drugs and pharmacology

Question 1

define a drug

Answer 1

any chemical agent that affects processes of living

Question 2

define receptor in pharmacology

Answer 2

A receptor is a signal transducing protein which changes its conformation upon agonist binding, but does not change the agonist itself.

Question 3

define Pharmacodynamics

Answer 3

what the drug does in the body

Question 4

define Pharmacokinetics

Answer 4

what the body does to the drug

Question 5

state five ways a substance can be toxic

Answer 5

–interfere with receptor-ligand binding
–interfere with membrane function
–interfere with cellular energy production
–bind to biomolecules
–perturb homeostasis (e.g. Calcium levels

Question 6

Definition of receptors

Answer 6

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

Question 7

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:

Answer 7

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

Question 8

what is the difference between the dose response curves of partial and full agonists

Answer 8

dose response curve will be the same ‘s’ shape but will reach a lower percentage of maximum response thus graph will be flatter

Question 9

what will the dose response curve of a full agonist in the presence of a partial agonist look like?

Answer 9

roughly same shape graph shifted to the right hence higher doses are needed to reach the same response level/maximal response

Question 10

what are the four types of drug target

Answer 10

Receptors
Enzymes
Carriers or transporters
Ion channels

Question 11

what are type 1 receptors give examples

Answer 11

ligand gated ion channels e.g. nAChR, GABAa receptors and glutimate receptors

Question 12

what are type 11 receptors give examples

Answer 12

G protein coupled receptors GPCRs e.g. mAChR, alpha and beta adrenergic receptors

Question 13

what are type 111 receptors give examples

Answer 13

Kinase linked receptors Receptor activation can be coupled to gene expression Cell division, apoptosis inflammation ect
e.g. cytokine receptors, insulin receptors

Question 14

what are type 1V receptors give examples

Answer 14

Nuclear receptors Ligand activated transcription factors e.g. receptors for steroid and thyroid hormones

Question 15

please sate the relative speed of action of receptor types 1-1V

Answer 15

1= miliseconds
11=seconds
111= hours
1V= hours/days

Question 16

what factors contribute to receptor diversity

Answer 16

alternate mRNA splicing
alternate editing
dimeriastion/hetromerisation.

Question 17

nAChR structure:

Answer 17

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

Question 18

state the general action of the following GPCR groups
Gs
Gi
Gq

Answer 18

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

Question 19

some GPCRs are PARs what are these

Answer 19

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.

Question 20

Gq GPCRs produce IP3 and Dag via stimulating PLC how do these second messengers act?

Answer 20

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

Question 21

state the types of G proteins that Alpha and beta adrenergic receptors interact with and and an example of the resulting effect.

Answer 21

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

Question 22

type 111 kinase linked receptor ligands

Answer 22

growth factors, hormones, cytokines.

Question 23

briefly note the kinase linked ras>raf>MAP kinase pathway

Answer 23

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

Question 24

what are the differences between class 1 and class 2 nuclear (type 1V ) receptors

Answer 24

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.

Question 25

what are the types of drug affects on channels

Answer 25

blockers or modulators- change probability of open state or indirect action e.g. changing ease of migration to plasma membrane

Question 26

possible effects of drugs on transporters

Answer 26

inhibitor e.g. cocaine inhibitor for mono amine transporters | false substrate> accumulates within cell

Question 27

types of drug action on enzymes

Answer 27

inhibitor false substrate producing abnormal metabolite prodrug- enzyme produces active drug form

Question 28

organize types of signaling by signaling distance

Answer 28

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

Question 29

define Chemotaxis

Answer 29

directed movement of cells up a concentration gradient

Question 30

state chronologically the generalized signaling response from cell surface membrane

Answer 30

-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

Question 31

how are kinases categorized

Answer 31

Kinases categorised on substrate Protein kinases Lipid kinase Sugar kinase (not common in signaling)

Question 32

Advantages of phosphorylation:

Answer 32

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

Question 33

common Sites of phosphorylation:

Answer 33

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

Question 34

possible consequences of phosphorylation

Answer 34

Change in conformation Change in enzyme activity Change in activation status e.g. creating a binding site for another protein

Question 35

what are the key differences and similarities of steroid and thyroxine hormones

Answer 35

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

Question 36

state the features of protein hormones

Answer 36

effects within minutes and last minutes within the blood released from vesicles receptors are on the plasma membrane and exert action through second mesengers

Question 37

how do tyrosine kinase receptors function

Answer 37

activation leads to dimerisation and trans phosphorylation of tyrosine residues on intracellular surface

Question 38

phosphorylated tyrosine kinase receptor residues then interact with:

Answer 38

proteins with SH2 domains

Question 39

Activation of SH2 domain can

Answer 39

Change in subcellular localisation Phosphorylation of proteins to change activity Allosteric activation Tyrosine phosphorylates with HS2 domain to switch off response

Question 40

describe signaling through notch receptors

Answer 40

notch ligands cause cleavage of exra and intracelluar domains with TM domain intracellular domain then goes on to be a transcription co activator

Question 41

what enzyme degrades cAMP

Answer 41

cAMP phosphodiesterase

Question 42

how dos Ca2+ activate down stream responses

Answer 42

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

Question 43

what is significant about Signaling via monomeric G protein RAS

Answer 43

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

Question 44

how can signalling pathway cross talk be regulated

Answer 44

by scaffolding proteins which can hold reactants and products to certain ratios of interaction by immobilizing the proteins.

Question 45

how is receptor desensitization often regulated?

Answer 45

Receptor desensitization can often be regulated by phosphorylation