|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. ß2 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.
- 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. ß-ARK)
- phosphorylated chain binds ß-arrestin, inhibiting G-protein activation
- agonist binding site is between
- the clustered transmembrane domains
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 Lineweaver-Burke plot. assuming no interaction between receptors and one drug molecule per receptor:
Plot of log (dose) vs effect is approximately linear for effect 20%-80% of Emax.
Plot of 1/dose vs 1/effect is linear
with y-intercept 1/Emax, x-intercept -1/KD and gradient KD/Emax.
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.
Kindly provided by Dr James Mitchell from his pharmacodynamics series.