A.

1 Pharmacodynamics
a. Explain the concept of drug action with respect to receptor theory, enzyme
interactions and physico-chemical interactions.
Drug action may occur by one of several means. A drug-receptor interaction
occurs where a drug binds to a specific ligand for an endogenous regulatory substance,
inducing or blocking a conformational change in the receptor which initiates a series of
cellular changes which characterize the effect of the drug. Many specific receptors have
been characterized and specific agonist and antagonist drugs are available (e.g. 2
adrenoceptors). The effect of a drug reflects its concentration, affinity for receptors, the
concentration of receptors (affected by up- or down-regulation) and the inherent agonist or
antagonist potency of the drug.
Some drugs act by interaction with the active or other site on enzymes, exerting
an effect by blocking the action of the enzyme and the metabolic pathway of which it forms
part (e.g. allopurinol).
At a molecular level, drug action occurs by physico-chemical interaction. This
may be by covalent bonding (e.g. organophosphates), ionic bonds, hydrogen bonds or van der
Waals forces. These interactions may be between drug and receptor or between a drug and
other compounds, e.g. chelating agents, antacids. Drugs operating by physico-chemical
interaction usually have non-specific effects, are less potent and are without specific
antagonists (e.g. ethanol).
b. Explain receptor activity with regard to: ionic fluxes, second messengers and G
proteins, nucleic acid synthesis, evidence for the presence of receptors,
regulation of receptor number and activity.
serpentine receptors
cell-surface receptors
seven transmembrane domains
amine terminal extracellular, carboxyl terminal intracellular
loop between domains V and VI (intracellular) is the binding site for G-proteins
C-terminal chain is phosphorylated to alter sensitivity (e.g. -ARK)
phosphorylated chain binds -arrestin, inhibiting G-protein activation
agonist binding site is between the clustered transmembrane domains
G-proteins
evidence for receptors
drug action is tissue-specific
log(dose)-response curve is sigmoid
ceiling effect suggests saturation of receptors
response is molecule-specific e.g. stereo-specific
antagonism is drug-specific
c. Define and explain dose-effect relationships of drugs, especially: graded and
quantal response, therapeutic index, potency and efficacy, competitive and noncompetitive antagonists, partial agonists, mixed agonist-antagonists and inverse
agonists.
d. Compare efficacy and potency on the basis of dose-effect curves.
e. Explain the Law of Mass Action and apply this to pharmacodynamics to
understand affinity and dissociation constants, the Hill plot and the LineweaverBurke plot.
assuming no interaction between receptors and one drug molecule per receptor:
Pharmacodynamics

2.A.1.1

James Mitchell (December 24, 2003)

drug + receptor drug-receptor

D + R DR
[R] + [DR] = [Rtotal ]
KD =

[D][R]
[DR]

K D [DR] = [D] ([R total ] [DR])

K D + [D] =

[D][R total ]
[DR]

[D]
[DR]
=
K D + [D] [Rtotal ]

= proportion of receptors occupied = effect

[D]
Effect = Emax
K D + [D]
plot of log (dose) vs effect is approximately linear for effect 20%-80% of Emax.
Lineweaver-Burke plot
plot of 1/dose vs 1/effect is linear
1
1
KD
=
+
Effect Emax Emax [D]
1
K
1
+ D
Emax Emax [D]
with y-intercept 1/Emax, x-intercept -1/KD and gradient KD/Emax.
=

Hill plot

E
is linear:
E max E
E
log
= n log(dose) log K D
E max E
where n is the number of molecules binding to each receptor
100

plot of log (dose) vs log

80
% of Emax

50

20
0

KD

log (dose)

for competitive antagonists, pA2 expresses their affinity with a receptor

pA2 = -log10 [antagonist] required to produce a doubling of KD for an agonist
f. Explain theories of action of general anaesthetic agents.
g. Explain the concept of side effects.
h. Explain the concept of toxicity.
Pharmacodynamics

2.A.1.2

James Mitchell (December 24, 2003)