{"id":393,"date":"2020-02-16T11:15:38","date_gmt":"2020-02-16T05:45:38","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=393"},"modified":"2020-02-16T11:15:38","modified_gmt":"2020-02-16T05:45:38","slug":"evaluation-of-anti-anginal-drugs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/evaluation-of-anti-anginal-drugs\/","title":{"rendered":"Evaluation of Anti-anginal Drugs"},"content":{"rendered":"\n

Eval of antianginals:<\/u><\/strong><\/p>\n\n\n\n

  1. Limitations of present drugs:
    1. Affect hemodynamic parameters.<\/li><\/ol>
      1. Do not protect the heart against stress induced adrenergic effects.<\/li><\/ol>
        1. Tolerance develops.<\/li><\/ol>
          1. Beneficial effects are short-lived.<\/li><\/ol><\/li><\/ol>\n\n\n\n

            In-vitro methods:<\/strong><\/p>\n\n\n\n

            1. Isolated heart (Langendorff) technique<\/li>
            2. Isolated heart-lung preparation<\/li>
            3. Calcium antagonism in isolated rabbit aorta<\/li>
            4. Relaxation of bovine coronary artery<\/li>
            5. Coronary artery ligation in isolated rat heart<\/li>
            6. Plastic casts from coronary vasculature in dogs<\/li><\/ol>\n\n\n\n

              Isolated heart (Langendorff) preparation<\/strong><\/p>\n\n\n\n

              • Principle: <\/strong>heart is perfused in a retrograde direction from aorta which closes aortic valves. So the perfusate enters coronary circulation. <\/strong><\/li><\/ul>\n\n\n\n
                \"\"<\/figure>\n\n\n\n
                • Procedure for excision of heart \u00e0 Anaesthesia \u00e0 Heart is excised along with aorta \u00e0 Cannulation of aorta \u00e0 Perfusion fluid \u00e0 Assessment of contractile function<\/li><\/ul>\n\n\n\n

                  Indices measured<\/strong><\/p>\n\n\n\n

                  1. Morphology of heart<\/li>
                  2. Biochemistry<\/li>
                  3. Cardiac rhythm and electrophysiology<\/li>
                  4. Contractile function of heart<\/li>
                  5. Coronary flow<\/li>
                  6. Pharmacology<\/li>
                  7. Arrhythmias<\/li>
                  8. K+ <\/sup>levels<\/li>
                  9. Calcium antagonism<\/li>
                  10. EDRF release from coronary bed<\/li>
                  11. Electrophysiological evaluation of CV agents<\/li><\/ol>\n\n\n\n

                    Advantages<\/strong><\/p>\n\n\n\n

                    • Highly reproducible, low cost and large numbers can be studied<\/li>
                    • Broad spectrum parameters can be measured<\/li>
                    • Absence of confounding factors (neurohormonal)<\/li>
                    • Allows induction of regional or global ischemia<\/li>
                    • Hypoxia can be imposed<\/li>
                    • Ischemia-reperfusion and arrhythmia studies<\/li><\/ul>\n\n\n\n

                      Disadvantage<\/strong><\/p>\n\n\n\n

                      • Constantly deteriorating preparation<\/li><\/ul>\n\n\n\n

                        Isolated heart-lung preparation<\/strong><\/p>\n\n\n\n

                        \"\"<\/figure>\n\n\n\n
                        \"\"<\/figure>\n\n\n\n

                        Isolated rabbit aorta:<\/strong><\/p>\n\n\n\n

                        Rabbit sacrificed \u00e0<\/p>\n\n\n\n

                        Abdominal aorta isolated, cut into small rings and mounted in tissue bath containing Krebs buffer \u00e0<\/p>\n\n\n\n

                        Addition of Kcl or NE induces contraction in the aortic rings.<\/p>\n\n\n\n

                        \"\"<\/figure>\n\n\n\n

                        Relaxation of bovine arteries<\/strong>:<\/p>\n\n\n\n

                        \"\"<\/figure>\n\n\n\n
                        • Coronary artery ligation<\/strong>:<\/li><\/ul>\n\n\n\n
                          \"\"<\/figure>\n\n\n\n
                          \"\"<\/figure>\n\n\n\n
                          • Plastic casts<\/strong>:<\/li><\/ul>\n\n\n\n
                            \"\"<\/figure>\n\n\n\n
                            • In-vivo methods:<\/strong>
                              • Occlusion of coronary artery<\/li><\/ul>
                                • Microspheres-induced acute ischemia<\/li><\/ul>
                                  • Isoproterenol-induced myocardial necrosis<\/li><\/ul>
                                    • Stenosis-induced coronary thrombosis model<\/li><\/ul>
                                      • Electrical stimulation-induced coronary thrombosis<\/li><\/ul>
                                        • Myocardial ischemic preconditioning model<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                          • Occlusion of coronary artery in dogs:<\/strong><\/li><\/ul>\n\n\n\n
                                            \"\"<\/figure>\n\n\n\n

                                            Using Barium sulphate coronary arteriograms are made and infarcted area measured using X ray.<\/p>\n\n\n\n

                                            P-Nitro blue tetrazolium is used to visualize infarcted area. These are compared between test and control.<\/p>\n\n\n\n

                                            • Microsphere induced acute ischemia<\/strong>:
                                              • Dog anesthetized.<\/li><\/ul>
                                                • Micro-spheres are injected into the LCA to induce ischemia.<\/li><\/ul>
                                                  • Test\/control administered.<\/li><\/ul>
                                                    • Parameters measured: Systolic and Diastolic pressure, LVEDP, HR, Pulmonary capillary pressure, PAP, COP between test and control.<\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                      • Isoproterenol induced Myocardial necrosis<\/strong>:<\/li><\/ul>\n\n\n\n
                                                        \"\"<\/figure>\n\n\n\n
                                                        • Parameters measured: Systolic and Diastolic pressure, LVEDP, HR, Pulmonary capillary pressure, PAP, COP and compared between test and control.<\/li><\/ul>\n\n\n\n
                                                          \"\"<\/figure>\n\n\n\n
                                                          \"\"<\/figure>\n\n\n\n

                                                          Ischemic preconditioning model<\/strong>:<\/p>\n\n\n\n

                                                          • Rationale is that preconditioning decreases the damage caused by ischemia-reperfusion injury and this model tests those drugs that help in up-regulating the ischemic preconditioning. <\/li>
                                                          • Rabbit are anesthetized.<\/li>
                                                          • The LCA is ligated for 5 min and then released for 10 min.<\/li>
                                                          • Test\/control or vehicle is administered.  <\/li>
                                                          • This is f\/b again ligating the LCA for 30 minutes and then re-perfusing.<\/li>
                                                          • The hemodynamic parameters are compared b\/w test and control.<\/li><\/ul>\n\n\n\n

                                                            Measurement of coronary blood flow:<\/strong><\/p>\n\n\n\n

                                                            1. Electromagnetic flowmeter<\/li>
                                                            2. Inert gas technique<\/li>
                                                            3. Radioactive technique<\/li>
                                                            4. Radioactive microsphere technique<\/li>
                                                            5. Thermodilution technique<\/li>
                                                            6. Coronary arteriography<\/li><\/ol>\n\n\n\n
                                                              • Electromagnetic flow-meter<\/strong>: Two opposite magnetic poles are placed on either side of a coronary vessel. Distally two chromium-vanadium electrodes are placed adhering to the coronary vessel. The magnetic field perpendicular to blood flow generates a voltage which is picked up by electrodes and recorded.<\/li><\/ul>\n\n\n\n
                                                                • Clinical evaluation:<\/strong><\/li>
                                                                • Criteria (Parameters) of efficacy:<\/li>
                                                                • Exercise capacity <\/strong>(total exercise time, maximum MET[metabolic equivalent of task] level achieved, maximum workload achieved, maximum heart rate and the double product.)<\/li>
                                                                • ECG characters:<\/strong> Time to onset of angina, time to ST depression (by 1 mm), magnitude of ST, time taken for normalization after ST depression, exercise induced ventricular arrhythmias<\/li>
                                                                • Coronary diameter<\/li>
                                                                • Frequency of anginal pain\/need to consume short acting nitrates<\/li>
                                                                • HRQOL<\/li>
                                                                • Morbidity and mortality (since the target of anti-anginal therapy is essentially symptoms control, at present, there is no requirement to prove beneficial effect on these variables in terms of efficacy)<\/li><\/ul>\n\n\n\n
                                                                  • Phase 1:<\/li>
                                                                  • Subjects:<\/li>
                                                                  • Patients with stable angina pectoris for preceding 4 weeks without any change.<\/li>
                                                                  • Patients with stable angina, 6 months after revascularization<\/li>
                                                                  • Patients with stable angina 30 days after MI<\/li>
                                                                  • Stable means last <20 minutes and relieved immediately by rest.<\/li><\/ul>\n\n\n\n
                                                                    • Parameters:<\/li>
                                                                    • Pharmacodynamic: hemodynamic effects at rest and during exercise (can be documented by MRI or myocardial perfusion imaging). EXERCISE PARAMETERS, EFFECT ON RENAL FUNCTION, PULMONARY FUNCTION, PLAETLET FUNCTION, GLUCOSE AND LIPID METAB.<\/strong><\/li>
                                                                    • PK: Cmax, Tmax, t1\/2, AUC<\/li>
                                                                    • Interactions: Pharmacokinetic and pharmacodynamic interactions should be investigated primarily with other frequently coadministered drugs in the target population.<\/li><\/ul>\n\n\n\n
                                                                      • Phase 2:<\/li>
                                                                      • Subjects: Same as phase 1<\/li>
                                                                      • Parameters: CRITERIA FOR EFFICACY EXPLAINED ABOVE<\/strong><\/li>
                                                                      • Design: randomized, placebo-controlled and double-blinded<\/li>
                                                                      • Wash-out: Withdrawal of ongoing anti-anginal meds<\/li>
                                                                      • Placebo run-in: 2 weeks atleast. Short acting nitrates for exacerbations are allowed in this period.<\/li>
                                                                      • Dosing interval: atleast 6 weeks to establish clinically useful dose range. Atleast 3 doses should be used.<\/li><\/ul>\n\n\n\n
                                                                        • Phase 3:<\/li>
                                                                        • Subjects: Same as phase 1<\/li>
                                                                        • Parameters: CRITERIA FOR EFFICACY EXPLAINED ABOVE<\/strong><\/li>
                                                                        • Design: randomized, active-controlled and double-blinded. Dose from phase 2 should be chosen. Should be of atleast 12 weeks.<\/li>
                                                                        • Studies where the new drug is administered as both monotherapy and add-on therapy should be carried out.<\/li><\/ul>\n\n\n\n

                                                                          <\/p>\n","protected":false},"excerpt":{"rendered":"

                                                                          Eval of antianginals: Limitations of present drugs: Affect hemodynamic parameters. Do not protect the heart against stress induced adrenergic effects. Tolerance develops. Beneficial effects are short-lived. In-vitro methods: Isolated heart (Langendorff) technique Isolated heart-lung preparation Calcium antagonism in isolated rabbit aorta Relaxation of bovine coronary artery Coronary artery ligation in isolated rat heart Plastic casts[…]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/393"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=393"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/393\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=393"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=393"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=393"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}