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screening of ans drugs screening of ans drugs Presentation Transcript

  • Screening of sympathomimetic And Sympatholytic drugs By Srota dawn M.Pharm(pharmacology) 1st year, 2nd semester
  • Introduction: These are the drugs which mimic the responses of epinephrine or stimulate the sympathetic nervous system. Secreted from : Adrenal medulla in mammals Sympathetic nerve activation occurs in response to the stimuli including physical activity, physiological stress, blood loss etc.
  • Sympathomimetic drugs may results in any of the following events like i. mydriasis in the eye ii. enhanced stroke volume iii. acceleration of the heart rate iv. dialation of the coronary arteries v. constriction of the pulmonery vessels vi. relaxation of bronchial muscles vii. inhibition of gastric secretion viii. constriction of gastrointestinal sphincters ix. stimulation of uterus and x. constriction of spleen capsule
  • Receptors in the ANS • Cholinergic receptors: Inhibitory or excitatory - Nicotinic: fast - Muscarinic: slow  Adrenergic receptors: slow, excitatory or inhibitory - α 1 and 2 - β 1 and 2 (and 3)
  • ANS - Adrenergic Drugs -Adrenergic Receptors  Divided into 1 and 2 receptors  Differentiated by their location on nerves 1-Adrenergic Receptors  Located on postsynaptic effector cells (the cell, muscle, or organ that the nerve stimulates) 2-Adrenergic Receptors  Located on presynaptic nerve terminals (the nerve that stimulates the effector cells)  Control the release of neurotransmitters Predominant -Adrenergic Agonist Responses  Vasoconstriction  CNS stimulation
  • ANS - Adrenergic Drugs -Adrenergic Receptors • All are located on postsynaptic effector cells – 1-adrenergic receptors—located primarily in the heart – 2-adrenergic receptors—located in smooth muscle of the bronchioles, arterioles, and visceral organs • -Adrenergic Agonist Response: – Results in: • Bronchial, GI, and uterine smooth muscle relaxation • Glycogenolysis • Cardiac stimulation
  • Screening of sympathomimetics
  • Screening of sympathomimetics can be done by the following methods: in vivo method: Cat spleen method  In vitro method: 1. Cat spleen method 2. Rabbit pulmonary method
  • in vivo method: Cat spleen method Purpose: This is one of the useful method for evaluation of substances affecting the release and subsequent fate of the adrenergic transmitter from the sympathetic nervous system. After injecting sympathetic amines electrical stimulation of the pre- and post- ganglionic nerves spleen contracts. Different doses of the test compound that alter the release of transmitter output of spleen are compared with the known standards. Released amount of NMT output can be measured by collecting spleen venous effluent and analyzing its NMT content. This is achieved by the labeling of neuronal stores with radioactive compound, which is taken up from the splenic arterial circulation and released after nerve stimulation.
  • Procedure (cat spleen method): 6.A ligature is placed around the portal vein 5.Adrenal glands are also removed(to avoid the effect due to release of pressor amines) 4.Spleenic nerves are also cut to avoid liberation of catecholamines from other sites 3.Vascular connection between the spleen & omentum are being cut 2.Abdomen is cut open (midline incision)& intestine is removed(from mid duodenum to terminal colon) 1.Healthy cats are selected and anaesthetized using chloroform
  • 7.Heparin is injected to avoid clotting of blood 9.Venous blood samples are collected by diverting effluent through a cannula by applying positive pressure 10.Blood is collected through chilled, silicon coated, calibrated centrifuge tubes 11.This method is enough for the collection of 80% of NA released. 12.The amount of NA present in the blood is estimated by `SCINTILLATION COUNTER for radioactivity measurement. 8.Abdominal cavity is filled with warm paraffin and aerated with 95% O2 & 5% CO2
  • In vitro method: 1.Cat spleen method: 1.This is the method for the estimation of NA content in IN VITRO PROCEDURE The method for removal of spleen is same as before The removed spleen is placed on a plethysmograph filled with liquid paraffin The organ is perfused at a rate of 7-16 ml/min with modified Krebs solution_(temperature- 37○c ,gassed with carbogen,dextran 3% for maintaining osmotic pressure) Ascorbic acid at 25 uGu/ml is added to prevent oxidation of NA The perfusion is started and the samples are collected and estimated for NA
  • 2. Rabbit pulmonary artery method: Purpose: The pulmonary artery is very sensitive to sympathomimetic agents . The artery is mainly consists of vascular smooth muscles innervated by postganglionic adrenergic sympathetic fibers . The NA is released in response to the nerve stimulation . The released adrenergic transmitter is measured by labeling the neuronal stores with radioactive NA & with the use of super fusion technique to reduce the dilution of amines.
  • Procedure (rabbit pulmonary artery method) 1.Rabbits(1-2kg) and sacrificed by exsanguinations followed by the removal of main pulmonary artery 2.The artery is cut transversely and spirally into vertical strips 3.The strip is suspended vertically in the organ bath (maintained at 37°c ) 4.The last end of the tissue is tied to glass support, whereas the other end is connected to the strain gauge transducer 5.Resting tension- 2gm 6.Krebs bicarbonate solution(physiological solution)
  • 7.The tissue is loaded with 3[H] NA by submerging it in 20 ml of Krebs bicarbonate solution at 37*c and gassed with 95% O2 & 5% CO2 8.Incubate for 60 min,the tissue is washed with fresh Krebs solution 9.During exp. Superfusates are collected in vials in every 3 mins.aliquots of collected samples are then assayed 10.The electric stimulations are given by the use of potassium electrodes 11.Responses to successive 2 min period of electrical stimulation are reproducible when applied at 16 min intervals
  • Screening of sympatholytics
  • Methods: In vivo method: 1.nictitating membrane prolapse in cats 2.alpha () & beta( β ) adrenergic antagonism in mouse eye In vitro method: 1.vas deferences of the rat 2.splenic strip of the cat 3.pithed rats for evaluation of sympathomimetic and sympatholytic activity 4.to assess β 1 and β 2 adrenoreceptors agonism & antagonism
  • 1.Nictitating membrane prolapse in cats 1.Anaesthsised cats are used, drugs are administered orally 2.Sympatholytics exert relaxant effect on the nictitating membrane of cats 3.For each test drug 5 – 10 animals are used 4.The relative activity of different compounds is calculated by dividing the mean duration of the membrane prolapse of a group in hours by the dose in mg/kg.
  • 2.Alpha () & beta( β ) adrenergic antagonism in mouse eye Nor epinephrine, epinephrine and isoproterenol have the property of inducing mydriasis,this effect is blocked by alpha () & beta( β ) adrenergic blockers.  blockers block the mydriatic effect of nor- epinephrine, β blockers block the effect of isoproterenol and  β blockers block the effect of epinephrine.
  • Procedure : Mice(15-20 gm) are used Animals are divided into groups as per requirement Vehicle is administered in sc route (for control) Test compounds are added to the test group Std Nor-epinephrine given in i.v. Pupil diameters are measured(before and after drug administration) The mean value is compared between groups
  • In vitro method: 1.vas deferences of the rat Male wister cats(275-300 gm)are used Animals are killed by stunning A midline abdominal incision is performed to disect out vas deferens Tissue is suspended in an organ bath(tyrode, aerated,35*c) Contractions are recorded(NA is administered repeatedly in concentration of 0.5,1,2,4 ug/ml Test drug is added are the reduction in response is recorded Phentolamine is used as standard)
  • 2.splenic strip of the cat Cat of either ser weighing around(1-2.8 kg) are used The spleen is removed and a25 to 30 mm long strips of spleen are prepared Strip is then suspended in an organ bath(krebs,38*c, aerated) Tension used – 0.5 gm,magnification- 5-6 times To induce contraction,NA/A is added Test drug is then added(followed by agonist) Phentolamine is used as standard(%reduction of activity of epinephrine or nor epinephrine is determined)