core pharmacology Flashcards
what are the 4 main classes of proteins targeted by drugs
receptor
enzyme
channel
transporter
if you increase drug concentration enough it will have an effect
true drugs are never completely specific
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
what is a pro-drug
a drug that needs to be metabolised in order to produce active form
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
how many phases in drug development
6
what is lead development
find key target of drug
what is preclinical development
safety margin
define max dose/conc
rescue treatments
obtain regulatory approval
exploratory studies
in vitro - mutagenecity testes by Ames test
arrythmia biomarker with hERG potassium ion channel
in vivo - repeat administration for 14 days
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
how many make it past clinical trial
11%
similarities in small molecule and biomolecule trials
1-, 3- ,6- month studies
developmental toxicity studies done
differences
small molecule shorter half life, more toxic metabolites as it can enter cell, can create mutants
occupancy =
No. of receptors occupied/No. of receptors - between 0-1
how do we measure occupancy
radioligand binding assay
what radioactive compound do we use
125I or 3H
stages of assay
tissue prep + ligand - create cell line mix incubate to reach equilibrium filter rinse - non bound ligands measure radioactivity
how can you reduce non specific binding
use anti-absorbant e.g. albumin/collagen
does not reduce non specific tissue binding
what must a radio ligand be
biologically active
pure
not easily degraded
labelled
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
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
main way of separating bound ligand from free
centrifugation
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
how do you calculate specific binding
scatchard plot
is specific binding saturable
yes specific number of receptors
non specific is not
what is the scatchard equation
B/F = (Bmax - B) / Kd
what does the langmuir equation calculate
relationship between occupancy, affinity and drug conc
low Kd ? affinity
high
EC50 calculates
potency
efficacy measures
response
what are the 5 types of antagonism
chemical pharmacokinetic physiological competitive non-competitive
chemical antagonism
substances chemically altered by antagonist
e.g. heavy metals inactivated when adding chelating agent
pharmacokinetic antagonism
- reduction in amount of drug absorbed
- change in drug metabolism e.g. warfarin
- change in excretion of agonist
physiological antagonism
interaction of 2 drugs with opposing effects e.g. noradreneline and histamine with BP
non-competitive antagonism
doesnt compete for active site but blocks a step in pathway
competitive antagonism
- reversible
can be overcome e.g. atropine in response to Ach
parallel right shift no change in max - irreversibe
cannot be reversed by adding more agonist
decreases max response
dose response =
conc of agonist with antagonist/conc of agonist
how much more agonist is needed in presence of antagonist
what does schild analysis measure
antagonist affinity
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%
where will lipophilic drugs most likely end up
fat as highly lipid soluble
BBB?
blood brain barrier
endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules
when do the tight junctions become leaky
inflammation - allows entry of e.g. penicillin during meningitis
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
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
routes of drug administration
oral/rectal - gut precutaneous - skin intravenous - plasma intramuscular - muscle intrathecal - CSF inhalation - lungs
routes of drug excretion
urine - renal - 20% small molecules
faeces - GI - bilebound
expired air - lungs
NSAID?
non steroidal anti-inflammatory drug
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
how
PG12 + PGE2 decrease sensation of pain
PGD2 promotes platelet aggregation
COX1
ubiquitous
constitutively active - all time
maintains homeostasis
common side effects are cause by this enzyme
COX2
only in inflammatory cells
induce transcription
COX3
splice varient of COX1
only in CNS
paracetamol favours this one
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
structure of COX enxyme
2 subunits each with two catalytic sites
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
symptoms of rheumatoid arthritis
swelling joints
pain
stiffness in morning
poor sleep
what immunosuppressant drugs can treat RA
cyclosporin
glucocorticoids
they bind to proinflammatory cytokines IL-2
what biopharmaceutical can be used
humanised monoclonal antibodies
neutralise proinflammatory cytokines
what drugs treat asthma
bronchodilators - salbutamol
what phases
early/intermediate - reversible airway obstruction inflammation due to increased mast cells late phase - cytokines can develop chronic asthma
what cells are overactive in regards to asthma
TH2 cells
what increases your susceptibility to asthma`
genetic factors: IgE production environmental allegens pollutants
new therapies for treating asthma
humanised monoclonal antibodies
PGD2-R antagonists (small molecules)
