Receptors and Drug Action Flashcards
what are opiates?
- analgesics for pain relief
- give euphoric and pleasurable experiences
- repeated use leads to addiction and drug-seeking behaviour
- increases activity of dopaminergic neurons
what is the active ingredient in opiates?
morphine
give an example of an opiate receptor:
mu-opioid receptor:
- GPCR
- endogenous molecules are endorphins and enkephalins which are produced by body in response to serious pain
what is a drug?
a chemical of known structure that when administered to a living organism produces a biological effect
what are the different types of drugs?
- synthetic chemicals e.g. heroin
- plant chemicals e.g. atropine
- biopharmaceuticals (made from DNA) e.g. oligonucleotides
- toxins
what is a medicine?
a chemical preparation that usually contains one or more drugs and is administered to produce a therapeutic effect
- they often contain compounds such as excipients, stabilisers and solvents
what are biopharmaceuticals?
- proteins: can be copies of endogenous proteins (e.g. insulin), engineered proteins or antibodies (monoclonal), recombinant hormones
- oligonucleotides: siRNA, mRNA (injected to body and can form antibodies)
- gene therapy: addition of genetic material to cells to help with disease
- regenerative medicine: engineered stem cells to replace irreparably damaged organs
what is the development of biologics?
- first generation: copies of endogenous proteins produced by recombinant DNA tech
- second generation: engineered proteins to improve performance
what are new biologics?
Engineered humanised monoclonal antibodies:
- fastest growing area of drug development for treating cancer and immune diseases
what does humanised mean?
body accepts the monoclonal antibody as a ‘self-antibody’
what is pharmacogenetics?
the study of genetic influences on responses to drugs, usually identifying risks of adverse reactions
- evolved into pharmacogenomics
what is pharmacogenomics?
complex analysis of an individual’s genome to guide choice of drug therapy
- personalised medicine
what is pharmacoepidemiology?
study of drug effects at the population level
- important for regulatory authorities in deciding to license a drug
what is pharmacoeconomics?
quantifies the cost-benefit of drugs used therapeutically
what do drugs interact with to exert their actions?
- proteins
- receptors, enzymes, transporters, ion channels - drug targets: other macromolecules with which drugs interact to produce their effect
what are receptors?
proteins found on surface of membranes whose function it is to recognise and respond to endogenous chemical signals or to sense the environment
how can receptors be classified?
classified by their structure, pharmacology and signalling mechanism
- receptors show specificity in the classes of drugs that they recognise
- malfunction/loss of receptors leads to disease
are drugs completely specific?
no: increasing the dose of drugs will cause it to affect other targets, leading to unwanted side effects
why is understanding of drug concentration so important?
key in predicted functional consequences of drugs:
low potency drugs -> the higher the dose needed -> more likely that other targets will be affected -> causes side effects
give an example of drugs which target receptors:
morphine (mu-opioid receptors)
humira
what is an agonist?
when bound to receptor, agonists induce signalling by that receptor to bring about a change to the cell
what is an inverse agonist?
when bound to receptor, they reduce the signalling of that receptor
what is an antagonist?
when bound, they do not induce signalling themselves, but do prevent the receptor’s response to an agonist
how do drugs directly effect receptors?
by acting as agonists, inverse agonists or antagonists
how do drugs indirectly effect receptors?
by interfering with transduction systems used by a receptor e.g. by binding to proteins/enzymes to prevent/enhance signalling
give an example of drugs which target ion channels:
lidocaine: blocks voltage-gated Na+ channels to modulate pain response
Valium
gabapentin: analgesic which affects trafficking of ion channels to plasma membrane
how do drugs affect ligand-gated ion channels?
drugs can block the channel by fitting into the pore to occlude it, so that ions can no longer flow through the channel
how do drugs modify the behaviour of ion channels?
they can bind to regions outside the pore to alter the channels activity:
- drugs may make it harder for the channel to open, causing a reduced channel function
- drugs may make it easier for the channel to open, causing an increased channel function
give examples of drugs which target enzymes:
Aspirin: inhibitor which binds to enzymes to inhibit activity
Viagra
what are false substrates in drug action on enzymes?
drugs can substitute for the usual endogenous substrate, undergo the reaction and produce an abnormal metabolite from the enzyme
what are prodrugs?
a substrate drug which undergoes a reaction with an enzyme to produce an active drug
give examples of drugs which target transporters:
Prozac
Digoxin: poison found in foxgloves which inhibits a transporter in the heart
what are transporters and why are they important?
- proteins that carry molecules across the plasma membrane
- important for molecules that are not sufficiently lipid soluble to cross membrane
what are multidrug resistance transporters?
they carry cytotoxic drugs out of cancer cells and microbes, causing resistance to the drug
what are drug inhibitors of transporters and give an example:
- they block access to the site that is used by molecules in the transporter
e.g. cocaine
what are false substrates of transporters and give an example:
some drugs can be carried across membrane by the transporter and be substituted for endogenous molecules
e.g. amphetamine
what is colchinine?
- used for the treatment of gout
- targets microtubules and prevents their assembly at sites of inflammation
what is paclitaxel?
- interferes with microtubules but prevents their disassembly
- interferes with cell division
- used as chemotherapy
what is the function of receptors?
- recognise stimulus
- transfer stimulus into cell
- amplification of cytoplasmic signal
- modulation of effector systems over time
- adaption of system through feedback
how can cells respond to stimuli specifically?
selective expression of receptors and the molecules involved in signal transduction allows cells to respond specifically to particular stimuli
how many receptors can cells express?
any one cell can express multiple receptors to allow integration of info from many sources
- there are multiple types of receptor to specific types of molecule
what is a ligand?
refers to any molecule that binds to a receptor, it may be an agonist, inverse agonist or antagonist
give example of agonists and antagonists that effect the mu-opioid receptor:
agonists: morphine, heroin, fentanyl (all opiates)
antagonist: naloxone
what are ligand-gated ion channels (type 1 receptors)?
ionotropic receptors:
- transmembrane domains form pore in plasma membrane
- protein subunits form either a heteromeric or homomeric receptor
- when ligand binds, pore opens so ions can flow through
- flow of ions leads to generation of current, causing change in membrane potential
what controls channel gating of ionotropic receptors?
ligand-binding
give an example of a drug which targets an ionotropic receptor:
Nicotine: acts on nAChRs
what are the 4 families of ionotropic receptors?
- cys-loop type
- 4 transmembrane domains e.g. nAChRs
- pentameric - ionotropic glutamate type
- 3 transmembrane domains e.g. NMDA
- tetrameric - P2X
- recognised by ATP, 2 transmembrane domains
-trimeric - Calcium release type
- found inside cells, ryanodine receptors
- trimeric
how does subunit composition of receptors impact pharmacology?
certain concentations/doses of drugs will impact certain receptors with specific subunit compositions around the body
e.g. small amount of nicotine effects nAChRs in the brain, but not in the rest of the body
what are GPCRs (type 2 receptors)?
metabotropic receptors:
- GPCR genome shows 800 types of these receptors
- 7 transmembrane domains
- intracellular carboxyl terminus binds G-proteins in the cell
- G-proteins act as a molecular switch to trigger signalling cascades inside the cell
- signal via second-messengers
what is the structure G-proteins?
made up of 3 subunits:
- alpha
- beta
- gamma
they are heterotrimeric
knowledge of G-proteins and their effectors gives insight into functional consequences of activation of certain GPCRs
how are GPCRs activated?
- in inactive state, G-protein is in normal conformation, with 3 subunits attached and alpha associated with GDP
- when ligand binds, G-protein undergoes conformational change and forms 2 subunits, alpha and beta-gamma
- alpha now has higher affinity to GTP so disassociates with GDP
- GTP-alpha and beta-gamma can now interact with downstream effectors to control function of cell
how are GPCRs terminated?
- action is terminated when ligand disassociates from receptor
- alpha subunit hydrolyses GTP to GDP
- alpha-GDP is now attracted to beta-gamma, so they reassociate and reform the inactive G-protein molecule
- signalling to the effector proteins is now switched off
give example of drug which targets metabotropic receptors:
agonist: endocannabinoids
ACh can also act on GPCRs via mAChRs
what second messengers are involved in GPCR signalling?
- adenylyl cyclase
- cAMP, IP3, DAG
- PKC
- Gq, Gs, Gi
- PLC-beta
- arrestin
what kind of assay assesses drug actions on receptors?
Fluorescence Imaging Plate Reader (FLIPR):
- detects level of second messengers to help assess if a drug is an agonist or antagonist of a specific receptor
what are kinase-linked receptors (type 3 receptors)?
- has enzymatic activity to phosphorylate to other proteins
- 1 transmembrane domain
- kinase is either built into the receptor itself, or is recruited by the receptor when needed
- activation of these receptors leads to changes in gene expression and transcription (affects nucleus)
what are growth factor receptors (type 3)?
e.g. tyrosine-kinase linked receptors
- phosphorylate tyrosine residues within the receptor
- receptor recruits kinases upon activation to intracellular domain, leading to downstream signalling
- regulates growth of cells
- mutations in these receptors can lead to cancers
what are cytokine receptors (type 3)?
- cytokines regulate inflammatory responses
- enzyme is already associated with the receptor (autophosphorylation)
- activation leads to signalling cascade
give an example of a kinase-linked receptor:
insulin receptor:
- 2 subunits join together and cause autophosphorylation which leads to changes in cell function
what are nuclear receptors (type 4)?
- 0 transmembrane domains so are not anchored to plasma membrane
- found in cytosol (class I) or nucleus (class II)
- contain a DNA-binding domain to directly bind DNA and regulate transcription of genes
- 10% of drugs target nuclear receptors
- agonists are lipophilic so can access receptor easily
what are class I nuclear receptors?
exist in cytosol and move into nucleus when agonist binds e.g. progesterone receptor
- homodimeric
what are class II nuclear receptors?
already exist in nucleus e.g. thyroid hormone receptor
- heterodimaric
give an example of diseases caused by receptor malfunction autoantibodies:
body makes antibodies that target self-receptors:
1. myasthenia gravis
- antibodies formed for nAChRs, leading to loss of skeletal muscle function
- thyroid hypersecretion
- hyperactivation causes Graves disease: high metabolic rate, increased skin temp, tremor, tachycardia, bulging eyes
give examples of mutations in receptors/proteins involved in signal transduction:
- ionotropic receptors associated with epilepsy
- GPCRs activating mutations causing endocrine disorders
- B2-adrenoreceptors reduce efficacy of asthma drugs - mutations in RTKs cause cancers
- mutations in NRs cause inflammation, cancer, diabetes etc
