Pharmacology Flashcards
List the four types of intracellular receptors
- Ligand-gated ion channels
- G-protein coupled receptors
- Kinase-linked receptors
- Nuclear receptors
Discuss the ligand-gated ion channel receptors, making mention of clinical correlations.
- ionotropic receptors
- mainly involved in synaptic transmission
- drugs that target ligand-gated ion channels can be agonists or antagonist
What are some examples of ligand-gated ion channel receptors?
- nicotinic acetylcholine
- glycine
- glutamate and GABA
What is the process of g-protein coupled receptors signalling?
- resting state
- occupied receptor
- activation of downstream targets
- GTP hydrolysis
What is the process of a kinase-linked receptor?
- a growth factor binds RTK, which results in dimerization with a neighbouring RTK
- the dimerised RTKs auto phosphorylate one another
- a SH2-domain protein binds to the intracellular active enzyme domain on the dimerised RTK resulting in phosphorylation of that SH2-domain protein.
- the SH2-domain protein goes on to activate Ras, a g-protein anchored to the cell membrane
- Ras is bound to GDP in its inactive state and GTP in its active state
- when activated, Ras activates RAF kinase
- RAF kinase goes on to phosphorylate and activate MEK kinase which then phosphorylates and activates MAP kinase
- finally, MAP kinase phosphorylates various transcription factors ultimately altering gene transcription
What is the process of nuclear receptors?
- hormones cross membranes and bind to receptors within the target cells
- they migrate together to the DNA within the nucleus, binding to key sequences in the DNA to cause transcription of desired proteins
- mRNA moves into cytoplasm for translation and biological action via newly made proteins
Why are their numerous time-frames for change in physiological processes?
- due to the diversity of receptors present and their connection to intracellular signalling mechanisms
Beyond the receptor types, what are the other ways that drugs can work?
- transporters
- enzymes
How do transporters as drug tests?
- by blocking the reuptake transporter on the presynaptic side of the synapse, the levels of serotonin stay increased for a longer period of time, increasing the chances that it may bind to receptors, thus improving signalling
True or false: all agonists are able to equally activate receptors?
False!
- an agonist may not fit as well into the receptor binding site so it comes off more quickly and does not activate the receptor to the same extent
What would it mean for low-affinity and high-affinity agonists in high concentrations?
- the number of activated receptors for the low-affinity agonists is still much lower than for the high-affinity agonists
When considering a log-scale graph of drug concentration and response (x- and y-axis respectively), what do these axes tell us, and how is it clinically significant?
- concentration (x-axis) tells us about potency: comparison of concentrations and effects of drugs
- response (y-axis) tells us about efficacy: comparison of effectiveness of drugs, or ‘activation of receptors’
When considering a log-scale graph of drug concentration and response (x- and y-axis respectively), what do these axes tell us, and how is it clinically significant?
- concentration (x-axis) tells us about potency: comparison of concentrations and effects of drugs
- response (y-axis) tells us about efficacy: comparison of effectiveness of drugs, or ‘activation of receptors’
What would you expect a full agonist to be compared to a partial agonist?
- full agonist is going to be very efficient
What would you expect a full agonist to be compared to a partial agonist?
- full agonist is going to be very efficient, partial agonist is going to be less so
Define ‘antagonists’.
- drugs that bind to receptors but do not activate them as they are unable to cause a shape change to enable signalling
- they prevent the binding of agonists to the receptors and so work against the agonists’ effects
What are the four types of antagonists?
- competitive
- non-competitive (allosteric modulation)
- uncompetitive antagonism
- functional/physiological antagonism
Discuss how competitive agonists work
- the high-affinity competitive agonist binds to the receptor, but does not activate its effectors
- no response!
What happens when a competitive antagonist and an agonist are at receptor sites?
- the competitive antagonist physically blocks the sites the agonist’s would be received by, so it reduces ability of the agonist to bin and cause a response
- the effect of this is a reduction in the effect of the agonist at each concentration
How do non-competitive antagonists work?
- the antagonist binds somewhere other than the active site on the receptor, which changes the shape of the binding site so it can no longer bind agonists
How does uncompetitive antagonism work?
- some of the receptors become permanently bound to antagonist, at the site as where the agonist binds
- when the agonist is applied, the maximum number of receptors available is less than 100% as some of them are permanently occupied by the antagonist
How does functional/physiological antagonism work?
- two drugs act on two different types of receptors and antagonise the action of each other
- may involve second messenger pathways
Provide a concise summary of what the effect of a drug is characterised by
- maximum effect (Emax) and the concentration that produces half-maximal effect (EC50)
How does drug tolerance develop?
- because of prolonged exposure of receptors to an agonist drug leading to a decrease in effect or receptor response because receptor numbers and signalling can change
What are the two mechanisms through which drug tolerance is developed?
- receptor uncoupling (desensitisation)
- receptor loss (down-regulation)
What does ADME mean?
- absorption
- distribution
- metabolism
- excretion
List the parental routes of drug administration, as well as some advantages and disadvantages of each.
Intravenous:
+ rapid action, complete dosing
- risk of toxicity, must be sterile, risk of sepsis
Intramuscular:
+ rapid absorption
- painful, possible tissue damage
Subcutaneous:
+ good for slower absorption
- variable dosage
Inhalation:
+ good for local application
- variable dosage
List the enteral routes, as well as some advantages and disadvantages of each
Oral:
+ convenient, non-sterile, self administration
- GIT irritation, inactivation, variable absorption
Sublingual:
+ avoids inactivation in GIT
- applicable to very few drugs
Rectal:
+ avoids inactivation in GIT
- inconvenient for patient
List the enteral routes, as well as some advantages and disadvantages of each
Oral:
+ convenient, non-sterile, self administration
- GIT irritation, inactivation, variable absorption
Sublingual:
+ avoids inactivation in GIT
- applicable to very few drugs
Rectal:
+ avoids inactivation in GIT
- inconvenient for patient
How do drugs get into the blood stream?
- GI tract
- skin
- blood brain barrier
- placenta
What does absorption depend upon?
- concentration gradient
- lipophilicity of drug
- blood flow at site
- surface area
- gut motility
- formulation - rate of drug releasing
- GI tract content
What is the impact on the liver in drug absorption?
- ‘first pass’ through hepatic vein: effect is that orally taken drugs (or entering through bloodstream) will pass through liver, where it metabolises the drug and reduces the concentration of the drug available to work on the rest of the body
Define bioavailability, and list what it is regulated by
- the fraction absorbed into the systemic circulation
Regulated by:
(Absorption) - GI tract contents, gut motility, gut blood flow
(Degradation) - gut microflora, acid stability, liver metabolism
How can the first-pass effect on absorption be avoided?
- administering drugs rectally, subcutaneously, intravenously, intramuscularly
What is the volume of distribution?
- the amount in body/plasma concentration
Once a drug is in the blood, what affects it’s ability to work on receptors? And how? Provide some examples.
Proteins! (i.e. human serum albumin, lipoproteins, etc.)
- the less a drug binds to the proteins in the blood, the more available it is to work on receptors
- thus, high protein binding will lead to a decrease in free drug, and low protein binding will mean that drug can more easily traverse cell membranes or diffuse to tissue receptors
What is the purpose of metabolism of drugs?
- increase the rate of elimination
- decrease likelihood of toxicity
What are the two major types of enzymatic reactions?
- Phase 1 reactions (oxidations, reduction, hydrolysis)
- Phase 2 reactions (add water-soluble moiety to drug: glucuronide, glutathione, sulphate, acetate)