Pharmacodynamics, therapeutics Flashcards
Drugs, receptors and pharmacological response:
What is a receptor?
Most drugs produce their effects by doing what?
What is affinity?
a macromolecule whose biological function changes when a drug binds to it.
by binding to specific receptors in target tissues.
the measure of propensity of a drug to bind to a receptor; the force of attraction between drug and receptor.
Drug-receptor binding triggers a cascade of events known as ___________
what are the 3 types of bonds between drug and receptor?
signal transduction
Van der Waals force
ionic
covalent interactions
Drug-receptor interaction:
When drugs bind to recepotors , in most cases, the binding is _______ .
Each binding triggers a _____ .
There are Two drugs that compete for the same receptor due to transient binding, how do you determine which will have a greater chance of binding?
transient
signal
the drug with the higher concentration
Equilibrium between drug molecule and its receptor - _______ and _______
association and dissociation.
Equation for drug-receptor interaction:
What is the equation at equilibrium?
Whats kd? and whats its equation?
whats Ka and whats its equation?
If you raise kd then what happens to affinity?
[D] x [R] x k1 = [DR] x k2
k2/k1 = kd (dissociation constant)
k1/k2 = ka (affinity constant)
ka decreases
Equation for drug-receptor interation:
What is [DR] ?
what is this a measure of? and what is it denoted as?
drug response
minimal effect or efficacy, denoted as Emax
How do we measure or quantify a drug - receptor interaction?
Dose-response curve
a Log dose- response graph has what type of curve?
which value is compressed?
proportionate doses occur at equal intervals and its easier to analyze mathimatically.
sigmoid
dose scale is compressed
dose response graph
Define EC50 :
Define Emax:
Define Efficacy(or Intrinsic Activity) :
Define Kd -
dose or concentration of a drug that produces 50% of maximal (half maximal) response
maximal effect produced by a drug. It is a measure of efficacy of a drug.
ability of a bound drug to change the receptor in a way taht produces an effect; some drugs posses affinity but NOT efficacy.
concentration of a drug that occupies 50% of the total number of receptors at equilibrium.
What variable is a measure of efficacy of a drug
Some drugs possess affinity but NOT _____
Emax
Efficacy.
Relative position of the dose-effect curve along the dose axis is referred to as the _______ of a drug.
This has ______ (little/alot) of clinical significance for a given therapeutic effect.
A more potent drug is clinically superior to another.
T or F?
Potency
little
False
Low potency is a disadvantage only when….
How is Potency calculated?
the dose is so large that it is awkward to administer
potency = affinity + intrinsic activity of drug.
Potency is generally compared between two or more drugs that ….
If you decrease the EC50 then what happens to the potency?
Rank these from most potent to least potent:
Ibuprofen
Indomethacin
Asprin
act by the same mechanism
Potency increases with a lower EC50
Indomethacin –> ibuprophen –> Asprin
There are no spare receptors when what two values are equal?
EC50 and Kd
What values would suggest the existence of spare receptors?
(for most organs)
EC50 > Kd
__________ allow maximal response without total receptor occupancy. This increases the _________ of the system.
These can bind (and internalize) extra ligand and prevent what ?
Spare receptors, sensitivity
an exaggerated response if too much ligand is present.
Agonists, partial agonists and antagonists
define an agonist:
define a partial agonist:
define an antagonist:
is a drug which binds to the receptor and produces an effect . Has affinity and Intrinsic activity.
has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor)
is a drug which binds (thus competes for binding against other ligands), but does not activate the receptor. It has affinity but NO intrinsic activity.
An antagonist can be reversible or irreversible.
is an antagonist reversible?
yes it can be.
Agonists, partial agonists
A partial agonist has less _____ and a lower ____ compared to an agonist acting at the same receptor.
Give an example of an agonist:
an example of a partial agonist:
(both must act on opiod receptors)
efficacy, Emax
morphine
buprenorphine
A partial agonist acts as a(n)_____ in the presence of a full agonist.
What are the uses of partial agonists such as buprenorphine:
antagonist
lower abuse potential
lower level of physical dependence
greater safety in overdose compared with a full agonist such as morphine.
What is Buprenorphine?
what happens with overdose?
an opioid analgesic
respiratory shutdown
Antagonist properties of a partial can be useful in what ways?
What is a clinical example of this?
provide some agonist activity and at the same time block the endogenous full agonists
clinical example: pindolol for high blood pressure and abnormal heart rythms
reduces the excessive stimulation due to the norepinephrine in a person with high sympathetic nervous system activity.
blocks adrenaline.
Pindolol is a _______ and acts on what type of receptors?
What is the effect of this drug on unoccupied receptors?
When adregnergic receptors are occupied, what is the effect of this drug?
partial agonst, a1 and B1 receptors
increase heart rate and blood pressure (not as much as full agonist)
pindolol becomes an antagonist for Norepinephrine and displaceses it, this reduces the blood pressure and heart rate.
When an agonist is alone, a lower dose can produce ______ effect. (minimal/maximal)
In the presence of a competitive antagonist what would you do to produce the same effect as previous?
What is an example of a agonist and a competitive antagonist?
maximal
introduce a higher dose of agonist to reach the required effect.
acetylcholine - agonist
atropine - competitive antagonist at muscarinic receptors
How does a dose-effect curve change with the introduction of a competitive antagonist?
What happens to the EC50?
Shifts to the right
increases.
Noncompetitive antagonism
in the presence of a ____________ even a higher dose of agonist cannot produce maximal effect.
What is an example of this?
non-competitive antagonist
noradrenaline - agonist
phenoxybenzamine - non-competitive antagonist at a-receptors
In the presence of a non-competitive antagonist , what happens to the Emax of the agonist?
If there is “less maximal effect” then what happens to the EC50?
Emax is depressed.
still increases.
Define Allosteric Interaction:
When a ligand(B) binds to a site close to the site of an agonist (A) on a receptor and it can affect the binding and/or response to agonist A.
Benzodiazepine drugs potentiate the response to ___________ when they bind to its receptor.
This is an example of a…
Gama aminobutyric acid (GABA)
amplifying Allosteric interaction
when ligand B will rduce or completely inhibit the response or binding of agonist A to the receptor…
this is called…
Diminishing or dampening allosteric interaction
How would you treat atropine poisoning?
Is this reversible receptor?
increase acetylcholine at the receptor and acetylchoinesterase inhibitor ( eg. physostigmine)
yes
Quantal dose response curve
Define a frequency distribution:
Define a cumulative frequency:
indicates sensitivity of a given population to the doses of a drug for a given effect.
each bar shows the number of people responding at that dose.
each bar shows the number of people responding to that dose and to previous doses.
What is the formula for Therapeutic index?
High Therapeutic index means…
Low index means…
TD50 / ED50 or LD50 / ED50
High index = safe
Low index = toxic
Define ED50:
Define TD50:
Define LD50:
The higher a ratio for therapeutic index the ______ (toxic or safer)
Effective dose in 50%
Toxic Dose in 50%
Lethal dose in 50%
__________ reflects a plasma concentration range that provides efficacy without unacceptable toxicity. Its the difference between the minimum effective concentrations for a desired response and an adverse response.
Therapeutic window
A drug-receptor interaction that produces a response. The events involved in this response is known as..
signal transduction
What are the 4 fundamental mechanisms or types of Signal transduction mechanisms?
- G
- I
- E
- N
Half of all known drugs work through what type of mechanism?
G-protein coupled receptor systems. (GPCRs, metabotropic receptors)
Ion channel receptors (Ionotropic receptors)
Enzymes as receptors - tyrosine kinase, serine/threonine kinase
Nuclear receptors
GPCRs (G-protein couple receptors)
When a GPCR is in an Resting or inactive state.. what enzyme is inactive?
What is bound to the Alpha subunit of the GPCR when its inactive?
adenylyl cyclase
GDP
When an agonist binds to a GPCR , what binds to the alpha subunit ?
When this happens, the activated subunits shift tward what enzyme in order to activate it?
GTP
Adenylyl cyclase
Pathways are activated by _________
GPCRs
What are the three major second messengers activated by GPCRs?
cAMP (cyclic adenosine monophosphate)
IP3 (inositol trisphosphate)
DAG (diacyl glycerol)
What structure/enzyme is activated in order to release Protein kinase A?
What structure/enzyme is activated in order to release Protein kinase C?
What structure /enzyme is activated in order to release Ca2+ and increase its concentration?
What channel is directly opened by an Activated G protein?
Adenylyl cyclase –> cAMP –> protein kinase A
Phospholipase C-b –> DAG –> protein kinase C
Phospholipase C-b –> IP3 –> increase in Ca2+
K+ channel
cAMP is used in bronchioles to cause _________
and is used in the heart to cause ________
IP3 causes an increase in _____
DAG causes an increase in ______ from storage.
relax
contract
Ca2+
Ca2+
Which enzyme receptor consists of a pair of protein molecules(monomers) that are separate when inactive?
When an agonist causes them to interact what happens?
What are some examples of this ?
Tyrosine kinase receptor
They form a dimer. The i_nteraction phosphorylates tyrosines_ in the intracellular region of the receptor and the receptor becomes an active enzyme. The active receptor enzyme then activates a number of other enzymes that interact with the active tyrosine of the receptor.
Insulin receptor, growth factor receptors
What type of receptor is a protein with a channel center?
What causes the channel to open?
Whats an example of this type of receptor and what does it conduct?
Ion channel receptor
an agonist
EG. Nicotinic acetylcholine receptor - conducts Na+ ions
- causes muscle depolarization and contraction.
Gamme aminobutryic acid (GABA) receptor - conducts Cl- ions
-inhibits neurotransmission
What type of signal transduction mechanism/receptor is the fastest?
Which is slowest?
ion channel
Nuclear receptors
Where are Nuclear receptors located?
What happens when an agonist binds to the receptor?
What does this lead to?
how long does this kind of signal transduction extend to?
What is an example of a Nuclear receptor?
cell cytosol
the drug-receptor complex then enters the nucleus and stimulates gene transcription
synthesis of new proteins and enzymes
hours / days
receptors for steroids,
retinoids, thyroid hormones
What do agonists tend to do to receptors? Eg. Asthma
What do antagonists tend to do to receptors?
desensitize receptors - treatment of bronchial asthma with B-receptor agonists (such as salbutamol) causes desensitization of receptors.
they tend to regulate receptors - treatment with a B-receptor antagonist causes a withdrawal rebound effect when the antagonist treatment is stopped suddenly.
IE treatment must be stopped GRADUALLY
