchange. Polysubstance use is associated with a variety of injuries, making it difficult to ascribe a particular respiratory complication to a single agent. Coexisting pulmonary pathology may worsen the acute and chronic physiologic effects of an addictive drug on the lungs.
COMMON PULMONARY COMPLICATIONS
Respiratory Depression
With the exception of nicotine, cocaine, and amphetamines/stimulants, all of the drugs discussed in this chapter inhibit respiration, causing respiratory depression or respiratory failure.
Atelectasis
In patients with respiratory depression, shallow respirations result in decreased functional residual capacity, which contributes to airway closure in dependent regions of the lung during expiration. Ineffective cough and aspirated oral and gastric secretions, with loss of surfactant, contribute to the development of atelectasis. Unventilated areas distal to closed airways maintain perfusion, resulting in shunting and subsequent hypoxemia.
Aspiration Syndromes
The risk of aspirating oropharyngeal or gastric contents into the lower respiratory tract increases with decreasing levels of consciousness. The common aspiration syndromes include aspiration pneumonitis, aspiration pneumonia, airway obstruction, and diffuse aspiration bronchiolitis.
Respiratory Infections
Chronic users of addictive drugs are susceptible to a variety of respiratory infections. Persons who use drugs are at risk of direct infection from nonsterile injection technique or bacterial contaminated injected substances. The types of respiratory infections in drug users include sinusitis, acute bronchitis, community-acquired and aspiration pneumonias, septic emboli, fungal infection, and mycobacterial infections.
Respiratory Complications of Contaminants
Illicit drugs vary greatly in purity. Adulterants, pharmacologically active substances used to increase quantities of the drug of interest or enhance drug delivery, are frequently identified in illicit drugs. Commonly used adulterants include mannitol and other sugars, cellulose, and talc, as well as other drugs such as phenobarbital, fentanyl, methaqualone, caffeine, procaine, noscapine, and levamisole. Additionally, drugs can be contaminated with manufacturing by-products such as lead, aluminum, and glass. The lungs act as a filter, trapping inhaled or injected foreign substances, which may incite local inflammatory or fibrotic responses. A 2011 review identified Bacillus and Clostridium species to be the most common microbiologic contaminants.
Respiratory Complications of Injected Drugs
Opiates, stimulants, and combinations thereof are commonly injected into the veins. The resulting pulmonary complications may be acute or chronic. Acute problems are likely to be severe, including respiratory failure and acute pulmonary edema. Chronic pulmonary problems include the development of interstitial and bullous lung disease, endovascular and respiratory infections, pulmonary hypertension, tuberculosis, and cancer. Talc granulomatosis can develop when talc (magnesium silicate) is used as a filler in medications such as buprenorphine, oxycodone, and methylphenidate. A syndrome similar to sarcoidosis may result, with insidious onset of granulomatous interstitial fibrosis. Dyspnea, particularly with exertion, and cough are the most common symptoms.
Pulmonary Hypertension
Intravenous drug users may develop chronic pulmonary hypertension from multiple mechanisms, including chronic hypoxemia related to interstitial lung disease and vasoconstriction, pulmonary embolization of particulate matter from crushed tablets used for injection, pulmonary arterial thrombosis at sites of foreign body granulomatosis, thromboembolic disease, and pulmonary arterial hypertension from the drug itself (e.g., cocaine) or from an adulterant.
Septic Thromboemboli and Drug/Needle Embolization
Septic pulmonary embolism is a common pulmonary complication among intravenous drug users and may result from tricuspid endocarditis or from infected injection site thrombophlebitis. Occasionally, needles may break off inadvertently during injection, or entire needles may embolize if left in place after injection.
Other Complications of Injected Drugs
Pneumothorax, empyema, mycotic aneurysms of the pulmonary vasculature, hemothorax, and bullous emphysema may also develop in intravenous drug users.
Respiratory Complications of Inhaled Drugs
Inhalation of talc or other fibrogenic substances may lead to the development of granulomatous inflammation or fibrosis, as discussed previously in this chapter. Smoke consists of gas and particulate phases, including carbon monoxide, oxidants, aldehydes, alcohols, nitrosamines, benzene derivatives, and other inorganic and organic substances, many of which cause mucosal injury and inflammation. Inhaled drugs may also cause chronic bronchitis, emphysema, bronchospasm, barotraumas, hemoptysis, and asphyxiation.
TOBACCO AND NICOTINE
Within the lung, smoking has profound effects, altering the immunologic and structural milieu. Cigarette smoke contains more than 4,500 components, which are associated with a high rate of lung cancer, chronic obstructive pulmonary disease, bronchitis, and airway reactivity. Smoking is also associated with acute and chronic lower respiratory tract infections (bronchitis and pneumonia) and obstructive and restrictive lung diseases. Smokers have a more rapid decline in forced expiratory volume in 1 second than do nonsmokers, which may lead to symptoms such as dyspnea on exertion and fatigue. Chronic airflow obstruction is common and, when associated with persistent hypoxemia, may lead to pulmonary hypertension, cor pulmonale, and right heart failure. Smoking may also cause interstitial lung disease such as desquamative interstitial pneumonia and pulmonary Langerhans cell histiocytosis. Finally, smoking can cause spontaneous pneumothorax, hemoptysis, hypersensitivity pneumonitis, and lipoid pneumonia
MARIJUANA
Smoking marijuana results in inhaling three times more tar than cigarettes and causing a fivefold higher carboxyhemoglobin level in the blood than cigarettes. While earlier studies have conflicting results, more recent data suggest that long-term marijuana use is associated with an increased risk of lung cancer. Heavy marijuana use is also associated with laryngeal cancer. Marijuana smokers may suffer some of the same complications as those who smoke tobacco, including chronic obstructive pulmonary disease and bullous emphysema. Furthermore, because marijuana remains illegal in most states, there are not stringent quality controls on production, which puts patients at risk for contaminating microorganisms such as Aspergillus.
COCAINE
Cocaine crosses the blood–brain barrier and stimulates the CNS where, in addition to the well-known effects on the limbic system, it can increase respiratory rate. Approximately 20% to 30% of the inhaled dose actually reaches the lung. Freebasing is the practice of using volatile solvents to convert cocaine from a salt to a base and to remove adulterants. This potentially incendiary chemical process can lead to extensive cutaneous and inhalational burns. The final freebase product is highly potent and has a rapid onset of action, and, therefore, it is likely to induce pulmonary, cardiac, neurologic, and other complications. Cocaine may induce lung injury through vasoconstriction, by impairing the integrity of the pulmonary capillary bed, and by cardiovascular effects on the pulmonary vasculature. Barotrauma is common with crack cocaine inhalation and is associated with prolonged and forceful deep inhalation. A variety of upper airway complications are associated with inhaled cocaine, primarily burns and mucosal irritation or inflammation. Cocaine inhalation, but not injection, causes measurable and clinically significant bronchospasm in asthmatic as well nonasthmatic, nonatopic individuals. Cocaine can also cause alveolar hemorrhage. Additionally, 70% of cocaine in the United States is contaminated with levamisole—an antihelmintic agent. Levamisole-contaminated cocaine is associated with an antineutrophil cytoplasmic antibody-mediated vasculitis. Finally, cocaine can cause both noncardiogenic and cardiogenic pulmonary edema, drug-induced pulmonary artery vasoconstriction and subsequent pulmonary infarction, and “crack lung”—a self-limited eosinophilic hypersensitivity pneumonitis.
AMPHETAMINES AND OTHER STIMULANTS
Effects of amphetamines are predominantly cardiovascular and neurologic. Amphetamines were used in the early part of the last century to treat respiratory illness because these have sympathomimetic effects and can induce some bronchodilation and vasoconstriction. Amphetamines have adverse effects on the immune system, including a decrease in CD4 T-helper cells and an increase in immunosuppressive cytokines. Such changes may adversely affect the delayed hypersensitivity response to microbial pathogens. Extreme agitation and hyperthermia during amphetamine intoxication may result in rhabdomyolysis and severe metabolic acidosis, which will be associated with an increased respiratory drive. A direct central effect also may increase respiratory drive. Pneumomediastinum, subcutaneous emphysema, and retropharyngeal emphysema have been reported with the use of inhaled 3,4-methylenedioxymethamphetamine (“Ecstasy”). Finally, amphetamines can cause noncardiogenic pulmonary edemas and pulmonary hypertension.
CAFFEINE
Caffeine, a phosphodiesterase inhibitor and an adenosine and benzodiazepine receptor antagonist that raises intracellular cyclic adenosine monophosphate, has pulmonary effects that are similar to theophylline, including smooth muscle relaxation and mild bronchodilator properties. Caffeine may also falsely elevate the serum theophylline level. Pulmonary complications are rare and usually are associated with a large overdose or unintentional ingestion by children. Respiratory alkalosis, chest pain, seizures, aspiration, respiratory failure, and pulmonary edema associated with cardiac arrhythmias may occur.
OPIOIDS
Opioids have their most dramatic effects on the respiratory system by acting on the CNS. Opioid binding to μ2 receptors causes a reduction in responsiveness to carbon dioxide and depresses the pontine and medullary centers that regulate respiratory automaticity and cough. Opioids may induce respiratory complications indirectly through the CNS and also have effects on airways, pulmonary vasculature, and the immune system. Opioids induce histamine release from mast cells, which may lead to pulmonary vein constriction, increased pulmonary capillary permeability and pulmonary edema, and bronchoconstriction. In addition, chronic opioid use is associated with increased rates of central and obstructive sleep apnea. Finally, intranasal heroin has been reported to cause hypersensitivity pneumonitis.
ALCOHOL
Alcohol ingestion may cause acute intoxication accompanied by respiratory depression and common pulmonary complications including atelectasis, hypoxemia, respiratory failure, respiratory acidosis, aspiration pneumonia, and acute respiratory distress syndrome (ARDS). Alcohol may cause metabolic acidosis from alcoholic ketoacidosis, with resultant compensatory respiratory alkalosis. The consumption of other toxic alcohols, including isopropanol, ethylene glycol, and methanol, continues to be a public health issue. Patients presenting with alcohol intoxication and high anion gap metabolic acidosis should be evaluated for the presence of an unexplained osmolar gap, which increases the concern for a coingestion. Among patients with cirrhosis, chronic respiratory alkalosis is common, even in the absence of metabolic acidosis. This condition may be due to the respiratory stimulant effect of poorly cleared progesterone and estradiol on the CNS. Patients with asthma may experience worsening of asthma symptoms after consumption of alcohol, particularly those who are histamine sensitive. Additionally, alcohol use is associated with adult-onset asthma.
Cirrhosis with ascites may lead to pleural effusions. Massive ascites, with or without hepatic hydrothorax, may restrict diaphragmatic and pulmonary excursion, leading to rapid shallow breathing, dyspnea, atelectasis, and hypoxemia in severe cases. Hepatopulmonary syndrome (HPS) affects 15% to 30% of patients with cirrhosis. HPS consists of portal hypertension, intrapulmonary microvascular vasodilatation, and an increased alveolar–arterial oxygen gradient with hypoxemia in patients with cirrhosis. Liver transplant reverses hepatopulmonary syndrome. Alcohol also causes pulmonary arterial hypertension, though the pathogenesis of this complication is not clear. Individuals who chronically abuse alcohol are twice as likely to develop ARDS and to die from ARDS once it develops. Chronic alcohol abusers with sepsis are more likely to develop ARDS and are at increased risk for transfusion-related acute lung injury.
SEDATIVE–HYPNOTICS
Sedative–hypnotic drugs may exert significant respiratory depressant effects when abused or when mixed with alcohol and opiates. Benzodiazepines, barbiturates, gamma-hydroxybutyrate, and zolpidem bind GABA receptors, which normally function as targets for inhibitory neurotransmitters and promote sedation, hypnosis, anxiolysis, anterograde amnesia, and anticonvulsant activity. Adverse respiratory effects are mainly related to respiratory depression from overdose. Benzodiazepines can worsen sleep-disordered breathing by decreasing the tone of the upper airway muscles resulting in increased obstructive events. Increased central apneas and reduced ventilatory response to carbon dioxide also lead to worse nocturnal hypoxemia.
VOLATILE SUBSTANCES
Abuse of inhalants is highly prevalent throughout the world (though overall use is decreasing), particularly among teenagers. Volatile substances are aromatic and short-chain hydrocarbons, such as toluene, gasoline, butane, butyl and amyl nitrites, and organofluorines, which are found in adhesives, paints, paint thinner, dry cleaning fluids, refrigerants, and propellants. When sniffed or vigorously inhaled within a hermetic container (“huffed”), these are readily absorbed in the lungs. Intoxicating and dysphoric effects follow within seconds. Pulmonary complications include severe respiratory depression, barotrauma (pneumomediastinum), persistent cough, noncardiogenic pulmonary edema, and asphyxiation. Butyl and isobutyl nitrites may cause methemoglobinemia, which manifests as cyanosis with low oxygen saturation of hemoglobin but with normal partial pressure of oxygen. CO-oximetry will specifically measure methemoglobin levels. Intravenous methylene blue may be administered for treatment. Metabolic acidosis may occur, with compensatory respiratory alkalosis, resulting from distal renal tubular acidosis or from increased anion gap acidosis. Nitrates and other inhalants may be directly irritating to airway mucosa, which can cause chronic cough. Finally, users of inhalants may develop asphyxiation from plastic bag suffocation, respiratory depression, displacement of oxygen in the inspired air, and acute noncardiogenic pulmonary edema.
NITROUS OXIDE
Nitrous oxide is a widely used inhalational anesthetic–analgesic agent, which also is used in a variety of commercial products (such as a propellant for whipped cream chargers). Pulmonary complications include pneumomediastinum, respiratory depression, and hypoxemia because of displacement of oxygen, leading to asphyxiation. Treatment is supportive, including supplemental oxygen and respiratory support.
ANABOLIC STEROIDS
Anabolic steroids induce a prothrombotic state and may cause pulmonary embolism, strokes, and other forms of thrombosis. Other respiratory complications are less common but may occur after stroke and include atelectasis, pneumonia, aspiration, neurogenic pulmonary edema, and sleep-disordered breathing.
KEY POINTS
1. A variety of addictive drugs present acute and chronic insults to the respiratory system and can overwhelm the capacity for recovery.
2. Inhalation, injection, or ingestion of addictive drugs can have adverse effects within the airways, lung parenchyma, and pulmonary vascular bed.
3. With the exception of nicotine, cocaine, and amphetamines/stimulants, all of the drugs discussed in this chapter inhibit respiration, causing respiratory depression or respiratory failure.
REVIEW QUESTIONS
1. Which of the following is a common side effect of amphetamine intoxication?
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