drugs and pharmacology Flashcards
define a drug
any chemical agent that affects processes of living
define receptor in pharmacology
A receptor is a signal transducing protein which changes its conformation upon agonist binding, but does not change the agonist itself.
define Pharmacodynamics
what the drug does in the body
define Pharmacokinetics
what the body does to the drug
state five ways a substance can be toxic
–interfere with receptor-ligand binding
–interfere with membrane function
–interfere with cellular energy production
–bind to biomolecules
–perturb homeostasis (e.g. Calcium levels
Definition of receptors
Proteins or macromolecules on or in
cells
•Recognition sites for endogenous ligands or drugs
•When a drug binds it initiates a response or blocks a response to an endogenous chemical
for Recognition The receptor protein must exist in a conformational state that allows for recognition and binding of a compound and must satisfy the following criteria:
Saturability –receptors exists in finite numbers.
Reversibility – binding must occur non covalently due to weak intermolecular forces (H) - bonding, van der Waal forces). irreversible drugs are toxins e.g. Sarin a nerve gas!
Stereoselectivity – receptors should recognize only one of the naturally occurring optical isomers (+ or -, d or l, or S or R).
Agonist specificity – structurally related drugs should bind well, while physically dissimilar compounds should bind poorly.
Tissue specificity - binding should occur in tissues known to
what is the difference between the dose response curves of partial and full agonists
dose response curve will be the same ‘s’ shape but will reach a lower percentage of maximum response thus graph will be flatter
what will the dose response curve of a full agonist in the presence of a partial agonist look like?
roughly same shape graph shifted to the right hence higher doses are needed to reach the same response level/maximal response
what are the four types of drug target
Receptors
Enzymes
Carriers or transporters
Ion channels
what are type 1 receptors give examples
ligand gated ion channels e.g. nAChR, GABAa receptors and glutimate receptors
what are type 11 receptors give examples
G protein coupled receptors GPCRs e.g. mAChR, alpha and beta adrenergic receptors
what are type 111 receptors give examples
Kinase linked receptors Receptor activation can be coupled to gene expression Cell division, apoptosis inflammation ect
e.g. cytokine receptors, insulin receptors
what are type 1V receptors give examples
Nuclear receptors Ligand activated transcription factors e.g. receptors for steroid and thyroid hormones
please sate the relative speed of action of receptor types 1-1V
1= miliseconds
11=seconds
111= hours
1V= hours/days
what factors contribute to receptor diversity
alternate mRNA splicing
alternate editing
dimeriastion/hetromerisation.
nAChR structure:
five homologous sub-unit composition
typicaly: A,A, beta, theta, gamma
ACh binds at interface of Alpha subunit and adjacent subunits
Kinked Alpha helical domain with negative residues form channel gate and cation selectivity
state the general action of the following GPCR groups
Gs
Gi
Gq
Gs- (alpha subunit) stimulates production of cAMP by adenylyl cyclase (AC)
Gi- (alpha subunit) inhibits AC (beta,gama subunit) can have multiple cellualr effects e.g. on GIRK channels
Gq- alpha subunit activates PLC generating IP3 and Dag from your favorite word
some GPCRs are PARs what are these
are activated by protease cleavage of the extracellular N-terminal tail (protease
activated receptors, PARs). They play a role in inflammation or tissue damage associated with
release of proteases.
Gq GPCRs produce IP3 and Dag via stimulating PLC how do these second messengers act?
IP3- activates receptors on ER causing calcium release having a number of effects via various proteins e.g. calmodulin
Dag- activates PKC which then can go on to phosphorylate multiple target proteins
state the types of G proteins that Alpha and beta adrenergic receptors interact with and and an example of the resulting effect.
Alpha receptor- Gs - in a cardiac myocyte cAMP production activates PKA opening CaV channels on the cell surface membrane Ca2+ influx and contraction
Beta receptor- Gq - in smooth muscle Ca2+ influx causes contraction
type 111 kinase linked receptor ligands
growth factors, hormones, cytokines.
briefly note the kinase linked ras>raf>MAP kinase pathway
growth factor ligand binding causes dimerisation
causing intracellular tyrosine residue auto-phosphorylation
SH2 domain binding protein binds and activates RAS swaps GDP for GTP activating MAPKKK>KK>K then transcription factors
what are the differences between class 1 and class 2 nuclear (type 1V ) receptors
Class 1 - present in cytoplasm homodimerises and migrates to nucleus with ligand binding (often steroid hormone receptors)
Class 2 - present in nucleus receptor for lipids ligand binding triggers dimerisation with retenoid receptor.
what are the types of drug affects on channels
blockers or modulators- change probability of open state
or indirect action e.g. changing ease of migration to plasma membrane
possible effects of drugs on transporters
inhibitor e.g. cocaine inhibitor for mono amine transporters
false substrate> accumulates within cell
types of drug action on enzymes
inhibitor
false substrate producing abnormal metabolite
prodrug- enzyme produces active drug form
organize types of signaling by signaling distance
endocrine -diffusible long range conections
paracrine e.g. neurotransmitters/ autocrine e.g. platelet release- diffusable short range
signaling by cell contact e.g. notch signaling
signaling by conjoined cytoplasm e.g. gap junctions
define Chemotaxis
directed movement of cells up a concentration gradient
state chronologically the generalized signaling response from cell surface membrane
-Triggering of response interaction between ligand and receptor
-Transfer of information across membrane Conformational change or Hydrophobic signal
-Amplification of signal
Early involvement of adenylyl cyclase
Movement of ions
-Location of signal Generation of hydrophobic second messenger Recruitment of proteins to cell surface membrane
-Divergence of one signal to multiple response proteins
Second messenger affects a large number of proteins e.g. Ca2+ Activation of kinases with multiple target substrates e.g. cAMP kinase
-Termination of response by Modification of receptor or Internalisation of ligand and receptor
Degradation
how are kinases categorized
Kinases categorised on substrate
Protein kinases
Lipid kinase
Sugar kinase (not common in signaling)
Advantages of phosphorylation:
Rappid
Direct use of cellular energy source
Addition specifically catalysed by an enzyme- kinase
Reversible but requires an enzyme to remove phosphate
Both enzymes show specificity
common Sites of phosphorylation:
Amino acid side chains with OH
In eucaryotes serine and threonine ~99% tyrosine~1%
OH groups on lipids e.g.inositol ring on head group of phospholipid
possible consequences of phosphorylation
Change in conformation
Change in enzyme activity
Change in activation status e.g. creating a binding site for another protein
what are the key differences and similarities of steroid and thyroxine hormones
similarities:
both have carrier proteins
both act through transcription
Differences:
steroids act within hours and last hours in the blood while thyroxine acts within days and lasts days in the blood
both have receptors in the nucleus but steroid hormones also have receptors in the cytoplasm
steroids are released by diffusion while throxine is released by proteolysis
state the features of protein hormones
effects within minutes and last minutes within the blood
released from vesicles
receptors are on the plasma membrane and exert action through second mesengers
how do tyrosine kinase receptors function
activation leads to dimerisation and trans phosphorylation of tyrosine residues on intracellular surface
phosphorylated tyrosine kinase receptor residues then interact with:
proteins with SH2 domains
Activation of SH2 domain can
Change in subcellular localisation
Phosphorylation of proteins to change activity
Allosteric activation
Tyrosine phosphorylates with HS2 domain to switch off response
describe signaling through notch receptors
notch ligands cause cleavage of exra and intracelluar domains with TM domain
intracellular domain then goes on to be a transcription co activator
what enzyme degrades cAMP
cAMP phosphodiesterase
how dos Ca2+ activate down stream responses
Many proteins regulated directly by increased Ca2+ levels
Calmodulin is a Ca2+ binding protein that interacts with many protein complexes e.g. calmodulin dependant kinases
sensitivity of response to Ca2+ can be determined by number of calcium binding sites
what is significant about Signaling via monomeric G protein RAS
Can be activated downstream of heterotrimeric G proteins
RAS is a GTPase
Requires gap proteins to regulate and switch off response
Can activate multiple downstream routes
Prominent activation rout id the map K ← map KK ← map KKK phosphorylation chain
Map K can the phosphorylate multiple things e.g. transcription factors
how can signalling pathway cross talk be regulated
by scaffolding proteins which can hold reactants and products to certain ratios of interaction by immobilizing the proteins.
how is receptor desensitization often regulated?
Receptor desensitization can often be regulated by phosphorylation
