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PHAR 300 > drug design 2 > Flashcards

drug design 2 Flashcards

1
Q

What is biggest death rates canda

A

Maglignant neoplasms = cancer, biggest issue
2nd = diseases of heart

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2
Q

Describe covid vaccine

A

4 years ago
Covid vaxxine = saved millions of lives
Now = many drugs
Drug development quic since was based on 10 years of research in labs

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3
Q

Describe drug development processes

A

Lead enhancement = discovery, asic rearsch
Safety and metabolism = preclinical
Clinical research = clinical trials

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4
Q

Describe drug devlopement process in Canada

A

Sophisticated
Drug and preclinical studies take 3-6 years

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5
Q

Why clinical trials important

A

In vitro - mice and rats, species differences can be big so mushy test drugs in humans
Huge variability in humans

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6
Q

Describe clinical trials - cost

A

2.6 billion
Huge cost
Up to 4 billion to get drugs on market
36 500 bucks per person = monitored all the time
Cost varies by type fo drug
And main expense = care and monitoring of each patient

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7
Q

What do clinical trials answer

A

Is it safe
Does it work
How does it compare to available drugs

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8
Q

What is first step of clinical trials

A

Must put drug in useable form to do clinical trials

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9
Q

Describe clinical trials = who does it

A

Health Canada
FDA

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10
Q

What are requirements for drug clinical trials

A

Double blind = test against placebo or other drug, must not know if getting which
Randomized = random group of ppl = get same age range, background, compare 2 similar groups

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11
Q

What does health Canada do

A

Health products and food branch
Regulates clinical trials and drug approval
Monitors post marketing surveillance = stage 4
Keep track of it
Advisories, warnings and recalls
Canadaian adverse reaction newsletter
Also monitors stuff sold on web and health food stores

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12
Q

Describe health call warning - health canda

A

Oct 10 2024
Unauthorized sexual enhancement products containing pdes vasodilators may pose serious health risks = not legal in Canada

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13
Q

Describe food recall warning

A

Aug 27 2024
Unauthorized hyaluronic acid dietary supplement contains prescription drugs = dexamethosone, diclofenac, omeprazole

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14
Q

What is phase 1 clinical trails

A

Safety
Pharmacokinetics
Is it safe= give to humans, small doses and monitor ten give more

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15
Q

Describe phase 1 clincial trials detailed

A

20-80 ppl
Paid for it
Up to several months
Assess safety dose and general safety of med/treatment and side effects and pharmacokinetics
70% success rate since has been testes well
If does not pass = usually bc side effects that are unacceptable

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16
Q

Describe phase 2

A

Pppl who have problem drug is for
More pppl = 100-300 pppl
Up to 2 years = lasts longer
Studies of reliability and side effects = see if reliable (see similar effects in wide range ppl),
33% success = hard, since most of them do work as well as what is available - impossible to predict since many mechanisms involved in humans

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17
Q

Describe what drugs compared to in phase 2

A

Placebo = still have effect, ppl respond to being cared for during clincial trials = treated nicely and cared for = will make feel better
Drug has to be better tha placebo

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18
Q

Describe what they document in phase 2

A

Side effects
Some side effects= bad at first then body compensates
Campath treatment

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19
Q

What can we do in phase 2- first time

A

Chance to figure out better idea of range of pharmacokinetics
Response to drugs
Expand pharmacokinetic stdies
Can see outliers too

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20
Q

Describe clincial trials phase 3

A

1000 - 3000 participants, see ranges of responses and hopefully detect rare side effects
1-4 years = sometimes longer
Efficacy of a therapy and monitor its adverse reactions = need to know if drug will be effective after years, will it wear off
25-30% success rate = low, more side effects / not as effective
Looking at how well drug works and side effects, some side effects, many only show up after years = cannot see in phase 2

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21
Q

Describe simple phase 3

A

Pop —> treatment vs control (placebo) and see outcome

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22
Q

Describe complciated phase 3

A

Randomized allocation= control and intervention then
Wash out period and then =switch in same group of ppl and see results

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23
Q

Describe what ppl do sometimes

A

Dedicate whole life to designing and interpreting clincial trials
Clever diesgns = cooperation between units of hospitals over Canada = use this data and anyalzue by computer = can see useful info bc all the variations in cancers
One drug, diff cancers or one cancer diff drugs

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24
Q

Describe diabetes prevention trial

A

Can also test drugs to prevent problem
Intensive lifestyle mod
Drug a
Drug b
Placebo
= test all of these
4000 patients

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25
Q

What has an effect on outcome of phase 3

A

Patient compliance - must monitor that ppl actually take drug
Hospitalization rates lower in ppl who following the regime and took drug all the time = fully adherent

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26
Q

Describe clofibrate

A

Help Prevent cardiovascular catastrophe drug
With >80% compliance = took meds every day and mortality the same for drug and placebo = not effective

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27
Q

Describe simvastatin drug exp

A

Drug to prevent heart failure and heart attacks, drugs much better than placebo but couldn’t see difference for first years
= gradually protects person

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28
Q

Describe ulcer healing exp

A

2 drugs heal ulcers
But down road = ulcer came back more for one of drugs

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29
Q

Describe sedation drugs exp - conclusions

A

Drugs can cause sedation, if sedation wore off= said more pain, if sedation continued = less pain
Side effects can bias patient reaction, both pos and neg
Sedation provides some pain relief, not really analgesic just sedation so react less to pain

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30
Q

What influences drug effect

A

Psychology of use r
Social factors
Need to control pychosocial context

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31
Q

Compare - hidden application vs open application

A

Report of pain relief
Iv vs actual Human
Medication administered by person = friendly, so effect greater when person there, placebo effect added to effect of drug

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32
Q

Describe Behavioral cosdition

A

Condition ppls response

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33
Q

Describe placebo -in Brain

A

Not as intense as effect of drug but simailrties between response in brian

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34
Q

Where can placebo happen

A

Everywhere =
Mood, pain, gi, immune, cvs, respirator

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35
Q

Describe placebo response by age

A

Highest in kids = children v repsonsive to enrviemnt, placebo response greater
As get older = less but still significant

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36
Q

Describe nocebo effects

A

Pl given placebo report side effects = generates feeling of side effects

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37
Q

Describe drug resistance - cancer

A

Many clincial trials focus on cancer
Tumours not homogenous = start as one cancer cell that divides, the more it divides = can accumulate more mutations= sub clones of cancer cells within us our
Tumour —> chemo —> apparent remission with low symptoms —> bit if resistance tumour = cells stilll there nad can lead to patient death since hard to kill

38
Q

Describe resistant tumours

A

Resistant Tumor cells continue uncontrolled growth despite treatment with chemotherapeutic drug
Even a slight increase in tumour cell resistance to anti cancer drugs leads to resistance tumours

39
Q

Describe ex= osteporpsis

A

Should be able to get enough exercise to no get this
Measure bone density as age, if any risk = given meds
3 year study = will one injection/year work=. Yes
Very successful, works, approved
Zoledronic acid

40
Q

Describe denosumab for osteoporosis

A

Lumbar spine
Injections 1-2 times per years
Bone strength increases
Continual inclrease in one strength
Decided it was not fair to keep ppl on placebo bc ppl getting actual drug had little side effects
21.7% increase at 10 years and 16.5% increase at 10 years
Monitor with time, need to treat for life
10 years, not blinded, open label

41
Q

Describe nda review

A

Review by gov
Phase 3
Evaluate data on safety and effigy

42
Q

Approach it review of safety data in nda

A

All info = characterize exposure database
Identify drugs elated adverse events
Estimate risk or rate of those adverse events
Identify risk factors for those adverse events

43
Q

Describe brining drug from lab to clinic

A

Takes 14-17 years and investment up to 4 billon with 95% risk failure
If approved = scale up production and get it onto market
Preclinical = 3-6 years
Clincial = 6-7 years
Scale up to manufacture/regulatory review =0.5-2 years
Post marketing surveillance = idnefine

44
Q

What is major proble for reasons of failure of devloepmt phase

A

Major issue = pathogens is still unclear
Do not understand much

45
Q

Describe trade name

A

Catchy

46
Q

Describe manufacturing requirements

A

Ideally pill bit sometimes need to be Injected

47
Q

Describe manufacturing conditions

A

Based on pharmacokinetics and pharmacodynamics that were worked out during clincial trials
Ideally = oral, soluble, economical, accessible chemistry, stable =

48
Q

Describe health Canada approving drugs

A

New generic and bio similar drugs approved
After patent expires —> patent ensures they get back the money they spent reasearching drug

49
Q

Describe drug delivery systems for 12 hours

A

Effort for strategies of administration
Pills that slowly release content in gi tract

50
Q

Describe quality control

A

Every pill and vial have same dose concentration,everything os perfect and sterile

51
Q

Describe phase.4 clincial trials

A

Thousands of ppl
1+ year
Monitor long term safety and efficacy of a therapy after its approval
70-90% success rate
Some are taken off = discover issue or drug withdrawn since something better comes out
Want to see drug in therapeutic window where see vey few side effects

52
Q

Describe efficacy

A

Identify end points in advance = know what we want
Hypothesis testing
Focus on individual studies

53
Q

Describe safety data

A

Don’t know endpoints in advance - use broad screening and careful observation
Exploration and estimation
Focus on pools of studies
Rare side effective

54
Q

Describe uncommon adverse drug reactions

A

For an adverse drug interact that occurs once in 1000 cases, one would have to study 3000 cases to have a 95% chance of observing event
Neeed to have many ppl to see effect

55
Q

Describe characterization of a new drugs safety profile before maekrtting

A

Most drugs approved by fda with average of 1500 patient exposures
Some drugs have rare toxicity profiles - bromefenac hepatotoxicty in 1 in 20 000 patients
For drugs with rare toxicity, more than 100,000 patients must be exposed to generation a signal - after drug is marketeted

56
Q

What do pharmacists do

A

Keep tack = ask if any any Sid effects

57
Q

Who vulnerable

A

V old and young= kids can get into meds, old ppl = may have risk of interactions, variability = Lowe p450s so metabolize slower = greater chance side effect +
Interactions

58
Q

Describe grapefruit juice problem

A

Affects drug metabolizes enzymes = blocks 3A4
Interactions between drugs and food

59
Q

What is black box warning

A

Need to take certain precautions
Valuable in a limited range of patients
Does it indicate drug is too dangerous just that maximum precaution must be taken

Way of flagging important safety info
Most serious medication warning required by fda
Used when meds can cause serious undesirable effects compared to potential benefit from drug
Indicates needs for extra precautions

60
Q

Describe fda adverse event reporting system

A

Safety warnings have even increasing
Phase 4 v improatnt = somethings only occurs after prolonged time

61
Q

Describe repurposing

A

May be promising for cance therapy = bc now drug is safe and can look at sides effects = can be used for sometime else
Mostly happens in paste 4 sometimes phase.3
Mutleiple advanatges = do not hav to redo lab work bc already done

62
Q

Describe special case -e mergern

A

Fast track
Condense trials
Or for fatal disease = request faster testing

63
Q

Describe orpha drugs

A

Funding and recognition - give ha made special provisions
Not worth time an money
For uncommon disease
Styludies more often now

64
Q

Describe debase targets of new drugs in clincial trials

A

Cns
infectious disease
Oncology

65
Q

2018 Nobel price immunotherapy for cancer

A

Pdl1 ligand interacts with T cell
Cancer = develop ability to inhibit te cell - blocks reocogniotn
Either or both = antibodies block inhibition = interrupt recognizing
Anti pd1, or anti ctla4
Removes brakes on T cells = tumor reocgnziiotn and detach, can kill cancer cells now =
Use antibody to block a built of cancer cell to inhibit T cells = T cell attack cancer
Works well

66
Q

What is pembrolizumab

A

Non small cell lung cancer = used to kill a lot
Most common category
Drug saved 40% of ppl with this therapy = antibodies block

67
Q

What is combinations immunotherapy for melanoma

A

Skin cancer
Combine 3 = antibodies and pd1 blockage = almost everyone survives

68
Q

Describe chronic lymphocytic melanoma

A

Therapy developed by understanding pathoegneiss
Looked at what went wrong = btk = enzyme involved in controlling proliferation of B cells

69
Q

What is ibrutinib

A

Selective inhibitor btk, blocks tangent for particular type of cancer

70
Q

What does imbrutinib do

A

Forms specific bond with cysteine 481 in btk
Highly potent btk inhibit
Orally administers with once daily dosing resulting in 24 hr target inhibition
Not cytotoxic effect on T cells or nk cells
In clll cells promotes apoptosis and inhibits cll cell migration and adhesion
Phase 1/2 data of single agent ibrutinib in 61 relapsed/refractory cll patients demonstrated high frequency durable response

71
Q

Describe btk - drug results

A

Enzyme blocker superior to chemo
Oral administration works better tahan if antibod- do not need it injections, minimal side effects
if detected early = everyone survives

72
Q

Describe summary ibrutinib

A

Administered as a single agent to patients > or equal to 65 years with treatment naive cll = understanding pathogenesis important
Overall survival = better if treated from day 1

73
Q

Describe new era cancer therapy

A

Monocoloncal antibodies
Murine - Momab - mouse
Chimeric - ximab
Humanize = Zumab
Human = umab

74
Q

Describe strategy for cancer tehapry

A

Anti cancer drug linked to monoclonal antibody =
Have antibody target something specific on cancer cell and deliver drug = proper effect it far less side effects than Iv admin

75
Q

Describe radioisotope

A

Onto monoclonal antibody = deliver to cancer cell
Fewer sides effects than a big area of tissue radiated

76
Q

Describe herceptin

A

Antibody against growth factor
Herceptin blocks receptor
Breast cancer cell = has great increase in growth factors
Growth slows = decrease replication rate and will kill tumour cells

77
Q

Describe antibody - drug conjugate

A

Allow rig to be taken into cancer cell and release cytosine agent in cell

78
Q

What does labelling tumour cells do

A

See how prostate cancer spread
Better diagnosis
It radicalize compound on monoclonal antibodies = target prostate cancer cells
Actinium

79
Q

Describe radioliand therapy

A

Target and destroy cancer cell

80
Q

Describe creating cancer vaccines

A

Take blood from patient
In lab = extract tumour cells, antigen linked to a cytokine, tumour cells circulate in blood
Create dendritic cell - matrices and infused back into patient
Triggers = T cell attacks cancer cell

81
Q

Treating migraines

A

3 ways to block CGRP - know to be part of pathognesis of migraines
3 diff antibodies to blocks it
Result of clinical trial = ajovy
All 3 antibodies effective and approved = on market

82
Q

How to treats cvs diseases

A

Ways to limit amount of cholesterol floating in blood
Receptor internalizes and gets rid of cholesterol

83
Q

Can lowing ldl by

A

Pcsk9 inhibitors = more cholesterol, taken up by receptors and then broken down in liver,increase breakdown
Statins - decrease synthesis

84
Q

Treating heart failure

A

Natriuretic and other vasoactove peptides = lower bp and promote sodium excretion
Natural peptides that lower bp
Neprilysin drug
Block metabolism so increase natural peptide
Survival doubled, quality of life improved

85
Q

Is hepatitis c curable

A

Used to kill everyone = now curvale
Sofosbuvir - sovaldi blocks rna rep of hep c

86
Q

Describe improvements - vaccines

A

Better
Against rsv = beyfortus = infant protection against rsv, v good immunization for it, serious in young kids

87
Q

Describe pharmacokinetics challenge - future

A

Avoid injection
Want oral drugs mostly
Targets in cns - need to understand Parkinson’s and Alzheimer’s, major site of challenge

88
Q

Describe future - targets

A

Intracellualr targets for bio pharmaceutical drugs

89
Q

Describe goals of pharmacological research

A

Anti viral drugs
Prevent of cancer and treat
Gene therapy
Proteomics - individual therapy
Prevention of dementia - not just treat
Extend health span and lifespan

90
Q

What else do drugs do = for others

A

If shown to work in humans = tested and often benefits animals= cats, dogs, birds
Many benefits extend to other species

PHAR 300 (22 decks)

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