test 2 part 3 Flashcards
Pharmacodynamics
- The actions of a drug on the body
- The influence of drug concentrations on the magnitude of the response
- Signal Transduction
- Alterations in biochemical and/or molecular activity of a cell initiated by the drug-receptor complex
what is a Drug
- Any substance that brings about a change in biologic function through its chemical actions
- Must have appropriate
- Size- small are less likely to be selective (can fit a lot of different receptors)
- Electrical charge
- Shape
- More than half of all drugs are chiral molecules
- Atomic composition
Drug Electrical Charge: Drug-Receptor Bonds
- Covalent (electron sharing)
- Very strong
- Not reversible
- Electrostatic
- More common than covalent
- Vary from strong to weaker hydrogen bonds to van der Waals forces
- Hydrophobic (most common)
- Relatively weak
- Important in highly lipid soluble drugs within lipids of cell membranes
- Drugs that bind through weak bonds are generally more selective than drugs that bind through very strong bonds
Drug Shape: Racemic Mixtures
- Majority of drugs available as racemic mixtures (2 different isomers)
- Potency and duration of action different in many cases
Receptor
• Any biologic molecule to which a drug binds and produces a measurable response • Enzymes • Nucleic acids • Structural proteins -1. needs to be selective for a ligand -2. pharmacological response -needs both to be a receptor
albumin as a binding site
- inert binding site
- does not have a direct biological effect
- drug binding to albumin does effect the volume of distribution and the amount of free drug in the bloodstream
Signal Transduction
- unoccupied receptor does not influence intracellular processes
- receptor with bound agonist is activated. It has altered physical and chemical properties, which leads to interaction with cellular molecules to cause a biologic response
The Drug-Receptor Complex
- Cells have many types of receptors
- Specific for particular agonist
- Produce unique response once activated
- Magnitude of response proportional to number of drug-receptor complexes
- Most receptors named for the type of agonist it interacts best with
- Not all drugs exert their effect through receptors
Receptor States
- Inactive (R)
- Active (R*)
- Reversible equilibrium usually favoring inactive state unless ligand bound to it
- Equilibrium shifts to R* when agonist binds
- Magnitude of effect directly related to fraction of R*
Major Receptor Families
- Ligand-gated ion channels
- G protein-coupled receptors
- Enzyme-linked receptors
- Intracellular receptors
Ligand-gated Ion Channels
- Ligand binding site on extracellular portion
- Opens channel for a few milliseconds
- Ions then move in or out
G Protein-coupled Receptors
- unoccupied receptor does not interact with G protein
- Occupied receptor changes shape and interacts with G protein. G protein releases GDP and binds GTP
- Alpha subunit of G protein dissociates and activates adenylyl cyclase
- When hormone is no longer present, the receptor reverts to its resting state. GTP on the alpha subunit is hydrolyzed to GDP, and adenylyl cyclase is deactivated.
- largest receptor family
- response lasts minutes
Enzyme-linked Receptors
• When activated, phosphorylate tyrosine residues on themselves and then other specific proteins • Acts as a molecular switch • Multiplication of initial signal • Response lasts minutes to hours -activates enzymes inside of the cell
Intracellular Receptors
• Ligand must diffuse into the cell to interact with receptor
• Primary target: transcription factors in cell nucleus
• Response lasts hours to days
-takes a little for a response and once the proteins are formed then the response lasts hours to days
-not easily reversible
Two Important Features of Signal Transduction
- The ability to amplify signals
2. Mechanisms to protect the cell from excessive stimulation
Signal Amplification
- G protein-linked and enzyme linked receptors
- Amplify signal INTENSITY and DURATION
- Ligand binding may only last milliseconds, but activated G proteins last longer
- Spare Receptors
- Only a fraction of total receptors needed to elicit maximal response
Protection from Excessive Stimulation
- Desensitization
- Results in diminished effect (tachyphylaxis)
- Down-regulation
- Receptors are internalized within the cell
- Recycled back to surface
- Degraded
- Receptors are internalized within the cell
- Refractory period
- Finite time required before receptors can be activated again (ion channels)
Potency
• The amount of drug necessary to produce an effect of a given
magnitude
• EC50: concentration producing 50% of maximal effect
-Potency differences can be overcome by simply giving more drug
Efficacy
• Magnitude of response a drug causes when it interacts with a receptor
• Dependent on
• number of drug-receptor complexes formed
• Intrinsic activity of the drug
-Efficacy is more clinically useful than potency
-we are trying to get to a certain point and if a drug won’t get there it is worthless
Law of Mass Action and Drug-Receptor Interactions
Drug + Receptor ↔ Drug-receptor complex → Effect
- The drug and receptor combine reversibly
- Occupancy of receptors by the drug is proportional to the dose of the drug and the number of the free receptors
- Magnitude of response is directly proportional to the fraction of total receptor sites occupied by drug molecules
- Effects plateau because they are limited by the total number of receptors
Agonist
- Binds to a receptor and produces a biologic response
- Intrinsic activity determines its degree of receptor activation
- Full agonist
- Partial agonist
- Inverse agonist
Full agonist
• Maximal biologic response
• Mimics endogenous ligand
-intrinsic activity of 1
Partial agonist
- Cannot produce same Emax
* Affinity can be >,
Inverse agonist
• Stabilizes receptors in inactive state to prevent spontaneous activation
• Opposite pharmacological effects of agonists
-intrinsic activity = <0
Antagonists
- Bind to a receptor with high affinity
- Zero intrinsic activity
- Block
- Drug binding to receptor
- Drug’s ability to activate the receptor
Competitive Antagonism
• Both the agonist and the antagonist bind to the same site reversibly
• Shift the dose response curve to the right
• Same Emax
• Increased EC50
-Inhibition can be overcome by increasing the concentration of agonist
-shifts dose response curve to the right
-just add more agonist to overcome effects
Non Competitive Antagonism
• Irreversible Antagonist
• Covalently binds to the receptor site (so not coming off)
• Decreases the # of available receptors for agonist
• Allosteric Antagonist (reversible)
• Binds to site other than the agonist binding site
• Prevents receptor from being activated
-changes shape of receptor
• Decreased Emax
• Same EC50
-Inhibition cannot be
overcome by increasing the
concentration of agonist
Functional Antagonism
• Drug acts at a completely different receptor to initiate an effect opposite to that of the agonist
Chemical Antagonism
• Drug binds the agonist itself (not the receptor) to counter its effects
Quantal Dose-Response Relationships
- Relationship between dose of a drug and proportion of a population that has a response
- Useful for determining appropriate doses (safety profile of drugs)
Therapeutic Index (TI)
TI = TD 50 / ED 50
• The ratio of dose that produces toxicity in 50% of the population and the dose that produces a specific therapeutic effect in 50% of the population
-TD = toxic dose
-ED = effective dose
Therapeutic Index
- Higher TI: safer
- Low TI (<2): used only to treat serious diseases
- risk of side effects outweighs risk of leaving disease untreated
