1) Drug Receptors and Ion Channels Flashcards
Pharmacodynamics
- Actions of a drug on the body
- Influence of drug concentrations on the magnitude of the response
Receptor effects
- Molecules that allow for therapeutic and toxic effects of drugs upon their interaction
- Responsible for selectivity of drug action
- Mediate action of agonists/antagonists
Receptors largely determine
- Quantitative relations between dose
- Concentration of drug and pharmacologic effects
Determination of whether and with what affinity a drug will bind to a particular receptor is dependent on
- Molecular size
- Shape
- Electrical charge
Dose-response curve example
- 81 mg (dose) Aspirin can cause blood thinning (response) which can be plotted on a graph termed
Affinity of a receptor to a specific molecule will determine
- The concentration needed for this molecule to
produce a response - The interaction between a drug and a receptor is specific
Agonist
- An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule
Antagonist
- An agent which prevents the action of an agonist on a receptor, but does not have any effect of its own
Characteristics of antagonists
- Do NOT activate a signal generation
- Do NOT produce a reverse signal of the agonist
- Occupy the receptor
- Block the ability of an agonist to activate the receptor
Signal transduction
- The binding of drug to its receptor generates signal transduction
- Elicits a biological response
Second messenger/effector molecules
- Part of the downstream cascade of events that translates agonist binding into a cellular response
Receptors exist in at least two states
- Inactive (R)
- Active (R*)
- R and R* are in reversible equilibrium with each other
Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect
Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect
Antagonists occupy the receptor but do not
- Shift the receptor state to R*
Partial agonists shifts receptor state to R, but the fraction of R is
- Less than that caused by an agonist
The magnitude of biological effect is directly related to
- The fraction of R*
The magnitude of the drug effect depends on
- Drug concentration at the receptor site
Drug concentration at the receptor site is determined by
- Dose of drug administered - Drug’s pharmacokinetic profile (such as rate of absorption, distribution, metabolism, and elimination)
As the concentration of a drug increases, its pharmacologic effect
- Also gradually increases until all the receptors are occupied (the maximum effect (Emax))
Plotting the magnitude of response (effect) against increasing doses of a drug (concentration) produces
- A graded dose-response hyperbolic curve
Two important properties of drugs that can be determined by graded dose–response curves
- Potency
- Efficacy
Usually used to determine
potency (EC50)
- The concentration of drug producing 50% of the maximum effect (EC50)
Efficacy
- Magnitude of response a drug causes when it interacts with a receptor
Efficacy is dependent on
- Number of drug–receptor complexes formed (its ability to activate the receptors and cause a cellular response)
Maximal efficacy of a drug (Emax)
- Used to compare the efficacy between different drugs
- Assumes that all receptors are occupied by the drug, and no increase in response is observed even if a
higher concentration of drug is administered
Drug affinity refers to
- Chemical forces that cause a substance to bind its receptor
- Tells how attracted a drug is to its receptors
- Measures tightness/strength with which a drug binds to the receptor
Kd represents
- Equilibrium dissociation constant for the drug from the receptor
The value of Kd can be used to determine
- Affinity of a drug for its receptor
The higher the Kd value
- The weaker the interaction and the lower the affinity, and vice versa
Full agonist
- Binds to a receptor and produces maximal biologic response that mimics the
response to the endogenous ligand - All full agonists for a receptor population should produce the same Emax
Partial agonists
- Have intrinsic activities greater than zero, but less than the full agonist
- Even if all the receptors are occupied, partial agonists cannot produce the same Emax as a full agonist
Partial agonist affinity
- May be greater, less, or equivalent to a full agonist
- It can bind to the receptor with same affinity as the full agonist, but its pharmacological action is less
Spare receptors
- Certain number of receptors that exist in excess of those required to produce a full effect
Allosteric site
- Part of receptor other than the active site (usually of the agonist)
- There are allosteric activator and inhibitors
Inverse agonists
- Exert the opposite pharmacological effects of agonists when they bind to the
receptors
Antagonists bind to a receptor with high affinity, but possess zero
- Intrinsic activity
An antagonist has no effect in the absence of an
- Agonist
- But it can decrease the effect of an agonist when present
Competitive antagonists
- Both the antagonist and agonist bind to the same site on the receptor in a reversible manner
- Competitive antagonist prevents an agonist from binding to its receptor and maintains the receptor in its
inactive state
Competitive inhibition can be overcome by
- Increasing the concentration of agonist relative to antagonist
Competitive antagonists characteristically shift the agonist dose-response curve
- To the right (increased EC50) without affecting Emax
Irreversible antagoinsts
- Bind covalently to the same active site of the receptor as the agonist
- Causes a downward shift of the Emax, with no shift of EC50 values
Irreversible antagonists are considered noncompetitive antagonists
- They cannot be displaced by increasing concentration of agonist
An antagonist that binds to the active site of a receptor is said to be “non-competitive” if
- The bond between the active site and the antagonist is irreversible or nearly so
Non-competitive antagonists reduce
- Agonist efficacy (decrease Emax)
Allosteric antagonists are also considered
- Non-competitive antagonists
Major classes/types of receptors
- Ligand-gated ion channels,
- G protein-coupled receptors,
- Transmembrane enzyme-linked receptors
- Transmembrane tyrosine kinase receptors
- Intracellular receptors
Intracellular receptors
- Several biologic ligands are sufficiently lipid- soluble to cross the plasma membrane and act on intracellular receptors
- Example: steroids (corticosteroids), and thyroid hormone
- Ligand lipophilicity
Transmembrane receptor example
- Receptors mediating the signaling of insulin, epidermal growth factor (EGF)
Transmembrane receptors consist of
- An extracellular ligand-binding domain, and a cytoplasmic enzyme domain which may be a protein tyrosine kinase
Upon binding of EGF, the transmembrane receptor
- Converts from inactive monomeric state (L) –> active dimeric state
(R), in which two receptor polypeptides bind noncovalently
Kinase refers to
- Adding a phosphate atom
The cytoplasmic domains of transmembrane receptors (kinases) become
- Phosphorylated on specific tyrosine residues and activated, catalyzing phosphorylation of substrate proteins
Ligand binding site is located
- The extracellular portion of ligand-gated ion channels
Depending on the ion conducted through these channels, gated channels mediate diverse functions, including
- Neurotransmission
- Cardiac or muscle contraction
Two types of gated channels
- Ligand-gated: ion-channels opens to allow passage of ion when ligand binds
- Voltage-gated: opens when a certain voltage change takes place
G-protein coupled receptors
- GTP-binding signal transducer protein
- The extracellular domain of this receptor contains the ligand-binding area
When the G-protein coupled receptor is activated by binding to a ligand
- The intracellular domain interact with a G- protein
Types of G-proteins
- Gs, Gi and Gq
- All composed of three protein subunits
- α subunit binds guanosine triphosphate (GTP)
- β and γ subunits anchor the G protein in the cell membrane
G-protein receptor binding
- Agonist binds to the receptor
- α subunit binding GTP dissociates from the βγ subunits
- Sometimes, the activated effectors produce second messengers > activate other effectors > signal cascade effect
Adenylyl cyclase
- A common effector
- Activated by Gs and inhibited by Gi
- Produces the second
messenger cyclic adenosine monophosphate (cAMP)
G-stimulatory (Gαs)
- Activates adenylyl cyclase
G- inhibitory (Gαi)
- Inhibits adenylyl cyclase
Gαq
- Activates Phospholipase C
Tachyphylaxis
- When a receptor is exposed to repeated administration of an agonist, the receptor becomes desensitized resulting in a diminished effect
- Diminished response due repeated administration
Up-regulation
- Receptors are sequestered within the cell
- Become unavailable for further agonist interaction
- These may be recycled to cell surface, restoring sensitivity
Down-regulation
- Receptors are sequestered within the cell
- Become unavailable for further agonist interaction
- May be further degraded, decreasing the total number of receptors available
Repeated exposure of a receptor to an antagonist may result in up-regulation of receptors, in which
- Receptor reserves
are inserted into the membrane, increasing the total number of receptors available - Makes cells more sensitive to agonists
Tolerance
- A gradual decreased response to a drug, requiring a higher dose of drug to achieve the same initial response
Tolerance versus tachyphylaxis
- Tolerance develops over a long period of time, and can be overcome by increasing dose
- Tachyphylaxis is an acute event
