pharmocodynamics target tissue receptors Flashcards
receptors
- component on or within a cell that a substance can bind to
- when drug binds to receptor, it initiates biochemical chain of events
- have a binding site located on outer surface of cell membrane (differeniate and respond to specific substances)
- transmit a message through the cell membrane to cause a change in cell activity
- surface receptors are often transmembrane proteins
surface receptors
directly affect cell function in one of these ways
* acts as an **ion channel **and directly altering membrane permeability
* acts enzymatically to directly influence function within cell
* linked to regulatory proteins that control other chemicals and enzymatic processes
surface receptors linked directly to ion channels
- receptors becomes an ion pore–> changes the membrane permeability
- ex: ACh receptor
-postsynaptic membrane of the neuromuscular junction
-gamma aminobutyric acid (GABA)- benzodiazepine- chloride ion channel complex
-neuronal membranes in the CNS
surface receptors linked directly to enzymes
drugs and endogenous chemicals that bind to receptor site can change the enzyme activity of the intracellular catalytic component
ex: tyrosine kinase protein for insulin and other growth factor
surface receptors linked to regulatory (G) protein and the role of the second messenger
- affect cell function by linking to an intracellular intermediate regulatory protein (G proteins), activated by binding guanine nucleotides (called G protein coupled receptors (GPCRs)
- drug may bind to the cell for only a short period but long enough to initiate the interaction of the G protein with the intracellular effector system (sustained influence).
What affects a drugs affinity?
- local regulators (allosteric modulators)
- environments (fludity of cell membrane critical to provide suitable environment for receptors to function)
drug receptor interactions
- ability depends on the drug’s size and shape relative to the configuration of the receptor’s binding site and electrostatic attraction between the drug and the receptor
- some drugs bind readily to the receptor, some moderately, some very little, or some not at all
affinity
- the amount of attraction between a drug and a receptor
- it is related to the drug amt. that is required to bind to unoccupied receptors
- super high vs high vs low affinity
- influenced by local regulators (allosteric modulators) and environments (membrane’s fluidity and organization)
functional aspects of drug receptor interactions
- drug selectivity and receptor subtypes
- dose response
- classification of drugs: agonist vs antagonist
- competitive vs noncompetitive antagonists
- partial agonists
- mixed agonist antagonists and inverse agonists
Drug selectivity and receptor subtypes
- drug selectivity
- a relative term b/c no drug produces only one effect (all drugs produce some side effects)
- related closely to subtypes of receptors based on structural and functional differences
- a selective drug affects only one type of cell or tissue and products a specific physiological response and fewer side effects than a nonselective drug
Dose-Response
- response typically proportional to the number of receptors occupied by the drug (not a linear relationship)
- increasing the dosage beyond the point at which the maximal effect is reached will not produce any further increase in reponse b/c all the receptors are bound by the drug
Classification of Drugs: Agonist vs Antagonist
- agonist has both affinity and efficacy
- antagonist has only affinity and it occupies the receptor to “block” the effect of another chemical
Competitive vs Noncompetitive Antagonists
Competitive
* vie for the same receptor as agonist
* equal opporunity
* whichever drug concentration is higher, predominant effect
* agonist. can overcome the antagonist
Non-Competitive
* premanent, irreversible bonds
* inability of agonist to compete with the antagonist
* terminated only with normal protein turnover, so the effect tends to remain long
Partial Agonists
if
strong agonist = 100% efficacy
And
strong antagonist = 0% efficacy
partial agonist= 1`99% efficacy
* it does not completely activate the receptor after it binds
* it is not caused by decreased drug- receptor affinity
Mixed Agonist-Antagonists
- will act as an agonist on one tisssue/ organ
- will act as an antagonist on another tissue/organ
- Ex: selective estrogen receptor modulators can act as an agonist on bone and on antagonist on breast tissues
inverse agonist
opposite effect of an agonist on cellular function
-decreased activity where the receptor is too active or overstimulated
Receptor Regulation
- overstimulation of postsynaptic receptors by endogenous substances (neurotransmitters, hormones) or by exogenous agonists (drugs) may lead to functional decrease in the appropriate receptor population
- a prolonged decrease in the stimulation of the post synaptic receptors can result in a functional increase in receptor. sensitivity
Receptor Desensitization
- brief and transient; return to normal within a few minutes after the agonist is removed
- associated with phosphorylation
Down Regulation
- slow and prolonged (remains several days after the agonist is removed)
- increased receptor removal, decreased receptor synthesis or both
drug tolerance
- the need to progressively increase the dose to achieve therapeutic effects
- may be due in part to changes in receptor sensitivity and function
efficacy
the drug will activate the receptor and change the function of the cell
agonist
a drug that can bind to a receptor and initiate a change in the cells function
- both affinity and efficacy
antagonist
- only affinity
- the drug will bind to receptor, but it will not cause any direct change in the function of the receptor or cell
- by occupying the receptor, they prevent the agonistic compound from having any effect on cell.
- blockers because ability to block effect of another chemical
receptor internalization
receptors are withdrawn from the cell membrane by endocyosis
receptor desensitization and down regulation purpose
negative feedback system to prevent overstimulation by an agonist
supersensitivity
decreased stimulation results in increase receptor numbers
Receptor Supersensitivity
prolonged decrease in stimulation of the post synaptic receptors can result in a functional increase in receptor sensitivity
Denervation in PNS (receptor supersensitivity)
- lack of presynaptic neurotransmitter release results in a compensatory increase in postsynaptic receptor numbers on muscle cell
(receptor supersensitivity) parkinson disease
- loss of the endogenous neurotransmitter dopamine result in supersensitivity of receptors for that neurotransmitter
taking receptor antagonist drugs for prolonged periods (receptor supersensitivity)
the postsynaptic neuron interprets this as the synapse being denervated and responds by maufacturing more receptors
