Pharmacodynamics (Konorev) Flashcards
Define pharmacodynamics
effects of drugs on the body including:
- drug receptors
- dose-response curves
- mechanisms of drug actions
Define receptor vs. ligand in regards to pharmacology
receptor: a specific molecule in a biological system that plays a regulatory role. Receptor interacts with a drug and initiates the biochemical events leading to drug effects
ligand: it is a molecule like a hormone or drug which binds to a receptor
What is a dose-response curve
the relationship between a drug and its effects is described quantitatively using a dose-response curve
when you plot drug dose arithmetically on the x-axis vs. drug effect on the y-axis you typically get what is called a hyperbolic curve
How is a concentration-effect curve commonly presented?
by graphing the logarithm of the drug dose vs. the response in which case you get a sigmoidal curve
Define Emax
Define ED50
Emax is teh maxmial effect that can be produced by the drug
ED50 is the effective dose 50 or the dose of the drug that produces 50% of its maximal effect
What is a graded response (curve)?
Answers: How Much?
- Magnitude of a response varies continuously
- typically represents the mean value within a population or a single subject
What is the quantal dose-response (curve)?
All or none, yes/no binary responses
answers the question: Does the response? occur, or how many?
- requires a pre-defined response
- used to examine the frequency of a response within a large population
What is a non-cumulative quantal dose response curve?
Number of % of individuals responding at a dose of a drug and only at that dose
What is a cumulative quantal dose response curve?
Number of % of individuals responding at a dose of a drug and at all doses lower than that dose
Define:
ED50
TD50
LD50
ED50: median effective dose
TD50: median toxic dose
LD50: median lethal dose
Drug safety index can be described by the therapeutic index
TI=TD50/ED50 (the higher the TI, the safer the drug)
What is the therapeutic window?
the range of doses of a drug or of its concentration in a bodily system that provides for the safe and effective therapy
Define drug potency
describes the amount of drug required to produce a specific pharmacological effect
- Describes the amount of a drug required to produce a specific effect
- represented by the ED50
- the lower the ED50, the more potent the drug
- determines the drug dose to be used clinically
Define drug efficacy
describes the maximal pharmacological effect that a drug can produce
- represented by the Emax
- the greater the Emax, the more efficacious the drug
- efficacy is related to the total number of receptors available to bind a drug
- determines the magnitude of clinical effect
What are the four ways a drug can interact with its receptor?
binding
affinity
selectivity
intrinsic activity
Describe covalent drug-receptor binding
irreversible, requires resynthesis of the receptor or enzymatic removal of the drug
Describe non-covalent drug-receptor binding
reversible, most drugs bind to receptors via non-covalent bonds
Describe affinity of a drug for a receptor
The affinity of a drug for its receptor describes how readily and tightly that drug binds to its receptor
- high affinity: strong drug-receptor interaction, less drug needed to produce a response
- low affinity: poor drug receptor interaction; more drug needed to produce a response
What is Kd?
describes affinity
drug concentration at which 50% of the drug receptor binding sites are occupied by the drug
unit is in molar concentrations
lower Kd indicates higher affinity for receptor
higher Kd indicates lower affinity of a drug for a receptor
Describe drug selectivity
Selectivity is a property of a drug determined by its affinities at various binding sites
measured by comparing affinities of a drug to different receptors
a more selective drug would have higher Kd ratio and affect fewer targets over a specific concentration range
How does selectivity relate to adverse effects
more selective drugs have fewer adverse effects
less selective drugs have more adverse effects
What is Intrinsic activity?
intrinsic activity describes the ability of a drug to change a receptor function and produce a physiological response upon its binding to a receptor
What is an agonist?
Does it have intrinsic activity?
an agonist binds to the receptor and stabilize it in a particular conformation, producing a physiological response
Has intrinsic activity
What is an antagonist?
Does it have intrinsic activity?
A receptor antagonist binds to the receptor but do no change its function. They prevent activation of the receptor in the presence of an agonist
Does not have intrinsic activity
What is a full agonist?
Fully activate receptors
produce a maximal pharmacological effect when all receptors are occupied
maximal intrinsic activity
What is a partial agonist?
partially activate the receptor upon binding
produce a sub-maximal pharmacological effect when all receptors are occupied
intrinsic efficacy caries depending on drug, but is always submaximal
What is an inverse agonist?
produces an effect opposite to a full or partial agonist
- decreases receptor signaling
- decreases response at receptors with a significant level of constitutive receptor activity
- intrinsic activity is present and related to the inhibition of receptor function
What is pharmacologic (receptor) antagonism?
action at the same receptor as endogenous ligands or agonist drugs
What is chemical antagonism?
When chemical antagonist makes the other drug unavailable
What is physiologic antagonism?
occurs between endogenous pathways regulated by different receptors
What are competitive antagonists?
- compete with endogenous chemicals or agonist drugs for binding the receptor
- can be displaced from the receptor by other drugs (effects are surmountable)
What are non-competitive antagonists?
- receptor inactivation is not surmountable
- irreversible antagonists: irreversibly bind to and occlude the agonist site on the receptor by forming covalent bonds
- allosteric antagonists: bind to a site other than the agonist site to prevent or reduce agonist binding or activation of the receptor
How does EC50 and Emax change in competitive antagonism?
Agonist EC50 increases
Emax does not change
How does Emax and EC50 change in noncompetitive antagonism?
EC50 does not change
Agonist Emax decreases
How do full agonists work?
mimic actions of endogenous chemicals at receptors
example: activation of mu opioid receptors by opioid analgesics such as morphine and codeine
How to antagonists, partial and inverse agonists, work?
block the actions of endogenous lignads at receptors
example: blockade of the a1 adrenoceptors receptors by the antihypertensive drug, prazosin
What are the major classes of drug targets?
membrane receptors
nuclear receptors
ion channels
transport proteins
enzymes
drugs are designed to target important regulatory proteins in the existing cell signaling pathways
G protein families:
Gs-AC activation
Gi-AC inhibition
Gq-PLC activation
G12/13-Rho GTPases, cytoskeletal rearrangements
GPCR signaling cascades are either
cyclic AMP second messenger pathway lead or DAg/IP3 lead
JAKs transmit the effect of a number of hormones and cytokines to activate the JAK-STAT pathway including
growth hormone (somatotropin)
erythropoietin
letpin
itnerferons
interleukins 1-10, 15
RTKs transmit the action of growth factors such as
IGF-1
insulin
VEGF
EGF
NGF
PDGF
RTK signaling pathways as drug targets for oncogenes in growth factor pathways including
overexpression or amplifications of GF
point mutations or amplifications of GF receptors
point mutations in RAS
point mutations in Raf
targeted anticancer drugs inhibit upregulated growth factor signalging
nuclear receptors are ligand-activated transcription factors that modulate gene expression
ligands are lipophilic molecules that are able to cross cell membranes including
steroids and thyroid hormones
vitamines A and D
lipid mediators
Ion channels as drug targets used for
maintaining resting membrane potential
shape action potentials
change the concentration of ions in cytosol
(used for arrythmias, angina pectoris, hypertension, constipation)
