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What is the part that binds and recognizes the drug called?



How does sterospecificity affect potency?

-either all activity will reside in one isomer or one of the isomers will be more potent than the other


What does the response depend on?

1. the amount of drug reaching its action site
2. the specific drug-receptor interaction at that site (coupling efficiency)
3. functional status of the receptor and target cell


Intracellular Receptors
Activated by:

Activated by: lipid soluble drugs

1. stimulate intracellular enzyme
2. regulate the cellular localization of the receptor and alter gene transcription


What receptors are gene active receptors? What does this imply?

-lag period
-gene active receptors may persist for hours or days after antagonist is gone
-effects will take time and decrease slowly
-no simple temporal relationship
-activation of the gene and its effect may long outlast the presence of the drug in the body

1. Intracellular
2. cytokine receptor


What is the difference between ligand-regulated transmembrane enzyme receptors and cytokine receptor mechanism?

Ligand regulated transmembrane enzyme: receptors like protein tyrosine kinase have an intracellular enzymatic domain (tyrosine, serine kinase or guanylyl cyclase)

Cytokine Receptor: utilize a separate protein tyrosine kinase that binds non-covalently and non intrinsic to the receptor


How does the autophosphorylation of ligand regulated transmembrane enzyme receptors affect the receptor activation? What is an example?

-can intensify or prolong the duration of receptor activation
-e.g. insulin receptor persists long after insulin dissociates from the receptor


How do transmembrane receptors get down-regulated?

-endocytosis and degradation of receptors -->may limit the intensity or duration of the drugs effects


What are some things that bind igand-regulated transmembrane enzyme receptors

1. insulin
2. epidermal growth factor
3. atrial natriuretic factor ANF


What are some things that bind cytokine receptor mechanism?

growth hormones and other regulators of growth and differentiation


What are the steps to the cytokine receptor activation?

1. ligand binding induces conformational change and receptor dimerization

2. dimerization allows JAKs to be activated and phosphorylate tyrosine residues on the

3. phosphorylation of tyrosine on the receptor facilitates the binding of STAT

4. The bound STATs are then phosphorylated by the JAKs

5. the stats dimerize and the dimmer dissociates and travels to the nucleus and regulates gene transcription


How does the ligand gated channel receptor work?--Nicotinic cholinergic receptor

1. Acetylcholine binding to the alpha subunits produce a conformational change and transient opening of the channel
2. Na flows in


How long does it take a for a ligand gated channel receptor to work?



What other neurotransmitters signal via ligand gated receptor mechanisms?

excitatory amino acids-glutamate and aspartate and GABA


What are 4 things about a g-protein linked receptor?

1. amino terminus outside and carboxy inside

2. 3rd intracellular loop regulates the ability to interact with specific G proteins while the carboxy terminus contains sites that are subject to phosphorylation and regulation of receptor function

3. activation of g protein conveys the effects of the drug to the second messenger enzyme

4. used in many neurotransmitters including: DA, NE, 5-HT, ACH


What the steps to the activation of adenylyl cyclase?

1. *Multiple G proteins activated
2. activation of *multiple catalytic units of adenyl cyclase
3. conversion of ATP-->cAMP
4. cAMP activates *multiple cAMP dependent kinases (PKA)
5. PKA phosphorylates *multiple downstream proteins
*large amplification


What are the activation steps of the phosphoinositide hydrolysis pathway?

1. Multiple G proteins activated

2. Activation of multiple
catalytic units of PLC

3. Conversion of PIP2 into DAG and IP3

4. DAG activates PKC enzymes (>9 types)

5. Multiple PKCs phosphorylate various downstream proteins

6. IP3 release of large intracellular stores of Ca2+

7. Ca 2+ activates multiple CaM kinases

8. Multiple CaM kinases phosphorylate multiple downstream proteins

9. Highly amplified/divers final response


What are the beneficial vs. toxic effects of the drugs?

1. Extension of Effects at the same receptor
-all mediated by same receptor
Strategies: Monitor Effect, Manage Dose

2. Effects mediated by same receptor in different tissue
Strategies: add other drugs to lower dose of first drug, give lowest dose of to achieve effect, limit effects via route of administration

3. Effects mediated by activation of different receptors
Strategy: give drug with greater selectivity


What is an idiosyncratic drug response?

an unusual response that is not frequently observed in the majority of patients


What is tachyphylaxis?

RAPID development of diminished responsiveness to a drug


What pharmacodynamic tolerance? (desensitization)

decreased responsiveness to hormonal stimulation that occurs slowly over with time


What are some mechanisms involved involved in desensitization?

1. Agonist-induced phosphorylation of the activated receptor and subsequent binding of B-arrestin

2. Receptor down-regulation

3. receptors become functionally uncoupled from post receptor components due to modification of G-protein or 2nd messenger enzyme


What way do desensitizations shift to what about sensitization?

desensitization: shift to the right -an increase in the ED50 (generally no change in Emax, unless receptor reserve is exceeded or post receptor defects)

Sensitization: left


What is homologous desensitization?

b-adrenergic receptors are phosphorylated by specific kinases (GRK2, GRK3)

-these kinases only recognize and phosphorylate sites on the agonist occupied receptor

-binding of beta arrestin

---only loss of activity to agonist interacting with this modified receptor


What is heterologous desensitization?

-receptors of that were not activated by the agonist also result in decreased responsiveness

-cAMP dependent PKA and PKC


What is supersensitivity?

a compensatory receptor mechanism in which the loss of activity on receptors leads to an increase in receptor density or enhanced receptor-effector coupling

-increased responsiveness to subsequent activation

---shift to left