Morphine: Characteristics and Usage - Essay Example

?Running head: MORPHINE Questions and Answers: Morphine Section Sources of variability in drug metabolism In relation to the metabolism of morphine discuss the influence of host (e.g. disease states) and environmental factors in terms of enzyme induction and/or inhibition on the metabolism of morphine. Studies have shown that morphine is metabolized to M6G which is a potent analgesic thereby increasing the effectiveness of the drug in some situations. As a rule, the metabolism of morphine comes through uridine diphosphate glucuronosyl transferase (UGT) enzymes which are found in the liver (Armstrong and Cozza, 2003). The enzymes form active analgesic metabolites and in some cases toxic metabolites as well. This would indicate that environmental factors that could inhibit or increase the effectiveness of morphine would include conjoint use of other drugs that reduce or inhibit the effect of liver enzymes; liver disease or a liver dysfunction and any drugs that can increase enzyme levels in the liver itself. Section 2. Drug-Drug Interactions For morphine: i. List all known drug-drug interactions involving the metabolism of morphine. According to Drugs.com Interactive drug-drug search tool for morphine there are 28 serious drug-drug interactions (Drugs.com, 2011). The sixteen most common ones are listed in the table below: Ambien (zolpidem) Ativan (lorazepam) Cymbalta (duloxetine) Flexeril (cyclobenzaprine) Klonopin (clonazepam) Lasix (furosemide) Lexapro (escitalopram) Lyrica (pregabalin) Neurontin (gabapentin) OxyContin (oxycodone) Phenergan (promethazine) Plavix (clopidogrel) Seroquel (quetiapine) Vicodin (acetaminophen/hydrocodone) Xanax (alprazolam) Zoloft (sertraline) ii. Explain the mechanism of each of the interactions (i.e. Drug A inhibits the metabolism of Drug B by Enzyme X). In all of the drugs listed above except lasix the drugs have a two way interaction that can impact the central nervous system and increase the risk of respiratory and central nervous systems dysfunction or failure. This interaction is considered additive or synergetic and applies specifically in elderly patients or those that are already seriously debilitated. This would suggest that as morphine metabolizes in the liver, that these other common drugs either match in action the effects of morphine when acted upon by the enzymes, or they increase the effectiveness of the enzymes resulting in a faster, or more concentrated catalytic effect (“Drugs.com”, 2011). In the case of lasix, which includes a psychotherapeutic and CNS-active agent the patient might experience hypotensive effects when the treatment is first administered or if either of the drugs dosage is increased. There is also a coadministration factor with vasodilators and alpha-blockers that can increase blood pressure and othostasis. This interaction is not consistent enough across all patients to come to a conclusion as to why this happens, but careful monitoring of any patient on this type of treatment method is advised (Hammack and Loprinzi, 1994). iii. Note the clinical consequences of each of the interactions (e.g. increases the plasma concentration of Drug B leading to an enhanced pharmacological effect and toxicity). In all of the drugs in the previous section (except lasix) the concern is that the drugs, when combined with morphine have an additive or synergetic effect on the toxicity and potency of both drugs thereby increasing effectiveness as well as possible side effects depending on how well individual patients metabolize the morphine. Factors that would need to be considered would include type of illness, health of the liver, enzyme production and any built up tolerance to either medication (American Pain Society, 1999). Lasix can interact with elements such as alpha blockers or vasodilators which would put more stress on the heart due to increased blood flow and/or respiratory system (American Pain Society, 1999). Section 3. Drug absorption For morphine: a. Determine and state the oral bioavailability According to Baxter (1999) and various prescription guides for morphine (Ligand Pharmaceuticals, 2005; Purdue Pharma, 2005; Xanodyne Pharmaceuticals, 2006) the oral bioavailability is ? 40%. This is measured from outputs of the GI tract (AHFS drug information, 2006). b. Discuss whether the bioavailability is influenced by gastrointestinal absorption, first pass hepatic extraction or both? According to the AHFS drug information (2006) the bioavailability is influenced by gastrointestinal absorption but the amount of bioavailability depends on the method that is used to administer it. In reality the bioavailability is almost 90% first pass hepatic extraction. This is supported by literature that suggests that the clearance rate for morphine is longer in those individuals who have hepatic impairment (Xanodyne Pharmaceuticals, 2006). In most cases the morphine is metabolized in the liver and dispersed through urination. The rate of conventional oral preparations (immediate release) and the extended release oral versions are about the same but there is a difference in peak plasma concentrations which are longer and lower with the extended release oral preparation (Actavis Kadian, 2009; Purdue Pharma, 2005). Morphine suppositories result in a better absorption rate that with oral treatments and intrathecal administration takes longer to absorb through systemic circulation so has a prolonged duration. If administered as an epidural then the absorption is rapid and the plasma concentration times are similar to those seen with morphine administered through an IV (AHFS drug information, 2006). c. If morphine is only available as a parenteral formulation discuss whether that is principally due to problems with gastrointestinal absorption or excessive first pass metabolism. Lundeberg et al (1996) found that in children the parenteral formulation given rectally, as opposed to an i.v injection that the presence of first-pass metabolism was evident through the rectum. However in the same study the authors noted that the morphine gel, rather than the solution, had a significantly higher rate of bioavailability. Section 4. Drug formulation and routes of administration For morphine: a. List all of the dose forms and strengths available in Australia. (Identify brand names only if they are important for distinguishing between dose forms or they describe combination products) There are four different brands of extended release capsules that have different peak times – Kadian, Avinza, MS Contin and Oramorph SR. Doses for the oral preparations range from 2 – 10mls depending on factors such as age, condition, and extent of pain – it is possible to get higher doses in the treatment of cancer patients for example. It is also possible to get an intrathecal or epidural preparations (immediate and extended release) (Ravenscroft, 1996). b. Discuss any administration issues that are followed for safe efficacious use. Morphine can be administered orally, via I.V., I.M. or rectally. In cases of oral administration there is no need to take with or without food. In the case of extended release capsules the pills should be swallowed whole and not chewed. Alternatively the extended release capsules can be split open and the contents added to a sweet source (such as applesauce for example) to help aid administration. However, the smaller modules in the capsule should not be chewed but swallowed whole to reduce the possibility of overdosing. If administering a morphine injection care should be taken to ensure that the preparation is not spilt on any cut or area of broken skin and if spillage occurs then the area of skin must be washed immediately (American Pain Society, 1999; AHFS Drug Information, 2006). Section 5. Drug distribution For morphine determine from the primary literature whether it is bound to plasma proteins a. State the percent bound: Olsen (1975) found that 34 – 37.5% of morphine was bound to human plasma proteins – in particular albumin and to a lesser extent gamma globulin. b. Calculate the unbound fraction: The unbound fraction would depend on the method administered and the patients’ health factors, but in the lab it would be between 62.5% and 66%. 6. For morphine, determine from the primary literature its volume of distribution (VD) in either litres per kilogram (L/kg) or litres (L): Kilpatrick and Smith (2005) give the volume distribution as 1-6 L/kg a. Is morphine’s VD small or large relative to blood volume? It is relatively high when compared to blood volume which is why there are warnings about its prolonged use especially in the elderly and very young children because of the added pressure to the heart due to the reduction of blood volume (Kilpatrick and Smith, 2005). b. What does the volume of distribution tell you about the way morphine is distributed throughout the body? (Discuss in terms of plasma protein and tissue binding, distribution into adipose tissue, etc). Depending on how it is administered morphine is distributed into the muscles, kidneys, liver, GI tract, lungs, spleen and to a small extent the brain (AHFS Drug Information, 2006). 20 – 36% of morphine is bound to plasma proteins with a further 54% bound to muscle tissue (American Pain Society, 1999). The AHFS (2006) also found that the plasma concentrations of the active metabolites exceed those of the unchanged drug and this in turn is what contributes to the drugs effectiveness. 7. For morphine (Answer 7a): a. If given as a loading dose, indicate the usual loading dose. Lvovschi et al (2008) determined that the typical loading does for morphine was 0.1 mg/kg to reduce acute pain however his studies indicated that this was not the most effective dosage. In his findings he notes that an initial dose of 0.1 mg/kg is fine if then supplemented with subsequent doses of 0.025 – 0.05 mg/kg added every five minutes would be more helpful to the patient. Section 6. Clearance Concepts For morphine (Answer 8b): b. If it is predominantly cleared by the kidney (i.e. if fe is > 0.5): 1. Determine systemic (total) clearance A study by Hasselstron and Sawe (1993) on seven healthy human subjects found that when taken orally or by a single intravenous shot that the clearance of morphine to form M3G and M6G was 57.3% and 10.4%, while renal clearance in the same subjects was identified at 10.9% of the total plasma clearance. They also noted that 20% of the dose remained as “unidentified residual clearance”. The M6G and M3G clearance performances were similar using either oral or intravenous administration. 2. What perturbations in physiological function impair renal clearance of morphine? In a study on patients requiring dialysis treatment it was found that metabolites can accumulate if there are problems with the patient’s renal function. The danger of this is that M6G for example has a high analgesic property and if left to build up at as a result of renal dysfunction can contribute to respiratory problems. This can mean that the patient could be at risk of CNS issues such as dizziness and hallucinations for quite some time after morphine delivery has stopped (Dean 2004). M3G build up on the other hand has little interaction with opiod recepters but it can still cause increased respiration and agitation – these problems get worse as the amount of M3G accumulation increases. Finally where dialysis is a treatment method the treatment itself will eliminate all aspects of morphine from the body which can result in a “rebound effect”. This includes complications such as analgesia and being overly sedated (Dean 2004). 3. Ascertain if there is the need to adjust dosage in the presence of cardiac impairment and/or renal dysfunction? If not why not, and if yes explain why. Administering morphine to patients that have heart problems or renal dysfunction has to be done carefully. Most studies on this issue have conceded that morphine can still be a useful tool in pain management for these special populations, but that the initial and subsequent dosages should be less than might be for a patient that does not present with these additional concerns and that the number of dosages should also be reduced. The reason for this is that morphine metabolites can build up in the patients system and in the case of M6G can cause respiratory problems and with an M3G build up increased agitation and respiration which puts undue pressure on the heart muscle (Arnoff, 1999). Section 7. Half-life For morphine: a. State the half-life. In cases where the morphine is administered by IV or IM the average terminal half life is 1.5 to 4.5 hours. In cases of epidural administration the plasma half life is 1.5 hours and in CSF is approximately 6 hours (American Pain Society, 1999). b. How long will it take (in hours) to reach steady-state after commencing oral administration? Steady state can be calculated from using morphine’s half life figures. If the half life of an oral administration is given at between 1.5 and 4 hours then the steady state would be approximately 4 times that number – so for example in a case where the half life is 3 hours then steady state should be achieved within 12 to 15 hours. The AHFS (2006) claim that if using the extended release oral preparations steady state can be achieved within 24 hours. c. If the systemic clearance of morphine decreased by 40% calculate the new half-life and time to steady state. If the systematic clearance of morphine was reduced then the half life of the drug would be increased because the body was taking longer to eliminate the drug and the time to steady state would also be increased because the steady state calculation is based on the half life figures (AHFS, 2006). In this situation with morphine if the clearance rate was decreased by 40% the half life would increase to 2.1 – 6.3 hours and the steady state would be evident at between 8.4 and 25.2 hours. Section 8. Therapeutic Drug Monitoring How is the response to morphine monitored pharmacodynamically when administered in the hospital setting? In a hospital setting the use of morphine is determined on a case by case basis. There are many factors that will impact the dosage and frequency of the dosage including the age, gender and overall health of the patient, the degree of pain he is reporting; his previous medical history including previous use of morphine as a pain relief, and his long term prognosis. Many studies have shown that patients can become dependent on morphine if used over a long period of time, and this dependency can cause its own set of additional health problems (American Pain Society, 1999). Morphine also has a number of side effects and these can increase in special populations such as the elderly, patients who have pre-existing heart conditions, respiratory illness, or renal dysfunction to name just a few of them. In these patients if morphine is prescribed the patient will be monitored consistently to ensure that issues such as respiratory failure, high blood pressure, agitation or even hallucinations do not occur (AHFS, 2006). In terminally ill patients, such as those with cancer, it is possible after a period of adjustment to morphine medication has occurred that the patient will have the opportunity to self-medicate through the day in accordance with their perceived level of pain, during their stay in hospital. Even in these cases nursing staff and doctors will keep up a regular monitoring process that will include heart rate, respiratory function, oxygen saturation (blood), and urinalysis to ensure that the drug is being eliminated from the body effectively (Hammack and Loprinzi, 1994). If morphine is used in the pre-hospital setting does the monitoring differ from the hospital setting? Middleton et al (2010) found that in situations where ambulances are called to accident scenes or similar morphine is the most effective drug of choice for pain relief. This is because the drug does have a short half life, and can be administered in a range of dose levels in accordance with vital sign readings and the patients self reporting of pain levels. However Mckinney et al (2009) were concerned that a number of studies showed a higher risk of mortality with the use of morphine in a pre-hospital settings for heart patients possibly due to the pain relief aspects of the drug which can mask any ongoing pain. They also cited the drug’s ability to lower blood pressure and slow down the respiratory system as necessary in some instances, but a potential hazard for others including those patients with heart conditions. It is often difficult for paramedic and similar medical staff to collect a comprehensive health history of the patients they treat. They can only rely on the patients’ ability to self report their condition, and an interpretation of results from vital sign checking and observations to make their diagnosis. These are all factors that will influence the decision of whether or not to use morphine as a short term pain relief agent (Middleton et al, 2010). Or, if morphine is used in a community setting how does this differ from the other settings? Morphine is often used as a pain reliever for cancer and other terminally ill patients so it is often found in a community setting. There are a number of key differences between the monitoring that would occur in a hospice home or even the patients own home for example that would differ from the hospital situation (Bercovitch, 1999). Morphine has to be prescribed by a doctor and even in places like retirement villages or hospice care the morphine ordered has to be allocated to the patient it is prescribed for. However the positive aspect of monitoring in a community setting is that the medical staff members have the opportunity to learn about their patients over time – especially in hospice situations. As trust develops between patient and medical staff then the use of morphine is not likely to be as regulated as it might be in a traditional hospital situation. As mentioned earlier in this paper it is possible to get morphine in an intravenous set up that will allow the patient to self medicate a certain number of times per day, thereby ruling out the necessity of a medical nurse to approve and administer every dose. This leniency in usage though does not rule out the necessity for monitoring morphine usage by individual patients. Familiarity with a specific patient could lead to a relaxing of vital sign monitoring for example (Bercovitch, 1999). The longer term use of morphine for some patients can also result in a dependency on the drug, which can result in increasing the dosage for the patient to a point where issues with the heart, respiratory system and other side effects might occur. References "Actavis Kadian." (2009). Kadian (morphine sulfate extended-release capsules) prescribing information. Morristown, NJ. AHFS drug information (2006). McEvoy GK, ed. Morphine Sulfate. Bethesda, MD: American Society of Health-System Pharmacists. 2117-24. American Pain Society. (1999). Principles of analgesic use in the treatment of acute pain and cancer pain. 4th edition. Glenview, IL Armstrong S.C. and Cozza K.L. (2003). Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I. Psychosomatics. 44, 167–171 Aronoff G.R. (1999). Drug Prescribing in Renal Failure. 4th ed. Philadelphia, PA: American College of Physicians. Baxter. J. (1999). Morphine sulfate injection prescribing information. Deerfield, IL Bercovitch, M., Waller, A. and Adunsky, A. (1999), High dose morphine use in the hospice setting. Cancer, 86, 871–877. Dean M. (2004). Opioids in renal failure and dialysis patients. Journal of Pain Symptom Management, 28, 497-504. "Drugs.com" (2011). Morphine Drug Interactions. RPH World. Accessed October 3 2011. http://www.rphworld.com/viewlink-1465.html Hammack J.E., and Loprinzi C.L. (1994). Use of orally administered opioids for cancer-related pain. Mayo Clinic Procedures, 69, 384-90 Hasselstrom J. and Sawe J. (1993) Morphine pharmacokinetics and metabolism in humans. Enterohepatic recycling and relative contribution of metabolites to active opioid concentrations. Clinical Pharmacokinetics 24, 344-54 Kilpatrick G.J., and Smith T.W. (2005). Morphine-6-glucuronide: actions and mechanisms. Med Res Rev. 25(5), 521-44. Ligand Pharmaceuticals. (2005). Avinza (morphine sulfate) extended-release capsules prescribing information. San Diego, CA. Lundeberg S., Beck O., Olsson G.L., and Boreus L.O. (1996). Rectal administration of morphine in children. Pharmacokinetic evaluation after a single-dose. Acta Anaesthesiol Scand, 40(4), 445-51. Lvovschi V., Aubrun F., Bonnet P., et al. (2008). 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