Pharmacodynamics Flashcards
pharmacodynamics
the actions of a drug on a living organism
- mechanism of action
- receptor interaction
a drug can modify a particular ____
cellular function or the rate of that function
a drug can’t impart ____ to a cell or target tissue
a new function
drug effect depends on ____
what the cell is capable of accomplishing
drugs must ____ to have an effect
interact with a molecular target
target is usually referred to as a ____
receptor
selectivity of drug action is due to ____
receptors
action of agonists and antagonists is mediated by ___
receptors
when a drug binds to a receptor, one of the following usually occur:
- an ion channel is opened or closed
- biochemical messengers (second messengers) are activated (initiate a series of chemical reactions)
- a normal cellular function is inhibited
- a cellular function is “turned on” (ex: DNA transcription)
Law of Mass Action:
-the combinations of drug (ligand) and receptor depends on ____
the concentrations of each
Law of Mass Action:
-the amount of drug-receptor complex formed determines the ____
magnitude of the response
Law of Mass Action:
-a minimum number of drug-receptor complexes must be formed for ____
a response to be initiated (threshold)
Law of Mass Action:
-as drug concentration increases, the number of drug-receptor complexes ____ and drug effect ____
increases;
increases
Law of Mass Action:
- a point will be reached at which all receptors are bound to a drug
- no further ____ can be formed
- response ____
complexes;
does not increase any further (saturation)
drug-receptor complex formation is proportional to the concentrations of drug and receptor, but the relationship is not ____; pharmacologists usually use a ___ graph to ____
linear;
semilogarithmic;
linearize the relationship
drug response is regulated by 2 properties:
1) affinity- the ability of the drug to bind to its receptor
2) efficacy- the ability of the drug to alter the activity of its receptor
affinity
the strength with which a drug forms a complex with its receptor
affinity is influenced by:
- size and shape of drug molecules
- types, number, and spatial arrangement of drug binding sites (stereochemistry)
- intermolecular forces between drug and binding sites
drug concentration effect on affinity
NONE
types of intermolecular forces
- Van der Walls forces
- hydrogen bonds
- covalent bonds
Van der Walls forces
- weak bonds
- transient
- reversible
hydrogen bonds
- intermediate bonds
- transient
- reversible
covalent bonds
- strong bonds
- long-lasting and/or irreversible
binding of drug to receptor usually involves ___ bonds
weaker
there is a continuous ____ of the drug with the receptor as long as the drug is present
association and dissociation
the ___ is a measure of a drug’s affinity
dissociation constant (Kd)
Kd represents the ____
concentration of drug needed to ensure that 50% of the total receptor population is bound to the drug
Kd does not always indicate ____
half-maximal response
each drug-receptor combination will have a characteristic Kd value;
high affinity= _____ value for Kd
low affinity= _____ value for Kd
small;
large
a cell will respond only to the spectrum of drugs that exhibit ____
affinity for the receptors expressed by the cell
the greater the affinity for one receptor, the ____, which ____
more selective the drug’s actions;
lowers the potential for side effects
few drugs are entirely ____ for one receptor;
many are ____ towards certain receptors based on affinity
specific;
selective
as concentration increases, the drug will bind to receptors for which it has ____
lower affinity
only those tissues ____ will respond to the drug
possessing receptors
the more restricted the distribution of drug receptor, the _____
more selective will be the effects of drugs that interact with that receptor
dose-response curve
gives representation of the relationship between amount of drug given and the anticipated effect
2 types of dose-response curves
- graded
- quantal
graded dose-response curve:
- measures ____
- similar shape to ____
- key points: ____
continual effect;
drug-receptor occupancy curve;
Emax, EC50
Emax (graded dose-response curve)
dose beyond which no further response is achieved (maximal effect); measure of efficacy
EC50
concentration (dose) that produces 50% of maximal response; measure of potency
quantal dose-response curve:
- measures ____
- gives the relationship between ____
- key points: ____
responses that are all or none;
drug dose and the frequency with which a biologic effect occurs;
ED50, Emax
ED50
dose of drug that produces a response in 50% of the population
Emax (quantal dose-response curve)
dose at which all of the patients respond to the drug
quantal dose-response curve:
-can be plotted for _____ effects
therapeutic, toxic, and lethal
TD50
dose that produces toxic effects in 50% of the patient population
LD50
dose at which 50% of patients die
therapeutic index (TI)
a measure of the safety of a drug (larger is better!);
found by dividing the LD50 (or TD50) by the ED50
agonist
binds to receptor and elicits a response
antagonist
binds to receptor but does not elicit a response
full agonists
produce maximum activation of the receptor and elicit a maximum response from the tissue
partial agonists
produce weaker activation than full agonist or endogenous ligand; must be bound to more receptors to produce same effect as full agonist
inverse agonists
inhibit receptors that exhibit activity in the absence of agonist binding; binding of inverse agonist reduces the baseline activity of the receptor; technically an agonist because it causes a response
antagonists
have zero intrinsic activity; do not cause a reaction, simply prevent the receptor from being occupied by another molecule
competitive reversible antagonists
- antagonist competes directly with the agonist molecule
- increasing the concentration of the agonist will eventually overcome the antagonism
- Emax is the same but curve shifted to the right
competitive irreversible antagonists
- compete directly with agonist for receptor binding site
- bond is so strong that it is irreversible
- permanently reduces number of receptors available to an agonist
- reduces the maximal agonist effect
noncompetitive antagonist
- do not compete with agonist for same binding site
- impair the ability of the agonist to bind to or activate the receptor
- both antagonist and agonist can be bound at the same time
- increasing concentration of agonist will not reverse the inhibitory action
- similar curve to irreversible agonist
- difference may be in duration of action
4 families of receptors
- ligand-gated ion channels
- G protein-coupled receptors
- enzyme-linked receptors
- intracellular receptors
ligand-gated ion channels
- regulates ion flow across membranes
- flow of ions through these channels is dependent on binding of a ligand (neurotransmitter, drug) to the receptor on the channel
- ion channel possesses a receptor for an endogenous ligand (agonist usually binds to same receptor)
- activation by endogenous ligand or agonist opens the channel (antagonists prevent activation of the channel or cause it to remain closed)
ligand-gated ion channel examples
- cholinergic receptors: found in nervous system, binding of agonist opens sodium channels and causes initiation of action potential
- GABA receptors: found in CNS, binding of agonist opens chloride channels, causing hyperpolarization (reduce probability of action potential)
voltage-gated ion channels
- change conformation in response to changes in membrane voltage
- binding of drugs to these channels causes a change in the response of the channel
- open, closed, or inactive state may be lengthened or shortened
- ex: local anesthetics
G-protein coupled receptors
- single peptide that has seven membrane-spanning regions
- linked to a G-protein
- binding of ligand to the extracellular region of the receptor activates the G-protein
G-protein has ___ subunits: ____
3;
alpha, beta, and gamma
activation of G-protein coupled receptors
- GTP replaces GDP on the alpha subunit
- alpha-GTP and beta-gamma subunits dissociate and interact with other cellular effectors (enzymes or ion channels)
- change the concentrations of intracellular second messengers that are responsible for further actions within the cell
- slightly slower response but lasts longer (several seconds to minutes, “slow on” and “slow off”)
second messengers are important in ____
conducting and amplifying signals from G-protein coupled receptors
enzyme-linked receptors
- have cytosolic enzyme activity as part of their structure and function
- binding of the ligand to the receptor activates or inhibits the activity of the enzyme
- receptor undergoes conformational change upon binding
- longer duration (minutes to hours)
enzyme-linked receptors:
- ____ can modify the three-dimensional structure of the target protein
- acts as a ____
- ____ that multiplies initial signal
- examples: ___
addition of a phosphate group;
molecular switch;
cascade activation;
insulin receptor, VEGF
intracellular receptors
- receptors are located intracellularly
- ligand must be lipid soluble
- example: steroid hormones
- binding of ligand with its receptor causes dissociation of a small repressor peptide and activates the receptor
- complex migrates to the nucleus where it binds to specific DNA sequences
- results in regulation of gene expression
- much longer time course (due to change in gene expression, 30 mins or more to observe response, response lasts hours to days)
spare receptors
- in some cases, a maximal response can be achieved when only a fraction of receptors are occupied (EC50 is much lower than the Kd)
- due to amplification of signal duration and intensity
- common with G-protein linked receptors
spare receptors:
amplification occurs by two phenomena
- a single ligand receptor complex can interact with many G-proteins
- an activated G-protein can persist for a longer duration than the original ligand-receptor complex
-because the amplification only involves a fraction of the total receptors for a specific ligand, the system is said to have spare receptors
receptor desensitization
- repeated or continuous administration of a ligand may lead to changes in the responsiveness of the receptor
- evolved to prevent cell damage
two mechanisms of receptor desensitization
- tachyphylaxis
- endocytosis
receptor desensitization: tachyphylaxis
receptor is still present but is unresponsive to the ligand
receptor desensitization: endocytosis
- binding causes conformational change in receptor
- receptor undergoes endocytosis and is sequestered from further activation
tolerance
- decreased response to a drug
- dose must be increased to achieve the same effect
- can be metabolic, cellular (downregulation), or behavioral
dependence
- patient needs a drug to function “normally”
- usually physical but CAN have a psychological component
withdrawal
- drug is no longer given to a dependent patient
- symptoms are often the opposite of the effect of the drug
there may be considerable variation in the way that patients respond to medication for multiple reasons:
- alteration in the concentration of drug that reaches the receptor
- variation in concentration of endogenous ligand
- alteration in number of receptors
- changes in components of response
most drugs interact with receptors that will determine ____
selective therapeutic and toxic effects of the drug
receptors largely determine the _____
quantitative relations between dose of a drug and pharmacologic effect
