Introduction Flashcards
target of diphenhydramine
- H1 R in PNS: antihistamine
- H1 R in CNS: sedative
- ACh R in CNS: antiemetic
- Histamine N-methyl transferase in CNS: (enhances actions of histamine on CNS)
atropine
blocks sm contraction
nicotine
blocks sk contraction
binding forces between drugs/receptors
covalent bond (irreversible) coordinate covalent bonds (irreversible) ionic bonds (electrostatic forces) hydrogen bonds (weak electrostatic forces) van der Waals forces (weak electrostatic forces) hydrophobic forces (weak interactions)
receptor occupancy theory
D + R —> DR
D=free drug
R=free receptor
DR=drug-receptor complex
k1 = associate rate k-1 = dissocation rate
equilibrium:
k1[D][R]=k-1[DR]
EQUILIBRIUM DISSOCIATION CONSTANT
Kd
[D][R] = Kd
[DR]
V =
V = [D] Vmax
Kd + [D]
D=free drug
V=amount of drug bound
Vmax=maximum occupancy of R
[R]
[R] = [Rt] - [DR]
R=free receptor
Rt=receptor total
DR=drug-receptor complex
[DR]
[DR] = [D] [Rt]
Kd + [D]
Kd apparent is also known as
EC50
E = [D] Emax
Kd ap + [D]
E = biological response
EC50
is the concentration of a drug that gives the half-maximal response
occupancy assumptions
- biological response = binding of D-R
- magnitude of response = directly porprotional to receptor occupancy
- conc of drug measured = same as conc of free drug in eq with receptor
advantage of log dose-response plot over arithmetic
expands the linear portion of curve = help determine Kd/Kd app
-draw line at 50% occupancy
therapeutic index
TI = LD50/ED50
lethal dose in 50% of population
effective dose in 50% of the population
High TI =better = more dose needed to reach lethal threshold
Scatchard
slope = -1/Kd
X intercept = Vmax
- drug binding with receptor
- only for binding
- not biological response
- linear curve
= reveal multiple drug binding sites ( at the top = slope larger vale = higher affinity = smaller Kd)
double reciprocal
X intercept = -1/Kd
Y intercept = 1/Vmax
- used for biological response
affinity
strength of binding
inversely proportional to Kd
smaller Kd
higher affinity
potency
ability of drug dose to elicit biological response
inversely proportional to Kd app
partial agonist
an agonist cannot generate full biological response = low efficacy
efficacy
the ability of drug once bound - modify the function of the receptor
occupation governed by
affinity
activation governed by
efficacy
partial agonists have
antagonist activity when combined with full agonist
competitive antagonist
binds reversibly to same site as agonist
curve shift RIGHT = less response
(same x intercept // shallower slope = larger Kd
(same y-intercept // x intercept bigger)
KI/KB
equilibrium dissociation constant for a competitive antagonist
KB and pA2
potency of an agonist
pA2
pA2 = -logKI
negative log of the concentration of agonist that would produce a two-fold shift in the Kd apparent of the agonist
noncompetitive antagonists
Binds reversibly to allosteric site or (rarely) irreversibly to same site as agonist
curve shift DOWN
(identical slope - shifted to lower value)
(x intercept = same
(y intercept = higher)
noncompetitive antagonist, when added to an agonist
partial agonist activity
inverse agonist
decreases the spontaneous activity of a receptor
opposite effect of an agonist
The addition of increasing amounts of a competitive antagonist will return the biological activity to the level observed in the absence of the inverse agonist
drug desensitization
The response of the body to long-term treatment will often decrease over time Multiple causes: conformational change in the receptor receptor endocytosis depletion of a mediator increased drug metabolism physiological adaptation
