Drug Receptor Interactions Flashcards
What is meant by a drug
A chemical substance that interacts with a biological system to produce a physiological effect.
List the different drug target sites
Receptors
Ion channels
Transport systems
Enzymes
What do the drug target sites all have in common
They are all proteins
How do drugs essentially illicit their response
By interacting with the drug target site
Summarise tolerance
Tolerance is the measured effect of repeated administration.
Doesn’t occur with all drugs
Limits the use of the drug
Where can receptors be found
Extracellularly (non-steroid)
Intracellularly (steroid)
Summarise receptors
Proteins within cell membranes (usually)
Activated by NT or hormone
Defined by agonists & antagonists
4 types of receptors
What are the 4 types of receptor
Ionotropic
GPCR
Enzyme-linked
Intracellular
What is each drug receptor defined by
By selective agonists and selective antagonists
e.g a compound that selectively stimulates dopamine receptors and not 5-HT or NA receptors
What are families of receptors defined by
By their structures and transduction systems used
What is meant by agonists and antagonists
Agonist- compound that stimulates the receptor
Antagonist- compound that blocks or inhibits the receptor
Give some examples of drugs that act on receptors
Acetylcholine (agonist for acetylcholine receptors)
Atropine (selective antagonist for muscarinic acetylcholine receptors)
What is atropine used for
pre-med before surgery- dry up secretions- particualry bronchial secretions
used to treat cardiac arrest, sinus bradycardia after myocardial infarction
side effects include dry mouth, dilated pupil, bronchodilatation, urinary retention
What is meant by an ion channel
Selective pores - allow transfer of ions down electrochemical gradients
What are the two types of ion channel
2 types 1) voltage-sensitive e.g. VSCC
2) receptor-linked e.g. nAChR
How are ion channels defined
By the gated mechanisms that they use
Describe receptor-linked ion channels
When Ach stimulates the nicotinic receptor- it changes its conformation opening a linked cation channel- allowing a current of Na+ to move into the cell- depolarising the cell- increasing the firing rate of the cell
What is important to remember about nicotinic receptors
They are excitatory
Describe how local anaesthetics work
Lots of action potentials generated in the wound by nociceptive receptors- which sends APs down sensory neurone to the sensory cortex via the thalamus- triggering pain
LAs (e.g lidocaine) get inside the Na+ channel and stereochemically inhibit it (preventing the influx of Na+ ions)- fewer APs- ‘numbing’ the pain
How are local anaesthetics administered
sub-cutaneous
How can calcium channel blockers be used to treat arrhythmias
ClassIV drugs (verapamil) block L-type Ca2+ channels, thereby decreasing the gradient of the pacemaker potential, slowing the rate of depolarisation in the SA node and prolonging the conduction delay in the AV node. They also have negative ionotropic effects by limiting the influx of Ca2+ during the plateau phase
What else can CCBs be used to treat
Hypertension- all blood vessels have sympathetic tone- CCBs prevent influx of Ca2+- reduced contraction of SM-dilation of the vessels- lowering BP
Can also be used to treat angina
What is meant by transport systems
Transport against the conc gradient- need ATP to function
glucose, ions, NTs
Summarise transport systems
Transport against concentration gradients (glucose, ions, NTs)
Specificity for certain species
Examples :Na+/K+-ATPase
: NA ‘uptake 1’
Give some examples of drugs that target transport systems
Tricyclic Anti-depressants (TCAs).
Cardiac glycosides.
What does each NT have
its own specific transporter system
e.g NA uptake 1 only found in NA nerve terminals
Describe tricyclic anti-depressants
Interfere with the function of NA uptake 1 protein
In clinical depression, the NA transport system is not functioning optimally in the CNS
TCAs slow down the uptake system of NA- so more remains in the synaptic cleft for longer enhancing NA.
Also enhances the activity of 5-HT- aiding in reducing the effects of depression.
Describe cardiac glycosides
Glycosides e.g digoxin have a central effect, stimulating the vagus nerve and increasing parasympathetic stimulation, thus slowing heart rate. It simultaneously exerts its positive inotropic effect by inhibition of Na+/K+ ATPase.
Inhibiting Na+/K+ ATPase increases the intracellular Na+, which increases I.C Ca2+- improving contractility.
What are enzymes
catalytic proteins that increase rate of reaction.
Summarise the drug interactions with enzymes
Drug interactions:-
i) enzyme inhibitors e. g. anticholinesterases (neostigmine) ii) false substrates e. g. methyldopa iii) prodrugs e. g. chloral hydrate trichloroethanol
Describe false substrates such as methyldopa
sympathetic nerve terminals make NA. one of the steps in the biosynthesis of NA is the conversion of dopa to dopamine using DOPA decarboxylase
when methyldopa is used- methyl noradrenaline is released instead which has less potent effects compared to noradrenaline
therefore you reduce the vasoconstrictive effects of NA and get more vasodilation- reducing BP
Describe prodrugs
chloral hydrate- hypnotic- used to treat insomnia
converted to trichloroethanol by enzymes in the liver- trichloroethanol is the hypnotic drug (i.e the active ingredient).
Describe how enzymes can mediate the toxic effects of drugs
If you take too much paracetamol, the enzyme system that metabolises paracetamol in the liver becomes saturate. this results in paracetamol being metabolised by a different set of enzymes which results in the production of toxic products- which can damage the liver and kidney.
How can we treat paracetamol overdose
Intravenous acetylcysteine or methionine - boosts the glutathione system- which mops up these reactive intermediates.
Summarise non-specific drug actions
The drug isn’t specific to a receptor etc.
Physiochemical properties :
antacids
osmotic purgatives
Describe antacids and osmotic purgatives
o Antacids – simple addition of a base to the acidic environment which evens acid-base balance- makes salt increasing pH- reducing symptoms of dyspepsia (usually magnesium or aluminium salts)
o Osmotic purgatives (laxatives) – draws water into the gut to decrease viscosity- softens the stool
What is dyspepsia
indigestion
Describe plasma protein binding
Drugs bind to albumin- leading to a reservoir of inactive drugs
No physiological response- not a drug target- more to do with pharmacokinetics as no response is mediated
Give an example of plasma protein binding
N.B. Some drugs bind very strongly to plasma proteins and so can provide a dangerous and untapped reservoir of the drug (e.g. warfarin).
Essentially, what are agonists and antagonists
Ligands
List some agonists
Agonist (ACh; nicotine)
List some antagonists
Antagonist (atropine; hexamethonium)
Hexamethonium is a nicotinic antagonist
Describe hexamethomium
It was formerly used to treat disorders, such as chronic hypertension, of the peripheral nervous system, which is innervated only by the sympathetic nervous system. The non-specificity of this treatment led to discontinuing its use.
Blocks autonomic ganglia
What does the potency of a drug depend on
‘Potency’ of a drug depends on:
i) Affinity
ii) Efficacy (‘intrinsic activity’)
conformational change of receptor
What is meant by the affinity of the drug
o Affinity – Strength-of-binding/Avidity of the drug to the receptor.
Describe partial agonists
o Drugs can also have FULL or PARTIAL agonistic effects.
o PARTIAL agonists can lead to some antagonist activity.
partial agonists never generate the full response- have antagonist activity when co-administered with full agonists.
Why do we use the word selective over specific
Selectivity – we don’t use the word specific as a drug may not be specific to the same receptors at a higher concentration (may bind to other receptors).
What can happen when we increase the conc of a drug
Can begin to have actions on other drug targets- leading to the onset of side effects
Explain the structure-activity relationship
Structure-activity relationship
‘lock and key’
agonists antagonists
pharmacokinetics
small changes in the structure of a drug can completely change its activity- potentially turning an agonist into an antagonist.
changes in structure can also slow down its metabolism- leading to pharmacokinetic changes.
Describe electrostatic forces
long range forces- bring drug to its target
What else does the efficacy of the drug involve
the transducer system- enzymes its linked to- opening an ion channel etc.
Describe the dose-response curve for agonists
when tissue response against conc- rectangular hyperbola
when tissue response against log of the conc– sigmoid
Why do we take the log of the conc of the agonist
Can see max response more easily- can be analysed mathematically due to long straight section of the graph.
What is the key property of antagonists
Affinity but no efficacy
Describe the two different types of antagonists
Competitive and irreversible
Describe competitive antagonists
- Competitive
same site as agonist
surmountable
shifts D-R curve to right
List some examples of competitive antagonists
atropine
: propranolol
Describe irreversible antagonists
- Irreversible
binds tightly or at different site (may bind to cation channel- agonist won’t be able to compete)
insurmountable
What is atropine
A competitive Ach muscarinic receptor antagonist
Describe how competitive antagonists work
In the presence of a competitive antagonist, the agonist occupancy (i.e proportion of receptors to which the agonist is bound) at a given agonist concentration is reduced, because the receptor can only accommodate one molecule at a time.
What happens to the log dose-response curve in the presence of a competitive agonist
A simple theoretical analysis predicts that in the presence of a fixed concentration of the antagonist, the log concentration-effect curve for the agonist will shift parallel to the right, without any change in slope or maximum.
What is this shift to the right expressed as
As a dose ratio (the ratio by which the agonist concentration has to be increased in the presence of the antagonist in order to restore a given level of response). Theory predicts that the dose ration linearly increases with the concentration of the antagonist.
What are the salient features of competitive antagonists
Shift of the agonist log concentration-effect curve to the right, without change of slope or maximum (i.e antagonism can be overcome by increasing the concentration of the agonist)
linear relationship between agonist dose ratio and antagonist concentration
evidence of competition from binding studies.
What do the characteristics of reversible competitive antagonists reflect
They reflect the fact that agonist and competitive antagonist molecules do not stay bound to the receptor but dissociate and rebind continuously.
The rate of dissociation of the antagonist molecules is sufficiently high that a new equilibrium is rapidly established on addition of the agonist.
In effect, agonist molecules are able to replace the antagonist molecules on the receptors when the antagonist unbinds, although they cannot of course, evict bound antagonist molecules.
How does displacement occur
Displacement occurs because, by occupying a proportion of the vacant receptors, the agonist effectively reduces the rate of association of the antagonist molecules; consequently, the rate of dissociation temporarily exceeds that of association, and the overall antagonist occupancy falls.
Describe how irreversible antagonists exert their effects
The antagonist binds to the same site on the receptor as the agonist but dissociates very slowly, or not at all, from the receptors, with the result that no change in the antagonist occupancy takes place when the agonist is applied.
Can also change the conformation of the active site.
Why is the distinction between reversible and irreversible antagonism not always so clear
Due to the phenomenon of spare receptors; if the agonist occupancy required to produce a maximal response is very small (say 1% of the total receptor pool), then it is possible to block irreversibly 99% of the receptors without reducing the maximal response.
The effect of a lesser degree of antagonist occupancy will be to produce a parallel shift of the log concentration-effect curve that is indistinguishable from competitive antagonism
Only when the antagonist occupancy exceeds 99% will the maximum response be reduced.
When does irreversible antagonism occur in drugs
In drugs that possess reactive groups that form covalent bonds with the receptor
A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. Which type of drug target is this drug acting on?
Transport protein
How will the log concentration- effect curve change in the presence of an irreversible antagonist
The curve will shift to the right and fall.
Can’t achieve max response- response blocked.
