Drug Profile of Pharmacology - Essay Example

? Naloxone Introduction: Opium, derived from the poppy seeds was used as early as the 3rd century. In the 19th century, morphine, a derivative of opium, was used as a narcotic agent. Opioids bind to the opioid receptors that are present in the central nervous system and peripheral nervous system and produce their therapeutic effects. Opioids are the morphine like synthetic drugs that produce the same effect as that of morphine for pain relief, respiratory depression, constipation and sedation. Opioids antagonists block the (µ , ? and ?) opioid receptors. (Flomenbaum et al. 2006). Opioid antagonists, when administered before treatment, block the opioid agonists by preventing their action. They also reverse the effect of the exogenous and endogenous opioid receptors by creating perceptible of opioid withdrawal in the opioid dependent patients. The common Opioid antagonists are naloxone and nalmefene and naltrexone are competitive antagonists for the opioid receptors. Naloxone is used primarily for the patients suffering from respiratory depression. 2. Naloxone – An introduction: Chemical name: “(-)-17-Allyl-4, 5a-epoxy-3, 14-dihydroxymorphinan-6-one.” (Sinatra, Jahr and Watkins-Pitchford, 2010). Generic Name: Naloxone Trade names: “Naloxone hydrochloride Injection (DBL or CSL brands), Naloxone Min-I-Jet Suboxone (in combination with Buprenorphine), Targin (in combination with oxycodone).” (Sinatra, Jahr and Watkins-Pitchford, 2010). Other Names: “L-Naloxone , N- Allylnoroxymorphone, Nalossone, Naloxona, Naloxone HCl, Naloxonum.” (Sinatra, Jahr and Watkins-Pitchford, 2010). Similar Ligands of Naloxone: Nalmefene, naltrexone, (+) – Naloxone, Naloxonazine, nalbuphine, naltriben and naltrindole, naloxone benzoylhydrazone, TRK820, beta – FNA, etorphine, diprenorphine, buprenorphine, nor-binalto and BNTX .(Sinatra, Jahr and Watkins-Pitchford, 2010). IUPAC Name : “(1S,5R,13R,17S)-10,17-dihydroxy-4-(prop-2-en-1-yl)-12-oxa-4 azapentacyclo [9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-14-one” (Sinatra, Jahr and Watkins-Pitchford, 2010). Chemical Formula : C19H 21NO 4 Molecular weight : 327.3743 Fig 1: Structure of Morphine and Naloxone. (Harvey and Champe 2008). The drug is approved for paramedic use in South Australia. It is mainly used for managing opiate dependence syndrome and respiratory depressions caused by overdose of Opioids. The paramedic indications are: 1. Antinarcotic agents. 2. Narcotic antagonists. 3. Depressants. 4. Opiate Antagonists. 5. Reverse sedations caused by Opioids. 6. Respiratory depressants in neonatal care. 3. Mechanism of Action: Naloxone reverses the effect of the opioid overdose. Naloxone competitively binds to the opioid receptors and replaces the opioid molecules. By doing so, it reverses the effect of the agonists such as heroin. Naloxone is competitive antagonists at the mu, kappa and delta receptors. They have 10 fold greater affinity for the mu receptors. (Harvey and Champe 2008). Naloxone does not have any effect on the normal individuals but they precipitate the withdrawal symptoms at the abuse users. Animal studies have suggested that Naloxone inhibits GABA release and stimulates the cholinergic activity. Similarly they do not reverse the effects of ethanol. Naloxone first increases the local blood flow. (Harvey and Champe 2008). Then the drug crosses the cellular membrane and increases the cellular metabolism. Finally it aids in cell repair. Fig 2: competition of Naloxone with the opioid agonists. (Harvey and Champe 2008). Pharmacology: Naloxone is a pure competitive antagonist for the mu receptors. Mu receptors are responsible for miosis, euphoria, feeding, sedation and respiratory depression. Naloxone binds to the competitive receptors such that their antagonists or partial antagonists or mixed agonist- antagonist binding without any independent action. (Flomenbaum et al. 2006). The pharmacokinetics of naloxone differs from the other antagonists. Some studies have also found that extreme low doses of naloxone (0.25 micrograms per kilogram per hour) will improve the analgesic ability of the opioid. They are also found to prevent the development of tolerance and dependence. Naloxone can be administered through oral, sublingual, intramuscular, endotracheal, subcutaneous, intranasal, nebulized and intralingual routes. (Flomenbaum et al. 2006). Oral Naloxone has less bioavailability because of the first pass effect. Similarly sublingual bioavailability of the drug is 10% only. Naloxone is well absorbed through other paranteral routes. Naloxone is highly soluble in lipids and the volume of distribution ranges from 0.8 – 2.64 L / kg. (Flomenbaum et al. 2006). The distribution half life is 5 minutes and the elimination half life is 90 minutes in adults. This may increase by 2 – 3 times in neonates. Positron electron system has detected that for 50% bioavailability of the drug in human body a dose concentration of 13 microgram per kg must be administered. (Flomenbaum, et al, 2006). 4. Clinical effectiveness of the drug in humans: Maintenance treatments for opiate dependent adolescent: To identify the “effectiveness of the maintenance treatment alone or in combination with the psychosocial intervention or the combination of other treatments” for improving the health of the patients, was the main objective of the study. . (Minozzi, Amatto and Davoli, 2009). In this study, randomized clinical trials and controlled clinical trials were checked for their efficiency for the improvement in the health condition of the patients vs. no intervention, placebo with no physiological intervention or pharmacological intervention for improving the treatment of the individual were assessed. The article, Maintenance treatments for Opiate dependent Adolescent written by S Minozzi, L Amato and M Davoli and published in the peer-reviewed journal Cochrane Database of systematic reviews, focuses on the Two trials, in which 187 patients was assessed. “The first trial compared methadone with LAAM as maintenance treatment for 16 weeks.” . (Minozzi, Amatto and Davoli, 2009). The second trial compared buprenorphine-naloxone with detoxified buprenorphine condition. Comparisons looked upon: 1. Pharmacological treatment verses no treatment 2. Pharmacological treatment versus any other pharmacological treatment 3. Pharmacological maintenance treatment along with psychological treatment versus psychological treatment alone. 4. Pharmacological maintenance treatment versus psychological treatment. 5. Maintenance treatment versus detoxified treatment. Primary outcomes: Trail 1: No urine positives for non-prescribed drugs. No other clinical differences were reported by the author. Trail 2: The results are in favor of maintenance treatment. No serious side effects were noted. Summary: The study proved that “there is no difference in the use of a substance abuse and social functioning.” (Minozzi, Amatto and Davoli, 2009). Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal: Removal of toxicity from the body is necessary for drug-free treatments. In this study, the effectiveness of administering opioid antagonists for opioid withdrawal with heavy sedation and detoxification was compared with the placebo trials and with the other antagonist induced withdrawals with heavy anesthesia. In the article, Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal written by L Gowing, R Ali and J White and published in Cochrane Database of Systematic reviews, “Five randomized controlled trials and one quasi-randomized controlled clinical trials” were assessed. . (Gowing, Ali and White, 2006). A total of 834 patients were reviewed for the present study. Primary outcomes: 1. Antagonist induced withdrawal was very good but the response was only for a short duration. 2. Withdrawal managed systems reduced the doses of methadone and naltrexone for blocking the opioid effects in the persons more quickly than withdrawal effects managed with clonidine and symptomatic medications. 3. “The sedation levels did not affect the intensity and duration of withdrawal. The rate of risk was very high for heavy sedation than light.” (Gowing, Ali and White, 2006). Summary: The comparison of heavy sedation and light sedation did not produce additional benefits for the naltrexone maintenance and withdrawal effects. (Gowing, Ali and White, 2006). 5. Renal Excretion of Drugs and their Metabolites. At this stage for your chosen drug ascertain if: • It is excreted unchanged (as parent drug) in urine. • It is excreted in urine principally as metabolites. Naloxone concentration in the biological fluids were assayed using the Reverse-phase HPLC with the electrochemical detection. The assay was performed in dogs to identify Naloxone, and its conjugates 6-beta naloxol and its hydroxyl conjugates. The percentage of Naloxone excreted unchanged in urine was 4 %. The conjugate excretion was dose dependent and ranged from 46% to 22% for high and low drug concentration. Due to incomplete biliary cannulation, 13- 18% of the conjugates were collected in bile cannulated dogs. As biliary secretion, there was negligible secretion of Naloxone. (Garrett, Shyu and Ulubelen 1986). 6. Drug Metabolism 1. Using a diagram (if possible) as an aid discuss its metabolism noting the types of reactions, that is either functionalisation or conjugation reactions, and identify the involvement of any CYP, UGT or other drug metabolising enzymes. 2. Identify the main metabolites (note those on your figure), and state the percent of the parent compound metabolised to the specific metabolite. Naloxone is metabolized in the liver into many small compounds. These compounds include a glucronide too. The half life of the drug at liver is 20 – 90 minutes depending on the administration concentration of the dose, route of administration of the dose, dose of the agonist and the rate of elimination of the drug and the agonist from the body. The time for the onset of action through various routes is summarized below. (Flomenbaum et al. 2006). S.No Route of Administration Time for action 1 Sub cutaneous 5.5 minutes 2 Intralingual 30 seconds 3 Intranasal 3.4 minutes 4 Nebulization ( 2 mg mixed with 3 ml of 0.9% sodium chloride solution) 5 minutes 5 Endothecal 60 seconds 6 Intravenal immediate After absorption, the peak plasma concentration occurs within one hour. It has a high volume of distribution and low plasma protein binding ability. Orally administered naloxone undergoes first pass metabolism in the liver. It has two phases. Functionalisation and conjugation reactions. In the functionalization step, the N-dealkylation and reduction of the ketone group occurs. During conjugation step, glucuoronidation occurs resulting in the production of naloxone - 3 – glucuoronide. As naloxone has a short elimination time, it is removed from the liver soon. 7. Section 3. Sources of variability in drug metabolism In relation to the metabolism of your drug: discuss the influence of host (e.g. disease states) and environmental factors in terms of enzyme induction and/or inhibition on the metabolism of your drug. The effect of Naloxone on the non-mitochondrial ATPase enzyme system was studied on synaptic plasma membranes of I and II type. “Na+, K(+)-ATP-ase, Ca(2+), Mg(2+)-ATP-ase and Mg(2+)-ATP-ase and of acetylcholinesterase (AChE) enzyme effects were studied on the synaptic plasma membranes.” .(Gorini et al. 2000). The treatment with naloxone created increased activity of the acetylcholinesterase enzyme and decreased enzymatic activity of the Ca(2+), Mg(2+)-ATP-ase. These effects created an increase in the calcium homeostasis in synaptoplasm resulting in the activation of the calcium dependent processes. Thus the administration of Naloxone is found to interfere with the “Ca2+ and Mg2+ ATPase enzyme systems” and also increases the acetyl choline catabolism in the cerebral cortex synaptic plasma membrane.(Gorini et al. 2000). Naloxone and Cytochrome enzymes: Naloxone is metabolized by the cytochrome P450 and UDP-glucoronosyl transferease enzyme systems. When naloxone is admistered with other drugs such as buprenorphine, they are metabolized by CYP450 isoenzymes and result in drug-drug interactions. It also results in glucuronidation. Pharmacokinetics of naloxone is still not understood properly. Many medications such as calcium channel antagonist, warfarin, barbituarates, protease inhibitors, ketoconazole and macrolide antibiotics were found to interact with naloxone. (Australian Public Assessment Report 2011). Some exogenous compounds may alter the Drug metabolizing enzymes. These exogenous compounds will up-regulate or down regulate the enzyme and this will result in the alteration of the enzyme activity. CYP iso-enzymes play such a role. Barbituarates and rifampicin are such exogenous compounds. (Australian Public Assessment Report 2011). Naloxone usage in many diseases and adverse drug effects: Naloxone is used in the emergency rooms as narcan. It is well known for its action in short time and is administered intravenously for better effect. Naloxone was used much in the Parkinson’s disease for their ability to reduce lipopolysaccharide- induced microglial activation. Similarly the Naloxone was used in the Alzheimer’s disease for similar effect. Many studies were conducted to check whether Naloxone isomers had any effect on the Abeta 1- 42- induced neuro-degeneration. Mid brain cultures were treated with Naloxone and the effect was studied. It was observed that they protected the dopaminergic neurons with equal potency and released the superoxide free radicals and pro-inflammatory factors. (Moore and Wilkinson 2008). The adverse effects are vomiting, Diaphoresis, yawning, lacrimation, rhinorrhea , diarrhea, elevations in the heart beat rate and increase in the blood pressure. (Flomenbaum, et al. 2006). 8. For your drug: 1. List all known drug-drug interactions involving the metabolism of your drug. 2. Explain the mechanism of each of the interactions (i.e. Drug A inhibits the metabolism of Drug B by Enzyme X) Oxycodone and Naloxone : The combination of Oxycodone and Naloxone have proved to reduce the opioid induced constipation in the non-cancer patients . It was found that the treatment of opioid induced constipation was safe and efficient for the oxycodone and naloxone combination and the efficiency reduced when oxycodone is used alone. (Simpson et al. 2008). Similarly “methylneltrexone is also used for the treatment of opioid induced constipation.” (Simpson et al. 2008) Naloxone and buprenorphine: This combination is gaining importance in the agonist opioid treatment replacing methadone. (Martinez-Raga et al. 2012). Naloxone and 7-Ni: Naloxone and 7-Ni, an nNOS inhibitor or iNOS inhibitors AG was used to reduce the effect of morphine in the rats. The withdrawal of morphine was started after 6 hours of morphine injection and the withdrawal effect of naloxone was studied. It was found that 7-Ni increased the naloxone precipitation and increased the Fos protein expression in the spinal cord of the rats induced with morphine. (Liu and Qian 2012). Buprenorphine – naloxone and tipranavir/ritonavir : HIV negative patients who are opioid dependence and require opioid replacement therapy are subjected to the use of beprenorphine and naloxone along with tipranavir/ritonavir in a open – label, twice daily study. References: Australian Public Assessment Report for Buprenorphine/Naloxone., 2011, Australian Government., Department of Health and ageing [Online] Available from: http://www.tga.gov.au/pdf/auspar/auspar-suboxone.pdf (Accessed on 20th August 2012. Flomenbaum, NE., Goldfrank, LR., Hoffman, RS., Howland, MA., Lewin, NA and Nelson, LS., 2012, Goldfrank’s Toxicologic Emergencies, Mc Graw Hill Professional publications. Garrett, ER., Shyu, WC and Ulubelen, A., 1986, Pharmacokinetics of Morphine and its Surrogates, Journal of Pharmaceutical sciences, Vol. 75, No. 12, pp. 1127 -1136. Gorini, A., Rancat, A., D'Angelo, A., Devecchi, E and Villa, RF., 2000, Effect of In Vivo administration of Naloxone on ATP-ase's enzyme systems of Synaptic Plasma Membranes from Rat Cerebral Cortex, Neurochemical research, Vol. 25, No. 6, pp.867 – 873. Gowing, L., Ali, R., and White, J., 2006, Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal, Cochrane Database of systematic reviews, Vol. 19, No.2, pp. 2. Harvey, RA and Champe, PC., 2008, Lippincott’s Illustrated Reviews: Pharmacology, Lippincott’s Williams and Wilkins. Liu, HL and Qian, YH., 2012, The different roles of the Spinal Protein nNOS and iNOS in Morphine Naloxone-precipitated Withdrawal response, Chinese Journal of Applied Physiology, Vol. 28, No. 3, pp. 249 – 253. Martinez-Raga, J., Gonzalez-Saiz ,F., Onate, J., Oyaguez, I., Sabater, E and Casado, MA., 2012, Budgetary impact analysis of Buprenorphine-Naloxone combination (Suboxone®) in Spain, Health Economic Reviews, Vol. 29, No. 21, pp. 3 Minozzi, S., Amato, L., and Davoli, M., 2009, Maintenance treatments for opiate dependent adolescent, Cochrane Database of systematic reviews, Vol. 15, No. 2, pp. 2. Moore, EA and Wilkinson, S., 2008, The Promise Of Low Dose Naltrexone Therapy: Potential Benefits in Cancer, Autoimmune, Neurological and Infectious Disorders, McFarland. Simpson K., Leyendecker, P., Hopp, M., Muller-Lissner, S., Lowenstein, O., De Andres, J., Troy Ferrarons, J., Bosse, B., Krain, B., Nichols, T., Kremers, W and Reimer, K., 2008, Fixed-ratio combination Oxycodone/Naloxone compared with Oxycodone alone for the relief of Opioid-induced Constipation in moderate-to- severe Non-Cancer pain, Current Medical Research And Opinion, Vol. 24, No. 12, pp. 3503 – 12. Sinatra, RS., Jahr, JS., and Watkins-Pitchford, M., 2010, The Essence Of Analgesia And Analgesics, Cambridge University Press. Read More