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Transcript
Experiment no. 2 FACTORS AFFECTING DRUG ACTION Influence of Chemical Structure C3 A. Macasaet, P. Macatangay, G. Madulara, C. Magno, P. Magsino, M. Malig, F. Mallari, S. Mamba, Jr., A. Manguba, Jr., M. Mangubat, S. Mansukhani, A. Manzana, C. Manzano, C. Maranion, K. Marasigan, E. Marayag, P. Marcelo, K. Marcial, E. Martin, M. Matematico, E. Matias, M. Maulion General Objective To determine the effects of Epinephrine, Dobutamine, and Terbutaline on heart rate and amplitude based on their chemical structure 2 Specific Objectives • To measure the rate and amplitude of baseline contractions of the turtle’s heart • To measure the rate and amplitude of contractions caused by each drug • To evaluate the results of each drug with p value set at 0.05 using oneway ANOVA 3 Animals 8 Turtles per drug Materials •Kymograph set-up •Dissecting set •Kymograph paper •Paste •Cotton thread •Surgical gloves •Tuberculin syringe •Tyrode solution •Heart hook • Surgical thread 4 Drugs Epinephrine (1:1000 ampule) Dobutamine (250mg/20mL) Terbutaline 2.5mg/mL 5 Methodology and Rationale 1. Apex of turtle’s heart was attached to a kymograph set up 2. Baseline rate and amplitude were obtained for 1 minute. 3. Drugs were directly instilled to the heart muscle (1 mL in 1 minute). 4. Rate and amplitude of contraction were recorded for three minutes from instillation 6 5. Tyrode or NSS solution was used to wash the heart after each drug administration 6. Results were recorded and subjected to statistical analysis. 7 8 Drugs Epinephrine • sympathomimetic, direct-acting • a potent vasoconstrictor and cardiac stimulant • acts on alpha-1, alpha-2, beta-1, and beta-2 receptors • increase peripheral resistance via alpha-1 vasoconstriction; beta-1 response is increased cardiac rate and output 9 Dobutamine • synthetic catecholamine • Beta agonist – beta-1 receptors >>> beta-2 receptors • lesser effect on alpha 1 receptors • primary activity: stimulation of the betaadrenoceptors of the heart – contractility, cardiac output • Used often in patients with heart failure – ( cardiac output ventricular filling pressure) 10 Terbutaline • Beta-2 selective • used as a fast-acting bronchodilator – often used as a shortterm asthma treatment • tocolytic to delay premature labour. 11 Rationale of Drugs • The structure of a sympathomimetic drug influences: – relative affinity for alpha and beta adrenergic receptors – intrinsic activity – pharmacokinetic properties 12 Structure-Activity Relationship Increase of the size of alkyl substituents on the amino group : increase beta receptor activity – activity is further increased if there is an isopropyl substitution at the amino nitrogen. – 2 selective agents: typically have a large amino substituent group. – as size of the substituent , activity at receptors . 13 DOBUTAMINE EPINEPHRINE TERBUTALINE 14 • Catecholamines have maximal and activity. – replacing the -OH groups at the 3 and 4 positions will reduce such activity – In terms of degree of reduction in potency at 3 & 4 positions: 3 position substitution > 4 position • Absence of the -OH groups – increases bioavailability & duration of action because the drug is no longer a substrate for COMT metabolism. • Replacing the -OH groups – also makes the resulting drug more widely distributed in the body 15 DOBUTAMINE EPINEPHRINE TERBUTALINE 16 • substitution at the carbon – prevents metabolism of a drug by MAO. – prolongs action of non-catecholamines. • substitution at the carbon is typical for direct-acting agonists. 17 DOBUTAMINE EPINEPHRINE TERBUTALINE 18 Expected Results Rate: Epinephrine>Dobutamine>Terbutaline Amplitude: Epinephrine>Dobutamine>Terbutaline 19 HYPOTHESIS Ho: There are no significant differences among the effects of drugs Ha: There are significant differences among the effects of drugs 20 Amplitude (% Difference) GROUPS EPINEPHRINE DOBUTAMINE TERBUTALINE A1 -20.0 -36.36 14.29 A2 -125.0 -30.0 0 B1 7.69 -50.0 37.5 B2 0.0 5.88 0 C1 -40.0 55.55 -14.29 C2 0 7.69 0 D1 -37.5 66.6 -25.0 D2 21.05 8.33 0 21 ANOVA: Single Factor SUMMARY Groups Count Sum Average Variance Column 1 8 -193.76 -24.22 2120.089 Column 2 8 -43.17 -5.39625 1123.22 Column 3 8 12.5 1.5625 345.7324 ANOVA Source of Variation SS Between Groups 2846.654 Within Groups Total df MS F P-value F crit 2 1423.327 1.189727 0.323997 3.4668 25123.29 21 1196.347 27969.94 23 22 • Since P value is not < 0.05, failed to reject null hypothesis. 23 RATE (% Difference) GROUPS EPINEPHRINE DOBUTAMINE TERBUTALINE 15.22 6.0 6.25 -8.11 -2.22 3.85 -4.08 -4.76 0 6.12 2.70 -11.90 A1 0.0 A2 -11.63 B1 8.16 B2 0.0 C1 8.33 C2 -11.63 D1 2.08 2.44 4.76 6.12 D2 -11.63 4.76 24 ANOVA: Single Factor SUMMARY Groups Count Sum Average Variance Column 1 8 -32.69 -4.08625 87.4814 Column 2 8 35.06 4.3825 41.50894 Column 3 8 -10.53 -1.31625 33.41308 df MS F P-value F crit 2.755321 0.086575 3.4668 ANOVA Source of Variation SS Between Groups 298.3157 2 149.1578 Within Groups 1136.824 21 54.13447 1435.14 23 Total 25 • Since P value is not < 0.05, failed to reject null hypothesis. 26 SOURCES OF ERROR • Bleeding • Trauma • Error on kymograph set-up 27 CONCLUSION • Epinephrine, which is a direct acting, mixed alpha and beta adrenergic agonist, has the greatest effect in increasing the rate and amplitude of contractions, followed by Dobutamine, a selective beta-1 agonist, and Terbutaline, a beta-2 selective drug, has the least effect. • The chemical structures of Epinephrine, Dobutamine, and Terbutaline indicates their selectivity and effect on heart rate and amplitude of contraction. • The rate and amplitude of baseline contractions of the turtle’s heart was measured using the kymograph. • Using One-Way ANOVA, the resulting P values of Amplitude and Rate are not less than 0.05, therefore, there are no significant differences among the effects of drugs. 28 Thank you! 29 Heart Rate A B C D Baseline Epinephrine Baseline Dobutamine Baseline Terbutaline 36 36 46 39 45 46 43 48 50 47 52 50 49 45 48 45 49 51 50 50 37 40 40 42 36 33 41 40 37 37 43 48 42 40 49 46 42 48 49 46 37 36 43 48 42 40 42 47 30 Amplitude A B C D Baseline Epinephrine Baseline Dobutamine Baseline Terbutaline 10 12 11 15 14 12 4 9 10 13 4 4 13 12 6 9 8 5 5 5 8.5 8 9 9 10 14 9 4 7 8 6 6 13 14 4 4 8 11 9 8 8 10 19 15 12 11 20 20 31 Recommendation 32