Week 4 Nordgren - Principles of Pharmacodynamics Flashcards
What is the basic definition of Pharmacology?
The study of substances (“drugs”) that interact with living systems through chemical processes.
(deals with both the beneficial & adverse effects)
How does Toxicology relate to Pharmacology?
Toxicology is viewed as a branch of pharmacology which deals with adverse effects on living systems.
“science of poisons”
What is a drug receptor?
A cellular macromolecule that interacts with a drug and in doing so initiates a series of biochemical events that result in the characteristic action of the drug.
What are the functions of the receptor?
- Recognition
- the receptor binds a drug or endogenous ligand
- Signal transduction
- transfer of information
- recognition of the drug needs to be communicated to the cell
What does the term “selectivity” mean in the context of drug-receptor interactions?
The drug binds to one receptor or a small number of receptor types.
The tissue localization of different receptor types imparts specificity of drug action.
Why is the drug-receptor interaction based on selectivity and specificity?
It would not be helpful if a drug bount to all receptors.
The drug is intended to exert a distinctive influence on the body.
What is receptor-mediated signal transduction?
The interaction of a drug with its receptor propagates a signal, i.e. it converts the “drug signal” into a tissue response.
What are the three ways transduction propagates a signal?
- Alters receptor function
- Generates a second messenger
- Impacts gene transcription
What were the four transduction mechanisms discussed in class?
- G-protein coupled receptor signal
- Ligand-Gated ion channel
- Receptors as enzymes
- Receptors regulating nuclear transcription
What do G-protein coupled receptors (GPCRs) do?
- regulate second messengers
- cAMP, cGMP, Ca2+, DAG, IP3,
- most common drug receptor group
- specific subunits dissociate and have their own characteristic actions
- ex. up/down regulation
What is the mechanism of Ligand-Gated Ion Channels?
- Ligand binds → channel opens → ions flow through and down electrochemical gradient
- drugs will interact with this channels
- cationic & anionic
- can lead to depolarization of the cell membrane
How do “receptors as enzymes” work?
- Intrinsic enzyme activity phosphorylates diverse effector proteins.
- phosphorylation proteins (kinases) at specific AA residues
- Cleave phosphate off (phosphatases)
- lots of receptors possess enzymatic activity
- can be inactivated or activated by ligand binding
How do “receptors regulating nuclear transcription” work?
- Receptors have the ability to bind directly to DNA
- Regulate expression of adjacent genes
- Often associate with a chaperone protein
- when receptor bound by ligand, will inactivate the chaperone
- Examples: sense steroids, thyroid hormones, etc.
- control development, homeostasis, & metabolism
What are the five major attributes of drug receptor-mediated processes?
- Highly compartmentalized
- Self-limiting on relatively short time scales
- Organized into opposing systems
- Provide opportunities for signal amplification
- Operate through a relatively small number of second messenger systems
What two attributes of drug receptor-mediated processes contribute to drug-drug interactions?
- Receptor-based processes tend to be organized into opposing systems.
- A large number of different receptors may operate through a much smaller number of secondary messenger systems.
What are the non-receptor modes of drug action discussed in class?
- Drugs interacting chemically with small molecules
- EDTA, dimercaprol
- Drugs producing physicochemical effects
- Mannitol, MgSO4
- Drugs that target rapidly dividing cells
- chemotherapeutic agents, cell cycle specific drugs, and cell cycle non-specific drugs that act on dividing cells
What are the two underlying assumptions of the Occupancy Theory?
- Effect is proportional to receptor occupancy
- Interaction is monovalent
What is EC50?
The concentration of drug producing 50% of the maximal response and is an estimate of the drug’s KD.
What is ED50?
The dose of the drug producing 50% of the maximal response.
What does affinity mean??
The ability of a drug to form a complex with a receptor.
- The greater the affinity, the lower the drug concentration required to produce an effect and occupy the receptor.
- small KDand EC50
- 1/KD
What is potentcy as it pertains to drugs?
A comparative term used to describe the relative positions of several agonist dose-response curves.
- High potency does NOT confer on a drug any inherent benefit.
What is efficacy as it pertains to drugs?
Capacity to produce a response.
(a. k.a. Intrinsic Activity)
* Response induced by the interaction of a drug and receptor is a function of BOTH the affinity of the drug for the receptor and the efficacy of the drug-receptor complex to produce a response.
What is a full antagonist drug?
A drug capable of inducing a maximum response.
(alpha = 1)
What is a partial agonist?
A drug whose maximal response is only a fraction of the maximum that can be elicited.
(0 < alpha < 1)
What is a “pure” antagonist?
A drug that can bind to a receptor (has affinity for the receptor), but induces no response.
i.e. zero efficacy (alpha = 0)
What are the effects of a competitive antagonist on the dose-response graph?
- Shifts to the right
- apparent affinity of agonist is reduced
- slope does not change
- maximal response can still be produced
- REVERSIBLE
What are the effects of a non-competitive antagonist on the dose-response curve?
- Slope reduced
- apparent affinity changes very little, if at all
- apparent numbers of receptors decreased
- maximal response reduced
- IRREVERSIBLE
What are physiological mechanisms of drug antagonism?
Distinct from the type of antagonism described before, as it involves interaction between regulatory pathways mediated by different receptors.
- does not involve binding to the same receptor
- counteract an effect by using a different pathway
- ex. insulin vs. glucocorticoids
What is an inverse agonist?
- A drug that preferentially binds to the inactive form, shifting equilibrium to the inactive form.
- This results in an effect the opposite of that produced by an agonist.
Describe the two-state theory of drug-receptor interactions.
- Postulates that the receptor exists in an active and inactive form.
- An equilibrium exists between these forms which results in a basal or “constitutive” level of activity in the absence of the drug.
What are spare receptors?
- A system behaves as if it has “spare” receptors
- more than it needs
- different EC50and KDvalues
- violation of simple occupancy theory
- may involve amplification and persistence of the original binding signal
- possible that limitations on the response to receptor occupancy exist “downstream” of the ligand-receptor interaction itself
Describe the Quantal Dose Effect.
- All or None
- quantal dose-effect curve is a frequency distribution curve of the population response to a drug
What information do/don’t quantal log dose-response curves provide?
- Do:
- Median effective dose (ED50) - the dose required to produce the response in 50% of the population.
- provides information on variability in the response of a population
- can be used to judge a drug’s potency relative to that of another drug
- Don’t:
- provide info on a drug’s KD value or maximum efficacy
What is the therapeutic index (TI) of a drug?
The ratio of the median lethal dose to the ED50
- a measure of relative safety of a drug
What is the Certain Safety Factor of a drug?
The ratio of the dose producing death in 1% of the population (LD1) to the dose of drug producing the therapeutic response in 99% of the population (ED99).
