Health and Disease Flashcards
define pharmacology
the science of drugs and how they act in biological system
What are the 4 main protein targets for drug action?
- receptors
- ion channels
- enzymes
- transporters
What do ion channels do?
they are present on cellular membranes and open in response to environmental cues, which allows the passage of channel-specific ions down a concentration gradient
What are the 2 ways in which drugs can affect ion channels?
blockers and modulators
What do blockers do to ion channels?
they block ion channels and prevent ion movement
What do modulators do to ion channels?
they don’t block the channel, but bind and increase or decrease the chance of the channel opening
What are the 3 ways in which drugs affect enzyme activity?
inhibitors, false substrates, prodrugs
How do inhibitors affect enzyme activity?
they block substrate from binding
How do false substrates affect enzyme activity?
the enzymes produce an abnormal metabolite
How do prodrugs affect enzyme activity?
drugs given to the patient are inactive, so enzymes convert them into active state
What do transporters do?
transport substances across membranes, can be against a concentration gradient- but only ONE side of membrane is open at once
What are the 2 ways in which drugs affect transporters?
inhibitors and false substrates
How do inhibitors affect transporters?
they block activity of the transporter, so it can’t transport substances across the membrane
How do false substrates affect transporters?
an abnormal compound will accumulate at the other side of the membrane
What are receptors?
proteins that typically sit on cell membrane and respond to exogenous cues and relay a signal into a cell to produce a response
What are the 3 ways in which a drug affects a receptor?
agonist, antagonist, modulator
How do agonists affect receptors?
activates the receptor when it binds
How do antagonists affect receptors?
bind to receptor, but produce NO response, and block activity of the receptor by endogenous activators
How do modulators affect receptors?
they bind to elsewhere on the receptor and increase or decrease the ability of the receptor to activate
define receptor
proteins, usually on the surface of a cell which receive and transduce signals
define ligand
something that binds, can be an agonist or antagonist
define agonist
something that binds and produces a response
define antagonist
something that binds and produces NO response
define second messenger
a molecule that relays a signal from a receptor to an effector
define signal transduction
a sequence of second messengers that elicit a biological response
How do receptors work?
- ligand binds to receptor
- causes a conformational change of the receptor protein
- results in a cellular effect
What are examples of cellular effects after a receptor is activated?
opening of a channel, activation of a linked enzymes. recruitment of an effector protein, intracellular transport
What are the 4 main families of receptor?
- ligand-gated ion channels
- G protein-coupled receptors
- Kinase-linked receptors
- nuclear receptors
How do ligand gated ion channels work?
when a ligand binds, it opens the channel, allowing the movement of channel-specific ions
What is an example of a ligand gated ion channel?
acetylcholine and nicotonic receptors
How do acetylcholine and nicotonic receptors work?
- an electrical impulse travels down the pre-synaptic neurone
- this triggers the release of acetylcholine
- acetylcholine acts on nicotinic acetylcholine receptors on the post-synaptic neurone
- this opens the channel, and allows sodium ion entry, which triggers an impulse in the next neurone
What is kinase?
a second messenger and an enzyme
What does kinase do?
it uses ATP to phosphorylate targets, and acts as a switch to turn target on or off and allows other 2nd messengers to bind to phosphorylated target protein
How do kinase-linked receptors work?
- the receptors is on the cell membrane as two halves
- when ligand binds to receptors it brings the two receptors halves into a dimer
- activates kinase activity of the receptors and a cascade and biological response
What is an example of a kinase-linked receptor?
epidermal growth factor receptor
How is epidermal growth factor receptor (EGFR) related to lung cancer?
EGFR can promote cell growth, and some patients with lung cancer may express many more EGFR receptors, so experience more growth
What is a G protein-coupled receptor?
a receptor with 7 transmembrane domains coupled to a G protein
How do G protein-coupled receptors work?
ligand binding activates the G protein bound on the intracellular surface, which interacts with an affector
How are G protein-coupled receptors activated?
- receptor is in resting state attached to G protein
- ligand binds and G protein is activated
- GDP is exchange for GTP by G protein
- GTP bound G protein interacts with the target effector, which causes a response
- the G protein then hydrolyses GTP to GDP and the G protein can dissociate from the effector
What is an example of a G protein-coupled receptor?
muscarinic receptors and smooth muscle contraction
How do muscarinic receptors work?
- muscarinic M3 G-protein coupled receptors are on intestinal smooth muscle
- acetylcholine activates M3 receptors
- the G protein is then able to bind to effector
- contraction of smooth muscle occurs
- therefore, antimuscarinics can be used to treat IBS
How do nuclear receptors work?
- the receptor is NOT associated with the cell membrane, but in the cyotplasm
- ligand enters the cell and binds to receptor in the cytoplasm
- ligand-receptor pair allows it to change conformation and it can move into nucleus
- it then binds to DNA and acts on gene expression
What is an example of a nuclear receptor?
oestrogen receptor
How are oestrogen receptors associated with breast cancer?
some patients with breast cancer may have more oestrogen receptors, so there is more growth
these receptors can be targeted by Tamoxifen
What is blood production controlled by?
multiple protein cytokines (release by WB cells) and growth factors
What detects blood vessel damage?
platelet surface receptors
What do platelets secrete? Why?
soluble factors to activate neighbouring platelets
What is required for a clotting cascade?
multiple blood proteins
What does thrombopoietin do?
regulate production of platelets
What does erythropoietin do?
regulate production of erythrocytes
What are the major precursors of platelets?
megakaryocytes
What kind of cells give rise to haematopoietic precursors of blood cells?
pluripotent stem cells
What creates a bruise?
when blood vessel endotheliums become damaged and blood leaks into surrouding tissues
What is the scientific name for blood clotting?
haemostasis
What 2 stages can clotting be broken down into?
- primary haemostasis
- secondary haemostasis
What happens in primary haemostasis?
platelets form a plug and are attracted to site of damage
What happens in secondary haemostasis?
a blood clotting mechanism is used to transform and stabilise the weak platelet plug into a clot by a fibrin network
What is the 1st step of platelet plug formation?
adhesion
What are the steps of adhesion in platelet plug formation?
- damage to endothelium cells exposes subendothelial tissue which is made up of collagen fibres
- collagen activates platelets and they adhere to these collagen fibres via an intermediate protein called von Willebrand factor (vWF)
- platelets binding to collagen causes a release of ADP and serotonin from their secretory vesicles, resulting in more platelet activation
What is the 2nd step of platelet plug formation?
platelet activation
What are the steps of platelet activation?
- release of ADP and serotonin from vesicles
- this causes change in shape and surface protein expression of platelets
What is the 3rd step of platelet plug formation?
platelet aggregation
What are the steps of platelet aggregation?
- platelets adhere to each other to form a plug
- synthesis and release of thromboxane A2 from arachidonic acid enhances more activation and aggregation
What stabilises the platelet plug?
fibrinogen bridges that form when receptors in the platelet surface become exposed during activation
What causes contraction of the plug?
actin and myosin
What do healthy endothelial cells do?
synthesis and release of Prostacyclin (PGI2) and nitric oxide, which both inhibit platelet activation
What is the scientific name for a clot?
a thrombus
What is a clot?
the transformation of blood into a gel consisting of fibrin polymers that occurs around the platelet plug
What does vessel damage activate?
a cascade of enzyme that results in the activation of an enzyme called thrombin
What does the enzyme thrombin do?
cleaves a protein called fibrinogen into fibrin molecules that create the fibrin network
Sequence of events
clotting factors -> prothrombin -> thrombin -> fibrinogen -> fibrin -> blood clot
What are the overall steps of blood clotting?
- damage to blood vessel lining triggers the release of clotting factors
- formation of the platelet plug and vasoconstriction limits blood flow
- development of the clot and fibrin strands adhere to form an insoluble clot
How is thrombin activated?
activated from prothrombin which then cleaves fibrinogen to fibrin (which is stabilised by activation of factor 8 by thrombin)
What are the steps in activating the clotting cascade for the extrinsic pathway?
- initiated by a tissue factor, not blood protein, on the outside of plasma membrane of cells in the sub-endothelial tissue
- tissue factors activates factor 7 and they both activate factor 10
- generates small amounts of thrombin
- thrombin then feeds back onto the intrinsic pathway to activate components and generate more thrombin
What are the steps of beginning the enzyme cascade in the intrinsic pathway of the clotting cascade?
- clotting factor 12 is activated by contact with collagen
What is the role of the liver in blood clotting?
- produces many clotting factors
- produces bile salts which are required for absorption of vitamin K needed for production of prothrombin
What does thrombin do?
it is an enzyme that recruits the intrinsic pathway and activates factor 5 and activates platelets
How does the protease activated receptor on platelets activate them?
- the enzyme thrombin binds and cleaves the thrombin receptor at a specific site on the N terminus on a platelet
- the cleaved N terminus can then bind and activate the receptor on the platelet
What are examples of clotting disorders?
damage to endothelium (myocardial infarction), clots (deep vein thrombosis), clotting disorders (haemophilia)
define pharmacology
the science of drugs and how they act in biological systems
What are the 4 main protein targets for drugs?
- receptors
- ion channels
- enzymes
- transporters
Which 2 ways do drugs affect ion channels?
blockers, modulators
How do blockers affect ion channels?
they block ion channels and prevent ion movement, paticularly VGNC
How do modulators affect ion channels?
they don’t block but they regulate how easily the channel opens or closes, and may need a lower or higher voltage -> so increase or decrease the chance of the channel opening
Which 3 ways do drugs affect enzymes?
- inhibitors
- false substrates
- prodrugs
How do inhibitors affect enzyme activity?
they block activity by binding to active site
How do false substrates affect enzymes?
they bind to the enzyme and produce an abnormal metabolite
How do prodrugs affect enzymes?
they are drugs in an inactive state and bind to enzymes to be activated
Which two ways do drugs affect transporters?
inhibitors and false substrates
How do inhibitors affect transporters?
blocks activity of the transporter so it can’t move substances across the membrane
How do false substrates affect transporters?
transporter thinks it is a different substrate, so an abnormal compound accumulates
What are the 3 ways in which drugs can affect a receptor?
agonist, antagonist, modulator
How do agonists affect receptors?
they bind to and activate the receptor
How do antagonists affect receptors?
they bind to the receptor and block activity by other activators -> do NOT activate it though
How do modulators affect receptors?
they bind elsewhere on the receptor and increase or decrease the ability of the receptor to activate
define receptor
proteins, usually on the surface of a cell which receive and transduce signals
define ligand
something that binds
define agonist
something that binds and induces a response
define antagonist
something that binds and produces NO response
define second messenger
a relay signal from a receptor to effector
define signal transduction
a sequence of second messengers that elicit a biological response
What are the steps of a basic ligand-receptor interaction?
- ligand binds to receptor
- this causes a conformational change of the receptor protein
- this results in a cellular effect e.g. opening of a channel
What are the 4 main types of receptor?
- ligand-gated ion channels
- G protein-coupled receptors
- kinase-linked receptors
- nuclear receptors
How do ligand-gated ion channels work?
substance binds to it and opens the channel, allowing movement of channel-specific ions
What is an example of a ligand-gated ion channel?
acetylcholine and nicotinic receptors
What is the function of kinase?
an enzyme and second messenger that uses ATP to add a phosphate to targets, activating them
How do kinase-linked receptors work?
the receptor is on the cell membrane as two halves and binding bring them together, which activates kinase activity and causes a cascade
What is an example of a kinase-linked receptor?
epidermal growth factor receptor and lung cancer -> EGFR promotes cell growth, so patients with more of these proteins experience mroe growth
How do G protein-coupled receptors work?
they are receptors with 7 transmembrane domains coupled to a g protein and ligand binding activates the G protein which interacts with an effector
What is an example of G protein-coupled receptors?
muscarinic receptors and smooth muscle contraction
How do nuclear receptors work?
the receptor is NOT on the cell membrane, but in the cytoplasm -> ligand-receptor pair allows it to change conformation and it can move into nucleus where it binds to DNA and acts on gene expression
What is an example of nuclear receptors?
oestrogen receptor and breast cancer
Which 2 factors determine a receptor response?
affinity and efficacy
define affinity
how well a drug binds to a receptor
define efficacy
how well a drug activates a receptor
How are receptor responses measured?
concentration-response curves
How are concentration-response curves plotted?
a chosen response is recorded e.g muscle contraction and the recorded response is plotted against LOG agonist concentration
describe and explain the concentration-response curve
- initial low concentration gives limited response as low receptor binding
- more agonist is added and there is more binding
- a plateau is reached as we either have full receptor occupancy or we have added all agonist and can’t get a higher biological response
define Emax
the maximum response produced by an agonist
define EC50
the concentration of agonist needed to give 50% of Emax
How can we compare agonist drugs in the same biological system?
compare the profile of their concentration-response curves, Emax and EC50 values
What does it mean if another agonist has a curve to the right?
it has a higher EC50, so a higher concentration of agonist is needed to give the same response, so the agonist is LESS POTENT that the other
What do different EC50 values indicate?
different potencies for the receptor
define partial agonist
an agonist that binds to a receptor but does not produce a FULL response - either poor efficacy or affinity
What does the concentration-response curve look like for a partial agonist?
it will have an Emax below a full agonist and different EC50