WEEK 2 Flashcards
What is a drug?
Any substance that interacts with a biological system and changes it
What are two types of drugs?
Low-molecular-weight drugs and Biologic
What is pharmacology good for?
knowing what drugs exist and their benefits and side effects, drug categorisation, quantifying drug action (proper dosing)=good prescription practise
Why do drugs that cause their effects by their physiochemical properties tend to need higher concentrations?
Due to non-specific effects
Give examples of drugs that produce their effects via their physiochemical properties
Antacids (Sodium Bicarbonate) Laxatives Heavy metal antidotes Osmotic diuretics General anaesthetics Alcohol Li+ ions
What are common drug characteristics?
effects occur at very low concentrations with high potency and can be very specific (biological or chemical specificity)
What is biological specificity?
specificity relating to the side of the receptor/biological system (receptor or target)
What is chemical specificity?
specificity relating to the substance added to the biological system (ligand or agonist)
Give an example of drug stereo-specificity
Thalidomide-two racemic forms->given as R form for pain relief but experienced in vivo racemisation to S form which had terrible side effects
What is an organoid?
A small and simplified version of an organ which is used to model a human disease
What is an organoid used for?
Monitoring disease development and drug testing
Give an example of organoid formation
Embryonic stem cell+skin fibroblast->Pluripotent stem cell culture-endoderm differentiation->sphenoid culture->matrigel culture->intestinal epithelial mesenchymal organoid
What is the receptor concept?
That drugs produce their effect by combining with specific receptor sites in cells and the response correlates to the number of occupied receptors
What is the lock and key hypothesis?
The shape of the drug is complementary to the shape of the receptor (chemical specificity)
What is drug affinity?
The binding ‘strength’ of the drug-receptor interaction or the ‘likelihood’ of binding
Equation for the drug-receptor interaction
A+R⇌AR->active AR
A=drug
R=receptor
What is an agonist?
A substance that binds to a receptor and produces a response-produces affinity and efficacy
What is an antagonist?
A substance that binds to a receptor but doesn’t produce a response and blocks agonist binding and response-possesses affinity but not efficacy
Equation for antagonist-receptor interaction
Ant+R⇌AntR-X->effect
What is quantitative pharmacology?
The assumption that drugs act by entering into a simple chemical relation with certain receptors in cells and that there is a simple relation between the amount of drug fixed by these receptors and the action produced (A+R⇌AR->active AR)
Relationship between drug concentration and response is:
continuous, saturating (hyperbolic curve, sigmoidal when log[agonist]) and exhibits threshold
What is EC50?
The drug concentration that produces half the maximum response/efficacy->model-free equivalent of Kd
What is specificity?
The capacity of a drug/receptor to manifest only one kind of action
What are two assumptions made when mapping the relationship between drug concentration and response?
1) ‘response’ scales with concentration of drug-receptor complexes
2) fixed number of receptors
Equation relating to law of mass action/drug-receptor interaction
A+R⇌ AR Kd=[A].[R]/[AR] units of Kd=mol/litre [A]=agonist conc. [R]=receptor conc. Kd=dissociation constant
What does the Kd (dissociation constant) equation derive to?
p(constant of response)=[A]/Kd+[A]
How do signalling cascades result in lower doses of the drug required?
Large signal amplification meaning low dose has larger effect than expected
What are the different natures of drug receptors?
Enzymes
Ion channels
Transporters (pumps, transport proteins)
‘Physiological’ receptors
Give two obscure natures of drug receptors
DNA/RNA and the ribosome
targets of monoclonal antibodies
What are “dirty drugs”?
Drugs that have many targets causing unwanted/unplanned effects
How are steroid hormones a type of “dirty drug”?
They bind to intracellular nuclear receptors but also activate membrane-bound GPCRs-effect is often the result of the interplay between the two mechanisms
Give an example of a “dirty drug” having different effects at different dosings
Aspirin:
lower dose=blood thinner (anti-thrombotic)
higher dose=pain killer
What are the ways of regulating cell function?
Alteration of membrane potential, alteration of enzyme activity, alteration of gene expression->most drugs affect cell function via (physiological) receptors, acting ‘hormone-like’
How are receptors classified?
On the basis of the selective action of drugs, they are named according to the transmitter/hormone with which they interact (eg. AChRs)
What are the 5 receptor super-families?
Integral ion channels (eg. nicotinic/glycine receptors)
Integral tyrosine kinases (eg. insulin receptor)
Steroid receptors (eg. oestrogen receptor)
GPCRs (eg. muscarinic receptors)
Cytokine receptors (eg. prolactin/EPO receptor)
What is the action of integral ion channels?
They transport ions causing a change in the voltage across the membrane
What is the action of integral tyrosine kinases?
They have a large extracellular domain which is busy in ligand binding and dimerisation, signal is transduced by conformational change which brings intracellular domain closer, phosphorylation of intracellular part=activation
Where do steroid receptors usually act?
In the nucleus, but are located in the cytoplasm
What are the two defining features of a steroid receptor?
DBD=DNA-binding domain->mediates receptor binding to genomic sites
LBD=ligand-binding domain->where ligand binds, functions like a folding sensor: without ligand=unfolded, with ligand=folded
What is the action of steroid (nuclear) receptors?
as long as domain hasn’t bound to ligand it’s unfolded, makes it a substrate to folding helper enzyme (heat shock protein-HSP), grabs and holds tightly, forms HSP/NR complex, hormone (ligand) binds to LBD, HSP removed, NR/hormone complex, dimerisation of NR, moves into nucleus, DBD binds NR to target gene
Why do GPCRs have multiplicity?
homo- and heterodimers and several G subunits with different effects
What is agonism?
Various ways drugs produce effects by binding to receptors
What is antagonism/desensitisation?
Various ways drugs block effects by binding to receptors
What is the % agonist response of a full agonist?
100%
What is the % agonist response of a super agonist?
> 100%
What is the % agonist response of a partial agonist?
0%>x>100%
What is the % agonist response of an antagonist/no agonist?
0%-binds and does nothing, doesn’t alter spontaneous openings
What is the % agonist response of partial/full inverse agonists?
<0%-reduces spontaneous activity
What is an allosteric effect?
The binding of a ligand to one site on a protein molecule in such a way that the properties of another site on the same protein are affected
Give an example of allosteric effects on receptors
benzodiazepine agonists bind to GABAaRs on a different site on the protein channel and increase GABA affinity to GABAaRs, increase channel opening, increasing Cl- ion influx
What is the allosteric effect of benzodiazepine antagonists/inverse agonists on GABAaRs?
their binding doesn’t cause Cl- ion efflux but will prevent the ion channel opening-reduced/no influx of Cl-
What are ‘super agonists’?
Highly efficacious agonists that produce a maximal response from the cell without binding to all the available receptors
What are partial agonists?
Low efficacy agonists that cannot produce the cell’s maximal response, even when they have bound to all available receptors
What is a competitive antagonist?
A substance with a relatively similar shape to the agonist, so binds reversibly to the same site as the agonist
What effect does a competitive antagonist have on agonist dose/response curves?
Parallel shift to the right due to a slower rate of response but no change in Emax
What is an irreversible antagonist?
A substance that binds irreversibly at the same site as the agonist, forming a covalent bond or binding tightly
What effect does an irreversible antagonist have on agonist dose/response curves?
Downward shift due to decreased maximal response to agonists so Emax is lower
What happens to a membrane receptor once it’s inactivated by an irreversible antagonist?
antagonist binds, signalling (or lack of), internalisation, receptors move into cell and fuse with lysosomes, receptor degradation, recycled
What is an allosteric antagonist?
A substance that binds irreversibly at a different site to the agonist and decreases agonist affinity by inducing inhibitory protein conformation
What is a channel blocker?
A substance that binds inside the channel (‘plug’) and prevents ion passage which tends to be increased by receptor activation (eg. local anaesthetics)
What is a ‘Physiological’ antagonist?
A substance that antagonises the physiological effect of some agonists
What is desensitisation?
A reduction in agonist response due to prolonged or repeated exposure to the agonist
