Pharmacodynamics II Flashcards
General Receptor Features
- Structural Specificity: there is some degree of specificity for the drug. The part of the receptor that recognizes and “binds” the drug is the __________________.
- Stereospecificity: all activity resides in one ____________ or one of the _______________s will be more potent than the other.
- Saturability: receptors exist in finite numbers and can be saturated by _______ concentrations, or doses, of drugs. Increasing dose _________ the response.
- Pharmacophore, or drug recognition site
- Isomer(s)- example given is SSRI antidepressant Lexapro (escitalopram) which is an isomer of Celexa (citalopram)
Fun fact: lexapro is the S enantiomer, select is the R enantiomer. - High concentrations or doses can saturate receptors. Increasing the dose increases the response.
General Receptor Features Cont.
- Response: there will be some quantitative relationship between the magnitude of response and the total number of receptors. This depends on what three things?
- Subject to Regulation: receptors are dynamic entities whose steady state levels (______) can be affected by pharmacological, physiological, and pathological factors.
- Response:
a) Amount of drug reaching the site of action
b) Drug-Receptor Interaction- coupling efficiency
c) Functional status of the receptor or cell and or/target cell (i.e. desensitization - Bmax= The maximum amount of drug that can bind specifically to the receptors in a membrane
Intracellular Receptors
Where are they found?
What do they bind?
Binding of a compound to a receptor can cause what two things to happen?
These receptors are NOT membrane bound- they exist in the cytosol
They bind biological compounds that are sufficiently lipid soluble to cross the plasma membrane
Drug + Receptor either:
- stimulate intracellular enzyme (i.e. guanylyl cyclase)
- Regulate cellular location of the receptor and alter gene transcription –> GENE ACTIVE RECEPTOR (bind to promoter to stimulate transcription of genes)
Ex: glucocorticoid receptor binding to a glucocortioid drug- the complex goes to the nucleus and can up regulate transcription of anti-inflammatory genes or repress expression of pro-inflammatory genes
Gene Active Receptors (Specific type of intracellular receptor)
Are they long or slow acting?
How long do the effects of an agonist last?
Therapeutic and toxic effects take time and will decrease slowly. Therefore activation of the gene, and its effects, may long ________ the presence of the drug in the body.
Gene active receptors (alter transcription) are slow-acting- there is a lag period of 30 minutes to a few hours, the time required for new protein synthesis.
Effects can last for hours or days after the agonist is no longer required. Due to the slow turnover of enzymes or proteins synthesized in response to receptor activation.
Outlast
Three Types of Plasma Membrane Receptors:
1.
2.
3.
- Ligand-Regulated Transmembrane Enzymes- Including Protein Tyrosine Kinase
- Ligand Gated Channel Receptors
- G-Protein Family or transmembrane enzymes
Ligand Regulated Transmembrane Enzyme Receptors (Including Protein Tyrosine Kinase)
They cross the membrane ______ times and consist of an _____________ binding domain and an ___________ enzymatic domain
Cross the membrane one time
Extracellular binding domain
Intracellular enzymatic domain
Intracellular enzymatic domain may be tyrosine or serine kinases or guanylyl cyclase
Once activated, transmembrane enzyme receptors can phosphorylate ________ or ___________ on various downstream proteins
Autophosphorylation of tyrosine on the receptor’s cytoplasmic side can do what to the duration of receptor activation?
How are transmembrane enzyme receptors down regulated?
Tyrosine or serine
Autophosphorylation can intensify or prolong the duration of receptor activation
Ex: insulin receptor persists long after insulin dissociates from the receptor
Endocytosis of the receptors from he cell surface followed by degradation of the receptor + ligand
Cytokine receptors closely resemble transmembrane enzyme receptors (variation of theme) except they utilize a separate protein tyrosine kinase that binds _______________ to the membrane.
How do they signal?
Non-covalently
Signaling:
- Ligand binds, induces conformational change & receptor dimerization
- Dimerization allows JAKs to be activated & phosphorylate tyrosine residues on the receptor.
- Phosphorylation of tyrosine on the receptor facilitates the binding of STAT proteins(Signal Transducers and Activators of Transcription).
- The bound STATs are then phosphorylated by the JAKs
- Two STATS dimerize & the dimer dissociates, travels to the nucleus & regulates gene transcription.
What endogenous factors bind transmembrane enzyme receptors?
Insulin, growth factors, ANF (atrial naturitic factor)
Ligand Gated Channel Receptors (the Nicotinic Cholinergic Receptor)
Transmit signals by increasing flow of relevant ______ and altering the _________ potential across the membrane.
Ions, electrical
Ligand Gated Channel Receptors (the Nicotinic Cholinergic Receptor)
Describe the structure of the channel.
How does ACh (acetylcholine) open the channel?
Opening of the channel allows for what?
Fast or slow response?
Structure: A pentamer consisting of 4 types of glycoprotein subunits (2 alpha, a beta, a gamma, and a delta) that form a cylindrical structure containing the channel.
ACh opens channel by binding to alpha subunit, which produces a conformational change and transient opening.
Sodium ions go from ECF into the cell when the channel is open.
Fast response! Milliseconds- rapid information transfer; much quicker than other signaling mechanisms that require seconds, minutes or hours to produce their effects.
Acetylcholine, GABA, and excitatory amino acids (glutamate and aspartate) use which kind of receptor?
Ligand Gated Channel Receptors (the Nicotinic Cholinergic Receptor)
G-Protein Family of Transmembrane Receptors
A single polypeptide chain that transverse the plasma membrane ______ times (serpentine receptors)
Amino terminus is found on the __________ side.
Pharmacophore is found on the ___________ side.
7, extracellular, extracellular
G-Protein Family of Transmembrane Receptors
Third intracellular loop (of 7) regulates the ability of the receptor to interact with what?
What AA residue is found on the carboxy terminus of the receptor?
Third intracellular loop interacts with: Specific G proteins
Carboxy terminus of the receptor contains sites (serine residues) that are subject to phosphorylation and regulation of the receptor function
Guanine Nucleotide Regulatory Proteins act as ____________ between G-protein receptors and the second messenger. They have alpha, beta, and gamma subunits and exist together as a trimer.
Intermediates
Neurotransmitters Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT) and ACh can all use what kind of receptor?
G-Protein linked receptors
Activation of G Proteins
Agonist binds to receptor and facilitates its association with G-protein- formation of a ___________ Complex.
Ternary Complex- formation of this facilitates binding of GTP rather than GDP to the G-protein. Binding to GTP to alpha subunit dissociates it from beta gamma subunits, receptor, and agonist. GTP bound G protein is the active intermediate which changes the activity of the effector component, usually an ion channel or enzyme (cAMP or phospholipase C)
Types of G Proteins All mediate stimulatory & inhibitor effects on adenylyl cyclase and the activation of phospholipase C. Gs Gi Gq
All differ based on which of their subunit (alpha, beta or gamma?)
Alpha subunit
G Protein Half Lives
Gs – 10-20 sec
Gq – 50 sec
Gz – 7 min
ACTIVATION OF ADENYLYL CYCLASE (G Protein mediated)
produces a single messenger: ________
cAMP, which has multiple levels of signal amplification
Pathway starts with G-coupled receptor–>G protein (intermediate)—>AC (adenyl cyclase)
Multiple G proteins activated–> Activation of multiple catalytic units of AC—-> Conversion of ATP to cAMP—->cAMP activates multiple cAMP dependent kinases (PKA)—->PKA phosphorylates multiple downstream proteins
Amplified Final Response
ACTIVATION OF THE PHOSPHOINOSITIDE HYDROLYSIS PATHWAY (G-protein mediated)
2nd messenger activation results in 2 subsequent messengers: ______ & ______
IP3 & DAG
Multiple G proteins activated—>Activation of multiple catalytic units of PLC—->Conversion of PIP2 to Two Second Messengers: DAG & IP3
DAG activates multiple PKC enzymes (> 9 types)
Multiple PKCs phosphorylate various downstream proteins
IP3 release of large intracellular stores of Ca+2
Ca+2 activates multiple calmodulin dependent kinases (PKA)—>Multiple PKAs phosphorylate multiple downstream proteins
HIGHLY AMPLIFIED/DIVERSE FINAL RESPONSE
Name two well established G-Protein Signaling Pathways. Which of the two has a more amplified response?
Adenylyl Cyclase pathway (cAMP)
Phosphoinositide Hydrolysis Pathway (IP3 and DAG)
Phosphoinositide Hydrolysis Pathway has greater signal amplification
Are drugs specific or selective in their actions?
Selective- because no drug causes a single specific effect, drugs are classified according to their principal action.
Selectivity: therapeutic vs toxic effects
Therapeuticl/Toxic Effects:
Actions at the Same Receptor
D + R DR—> X —> Toxic/Beneficial
How do you minimize toxic/side effects?
Beneficial Vs. Toxic Effects of Drugs
D + R DR (receptor) —> X (effector)—> Toxic/Beneficial (response)
Beneficial response; anticoagulant activity
Toxic response: excessive bleeding
Strategies: manage dose, monitor the effect
Therapeuticl/Toxic Effects: 2. Effects Mediated by the Same Receptor in Different Tissues
D + R DR—>Tissue X —> Beneficial or
D + R DR—> Tissue Y–>Toxic
How do you minimize toxic/side effects?
Example:
Beneficial: glucocorticoid treating inflammatory disease
Toxic: too much glucocorticoid, starts to bind muscle tissue receptors and protein catabolism occurs
Avoid this by: administering lowest dose of drug that provides benefit, administer adjunctive drugs (may allow lowering the dose of the first drug), limit the drug’s effects to specific parts of the body (i.e. aerosol administration of glucocorticoid to treat asthma- stays in bronchi)
Therapeuticl/Toxic Effects: 3. Effects Mediated by Activation of Different Receptors
D + R1 DR1—> X —> Beneficial
D + R2 DR2—> Y–>Toxic
How do you minimize toxic/side effects?
Minimize toxic or side effects by prescribing drugs with greater receptor selectivity
Variation in drug response:
________ Drug Response – an unusual response that is not frequently observed in the majority of patients. Individual may have unique response
____________ Variations in drug response are more common- the intensity of effect for a given dose of drug may be greater (hyper-reactive ) or less (hypo-reactive) in comparison with the response observed in most individuals.
Idiosyncratic
Quantitative
Variations in Receptor Responsiveness to Drugs :
Receptor Desensitization- a response to _____-stimulation
Receptor Supersensitivity a response to ___-stimuliation
Desensitizaiton: Over stimulation
Supersensitivity: Understimulaiton
These are compensatory responses, invoked to counter the drug effect imposed on system, in order to re-establish some degree of homeostatic functon
Tachyphalaxis
The rapid development of diminished responsiveness to a drug
Pharmacodynamic Tolerance (Desensitization)
Decreased responsiveness to hormonal stimulation that occurs slowly over with time. Repetitive stimulation via the agonist over a slow period of time
(e.g. the loss of vasoconstriction responses after using adrenergic agonists as decongestants for a period of time)
Reduced Responsiveness Upon Drug Exposure
Mechanisms:
-Agonist-induced phosphorylation of the activated receptor
-Receptor down-regulation
-Post-Receptor Adaptations
Do these shift dose response curves to the right or left? Why?
These will result in a shift to the right in the agonist dose-response curves (an increase in the ED50) and generally no change in Emax, unless “receptor reserve” is exceeded.
Which way does desensitization shift the dose response curve? Why?
Desensitization – generally results in a shift to the right in the agonist dose-response curve without a reduction in Emax
Desensitization Induced reduction in EMax is seen if receptor reduction exceeds receptor reserve OR if there are post receptor defects (changes in G-proteins, enzyme activity, etc)
Homologous Desensitization
Only the activated receptor is affected!
D + R–>DR–>Response; Respones causes desensitization of the activated receptor.
Ex: Beta-adrenergic receptors are phosphorylated by specific kinases (aka GRK2, GRK3).
These kinases only recognize and phosphorylate sites on the agonist occupied receptor. Very specific. Only if the agonist is bound can the GRKs bind!
This is followed by the binding of beta arrestin to the phosphorylated receptor. Thus there is a loss of activity only to agonists interacting with the modified receptor.
Homologous Desensitization
Which way does this shift the dose response curve?
What effect does it have on Emax?
Desensitization is restricted to only the receptor population that was activated by the drug
Shifts curve to the right- desensitization will result in a right shift since higher fractional occupancy is required to achieve responses comparable to what was achieved in non-desensitized systems
EMax is the same unless receptor reserve is exceeded.
Heterologous Desensitization
Desensitization is NOT restricted to only the receptor population activated by the drug.
Receptor Supersensitivity
What causes it?
Which way does it shift the dose response curve?
Supersensitivity – a compensatory receptor mechanism in which the loss of activity (removing activation) on receptors leads to an increase in receptor density and/or an enhanced receptor-effector coupling.
This results in an increased responsiveness to subsequent receptor activation and a shift to the left in the dose response curve
