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BMS242- Physiology and Pharmacology > core pharmacology > Flashcards

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

new therapies for treating asthma

humanised monoclonal antibodies
PGD2-R antagonists (small molecules)