Patient: Channels, receptors and enzymes as drug targets Flashcards
Define pharmacokinetics
What the body does to a drug
Define pharmacotherapeutics
The use of drugs to prevent and treat disease
Define pharmacodynamics
What the drugs does to the body
How does a drug produce an effect?
A drug interacts with (binds to) its target usually in/on a cell. Targets forms tight bonds with the drug dependent on the size, shape and stereo-specificity.
When a drug produces a response, what is it dependent on?
The type of target and what the target is linked to
Affinity - degree of attraction
Efficacy (intrinsic activity) ability to change target in a way that produces an effect
Target interaction is due to what 3 types of charge distribution?
ions
dipoles
van der Waals forces
What are ionic bonds dependent on?
Related to drugs being weak acids or bases
pH and pKa influence the degree of ionisation
What are dipoles due to?
Uneven distribution of electrons between atoms in molecules
What are van der Waals forces due to?
flexible movement of charge (electrons) through chemical groups
What are the 3 types of agonist?
Full, partial and inverse
What do agonists do?
They have affinity and they have efficacy
All bind to the binding site/active site
Name the 3 types of allosteric modulators
Positive, negative and neutral
What do allosteric modulators do and how do they do it?
Indirectly influence the binding of an agonist
Alter affinity and efficacy
Binds to a different site on receptor compared to the agonist
What do antagonists do?
They prevent agonist binding
Name the 4 types of binding of anatagonists
competitive
non-competitive
reversible (always competitive)
irreversible (competitive or non-competitive)
Reversible antagonists have what kind of bonds?
Short lived bonds - dissociates easily
Irreversible anatagonists have what kind of bonds?
Strong (covalent) bonds - does not dissociate
Name 4 types of target receptor
Ion channels
G-proteins
Protein kinases
Cytoplasmic/nuclear receptor
Opening of Na+ or Ca2+ ion channel causes…
the opening of Na+/Ca2+ channels cause further depolarisation
Ca2+ channels open
Increase in Ca2+
Hence increase in cellular activity
Opening of K+ channels causes…
hyperpolarisation
Ca2+ channels close
Decrease in Ca2+
Hence decrease in cellular activity
What does GTP stand for?
Guanosine triphosphate
How many lipophilic membrane domains does a GTP receptor have?
7
Describe how GTP coupled receptors work
Ligand binds to exterior section of the receptor
Interior section linked to G-protein
ligand binding changes conformation activates G-protein
G-protein linked to enzyme systems or ion channels
Describe how GTP coupled receptors work in terms of alpha, beta and gamma subunits
Receptor occupied by agonist
GTP hydrolysed to GDP
causes alpha and beta-gamma subunits to dissociate
alpha one binds to target 1
beta-gamma one binds to target 2
effect repeats if presence of drug still there
Describe how adenylyl cyclase works with G proteins
ATP becomes cAMP (catalysed by adenylyl cyclase)
cAMP can become 5’AMP via a phosphodiesterase
OR
cAMP can activate protein kinase A
this then leads to protein phosphorlyation and a change in Ca2+ concentration
Which then leads to biological response
OR the phosphorylated protein can be dephosphorylated by phosphatase enzyme
Give an example of a G-protein receptor
Gs-GTP
beta-adrenoreceptors
Differentiate Gs-GTP and Gi-GTP
Gs-GTP = stimulatory (activates adenylyl cyclase) Gi-GTP = inhibitory (inhibits adenylyl cyclase)
Give an example of a G-protein receptor
Gi-GTP
opiod receptors
What about Gq-GTP?
Different enzyme - activates phospholipase C (PLC)
PLC–>inositol triphosphate (IP3)–>change in Ca2+ conc
then biological response
OR
PLC–>diacylgylcerol (DAG)–>activates protein kinase C–>protein phosphorylation–>biological response
Give an example of a Gq-GTP receptors
muscarnic receptors and alpha-adrenoceptors
Describe the Na+/K+ ATPase (Na+ pump)
3Na+ out of cell
2K+ into cell
Powered by ATP hydrolysis
Contributes to resting membrane potential
What kind of drug is digoxin?
cardiotonic
used in heart failure
How does digoxin work?
Blocks Na+/K+ ATPase Increase in intracellular Na Na+/Ca2+ exchanger stimulated Increase in Ca2+ Increase in force of contractions
Give an example of a tyrosine kinase receptor
Insulin receptor
How does a tyrosine kinase receptor work?
Signal molecule binds
Dimerisation of receptor
Activate of tyrosine-kinase regions and phosphorlyation of the dimer.
Dimer goes on to phosphorlyate tyrosine molecules and activate inactive relay proteins via this mechanism
Give examples of nuclear receptor drugs
steroids and thyroid hormones (lipophilic drugs)
Name some illnesses associated with malfunctioning nuclear receptors
inflammartion, cancer, diabetes, cardiovascular disease, obestiy and reproductive disorders
describe speed of: ligand gated ion channels g protein coupled receptors kinase-linked receptors Nuclear receptors
Milliseconds
seconds
hours
hours-days
Look at dose response curves!
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