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Experiment 2: Factors Affecting Drug Action
A. INFLUENCE OF ROUTE OF ADMINISTRATION 2A – Med Subsection A2 Anacta, Klarizza Aquino, Unica Andal, Charlotte Ann Aramburo, Jan Christian Ang, Jessy Arcilla, Juan Martin Ang, Joanne Marie Argana, Desiree Ang, Kevin Francis Aribon, Pamela Ann Ang, Kimberly Arquiza, Paula Aningalan, Arvin Asuncion, Gewelene Antonio, Abigaille Ann Atienza, Vyron Aquende, Hershe Austria, Mary Martha Aquino, Arnold Cedric
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Objectives General Objectives
To determine how the route of administration influences the action of ketamine hydrochloride
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Objectives Specific Objectives
To determine the latency (sec) and duration of effect (sec) of ketamine hydrochloride when administered intravenously and intramuscularly To statistically determine if there is a significant difference between the (a) latencies and (b) durations of effect of ketamine hydrochloride in the IV and IM group To determine the effect of route of administration in the absorption and efficacy of ketamine hydrochloride
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Definition of terms: Latency/Time to Peak Effect - Time between initial administration and onset of the maximum expected effect. Duration of Effect - Length of time peak effect can be expected to last after a single administration of an anesthetic dose. Righting reflex - A reflex resulting in the body or a body segment tending to regain its former body position when it is displaced. ESSENTIALS FOR ANIMAL RESEARCH: A PRIMER FOR RESEARCH PERSONNEL Second Edition Marilyn J. Brown, D.V.M., M.S
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METHODOLOGY
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Ketamine hydrochloride
Preparation : 50mg/mL Dosage : 5mg/Kg 2-(O-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride
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Ketamine hydrochloride
water-soluble white crystalline pKa=7.5 commercially available pharmaceutical form is in aqueous solution
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2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone
Ketamine 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone
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Ketamine anesthetic drug
blocks the N-methyl-D-aspartate (NMDA) glutamate receptor = non- competitive NMDA-receptor antagonist inhibits activation of NMDA receptor by glutamate reduces presynaptic release of glutamate potentiates effects of GABA
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Experimental Animal: Rabbit
1 4 2 3 1 4 2 3 SECTION A SECTION B 1 4 2 3 1 4 2 3 SECTION C SECTION D
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Weighing
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Dosage Dosage of drug =(weight of rabbit)(5mg/kg)(1mL/50mg) e.g.: (1.5kg)(5mg/kg)(1mL/50mg) = 0.15mL
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Intramuscularly (IM) 1 3
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Intravenously (IV) 2 4
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Time of injection Time the righting reflex was lost Time the righting reflex was regained
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Righting reflex “static reflex”
bring the body into normal position in space resist forces acting to displace the body out of normal position turns a falling animal's body in space so that its paws or feet are pointed at the ground; hence, returns the animal to sternal recumbency after being placed on its back or side
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Rabbit with no righting reflex
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RESULTS and DISCUSSION
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Tabulation of results- Route of Administration
SECTION Latency Duration of Effect Intramuscular (seconds) Intravenous A 1 335 11 472 876 2 129 10 322 1112 B 3 170 31 172 371 4 217 30 147 361 C 5 76 7 852 995 6 150 9 517 1357 D 232 906 880 8 193 898 662 Mean 187.75 14 535.75 826.75 SD Variance 93.75
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Actual Results
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Actual Results
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Actual Results Latency (Mean) Duration (Mean) Intravenous = 14 seconds
Intramuscular = seconds Duration (Mean) Intravenous = seconds Intramuscular = seconds
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Hypothesis Ho: there is no significant difference in the latency/duration between intramuscular and intravenous administration H1: there is significant difference in the latency/duration between intramuscular and intravenous administration
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Formula for calculating independent t statistics
Test statistic Its value is used to decide whether or not the null hypothesis should be rejected in our hypothesis test = difference between population means = Pooled standard deviation
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Latency = √ 5275.44(8-1) + 93.75(8-1) t = (187.75 – 14) – 0
Count mean variance Standard deviation Intramuscular 8 187.75 72.63 Intravenous 14 93.75 9.68 = √ (8-1) (8-1) √ = 51.81 t = ( – 14) – 0 √1/8+1/8 = 7.00
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Critical region Set of values of the test statistic for which the null hypothesis is rejected in a hypothesis test df = n1+n2 -2 df = 14 Critical region =
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t = 7.00 Critical region = 1.76 Reject Ho Fail to reject Ho 1.76 7.00
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Duration Count mean variance Standard deviation Intramuscular 8 535.75 296.20 Intravenous 826.75 325.55 Sp= √ (8-1) (8-1) 8+8-2 Sp =311.22 t = ( – ) – 0 311.22√1/8+1/8 = -2.64
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Duration t = -2.64 Critical region : 1.7613 Reject Ho
Fail to reject Ho 1.76
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Actual Results: Statistics
Student t test t test for two independent variables Significance level = 0.05 Latency Intramuscular vs Intravenous P value < 0.05 There is significant difference Duration P value > 0.05 There is no significant difference
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Expected results IV route has faster onset of action than IM route
Duration of action is greater in IM than the IV route
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Intravenous Drug Administration
Intravenous (IV) [drug administered directly into the bloodstream] Avoids first pass metabolism Rapid and complete absorption [100% Bioavailability] Fastest rate of drug delivery and onset of action
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Intravenous Drug Administration
Maximal degree of control over drug circulating levels No way to stop response to drug (no recall)
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Intramuscular Drug Administration
Intramuscular (IM) - Rapid absorption and onset of action Uptake of drug dependent on blood flow at the injection site and solubility of the drug.
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IV versus IM Drug Administration
Onset of action is indeed faster in the IV route.
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DURATION OF ACTION
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Sources of Error Human Error:
The administration of drug was done by different experimenter The time of observation of latency and duration was done by different people
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CONCLUSION
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Onset of action IV route has faster onset of action than IM route
The onset of action is dependent on the route of administration
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Duration of action Duration of action in the intramuscular route is dependent on the solubility of the drug The IM route has a longer duration of action than the IV route
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References Howland, Richard and Mycek, Mary. Lippincott's Illustrated Reviews. Lippincott Williams and Wilkins, Katzung, Betram G. Basic and Clinical Pharmacology, 10th ed. The McGraw-Hill Companies, Inc, 2007.
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THANK YOU!
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Tolerance Repeated use of ketamine
users can develop a tolerance and/or dependence to the drug. Rises quickly with regular use and lasts about three days Can be very high and develop rapidly to the point where after a period of time users will no longer experience the dissociative effects they first began using Chronic use can cause development of a very high, almost permanent, tolerance to the drug.
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Ketamine Absorption Ketamine is rapidly absorbed when administered through the intramuscular (Tmax 5-15 min), nasal (Tmax 20 min) or oral route (as a solution) (Tmax 30 min). Bioavailability is low when ketamine is given orally (17%) or rectally (25%). Extensive first pass metabolism in liver and intestine is largely responsible for this effect. Bioavailability after nasal administration is approximately 50% (Malinovsky et al., 1996)
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Ketamine Distribution
Ketamine has a high lipid solubility and low plasma protein binding (12%), which facilitates rapid transfer across the blood- brain barrier. Initially it is distributed to highly perfused tissues, including the brain, to achieve levels 4-5 times those in plasma (distribution half-life after i.v. 24 sec.). CNS effects subside, following redistribution to less well-perfused tissues (re-distribution half-life 2.7 min.).
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Ketamine Metabolism Biotransformation primarily takes place in the liver. The most important pathway is N-demethylation to norketamine. When administered orally or rectally, initial plasma norketamine concentrations are higher than those of ketamine are, but the plasma area under the curve (AUC) for norketamine is similar for all routes of administration. Norketamine has one-third the anaesthetic potency of ketamine and has analgesic properties. Norketamine may be metabolised through multiple pathways, but the majority is hydroxylated and subsequently conjugated.
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Ketamine Elimination The predominant route of elimination is by liver metabolism. The high extraction rate (0.9) makes ketamine clearance susceptible to factors affecting blood flow. The conjugated hydroxy metabolites are mainly excreted renally. Terminal elimination half-lifes are ranging from minutes.
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