Pharmacodynamics Flashcards
What is pharmacodynamics?
The drug’s actions and effects on the body
How do drugs target certain organs and tissues?
By interacting with specific proteins like receptors
What is the process of signal transduction?
Drug (signal)
Membrane protein (receptors) (signal detector and transducer)
Effectors
Second messanger
What is a signal cascade effect and when does it happen?
It occurs when activated effectors produce second messengers that further activate other effectors.
What is the effect of receptor activation?
Induces cellular response that lasts several seconds to hours
What are ligands?
Biologically active substances that exert its action via a receptor.
What is the difference between hydrophilic and hydrophobic ligands?
Hydrophilic ligands: interact with receptors that are found of the cell surface
Hydrophobic ligands: enter cells through the lipid bilayers of the cell membrane ti interact with receptors found inside the cell.
What are receptors?
Proteins that transduce extracellular signals and intracellular responses
How can receptors be activated?
Endogenous agonists (hormones and neurotransmitters)
Exogenous agonists (drugs)
What does the activation of receptors lead to?
Biological response
What are the different kinds of receptors?
Ionotropic receptors, ligand receptors
G protein-coupled receptors
Enzyme-linked receptors
Intracellular recptors
What part of the ligand-gated channels contains the ligand binding site?
The extracellular portion
When do the ligand-gated channels open?
When the receptor is activated by a ligand
What does the ion conducted control?
Whether an action potential is generated or inhibited
What does stimulation of the nicotinic receptor by acetylcholine result into?
Sodium influx, because sodium is positively charged it generates an action potential.
Does sodium influx increase or decrease neuronal conduction?
It increases it
What results in a chloride influx?
Stimulation of the GABA receptor
What other effect does the stimulation of GABA have?
Hyperpolarization of neurons which decreases neuronal conditions
Which receptor type has the most rapid time response?
Ligand-gated ion channels
What kind of receptors are G-protein coupled receptors?
Transmembrane proteins
What does the extracellular domain of the GPCRs interact with?
Interacts with the ligand via ligand binding site
What does the intracellular domain of the GPCRs interact with?
Interacts with a G protein or effector molecule
What are G-proteins composed of?
Three different subunits: α, β, γ.
What does the α subunit bind to?
Guanosine diphosphate, inactive G protein.
Guanosine triphosphate, active G protein.
At what point does Gα bind to a GDP molecule?
At steady state
What happens if there is binding of an antagonist to the receptor?
GTP binding to Gα increases, causing dissociation of the Ga-GTP complex from the Gβγ complex.
How can the Gα complex and Gβγ complex interact with other cellular effectors?
Usually through an enzyme, protein, or an ion channel.
What happens to enzyme-linked receptors when activated?
They undergo conformational changes resulting in increased cytosolic enzyme activity
What structure do the most common enzyme-linked receptors possess?
Tyrosine-kinase activity
What happens if an enzyme-linked receptor is activated by an agonist?
The intrinsic tyrosine kinase activity causes autophosphorylation on the receptor itself.
What does the phosphorylated receptor do to other proteins?
It phosphorylates other proteins that subsequently activate other important cellular signals.
What does the cascade of enzyme-linked receptors lead to?
Multiplication of the initial signal
What is one of the characteristics of the ligands that bind to intracellular receptors? Why?
They need to have sufficient solubility, they need to be lipophilic to cross the membrane and interact with the receptor, since the receptors are completely intracellular.
What happens when intracellular receptors are activated by an agonist?
Intracellular receptors translocate to the nucleus, dimerizes before binding to transcription factors.
What is the function of the transcription factors?
Regulate gene expression.
What is the rate of the pharmacological responses of intracellular receptors?
Slower in onset but longer in duration
What are the two important features of signal transduction?
Amplify small signals
Protect cell from excessive stimulation
What is one of the characteristics of GPCRs and enzyme-linked receptors? What does that mean?
Ability to amplify signal intensity and duration.
Only a fraction of the total receptors may need to be occupied to elicit a maximal response.
What can one activated GPCR or enzyme-linked receptor do?
Activate many G proteins, multiplying the signal.
Each activated G protein then activates more receptors and persists for a longer duration.
Are cellular responses short or long?
Short, seconds to minutes
What is done to prevent the production of an intensified cellular response and potential damage to the cell?
Many molecular mechanisms evolve to deactivate signaling pathways and attenuate the sensitivity of the tissue
What happens if a receptor is internalised?
Movement of receptors from plasma membrane to inside the cell, unavailable for further agonist interaction
What does the magnitude of the drug effect depend on?
Drug concentration at the receptor site.
What determines the concentration at the receptor site?
The dose of the drug administered and drug’s pharmacokinetic profile.
What falls under the drug’s pharmacokinetic profile?
Rate of absorption, distribution, metabolism and elimination
What is the dose-response curve?
As the concentration of the drug increases, the pharmacologic effect also gradually increases.
When is the maximum effect of the drug reached?
When all the receptors are occupied which causes the plateau of the curve
What is the dose-response curve described as?
SIgmodial hyperbola
What does the pharmacological effect depend on?
Potency and efficacy
What is potency?
A measure of the amount of drug necessary to produce an effect of a given magnitude.
What usually determines the potency of a drug?
The concentration of the drug that produces 50% of the maximum effect (EC50)
Compare drug with high potency to one with lower?
A drug of high potency evokes a given response at lower concentrations, while one with lower potency would evoke the same result but in higher concentrations.
What is efficacy?
The magnitude of response a drug causes when it interacts with a receptor.
What controls efficacy?
The number of drug-receptor complexes formed and the intrinsic activity of the drug.
What is the intrinsic activity of the drug?
The ability to activate the receptor and cause a cellular response.
What is maximal efficacy?
All receptors are occupied by the drug, so response should not increase even when concentration increases.
What is the equation between drug concentration and receptor occupancy?
(DR)/(Rt) = ((D) / (Kd + D))
D = concentration of a drug
DR = the concentration of bound drug
Rt = the total concentration of receptors
Kd = the equilibrium dissociation constant for the drug from the receptor
What determines the equilibrium dissociation constant for the drug from the receptor (Kd)?
The concentration of ligand required to occupy 50% of the total population of receptors.
How is affinity determined?
Through the value of Kd
What is affinity?
Strength of the interaction between a ligand and its receptors
What does it mean when Kd is high?
Drug-receptor interaction is weak and the affinity of the ligand for the receptor’s binding site is low, and vice versa.
What is an antagonist?
Bind to receptors with high affinity and produce zero intrinsic activity
What happens to an antagonist in the presence of an agonist?
Antagonism may also occur either by blocking the drug’s ability to bind to the receptor or by blocking its ability to activate the receptor
What are the different kinds of antagonists?
Chemical antagonist
Irreversible antagonist
Allosteric antagonist
What is a chemical antagonist?
Interacts directly with the agonist and not the receptor
What kind of antagonist binds covalently to the active site of the receptor?
Irreversible antagonist
What is an allosteric antagonist?
It binds to a site other than the agonist-binding site and prevents the receptor from being activated by the agonist.
What are the two kinds of irreversible antagonists?
Agonist alone
Agonist-antagonist
What are the types of allosteric antagonists?
Agonist alone
Agonist - antagonist
Will the presence of irreversible or allosteric antagonist change the affinity of the agonist to the receptor?
No, it will not be changed however Emax will be reduced in both cases.
What kind of antagonists are irreversible and allosteric?
Non-competitive
What does a non-competitive antagonist mean?
Adding more agonist will not increase the binding of the agents, same affinity for binding
What do noncompetitive antagonists do?
They bind and inactivate a portion of receptors, which will reduce agonist efficacy (Emax)
What is the effect of non-competitive antagonists?
Downward shift of Emax with no shift of potency
What is a functional antagonist?
May act at a completely separate receptor, initiating effects that are functionally opposite than those of the agonist.
What are competitive antagonists?
Compete with the agonist for the same binding site on the receptor.
Why would a higher amount of agonist be needed if dealing with competitive antagonists?
The antagonist will try to displace agonist from their binding receptors
What happens to the agonist’s affinity in the presence of a competitive antagonist?
Affinity for binding will be decreased
What happens to competitive antagonists at high concentrations of agonist?
Competitive antagonists will be displaced from the receptor binding sites, Emax of agonist alone will be similar to Emax of agonist-antagonist.
What are competitive antagonists used for in clinical scenarios?
Used to prevent the activity of drugs, and to reverse the effects of the drugs that have been consumed
How does the presence of a competitive antagonist impact the affinity of the agonist?
It will affect it, increase the EC50, but Emax will be similar at high dose of antagonist.
What are quantal dose-repose curved useful for?
Determining doses to which most of the population responds.
What is the therapeutic index?
The ratio of the dose that produces toxicity in half the population to the dose that produces a clinically desired response in half the population.
What is the therapeutic index used for?
Measure the drug’s safety
Interpretation of therapeutic index:
A larger value indicates a wide margin between doses that are effective and doses that are toxic.
