Intravenous Anesthetics - Research Proposal Example

Intravenous anaesthetics 0 INTRODUCTION 1 SECTION Background of intravenous anaesthetics Intravenous (IV) anaesthetic agents are commonly used to induce anaesthesia since induction is often smoother as well as more rapid as compared to that associated with the majority of the inhalational agents as per McKenzi, (2008). Intravenous anaesthetics can as well be used for maintenance, either alone or in together with nitrous oxide (Davies & Cashman, 2006). These anaesthetic agents may be given as continuous I.V infusion or repeated bolus doses. Other uses are sedation during regional anaesthesia and in the intensive therapy unit (ITU) along with management of status epilepticus. 1.1 .1 Properties of ideal intravenous anaesthetics For an intravenous anaesthetic to be considered ideal, it should have some properties. However, no agent meets the entire properties needed. An ideal intravenous anaesthetic agent should have a rapid onset. This is attained by an agent that is largely unionized at pH of the blood pH and should be highly soluble in lipid. These properties allow penetration into the blood–brain barrier (Pandit, 2011). Secondly, the agent should depict a quick recovery. Early recovery of consciousness often results from rapid drug redistribution from the brain into other well-perfused tissues, principally muscles. The drug plasma concentration reduces, and the drug diffuses from the brain along a concentration gradient (Pandit, 2011). The eminence of the later recovery time is related more to the drug metabolism rate. Agents with slow metabolism are associated with a prolonged ‘hangover’ effect and builds up if used in repeated doses. Thirdly, the ideal agents should depict analgesia at sub-anesthetic concentrations. It should have minimal cardiovascular as well as respiratory depression as an effect (Evers, Maze & Kharasch, 2011). Moreover, it should not side effects like emesis, pain on injection, the release of histamine, hypersensitivity reaction, and e.t.c. Like any other drug, IV anesthetic agents should not have toxic effects on other organs and should have long shelf-life (Pandit, 2011). 1.1.2 Pharmacokinetics of intravenous anaesthetics. Following IV administration of a drug, there is an instant quick increase in plasma concentration then followed by a slower decline. Anaesthesia is come by the diffusion of drug from the arterial blood into the brain across the blood–brain barrier. The anaesthetic effect, as well as the rate of transfer into the brain, is regulated by; blood flow to the brain, protein binding; extracellular pH and drug pK, the relative solubilities of the drug in water and lipid, and speed of injection (Evers, Maze & Kharasch, 2011). Distribution After administration of IV anaesthetic agent, the concentration of the agent in the blood reduces as the distribution occurs in the viscera, especially the muscle. Davies & Cashman, (2006) asserts that the drug diffuses into blood from the brain along the changing concentration gradient, and the patient regains consciousness. Metabolism and Excretion Metabolism of most IV anaesthetic drugs takes place mainly in the liver. Metabolism is fast designated by a short elimination half-life. Because of the large distribution volume of intravenous anaesthetic drugs, total elimination takes several hours, or, in some cases, days. A small part of the drug may be excreted unchanged in the urine; the amount is determined by the degree of ionization as well as urine pH as per Davies & Cashman, (2006). 1.1.3 Most common intravenous anaesthetics used for urodynamic procedures Urodynamic procedures are conducted to assess and treat the possible disorders likely to occur in the lower urinary tract. It also manages the coordination between detrusor muscles and the sphincter muscles. The typical used intravenous anaesthetics in the procedure are only three. They are midazolam, ketamine, and propofol. They mostly reduce the contractile responses of the smooth muscles of several organs of the body. These intravenous anaesthetics affect the contractile activity performed by detrusor smooth muscle (Miller, 2010). 1.1.4 Reasons for compare intravenous anaesthetics: The intravenous anaesthetics work differently and so have different effects on their use (Ceran, 2010). They have to be compared so as to identify which one is the best to use for a particular case. In their comparison, one needs to look at a number of issues. Recovery duration needs to be considered. The drug with the rapid recovery is better to use since it has a minimal likelihood of health complications (Shah et al., 2010). They can also be compared on the issue of side effects the anaesthetic may contribute after the procedure. The characteristics of the drugs will help in analyzing to determine their different qualities. It will help identify what agent to prefer for better performance. 1.2 SECTION 2: Pharmacology of most common intravenous anaesthetics 1.2.1 Ketamine Pharmacology Ketamine is a fast-acting general anaesthesia producing an anaesthetic state characterized by normal pharyngeal-laryngeal reflexes, profound analgesia, normal or slightly enhanced skeletal muscle tone, respiratory and cardiovascular stimulation, and sometimes a transient and negligible respiratory depression. Shah et al., (2010) asserts that after intravenous administration, the ketamine concentration has a first phase that lasts about 45 minutes with a half-life of about 15 minutes (Tang et al,.2014). This initial phase corresponds clinically to the drugs’ anaesthetic effect. The anaesthetic action ends due to the redistribution from the CNS to slower equilibrating peripheral tissues as well as by liver biotransformation to metabolite I. This metabolite is approximately 33% as active as ketamine in lowering halothane requirements of the rat. The later half-life of ketamine (beta phase) is about 2 hours 30 minutes. According to McKenzi, (2008) ketamine produces an anaesthetic state that is considered dissociative anaesthesia since it appears to interrupt selectively brains’ association pathways prior to producing somesthetic sensory blockade. It can selectively depress the thalamoneocortical system before considerably obtunding the more primordial cerebral centres and pathways. A rise in blood pressure starts shortly after injection and reaches a maximum after a few minutes. It then returns to pre-anaesthetic values within 15 minutes following administration. In most cases, the diastolic and systolic blood pressure peaks from 10% to 50% above pre-anaesthetic levels in a while after induction of anaesthesia, but the rise can be longer or higher in individual cases. Ketamine has a wide safety margin; when administered in overdoses it leads to prolonged but total recovery (Dzikiti, 2010). 1.2.2 Propofol Pharmacology Propofol has sedative-hypnotic properties. It is formulated as an emulsion for clinical use because of its slight solubility in water. Moreover, it is highly lipophilic and distributes expansively in the body. Propofol blood concentration-time profile following an IV bolus injection depicts a three-compartment model with 2-4 min, 30-45 min, and 3-63 h half-lives respectively. The drug is comprehensively metabolised by the liver before being eliminated by the kidney. After an IV dose of 2-2.5 mg/kg, loss of consciousness results in less than a minute and lasts for about five minutes (Shah et al., 2010). Blood concentrations of 1.5-6 micrograms/mL of propofol can maintain hypnosis in the presence of N2O/O2 at 60:40 ratio or other anaesthetic agents. During induction, propofol reduces the diastolic and systolic blood pressure by about 20-30 percent with a minute change in pulse rate; apnea is as well common. Because of its pharmacokinetic profile, the drug is commonly used in the continuous infusion for anaesthesia maintenance as established by Dzikiti, (2010). When used as the primary anaesthetic agent, it produces suitable anaesthesia with fast recovery and with no major adverse effects. Propofol can be used as an alternative to inhalation anaesthetics in continuous infusion. 1.2.3 Midazolam Pharmacology Midazolam is an imidazobenzodiazepine with distinctive properties as compared to other benzodiazepines. It is highly lipid soluble in vivo but water soluble in its acid formulation. Furthermore, it has a moderately rapid onset of action as well as high metabolic clearance as compared to other benzodiazepines (Dzikiti, 2010). After administration intramuscularly, orally, or intravenously, the drug produces amnesia, reliable hypnosis, and antianxiety effects. Midazolam is used in the perioperative period that includes premedication, induction and maintenance, as well as sedation for therapeutic and diagnostic procedures (Shah et al., 2010). Midazolam is preferred than diazepam in most clinical situations since it has fast, non-painful induction and does not have venous irritation. 1.3 SECTION 3 Bladder Anatomies The bladder anatomy makes muscular sac-like that acts as a urine reservoir that lies within the pelvis. Health bladder coordinates musculoskeletal, psychological and neurological functions to allow filling and emptying of its contents. The bladder has several parts as seen in the diagram. The ureters transports materials collected by the kidney for excretion and move them to the urinary bladder. The ureter finds its path towards the posterior end. It is muscular and has three tissue layers that are the fibrous outer coat, muscular layer, and inner mucosal layer (Colville & Bassert, 2015). The muscle layer propels urine towards the opening of the bladder through peristalsis. The urinary bladder has fibrous connective tissues on the outer surface that have an inside layer called detrusor muscles. They contract to remove urine out of the bladder. Submucosa tissue is elastic fibrous membrane and supports mucosa inside the bladder. The mucosa has transitional epithelium. When the bladder is, empty mucosa forms fold called rugae. The traditional epithelium and rugae enable the bladder to stretch when urine flows into it. Sphincter muscles lie at the bottom of the bladder. It’s innervated so that when the bladder is almost full the animal feels to urinate. The urethra creates a passage of urine out of the body (Reece, 2013). 1.4 SECTION 4: Organ bath Technique The organ bath technique is a set-up that is usually used to investigate the pharmacology and physiology of in vitro tissue preparations. Perfused tissues can be maintained for some hours in an organ bath that has temperatures controlled for some time; after that the researcher can start the experiments. Typical experiments entail the adding up of drugs to the organ bath or direct stimulation of the tissue. The tissue reacts by relaxing/ contracting, and an isotonic/ isometric transducer is used to gauge displacement or force, respectively (Andersson & Arner, 2004). Dose-response curves are then generated i.e. tissue response against dosage of drug or stimulus potency. For this case, smooth muscle of the bladder will be used as the tissues. Tissues are normally prepared in a petri-dish that has a physiological solution like Kreb’s solution. The tissue ends are then fixed to the transducer and mounting hook using silk. Fig 2: Extracting Detrusor muscle Fig 3: Organ Bath setting 1.5 Objectives To find out if there is possible interactions between anaesthetic agents and the contractile activity of detrusor muscle. 1.6 Aims and Hypothesis The aim of the study is to find out the effects of intravenous anaesthetics on the bladder smooth muscle contractile activity. Hypothesis: Propofol, midazolam and ketamine alter the detrusor smooth muscle contractile activity. 1.7 References Andersson KE, Arner A.(2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84:935-86. Ceran C, Pampal A, Goktas O, Pampal HK, &Olmez E (2010). Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder. Indian journal of urology : IJU : journal of the Urological Society of India, 26 (3), 364-8 PMID: 21116355 Colville, T. P., & Bassert, J. M. (2015). Clinical anatomy and physiology for veterinary technicians. Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder. (n.d.). Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978435/ Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder. (n.d.). Retrieved from http://www.pubfacts.com/detail/21116355/Commonly-used-intravenous-anesthetics-decrease-bladder-contractility-An-in-vitro-study-of-the-effect Davies, N. J. H., & Cashman, J. N. (2006). Lees Synopsis of anaesthesia. Philadelphia: Elsevier/Butterworth Heinemann. Dzikiti, T.B., Stegmann, G.F., Dzikiti, L.N. &Hellebrekers, L.J., 2010, ‘Total intravenous anaesthesia (TIVA) with propofol-fentanyl and propofol-midazolam combinations in spontaneously breathing goats’, Veterinary Anaesthesia and Analgesia 37, 519–525. http://dx.doi.org/10.1111/j.1467-2995.2010.00568.x, PMid:21072973 Evers, A. S., Maze, M., & Kharasch, E. D. (2011). Anesthetic pharmacology. Cambridge: Cambridge University Press. Hong Chai Tang, Wai Ping Lam, Xin Zhang, Ping-Chung Leung, David T Yew, Willmann Liang. Chronic ketamine treatment-induced changes in contractility characteristics of the mouse detrusor. Int Urol Nephrol 2014 Aug 12;46(8):1563-71. Epub 2014 Mar 12. McKenzi, G., 2008, ‘Total intravenous anesthesia – TIVA’, Iranian Journal of Veterinary Surgery suppl. 2 (2nd ISVS and 7th ISVSAR), 108–117 Medknow Publications: Publisher of peer reviewed scholarly journals (Open access / subscription based). (n.d.). Retrieved from http://www.medknow.com/aim_full.asp?i=11F9C8091EB6D18D5DABFA31032C3CFEB89508C7F0493C0448CE9B0465C732AD Miller, R. D. (2010). Millers anesthesia: 1. Philadelphia, PA: Churchill Livingstone/Elsevier. Pandit, J. J. (2011). Intravenous anaesthetic agents. Anaesthesia & Intensive Care Medicine. doi:10.1016/j.mpaic.2010.12.010 Reece, W. O. (2013). Functional Anatomy and Physiology of Domestic Animals. Arnes, AI: Wiley Shah, P., Dubey, K., Watti, C., & Lalwani, J. (2010). Effectiveness of thiopentone, propofol and midazolam as an ideal intravenous anaesthetic agent for modified electroconvulsive therapy: A comparative study. Indian Journal of Anaesthesia. doi:10.4103/0019-5049.68371 Somogyi GT, Yokoyama T, Szell EA, Smith CP, de Groat WC, Huard J, Chancellor MB: Effect of cryoinjury on the contractile parameters of bladder strips: a model of impaired detrusor contractility.Brain Res Bull 2002, 59:23-28. PubMed Abstract | Publisher Full Text OpenURLJNeurosci 2005, 115:405-410. OpenURL Unbound MEDLINE : Chronic ketamine treatment-induced changes in contractility characteristics of the mouse detruso. (n.d.). Retrieved from http://www.unboundmedicine.com/medline/citation/24615617/Chronic_ketamine_treatment_induced_changes_in_contractility_characteristics_of_the_mouse_detrusor West, G., Heard, D., & Caulkett, N. (2013). Zoo Animal and Wildlife Immobilization and Anesthesia. New York, NY: John Wiley & Sons Read More