Flashcards in core pharmacology Deck (63)
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1
what are the 4 main classes of proteins targeted by drugs
receptor
enzyme
channel
transporter
2
if you increase drug concentration enough it will have an effect
true drugs are never completely specific
3
in terms of channels what is a modulator and what is a blocker
modulator - drug binds to allosteric site and changes behaviour of channel
blocker - drug binds to active site blocking channel
4
what is a pro-drug
a drug that needs to be metabolised in order to produce active form
5
what are the 4 receptor families and how many TMDs
ion channels - 4/5 TMD
GPCR - 7 TMD
kinase linked - 1 TMD
nuclear receptors - 1 TMD
6
how many phases in drug development
6
7
what is lead development
find key target of drug
8
what is preclinical development
safety margin
define max dose/conc
rescue treatments
obtain regulatory approval
9
exploratory studies
in vitro - mutagenecity testes by Ames test
arrythmia biomarker with hERG potassium ion channel
in vivo - repeat administration for 14 days
10
describe 3 phases of clinical trial
phase 1 - is it safe? how well is it tolerated? what are the pharacokinetic properties?
phase 2 - proof of concept? how much so its effective? how well does it work/
phase 3 - 1000+ patients
11
how many make it past clinical trial
11%
12
similarities in small molecule and biomolecule trials
1-, 3- ,6- month studies
developmental toxicity studies done
13
differences
small molecule shorter half life, more toxic metabolites as it can enter cell, can create mutants
14
occupancy =
No. of receptors occupied/No. of receptors - between 0-1
15
how do we measure occupancy
radioligand binding assay
16
what radioactive compound do we use
125I or 3H
17
stages of assay
tissue prep + ligand - create cell line
mix
incubate to reach equilibrium
filter
rinse - non bound ligands
measure radioactivity
18
how can you reduce non specific binding
use anti-absorbant e.g. albumin/collagen
does not reduce non specific tissue binding
19
what must a radio ligand be
biologically active
pure
not easily degraded
labelled
20
how would you reduce degradation of ligand
free radical scavenger i.e. ethanol
store at low temp
avoid light
incorporate anti-oxidant such as ascorbic acid
21
advantages and disadvantages of H/I
H - indistinguishable from native compound
very specific activity
good stability when stored properly
long half life
need specialist labs
expensive and difficult to label
I- higher specific activity if aromatic OH group added
easy and cheap
more readily degraded
short half life
22
main way of separating bound ligand from free
centrifugation
23
why is rate of dissociation a problem
if there is a low affinity then a quick separation time is needed or else all ligand will separate
very low affinity is too fact to calculate
24
how do you calculate specific binding
scatchard plot
25
is specific binding saturable
yes specific number of receptors
non specific is not
26
what is the scatchard equation
B/F = (Bmax - B) / Kd
27
what does the langmuir equation calculate
relationship between occupancy, affinity and drug conc
28
low Kd ? affinity
high
29
EC50 calculates
potency
30
efficacy measures
response
31
what are the 5 types of antagonism
chemical
pharmacokinetic
physiological
competitive
non-competitive
32
chemical antagonism
substances chemically altered by antagonist
e.g. heavy metals inactivated when adding chelating agent
33
pharmacokinetic antagonism
1. reduction in amount of drug absorbed
2. change in drug metabolism e.g. warfarin
3. change in excretion of agonist
34
physiological antagonism
interaction of 2 drugs with opposing effects e.g. noradreneline and histamine with BP
35
non-competitive antagonism
doesnt compete for active site but blocks a step in pathway
36
competitive antagonism
1. reversible
can be overcome e.g. atropine in response to Ach
parallel right shift no change in max
2. irreversibe
cannot be reversed by adding more agonist
decreases max response
37
dose response =
conc of agonist with antagonist/conc of agonist
how much more agonist is needed in presence of antagonist
38
what does schild analysis measure
antagonist affinity
39
what are the major body compartments and there %
EC: plasma - 45%, interstitial fluid - 16%, lymph - 1-2%
IC: 30-40%
Trancellular fluid: 2.5%
Fat: 20%
40
where will lipophilic drugs most likely end up
fat as highly lipid soluble
41
BBB?
blood brain barrier
endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules
42
when do the tight junctions become leaky
inflammation - allows entry of e.g. penicillin during meningitis
43
what are the 2 biochemical reactions in drug metabolism
phase 1 catabolic reactions produce more reactive drug
phase 2 synthetic anabolic reactions produce inactive drug through conjugation
44
what organ is the main site of drug metabolism and why
liver
contains microsomal enzymes such as P450, alcohol dehydrogenase and MAO
must be lipid soluble to cross membrane
produgs become activated
metabolism can alter or prolong pharmacological actions of drug
45
routes of drug administration
oral/rectal - gut
precutaneous - skin
intravenous - plasma
intramuscular - muscle
intrathecal - CSF
inhalation - lungs
46
routes of drug excretion
urine - renal - 20% small molecules
faeces - GI - bilebound
expired air - lungs
47
NSAID?
non steroidal anti-inflammatory drug
48
what do they do
decrease production of inflammatory mediators e.g. prostaglandins
bronchoconstriction
promote platelet aggregation
regulate contraction of uterus
decrease sensitivity to pain by inhibiting nociceptors
49
how
PG12 + PGE2 decrease sensation of pain
PGD2 promotes platelet aggregation
50
COX1
ubiquitous
constitutively active - all time
maintains homeostasis
common side effects are cause by this enzyme
51
COX2
only in inflammatory cells
induce transcription
52
COX3
splice varient of COX1
only in CNS
paracetamol favours this one
53
what do NSAIDS do
decrease vasodilation therefore oedema
cannot be used against pre-existive mediators
analgesic -reduce pain
antipyretic - lower temp via IL-1 inducing COX2 production of PGE
54
structure of COX enxyme
2 subunits each with two catalytic sites
55
side effects of NSAIDS
PGs inhibit acid excretion in gut - GI problems
PGs maintain renal blood flow - renal failure
liver damage if take too much as intermediate is hight toxic and can build up
bronchospasm in asthmatics
rashes
56
symptoms of rheumatoid arthritis
swelling joints
pain
stiffness in morning
poor sleep
57
what immunosuppressant drugs can treat RA
cyclosporin
glucocorticoids
they bind to proinflammatory cytokines IL-2
58
what biopharmaceutical can be used
humanised monoclonal antibodies
neutralise proinflammatory cytokines
59
what drugs treat asthma
bronchodilators - salbutamol
60
what phases
early/intermediate
- reversible airway obstruction
inflammation due to increased mast cells
late phase
- cytokines
can develop chronic asthma
61
what cells are overactive in regards to asthma
TH2 cells
62
what increases your susceptibility to asthma`
genetic factors:
IgE production
environmental
allegens
pollutants
63
