Pharmacodynamics 1 Flashcards
Pharmacokinetics
study of what the body does to the drug
pharmacodynamics
study of the action of drugs on the body
drug nomencleture
- chemical name
- generic name
- trade name
drugs often
mimic or block the action of our own signalling molecules
examples of natural drug sources
yew, fox glove, penicillium
receptor
generally used to describe the target molecules through which double physiological mediators produce their effects
protein targets of drugs
enzymes, transporters, ion channels, receptors
non protein targets of drugs
DNA, lipids
Principles of drug action
binding, agonism/antagonism, receptor classification, second messengers/signal amplification
4 receptor families
ligand gated ion channels
G protein coupled receptors
Kinase linked
nuclear receptors
ligand gated ion channels
ionotrophic receptors
passageway through membrane
conformational change
fast siganlling
example of ligand gated ion channel
nicotinic acetyl choline receptor
GPRC
Metabotrophic
protein with multiple subunits
example GPRC
post synaptic muscaranic acetylcholine receptor
kinase linked
inside the membrane
gene transcription and protein synthesis
response takes hours
example kinase linked
cytokine receptor - insulin receptors
“metabolic change”
Nuclear receptors
action in the nucleus - may not be specifically located in the nucleus
hours
gene transcription and protein synthesis
example of nuclear receptor
hormone - lipophilic eg oestrogeen receptor
Is a drug ever 100% specific?
no - only selective for the receptor over another
Specificity
the ability to identify the true negatives
eg 100% - correctly identify all the patients without the disease
Can therapeutic dose affect specificity?
yes - which receptors are activated
side effects at higher doses
binding is …. in 99% of situations
transient - on/off
rate of on and off
K↓1 and K↓-1
higher affinity
will bind more readily to its receptor
endogenous ligand
binds toa receptor - produced in the body
what is K↓D
the dissociation constant which is a measure of the tendency of the drug-receptor complex to dissociate
[D] [R] [DR]
K↓1 forwards and K↓-1 reverse reaction
K↓D =
k-1 = [D] [R] =?
k1 [DR]
1/K↓A
K↓D
smaller the K↓D
the higher the affinity
Fractional occupancy
how may of the receptors are bound out of all the receptors
Dissociation constant from conc/occupancy graph
the conc. of the drug required to occupy 50% of the available receptors
p↓A (fractional occupancy) =
([D] / K↓D)
[D] / K↓D + 1
saturation binding experiments
radiojlabel the drugs - work out the affinity or K↓D of a receptor.
or density (Bmax) of receptor for a specific tissue
what is Bmax
density of a specific receptor in a tissue
saturation binding: TB, SB, NSB
TB = Total Binding (some to other receptors) SB = Specific Binding NSB = Non-specific Binding (to other receptor (control used))
axis for saturation binding
x - conc
y - %total bound
what is a Scatchard Plot?
showing the amount of receptor bound (X) against bound/free (Y)
what line should you see in a Scatchard plot?
straight line
what is the gradient equal to in a Scatchard plot?
-1/ KD
what is the X intercept in a Scatchard plot?
Bmax - the total density (concentration) of receptors in a sample of tissue
B (bound) =
Bmax [D]
[D] + KD
how would you investigate competitive binding?
competing off the amount of radio labelled drug - compete for the receptors
fixed conc of drug A incubated with increasing conc of drug B
IC50
concentration of an inhibitor where the binding is reduced by half
Cheng prusoff graph
X - log (B) concentration (M)
Y = binding to protein (pmol/mg)
what is Ki? (cheng prusoff)
the dissociation constant (KD) of the unlabelled drug
what is KA - cheng prusoff
Dissociation constant (KD) of the radiolabelled drug
Cheng prusoff equation - Ki =
IC50 / (1 + ( [A] / KA)
does binding a drug to a receptor mean there will be a reponse?
no - antagonist (won’t have a response)
agonist
activates a receptor to cause a response
activation of a receptor leads to
a measurable response
contraction, ion flow, change in HR
concentration response curves
X = concentration (M) Y = response
drugs effect is proportional to…
drug concentration
EC50
concentration of drug required to bring about a response in 50% of the receptors (50% of maximal response)
EC50 or Kd bigger?
EC50 is much less than the KD
what would influence whether max effect is able to be achieved
whether it is a full or partial agonist
reserve / spare receptors - maximal response
Often, not all receptors need to be occupied for max. effect
graded agonis effect
full, partial or inverse agonist
“Full” agonists
elicit 100% effect of the endogenous agonist
Partial” agonists
elicit < 100% effect
Inverse” agonist
does what?
reduce basal receptor activity
- moved the equilibrium back towards the resting state (reducing the effect)
what must you be careful not to confuse an inverse agonist with?
antagonist - as they have zero efficacy - not exerting a biological effect - where as inverse agonists are exerting an effect
Potency
concentration to observe a response - more potent need less to see a response
Agonist Drug “Potency” involves:
affinity + efficacy
what is a dose?
concentration given of a dog depending on weight
how to you establish what dose to give?
quartal dose response curves.
looking at serried effect
histogram - normal distribution
cumulative quantal dose response
ED 50
ED50
the effective dose to produce a therapeutic effect
