MP428 Lectures - Part II

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183 Terms

1
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what is thought to trigger RA?
immuno-genetically suceptible host exposed to an arthritogenic microbial antigen
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what is TNF-alpha's role in RA
induction of further cytokine production ; activator or expression of adhesion molecules ; growth stimulation
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what does TNF-alpha mediate
acute inflammation ; anti-tumour responses ; infection
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what are the two forms of TNF-alpha
membrane bound ; soluble
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what is TACE
TNF-alpha concerting enyme - converts membrane bound TNF-alpha to soluble via cleavage
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what are the two TNF-alpha receptors
TNFR-1 and TNFR-2
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what does TNFR-1 do
inducing cell death through a 'death domain' in the intracellular portion of the receptor. TNF binds and then is internalised where it recruits TRADD which leads to DNA degradation and cell death
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what does TNFR-2 do
incapable of apoptosis as no death domain - acitvation leads to the recruitment of TRAF2 which then activates NFkappaB pathway leading to cytokine production and inhibition of apoptosis
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what are the pro-inflammatory products of TNF-alpha transcription
TNF-alpha ; IL-1beta ; upregulation of adhesion molecules ; cytokines that further enhave immune response ; activators of inflammatory pathways
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what biologics can be used in RA
infliximab ; etanercept ; adalimumab ; golimumab
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when are biologics used in RA
in pt wh ohave failed tx with DMARDs
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what type of antibody is infliximab
recombinant chimeric antibody
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what are the MoAs of infliximab in RA
binding and neutralising solible an dmembrane bound TNF-alpha ; antibody dependant cell mediated cytotoxicity or complement dependent cell mediated cytotoxicity
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how is infliximab administered
by IV infusion withing 4 hours of reconstitution. supervised for 2 hours during infusion and 2 hours after in hospital
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what are the most common s/e of infliximab
infusion reactions ; headache ; abdominal pains
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what are examples of infusion reactions
itching ; flushing ; nausea
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what are short term s/e of infliximab
runny nose ; headahces; dizziness ; flushing ; rash ; stomach pain ; indigestion
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what are the potential anti-TNF-alpha targets
TNF-alpha molecule ; TNF-alpha receptors ; TACE ; molecules in TNF-alpha signalling pathway ; NFkappaB, MAP kinase, SAP kinase pathways
19
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what class of arthritis is RA
inflammatory seropositive
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what are the biggest issues in RA
fatigue, impaired ability, and pain
21
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what can be tested for in RA diagnosis
rheumatoid factor ; anti-cyclic citrullinated peptide antibodies ; serology
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why is rheumatoid factor no the best diagnostic tool
can be positive in people with other inflammatory conditions or in those who are healthy
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what is the benefit of anti-cyclic citrullinated peptide antibodies as a diagnostic tool in RA
just as sensitive but more specific than rheumatoid factor
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what does a positive serology mean
predictor of worse dx, mores erosions, and resistant disease
25
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what history is important to consider when diagnosing RA
number of joints involved ; type o fjoints involved ; involvement of other tissues/organs (skin, nailes, eyes, mouth, genitalia)
26
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what is synovitis charaterised by
pain (worse at rest) ; stiffness (worse inmoring for \>1 hour) swelling (joint feels boggy on palpitation) symptoms are helped with movement and improve with NSAID use
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what are the stages of sinovitis examination
LOOK - swelling erthema FEEL - tenderness, warmth, swelling (hard/soft) MOVE - restricted movement, assess function
28
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what is the DAS28-CRP disease activite score
severity of RA activity using 28 tender jpint count and swollen joint count - pt self-reported healthscore, and recent CRP
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what is the one main draw back of the DAS28 score
does not include feet
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what are the score ranges for DAS28
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what is RA remision classed as a DAS28 score
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what DAS28 score is eligible for biologic therapy
over 5.1
33
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what is the patient resource for RA?
Versus Arthritis
34
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what are the two ways to conjugate a drug to a linear polymer
pendent chain conjugation ; terminal conjugation
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what is the polymer analogues reaction
a leaving group is conjugated to the polymer (reactive polymer precursor) and is subsequently replaced with the drug molecule
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what is polymerisation in polymer drug conjugation
drugs attached to monomers before monomers under go polymerisation with non-drug-conjugated monomers. drug has to be stable during polymerisation process
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what are the four classes of water soluble polymers
synthertic polymers (non-degradable) synthetic polymres (degradable) natural polymers dendrimirs
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what are the two types of linkers
enzymatically labile (peptide) ; pH sensitive (hydrazone)
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what are the required characteristic of an enzymatically labile linker
stable in blood but cleaved by lysosomal enzymes to release drug (3rd order targeting)
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what are the required characteristics for pH labile linkers
stable in a neutral pH (blood) and degraded in high or low pH (usually acidic)
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what are polydispersed systems
chains can be different lengths - most polymer systems are polydisperssed
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what are monodispersed systems
all chains will be the same length - aim for polymer systems but very hard to achieve
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how can polymers be used to target inflammation
inflammation causes leaky vasculature allowing exploitation of the enhanced permeation and retention (EPR) effect
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what are the new developments for polymer drug therapies
combination therapies (multiple drugs conjugated to same polymer) ; drug inserted into polymer chain rather than pendents ; dendrimers
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what are polymer-protein conjugates are composed of
several polymers (usually PEG) attached to on protein
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what are challenges of protein drugs face (IV/SC administration)
rapid renal excretion ; proteolyti degradation ; immunogenecity ; antigenicity ; aggregation ; solubility ; difficulty formualting
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what is the purpose of the polymer chains in the protein-polymer conjugates
protect protein from proteolytic degradation and immunogenicity ; increase hydrodynamic radius reducing renal clearance ; prevent aggregation
48
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what is a negative effect of polymers in polymer-protein conjugates
can reduce interaction with receptor depending upon location of polymer conjugation
49
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what are the best amino acids for conjugation with polymer
tyrosine ; serine ; cysteine ; lysine ; histidine
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what type of polymer is the best for protein-polymers
monofunctional as polyfunctional can cause crosslinking with other protein-polymer conjugates
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what else can monofunctional polymers be called
semi-telechelic polymer
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what happens to non-biodegradable linkers like PEG
exocytose and accumulate in kidneys which can cause toxicity, but only in extremely high concentrations which is not found when used in conjugation
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what are the alternatives to PEG
XTEN which is a polypeptide and made at the same time as the protein leading to homogenous product
54
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what is zero order
when a constant amount of drug is eliminated per unit time but the rate is independent of the concentration - no matter how much is given it will always be released at the same rate
55
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how to implants release drugs
erosion or diffusion (usually both but one will dominate)
56
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what are gliadel wafers
biodegradable wafers containing carmustine, placed in gap where glioma is removed in brain
57
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how is carmustine activated and deactived
by hydrolysis
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what kind of effect do gliadel wafers have
local
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what is the properties of the polymer in gliadel wafers
hydrophobic and so keeps water out to prevent premature activation
60
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what are the advantages of polymer implants
local adminstration (reduced toxicity) ; put in a time of surgery ; tumour debulking prior to other treatment if injected into tumour ; good pt compliance
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what are disadvantages of polymer implants
limited drug loading, need a potent drug ; need a non-immunogneic polymer ; difficult to remove if ADR occur
62
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what are auto-antibodies
mainly IgM, attack self-antigens, in healthy individuals they target dead cells and wast products, in pathology they target specific self-antigens in the body, developing autoimmune diseases
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what are the risk factors of autoimmune disease
women 2x as likely (specifically childbearing) ; ethnicity ; genetic predisposition ; diet (western) ; bacterial/viral infection ; adverse drug reactions ; chemical toxins/environmental pollutants ; prior hx of AuID
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what are common sings and symptoms of NS autoimmune diseases
fatigues ; fever ; swelling/pain ; numbness/tingling in extremites ; rash ; muscle pain/weakness
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what diagnositc tools are used in MS and MG etc
MRI ; lumbar puncture ; antinuclear antibody test ; physical examination/symptoms (walking, eye examination, muscle tests, chest and lungs)
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what tx are used in MG and MS etc.
immunosuppressants (steroids, mAbs, disease modifying therapies) ; plasma exchange ; immunoglobulines ; analgesics ; lifestyle (diet, exercise, supplements)
67
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what are the different types of myasthenia
myasthenia gravis ; occular myasthenia ; lambert-eaton myasthenic syndrome
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what is myasthenia caused by
acetylecholine receptors are targeted by antibodies leading to interruptions in neurotransmission
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what can the interruption of Ach neurotransmission cause
weakness and fatigue in some/all muscles which is worse on exertion and towards the end of the day. it affects voluntary muscle movements.
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what are the symptoms of myasthenia
double vision ; weakness in limbs ; fatigue ; face can also been affected
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in which groups of people are most effected by myasthenia
early adult hood ; females
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what does myasthenia tx include
oral pyridostigmine ; steroids (prednisolone) ; immunosuppresants (azathioprine, MTX, mycophenolate, ciclosporin) ; plasmapheresis ; IVIG ; thymectomy
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what drugs should be avoided in myasthenia
antibiotics ; anti-psychotics ; beta-blockers
74
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what is gullian-barre syndrome
often occurs after (1-3 weeks) an infection. caused by T-cell mediated reaction against peripheral nerve myelin - weakness/numbness and pain in hands, feet, and limbs, as well as breathing and swallowing issues in severe cases.
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how is gullian-barre syndrome diagnosed
nerve tests such as nerve conduction studies, electromyography. lumbar puncture - CSF protein is elevated (usually takes 1-2weeks). exclusion of other diseases
76
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how is gullian-barre syndrome treated
IVIG ; plasmapheresis to speed up recovery
77
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what monitoring is required for gullian-barre syndrome
FVC to check for resp failure
78
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how is MS diagnosed
usually during mid life - neurological sx history ; MRI of CNS ; LP - Ab in brain ; rule out other possible conditions
79
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what is the tx of relapsing and remiting MS (RRMS)
DMTs (alemtuzumab, ocrelizumab, beta-interferons) ; steriods for acute relapses (methylprednisolone)
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what can primary progressive MS (PPMS) treated with
ocrelizumab
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what happens in harmful drug-drug interactions?
toxicity or reduced efficacy
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what happens in beneficial drug-drug interactions
synergism, increased convenience, reduced toxicity, cost reduction
83
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what is a pharmacokinetic drug-drug interactions
where one drug alters the level of another
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what is a pharmacodynamic drug-drug interaction
where there is no change in the drug level but the activity of the drug is altered by another drug
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what are the five areas drug interactions can occur
site of absorption, plasma protein, site of metabolism, site o faction, site of excretion/reabsorption
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what is an example of a chelating interaction
tetracycline will chelate with dairy, iron, and antacids, and so is administered before food and cannot take indigestion remedies 2 hours before or 2 hours after
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what is an example of adsorption interactions
warfarin, thyroxine, and digoxin are all adsorbed into colestyramine -\> reduced absorption
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what is an example of a stomach pH interaction
ketoconazole absorption is pH dependant and best at low pHs - any drug that increases stomach pH will decrease ketoconazole absorption - anti-fungals are weak bases with acidic dissociation constant of ~3 - nearly insoluble at pH\>4
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what is an example of a gut motility interaction
metoclopramide and domperidone increase GI motility meaning that drugs that dissolve and absorb in he stomach had a decreased absorption and those that absorb in the small intestine have an increased absorption opioids and anticholinergics will decrease gastric emptying
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what is an example of plasma protein binding interaction
quinidine binds to proteins, releasing digoxin from being protein bound and increasing free digoxin plasma concentration leading to digoxin toxicity
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why is the plasma protein binding interaction controvesial
do definitive evidence that it has any actual effect on therapeutic activity by itself, it is only seen as an issue where there is issues with drug excretion
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what effect do CYP450 inducers have
can lead to therapeutic failure, toxic metabolites, BUT removal of the inducer may lead to toxic levels (re: warfarin and smoking)
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what effect do CYP450 inhibitors have
will keep plasma concentration levels high and can lead to toxic levels due to accumulation
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what is a beneficial use of CYP450 inhibitors
carbidopa use along side levodopa
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how can PK interactions affect absprtion
pH changes ; chelation and other complexing mechanisms ; changes in GI motility ; induction/inhibition of drug transporter proteins ; malabsorption caused by drugs
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how can PK interactions affects distribution
protein binding ; induction/inhibition of drug transporter proteins
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how can PK interactions affect metabolism
changes or induction/inhibition in first pass metabolism ; genetic factors
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how can PK interactions affect excretion
changes in urine pH ; changes in active renal tubular excretion ;changes in renal blood flow ; biliary excretion and entero hepatic shunt
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what can happen when a CYP inhibitor and substrate in administered together
increased substrate concentration, risk of toxicity
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what can happen when a CYP substrate and inducer are administered together
decreased concentration of substrate and a reduction in substrate efficacy