Mechanisms of Drug Action Flashcards
State the four types of drug antagonism.
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
What is meant by ‘use dependency’ in terms of receptor blockade?
This refers to ion channel blockers The more the tissue on which a drug is acting is being used (i.e. the more active they are), the more effective the blocker will be E.g. normal neurons fire at a relatively low rate so if you put local anaesthetic on them there’ll be fairly limited effects. Nociceptor neurons fire rapidly so their iron channels are open more often meaning that the local anaesthetic can get inside the iron channel and block it more easily.
What is physiological antagonism?
When two drugs act on different receptors in the same tissue and have opposite effects E.g. noradrenaline will bind to alpha-1 receptors and cause vasoconstriction, histamine will bind to histamine receptors and cause vasodilation
What is chemical antagonism?
Interactions of drugs in solution E.g. dimercaprol is a chelating agent that forms heavy metal complexes that are more easily excreted by the kidneys
What is pharmacokinetic antagonism?
When one drug reduces the concentration of another drug at the site of its action
A drug may reduce the absorption, increase the metabolism or increase the excretion of the other drug
Define drug tolerance.
Gradual decrease in responsiveness to a drug due to repeated administration of the drug
What are the five main mechanisms of drug tolerance?
Loss of receptors
Change in receptors
Pharmacokinetic factors
Physiological adaptation
Exhaustion of mediator stores
Describe each of these mechanisms briefly.
Loss of receptors – overstimulation can lead to endocytosis of receptors so there are fewer receptors available on the cell membrane
Change in receptors – conformational change in the receptors so that they are desensitized, so a proportion of the receptors are no longer effective
Pharmacokinetic factors – metabolism of the drug is increased after repeated use (e.g. alcohol)
Physiological adaptation – sort of like a homeostatic response to maintain a stable internal environment
Exhaustion of mediator stores – this happens with amphetamines –they get into the central noradrenaline synthesis system and replaces noradrenaline in the vesicles so you get a big increase in the production of noradrenaline
What are the four receptor families? Describe how their transmission varies.
Type 1 – ionotropic
Type 2 – metabotropic (G protein coupled)
Type 3 – tyrosine kinase linked
Type 4 – intracellular steroid type They increase in transmission time from 1-4
Describe the structure of type 1 receptors.
Consists of 4 or 5 subunits with transmembrane alpha helices
Describe the structure of type 2 receptors.
Consists of 1 subunit but with 7 transmembrane domains
Describe the structure of type 3 receptors.
Single protein with 1 transmembrane domain Inside the cell there is an intracellular domain When the agonist stimulates the receptor it activates the catalyst
Describe the structure of type 4 receptors.
These are steroid receptors that are found in the nucleus
What is another name for the DNA binding domain of the steroid-receptor complex?
Zinc fingers
Define Pharmacokinetics and Pharmacodynamics.
Pharmacokinetics – the effect that the body has on the drug Pharmacodynamics – the effect of the drug on the body
Define the word ‘drug’.
A chemical substance that interacts with a biological system to produce a physiological response
State the four main target sites for drugs.
Receptors Ion Channels Transport Systems Enzymes
What are the two types of ion channels?
Voltage-Gated Receptor Linked
Give an example of a group of drugs that act on ion channels.
Local anaesthetics – they block the voltage gated sodium channels of nociceptor neurons to prevent the conduction of pain signals to the CNS
Give an example of a drug that acts on transport systems.
Tricyclic antidepressants
Cardiac glycosides – it slows down the Na+/K+ pump thereby increasing the intracellular calcium ion concentration, which leads to an increased force of contraction
What are the three ways in which drugs can interact with enzymes?
Enzyme inhibitors (e.g. anticholinesterases)
False substrates (e.g. methyldopa)
Prodrugs (e.g. chloral hydrate)
What is a common example of the unwanted effects of drug interaction with enzymes?
Paracetamol overdose – this will saturate the microsomal enzymes in the liver so the paracetamol is then broken down by another set of enzymes (P450) which generates toxic metabolites
Name three groups of drugs that are exceptions to the four target site rule.
General anaesthetics – reduce synaptic transmission without interacting with transport systems or receptors
Antacids – these are basic so they simply neutralize some of the stomach acid
Osmotic purgatives – draw water into the bowel due to its physicochemical properties
Define agonist.
A molecule that binds to a receptor and generates a response
HAS AFFINITY AND EFFECIACY
Define antagonist.
A molecule that binds to a receptor but do NOT generate a response
ie has Affinity but NO EFFICACY
Define potency. What is it dependent on?
How powerful the drug is It depends on affinity (how willingly the drug binds to the receptor) and efficacy (the ability of a drug to generate a response once bound)
What is a full agonist?
An agonist that generates a maximum response
What is a partial agonist?
An agonist that generates a less than maximum response
What is selectivity?
Drugs have a preference for binding to certain receptors (it is rarely specific – they normally bind to a few different receptors)
What is the difference between full agonists with a high affinity and full agonists with a lower affinity?
Full agonists with a lower affinity can still generate a maximum response but requires a higher dose than the full agonist with lower affinity
Describe antagonists in terms of affinity and efficacy.
Antagonists have affinity but NO efficacy
What are the two types of antagonist?
Competitive – they bind to the same site as the agonist on the receptor – they are surmountable
Irreversible – could bind to the same site as the agonist but will bind more tightly with covalent forces so that they can’t be moved – some irreversible antagonists will bind to sites different to the site that the agonist binds to – insurmountable
What effect do these two types of antagonist have on dose-response curves?
Competitive – shifts the D-R curve to the RIGHT Irreversible – shifts the D-R curve to the RIGHT and LOWERS the response elicited (it can no longer generate a full response)
What is receptor reserve?
In some tissues, not all the receptors need to be stimulated to generate a maximum response (sometimes as little as 1% of receptors may need to be activated) This increases the sensitivity of the tissue to the agonist
True or false: full agonists that are selective for a given receptor will have the same efficacy.
True if They are full agonists so they all elicit a maximum response hence they have the same efficacy
