1. 1 59-291 Section 1, Lecture 8 Receptor Classification according to: -which drugs they interact with (  -adrenergic –binds norepinphine with high affinity ;  - adrenergic binds epinephrine with high affinity) -tissue location -molecular structure (protein sequence)

2. 2 Receptor Regulation and Drug Tolerance -the number of receptors on a given cell is a dynamic process If too much drug is present the cell responds by decreasing the # of receptors this is termed Down-regulation. -in contrast in response to too much exposure to antagonists cells produce more receptor this is termed Up-regulation

3. 3 Receptor downregulation is responsible for pharmacodynamic tolerance. The rapid onset of this is termed Tachyphlaxis. In contrast Pharmacokinetic tolerance results from increased rate of elimination. Dose-Response Relationships Graded Dose-Response relationships ED 50 -median effective dose [Drug] that gives 50% of maximal response. % of response (i.e. drop in BP) plotted against log of [Drug] Drugs R and S are full agonists Drug T is a partial agonist Drugs R is more potent than S and T

4. 4 Efficacy: the maximal response produced by a drug –Full agonist >> maximal efficacy –Partial agonist >> sub maximal efficacy Antagonist has no efficacy –Can be an effective medication? –Adrenergic receptor antagonist (  blocker)

5. 5 X-Agonist alone Y- Agonist + a competitive Antagonist Z- Agonist + a noncompetitive Antagonist effect cannot be reversed by a reasonable amount of extra agonist The effect of antagonists on agonists:

6. 6 Quantal Dose-Response Relationships All or none effect- i.e. do you feel a pinprick as the dose of a local anesthetic is increased; or sleep as dose is increased. ED 50 = [Drug] that produces the defined effect in 50% of the subjects TI- Therapeutic index= LD 50 / ED 50 CSF- Certain Safety Factor= [Drug] that is lethal in 1 % of the subjects (LD 1 )/ [Drug] that is therapeutic to 99% of the subjects (ED 99 ) Phenobarb- TI=10; CSF=2 a good margin of safety!

7. 7 Practice Questions What are orphan receptors? Receptor-like proteins that no endogenous ligand has found for them The structure is predicted from gene sequencing

8. 8 What is not the consequence of Ser/Thr phosphorylation of receptors Desensitization Tachyphylaxis Internalization Supersensitivity down-regulation

9. 9 Determine the mechanism of action of the following receptors Insulin receptors –Activation of tyrosine kinase Steroid receptors –Activation of gene transcription  -adrenergic receptors –Stimulation of adenylyl cyclase  1 -adrenergic receptors –Activation of phospholipase C