Pharmacodynamics 2 Flashcards
DR complex causes ..
biological effect
drug binding to the receptor is governed by
affinity for the receptor
how does the drug create the biological effect
by causing a conformational change - efficacy or intrinsic activity
partial agonist
– no matter how much drug – cannot achieve full response in tissue
what can a log conc. curve tell you
what drug is more potent
what would you use to compare potencies from a conc response curve?
EC50 values
Antagonists have
affinity for a receptor - but they have zero efficacy
Antagonists - zero efficacy
do not activate a receptor they just block
- con observe an effect but there is no response
beta blocker
antagonist which stops the endogenous ligands binding - lowers HR
agonist potency only involves
affinity
antagonists
block the action of agonists
agonist and increasing agonist cone-response curve
shifts the curve rights
drug - receptor interaction is reduced
alters the effective association - changing the apparent affinity of the drug
concentration ratio (r)
EC50 Antagonist /EC50 agonist
r - 1
[B] /Kb
what should the axis for the Schild plot be?
X - Log [B] M
Y - Log (r-1)
what is the X intercept on the Schild plot
Kb
Log (r-1) =
Log [B] - LogKb
Think that B is the conc of the antagonist
what is the gradient of the schild plot slope for a competitive antagonist?
gradient 1
pA2 =
- Log KB
what measures of affinity do we use for agonist or antagonist
agonist - Kd
antagonist - pA2
what would the child plot slope being less than 1 suggest?
negative cooperativity - something happening to deplete it - overestimated the affinity of the agonist to start
- agonist acting on a second receptor type
what would schild slope being greater than 1 suggest?
cooperativity between the agonist and the antagonist - r the antagonist is being inhibited by being bound to somewhere else
- non specific binding, depletion of agonist
what must hold true for the child plot to work?
one molecule binding to one receptor (agonist or antagonist)
what wold you see in a IRREVERSIBLE competitive antagonist graph?
the graphs shift down - get less response with higher conc of antagonist
(could also see some parallel shift but draw above in exam)
what happened to Kd with a irreversible competitive antagonist?
KD stays the same as the amount required to occupy receptors stays same – reducing amount of receptors
(not changing the affinity)
what allows irreversible antagonism?
a covalent bond being formed
what is non-competitive antagonism?
Preventing receptor activation or significantly reducing the receptor activation – reduced
what is chemical antagonism?
Two substances combine in solution
Result effect of active drug is lost
what are 2 examples of chemical antagonists?
- Dimercaprol -
- infliximab
what do collating agents do?
mop up the excess - for excretion
what does Dimercaprol do?
use to to treat heavy metal poisoning – lead – makes lead excretal by the body
what does Infliximab do?
– anitinflamatory drug that targets tumor nercrosis factor – mops up TNF – less inflamation – antibody concept
what receptors in the heart does noradrenaline act on? Effect?
B2 receptors
increase HR
what receptors in the heart does Acetylcholine act on? Effect?
mAchR
decrease HR
explain biased agonism
1 receptor type - 2 different agonists - would produce both responses equally or favour making more of one response than the other - but creates more of one response than the other
- select which pathway becomes activated on binding
what is pharmacokinetic antagonism?
injected somethnig – another drug affects something making the first drug less effective
(one drug affecting another metabolism - dangerous)
what is allosteric modulation?
a substance which indirectly influences (modulates) the effects of a receptor agonist or inverse agonist at its receptor protein target.
how would a positive modulator affect the conc. response curve?
curve would shift left – positive effect on affinity
what would happen to the conc response curve if there was an allosteric modulator which has a negative affect on efficacy?
would become more squished down
what is efficacy? (Emax)
maximum response achievable from an applied or dosed agent, for instance, a small molecule drug. Intrinsic activity is a relative term that describes a drug’s efficacy relative to a drug with the highest observed efficacy.
what is the therapeutic index equation?
TD50 / ED50
TD - toxic dose
ED - effective dose
what is the therapeutic window between?
MED and MTD
minimum effective dose and maximum tolerated dose
what would a therapeutic index of 2 or less be
very risky
what do the allosteric modulators valium/diazapan do?
positively modulate and calm down inhibitory neurones GABA receptor
Ion-Channel Linked Receptors: Location/effector
membrane channel
Ion-Channel Linked Receptors: coupling
direct
Ion-Channel Linked Receptors: time
milliseconds
Ion-Channel Linked Receptors: Structure
Many different sub-units, generally 4-5 f
Ion-Channel Linked Receptors: Examples
Nicotinic ACh
GABAA
G-protein Coupled Receptor: location and effector
membrane, enzyme or channel
G-protein Coupled Receptor: coupling
G - protein
G-protein Coupled Receptor: time
seconds
G-protein Coupled Receptor: structure
A single protein with no subunit. Has 7 transmembrane α-helices as the binding domain with an intra-cellular G-protein coupling domain
G-protein Coupled Receptor: examples
Muscaranic Ach
adrenorerceptors
Tyrosine-Kinase Linked Receptors: location and effector
membrane, enzyme
Tyrosine-Kinase Linked Receptors: coupling
direct or indirect
Tyrosine-Kinase Linked Receptors: time
mins - hours
Tyrosine-Kinase Linked Receptors: structure
A single α-helix which passes through the membrane. The catalytic domain contains the tyrosine kinase which phosphorylates tyrosine
Tyrosine-Kinase Linked Receptors: examples
insulin and cytokine receptors
Receptors Linked to Gene Transcription (nuclear receptors : locations and effector
intracellular and geen transcription
Receptors Linked to Gene Transcription (nuclear receptors: coupling
via the DNA
Receptors Linked to Gene Transcription (nuclear receptors time
hours
Receptors Linked to Gene Transcription (nuclear receptors - structure
Close to nucleus and causes changes in DNA transcription. Has a binding domain and a DNA-binding domain (“zinc fingers”)
RTK examples
Steroid receptors
Thyroid Hormone receptors
ligand gated ion channels - where does the drug bind
N terminus tail outside the cell
C terminus is also outside the cell
where is the N terminus on the RTK
on the top - where the drug binds - C terminus inside the cell
Gas
coupled to adenylate cyclase which converts ATP –> cAMP
cAMP acts as a second messenger to phosphate kinase
Gai
inhibitory
inhibits cAMP formation - less PK action
Gaq
coupled to phospholipase C (membrane bound)
PLC activates and cleaves PIP2 to form DAG and IP3
DAG activates PKC and IP3 regulates [Ca} intracellularly
which G protein dos the cholera toxin activate?
Gas - which blocks GTPase activity preventing inactivation
GPCRs how much genome
1% of the human genome
huge diversity
in GPRCs which ion channels activated how
Betagamma subunit principly activates K channels and inactivate voltage-gated calcium channels
what is pharmacogenomics?
Genetic variability in the way drugs behave in the body
Pharmacodynamic:
receptor variants
