Chemical Structure of Lignocaine - Essay Example

Begin your drug profile by stating the chemical generic and the Australian trade s for your chosen drug. Chemical Acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-2-. (diethylamino)-2'6'-acetoxylidine. (Upfal 2006). Generic Name: Lidocaine Trade Names: lignocaine injection, Xylocaine, Xylocaine with adrenaline, Xylocard, Xyloproct suppositories, many ointments, gel, lotions and creams contain lignocaine (Upfal 2006). Other names: Anestacon, Esracaine, Gravocain, Leostesin, Lidoderm, Maricaine, Cappicaine. (Upfal 2006). Molecular weight : 234.33728. (Upfal 2006). Molecular formula: C14H22N2O. It is a generic and prescribed drug under Schedule S.3, 4 in Australia. Figure1: Chemical structure of Lignocaine. 2. a. List the approved indications for your drug. Approved indications of the Drug: Rectal: Pain and itching are relived temporarily from the area caused due to anorectal disorders. (Butler and Govindan 2010). Topical: it is mainly used as a local anesthetic for the cosmetic, laser and small surgeries and also for small burns, cuts and abrasions of skin. Patch: for the relief of pain associated with postherpetic neuralgia. It is used to relieve pain, to treat ventricular arrhythmias. (Butler and Govindan 2010). b. Determine whether your drug is approved for paramedic use in Australia, and if it is, list the approved paramedic indications for your drug. Paramedic Applications: This drug is approved for paramedic applications in Australia. Paramedic indications are 1. Suppression of ventricular arrhythmias 2. Prophylaxis against decreased ventricular tachycardia and ventricular fibrillation. 3. Frequent PVC’s 4. Pre-intubation for head trauma and for suspected Intra cranial hemorrhage. 5. Hypotension. (Stoller, Michota and Mandell 2009). 3. Add to your drug profile: 1. A list of conventional over-the-counter (OTC) medicines, complementary alternative medicines (CAMs) and prescription medicines that are known or suspected to undergo clinically relevant interactions with your profile drug IN HUMANS. Lidocaine Hydrochloride Xylocaine Zilactine –L AneCream Anestafoam Burn Jel Plus Burn Jel® L-M-X® 4 L-M-X® 5 LidaMantle Lidoderm LidoPatch LTAPremjact Regenecare RegenecareSolarcaine Topicaine Unburn (Kids health.org, 2012). 2. List the source(s) of information you have used and indicate the strength of the evidence (e.g. anecdotal report, clinical case, clinical trial, etc) for each of the interactions that you have identified. Rome, J.,2006. Mayo Clinic on Chronic Pain, Orient paperbacks. Kidshealth.org, 2012.kidshealth, Medications: what you should know, http://kidshealth.org/parent/medications/lidocaine_topical.html . 4. For your chosen drug: A. Describe the mechanism of action. Answer should: 1. Identify how the interaction of the drug with its molecular target(s) accounts for the major therapeutic effect (i.e. the effect you want the drug to cause in clinical practice; e.g. for paracetamol - pain relief) Lignocaine reversibly inhibits the conduction of action potentials in nerves and other excitable membranes. Lignocaine blocks the Voltage-gated Na + channels present in the neuronal membrane by acting as local anaesthetic. This type of blocking is very effective on all type of nerve fibres. The nerve fibres are first affected followed by the sensory and motor nerves. In the phase O of the cardiac potential, the antiarrhythmic effects of lignocaine occurs resulting in the blockage of the Na+ channels and leading to the reduced influx of the Sodium ions into the myocardial cell. The potential of the pacemaker is reduced by lignocaine resulting in the decreased heart beat rate. The duration of the action potential is reduced by increasing the effective refractory period and thus reducing the maximum rate of depolarization of the cardiac action potential. (Saeb-parsy etal, 1999). Lignocaine binds more readily with the inactivated Na+ channel. Lidocaine initially produces vasoconstriction but at later stages, it increases the vasodilation. This biphasic action increases the effects on the smooth muscle and sympathetic nerves. (Golan et al., 2011). 2. Include a description of how the drug alters function at the cellular level. Lidocaine was used as a tinnitus suppressing drug. Tinnitus is the perception of sound in the inner ear on the absence of the external sound. Lidocaine was found to suppress the effect of tinnitus by 40 – 80 5 when administered intravenously. (Langguth 2007). Lidocaine is a hydrological molecule, so it easily crosses the cellular membrane and reaches the blood brain barrier region. As Lidocaine reaches the round window, the diffusion into the cochlea cells occurs, thereby reducing the cochlear action potentials (CAPs) and cochlear micro phonics (CM). At the liver, lidocaine is metabolized by multifunction oxidases into monoethylglycine and xylide. (Langguth 2007). These metabolites have the partial antiarrythmic activity and also local anesthetic and toxic properties. Auditory brain stem response is produced in the Central nervous system after 60 minutes of administration of the drug. (Langguth 2007). 3. Include a description of how the altered cellular function manifests as a change in body system function and the eventual major therapeutic response Similarly abnormal sodium channels are the site of action of lidocaine for pain suppression. Lidocaine affects the hyper excitable neurons without affecting the normal nerve condition, thus proves that it has action on central nervous structures. (Langguth, 2007). Lidocaine was found to inhibit the production of T cell inflammatory cytokines. They are interleukin- 2, Tumor necrosis factor – alpha and interferon Gamma. This type of down regulation is found to be the result of inhibition of the mRNA expression. (Saeb-parsy etal, 1999). It was also concluded that Lidocaine does not cause cell death but it causes cell proliferation inhibition. The Potassium ion channels are blocked by the lidocaine and this in turn inhibits the NF-kappa B signaling pathway. (Lahat et al. 2008). The TNF- alpha expression was also found to be reduced in the presence of minimal concentration of lidocaine. (Lahat et al. 2008). 5. Critically review 2 ORIGINAL RESEARCH PEER REVIEWED journal articles that provide evidence for the clinical effectiveness of your drug IN HUMANS. Your response should identify and critique the: Article 1: Prevention of Propofol injection pain in Children: a Comparison of pretreatment with Tramadol and Propofol-Lidocaine mixture by Borazan et al. and published in 2012. Propofol injection is considered to be a most important problem for elimination in children. In this study, the efficiency of pretreatment with Tramadol and Propofol – Lidocaine was analyzed. This study was a controlled, placebo trial to compare the efficacy of pretreatment with Tramadol and Propofol Lidocaine mixture for the prevention of Propofol induced pain in children. (Borazan et al. 2012). This study comprises of 121 ASA I-II patients and they were divided to 3 groups. These patients were undergoing orthopedic and otolaryngological surgery. (Borazan et al. 2012). The first group received normal saline placebo and the second group received 180 mg of 1% Propofol with 1mg/kg Tramadol for 60 seconds. (Borazan et al. 2012). The third group received normal saline placebo before the administration of Propofol- Lidocaine mixture. It was found from this study that there was no significant difference in the characteristics and post operative variables among all the groups. Tramadol and Lidocaine reduced the Propofol pain in the children when compared to the control group. (Borazan et al. 2012). Article 2: Efficacy of combination Intravenous Lidocaine and Dexamethasone on Propofol injection pain: a Randomized, Double-blind, prospective study in adult Korean surgical patients written by KH Kwak, J Ha, Y Kim and Y Jeon and published in 2008 Propofol is a fast onset and smooth anesthetic induction method used for rapid recovery. Propofol is a popular intravenous anesthetic agent. But this method creates lot of pain in children when they are administered through the small vein on the dorsum of the hand. To overcome this pain, the vein is pretreated with Lidocaine. But this method is not effective for all children, so modification in the administration of lidocaine was analyzed in many studies. (Kwak et al. 2008). This study evaluates the analgesic effect of Dexamethasone alone and in combination with Lidocaine in Propofol injection. This is a double-blind, prospective trial with patients selected undergoing the elective plastic surgery. 140 patients were divided into four groups and the drugs were given randomly. (Kwak et al. 2008). Lidocaine 20 mg, Dexamethasone 6 mg, a combination of Lidocaine 20 mg and Dexamethasone 6 mg and normal saline were given as venous occlusion for 1 minute and Propofol was administered slowly through the dorsal hand vein. (Kwak et al. 2008). The pain intensity and incidence were calculated with scores ranging from 0 – 3. The patients were monitored for 24 hours after the injection for testing the efficacy. (Kwak et al. 2008). It was found that the patients who received the combination drug of Lidocaine and Dexamethasone with venous occlusion for one minute was very effective in relieving the Propofol injection pain in children. 6. 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. The renal clearance of Lidocaine is 3-5% for the adults. (Sdrales, Sdrales, and Miller 2012). The elimination half life of Lidocaine is twofold higher in the new born than adults. (Sdrales, Sdrales, and Miller 2012). The volume of distribution of Lidocaine is large in new born. The elimination causes decreased renal function. The reason for decreased effect is due to the primary metabolism in the liver and reduced hepatic blood flow. The water solubility of the Lidocaine limits the renal excretion. The clearance of Lidocaine form the body parallels the hepatic blood flow. The rate of metabolism of Lidocaine may be decreased due to congestive heart failure or liver disease. (Sdrales, Sdrales, and Miller 2012). Lidocaine has a very less pKa value and the drug is present in the neutral form, this characteristic of the drug is very essential for the drug to undergo a rapid diffusion in the cell membrane and quick onset of the response. Lidocaine has two methyl groups on its aromatic ring and enhances the hydrophobicity. (Lemke and Williams 2007). This hydrophobicity of the drug enhances the binding potential of the drug on the sodium channels. The onset of action is 1-3 minutes for Intravenous administration and 5 – 15 minutes for intramuscular administration and peak effect is shown within 15 minutes. (Golan et al. 2011). The drug has bioavailability of only 3 % when administered orally as they are inactivated during the first pass through the liver. (Langguth 2007). So, lidocaine should be administered parenterally. Due to metabolization in the liver, the bioavailability of the drug is around 30 percentage and experience a half life at the systemic circulation of 90 – 100 minutes only. (Langguth 2007). But it has a greater half life at the cerebrospinal fluid. Drug Metabolism For your chosen drug: 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. The drug is metabolized in the liver. At liver, the first nitrogen compound is dealkylated by the P450 enzymes. (Golan et al. 2011). The metabolites of lidocaine have very weak activity. . “Hepatic metabolism of lidocaine involves deethylation, leading to the formation of monoethylglycyl xylidine (MEGX) and glycine xylidine (GX). MEGX and GX have 83% and 10%, respectively, of the antiarrhythmic activity of the parent compound.” (Valdes, Jortani and Gheorghiade 1998). The inactive glycine xylidine is metabolized again into monoethylglycine and xylide. MEGX is a less potent metabolite than the parental drug and hence will accumulate because of its longer half life. Lidocaine toxicity is found to develop in the central nervous system and cardiovascular system. Lidocaine enters rapidly into the brain causing central nervous system dysfunction mainly seizures. (Langguth 2007). Depression of the cardiac pace makers also occurs. Hence care should be taken not to take more than 2mg/min of Lidocaine. (Flomenbaum et al. 2006). If the concentration increases then the toxicity occurs in 6 – 15 5 of the patients. Oral administration causes heavy toxicity than other routes. (Flomenbaum et al. 2006). If the hepatic metabolism is bypassed by administering lidocaine through mucosal surfaces, skin, subcutaneous tissues and oropharynx routes, the bioavailability of the parental compound increases and better the effects. (Flomenbaum et al. 2006). Side effects: Nervousness, anxiety, restlessness, dizziness, blurred vision, tremor, loss of consciousness, slowed pulse, low blood pressure, abnormal rhythm of the heart, rarely allergy, swelling of the lips, mouth and tongue. (Upfal 2006). 2. Identify the main metabolites (note those on your figure), and state the percent of the parent compound metabolised to the specific metabolite. Monoethylglycyl xylidine (MEGX) and glycine xylidine (GX) are the main metabolites of lidocaine due to deethylation. Glycine xylidine is inactive and it leads to monoethylglycine and xyllidine. 7. 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. Lidocaine and enzyme systems: Cytochrome P-450 enzymes were used in the N-deethylation of Lidocaine. CYP1A2 and CYP3A4 are found to catalyse the formation fo the metabolites MEGX and 3-OH-Lidocaine. (Wang et al. 2000). CYP1A2 is the major isoform that catalyzes the Lidocaine N-deethylation at low concentrations, whereas at high Lidocaine concentrations CYP3A4 is very important. (Wang et al. 2000). 3 –OH- Lidocaine was catalyzed less by CYP1A2 and CYP3A4. Chemical inhibition studies and immunoinhibition studies prove the same. Lidocaine is the local anesthetic used to relieve the symptoms of neuralgia. It was found that calcium dependent ATPase enzyme activity was inhibited by Lidocaine. (Sanchez et al. 2010). Calcium ionophore absence and preincubation of the sarcoplsmic reticulum membranes with Lidocaine increased the efficiency of calcium dependent ATPase activity. (Sanchez et al. 2010). This effect was due to the interaction of the drug with the enzyme. 8. For your drug: 1. List all known drug-drug interactions involving the metabolism of your drug. 1. Antiarrhythmic agents and lignocaine. 2. Beta- adrenergic blockers with lignocaine. 3. Cimetidine / Lignocaine. 4.lidocaine/nitrates and prenylamine. 2. Explain the mechanism of each of the interactions (i.e. Drug A inhibits the metabolism of Drug B by Enzyme X) Interactions with other Drugs: 1. Antiarrhythmic agents and lignocaine: The Combination of these drugs increases the risk of myocardial depression. 2. Beta- adrenergic blockers with lignocaine: The narrow therapeutic index of lignocaine increases the complication and this is reduced by the co- administration of propranolol. Propranolol increases the metabolic clearance and finally increases the risk of myocardial depression. (Griffin and D’arcy 1997). 3. Cimetidine / Lignocaine: Cimetidine on combination with lignocaine increases the risk of toxicity. To prevent and reduce the toxicity, lignocaine is infused very slowly to the patients. 4. The drug is also administered with nitrates and prenylamine. (Griffin and D’arcy 1997). References : Borazan, H., Sahin, O., Kececioglu, A., Uluer, MS and Otelcioglu, S., 2012. Prevention of Propofol injection pain in Children: a Comparison of pretreatment with Tramadol and Propofol-Lidocaine mixture, International Journal of Medical Sciences, Vol.9, No.6, pp. 492-497. Butler, S and Govindan, R., 2010. Essential Cancer Pharmacology: The Prescriber's Guide, Lippincott Williams and Wilkins. Flomenbaum, NE., Goldfrank, LR., Hoffman, RS., Howland, MA ., Lewin, NA and Nelson, LS., 2006. Goldfrank’s Toxicologic Emergencies, McGraw- Hill Professional. Golan, D., Tashjian, AH., Armstrong, EH and Armstrong, A., 2011. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, Lippincott Williams and Wilkins. Griffin, JP., and D’arcy, PF., 1997. A Manual Of Adverse Drug Interactions, Elsevier. Kidshealth.org, 2012.kidshealth, Medications: what you should know, http://kidshealth.org/parent/medications/lidocaine_topical.html , last retrieved on August 12, 2012. Kwak, KH., Ha, J., Kim, Y and Jeon, Y., 2008. Efficacy of combination intravenous Lidocaine and Dexamethasone on Propofol injection pain: a Randomized, Double-blind, prospective study in Adult Korean surgical patients, Clinical therapeutics, Vol.30, No.6, pp. 1113-9. Langguth, B., 2007. Tinnitus: Pathophysiology and Treatment, Elsevier. Lahat, A., Horin, SB., Lang, A., Fudim, E., Picard, O and Chowers, Y., 2008. Lidocaine down-regulates Nuclear factor-?B signalling and inhibits Cytokine production and T cell proliferation, Clinical and Experimental immunology, Vol.152, No.2, pp. 320- 327. Lemke, TL and Williams, DA., 2008. Foye's Principles of Medicinal Chemistry, Lippincott Williams and Wilkins. Rome, J.,2006. Mayo Clinic on Chronic Pain, Orient paperbacks Sanchez, GA., Casadoumecq, AC., Alonso, GL and Takara, D., 2010. Inhibitory effect of Lidocaine on the Sarcoplasmic reticulum Ca2+-dependent atpase from Temporalis muscle, Acta Odontologica Latinoamericana, Vol.23, No.2, pp. 92-98. Saeb-Parsy, K., Assomull, RG., Khan, FZ., Kelly, E., 1999. Instant Pharmacology, John Wiley and Sons. Stoller, JK., Michota, FA and Mandell, BF., 2009. The Cleveland Clinic Intensive Review of Internal Medicine, Lippincott Williams and Wilkins. Sdrales, LM., Sdrales, L and Miller, RD., 2012. Miller's Anesthesia Review: Expert Consult - Online and Print, Elsevier Health Sciences. Upfal, J., 2006. Australian Drug Guide, Black Inc., Valdes, R Jr., Jortani, SA and Gheorghiade, M., 1998. Standards of Laboratory Practice: Cardiac Drug monitoring, Clinical chemistry, Vol.44, No.5, pp. 1096- 1109. Wang, JS., Backman, JT., Taavitsainen, P., Neuvonen, PJ and Kivisto, KT., 2000. Involvement of CYP1A2 and CYP3A4 in Lidocaine N-deethylation and 3- Hydroxylation in Humans, Drug metabolism and Disposition: the Biological fate of Chemicals, Vol.28, No. 8, pp. 959 - 965. 1a. Metabolic pathway of paracetamol with the enzymes UTP, CYP and SULT: 1. Figure 1: metabolic pathway of Paracetamol (acetaminophen). (Lee and Williams 1996). b. Explain how the metabolism of paracetamol contributes to the hepatotoxicity caused by this drug. A drug can produce toxicity in different mechanisms. Paracetamol in normal doses it gets conjugated to the UDP- glucoronyl tranferase enzyme and sulfotransferase enzyme and gets converted into glucuronate and sulfate derivative. This is a conjugated pathway. After glucuronidation and sulfation , the compound gets converted into N-acetyl –p-benzoquinoneimine. Glutathione (GSH, gamma – glutamyl – cysteinyl – glycine tripeptide) combines with the benzoquinbone intermediate and produces mercapturic acid metabolites. During the overdoses, the complete reserve of GSH molecules are used by the benzoquinone intermediates and the toxic products are formed. The hepatotoxic effect of acetaminophen is increased by the increased concentration of NAPOI. The depletion og glutathione creates hepatotoxicity. (Lee and Williams 1996). c. Explain the mechanism of action of N-acetylcysteine as an antidote for the treatment of paracetamol overdose Paracetamol overdose can be treated with acetylcysteine, which is the natural precursor of glutathionine (GS). GSH is replaced by acetylcysteine and thus avoids the formation of toxic Benzaquinone metabolites. N-acetyl cysteine has been used for many decades for the treatment of overdoses of paracetamol. N-acetylcysteine is used as an antidote. N-acetyl cysteine is given as both oral and intravenous administration. N-acetyl cysteine must be administered within a few hours of drug administration. N-acetyl cysteine is rapidly hydrolysed to cysteine. Cysteine acts as a precursor to glutathione in the liver and the erythrocytes. N-acety cysteine also binds with the Paracetamol to form a conjugate. Thus Paracetamol induced hepatic necrosis is prevented by n-acetyl cysteine. (Maddison, Page and Church 2008). 2a. Explain briefly the mechanism of action of opioid agonists, such as morphine At the receptor regions, opioids act as agonists. These receptors are of three types. They are mu, kappa and delta receptors. The opioid receptors are the first neurotransmitters identified for their binding approaches. Each receptor has many sub types. They are found distributed in the brain, spinal cord, peripheral and autonomic nerves. Each receptor exhibits specificity for each drug. The opioid receptors belong to the family of G-protein coupled receptors. Morphine binds to the opioid receptors present in the central nervous system, gastrointestinal tract and urinary bladder. Hyperpolarization of the nerve cells and inhibition of the nerve firings and the transmitter are done by the opioids such as morphine. At the laminar I and II of the spinal cord, morphine acts at the kappa receptors and decreases the release of the pain perception substance from the spinal cord. Morphine also reduces the pain stimuli from the excitatory nerve transmitters. (Harvey and Champe 2008). b. List the physiological effects observed with opioid overdose 1. Bradycardia, tachycardia. 2. Respiratory depression. 3. Reduce oxygen consumption, cerebral blood flow and intracranial pressure. 4. Biliary colic 5. Slowing peristalsis. (Glodenberg and Glodstein 2010). c. Explain the pharmacological basis for the treatment of opioid overdose with naloxone, including the time-course of naloxone treatment. Naloxone reverses the opioid overdose effect; Naloxone competitively binds to opioid receptors and replaces the heroin molecules. Naloxone competitively binds to the mu, kappa and delta receptors. The patients with severe respiratory depression are given naloxone, a mu receptor antagonist, for increasing the oxygen flow rate and blood flow rate. Mechanical ventilation is also given to the patients. Initial intravenous dose of 0.4 – 0.8 mg is given for the recovery from respiratory depression and to reverse the neurologic depression. The onset of action is within 2 minutes. (Ries et al. 2009). 3a. Explain briefly the mechanism of the pharmacokinetic interaction between amiodarone and warfarin. Comment on the potential clinical implications of this interaction. Clinical implications of Amiodarone and Warfarin: Warfarin is the common oral anticoagulant given for inhibiting clotting factors which depends on vitamin k for synthesis and the coagulation inhibition proteins C and S. The half life of warfarin ranges from 6 to 60 hours. This drug is used for anticoagulation therapy in cardio version patients. Amiodarone is used for maintain the NSR in the AF patients. Amiodarone inhibits the warfarin metabolism and there by lead to extensive anticoagulation and increased bleeding risk. Amiodarone cause hyper or hypothyroidism in the patients under warfarin therapy. As amiodarone has a very long half life, it takes many days to reach the steady state. Similarly the coadminstration of warfarin and amiodarone requires INR monitoring for at least two weeks. (Dager, Gulseth and Nutescu 2011). b. Explain briefly the mechanism of the pharmacokinetic interaction between St John's wort and midazolam. Comment on the potential clinical implications of this interaction St.John’s Wort reduces the concentration of midazolam drug in the blood. The oral clearance was two times greater for the midozolam patients with St.John’s Wort. St.John’S wort is taken to clear the depression symptoms. It contains certain chemicals that mimic the CYP enzymes. The potential implications are the therapeutic failures, head ache, unplanned pregnancy, tremors and autonomic instability. (Bryant et al. 2010). References: Bryant, B., Bryant, BJ., Knights, KM and Salerno, E., 2010. Pharmacology for Health Professionals, Elsevier Australia. Berger, AM., Shuster, JM and Von Roenn, JH., 2006. Principles and Practice of Palliative Care and Supportive Oncology, Lippincott Williams & Wilkins. Dager, WE., Gulseth, MP and Nutescu, EA., 2011. Anticoagulation therapy: A point -of –care Guide, ASHP. Goldenberg, D and Goldstein, B., 2010. Handbook of Otolaryngology: Head and Neck Surgery, Thieme. Harvey, RA and Champe, PC., 2008. Lippincott’s Illustrated Reviews: Pharmacology, Lippincott’s Williams and Wilkins. Lee, WM and Williams, R.,1996. Acute liver failure, Cambridge University press. Maddison, JE., Page, SW and Church, D., 2008. Small Animal Clinical Pharmacology, Elsevier Health Sciences. Ries, RK., Miller, SC., Fiellin, DA., and Saitz, R., 2009. Principles of Addiction Medicine, Lippincott’s Williams and Wilkins. Read More