Side Effects of Central Analgesic Drugs
- PDF / 201,000 Bytes
- 13 Pages / 547.087 x 762.52 pts Page_size
- 44 Downloads / 177 Views
I.J.1 I.J.2 I.J.3 I.J.4 I.J.5 I.J.6 I.J.6.1 I.J.6.2 I.J.6.3
General Considerations . . . . . . . . Test for Respiratory Depression . . . . . . . . . . . . . . . . . . . . . Decrease of Body Temperature . . . . . . . . . . . . . . . . . . . Methods for the Study of Tolerance . . . . . . . . . . . . . . . . . . . . . . Tests for Physical Dependence . . Tests for Abuse Liability . . . . . . . . General Considerations . . . . . . . . . . Drug Discrimination Studies . . . . . Conditioned Place Preference Paradigm . . . . . . . . . . . . . . . . . . . . . . .
219 219 220 220 221 224 224 224 228
I.J.1 General Considerations Morphine, as the prototype of a central analgesic drug, has characteristic adverse effects that are relevant to the treatment of patients. Important among these effects are the following: • • • • •
(e.g. µ, κ, and δ receptor) allows a more selective classification of agonists and antagonists.
Respiratory depression, Decrease of body temperature, Tolerance, Physical dependence, Abuse liability.
Since the ratio between therapeutic effect and adverse effects varies among opioids, great effort has been made to synthesize compounds with a better ratio of antinociceptive activity versus adverse side effects. This effort to discover better, safer compounds necessitated the development of laboratory methods that are sensitive to and, therefore, could be used to quantify the adverse effects of opioids. Moreover, the discovery of several distinct types of receptors that can interact with opioids or with endogenous peptides Contributed by Charles P. France, Ph.D., on the basis of Chapter H.1.3: Side effects of central analgesic drugs in the book “Drug Discovery and Evaluation – Pharmacological Assays”, second Edition, Springer Verlag 2002.
I.J.2 Test for Respiratory Depression PURPOSE AND RATIONALE
Respiratory depression is one of the most prominent adverse effects of µ opioid agonists (e.g., morphine). The frequency of breathing and the inspiratory volume can be affected differently by drugs and have to be measured. PROCEDURE
Male or female rabbits with a body weight between 2.5 and 3 kg are placed in restraining cages. A mask is placed over the nose of the animals which is connected with a valve opening on exhaling and closing on inhaling. The frequency of breathing is recorded from the opening and closing of the valve. The inspiratory volume is measured with a gasometer. Intravenous injection of morphine in doses between 1 and 10 mg/kg results in a dose-dependent decrease in respiratory frequency and respiratory volume. The doses are increased logarithmically after the effect of the preceding dose has subsided. EVALUATION
Three animals are used for the test compound and the standard. Dose-response curves of the effect on respiratory frequency and volume are compared. While µ opioid agonists decrease respiratory function, κ opioid agonist either increase or have no effect on respiratory function. The magnitude of respiratory depression produced by µ opioid agonists is related to their efficacy at opio
Data Loading...
