Lecture 6 Flashcards
What is receptor plasticity?
Receptors states and populations are not static and can be desensitized to a specific stimuli or can be up or down regulated by cellular process’
What are the changes to receptor states that can alter their effectiveness as a drug target?
Rapid, pronounced desensitization of metabotropic receptors this may be homologous, or heterologous
What is homologous desensitization?
When an agonist desensitizes a receptor against itself
What is heterologous desensitization?
When an agonist desensitizes a receptors response to a different agonist
What is an example of receptor desnsitization?
When the beta1 adrenoceptor does not have its binding affected but it is unable to activate adenylate kinase, due to a phospohorylation of a serine residue by BARK
What can lead to receptor population down regulation and what is an example?
Chronic agonist administration, such as chronic salbutamol can cause internalisation of receptors reducing receptors available for ligand binding reducing the effect of the drug
What can lead to receptor population up regulation and what is an example of this?
Chronic antagonist administration such as chronic propanolol which can cause increased synthesis of beta1 receptors in the heart, causing less antagonism and decreased drug effect
What is the clinical significance of changes in receptor populations?
Tolerance where down regulation necessitates an increase in drug does to maintain effectiveness
However increasing the dosage does increase the adverse effects of the drug
What is an example of the tolerance leading to adverse effects?
Chronic administration of haloperidol (striatal D2 antagonist) results in an increase in striatal D2 receptors which can cause tradive dyskinesia to develop after months or years of taking the drugs
What is the clinical significance of receptor population change with regards to antidepressants?
Tricyclic antidepressants take 2-4 weeks to have a therapeutic effect which is consistent with down regulation of beta and alpha2 adrenoreceptors and 5HT receptors
What does NSAID stand for?
Non-steroidal anti inflammatorys
What are two examples of enzymes and drug targets?
Cyclooxygenase is inhibited by NSAIDs which treat pain in inflammation as well as Angiotensin Converting Enzyme and ACE inhibitors which are used to treat hypertension
What are the effects of cyclooxygenase inhibition by NSAIDs?
Inhibits actions of both COX 1 (Homeostatic) and COX 2 (inflammatory) leading to reduction in inflammation, pain and fever but the adverse effects of reductions in kidney function (acute renal failure- ketorolac) and maintenance of gastric mucosa (ulcers- diclofenac, asprin) resulting in gastric beelds
Why did COX-2 selective inhibitors seem to show promise and then fail to meet this?
COX-2 is typically inflammatory while COX-1 is primarily homeostatic, suggesting that selective COX-2 inhibitors could be used without any of the adverse effects of NSAIDs (like gastric bleeds)
However they had adverse effects on other parts of the body such as the cardiovascular system, the renal system and hepatic effects
What are examples of drugs that interact with carrier proteins?
Fluoxetine (Prozac)- SSRI which is an antidepressant
Sibutramine (Reductil)-SNRI which increases sympathetic nervous activity
