MP428 Lectures - Part II

what is thought to trigger RA?

immuno-genetically suceptible host exposed to an arthritogenic microbial antigen

what is TNF-alpha's role in RA

induction of further cytokine production ; activator or expression of adhesion molecules ; growth stimulation

what does TNF-alpha mediate

acute inflammation ; anti-tumour responses ; infection

what are the two forms of TNF-alpha

membrane bound ; soluble

what is TACE

TNF-alpha concerting enyme - converts membrane bound TNF-alpha to soluble via cleavage

what are the two TNF-alpha receptors

TNFR-1 and TNFR-2

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

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

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

what biologics can be used in RA

infliximab ; etanercept ; adalimumab ; golimumab

when are biologics used in RA

in pt wh ohave failed tx with DMARDs

what type of antibody is infliximab

recombinant chimeric antibody

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

how is infliximab administered

by IV infusion withing 4 hours of reconstitution. supervised for 2 hours during infusion and 2 hours after in hospital

what are the most common s/e of infliximab

infusion reactions ; headache ; abdominal pains

what are examples of infusion reactions

itching ; flushing ; nausea

what are short term s/e of infliximab

runny nose ; headahces; dizziness ; flushing ; rash ; stomach pain ; indigestion

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

what class of arthritis is RA

inflammatory seropositive

what are the biggest issues in RA

fatigue, impaired ability, and pain

what can be tested for in RA diagnosis

rheumatoid factor ; anti-cyclic citrullinated peptide antibodies ; serology

why is rheumatoid factor no the best diagnostic tool

can be positive in people with other inflammatory conditions or in those who are healthy

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

what does a positive serology mean

predictor of worse dx, mores erosions, and resistant disease

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)

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

what are the stages of sinovitis examination

LOOK - swelling erthema FEEL - tenderness, warmth, swelling (hard/soft) MOVE - restricted movement, assess function

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

what is the one main draw back of the DAS28 score

does not include feet

what are the score ranges for DAS28

what is RA remision classed as a DAS28 score

what DAS28 score is eligible for biologic therapy

over 5.1

what is the patient resource for RA?

Versus Arthritis

what are the two ways to conjugate a drug to a linear polymer

pendent chain conjugation ; terminal conjugation

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

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

what are the four classes of water soluble polymers

synthertic polymers (non-degradable) synthetic polymres (degradable) natural polymers dendrimirs

what are the two types of linkers

enzymatically labile (peptide) ; pH sensitive (hydrazone)

what are the required characteristic of an enzymatically labile linker

stable in blood but cleaved by lysosomal enzymes to release drug (3rd order targeting)

what are the required characteristics for pH labile linkers

stable in a neutral pH (blood) and degraded in high or low pH (usually acidic)

what are polydispersed systems

chains can be different lengths - most polymer systems are polydisperssed

what are monodispersed systems

all chains will be the same length - aim for polymer systems but very hard to achieve

how can polymers be used to target inflammation

inflammation causes leaky vasculature allowing exploitation of the enhanced permeation and retention (EPR) effect

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

what are polymer-protein conjugates are composed of

several polymers (usually PEG) attached to on protein

what are challenges of protein drugs face (IV/SC administration)

rapid renal excretion ; proteolyti degradation ; immunogenecity ; antigenicity ; aggregation ; solubility ; difficulty formualting

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

what is a negative effect of polymers in polymer-protein conjugates

can reduce interaction with receptor depending upon location of polymer conjugation

what are the best amino acids for conjugation with polymer

tyrosine ; serine ; cysteine ; lysine ; histidine

what type of polymer is the best for protein-polymers

monofunctional as polyfunctional can cause crosslinking with other protein-polymer conjugates

what else can monofunctional polymers be called

semi-telechelic polymer

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

what are the alternatives to PEG

XTEN which is a polypeptide and made at the same time as the protein leading to homogenous product

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

how to implants release drugs

erosion or diffusion (usually both but one will dominate)

what are gliadel wafers

biodegradable wafers containing carmustine, placed in gap where glioma is removed in brain

how is carmustine activated and deactived

by hydrolysis

what kind of effect do gliadel wafers have

local

what is the properties of the polymer in gliadel wafers

hydrophobic and so keeps water out to prevent premature activation

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

what are disadvantages of polymer implants

limited drug loading, need a potent drug ; need a non-immunogneic polymer ; difficult to remove if ADR occur

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

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

what are common sings and symptoms of NS autoimmune diseases

fatigues ; fever ; swelling/pain ; numbness/tingling in extremites ; rash ; muscle pain/weakness

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)

what tx are used in MG and MS etc.

immunosuppressants (steroids, mAbs, disease modifying therapies) ; plasma exchange ; immunoglobulines ; analgesics ; lifestyle (diet, exercise, supplements)

what are the different types of myasthenia

myasthenia gravis ; occular myasthenia ; lambert-eaton myasthenic syndrome

what is myasthenia caused by

acetylecholine receptors are targeted by antibodies leading to interruptions in neurotransmission

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.

what are the symptoms of myasthenia

double vision ; weakness in limbs ; fatigue ; face can also been affected

in which groups of people are most effected by myasthenia

early adult hood ; females

what does myasthenia tx include

oral pyridostigmine ; steroids (prednisolone) ; immunosuppresants (azathioprine, MTX, mycophenolate, ciclosporin) ; plasmapheresis ; IVIG ; thymectomy

what drugs should be avoided in myasthenia

antibiotics ; anti-psychotics ; beta-blockers

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.

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

how is gullian-barre syndrome treated

IVIG ; plasmapheresis to speed up recovery

what monitoring is required for gullian-barre syndrome

FVC to check for resp failure

how is MS diagnosed

usually during mid life - neurological sx history ; MRI of CNS ; LP - Ab in brain ; rule out other possible conditions

what is the tx of relapsing and remiting MS (RRMS)

DMTs (alemtuzumab, ocrelizumab, beta-interferons) ; steriods for acute relapses (methylprednisolone)

what can primary progressive MS (PPMS) treated with

ocrelizumab

what happens in harmful drug-drug interactions?

toxicity or reduced efficacy

what happens in beneficial drug-drug interactions

synergism, increased convenience, reduced toxicity, cost reduction

what is a pharmacokinetic drug-drug interactions

where one drug alters the level of another

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

what are the five areas drug interactions can occur

site of absorption, plasma protein, site of metabolism, site o faction, site of excretion/reabsorption

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

what is an example of adsorption interactions

warfarin, thyroxine, and digoxin are all adsorbed into colestyramine -\> reduced absorption

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

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

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

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

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)

what effect do CYP450 inhibitors have

will keep plasma concentration levels high and can lead to toxic levels due to accumulation

what is a beneficial use of CYP450 inhibitors

carbidopa use along side levodopa

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

how can PK interactions affects distribution

protein binding ; induction/inhibition of drug transporter proteins

how can PK interactions affect metabolism

changes or induction/inhibition in first pass metabolism ; genetic factors

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

what can happen when a CYP inhibitor and substrate in administered together

increased substrate concentration, risk of toxicity

what can happen when a CYP substrate and inducer are administered together

decreased concentration of substrate and a reduction in substrate efficacy