Drug-Receptor Interactions Flashcards
What are the two divisions of pharmacology?
Pharmacokinetics and Pharmacodynamics
Define pharmacokinetics.
The effect that the body has on the drug (how the drug is absorbed, distributed, metabolised, excreted)
Define pharmacodynamics.
The effect of the drug on the body (responses produced, mechanism of action)
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 NOTE: all proteins
What are receptors?
Proteins within cell membranes or within cells (steroid receptors)
Give an example of a drug which targets receptors.
Atropine - muscarinic receptor antagonist; used as an anaesthetic premedication to dry up secretions (PNS promotes secretions
NOTE: ACh is not administered as a drug but it is a muscarinic agonist as it promotes receptor action (downstream response) when it binds
What are ion channels?
Selective pores within lipid bilayers that allow the passage of ions in or out of the cell depending on the electrochemical gradient
What are the two types of ion channels?
Voltage-Gated
Receptor Linked
Give examples of the two types of ion channels
Voltage-gated - VGSC, VGCC
Receptor-linked - nicotinic ACh receptor
Give an example of a group of drugs that act on ion channels.
Local anaesthetics
Calcium channel blockers
How do local anaesthetics work?
Local anaesthetics – they block the VGSCs of nociceptor sensory axons by binding to prevent the conduction of pain signals to the CNS (prevents AP propagation along neurone to prevent pain sensation by actually binding inside the ion channel, blocking ion flow)
NOTE: nociceptor = type of sensory neurone (responds to ‘danger signals’)
How do calcium channel blockers work?
The block VGCCs - used to treat cardiovascular conditions like hypertension (end in -dipine)
NOTE:
VGCCs required for excitation contraction coupling so by blocking these it can cause vasodilation, and reduce force of contraction
VGCCs also involved in cardiac APs so blockers also reduce HR
What is a transport system?
Carrier which transports substances against their concentration gradients
Give an example of a transport system.
Na+/K+ pump
NA uptake 1
Give an example of a drug that acts on transport systems.
Tricyclic antidepressants (TCAs) Cardiac glycosides
How do TCAs work?
Block reuptake of certain neurotransmitters, e.g. serotonin and NA (block uptake 1), to increase their levels in brain (increase synaptic concentrations and neurotransmission) to improve mood
How do cardiac glycosides work?
They slows down the Na+/K+ pump, which has a knock-on effect of increasing the intracellular calcium ion concentration (by reducing action of Na+/Ca2+ exchanger), which leads to an increased force of contraction of the heart
What are the three ways in which drugs can interact with enzymes?
Enzyme inhibitors
False substrate
Prodrugs
How do enzyme inhibitors work?
EXAMPLE: anticholinesterases (neostigmine)
Increases the concentration of acetylcholine in the synapse by decreasing the rate of breakdown of acetylcholine
How do false substrates work?
EXAMPLE: methyldopa - hypertension treatment Methyldopa will be taken up by the NA nerve terminal and it'll take the place of DOPA in the NA synthesis pathway so it'll reduce the amount of DOPA being converted to dopamine - you’ll produce methyl dopamine instead Methyl noradrenaline (from methyl dopamine) is not as effective at causing vasoconstriction as NA on α1 receptors so you get reduced TPR and hence reduced blood pressure
How do prodrugs work?
EXAMPLE: chloral hydrate → tricholoethanol
Essentially the pro-drug is a precursor and needs to be converted into its active form by endogenous enzymes
What is a common example of the unwanted effects of drug interaction with enzymes?
Paracetamol overdose – this will saturate the microsomal (ER vesicles) enzymes in the liver so the paracetamol is then broken down by another set of enzymes (P450) which generates toxic metabolites
Toxic metabolites causes hepatocyte damage (liver failure) and can also lead to other problems within the body (e.g. kidney failure)
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 (laxative) – draw water into the bowel due to its physicochemical properties (high osmolarity substance which softens stool to allow easier voiding)
What is the relationship between drugs and plasma binding proteins?
drugs bind to plasma proteins but this does NOT generate a response so it is not a drug target site - it is just a reservoir of the drug
Define potency. What is it dependent on?
How powerful the drug is (i.e. more potent you can use a lower concentration to get the same level of response)
It depends on affinity AND efficacy
What is affinity?
How strongly the drug binds to its receptor
What is efficacy?
The ability of a drug to generate a response once it has bound to its receptor - usually involves some sort of conformational change of receptor (this determines downstream signalling)
Define agonist.
A molecule that binds to a receptor and generates a response (e.g. nicotine, ACh)
Define antagonist.
A molecule that binds to a receptor but does NOT generate a response (get in the way of the agonist; inhibitor - e.g. atropine)
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
NOTE: probably because it has a different structure/properties so doesn’t cause the same conformational change of receptor; different/less downstream signalling means reduced response
What happens if you administer a full agonist with a partial agonist?
if you administer a partial agonist with a full agonist you will get an effect similar to an antagonist
Not all receptors occupied by full agonist, some are occupied by partial agonist instead
Therefore, you have a reduced response as the partial agonist has a lower efficacy
Reduced response means antagonist-like activity by the partial agonist
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
True or false: full agonists that are selective for a given receptor will have the same efficacy.
True
They are full agonists so they all elicit a maximum response hence they have the same efficacy
What is selectivity?
Drugs have a preference for binding to certain receptors (drugs are rarely specific to just one receptor – they normally bind to a few different ones)
What is structure-activity relationship?
Emphasises the relationship between the structure of the drug and its activity - a small structural change can turn an agonist into a partial agonist or antagonist
Analogy - lock and key - key has a very specific structure which is required to fit in the lock (i.e. for full efficacy)
Describe antagonists in terms of affinity and efficacy.
Antagonists have affinity but NO efficacy
What are the two types of antagonist?
Competitive
Irreversible
How does a competitive antagonist work?
Binds to the same site as the agonist on the receptor - surmountable (i.e. by increasing the concentration of the agonist, you can overcome the effect of the competitive antagonist)
How does an irreversible antagonist work?
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 (i.e. inhibition cannot be overcome as it is not competing with the agonist)
Give an example of a competitive antagonist.
Atropine - competitive muscarinic cholinoceptor antagonist
Propranolol - competitive beta blocker (blocks beta adrenergic receptor)
What effect do these two types of antagonist have on dose-response curves?
Competitive – shifts the D-R curve to the RIGHT (higher concentration of agonist needed to generate a maximal response)
Irreversible – shifts the D-R curve to the RIGHT and LOWERS the response elicited (you won’t have the max number of receptors available for max response to be generated )
Give an example of an irreversible antagonist.
Hexamethonium - irreversible nicotinic cholinoceptor antagonist (it waits until the ion channel is open and then blocks the ion channel rather than just blocking a receptor – so binds to a different site from the agonist; insurmountable antagonism)
What is receptor reserve?
Essentially means when ‘spare receptors’ are present
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
What is sensitivity in the context of drugs?
How strong the drug dose needs to be (i.e. drug concentration) before the tissue responds to it)
Lower drug dose needed to generate tissue response → more sensitive tissue
