Drug Dependence and Abuse - Essay Example

? SALBUTAMOL SULFATE Chemical a1 tert-butylamino)methyl] -4-hydroxy-m-xylene-a, a'-diolsulfate (2 salt) Generic Salbutamol Sulfate Trade Names: As listed by Australia’s Department of Health and Ageing, Salbutamol sulfate is available in the market as Ventolinrotacaps or Ventolin syrup. It is also is available in the form of 2.5 or 5 single dose nebuliser solution. Brand names for such are Asmoluni-dose, GenRx Salbutamol, Butamol 2.5, Pharmacor Salbutamol, Salbutamol Sandoz, Salbutamol GA, VentolinNebules, and Salbutamol Sulfate. CFC-free oral free inhalers are available as Asmol CFC-free, Ventolin CFC-Free, Airomir and AiromirAutohaler (with breath actuated device), and APO Salbutamol inhaler. Indications: - bronchial asthma (RACGP, 2006; Lullman et al., 2000), - bronchitis (RACGP, 2006) - exercise-related dyspnea (RACGP, 2006) - other breathing problems (RACGP, 2006). - pre-term labour (Morgan et al., 1987). According to the Medical Reference Manual by Adult Retrieval Victoria (2011), Salbutamol (5-10 mg or 8 puffs 10-15 minutely) is one of the standard therapies for refractory asthma. Continuous nebulised Salbutamol is also used for maximum pre-intubation therapy. As well, the Queensland Ambulance Service (2011) lists approved emergency indications as bronchospasm and suspected hyperkalaemia with QRS widening and/or AV dissociation (Medical Director’s Office 2011 p. 69) for adult and paediatric administration (p. 70). Contraindications against paramedic use of salbutamol have been reported to include potential synergism with other sympathomimietics. It should also be used with caution in patients with diabetes, hyperthyroidism, and cerebrovascular disease (Albuterol 1999, p. 1). List of drug-drug interactions with Salbutamol (Albuterol 2011) Medicine name Strength Atomotexine – may cause CVS effects such as tachycardia and hypertension case reports Digitalis – hypokalemia induced by salbutamol may cause cardiac glycoside toxicity Mechanism already elucidated Diuretics – hypokalemia Steroids – hyperglycemia or hypokalemia Sympathomimetics – additive effects Theophylline – additive effects Xanthine derivatives –hypokalemia Bendrofluazide – augments hypokalemia, cardiac effects, arrhythmia Signal Transduction Mechanisms for ?2 Receptors Figure 1.The messenger system starting with the activation of receptor, which stimulates the G-protein to dissociate into its subunits. The ?-subunit then activates the enzyme converting ATP to cAMP. Figure from Guyton, A. C. and Hall, J. E. 2006. Textbook of Medical Physiology. Philadelphia: Elsevier. Salbutamol is an agonist of the beta 2 adrenergic receptors found on the smooth muscle lining airways of the lungs (Lullman, 2000). The intracellular components of the receptor are associated with G protein. In turn, G protein has three sub units (alpha sub unit, plus tightly associated beta, and gamma sub units). Upon binding of salbutamol to ?2 receptor, the latter activates the G protein, causing GDP (guanosine 5'-diphosphate) associated with the G protein to be phosphorylated to GTP (guanosine 5'- triphosphate), which initiates detachment of alpha subunit. The alpha subunit binds with adenylyl cyclase, which catalyses the conversion of ATP to cAMP (adenosine 5'-triphosphate to adenosine 3',5'-monophosphate) (Guyton and Hall, 2006). cAMP then inhibits myosin light chain kinase which is responsible for the contraction and hence constriction of bronchial smooth muscle (Klabunde, 2008). The inhibition of myosin light chain kinase promotes the physical relaxation and hence dilation of the smooth muscle lining of the affected airways which improves the potential for improved respiration which is key to addressing several pulmonary disorders Evidence of Clinical Effectiveness Despite being the most used ?2-agonist, research on the clinical effectiveness of Salbutamol had contradicting results. In a randomized control trial on salbutamol against preterm labor, 100 women, ages 17-32 years old and between 20-37 weeks pregnant, were recruited. The sample size was said to be more than enough to detect at least 10% difference between the sample groups. Unfortunately, it is unethical to use a placebo in this study because of the mortality and morbidity risk of potential outcomes for participating women. However, it might have been better if a matched-pair analysis was conducted, because the risks are different among pregnant women at different weeks of gestation. The primary outcome being measured was the prolongation of pregnancy for 48 hours, but vital signs, uterine contractions, and maternal blood pressure were measured regularly as well. The newborns were also checked up on after delivery. The results show that salbutamol was effective in increasing the pregnancy by 48 hours for most participants (84%). However, there were nine patients treated with salbutamol that had complications such as tachycardia, palpitations, anxiety and chills upon treatment. Neonates born from salbutamol-treated women also weigh less than those from terbutaline-treated women (Motazedian et al., 2010). In a double-blind study on children under 3 years of age with recurrent cough and wheezing found, two 1-week treatment periods using metered-dose inhaler of 100 µg Salbutamol was found to subjectively, using a five-level scoring system, relieve the symptoms of asthma. Unfortunately, no objective measurement was conducted, because of unfeasibility of such at that time (Conner et al., 1989). However, researcher bias and patient perception of the treatment’s effectiveness may affect the used subjective measure of the true outcomes. On the other hand, Chavasse et al. (2000) found that 200 ?g Salbutamol three times daily for two consecutive four-week treatment periods given to healthy infants aged 3 months-1 year with history of recurrent wheeze or night cough (more than 3 days/nights per week for at least six weeks) and atopy were only similar with placebo in respiratory effects determined both subjectively and objectively. In this double blind, randomised, placebo controlled, crossover trial, with each patient acting as their own control, four weeks were chosen to maximise the probability of the infant having at least one episode of upper respiratory tract infection (URTI) during each treatment period. Although not clarified, URTI was sought after to probably induce an episode/s of bronchoconstriction among the infants (Conner et al., 1989). The effects of the treatment were assessed by asking the parents to regularly monitor their children for certain parameters (presence of cough and wheeze, etc.). After which, pulmonary effects of 400 µg of Salbutamol were objectively assessed using laboratory tests. Although the authors concluded that salbutamol is not effective for infants, more studies should be conducted to verify the findings. It may be possible that salbutamol provided long term protection, or that the drug should be given using a different route (for example, oral). In the randomized, double-blind, controlled trial by Chang et al. (1998), 2 puffs a day of salbutamol (100 µg/puff) for 5-7 weeks did not prove to be better than placebo in decreasing the frequency of non-asthma related recurrent cough (2 episodes of cough, each lasting for two weeks in the past 12 months) in children (n=21 per treatment group), aged 4-17 years. The type of study was appropriate so that any psychological factors would not affect the results. Included in the exclusion criteria was URTI. Although not mentioned, it may have been included because they can only be treated with appropriate antibiotics. In measuring the cough, both objective (spirometry and cough meter) and subjective (cough score charts) means were used. These measures seem to be enough in achieving the objective. Despite the seemingly poor performance of salbutamol, the amount of Salbutamol given during this study may not be enough in producing significant benefits among the children. Renal Excretion of Salbutamol and its Metabolites Salbutamol sulfate is excreted renally (urine) and metabolized in the liver, typically byconjugation to the inactive salbutamol-4’-o-sulphate. Studies have found that peak plasmaconcentrations occur within 2-5 hours after ingestion. Half-life of salbutamol’s plasma is reported to be 2.7 to 5 hours after administration and indirectly estimated renally at 3.8 hours after inhalation. Unchanged drug and its metabolite are 72% excreted in the urine within the first 24 hour. Salbutamol Metabolism Figure 3. Salbutamol metabolism via sulphate conjugation through phenolsulfotransferase (PST), resulting to Salbutamol sulphate. Figure from Walle, T, Eaton, EA, Walle, UK, Pesola, GR: Stereoselective metabolism of RS-Albuterol in humans Clinical Reviews in Allergy and Immunology 1996, 14: 101-113. Sulfonation in the small intestine, liver and lung using phenolsulfotransferase, also known as sulfotransferase IA3 enzyme (SULTIA3), denoted in the figure as PST. The resulting Salbutamol sulphate (in red) is then released unto the urine. However, the rate of sulfation of bronchodilating R-Salbutamol is greater than the potentially toxic S-enantiomer. The former thus has a lower bioavailability than the latter (Walle et al., 1996). Sixty percent of the excreted drug is the metabolite (Albuterol, 2011). Sources of Variability in Salbutamol Metabolism The plasma levels of Salbutamol were found to be greater among asthmatics than healthy adults. This had been attributed to the higher intestinal permeability among asthmatics, or the lower amounts of inorganic sulphur needed for the conjugate reaction during the drug’s metabolism (Sjosward et al., 2003). In comparing the pharmacokinetics of the drug in pregnant females to that in males and non-pregnant females, it was observed that its renal clearance and urinary recovery of unmetabolized Salbutamol are significantly less for the former, showing slightly lower absorption of the drug during pregnancy (Hutchings et al., 1987). Drug-Drug Interactions i. There is no drug-drug interactions based on metabolism, because the drugslisted in RCAGP (2006) as those that interact with Salbutamol do so by aggravating its adverse effects or inhibiting its benefits. ii. This lack of interaction through metabolism is due to 2 factors. First, the inhaled route that Salbutamol usually takes has a relatively low systemic absorption. Most of the drug dose, if not innervating beta 2 receptors, is thus expired back into the air. Second, sulphotransferase binding specificity to inhibit the ?2-adrenoreceptor binding of salbutamol is quite rare. iii. Not applicable as there are no drug-drug interactions based on Salbutamol metabolism The oral bioavailability of salbutamol is 0.4 ± 0.72 µg (oral), 12.13 ± 3.66 µg (inhaler) and 14.97 ± 3.85 µg (nebuliser) (Silkstone, Corlett and Chrystyn, 2002). Drug Absorption For orally-administered Salbutamol, the R-enantiomer absorption occurs largely in the intestine, and this particular stereoisomer has a high first pass metabolism (Burton, 2006). The bioavailability of the drug is affected both by gastrointestinal absorption and first-pass hepatic extraction as both organs contain SULTIA3. Drug Formulation and Routes of Administration a. List of dose forms and strengths available in Australia (Department of Health and Ageing) Capsule, 200 µg (base) powder for oral inhalation Syrup, 2mg (base) / 5 ml single-dose nebuliser solution, 2.5 mg (base) / 2.5 ml single-dose nebuliser solution, 5 mg (base) / 2.5 ml nebuliser solution, 5 mg (base) / 1 ml (0.5%) CFC-free oral pressurized inhalant, 100 µg (base) / dose Salbutamol tablets can produce paradoxical bronchospasm. If such occurs, the drug should be discontinued. As well, it can produce cardiovascular effects, and as such must be used with caution when given to patients with cardiovascular disorders such as hypertension coronary insufficiency and arrhythmia. If asthma continues to worsen despite the medication, the patient and treatment regimen should be re-evaluated so that a different mode of delivery or drug may be used. Large doses of Salbutamol given IV should also be done with caution among diabetic patients as well, because of its effects in prolonging preterm labour, asthma patients who get pregnant should always seek medical advice. Drug Distribution Salbutamol binds to alpha acid protein, which binds basic drugs, at around 36-93%. However, the drug does not bind to albumin or lipoproteins (Burton, 2006). As such, the unbound fraction of Salbutamol is between 7-64% Volume of Distribution Volume of distribution of intravenously-administered Salbutamol is 130 ± 36 liters (Hutchings et al.?1987). It is thus high relative to the blood volume. The value of volume of distribution gives a clue on the tissue perfused with blood. A high volume of distribution implies that most of the dose has already reached the tissues, and that only little part of it remains in the blood. It may also mean that most of it is protein-bound (Kopacek, 2007). Loading Dose The loading dose of IV Salbutamol is 200 µg/min (Morgan et al., 1986). First-Pass Metabolism Orally-administered salbutamol has a high first-pass metabolism (Albuterol 2011). Thus, hepatic enzyme induction will cause a greater proportion of dose to be inactivated, while inhibition will cause a greater amount of dose to be active. Clearance Concepts Systemic total clearance is 501 ± 185 ml/min (Hutchings et al., 1987). Information available indicates intermediate hepatic clearance (Albuterol 2011). It takes 8 hours for 4 mg oral Salbutamol to reach steady-state (Morgan et al., 1986). Half-life The half-life of Salbutamol depends on the enantiomer in consideration and the route of delivery of the drug. In general, S-enantiomer (4.47 – 6.03 hours) has a longer half-life than the R-enantiomer (2.04 - 2.85 hours), regardless of the mode of delivery. In comparing IV, oral and intranasal route, IV has the shortest half-life, while oral has the longest (Burton, 2006). Therapeutic Drug Monitoring The pharmacodynamics parameters used to monitor the drug in a hospital setting include tachycardia, tremor, hypokalemia, arrhythmia, excessive sweating, nervousness and anxiety (Burton, 2006). Such may also be used in a community or emergency setting. The required dosage for salbutamol is age-dependent. A 2 mg dose of tablets given every 6 hours is recommended for children between the ages of 6 to 12 years. In cases in which the dose does not cause relief, it may be increased gradually to 24 mg/day (4 mg every 6 hours). As one grows up to 12 years and above, the dose of Salbutamol may be increased to 4 mg every 6 hours as needed. However, when such is not effective, the dose may be increased up to 8 mg four times a day if tolerated (Albuterol, 2011). The adjusted dosage in the administration salbutamol is mainly due to pharmacodynamic factors rather than pharmacokinetic factors. The significant differences prevalent with ageing groups are mainly morphological. Such variation may include such aspects as lung volumes, breathing patterns, and inspiratory flows. Other factors are minute ventilation, tidal volumes, and respiratory rates. These factors differ with age and, hence, how the drug can affect physiological function becomes different as well. Impact of disease states - Usually adjusted in individuals suffering hepatic disease. - adjustment in liver disease may be due to pharmacokinetic factors such as the effect of the drug in increasing the concentration of blood sugar and its activity in reducing the number of white blood cells (Johansson F 1996). Drug dependence, misuse and abuse Overdose may occur if an uninformed patient increases the dose beyond the limit to get relief of asthma. Salbutamol is prone to overdose because its action ?2 receptors may not be enough to induce significant bronchodilating effects to provide the patient adequate relief. As such, it may instead attach to other ? receptors, causing the sympathomimetic effects described earlier. The clinical signs and symptoms that can be seen from an overdosed patient include seizures, angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia, cardiac arrest and even death may also occur. As initial treatment for overdose, the patient should immediately discontinue the use of Salbutamol. Use of cardioselective beta-receptor blocker may also be considered, although it may cause bronchospasm (Albuterol, 2011). References Albuterol. (2011). Micromedex (updated Oct 20th, 2011). [Online]. Available from http://www.drugs.com/albuterol.html [Accessed November 1, 2011]. AlbulterolSulfate. (1999). Drug Profile for AlbuterolSulfate. Department of Health and Human Services. [Online.] Available from http://www.azdhs.gov/diro/admin_rules/guidancedocs/gd-028-phs-ems.pdf [Accessed October 31, 2011] ______. (2010). ‘GenRx Salbutamol Inhalation Ampoule’, Product Information – Australia (Jan.15). [Online]. Available from http://www.medicines.org.au/files/gxpsalbu.pdf [Accessed October 29, 2011] Burton, M.E. (2006). Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring. New York: Lippincott, Williams and Wilkins. Chang, A.B., Phelan, P.D., Carlin, J.B., Sawyer, S.M., & Robertson, C.F. (1998). A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 79: 6-11. Chavasse, R.J., Bastian-Lee, Y., Richter, H., Hilliard, T., &Seddon, P. Inhaled salbutamol for wheezy infants: a randomised controlled trial. Arch Dis Child 82: 370-375. Chen, X., Baker, S.M., & Cheng G. (2005). Methotrexate induction of human sulfotransferases in HepG2 and Caco-2 cells. Journal of Applied Toxicology, 25(5): 354-360. Conner, W.T., Dolovich, M.B., Frame, R.A., & Newhouse, M.T. (1989). Reliable Salbutamol Administration in 6- to 36-month-old Children by Means of a Metered Dose Inhaler And Aerochamber with Mask. Pediatric Pulmonology, 6: 263-267. Harvey, G. (2009). Rural Ambulance Victoria Community First Responder Program. [Online]. Available from http://www.health.vic.gov.au/archive/archive2009/bshconference/ppts/harvey_geof.pdf [Accessed October 30, 2011] Hutchings, M.J., Paull, J.D., Wilson-Evered, E., & Morgan, D.J. (1987). Pharmacokinetics of salbumatol in premature labour. Br. J. Clin. Pharmac, 24: 69-75. Johansson F., Rydberg I., Aberg G., & Andersson R.G. (1996). Effects of albuterol enantiomers on in vitro bronchial reactivity. Clin Rev Allergy Immunol, 14(1):57-64. Kenakin, T. (1993). Pharmacologic Analysis of Drug Receptor Interaction. 2nd Edition, RavenPress. Khan, M.H., & Javaid, A. (2007). Bronchodilator Response to Nebulized Salbutamol in Elderly Patients with Stable C.O.P.D. JPMI, 21(3): 222-226. Klabunde, R.E. (2008). Beta-adrenoceptoragonists (?-agonists). [Online]. Available from http://www.cvpharmacology.com/cardiostimulatory/beta-agonist.html [Accessed January 3, 2012] Kopacek, K.B. (2007). Drug Distribution to Tissues. [Online]. Available from http://www.merckmanuals.com/professional/clinical_pharmacology/pharmacokinetics/drug_distribution_to_tissues.html Lullman, H., Ziegler, A., Mohr, K., & Bieger, D. (2000). Color Atlas of Pharmacology. 2nd edition. New York: Thieme Stuttgart. Ma, B., Shou, M., & Schrag, M.L. (2003). Solvent effect on cDNA-expressed human sulfotransferase (SUKT) activities in vitro. Drug MetabDispos, 31(11): 1300-1305. Medical Director’s Office. (2011). Drug Therapy Guidelines (January to June 2011). Brisbane: Queensland Ambulance Service. Motazedian, S., Ghaffarpasand, F., Mojtahedi, K., & Asadi, N. (2010). Terbutaline versus salbutamol for suppression of preterm labor: a randomized control trial, 30(5): 370-375. Neipris, L. (2010). ‘Safe use of bronchodilators for asthma’, The Asthma Foundation of Victoria. ‘Salbutamol Sulfate’, Department of Health and Ageing. [Online]. Available from http://www.pbs.gov.au/medicine/item/1099W-1103C-2000G-2001H-2003K-3495Y-3496B-3497C-8288F-8354Q Silkstone, V.L., Corlett, S.A., & Chrystyn, H. (2002). Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulisation. Br J Clin Pharmacol, 54: 115-119. Sjosward, K.N., Josefsson, M., Ahlner, J., Andersson, R.G.G., & Schmekel B. (2003). Metabolism of salbutamol differs between asthmatic patients and healthy volunteers. Pharmacology and Toxicology, 92: 27-32. Sankar, M. et al. (1998). Molecular Pharmacology, 53, 347-354. Tay, T.; Das, S.; & Stewart, P. (2010). ‘Magnesium stearate increases salbutamol sulphate dispersion: what is the mechanism?’, Int J Pharm. (Jan 4), 383, 1-2, 62-69.Formatted: French (France). Travers A., Jones A.P., Kelly K., Barker S.J., Camargo C.A., & Rowe B.H. (2001). Intravenous beta2-agonistsfor acute asthma in the emergency department. Cochrane Database Syst Rev (2):CD002988. Ventolin. (2011). ‘NetDoctor’, referred from the Institute for Safe Medication Practices, Australia. [Online]. Available from http://ismp.org [Accessed November 1, 2011]. Ventolin. (2010). ‘Prescription Medicines’, GlaxoSmithKline. [Online]. Available from http://www.gsk.com/products/prescription-medicines/ventolin.htm [Accessed October 29,2011] VentolinNebules. (2009). eMC (Aug 27). [Online]. Available from http://www.medicines.org.uk/emc/medicine/102/SPC/Ventolin+Nebules+2.5mg,+5mg/ [Accessed November 1, 2011] Walle, T., Eaton, E.A., Walle, U.K., & Pesola, G.R. (1996). Stereoselective metabolism of RS-Albuterol in humans. Clinical Reviews in Allergy and Immunology, 14: 101-113. [Online]. Available from http://www.asthma.org.au/Publications/tabid/62/Publications/36/Safe-use-ofbronchodilators-for-asthma.aspx [Accessed October 29, 2011] ______. (2006). ‘Salbutamol Inhalation Solution’, Royal Australian College of General Practitioners (RACGP). [Online]. Available from http://www.racgp.org.au/cmi/pucsalbu.pdf [Accessed January 2, 2011] ______. (2001). ‘New Drugs’, Australian Prescriber, 24, 43-47. ______. (1999). ‘New Drugs’, Australian Prescriber, 22, 147-51. Read More

 

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