Lecture 4 - Drug-receptor theory III - antagonists Flashcards
What type of drugs are the majority of clinically useful drugs?
Antagonists
What is an antagonist?
A drug that prevents the response of an agonist
What 5 different classes can antagonism be broken down into?
- chemical antagonism
- pharmacokinetic antagonism
- physiological antagonism
- non-competitive antagonism
- competitive antagonism
What is chemical antagonism?
- Molecule binds in a way that the drug can’t bind to its usual receptor in its usual way.
- Substances combine in solution so that the effects of an active drug lost - i.e. the agonist is chemically altered by the antagonism
- e.g. inactivation of heavy metals (e.g. mercury, lead and cadmium) who toxicity is reduced with the addition of a chelating agent (e.g. dimercaprol)
- Monoclonal antibodies can work in a similar way
What is pharmacokinetic antagonism?
- Reduction in amount of absorbed, metabolised or excreted by another.
- Pharmacokinetics are the mechanisms that control the absorption, metabolism or excretion of a drug
- change in drug metabolism - e.g. for patients taking warfarin (anti-coagulant and thins blood, reduces risk of heart attack and stroke) have to be careful when treat with some antibiotics as they may stimulate the metabolism of warfarin so reducing its effective concentration in the blood stream. Levels of warfarin need to be carefully regulated.
- drug-drug interactions are important when looking at pharmacokinetic interactions.
- stimulation of drug metabolism may reduce the concentration of the drug in their system
What is physiological antagonism?
The interaction of 2 drugs (agonists) with opposing actions in the body. This is where the 2 agonists are working at 2 different receptors.
Example 1 - Noradrenaline raises arterial blood pressure by acting on the heart (beta 1 receptors) and peripheral blood vessels (alpha 1 receptors), while histamine (H1 receptors) lowers arterial pressure by causing vasodilation
Example 2 - Histamine acting through H2 receptors increases acid secretion in the gut, while omeprazole counteracts this effect by inhibiting the proton pump
What is non-competitive antagonism?
Blocks some steps in the process between receptor activation and response - i.e. doesn’t compete with the agonist for the receptor site, and so is termed non-competitive.
Not necessarily working on the receptor, but on the signalling pathway.
E.g. Verapamil and Nifedipine inhibit L-type calcium channels to cause relaxation of smooth muscle and lowers blood pressure
Ketamine is a non-competitive inhibitor of NMDA (glutamate) receptors. It blocks the channel pores. It binds to somewhere on the receptor that is different to where glutamate (the usual agonist would bind).
What is a competitive antagonist?
Binds to the same site on the receptor as the agonist. You can measure the affinity of a competitive antagonist using bioassays.
Competitive antagonists competes with agonist for occupancy of the receptor
What is reversible competitive antagonism?
Competitive reversible antagonism can be overcome by increasing agonist concentration - e.g. effects of atropine on response to acetylcholine for guinea-pig ileum
Describe what happens when there is an increase in antagonist concentration
There is a parallel rightward shift in concentration-response (no change in max)
What is the dose ratio?
How many more times agonist is needed in the presence of an antagonist
What is the dose ratio equation?
conc. of agonist in presence of antagonist//conc. of agonist in absence of antagonist
What is a Schild analysis?
can determine the affinity of an antagonist
What does a Schild plot show?
The relationship between Dose ratio and antagonist concentration
What is Schild equation?
Dose ratio (DR) = concentration of antagonist/antagonist affinity constant (KD) + 1
