Posted by Phillipa on October 28, 2007, at 0:17:35
In reply to Re: Med Induced Respiratory Depression, Anyone? » Brody, posted by Phillipa on October 28, 2007, at 0:01:46
Brody think you'll be okay no alchohol right? Phillipa
21:12
Drug-Induced Respiratory Depression
C. Michael White, Pharm.D.--------------------------------------------------------------------------------
Studies have demonstrated that billions of dollars and thousands of lives are lost each year due to drug-induced diseases,1 and 41% of all patients receiving drug therapy for >2 years experience an adverse drug event.2 Only 0.5%1.2% of total adverse drug events are respiratory in nature but account for an astounding 12.3% of life-threatening drug-induced disease and 25%30% of drug-induced deaths. 2 This may be attributable to the high blood flow received by the two main organs involved: the lung, which is the only organ to receive 100% of the blood supply, and the brain.
This article describes the pathophysiology of centrally mediated respiratory depression and then presents implicated drugs, patients most at risk, the utility of potential antidotes and possible alternative agents. New agents discussed include tramadol, nalmefene and flumazenil.
Pathophysiology
The medulla determines the need to breathe primarily through partial pressure of carbon dioxide (PCO2) levels detected by chemoreceptors located in the carotid arteries. 3,4 In times of PCO2 accumulation, the medulla stimulates the pulmonary musculature (diaphragm and intercostals) to breathe deeper, faster, more rhythmically, or a combination of the three. This facilitates a drop in PCO2 levels while simultaneously increasing oxygenation. A back-up mechanism to stimulate ventilation is the partial pressure of oxygen (PO2) chemoreceptor system (hypoxic drive). Unfortunately, this system is much less sensitive than the PCO2 system and only initiates breaths when PO2 is significantly depressed. 3,4 In the presence of medullary desensitizing drugs, the brain is unaware of accumulating levels of PCO2 and subsequently understimulates the lung musculature. 2 The result is respiratory depression, which can vary from mild to severe depending on the particular agent(s) involved and the presence of concurrent diseases.
Patients at Risk
Based on the previously mentioned physiologic mechanisms, certain patient populations can be identified as having an excess risk of developing and dying from respiratory depression when exposed to implicated agents. 2,5 These populations include patients with chronic obstructive pulmonary disease (COPD), patients receiving concurrent oxygen supplementation, the elderly and patients who are hepatically or renally compromised. 2,5
Patients with COPD are unable to ventilate properly due to either a loss of alveolar surface area (emphysema) or an accumulation of mucus plugs (chronic bronchitis). 6 COPD causes a chronic retention of CO2 and over time can lead to medullary desensitization with subsequent CO2 accumulation (hypercarbia). These patients, therefore, have an exaggerated response to respiratory depressants since they possess preexisting medullary compromise. 2 Additionally, COPD patients receiving respiratory depressants with concurrent O2 administration are at an increased risk for poor outcome because their final back-up mechanism for ventilation, the O2 chemoreceptor system (hypoxic drive), is blunted. 2
Finally, the elderly and those with reduced hepatic or renal function are at increased risk for respiratory depression due to decreased metabolism and/or elimination of respiratory depressants leading to drug accumulation. 7,8 Hepatic and renal compromise can lead to respiratory depression in patients taking low or normal doses of respiratory depressants.
Implicated Agents
Alcohol: Alcohol, when consumed in the absence of other respiratory drive mediators, depresses the areas of the brain with higher complexity and more integrated functions first. 9 In general, when one to two drinks are consumed (0.02%0.03% blood alcohol content) the cerebral cortex begins to be affected, resulting in diminished levels of reason and caution. It isnt until the blood alcohol content reaches 0.6% (10 or more drinks) that vital centers of the brain, including respiratory drive, are affected. 9 However, when alcohol is consumed in combination with other respiratory depressants or combined with additional alcohol from over-the-counter (OTC) medications, the results can be seen at much lower doses. Alcohol reduces respirations by diffusing into the cell membranes of nerve cells and inhibiting the passive neuronal flux of sodium. This mechanism is similar to that of anesthetic agents. Ultimately, Na/K ATPase is inhibited and cAMP and GABA synthesis is impaired. 10 This means that no receptor antagonists or other antidotes can be employed in an emergency to reverse the alcohol-induced component of respiratory depression. 9,10
The liver metabolizes 98% of the consumed alcohol, but does so in a zero-order fashion. This means that a constant amount of alcohol will be metabolized in a certain period of time and that increasing the amount of alcohol consumed does not increase the rate of metabolism. 9 In general, the liver will metabolize one 12 oz. bottle of beer (4.5% alcohol) or one mixed drink per hour. 9 When measuring blood alcohol content, 0.015% will be metabolized per hour. However, some patients with impaired liver function may have a decreased rate of metabolism and require more time to metabolize the alcohol load.
Whenever a respiratory depressant is dispensed, it is vitally important to assess the patients medication profile to check for agents with alcohol in the formulation. Pharmacists should counsel patients against the use of recreational alcohol and, if applicable, make suggestions of alternative alcohol-free OTC medications. In addition, pharmacists should be aware that some IV home infusion solutions have alcohol combined with dextrose in their formulations to provide more calories per unit volume. 5 Tables 1 and 2 list some common over-the-counter products containing 5% or more alcohol. 11
Table 1.Oral Cough/Cold Preparations with at Least 7% Alcohol
Aller-chlor syrup 7%
Ambenyl-D liquid 9.5%
Benadryl Cold Nighttime Formula liquid 10%
Cheracol D liquid 4.75%
Cheracol Sore Throat Spray spray 12.5%
Comtrex liquid 20%
Contac Severe Cold & Flu Nighttime liquid 18.5%
Formula 44 Cough Medicine liquid 10%
Formula 44 Multisymptom Cough and Cold Medicine liquid 20%
Formula 44e Cough and Expectorant Medicine liquid 10%
Genahist elixir 14%
Genite liquid 25%
Medi-flu liquid 20%
Novahistine DMX syrup 10%
Novahistine Expectorant liquid 7.5%
NyQuil Adult Nighttime Cold/Flu Medicine liquid 25%
Nytcold Cough & Cold Medicine liquid 25%
Orthoxicol liquid 8%
Pertussin AM liquid 10%
Primatuss 4 Cough Mixture liquid 10%
Primatuss 4D Cough Mixture liquid 10%
Tolu-Sed DM liquid 10%
Tylenol Cold Night Time Liquid liquid 10%
Tylenol Cold Maximum Strength Medication liquid 10%
Tylenol Cold Maximum Strength with Decongestant liquid 10%Adapted from Reference 11
Table 2.
Oral Non-Cough/Cold Products with at Least 5% Alcohol
Laxatives Cascara Sagrada Aromatic Fluid liquid 18%
Senokot syrup 7%
Analgesic Products Tylenol Extra Strength Adult Liquid Pain Reliever liquid 7%
Aceta elixir 7%
Iron Products Fer-In-Sol Iron Syrup syrup 5%
Feosol Elixir elixir 5%
Niferex Elixir elixir 10%
Vitamins Geriplex-FS liquid 18%
Secran B Vitamin Supplement liquid 17%Adapted from Reference 11
Barbiturates: Barbiturates are highly associated with drug-induced respiratory depression 2 and are contraindicated in patients with severe preexisting respiratory disease. 12 Although the exact mechanism of action of barbiturates is not known, it is thought to induce respiratory depression by desensitization of the medulla to hypercapnia. These agents inhibit the rate, depth and volume of inspirations. 13 Barbiturates are hepatically metabolized and renally eliminated, which necessitates careful monitoring for accumulation in the geriatric population or in patients with compromised hepatic or renal function. 5 Combination of barbiturates and other respiratory depressants can cause synergistic effects on ventilatory drive suppression. 5
Opioid Analgesics: The brain and spinal cord contain five types of opioid receptors with varying abilities to induce analgesia and respiratory depression. 14 Each opioid analgesic differs in the types of opioid receptors it will interact with and the affinity for each receptor. Opioid analgesics can be full agonists or partial agonists. 14 Examples of full agonists include codeine, oxycodone, fentanyl, morphine, methadone and levorphanol. Partial agonists include pentazocine, butorphanol, nalbuphine and buprenorphine.
Full Opioid Agonists: Equianalgesic doses of all narcotics can potentially reduce respiratory drive to the same extent. 14 However, full agonists are seldom associated with significant respiratory depression when administered as monotherapy and when given to non-high-risk patients. This is attributable to the respiratory stimulant effects of pain itself. 16 The opioid drug levels necessary for analgesia are always lower than the levels required for significant respiratory depression. Unfortunately, if the pain stimulus is acutely alleviated by an intrathecal nerve block, previously tolerated doses can induce significant respiratory depression. 16
Tolerance to the respiratory depressant effect, as with the analgesic effect, is seen over time for all opioids and allows for dosage escalation when the patient begins to experience breakthrough pain without concern for inducing respiratory depression. 14,17 However, different narcotics interact with the five different types of opioid receptors to differing degrees and therefore complete narcotic cross-tolerance cannot be assumed. 14,18 This is important to remember when using any narcotic conversion table and should precipitate initial dosage reductions of up to 25% in the average patient and 50% in patients at risk for respiratory depression. 14
In general, continuous IV infusions and patient- controlled analgesia pumps cause less respiratory depression than oral or rectal routes of administration. This is attributable to the finer degree of titration possible (with lower peak drug effects on respiration) with these forms of dosing. 19,20 Since all full opioid agonists are primarily metabolized by the liver with less than 11% of administered drug eliminated unchanged, caution is required in the cirrhotic or the geriatric patient. 21 Finally, high-risk patients for respiratory depression should be considered for non-opioid analgesics or nonsteroidal anti-inflammatory drugs to reduce the opioid analgesic doses required. This is especially true in cancer-induced bone pain where NSAIDs, not opioids, are the drugs of first choice. 17
Narcotic Antagonists: All narcotic or partial-agonist narcotic-induced respiratory depression can be reversed by administering naloxone (Narcan). 5,17 A modified dosing schedule of naloxone should be employed unless an overdose or life-threatening condition exists because overantagonism will acutely reverse the narcotic analgesic effect. To use the modified dosing schedule, give 0.10.2 mg IV bolus at 23 minute intervals until the desired response is achieved. 5,17 However, if immediate reversal is indicated, dose naloxone at 0.42 mg IV bolus at 23 minute intervals until the desired response or 10 mg have been given. 5 It should be noted that the clinical effects of naloxone are short-lived and respiratory depression can recur after about one hour. 22 Additionally, doubling or quadrupling the dose of naloxone has no effect on the duration of action. 22 However, it should be noted that buprenorphine-induced respiratory depression has to be treated differently. Buprenorphine, a partial agonist, has a higher affinity for the opioid receptor than other opiates, and higher doses of naloxone should be employed to reverse the respiratory depressant effects. 23 In a study of healthy volunteers, 1 mg of naloxone IV produced minimal changes in depression; doses of 510 mg were necessary to produce a consistent reversal of respiratory depression in the study group. Additionally, the effects were not appreciable during the first 30 minutes post-administration, a stark contrast to other opioids in which the antagonism of respiratory depression occurs in under a minute. 23 This suggests that buprenorphine is not a convenient drug to use for pain in high-risk patients because the potential exists for serious hypoxia to develop before naloxone starts to work. 23,24
A new narcotic antagonist, nalmefene (Revex), has a longer duration of action, which increases as the dose of drug is increased. 22 A single 2 mg dose has a duration of effect of more than eight hours, which is greater than the duration of action of most narcotics. However, this presents a risk of overantagonism in the patient with chronic pain who will be unable to reestablish adequate analgesia with narcotics for an extended period. Therefore, the lower dose nalmefene 0.5 mg dose, which exhibits a duration of action of 23 hours, seems more appropriate. 22 Nalmefene doses of 0.51 mg have been shown to reverse the respiratory depression associated with narcotics without inhibiting the analgesic effects. 25
Tramadol: Tramadol (Ultram) is not a narcotic but similarly works at opioid receptor sites. 5,19 Unlike narcotics, though, tramadol also inhibits the reuptake of serotonin and norepinephrine. 26 Due to this secondary tricyclic antidepressant-like mechanism of action, monoamine oxidase inhibitors such as phenelzine and tranylcypromine are not to be given concurrently due to the risk of hyperpyretic crises and seizures. 26,27 Usual doses of tramadol, 400 mg/day in four divided doses, without concurrent use of other respiratory depressants have not been associated with respiratory depression; 100 mg orally has the analgesic potency of aspirin (650 mg) with codeine (60 mg). 5,26 Unfortunately, tramadol in overdose or in combination with anesthetics, hypnotics or alcohol has been associated with life-threatening respiratory depression, with naloxone only partially reversing the effect. 5,26 Based on this, dosage modification for special populations is recommended. 5 Tramadol is both hepatically metabolized and renally eliminated, so dosage adjustment to 200 mg/day in four divided doses is advocated for hepatic or renal impairment; a maximum daily dose of 300 mg is advocated in the elderly (>75 years old). 5
Benzodiazepines: Benzodiazepines are weak respiratory depressants, much safer for monotherapy than barbiturates, and are indicated for anxiolysis and sedation. 12 For example, when diazepam is administered as monotherapy, respiratory depression is not detectable until a 0.2 mg/kg (14 mg dose for a 70 kg person) dose is administered. 28 Additionally, the resulting increase in CO2 is slight, not clinically significant, and attributable to a decreased tidal volume. 28 However, benzodiazepine-induced respiratory depression can be clinically significant when used in combination with other respiratory depressants, when consumed in overdose, or if allowed to accumulate to toxic levels. 2,5,12 Elderly patients are at particular risk from longer acting agents such as flurazepam (50100 hours), diazepam (2050 hours) and prazepam (3670 hours). 12,28 Patients taking cimetidine are more likely to exhibit accumulation of benzodiazepines as a result of impaired metabolism via the cytochrome P-450 system. 28) However, lorazepam, oxazepam and temazepam are the only benzodiazepines eliminated primarily by glucuronidation, which is less dependent on microsomal enzymes, and are unlikely to be influenced by hepatic dysfunction, increasing age or cimetidine administration. These drugs do not have active metabolites and have elimination half-lives from 5 hours (oxazepam) to 15 hours (lorazepam, temazepam). 28
Flumazenil, a benzodiazepine receptor antagonist, reverses the sedation and psychomotor impairment associated with benzodiazepines but has only mild and unpredictable effects on reversing respiratory depression. 5,29,30 Unfortunately, this means that respiratory depression necessitates emergent supportive therapy when it occurs, even though the incidence of benzodiazepine-induced respiratory depression is low. 28
Buspirone: Buspirone is a nonbenzodiazepine, nonsedating anxiolytic that works at the benzodiazepine receptor without precipitating respiratory depression. 31 It is a safe anxiolytic alternative for patients with COPD or the elderly, since it has no effects on CO2 response or ventilation. 32 Buspirone is dosed at 515 mg orally TID. It requires approximately three weeks to exhibit its anxiolytic effects, and dosage adjustments are unnecessary in the interim. 5
Zolpidem: Zolpidem (Ambien) is a nonbenzodiazepine that works at the benzodiazepine receptor. It has no anxiolytic properties but induces sedation and hypnosis. 5 Preliminary studies of zolpidem have not elucidated any respiratory depression. 5 However, a case of zolpidem overdose, with concurrent alcohol ingestion, has resulted in respiratory depression that resolved following the administration of flumazenil. 33 Until further information is available on the respiratory depressant effects of zolpidem, caution should be used with all patients with preexisting respiratory disease, and the starting dose should be reduced by 50% (5 mg QHS) for elderly or debilitated patients. 5 Additionally, remember that zolpidem, like all sedatives, is indicated only for short-term use and the patient should be counseled on good sleep hygiene (Table 3). 34 Finally, alert physicians that doses above 20 mg are less effective than doses below that range, since they decrease the amount of time in REM sleep, the sleep stage associated with the most restful sleep. 34,35
Table 3.Components of Good Sleep Hygiene
Set a regular time to go to sleep and wake up
Engage in regular, moderate exercise during the day; do not exercise vigorously in the evening
Avoid daytime naps
Avoid routine use of hypnotics
Eat a light snack before bed if hungry; do not eat heavy or spicy food before bed
Avoid or minimize caffeine, alcohol and tobacco
Use the bedroom for sleep; not for eating, paying bills, or watching TV
Make the bedroom conducive for sleep; make it dark, quiet, cool
Sleep only as much as needed to feel refreshed and alertAdapted from Reference 34
Conclusions
Drug-induced respiratory disease has a low incidence but is associated with a high mortality when manifest. Patients with COPD, reduced hepatic and renal function, and the elderly are particularly at risk. Additionally, patients receiving combination therapies with other respiratory depressants and/or oxygen supplementation are at even greater risk.
Alcohol is particularly important when consumed in combination with other respiratory depressants, and patients should be counseled to avoid alcohol or alcohol-containing products.
Opioid analgesics are highly associated with respiratory depression, but tolerance develops over time. Additionally, in the non-COPD patient the drug level for pain relief is below the level for respiratory depression. However, pharmacists must be aware that COPD patients may have a much smaller therapeutic range and opioids should be initiated at lower doses and the dosage titrated slowly. Furthermore, complete cross-tolerance from one opioid analgesic to another cannot be assumed, and a 25% (normal patient) to 50% (COPD patient) decrease in initial conversion dose should be sought. Finally, naloxone and nalmefene can reverse the respiratory depression associated with narcotics, but should be dosed until the desired effect is achieved while avoiding precipitation of an acute return of pain.
Tramadol is a reasonable alternative agent to narcotics for the patient at risk. Unfortunately, care must be taken to avoid overdose and/or concomitant use of other respiratory depressants since the respiratory depression that can result is not fully reversible with naloxone or nalmefene. Also, concurrent use of tramadol with phenelzine or tranylcypromine is contraindicated.
Benzodiazepines are weakly associated with respiratory depression and flumazenil may not reverse a benzodiazepine-induced respiratory depression. Hence, using lorazepam, oxazepam or temazepam is recommended for patients with liver disease and drugs with the shortest half-lives are recommended for use in the elderly or those with renal insufficiency. Benzodiazepines should be avoided and alternatives sought if the patient at risk is already on respiratory depressants. Buspirone has not been associated with respiratory depression and can be used in anxiolysis. Additionally, when filling benzodiazepine prescriptions for insomnia, the pharmacist can counsel the patient on good sleep hygiene, which can lessen the duration of therapy and reduce the risk of respiratory depression. Finally, zolpidem may have less respiratory depressant effects than benzodiazepines, but the dosage should be reduced to 5 mg in elderly or debilitated patients and doses greater than 20 mg should be avoided in all patients.
poster:Phillipa
thread:791889
URL: http://www.dr-bob.org/babble/20071027/msgs/791895.html