Mechanisms of drug action Flashcards
What are the 4 different types of drug antagonism?
- Receptor blockade
- physiological antagonism
- Chemical antagonism
- Pharmacokinetic antagonism
What is receptor blockade?
Antagonist binds to receptor, preventing the binding of the agonist.
What is use dependency?
“Use dependency” refers to the idea that the more the tissue is used, the more active the tissue is and the more effective drugs like ‘ion channel blockers’ will be. E.g. local anaesthetics. LAs work by binding to the inside of ion channels once they are open. They block the further influx of Na+. The more the channel is open, the more effective the LA is.
What is physiological antagonism?
This is when two agents are given with opposite effects. Their effects tend to cancel each other out. For example, NA and histamine. NA leads to constriction of smooth muscle. Histamine, however, causes vasodilation leading to relaxing of smooth muscles.
What is chemical antagonism?
When the antagonist binds to the agonist, inactivating it. Dimercaprol is a chelating agent. It forms heavy metal complexes which are excreted by the kidneys. This is useful for things like lead poisoning. Interaction in solution.
What is pharmacokinetic antagonism?
This is when the antagonist can reduce the concentration of the agonist at the site of action. A drug may reduce its absorption, increase the metabolism or increase the excretion of another drug. This is a problem when administering more than one drug- as there might be interference.
Give an example of a drug that acts with pharmacokinetic antagonism
Barbiturates- if this drug is regularly administered, there is an increase in microsomal enzymes in the body. Therefore, if another drug is administered, it is metabolised by the same enzymes more quickly and therefore the response to the drug is reduced.
What is the definition of drug tolerance?
the gradual decrease in responsiveness to drug with repeated administration
Give the 5 reasons as to why tolerance to a drug may develop?
- Pharmacokinetic factors
- Loss of receptors
- Change in receptors
- Exhaustion of mediator stores
- Physiological adaptation
Explain the “pharmacokinetic factors” reason as to why tolerance may develop
increase in the production of the metabolising enzymes. The drugs are therefore broken down more quickly and are less effective in bringing about a response. This is seen in the tolerance to alcohol and barbiturates.
Explain the “loss of receptors” reason as to why tolerance may develop
From the cell surface by endocytosis. This is receptor downregulation. This is seen a lot in beta-adrenoreceptors
Explain the ‘change in receptors’ reason as to why tolerance may develop
The receptors essentially undergo desensitization. If there is a stimulation of certain receptors over a long period of time, they undergo a conformational change. Therefore, there are a smaller proportion of receptors that are still effective for bringing about a response. Seen with nAChR receptors at NMJs.
Explain the “exhaustion of mediator stores” reason behind why tolerance may develop using an example
e.g. amphetamine.
Amphetamine is a CNS stimulant and it is very lipid soluble- it crosses into the bloodstream and into the BBB. It acts on the noradrenergic neurones in the brain.
It binds to the uptake 1 protein in the pre-synaptic neurone, increasing the NA concentration in the cleft. This causes euphoria and excitation. However, by the second dose, there is the exhaustion of the NA stores and there is no more to be released.
Explain the “physiological adaptation” reason as to why tolerance may develop
This is a homeostatic response (maintaining levels at a particular range). Reducing the side effects, developing a tolerance to them.
What is denervation supersensitivity?
At times there can be receptor upregulation too (e.g. when someone has had very severe burns)- this is denervation supersensitivity
How many types of receptors are there?
4
What are the 4 types of receptor families?
TYPE 1- ion channel linked receptors
TYPE 2- G-protein coupled receptor
TYPE 3- Tyrosine Kinase-linked receptor
TYPE 4- Intracellular steroid type receptors
Describe type 1 receptors and give examples of receptors
They elicit VERY FAST responses (ms). E.g. nAChR and GABA. They are made up of protein subunits which form a central pore.
Describe type 2 receptors and give examples
Located on the membrane, they are much slower (seconds).
Coupled with G protein/ secondary messengers
They have 7 membrane-spanning helices.
e.g. mAChR, adrenoreceptors
Describe type 3 receptors and give examples
Membrane located and they result in the phosphorylation of intracellular proteins. They include insulin receptor and growth factor receptors. Response takes minutes.
Describe type 4 receptors and give examples
Activated by steroids and thyroid hormones (they are not found on the cell membrane- found intracellularly).
They regulate DNA transcription and therefore protein synthesis. The drug needs to pass through the cell membrane fist and access the nucleus before it has an effect. This response takes HOURS.
Describe the structure of type 1 receptors
4 or 5 different subunits. There are some transmembrane segments (alpha helices). The transmembrane segments form together to form receptor.
Describe the structure of type 2 receptors
One subunit and 7 transmembrane domains. There is an external binding domain which is responsible for activating the G protein.
Describe the structure of type 3 receptors
Kinase linked and single protein. There is one transmembrane domain and an intracellular domain. When the agonist binds, the catalyst is activated inside the cell. Proteins are phosphorylated and activated leading to a response.
Describe the structure of type 4 receptors
Found in nucleus. The DNA binding region is called zinc fingers, leading to DNA binding and increased transcription.
