Lecture 11: Mechanisms of drug action Flashcards
Why is the dose-response relationship important in pharmacology?
Concentration of a drug at its site of action controls its effect. Investigating the effects of drugs helps to establish a framework for hazard assessments.
What is a normal dose-response relationship?
Normal, excited, getting tired, sedated, coma/death
What are agonists?
A chemical that binds to and activates a receptor to produce a biological response; often applies drug response.
What are antagonists?
An agent that blocks the actions of an agonist.
What are true (silent) antagonists?
A true (silent) antagonist does not produce any biological response on its own.
What are competitive antagonists?
Antagonist competes with agonist for the same receptor, e.g. atropine at acetylcholine receptors.
Can maximum response be achieved even with a competitive antagonist?
Maximum response can still be obtained if agonist out-competes antagonist.
What are non-competitive antagonists?
Antagonist binds irreversibly with the receptor or antagonist interacts with a different part of the receptor and inactivates it (allosteric effect).
Can maximum response be achieved even with a non-competitive antagonist?
Maximum response cannot be obtained.
Describe the drug-receptor interaction
Lock-and-key model; results in biological response
What are the 3 states that drug receptors are found in?
Resting (R) and Active (R*) and Constitutively-active
What is drug affinity?
The attractiveness of a drug to its receptor
What is the drug dissociation constant?
The ease in which drugs can dissociate from receptor
What is the intrinsic activity of a drug?
Refers to the maximal possible effect that can be produced by a drug; activity of drug within the cells
What are constitutively-active receptors?
Constitutively-active receptors have a background activity even when an agonist is not present.
What causes the background response in constitutively-active receptors?
Slightly more receptors are in the Active (R*) state and this generates a background response. Do not need agonist presence.
What are inverse agonists?
Agonists that interact with the same receptor but produce an opposite response. Trigger more receptors to move into resting state.
What are partial agonists?
Partial agonists are drugs that bind to receptors and cause them to produce a response but to a lesser extent than full agonists
How is agonist affinity effected by activity of receptors?
Agonists have a higher affinity for the receptor in its active state. When R* is activated by an agonist, an increased response is obtained. The equilibrium below moves towards the active state R*.
What are the 4 types of drug receptors?
Type 1: receptors on ion channels, eg. GABA-modulated Chloride Channel
Type 2: G-protein-coupled receptors
Type 3: enzyme-coupled receptors
Type 4: Nuclear (intracellular) receptors
How do competitive antagonists effect dose-response curves?
Shift curve right; more agonist needed to get a response
How do non-competitive antagonists effect dose-response curves?
Maximal response decreases
How do type 1 drug receptors work? Receptors on ion channels
GABA molecule interacts with GABAA receptors on chloride channels which triggers chloride to enter cell. Chloride makes depolarisation difficult and so stabilises tissue and triggers sedation.
How do type 2 drug receptors work? G-protein-coupled receptors
In asthma, salbutamol binds to beta-2 receptor and activates G protein. G protein triggers adenylate cyclase to convert ATP to cAMP. cAMP triggers PKA to trigger smooth muscle relaxation which causes bronchodilation and lessens symptoms of asthma.
How do type 3 drug receptors work? Enzyme-coupled receptors
Binding of drug to enzyme-linked receptor. Triggering of protein phosphorylation cascade which effects gene and protein synthesis to trigger cellular response.
How do type 4 drug receptors work?
Receptor moves to nucleus when they bind to ligands and form a complex. Movement of receptor to nucleus allows for control of gene expression and leads to new protein synthesis which has a physiological response.
Why do some individuals with asthma not respond to salbutamol?
Some people do not respond to β2 receptor agonists such as Salbutamol due to genetic differences in the molecular structure of their β2 receptors.
What is refractoriness?
Loss of therapeutic efficacy in drugs
How can drug receptor activity be altered?
- Receptor desensitisation
2. Receptor down-regulation
What is receptor desensitisation?
Loss of intrinsic activity of receptor complexes; short term.
What is receptor down-regulation?
Loss of number of receptors from cell surface; longer term.
