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CD Flashcards

1
Q

Pathways linking lower socioeconomic status to increased risk for infectious illness

A

Increased exposure to infectious agents

  • Greater crowding and family size
  • Poorer sanitation
  • Poorer hygienic practices

Decreased host resistance to infection

  • Less access to immunizing vaccinations
  • Poorer nutrition
  • More smoking (passive and active)
  • More psychological stress
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2
Q

Closing the widening health gap between rich and poor

Key points:

  • Read over
A
  • Increase in infectious diseases by 50%
  • Maori, Pacific Peoples, and low income are twice as likely to be hospitalised
  • Inequalities becoming much larger globally
  • Maori are 10 x more likely to be living in extreme crowding
  • Children spend 90% of time at home
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3
Q

Leading causes of morbidity and morality

A
  • In young people, diarrhoea, lower respiratory infections are leading causes
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4
Q

Paediatric focus

What respiratory infections made the largest contributions to hospitalisations for medical conditions with a social gradient?

A
  • Asthma and wheeze
  • Bronchiolitis
  • Acute respiratory infections
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5
Q

Skin infections

  • read over
  • Health literacy on L2, pg 15
A
  • New Zealand has one of the highest rates for childhood skin infections in the western world
  • Maori children are more than 1.5 times more likely than non-Maori to be hospitalised due to skin infections
  • In many cases hospitalisation means intravenous antibiotics and even surgery
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6
Q

What can a pharmacist do?

  • read over
A
  • Health literacy skills are essential - learn as much as you can in skills
  • Know what funding is available in your community - 20 Rx subsidy scheme
  • If people dont pick up their antibiotics, follow up and find out why. Be ready to help with solutions (delivery, easy payments, Rx subsidy)
  • Have written information for whanau/parents/caregivers
  • Education on what to do if this happens again and prevention advice
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7
Q

Social determinants of health

A
  • Household crowding
  • Material hardship
  • Education
  • ## Transport
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8
Q

What is being done?

A

Policy - housing

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9
Q

Research from housing, insulation and health study

  • read over
A
  • Cluster randomised trial of insulating houses in low income areas
  • 1350 uninsulated houses with at least on inhabitant with respiratory symptoms in last year
  • Baseline measures, half houses insulated, follow-up, other half of houses insulated at and of trial
RESULTS
In intervention group
- Self-reported health improved
- Halved odds of respiratory symptoms
- Children had fewer days off school
- Fewer hospitalisations for respiratory conditions
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10
Q

Rheumatic fever

  • read over
A
  • Government investment $12 million
  • School based throat swabbing
  • Drop in clinics in Auckland
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11
Q

Characteristics of bacteria

  • read over
  • Draw a prokaryote and eukaryote on L4, pg 5
A

They are prokaryotes

  • No nucleus, ds DNA genome in cytoplasm
  • No cellular organelles such as mitochondria & endoplasmic reticulum
  • Cell wall
  • +/- capsules, spore forming
  • Unicellular
  • Extra-chromosomal DNA (plasmids)
  • Reproduce by binary fission, logarithmic growth
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12
Q

Characteristics of bacteria that are selective drug targets

1

A

Folic acid synthesis

  • Used in making DNA & proteins
  • We get folic acid from our diet
  • Bacteria make their own dihydrofolate (DH) - selective drug target for sulfonamides
  • Trimethoprim is a dihydrofolate reductase (DHFR) inhibitor, higher affinity for the bacterial enzyme
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13
Q

Characteristics of bacteria that are selective drug targets

2

A

Bacterial cell wall

  • Our cells dont have a wall just a membrane
  • Major component is peptidoglycan, synthesis of peptidoglycan is a major drug target (B-lactams, glycopeptides)
  • Mycobacterium sp - mycolic acid (isoniazid) & arabinogalactan (ethambutol)
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14
Q

Bacterial cell wall

  • read over
A
  • Gram negative cell walls have an outer membrane (OM)
  • Barrier to some antimicrobials
  • It is a lipid membrane - not phospholipids like the cell membrane
  • It is formed from glycolipids, mainly lipopolysaccharide (sugar lipid) & proteins (OMP)
  • Some OMP act as pores (porins)
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15
Q

Characteristics of bacteria that are selective drug targets

3

A

Cytoplasmic membrane

  • Prokaryotic membranes do not contain sterol and in gram negatives the membrane is associated with LPS (polymixins)
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16
Q

Characteristics of bacteria that are selective drug targets

4

A

Protein synthesis

  • Process same in pro- & eukaryotes, but there are some differences in the ribosome subunits
  • eukaryotes - 40S and 60S
  • Prokaryotes - 30S & 50S
  • Aminoglycosides (eg Stp), tetracyclines, macrolides (eg Ery), oxazolidinone (eg Lnz), chloramphenicol (Cam)
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17
Q

Characteristics of bacteria that are selective drug targets

5

A

replication as a target for anti-bacterial drugs

  • Differences in some enzymes
  • DNA gyrase (quinolones)
  • RNA polymerase (rifampicin)
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18
Q

Characteristics of fungi

A
  • They are eukaryotes
  • Bigger than bacteria
  • Have a nucleus & cellular organelles such as mitochondria & endoplasmic reticulum
  • Unicellular - yeast eg candida or multicellular - micro-fungi (moulds) or macro-fungi (mushrooms)
  • Mitotic division (division time 20 hours cf 20 min)
  • Have a cell wall
  • No extra-chromosomal DNA
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19
Q

Drug targets - cell membrane

A
  • Cell membrane contains ergosterol rather than cholesterol
  • Inhibit sterol synthesis (azoles and allyamines) or…
  • Selectively bind to egosterol and influence cell membrane permeability (polyene anti-fungals eg amphotericin B)
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20
Q

Drug targets - cell wall

A
  • Complex network of proteins and carbohydrates
  • Glucan & chitin provide strength
  • Glucan synthesis inhibitors (echinocandins)
  • Chitin synthase inhibitors (nikkomycin and polyoxins)
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21
Q

Microbial infection - exposure

A

Normal microflora

  • Mostly protective
  • Can/may cause disease
    • Translocate to sterile area eg via a wound

Depends on:

  • Host factors
  • Microbial factors
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22
Q

Host factors

  • read over
A
  • age
  • pregnancy
  • gender
  • illness

etc

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23
Q

Pathogenesis of infection

A

L4, pg 19

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24
Q

Microbial infection & disease

  • read over
  • wee diagram on L4, pg 20
A

The outcome of infection (disease vs health) depends on interplay b/w

  • Microbial factors
  • Host factors
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25
Q

Microbial infection & Disease

  • graph on L4, pg 21
A
  • Damage to cells/tissue from infection results in signs & symptoms of disease which reflect the type of damage and can be useful diagnostically
  • Antimicrobials used when immune response can not control infects
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26
Q

Fever from infection

A
  • A response to LPS (endotoxin) also known as an ‘exogenous pyrogen’
  • Stimulates the immune system to release soluble mediators (pyrogenic mediators, endogenous pyrogens)
  • Causes fever
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27
Q

Fever - the good & the bad

  • read over
A
  • Evolutionary response to enhance immune function
  • An increase in temp of 1-4 *C is associated with improved survival and resolution of infection
  • Use of anti-pyretic drugs associated with a 5% increase in influenza morality
  • BUT in extreme cases of infection (sepsis) is associated with worse outcome
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28
Q

Fever - the good & the bad

A
  • Table on L4, pg 25
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29
Q

Fever - the good & the bad

  • read over
A

Usefulness in diagnosis?

  • Young children have 3-6 fevers/year, makes parents anxious, most common reason for presenting to GP/ED
  • Most cases is self limiting, 5-10% serious bacterial illness
  • Highest predictor of serious bacterial infection
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30
Q

What is an antibiotic and is it the same as an anti-bacterial?

A

Antibiotic
- Is a substance produced by a microorganism which inhibits the growth of other microorganisms

Antibacterial
- Substance (biological or chemical) that inhibits the growth of bacteria

Antimicrobial
- Substance (biological or chemical) that inhibits the growth of microbes

  • Can be either bacteriostatic or bactericidal
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31
Q

Go through L4 and answer these questions

A
  • Describe briefly x selective drug targets in bacteria/fungi
  • Describe the pathogenesis of fever
  • Define bactericidal/bacteriostatic antibiotic/antibacterial
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32
Q

Antimicrobials vs other drugs

read over first, write the second

A
  • Antimicrobials are DIFFERENT to other medicines as they dont just affect the patient receiving treatment. They also affect:
  • The patients immediate community
  • Global community

Goals of antimicrobial therapy:

  • Cure a diagnosed infection (individual)
  • Minimise adverse events (individual)
  • Minimise adverse events (society)
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33
Q

Is the patient infected?

  • read over
A
  1. Obtain a thorough history of the patients symptoms and presentation
    - Feeling hot/cold
    - Swelling, heat, or erythema
    - Purulent discharge
    - Sputum production (change in amount/colour/SOB)
    - Diarrhoea or vomiting
    - Confusion
    - Duration of symptoms
    - What has helped so far?
  2. Are there tests (signs) which may indicate an infective process?
    - Fever (>38*C)
    - inc. HR, RR
    - Inc white cell count (WCC)
    - Inc. CRP
    - Inc. ESR
    - X-rays
    - Cultures (eg urine, stool, spatum)
    - Gram stain
  • Need to build a clinical picture
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34
Q

Consider risk factors for infection

  • read over
A
  • recent surgery/procedures?
  • Immunosuppressed? (medication, HIV)
  • Co-morbidities? (eg diabetes)
  • recent exposure to infected individuals or sources of infection? (eg contact tracing in COVID-19 pandemic)
  • Vaccination status?
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35
Q

Consider the probable source

read over

A

Endogenous infections: from human microflora

  • E.coli UTI
  • Staph aureus skin infections (eg infected IV lines)
  • more common in immune-compromised

Exogenous infections: person-person, animal-person, point-of-source, vector-born

  • Cholera (point of source)
  • COVID-19 (person to person)
  • worms, head lice, scabies (parasites and helminths)
  • Lyme disease, malarie (vector born)
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36
Q

Practice example on L5, pg 16

A

rfyu

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37
Q

Empiric Therapy: Bug, Drug, Patient

A
  1. Infection factors (bug)
    - Likely organism
    - Severity of infection: Systemic? Localised?
  2. Antimicrobial factors (Drug)
    - Spectrum of activity (broad vs narrow)
    - PK/PD: Distribution, Half life
    - Toxicity and ADR profile (risk/benefit)
    - Local sensitivities
    - Formulations available
    - Funding considerations
  3. Patient factors
    - Allergy status
    - Age - neonates, elderly
    - renal function
    - Hepatic function
    - Co-morbidities (including immunosuppression)
    - Pregnancy/Breastfeeding
    - Previous antimicrobial exposure
    - drug interactions
    - Clinical setting: inpatient/outpatient
    - Site of infection: eg: CNS infection vs eye infection
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38
Q

De-escalate therapy

A

What?
- Narrowing the antimicrobial spectrum (target)

Why?
- Aim of de-escalation is to reduce the risk of antimicrobial resistance (AMR) and improves efficacy by selecting therapy that targets specific infective organisms

When?

  • Once cultures and sensitivities are back
  • Patient is clinically improving (IF NOT, aim for broader coverage)
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39
Q

Monitor Progess

  • read over
A

Essential to monitor clinical improvement (patient)

  • Symptoms (local and systemic)
  • Observations (HR, RR etc)
  • Physical exam (chest sounds, abdo exam)
  • Bloods (CRR, WCC)
  • Imaging (CXR)
  • Possible new -onset ADRs (drug safety)

Therapeutic Drug Monitoring (drug)

  • Serum levels
  • MIC -> time dependent killing
  • Cmax -> Conc dependent killing
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40
Q

Action

  • read over
A
  • Review antimicrobial choice, sensitivity
  • Review antimicrobial dose, route and interactions
  • Review antimicrobial duration
  • Consult AMS team (see L13)

If non-compliance apparent, why?

  • Intolerance
  • Complexity of medication regime
    • Dose frequency
    • Pill burden
    • Special instructions
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41
Q

Summary of process

A

L5, pg 26-32

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42
Q

How does resistance develop?

Why does acquired resistance develop so quickly?

  • read over
A
  • Bacteria can be innately resistant to an antimicrobial or resistance can develop (be acquired) due to a genetic mutation
  • Due to unique properties of bacterial replication
  • Reproduce quickly - vertical transmission of mutations that provide a survival advantage eg AMR
  • Extra-chromosomal DNA (plasmids) facilitates spread of AMR horizontally, within and b/w bacterial species (conjugtaion, transformation, transduction)
  • Many types of resistance. can & will develop
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43
Q

Plasmids & AMR

  • Read over
A
  • 1959 it was found that AMR was being readily transferred from one bacteria to another
  • Found the genes conferring resistance could be carried on plasmids
  • A sing plasmid may contain > 1 resistance genes
  • Can transfer across species
  • Metabolic burden to the bacteria, should be lost when selective pressure is removed

… but not always

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44
Q

Innate/Intrinsic Resistance

A

Innate/intrinsic resistance is due to an inherent feature of the bacteria, for example

  • Drug target is not present
  • Drug cant cross the OM of a gram negative cell
  • Or the bacteria may naturally have efflux pumps which remove the drug
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45
Q

Acquired Resistance: 1) drug accumulation

A 
1. Dec. entry (influx)
Aquire mutations that:
- Reduce the number of pores
- Change the type of pore
- Impair pore function
  1. Inc. exit (efflux)
    - Genes for efflux pumps can be encoded on plasmids and cause acquired AMRs as bacteria gain new efflux pumps
    - Mutations can also inc. expression of pumps
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46
Q

Acquired resistance: 1) the target

A
  • Replace the target - via gene transfer with one that has low affinity for the drug
  • Modification of the target - via mutation of the binding site while retaining function
  • Protection of the target - dislodge drug or compete with drug for target
  • Overproduce the target - via mutation to retain function
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47
Q

Acquired Resistance: 1) the drug

A

Acquire an enzyme that:

  • Inactivates/breaks down the drug
    • Many enzymes identified, chromosome and plasmid encoded
    • eg B-lactamases, carbapenemases
    • Transfers quickly
  • Changes/modifies the drug
    • Modifies the drug through addition of acyl, phosphate, nucleotidyl and ribitoyl groups
    • Can no longer interact with target
    • Large antibiotics (aminoglycosides) more susceptible
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48
Q

Resistance

  • read over
A
  • Resistance is slower to develop to drugs with multiple mechanisms of action

Can we give more drug???

  • With some types of resistance increasing the conc. of drug can be effective
  • eg overproduction of target, dec. influx, inc. efflux, enzymatic modifications or degradation of drug
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49
Q

What social factors impacts on development of drug resistance

  • read over
A
  • Misuse/Overuse of antibiotics
  • OTC supply of antibiotics
  • Incorrect prescribing (viral infections)
  • Empirical use of antibiotics
  • Prophylactic use
  • Inc. use of broad spectrum antibiotics
  • use of antibiotics in animal feeds
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50
Q

What causes drug resistance to develop?

  • In NZ
A
  • Antibiotic use in animals
  • Maybe read over
  • L6, pg 15
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51
Q

Not taking the entire course of antibiotics

  • read over
A
  • Common misconception - has no impact on resistance
  • May impact on disease control
  • Dose & courses are more associated with resistance (more likely to get missed doses and sub therapeutic levels)
  • New guidelines are emerging for shorter courses, based on cure rates
  • Symptom resolution is a good indicator for mild/moderate infections (in a person with a good immune system)
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52
Q

What causes drug resistance to develop?

  • read over
A
  • Misuse/Overuse of antibiotics - 50% inc. from 2006-2014 driven by increased use of penicillins, particularly amoxicillin
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53
Q

Antimicrobial resistance: New Zealands current situation and identified areas for action

  • read over
A
  • How fast resistance develops can be regulated by cautions use of antibiotics in appropriate situations = Antimicrobial stewardship
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54
Q

How bad is it?

read over

A

L6, pg 20 & 21

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55
Q

Drug resistance & fungi

A

Do fungi become multi drug resistant (MDR)?
- Yes - but is not such a big problem as with bacteria

why not?

  1. Bacterial replication rate is much faster
  2. Bacteria can transfer resistance on plasmids
  3. Bacterial replication has more mutations
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56
Q

Study questions

  • go over L6 to answer
A
  • Difference between innate and acquired resistance
  • Examples of mechanisms of each
  • Biological (replication rate, gene transfer etc) and social reasons that microbes acquire resistance
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57
Q

How are antibiotic drugs classified?

  1. By their effect on bacteria
A

Bacteriostatic agents

  • Inhibit bacterial growth and replication
  • Host immune system completes elimination
  • Care! immunocomprimised patients

Bactericidal agents

  • Kill bacteria
  • Need to be present at adequate concentration
  • Some more effective when cells are dividing
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58
Q

How are antibiotic drugs classified?

  1. By their spectrum of activity
    - diagram on L7, pg 6
A
  • Some antibiotics cant penetrate this more complex cell wall
  • Less active against Gram - than gram +

Narrow spectrum: Limited to specific microbe families

Broad spectrum: Extensive, affects Gram +/Gram +

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59
Q

How are antibiotic drugs classified?

  1. Mechanism of action
    - Lil diagram on L7, pg 7
A

Class I

  • Host and organism similar
  • Bacteria can use alternate energy sources

Class II
Unique pathways of differing sensitivities
- Synthesis of essential growth factors
- Eg folate synthesis

Class III
Assembly of macromolecules
- DNA, RNA, Proteins
- Peptidoglycans (Lecture CD9)

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60
Q

A note on unwanted effects of antibiotics

TYPE A

  • read over
A
  • Dose-dependent, predictable based on pharmacology
    Most common are
  1. Gastrointestinal toxicity
    - Affect ‘good’ bacteria as well as ‘bad’
    - change to microbiota/flora
    - Nausea, pain, vomiting, diarrhoea
  2. Nephrotoxicity
    - With antibiotics metabolised/excreted by kidney
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61
Q

A note on unwanted effects of antibiotics

TYPE B

  • read over
A
  • Idiosyncratic reactions
  • Cant be predicted by pharmacology
  • Rare
  • Dont occur in most patients at any dose
  • Can affect any organ system, but usually
    • Skin
    • Liver
    • Blood cells
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62
Q

Drugs interfering with the synthesis or action of folate

  1. Sulphonamides (e.g. causes nausea, vomiting, headaches)
  2. Trimethoprim (anaemia, nausea, vomiting, blood disorders, rashes)
  • diagram on L7, pg 14
  • read over
A

What is folate required for?
- DNA/RNA synthesis (bacteria and mammalian cells)

Source

  • Humans: folate from diet
  • Bacteria: de nova
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63
Q

Sulphonamides

  • diagram on L7, pg 15
A

eg sulfadiazine

  • Structurally similar to PABA
  • Competes for key enzyme in folate synthesis
  • BacterioSTATIC (Gram +/-)

Pharmacokinetics

  • Well absorbed orally
  • Metabolised in liver (acetylation), genetic polymorphisms
  • Products have no antibacterial action (but risk of toxicity)
  • Exreted by kidney (t1/2 = 12h)
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64
Q

Sulphonamides Unwanted effects

Clinical Use

  • Limited by resistance
  • Inflammatory bowel disease (sulphasalazine)
  • For infected burns (topical:silver sulfadiazine)
A
  • Nausea, vomiting, headache

Serious adverse effects (stop therapy)

  • Hepatitis
  • Bone marrow suppression
  • Hypersensitivity reactions (eg rash, fever, anaphylaxis)
  • Stevens-Johnson Syndrome (toxic epidermal necrolysis)
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65
Q

Trimethoprim

  • diagram on L7, pg 17
A
  • Inhibits dihydrofolate reductase
  • Synergistically prevent folate synthesis
  • BacterioSTATIC (Gram +/-)
  • Synergism with sulphamethoxazole (co-trimoxazole)

Pharmacokinetics

  • Given orally
  • Fully absorbed from GI tract
  • High conc. in lung, kidney, CSF
  • Weak base, eliminated by kidney (t1/2 = 24)
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66
Q

Trimethoprim unwanted effects

  • Folte deficiency -> megaloblastic anaemia (long term use)
  • Nausea, vomiting
  • Blood disorders
  • Rashes
A

Clinical Use

Alone
- Urinary tract infections

As co-trimoxazole
- Toxoplasmosis (protozoal)

Nocardiosis (bacterial)

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67
Q

Quinolones (fluoroquinolones)

A

eg ciprofloxacin, moxifloxacin

  • Inhibits DNA gyrase (gram -ve-
  • Inhibits topoisomerase IV (Gram +ve)
  • BacteriCIDAL (broad spectrum)

Pharmacokinetics

  • Well absorbed orally
  • Accumulate in kidney, prostate, lung
  • Dont cross BBB (except oflocacin
  • Excreted predominantly by the kidney (dosage adjusted in renal failure
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68
Q

Quinolones (fluoroquinolones)

Unwanted effects

  • Infrequent, usually mild, reversible

Most frequent

  • GI (ciprofloxacin, c.difficile colitis)
  • Skin rashes
  • Tendon rupture (elderly + corticosteroids)
  • Arthropathy (young patients)

CNS symptoms
(headache, dizziness)

A

Clinical use

  • Travellers diarrhoea (moderate/severe)
  • Gonorrhoea
  • Prostatitis, bone and joint infections (if no alternative)
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69
Q

Important interactions for quinolines

A
  • maybe read over L7, pg 23
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70
Q
  1. Tetracyclines
A

eg doxycycline, minocycline

  • Bind to 30S, inhibit binding of aa-tRNA
  • BacterioSTATIC (Broad spectrum)

Pharmacokinetics

  • Given orally, parenterally
  • Absorption irregular, incomplete -> give on empty stomach
  • Dairy, antacids, Fe supplements (decrease absorption)
  • Doxycycline excreted unchanged (bile and urine),
  • Minocycline (hepatic metabolism)
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71
Q

Tetracyclines Unwanted effects

  • GI disturbances
  • Ca2+ chelation
  • > deposited in bones and teeth
  • avoid in children & pregnancy
  • Photosensitivity
  • Hepatotoxicity (renal failure, parenteral)
A

Clinical use

  • Declined due to resistance, but staging a comeback
  • Respiratory infections (chronic bronchitis, Cap)
  • Acne
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72
Q

Aminoglycosides

A

Eg gentamycin, tobramycin

  • Irreversible inhibition of 30S subunit
  • Misreading of codons on mRNA -> improper protein expression
  • BacteriCIDAL (some gram +, many Gram -)

Pharmacokinetics

  • Iv or I.m administration (not absorbed from GI tract)
  • Cross placenta but not BBB
  • Elimination entirely via glomerular filtration in kidney
  • Renal failure -> accumulation
  • Monitoring [serum] can prevent toxicity
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73
Q

Aminoglycosides Unwanted effects

In general, little allergenic potential

  • Ototoxicity (cochlea, vestibular)
  • Nephrotoxicity (tubule damage)

Most common in elderly, renal impairment

rare but serious
- Paralysis from neuromuscular blockade

A

Clinical use

  • Hospital only serious infections
  • Pneumonia
  • Meningitis
  • Synergism with penicillins (CD9)
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74
Q

Macrolides

A

eg erythromycin, clarithromycin, azithromycin, roxithromycin

  • reversible binding to 50s ribosomal subunit
  • Dissociation of tRNA -> interferes with bacterial protein synthesis
  • BacterioSTATIC (most active against Gram +)

Pharmacokinetics

  • Administered orally or parenterally
  • t1/2 short (azithromycin longer >12h)
  • Hepatic metabolism
  • CYP1A2, 3A4 –> affect bioavailability of other drugs
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75
Q

Macrolides Unwanted effects

  • GI effects (erythromycin >others)
  • Cardia toxicity
    • Arrhythmias
    • QT prolongation
  • Hepatotoxicity
A

Clinical use

  • respiratory infections (pertussis, legionella)
  • Chlamydia
  • Mycoplasma infections
  • Skin infections
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76
Q

Summary on L7, pg 33

A

lkjh

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77
Q

People/person/patient-centred care

  • read over
A
  • People/person/patient-centred care can be defined as “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions
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78
Q

jjhgvfcdxfghbjknbhgvf

A

sdfghjklkjhgfdsgbhnkjbhgvf

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79
Q

What does People/person/patient-centred care mean

  • read over
A
  • Listening to what matters to patients
  • Sharing decision-making (not ‘pharmacist knows best’)
  • Active (not passive) patients
  • Person with a condition, not a condition in a patient
  • Engaging and sharing in real conversation rather than telling people what to do
  • Attempting to understand peoples lives/context
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80
Q

Why peoples perspectives, practices and experiences are important

  • read over
A
  • biomedical account focuses on symptoms, biological aspects of illness BUT
  • Also important for pharmacists to understand peoples ideas, behaviour, feelings, experiences associated with illness AND
  • includes medicines - main treatment for many illnesses
  • For medicines to work people have to take them
  • Many factors influence medicine-taking
    • Barriers and enablers
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81
Q

Medicines and long-term conditions: scale of the problem

  • read over
A
  • Poor adherence to treatment of chronic diseases is a worldwide problem of striking magnitude. Adherence to long-term therapy for chronic illnesses in developed countries averages 50%. in developing countries, the rates are even lower. It is undeniable that many patients experience difficulty in following treatment recommendations
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82
Q

Help-seeking behaviour

  • read over
A
  • People evaluate physical and emotional sensations on basis of
    • Previous health-related experiences
    • Social environment (learnt responses to symptoms)
  • Evaluate meaning and seriousness of bodily experiences
  • Variety of possible and competing explanations
  • Most symptoms do not result in consultation with a health professional; self-care very common response
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83
Q

how do people DECIDE whether to seek help?

  • read over
A
  • Evaluate what would happen if treatment sought or not
  • triggers to consultation
    • Perceived interference with normal life activities
    • Perceived interference with social or personal relationships
    • risk to others
    • Symptom persisting
    • Pressure from family or friends
  • Experience of health care (decisions made/advice, medicines given)
  • Cost barriers (eg money, time)
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84
Q

Biographical disruption

  • read over
A
  • Loss of previously taken for granted continuity, need to
    • Make sense of bewildering symptoms
    • Reconstruct order
    • Maintain control over life
  • Normalising illness: finding ways to minimise impact of illness, disability, regimen on daily life
  • Constructing illness narrative, making sense of experience
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85
Q

Burden of care/ Treatment burden

  • read over
A
  • Symptoms impact on people, but care can add burden (care by the person or by others). Burden of care is a concept that describes the physical, emotional, social, and financial problems that can be experienced
  • The WORK of being a patient: medication management, self-monitoring, visits to the doctor and other healthcare professionals, tests, lifestyle changes, paperwork

Note: The SICK ROLE (Talcott Parsons 1951)

  • People have to want to get better
  • And comply with treatment
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86
Q

Stigma

  • read over
A
  • Is a negative attitude on prejudice and misinformation triggered by a marker of illness
  • Often described as the main barrier to receiving effective mental healthcare, but people also feel this with other health problems
  • Adverse effects of stigma well documented and well known - lead to delays in help -seeking, lowered self-esteem, social withdrawal, poor self-care and substance abuse
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87
Q

Patient’s Lived Experience with Medicines (PLEM)

  • read over
A

Three inter-related themes contribute:

  • Medication related burden - nature of the medicine, routine, adverse effects, healthcare, social
  • beliefs about medicines - family/friends and health professionals, ability to cope, general attitudes
  • Medicine-taking practice - accepting medicine, following therapy instructions, modifying
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88
Q

Patient’s Lived Experience with Medicines (PLEM)

  • these lead to
  • read over
A
  • Patients undergoing a continuing process of reinterpretation of their experience with medicines during their treatment journey
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89
Q

Peptidoglycan biosynthesis

L9, pg 9

A
  1. Cytoplasm: Synthesis of murein monomers
  2. Membrane: Export to inner membrane linked to transport lipids, flipped externally
  3. Incorporated into peptidoglycan polymer Crosslinking of glycan strands (transpeptidase)
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90
Q

Drugs affecting the bacterial cell wall - B Lactams

  • useful, most frequently prescribed common B lactam ring
  • Different structure –> spectrum of activity
  • Kill susceptible bacteria (MoA incomplete)
A
  1. Inhibit peptidoglycan transpeptidase (no cross linking)
  2. Target penicillin-binding proteins (PBPs)

L9, pg 10

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91
Q

Factors influencing activity of B lactams

More description of each on L9, pg 11

A
  1. Resistance (L CD6)
  2. Enzymatic destruction
  3. Biofilms
  4. Density and age of infection
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92
Q

B lactamase inhibitors

Have a look at L9, pg 12 (idk if need to know this slide)

A

Clavulanic acid

  • Poor intrinsic antimicrobial activity “suicide” inhibitor Irreversibly binds to B lactamases
  • Good oral absorption, also parenteral combined with amoxicillin (Augmentin)

Sulbactam
Similar structure to culvulanic acid

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93
Q

Penicillins

eg ampicillin, amoxicillin, flucloxacillin

  • Frequently administrated with B lactamase inhibitor (clavulanic acid, sulbactam)
  • Extended antimicrobial activity for Gram -
  • BacteriCIDAL
A

Pharmacokinetics

  • Oral use (amoxicillin absorption > ampicillin)
  • [therapeutic] in joint, pleural (lung), pericardial (around the heart) fluid and bile
  • t1/2 short (30-60mins)
  • Rapid elimination (GF and tubular secretion)
  • High [drug] urine
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94
Q

Penicillins unwanted effects

  • Act synerg
  • Normally well tolerated, High TI*
  • Hypersensitivity (1-10%)
    • Hapten carrier conjugates promote immune response
    • Anaphylaxis, itching, rash
  • GI (change to gut flora)
    • Diarrhoea
A

Clinical use

  • Upper respiratory tract infections (URTIs)
  • Urinary tract infections (UTIs)
  • Meningitis
  • Salmonella infections
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95
Q

Cephalosporins

Eg cephalexin (1st gen), cefaclor (2nd gen), Ceftriaxone (3rd gen), cefepime (4th gen)

  • Similar MoA to penicillins
  • More resistant to B lactamase
  • Generations: inc. activity for Gram -, Inc. BBB penetration, longer t1/2 (ceftriaxone >8h)
A

Pharmacokinetics
- Readily absorbed after oral administration (except ceftriaxone, i.v. or i.m.)

  • Renal excretion, so dose adjust in patients with renal insufficiency
  • Ceftriaxone sufficient CNS penetration for meningitis Tx
  • [high] synovial, pericardia fluid
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96
Q

Cephalosporins Unwanted effects

Hypersensitivity

  • Similar to that caused by penicillins
  • Anaphylaxis, bronchospasm, urticardial (immediate)
  • Maculopapular rash (delayed)
  • Cross reactivity with penicillins
A

Clinical Use

  • Skin, soft tissue infections (1st gen)
  • Pneumonia, resistant/pregnancy UTIs (2nd gen)
  • Gonorrhoea, meningitis, CAP (3rd gen)
  • Hospital acquired (nosocomial) infections (4th gen)
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97
Q

Carbapenems

Eg imipenem, meropenem, ertapenem

  • Similar mechanism to penicillins
  • Very resitant to B lactamases
  • Broader spectrum than other B lactams
A

Pharmacokinetics

  • Imipenem not orally absorbed
  • Renal excretion, short t1/2 (except ertapenem, once daily dosing)
  • Imipenem: rapid hydrolysis, partial inactivation (kidey) given with cilastatin (dihydropeptidase inhibitor)
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98
Q

Carbapenems unwanted effects

  • Similar to other B lactams
  • Nausea and vomiting
  • Neurotoxicity, seizures (high doses, renal failure, CNS injury/disease)
A

Clinical use

Severe hospital acquired infections (not MRSA)

  • Septicaemia
  • Hospital-acquired pneumonia
  • Intra-abdominal infections
  • Complicated UTIs
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99
Q

Monobactams (monocyclic B lactam)

eg azreonam

  • Interacts with PBPs and causes formation of long filamentous bacteria
  • Resistant to many B lactamases
  • Antimicrobial activity more like aminoglycosides
  • Limited spectrum ONLY gram -
A

Pharmacokinetics

  • i.v or i.m administration
  • Renal excretion (drug unaltered), short t1/2
  • Dose reduction in renal insufficiency
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100
Q

Monobactams (monocyclic B lactam) Unwated effects

  • Generally well tolerated
  • Similar to other B lactams
  • Little cross reactivity with penicillins
  • (Except ceftazidime, structurally similar)
A

Clinical Use

  • gram-negative infections
  • Pseudomonas aeruginosa
  • Haemophilus influenza
  • Neisseria meningitidis
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101
Q

Glycopeptides

eg vancomycin, teicoplanin, daptomycin

  • Prevent addition of murein monomers to peptide chain
  • Bactericidal
  • Active against gram +ve infections (MRSA)
A

Pharmacokinetics

  • poor oral absorption –> i.v. infusion, t1/2 = 8h, i.m (teicoplanin)
  • Excreted renally
  • Dose adjusment in renal impairment
  • [drug]plasma monitoring (vancomycin) -> minimise toxicity
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102
Q

Glycopeptides unwanted effects

  • Nephtrotoxicity (worse + aminoglycoside)
  • Hypersensitivity, rashes, SJS/TEN
  • “Red man syndrome” (rapid i.v injection, histamine release)
A

Clinical Use

  • Serious Gram + infection
    • MRSA
    • Bacterial endocarditis
  • C difficile colitis (oral)*
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103
Q

Post antibiotic effect

Suppression of bacterial growth that persists after a brief exposure to antibiotics

  • Related to the kill characteristics (time, conc. or both)
  • [antibiotic] < MIC but retains effectiveness
  • less frequent dosing, better patient adherence
A

Proposed mechanism include

  • Slow recovery after non lethal damage to cell structures
  • Persistence of drug at binding site/periplasmic space
  • Need to synthesise new enzymes before growth can resume
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104
Q

What is the post antibiotic effect, and why is it clinically important?

A
  • Suppression of bacterial growth that persists after a brief exposure to antibiotics
  • guides antibiotic dosing regimens
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105
Q

Gathering Information

A

SCHOLAR

  • What are the Symptoms
  • What are the Characteristics of the symptoms
  • What is the History of the symptoms?
  • When is the Onset
  • Where is the Location?
  • What factors Aggravate the symptoms?
  • What factor Remit the symptoms

MAC(S)

  • Medicines
  • Allergies & adverse effects
  • Medical Conditions
  • Social history (if relevant)
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106
Q

Three steps to better health literacy

A
  1. Determines baseline understanding
  2. Links new information to what the person already knows
  3. uses the Teach-Back method
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107
Q

Teach-Back

A

Potential shit to say on L10, pg 26

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108
Q

Encourage questions

A

L10, pg 27

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109
Q

Drugs, bugs & people

A

Diagram on L11, pg 4

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110
Q

Terminology

  • Minimum bactericidal concentration (MBC)
  • Minimum inhibitory concentration (MIC)
A

MBC
- The lowest conc. of antibiotic required to KILL a particular bacterium

MIC
- Lowest conc. of an antimicrobial that will INHIBIT the visible growth of a microorganism AFTER OVERNIGHT INCUBATION

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111
Q

Antibiotics vs Antibacterials

  • read over
A
  • Antibiotics are antibacterials that are produced by a micro-organism to reduce competition for resources
  • Antibiotics (originally produced by other micro-organisms):
    • Gentamicin is an antibiotic produced from: Micromonospora
    • Tobramycin is an antibiotic produced from: Streptomyces
  • Antibacterial (only synthetically produced)
    • Sulphonamides
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112
Q

Pharmacokinetics vs Pharmacodynamics

  • read over
A
  • Pharmacokinetics = the change in conc. over time in the plasma after administration of the drug
    • ie what the body does to the drug
  • Pharmacodynamics = the effect of the drug conc. on the body
    • ie what the drug does to the body
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113
Q

Gentamicin

A
  • Aminoglycosides (eg gentamicin, tobramycin, …) are used for serious infections due to aerobic gram -ve baccilli
  • Genamicin is used for
    • E. coli, influenzae, others
    • Generally the dose is 5-7 mg/kg IBW given once daily
  • Usually only ever given in a secondary or tertiary hospital setting
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114
Q

Gentamicin PK

A
  • Administration - Usually give by IV infusion over 30 mins

PK data

  • Data fits a one-compartment model
  • Renally cleared (NOT metabolised) - base dose on ideal body weight (IBW)
  • CL = 4L/h = 80% of GFR
  • V = 18L = Extracellular fluid volume (EFV)
  • F = 0 so there is no oral formulation
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115
Q

Gentamicin PK

model on L11, pg 13

Graph on L11, pg 14

A

One compartment model:

  • Infusion input
  • Conc. measured in the central compartment (blood)
  • Drug eliminated into urine
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116
Q

Gentamicin PD

A

PD Effect on microorganisms

  • Conc-dep. bactericidal effect
  • Post-antibiotic effect
  • Adaptive resistance

PD Effect on the body (side effects)
- Saturable uptake into kidneys and cochlear –> prolonged high conc. lead to toxicity

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117
Q

Gentamicin - conc-dep. bacterial kill

  • graph on L11, pg 16
A

Conc.-dep. killing

  • DOSE is important
  • Bigger Cmax = bigger bacterial kill
  • Extent of bacterial kill is related to Cmax
  • Rate of bacterial kill is related to Cmax
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118
Q

Gentamicin Conc.-Time Curve

  • Graph on L 11, pg 17
A
  • Antimicrobials are usually regarded as bactericidal if the MBC is no more than four times the MIC
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119
Q

Adaptive Resistance

A
  • Graph on L11, pg 18
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120
Q

Side effects with aminoglycosides

A
  • Nephrotoxicity
  • Ototoxicity
    • Due to saturable uptake into the kidneys and cochlear

Risk factors predisposing patients to toxic side effects

  • Major:
    • Duration of treatment
    • Dose
  • Minor
    • Liver disease
    • Prior aminoglycoside exposure
    • Female
    • Other nephrotoxic drugs
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121
Q

Goal of treatment

A
  • To reach the highest Cmax: MIC ratio within an acceptable exposure level
    • Exposure is taken as AUC of the plasma conc. time curve
    • But it may also be estimated as Cmin
  • Target Cmax&raquo_space; 10 mg/L & Cmin &laquo_space;0.5mg/L
  • The aim is to ensure that high peal levels are achieved but that drug is cleared before the next dose
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122
Q

Gentamicin nomogram

  • Graph on L11, pg 21
A
  • Dose = 5-7 mg/kg given once daily by 30 min intermittent IV infusion
123
Q

Flucloxacillin

A
  • Penicillins are used for minor and serious infections due to aerobic gram-positive baccilli
  • Flucloxacillin is used for
    • Staphyllococcal spp, Streptococcal spp
    • It has better activity against beta-lactamase producing bacteria than other penicillins
  • It is often given in the community setting (PO) for uncomplicated but is also given in hospital (PO or IV) for complicated infections
124
Q

Flucloxacillin

A

Administration - PO, or IV push over 3-5 minutes or IM

PK

  • Fe = 0.7
  • CL (total) = 8.2L/h
  • CL (renal) = 5.4 L/h
    • renal active secretion (can be blocked by probenecid)
  • V = 10 L
  • t1/2 = 50 min
  • F = 0.3
125
Q

Flucloxacillin PK

  • Model on L11, pg 24
A

Three compartment model

  • Oral input
  • Conc. measured in the central compartment (blood)
  • Drug eliminated into urine
126
Q

Conc.-Time profile

A
  • Graph on L11, pg 25
127
Q

Flucloxacillin PD

A
  • Time-dependent bactericidal effect (tim above MIC)
  • Post-antibiotic effect
  • Minimal toxicity - some bleeding at high doses (quite rare)
  • Doses generally provide a much higher conc. than the MIC in order to account for the short half-life
128
Q

Flucoxacillin Conc effect

A
  • graph on L11, pg 27
129
Q

What is the goal dosing regimen for flucloxacillin

A

A concentration above the MIC for the longest period of time (i.e. for at least 40% of the dose interval)

130
Q

Patients reaching the 40% success level - when does is given q6h

A
  • graph on L11, pg 29
131
Q

Dosing of drugs with short half-lives

A
  • L11, pg 30
132
Q

Constant infusion

  • read over
A
  • An alternative method to achieve more than 40% cover over a dose interval is to give the penicillin as a constant infusion - just above the MIC
  • This is relatively uncommon but may be done in clinical practice either in hospital or at home in a few cases eg for osteomyelitis (Duration of treatment is 2-3 months)
133
Q

PD properties of antibacterials

A

Time-dependent

  • Beta-lactams
  • Vancomycin
  • Macrolides
  • tetracyclines

Conc.-dep.

  • Aminoglycosides
  • Fluoroquinolones
134
Q

Staphylococcus aureus

  • pic on L12, pg 6
A
  • Distinguished by the golden color of colonies (S.epidermidis - white colonies), has coagulase enzyme
  • Commensal carried asymptomatically
  • A Wide range of infections range from benign to life-threatening
    • Skin and soft tissue inffections (SSTI)
    • Joints, bones (osteoarticular)
    • Blood, Lung, Heart
    • Gi, Urinary, reproductive tracts, mastitis
135
Q

Staphylococcus aurus - epidemiology

  • read over
A
  • Carried by 30-50% of people
  • Carriage increases risk of infection
  • Infections also via exposure to a carrier (community or hospital) or environmental source
  • Drug resistance - B-lactamase inactivates penicillin; mecA gene encodes a low-affinity penicillin0binding protein, VanA modifies the target
136
Q

Staphyloccoccus aureus - pathogenesis

A
  • Damage to an epithelial barrier - colonization of bacteria in tissue or blood
  • Phagocytosis of bacteria by macrophages
  • Activated macrophages attract neutrophils which secrete mediators
  • Bacteria fight back - destroy NETS, produce toxins & superantigents
  • Abscesses form to contain bacteria, do not always work - spread to blood
137
Q

Streptococcus

A
  • arranged in chains
  • classified based on ability to rupture red blood cells (hemolysis) & cell wall polysaccharides (Lancefield group)
  • Group A Streptococcus (GAS) have many virulence factors including capsules, toxins and superantigens
138
Q

Streptococcal pathogenesis

A

Multiple virulence factors impact on pathogenesis

  • Direct tissue damage
  • Induction of coagulopathy
  • Inactivation of cytokines & immune cells
  • Extensive tissue damage, bacteremia, organ damage
139
Q

group A Streptococcus - S. pyogenes

A
  • Gas colonizes epithelial surfaces
  • Most disease is from superficial infections, but can have serious sequelae
  • Invasive disease follows a breach of epithelia - variety of disease with high morbidity & mortality
140
Q

group A Streptococcus - S. pyogenes

A
  • rates higher with deprivation
  • patients die with 7 days of infection
  • Most common invasive diseases - SSTI & bacteremia
  • May be complicated by development of STSS
141
Q

Staph & Strep Skin Infections

A

Benign/Superficial

  • hair follicle infections
  • Impetigo

Serious/invasive

  • Cellulitis
  • (toxic shock syndrome)
  • Necrotizing fasciitis
142
Q

Cellulitis

A
  • bacterial infection of the skin and sub-cutaneous tissue (fascia, muscles, tendons)
  • Commonly caused S. pyogenes; S. aureus
  • Organism must gain entry through a wound (cut, abrasion, burn, sting, bite, surgery)
  • Commonly occurs in the leg
  • S. pneumoniae, H. influenzae caused periorbital cellulitis - sinusitis complication in children
143
Q

Cellulitis

  • read over
A
  • Pre-disposing factors
  • Symptoms - ill defined lesions, red, painful, swollen, may/may not have systemic symptoms - fever, chills, regional lymphadenopathy
  • Diagnosis - biopsy + culture only used in situations where complications may occur (old, young, immune compromised etc)
144
Q

Cellulitis

A

treatment

  • Uncomplicated cellulitis (small area of involvement, no risk factors, no systemic symptoms, minimal pain) oral antibiotics
  • Complicated cellulitis (systemic symptoms + risk factors) hospitalisation, i.v. antibiotics, surgical drainage/debridement
145
Q

Toxic Shock Syndrome

  • pic on L12, pg 20
A
  • Caused by release of Staph and Strep toxic ‘superantigens’
  • Widespread immune system activation - cytokine storm multi organ failure & high mortality
  • Early symptoms
    • redness, swelling & pain at wound site
146
Q

Toxic Shock Syndrome

A

Late symptoms

treatment
- aggressive - supportive care, antibiotics, wound care (drainage &/or debridement)

147
Q

Necrotising Fasciitis ‘flesh eating bacteria’

A
  • Tissue infection in which extensive necrosis accompanies the cellulitis massive destruction of soft tissue, damage to blood vessels, muscle liquefaction, potentially fatal
  • Also known as streptococcal gangrene
  • Caused by S. pyogenes & S. aureus
  • Organism must gain entry through a wound
  • Risk factors - age, vascular disease, diabetes, immune suppression
148
Q

Necrotising Fasciitis

A
  • Median length of hospitalization - 20 day
  • Median number of surgeries - 3.5
  • 13 patients required amputations
  • 21.7 mortality
149
Q

necrotising Fasciitis

A

Early symptoms
- Slight trauma - local discomfort in area of trauma, general malaise, headache, fever, joint & muscle paint

Advanced symptoms - pain gets worse, seem out of proportion to the small wound visible, blisters, skin & tissue looks dead

  • Critical symptoms - Disease progresses, less local pain, more systemic symptoms from bacterial toxins, coma & death
150
Q

necrotising Fasciitis treatment/prevention

A
  • Seek treatment early
  • Hospitalisation, i.v. antibiotics, supportive therapy, surgical drainage and debridement
  • Amputation
  • Cosmetic surgery - Skin grafts (patients can end up having up to 50% of their skin removed in severe cases
151
Q

Antimicrobial Resistance (AMR)

  • read over
A

“Antimicrobial resistance occurs when microorganisms such as bacteria, viruses, fungi and parasites change in ways that render the medications used to cure the infections they cause ineffective” - WHO

152
Q

Cool wee diagram on L12, pg 8

A

degtyh

153
Q

AMR significance in NZ

  • read over
A
  • NZ has relatively LOW RATES of AMR in humans BUT
  • Significant rise in infections caused by antibiotic-resistant bacteria
  • Total usage of antibiotics is HIGH across human (MoH), animal and agriculture sectors (MPI)
  • Emersgence of MRSA, ESBL, VRE, MDR Neisseria gonorrhoeae over the past 20 years
154
Q

WHO GLOBAL ACTION PLAN

A
  1. Improve awareness and understanding of antimicrobial resistance (through effective communication, education and training)
  2. Strengthen the knowledge and evidence base (through surveillance and research)
  3. Reduce the incidence of infection (through effective sanitation, hygiene and infection prevention measures)
  4. Optimize the use of antimicrobial medicines in human and animal health
  5. Develop an economic case for sustainable investment
155
Q

NZ AMP Action Plan

A
  1. Awareness and understanding
  2. Surveillance and research
  3. Infection prevention and control
  4. Antimicrobial stewardship: Optimise the use of antimicrobial medicines in human health, animal health and agriculture, including by maintaining and enhancing the regulation of animal and agriculture antimicrobials
  5. Governance, collaboration and investment
156
Q

What is Antimicrobial Stewardship? (AMS)

A

A directed approach to:

  • Promote the appropriate use of antimicrobials
  • Decrease the spread of MDR infections
  • Improve patient outcomes

Important:
- AMS directly addresses objective 4 of the NZ AMR action plan, and WHO action plan

157
Q

AMS Interventions usually fall into two categories

A
  1. Broad, higher level activities

2. Specific, ground level activities

158
Q

Broad interventions

  1. Guideline and clinical pathway development and review
A
  • Set a local empiric antibiotic guideline: L5
  • Based on evidenced based medicine and local antibiotic sensitivities
  • Promotes appropriate use
159
Q

Reading Antibiograms

  • read over
A

Utilised in practice to:

  • Rationalise antibiotic use through targeted therapy
  • Inform guideline creation
  • Improve treatment outcomes
  • Slow down antimicrobial resistance
160
Q

Broad interventions

  1. Antimicrobial restrictions
A
  • Certain medicines require specialist approval before use (local or national policy)
  • Save for severe situations, avoid overuse
  • Funding restrictions
161
Q

Broad Interventions

  1. Auditing
A
  • Surveillance of restrictions
  • What is being used and why
  • Used to measure effectiveness of interventions
162
Q

Audit Example

A

L12, pg 25

163
Q

Specific Interventions “ground level”

A

IV to PO switch

  • using PO where appropriate
  • Reduces need for IV line (risks associated)

Dose optimisation

  • Therapeutic drug monitoring (TdM)
  • Avoid sub-therapeutic treatment

Eliminate duplicates:
- Rationalise combination therapy to avoid overlapping spectrums

164
Q

Specific Interventions

A

De-escalation:

  • Cultures
  • Empiric therapy –> Targeted therapy

Duration

  • Follow-up antibiotic charting, cease course when appropriate
  • Automatic-stop orders (eg; perioperative)

Interactions
- Review for interactions that may increase or decrease the dose requirement

165
Q

Fungal infections (mycoses) are widespread

Associated with:

  • read over
A
  • Skin

- Mucous membranes

166
Q

Why do we care about fungi?

  • read over
A
  • Fungi are eukaryotic
  • More complex and evolved than bacteria
  • Inc. prevalence of opportunistic infections
    • particular risk for older people, diabetic, pregnant, burn wounds
167
Q

Clinically important fungi

  • L13, pg 4
  • read over
A

True pathogens

  • Cutaneous
  • Subcutaneous
  • Systemic
    • Coccidoides immitis

Opportunistic pathogens

  • Aspergillus fumigatis
  • Candida albicans
  • Cryptococcus neoformans
168
Q

Antifungal strategies

L13, pg 6

  • read over
A

Targets

  • Synthesis of membrane, cell-wall components
  • Membrane permeability
  • Synthesis of nucleic acids
  • Microtubule/mitotic spindle function
169
Q

Antifungal antibiotics - Amphotericin (B)

  • Polyene antibiotic
  • Binds to ergosterol in fungal membrane
  • Relative specificity (main sterol in humans is cholesterol
  • Form pores/channels -> inc permeability, leakage

L13, pg 9

A

PK

  • GI absorption of all amphotericin B formulations is negligible
  • Used topically, systemic Tx with slow i.v. infusion (lipid formulation)
  • Highly protein bound
  • Excreted v. slowly by kidneys
170
Q

Antifungal antibiotics - Amphotericin (B) Unwanted effects

Commonest, most severe
- Renal toxicity (80% of patients)

  • Hypokalemia (20%)
  • Acute response to i.v
    • fever, chills
    • Worst with ABCD, best with LAMB
  • Irritant, thrombophlebitis
A

therapeutic use

  • Candida oesophagitis (HIV/AIDS)
  • Mucormycosis (weakened immune system eg organ transplant)
  • Meningitis
  • Cryptococcus
171
Q

Nystatin

  • Tetraene macrolide (streptomycesnoursei
  • Structually similar to Amphotericin
  • Same mechanism of action
A

PK

  • Not absorbed from the GI tract, skin, or vagina

–> Good for ‘topical’ use

172
Q

Nystatin unwanted effects

  • none of note
  • allergic reactions very common
A

therapeutic use

  • Only for candidiasis (thrush)
  • Supplied in preparations for cutaneous, vaginal, or oral administration
173
Q

Griseofulvin

  • Narrow spectrum (penicillium griseofulvin)
  • FungiSTATIC
  • Interacts with fungal microtubles, interferes with mitosis
A

PK

  • Given orally, poorly soluble in water
  • taken up selectively by newly formed skin, conc.ed in keratin
  • t1/2, retained much longer
  • CYP1A2 inducer –> Clinically significant drug interactions esp. warfarin
174
Q

Griseofulvin unwanted effects

Infrequent

  • Gi upset
  • Headache
  • Photosensitivity
  • Not for use in pregnant women (teratogenic)
A

therapeutic use

  • Dermatophyte infections of skin, hair, nails

= ringworm

175
Q

Echinocandins

  • eg Caspofungin, micafungin, anidulafungin
  • inhibit synthesis of 1,3-B-D-glucans -> dec. structural integrity -> death
  • FungiCIDAL
  • L13, pg 16
A

PK

  • No oral bioavailability, given i.v.
  • Extensive protein binding (>97%)
  • Dont penetrate into CSF
  • No renal clearance
176
Q

Echinocandins unwanted effects

  • Remarkably well tolerated
  • Phelbitis at injection site (caspofungin)
  • Histamine-like effects (rapid infusion)
A

Therapeutic Use

  • Deeply invasive candidiasis
  • Salvage therapy* for invasive aspergillosis
177
Q

Clinically important interactions

A

Particularly for immunocomprimised patients

  1. Caspofungin and microfungin are mild inhibitors of CYP3A4
    - inc. [drug]plasa of immunosuppressant tacrolimus (organ rejection)
  2. Drugs that are inducers of CYP3A4
    - rifampicin (antiboitic for TB) dec [drug]plasma of caspofungin
178
Q

Synthetic antifunagal agents - Azoles

  • eg fluconazole, itraconazole, miconazole, voriconazole, posaconazole
  • Inhibit 14-a-sterol demethylase (microsomal CYP) -> impairs ergosterol synthesis
  • Some inc. permeability of plasma membrane (topical use)
  • FungiSTATIC (broad spectrum)
  • Voriconazole, posaconazole have expanded spectrum c.f fluconazole
A

PK

  • Can be given orally or i.v (miconazole generally topical/oral gel)
  • Latroconazole absorption variable, extensive hepatic metabolism
  • Short t1/2 ~6-8h (miconazole, voriconazole)
  • Long t1/2 ~30-40h (fluconazole, itroconazole, posaconazole)
179
Q

Synthetic antifunagal agents - Azoles Unwanted effects

Generally mild

  • Nausea
  • Headache
  • Abdominal pain
  • Rare reports of allergic skin reactions (SJS)
  • Teratogenic: avoid during pregnancy
  • > Need effective contraception during treatment
A

Therapeutic use

  • Candidiasis
  • Seborrheic dermatitis
  • Cryptococcal meningitis (AIDS)
  • Invasive aspergillosis
180
Q

Clinically important interactions

  • table on L13, pg 22
A
  • Azoles interact with hepatic CYPs inhibitors
181
Q

A note on clotriamzole

  • OTC topical treatment
  • Superficial fungal infections
  • Thrus (candidiasis), tinea, fungal keratitis, nappy rash
A
  • Interferes with amino acid transport into fungus
  • Small amount absorbed is metabolised by liver and excreted in bile
  • may still be used to treat yeast infections in pregnant women
  • may cause stinging, redness, itching
182
Q

Flucytosine

  • Converted to antometabolite 5-fluorouracil in fungal (not human cells)
  • 5-FU inhibits thymidylate synthetase and DNA synthesis
  • Limited spectrum, combined with amphotericin and/or azoles
  • Resistance common
A

PK

  • Given by i.v infusion, can also be given orally
  • t1/2 ~3-5 h
  • 90% excreted unchanged by kidney
  • Dosage should be reduced in renal impairment
183
Q

Flucytosine Unwanted effects

Infrequent

  • Gi disturbances
  • Anaemia
  • Neutropenia
  • Alopecia
A

therapeutic use

  • Serious fungal infections
  • Crytococcal meningitis in patients with AIDS
  • Candidiasis
  • Chromomycosis
184
Q

Terbinafine (lamisil)

  • Selective inhibitor of squalene epoxidase (ergosterol synthesis)
  • Highly lipophilic and keratinophilic
  • FungiCIDAL
A

PK

  • Topical or oral
  • well absorbed (dec. bioavailability due to first pass metabolism)
  • Accumulates in skin, hair and nails
  • Metabolised in liver, excreted in urine
185
Q

Terbinafine (lamisil) unwanted effects

  • well tolerated
  • Low incidence of GI distress, headache or rash
  • not recommended in hepatic failure
  • Systemic therapy avoided during pregnancy
A

Therapeutic use

  • Nail onychomycosis (oral)
  • Tinea (cream or spray)
186
Q

Findings from the consultation

  • read over
A
  • Most eczema treatment failures were due to lack of use stemming from lack of knowledge about how to use products effectively
  • The problems were particularly bad for young children where there was a major impact on the whole family
  • And for elderly who might experience practical difficulties with the application of topical treatments
  • Prescribers did not have time to explain everything about dermatological treatments
  • But the problem could be remedied by easy and quick access to suitably trained personnel
187
Q

Drug gets into the skin from a topical preparation by diffusion

L15, pg 10

A

Flux equation

188
Q

Does the effect of skin Age and Location have a relevant clinical effect on drug absorption?

A
  • See on kura clout-LT 15
189
Q

Histamine

A

Histamine = mediator of immediate allergic (urticaria) and inflammatory conditions

  • Also has a role in gastric acid secretion and functions as a neurotransmitter and neuromodulator
  • Most histamine is stored in granules within mast cells or basophils
  • Stimuli trigger its release - then histamine exerts its effects
190
Q

What triggers histamine release?

A
  • Immunological stimuli - accounts for most of histamine release
  • Chemical and Mechanical release
    • Other compound can displace histamine from its bound form within cells - e.g. other amine compounds
191
Q

Histamine receptor subtypes

A

L15, pg 21

H1
H2
H3
H4

192
Q

Antihistamine drugs - acting at H1 - receptor

  • L15, pg 22
A

first generation - more sedating

Second generation - reduced distribution to the central nervous system -> less sedating

193
Q

H1-antagonists

L15, pg. 23

A

Classification based on structure

  • general structure of H1-antagonist drugs and examples of the major subgroups
  • Subgroup names are based on shaded moieties
194
Q

H1-antagonists

A
  • First generation H1 antagonists enter the CNS readily
  • First generation H1 antagonists have anitcholinergic side effects since they interact with muscarinic cholinergic receptors
  • The active metabolites of hydroxyzine, terenadine, and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively).
  • Reduce the actions of histamine by reversible binding to the H1 receptor
195
Q

Side-effects: First generation

  • L15, pg 25
A
  • Low H1 selectivity and high BBB permeability
196
Q

Drugs

  • L15, pg 26
A

dfvtvred

197
Q

Acne (Acne vulgaris)

L16, pg 7

  • Very common skin disease, chronic inflammation of sebaceous gland
  • Common at puberty, also present in adults
A

Pathogenesis

  1. & 2. hyperseborrhoea & abnormal follicular keratinization
  2. & 4. Bacterial proliferation & inflammation
198
Q

Acne - hyperseborrhoea

L16, pg 9

A

Androgens - crucial role in pathogenesis, does not develop in their absence

  • Stimulate the growth of sebaceous glands and stimulate sebum production
  • Anabolic steroids further increase sebum production, estrogens decrease sebum production by decreasing androgen production

Other receptors - also modulate sebum production in response to stress & diet

199
Q

Acne - Follicular keratinization

  • L16, pg 9
A
  • Spontaneous changes in keratinocytes - increased turnover
  • Altered pattern of kertinisation
  • Keratinous material becomes denser, altered lipid metabolism
200
Q

Acne - Bacterial proliferation & inflammation

  • L16, pg 10
A
  • Commensal bacteria associated with sebaceous glands are –
    • Staphyloccocus epidermis - top of the follicle
    • Propionibacteria: P. acne, P. granulosum, P. parvum - Lower, initiates inflammation through interations with keratinocytes
201
Q

Acne

A

Genetics - polygenic
- Twin study - 82% concordance in monozygotic twins, 40% dizygotic

Environment
- No link b/w ‘cleanliness’ and acne

202
Q

Acne - Treatment

A
  • usually heals spontaneously, main treatment aim is to reduce scarring and prevent new lesions
203
Q

Dermatitis - classification

A
  • Atopic dermatitis (atopic/allergic eczema)
  • Contact dermatitis (contact eczema) - can occur in ‘normal’ and allergic/atopic individuals, some evidence for increased rates of ACD in atopic individuals
  • irritant contact dermatitis (ICD)
  • allergic contact dermatitis (ACD)
  • Protein contact dermatitis (PCD)
204
Q

Atopic dermatitis/eczema

L16, pg 14

A
  • Chronic allergic hypersensitivity disease, immune dysfunction
  • Immune mediated (Th2) to allergens (not-dangerous)
  • Main symptoms - dry, red, cracked, weeping, itching skin
  • Predisposes to infections (viral, bacterial & fungal) & ACD not ICD
  • Associated with other inflammatory conditions ** asthma (atopic march), arthritis, inflammatory bowel disease
  • Major impact on quality of life
205
Q

Atopic dermatitis/eczema

L16, pg 15

A
  • Commonly diagnosed in childhood
  • Distinct geographic variations in prevalence
  • Increasing in some countries, stabilized at high levels in others
  • Complex disease - genes and environment
  • Strongest risk factor - family history
206
Q

AD - pathogenesis

  • L16, pg 16
A

Acute
- Allergens enter via damaged skin & stimulate mast cells etc to degranulate

Chronic

  • Driven by cytokines released by T cells
  • Keratinocyte (KC) dysfunction
207
Q

Contact dermatitis

A

Irritant Contact Dermatitis (ICD)

  • Physical (UV, heat, cold, damp) or chemical (detergents, solvents, bleaches) agents causing direct injury
  • Can be acute (minutes to hours) or chronic/cumulative, mild or severe, recurrent

Allergic Contact Dermatitis (ACD)

  • Immune response to small organic & inorganic allergens that can penetrate skin eg nickel
  • Sensitizing phase (asymptomatic) of weeks to months then an inflammatory phase
  • Type 4 response - cellular Th1 cells
208
Q

Contact Dermatitis

A

Protein Contact Dermatitis (PCD)

  • Immune response to large protein allergens
  • Can not penetrate intact skin
  • Sensitizing phase (asymptomatic) of weeks to months then an inflammatory phase
  • IgE & cellular response - similar to allergic dermatitis

CD Presentation
- Varied clinical presentation - erythema, scales, crusts, erosion, ICD usually dryer than ACD

209
Q

Nappy rash (ammoniacal dermatitis)

  • Pic on L16, pg 21
A
  • ICD caused by irritants (ammonia in urine, proteolytic enzymes in faeces), friction, damp
  • Redness, swelling, initially scaly, progresses to erosions, can be acute or chronic
  • Complication is yeast infection (pustules) or bacterial (crusty) secondary infection

Treatment

  • uncomplicated - regular nappy changes, careful cleaning, barrier creams
  • Complicated - treat infections
210
Q

Urticaria

Pic on L16, pg 22

A
  • common
  • Itchy wheals (hives), localized oedema of the upper dermis, or can occur in deeper dermal layers (angiodema)
  • Can be acute or chronic - self resolving
  • Pathophysiology mediated by mast cell degranulation
  • Causes - idiopathic/ ‘one-off’, physical triggers - pressure (scratching), heat, cold, chemical contact, allergies
  • Treatment - avoid triggers, pharmacotherapies
211
Q

Psoriasis vulgaris

  • Pic on L16, pg 23
A
  • Chronic T cell mediated inflammatory disease that can develop into psoriatic arthritis (within 10 years)
  • Onset in young adults
  • Lesions variable, sharp borders, erythema, scale, pustules
  • 1 in 4 patients experience psychosocial distress
  • Common co-morbidities - psoriatic arthritis, cardiovascular disease
212
Q

Psoriasis vulgaris

  • read over
  • L16, pg 24
A
  • Limited good quality data on prevalence
  • 0.1 & 2%
  • Higher prevalence in:
    • adults
    • Higher income countries
213
Q

Psoriasis vulgaris

  • read over
A

Genetics

  • twin studies 73% concordance
  • Polygenic - skin and immune genes

Environment

  • drugs
  • infection
  • trauma
  • smoking alcohol
214
Q

Psoriasis vulgaris - pathogenesis

A

Initiation
- Damaged KC release ‘danger’ molecules that activate DC, go to lymph node & activate T cells

Inflammation

  • Th cells release cytokines - activate KC, neutrophils, mast cells, macrophages
  • Dermal hyperplasia, impaired KC differentiation - plaque formation
215
Q

Psoriasis - CAM

  • idk if need to know
  • L16, pg 28
A
  • usually used along with instead of replacing traditional therapies
216
Q

AD vs psoriasis

A
  • Both immune mediated & can be treated with cytokine antagonists & immune suppression
217
Q

HPA axis and immune inflammatory network

A

Diagram on L17, pg 6

218
Q

Maybe have a look at L17, pg 8

A

dertdsfvbr

219
Q

Regulation of Cortisol Secretion

A

3 major mechanisms

  1. Diurnal variation
  2. Stress
    • Physical
    • Psychological

Negative feedback

220
Q
  1. Anti-inflammatory drugs Glucocorticoids
A

Anti-inflammatory and immunosuppressant drugs

Routes of administration

  • Oral prednisone, budesonide
  • IV methylprednisolone, hydrocortisone (HC)
  • Enema (HC) and rectal foams (HC)
  • Topical (HC) and betamethasone
221
Q

Glucocorticoid Mechanism of Action

  • L17, pg 11
A
  • Activated GR complex up-regulates the expression of anti-inflammatory proteins
  • Activated GR complex decreases the expression of pro-inflammatory proteins
222
Q

Glucocorticoid Mechanism of Action

A

L17, pg 12

223
Q

negative feedback cortisol

A

L17, pg 13

224
Q

Glucocorticoids

L17, pg 14

A
  • Not stored - rate of synthesis = rate of release
  • Synthesized rhythmically and controlled by irregular pulses of ACTH
  • Influenced by light and major pulses occur in the morning and after meals
  • Glucocorticoids act via their receptors (GR) in the nucleus
  • GRs are widely distributed and located in almost all cells in the bods
225
Q

Steroid hormone target cellular effects

read
- Most of the physiological effects of glucocorticoids and mineralocorticoids hormones are mediated through binding to intracellular that operate as ligand-activated transcription factors to regulate gene expression. Mineralocorticoid and glucorticoid receptors are closely related and share similarities in their ligand and DNA binding domains

A

They are classified into

  1. Types I
    - Type 1 receptors are specific for mineralocorticoids but have a high affinity for glucocorticoids
  2. Type II
    - Type 2 receptors are specific for glucocorticoids and are expressed in virtually all cells
226
Q

Long term risks of glucocorticoids

  • read over
A

Adrenal axis suppression

  • Risk of death with abrupt cessation of dosing
  • Requirement for dose-tapering

Effects on carbohydrate, protein and fat metabolism

  • Promotes gluconeogenesis
  • Can precipitate hyperglycemia (diabetics need to monitor)
  • Skeletal muscle wasting
  • hypertension (mineralocorticoid effects)
  • Redistribution of body fat (‘moon face’ ‘buffalo humps’)
  • Elevation of mood
  • Skin thinning (Striae)
  • Acne
  • Bruising
227
Q

Glucocorticoids adverse effects pic on L17, pg 17

A

jhvgv

228
Q

Topical corticosteroids

read over

A
  • Topical corticosteroids are used for the treatment of inflammatory conditions of the skin (other than those arising from an infection), in particular eczema, contact dermatitis , insect stings, and eczema of scabies
  • Corticosteroids suppress the inflammatory reaction
  • They are not curative and on discontinuation a rebound exacerbation of the condition may occur
  • They generally used to relieve symptoms and suppress signs of the disorder when other measures such as emollients are ineffective
229
Q

What is topical

A
  • Powder
  • Paste
  • Cream
  • Lotion
  • Ointment
  • Drops
230
Q

Absorption in the skin

A

L17, pg 22

231
Q

How much is absorbed systemically?

  • reada over
A

There is little evidence as to what percentage of a topical corticosteroid dose is absorbed systemically

Studies investigations systemic effects do not measure how much of the corticosteroid is in the blood, but instead focus on measuring cortisol as a marker of hypothalamic-pituitary-adrenal (HPA) axis suppression

  • After a few weeks’ treatment with potent or very potent topical corticosteroids temporary HPA axis suppression does occur
  • However, this resolves upon cessation of the topical corticosteroid, without the need for dose tapering
232
Q

corticosteroids cutaneous adverse effects

  • read over
A

uncommon or rare if used appropriately

  • Skin thinning
  • Stretch marks
  • Easy bruising
  • Enlarged blood vessels
  • Susceptibility to skin infections
  • Localised increase in hair thickness and length
  • Allergy
233
Q

Some pics on L17, pg 25

A

mknjbhvgg

234
Q

Minimising adverse effects - using appropriately

A
  • Apply it to affected areas only
  • Do not apply more frequently than twice daily - once daily is often sufficient
  • Use the least potent formulation which is fully effective
  • use appropriate quantity
  • Use for the shortest time possible (but still ensure skin condition clears)
235
Q

Fungal infections - Athletes foot, Tinea pedis

  • Photo on L18, pg 4
A
  • Superficial mycosis
  • Tinea = fungus infection
  • Prevalence rates 15-20 %
  • Causative agents
    • on L18, pg (dont need to know the names_
  • Common in teenage & adult males
  • Rare in children under 12
236
Q

Athlete’s foot

A
  • spores found in shoes, carpet, bath mats, showers (can survive for months)
  • It is NOT highly infectious, but loves warm, moist environments (inside sweaty socks & shoes)
  • Chronic recurrent disease
  • Predisposing factors - immune deficiency, poor circulation, sweaty feet
237
Q

Athletes foot

A
  • Symptoms - variable
  • Interdigitating scalping, splitting
  • onychomycosis
  • ‘moccasin’ type - dry, scaly, red, itchy (heels, toes, side of feet)
  • Blistering
  • Complications - secondary bacterial infections in broken skin (needs to be treated)
  • Treatment - OTC preparations
238
Q

Ringworm - Tinea corpis

A
  • Different causative agents - often zoonotic
  • Can be acute or chronic
  • Inflamed red patches, white healing middle, itchy, inflamed, pustular
  • Commonly confused with non-fungal conditions such as impetigo, psoriasis, discoid eczema, allergic dermatitis
  • Quick test to distinguish fungal & non-fungal conditions is to use a Wood’s light
239
Q

Tinea Capitis

A
  • Scalp infection - inflammation, hair loss
  • Common in school age children
  • In NZ commonly from infected kittens/cats
    • M. canis
  • Transmissable via spores on hairbrushes, clothin

Treatment - Tinea corpis & capitis
- OTC ointments & shampoos

240
Q

Viral infections - Warts

A
  • Warts (verruca vulgaris) are cutaneous tumours caused by human papillomaviruses (HPV)
  • Very common caused by large number of HPV, many different types of lessions
  • Human - human transmission, long incubation time, also get auto-inoculation
  • Differential diagnosis - if it looks like a wart it probably is, only refer elderly patients or immunocomprimised patients with atypical warts
241
Q

Warts treatment

A
  • No therapy as will generally disappear by themselves (but this may take years)
  • Cosmetic removal of warts (laser, chemical, surgical removal)
  • cytostatic agents, keratolytic agents
  • Stimulate the immune system to kill warts
    • Imiquimod cream
242
Q

Viral infections - Cold sores

A
  • Causative agent - Herpes simplex virus Type 1 (HSV 1)
  • Viruses are endemic, virus remains latent in nerve endings
  • 1* infection usually occurs in childhood, 7 day incubation, widespread sores (red bump, blister, crust, drops off 7-10 days). usually there is no scarring
  • Recurrence - fewer or no sores, sores maybe preceded by burning or itching
  • Triggers for recurrence - sunlight, fever, menstruation, immune suppression
  • Treatment - acyclovir
243
Q

Infections of the skin - Bacterial

A

Superficial

  • Follicle infections
  • Impetigo
  • Leprosy

Invasive

  • Cellulitis (CD13)
  • Clostridial infections
244
Q

Hair follicle infections

  • Pic on L18, pg 13
A
  • Folliculitis, boils (furuncles or carbuncles)
  • Hair follicle is infected generally by a bacteria (staphylococcus aureus) but may be a fungal or viral infection
  • Occurs commonly in groin, arm pits, scalp - moist, warm environment
  • Often occurs as a complication to acne
245
Q

Hair follicle infections

A
  • Folliculitis - Localised small inflamed pustules, itchy or painful
  • Boils (furunculosis) - more severe, deeper infection of one or more follicles, often has a central yellow ‘plug’, bigger lesions, commonly in areas of friction, usually will drain themselves, systemic symptoms
  • Carbuncle - conglomeration of several furuncles - massive amounts of necrosis and bacteria (pus), systemic symptoms , will need to be drained
246
Q

hair follicle infections treatment

A

Treatment - depends on severity and if it needs drainage
- antibiotic - topical, local or iv

Complications - endocarditis, sinus thrombosis

247
Q

Impetigo

  • pic on L18, pg 16
A
  • Superficial infection of the epidermis caused by Staphylococcus aureus or Streptococci pyogenes
  • In NZ & Australia commonly known as ‘school sores’
  • Highly infectious
  • Risk factors - broken skin (viral infections, trauma, scratching)
  • No systemic symptoms, resolves without scarring
248
Q

Impetigo

Two types

  • Pics on L18 & 19, pg 17
A
  • Nonbullous (impetigo contagiosa)
    • Immune response to bacteria - vesicle to erosion to honey-coloured crust. Highly contagious often around nose & mouth
  • Bullous - due to toxin, fluid filled blisters, when burst get crust. Less contagious, can occur in arm pits, neck folds etc (moist areas)
249
Q

Impetigo

Transmission:

Treatment:
- other options on L18, pg 19

Complications:

A
  • Autoinnoculation from nose, person-person, towels, face cloths
  • Treatment - “clean, cut (fingernails), cover”, topical or systemic antibiotics, child can return to school 24 hours after starting treatment
  • Systemic spread -glomerulonephritis or scarlet fever (rare)
250
Q

Clostridial skin infections

A
  • Gram positive, anaerobic, rod shaped & spore forming & toxin producing
  • Environmental infection of deep tissue through an open wound, no person-person transmission
  • Minor cause of serious skin infections in NZ, vaccin for C.
    • L8, pg 20 (not sure if need to know)
251
Q

C. tetani

L18, pg 21

A

14-28 day,

  • Early symptoms - tissue infection, weakness, stiffness, cramps
  • Late - spasms, seizures
  • After infection exotoxin (tetanospasmin) is secreted binds to presynaptic nerve endings and prevents release of GABA & glycine - no inhibition - spasms & seizures
252
Q

C. tetani

  • read over
A
  • Vaccine widely used
  • Neonatal infection in low income countries
  • Vaccine on schedule - toxoid vaccine requires scheduled boosting plus boosting post injury if doubt regarding immunisation status & consider tetanus Ig (TIG) for immediate protection from toxin
  • Anti-microbial therapy is given but minor impact
253
Q

C. perfringens

  • Pic on L18, pg 24
A
  • Risk factors - vascular disease, diabetes, trauma, surgery
  • Necrotising disease similar to Streptococcal NF but progresses faster, major toxin is a-toxin
  • Early: pale skin - fluid filled blisters - discharge - gas production
  • Late: severe pain, tachycardia, fever - progresses to hypotension & organ failure
  • i.v antibiotics and debridement, hyperbaric oxygen therapy
254
Q

Leprosy

A

WHO in 1991 developed a programme to eliminate leprosy. To do this need:

  • An effective vaccine
  • Understand transmission
  • Better diagnostics
  • better therapies
255
Q

Leprosy (Hansens disease)

A
  • Chronic, minimally contagious infection caused by Mycobacterium leprae
  • Curable
  • Involves skin, mucosal membranes and nerve endings in skin
  • Can infect any age group
  • Social implications
  • historically patients sent to leprosy colonies
  • Transmission - person-person, respiratory?, insect?
256
Q

Leprosy - Pathogenesis

A
  • Long incubation time - average 5 years

- Two main types of leprosy - tuberculoid and lepromatous, with 3 intermediate borderline classifications

257
Q

Leprosy - pathogenesis - Tuberculoid Leprosy

A
  • Non-infectious
  • Paucibacillary
  • Systemic defined dry, scaly lesions, slow growing, hair loss
  • Systemic nerve damage
  • trauma to extremities common
258
Q

Leprosy pathogenesis - Lepromatous Leprosy

A
  • Progressive
  • Contagious infection
  • Multibacillary
  • Involvement of the face, earlobes and nose
  • Chronic nasal discharge
  • Systemic nerve damage - slow to develop
259
Q

Leprosy treatment

  • Not sure if need to know - Maybe just know that the treatment takes a long time
A
  • Are a number of drug available
  • To combat resistance multi-drug therapy is used, generally for 12 months
  • Dapsone, rifampicin, clofamizine
  • Surgical reconstruction
260
Q

Leprosy prevention

A
  • Tuberculosis vaccine, Bacillus Calmette-Guerin (BCG), some efficacy
261
Q

Topical vs. transdermal delivery

A

Topical is for the localized treatment of a dermatological condition

  • eg Zinc and Castor Oil Ointment
  • Topical corticosteroids (CCs)

Transdermal refers to producs that use the skin surface as a portal for systemic delivery of bioactives
- eg Voltaren Emugel

262
Q

Drug transport through human skin: the basics

A
  • Model on L19, pg 7
263
Q

Normal vs. atopic skin

A

model on L19, pg 10

264
Q

Atopic conditions: therapy

A

Mainstay (hydration! Hydration! Hydration!)

  • Moisterisers
  • Soap substitute

Medicated products

  • Keratolytics
  • Topical corticosteroids

Products (topical) or vehicles

  • Oils
  • Lotions
  • Creams
  • Ointments

Pain relief (if required)

265
Q

Moisturisers

  • L19, pg 12
A

Humectants

  • Attract water into skin cells
  • eg glycerine, hyaluronic acid, urea

Emollients

  • Soften/smooth skin
  • ‘fill’ voids b/w rough/peeling skin cells
  • Oils, shea/cocoa butter

Occlusive

  • Form a barrier on the stratum corneum
  • Vaseline (petroleum), mineral oil, lanolin, silicone
266
Q

Soap substitutes

What base do they typically contain?

Why can these be used as soap substitutes

A
  • Absorption bases (contain w/o emulsifying agent)

- Can absorb large amounts of water (~50% of their volume) and thereby produce w/o or o/w emulsions

267
Q

Topical corticosteroids (CCs)

A
  • Synthetic analogues of HC
  • Anti-proleferative: atopic condition eg eczema and psoriasis
  • Ideal topical CCS: permeate SC into the dermis (but not into systemic circulation)
    • lipophilicity
  • Modification ring structure +/- side chains -> potency and ADRs
268
Q

Dont memorise but be familiar with changing CCS chemistry to change potency

  • L19, pg 17
A

daefgrthyjgu

269
Q

Topical steroid formulation

Efficacy (‘potency’) = potency (CCs chemistry) + vehicle (formulation)

A

Potency

  • Very potent or superpotent
  • Potent (100-150 times as potent as hydrocortisone)
  • Moderate (2-25 times as potent as hydrocortisone)
  • Mild

Formulation
- Creams, ointments, lotions, gel/hydrogel, sprays, shampoo and foams

270
Q

Percutaneous absorption of CCs

A

L19,pg 19

271
Q

Percutaneous absorption of CCs

  • pic on L19, pg 21
A
  • Skin properties determine bioavailability

- look over

272
Q

Topical CCs available in NZ

A
  • Look at table on L19, pg22
273
Q

Effects (usual) of common vehicles on skin hydration and drug permeability

A
  • Look at table on L19, pg 24
274
Q

Formulation and potency

A

At any given strength of corticosteroid:

Ointments > cream formulation > lotions

  • Occlusive vehicles -> trap transepidermal moisture -> inc. skin water content -> inc. drug permeability
  • Hydration of the SC -> swells the membrane -> inc. drug permeability
275
Q

Penetration enhancers

  • Some examples on L19, pg 26
A
  • Reversibly dec. the barrier resistance of the SC without damaging any viable cells -> inc drug absorption
    • interact with headgroup or insert b/w bilayer -> affect lipid packaging -> disorder
276
Q

Betamethasone dipropionate eg Diprosone vs Diprosone OV

A
  • look at L19, pg 27
277
Q

What is a differential diagnosis?

A
  • The process of distinguishing a particular disease or condition from other conditions that present with similar clinical features
  • We apply a process to identify the disease or condition causing a patients symptoms
278
Q

Differential diagnosis is a bit like a more complex version of “guess who?

A
  • Your aim is to narrow down possible diagnoses through a process of observation, careful questioning and judgement, to arrive at a likely diagnosis for the patient
  • The method you use to help narrow down the possible diagnoses are important and eventually help you make sensible decisions about the care of a patient
279
Q

the pharmacists role may be

L20, pg 13

A

1.

2.

280
Q

What are the steps in a differential diagnosis?

A
  1. Gather information
  2. Make a list of possible diagnoses
  3. Prioritise the list
    - more dangerous at the top to least dangerous at the bottom
  4. Rule out, treat or refer
281
Q

What are the steps in a differential diagnosis?

A

L20, pg 16-22

282
Q

Example

  • L20, pg 24 & 36 - 37 - 38 - 39 - 41
A

fdgh

283
Q

“When you hear hoofbeats, think of horses not zebras”

A

L20 pg 32 - 35

284
Q

Some other diagnostic tools

  • Algorithms
  • recognising patterns of symptoms
A
  • L20, pg 47 - 48 - 48
285
Q

Development of new anti-bacterial agents

Problem:

Solutions:

L21, pg 5

A

Problem:
- Patents expire relatively soon after market introduction

Solutions
- Tax incetives, patent extentions

286
Q

Development of new anti-bacterial agents

A
  • 2015 - Teixobactin
287
Q

Teixobactin

A
  • Isolated from a soil organism (using new culturing techniwue) - Binds to peptidoglycan precursor in gram +ve organisms, active against MRSA
  • Years away from clinic… isues:
    • Difficult to synthesize
    • Low oral bioavailability
288
Q

What else

A

L21, pg 9

289
Q

Alternative Therapies

A

Immunotherapy

  • Cytokines
  • TLR agonists
  • Antibodies
  • Vaccines

Anti-microbial therapies

  • Peptides
  • Bacteriophages
  • Predatory bacteria
290
Q

Immunotherapy

A

Prophylactic

  • Boost immunity or Provide immunity (passive immunization) in vulnerable populations
  • Active immunization

Trea infection

  • Act on the immune system to boost existing immune response
  • Act on the pathogen directly
Treat inflammation (pathology mediated by immune system)
- Act on the immune system to modulate inflammation
291
Q

Vaccines

A

Prophylactic vaccines - used to prevent disease in individuals and decrease spread through a community (herd immunity)

= Active immunization - vaccines on NZ immunisation schedule

= Passive immunisation - antibody given when not able/no time for active immunisation

Therapeutic vaccines - used to treat individuals already sick, still experimental - HIV, Hepatitis

292
Q

Antibodies

A
  • use of antibodies was one of the first anti-microbial therapies
  • Used before the discovery of antibiotics to treat diseases such as diptheria, tetanus
  • Excellent therapy
  • Reduce/remove/reverse toxicity from exotoxins, immune mediators
  • Kill - pathogens & pathogen infected cells
  • Modulate cell activity
293
Q

Antibodies for infections

A
  • L21, pg 15 & 16

Limitations on L21, pg 17

294
Q

Cytokines

A
  • Soluble messengers of the immune system
  • Proteins - need to be given by injection
  • Most act at short range (cell to cell)
  • Act at low conc.
  • Short half life
  • Multiple, overlapping activities
  • Produced by many cells or few cells
  • Potential therapeutic use in infections, cancer, autoimmunity
295
Q

Cytokine clinical examples

  • L21, pg 19
A
  • Actimmune (IFNy)
  • Pegasys (Peg-IFNy)
  • G-CSF (Neupogen), IL-2 (Proleukin), IL-7 and IL-15
296
Q

Cytokine clinical examples

  • L21, pg 19

Cytokine limitations
- L21, pg 20

A
  • Actimmune (IFNy)
  • Pegasys (Peg-IFNy)
  • G-CSF (Neupogen), IL-2 (Proleukin), IL-7 and IL-15
297
Q

Agonists for immune activating receptors

  • L21, pg 21
A
  • Pattern recognition receptors (PRR) on cells of innate imune system recognize conserved ‘patterns’ from microbes e.g Toll-like & NOD-like receptors (TLRs & NLRs)
  • Agonists can be used to stimulate innate immune response
  • Antagonists can suppress pathological inflammation
298
Q

Agonists for immune activating receptors

Advantages:

Disadvantages:

A

Advantages:
- Target the host not the pathogen - no selective pressure/resistance

Disadvantages:
- Overactivation of innate immunity - pathologic inflammation, autoimmunity

299
Q

Anti-microbial therapies

A
  • Anti-microbial peptides
  • bacteriophages
  • Predatory bacteria
300
Q

Anti-microbial peptides

A
  • Can be isolated from both eukaryotes and prokaryotes
  • New, natural “antibiotics” from bacteria, sea sponges, trees, plants, animals, milk…
  • Small - 10-15 amino acids (aa) usually cationic
  • Many in clinical trials, mostly topical
  • Issues with bioavailability & stability
  • Resistance will develop
301
Q

Anti-microbial peptides

  • L21, pg 25
A
  • Activity against bacteria, viruses & fungi
  • Also have effects on the immune system
  • Activity related to aa composition and properties, such as positive net charge, flexibility, size, hydrophobicity
302
Q

Phage Therapy

  • L21, pg 26
A
  • Viruses of bacteria
  • Specific host ranges
  • Can kill bacteria very quickly - new phage produced within 30 minutes
303
Q

Phage therapy

Advantages:

Disadvantages:

A

Advantages:

  • Very specific
  • Easy to grow and isolate
  • Little toxicity
  • Self-replacing and self-limiting
  • Good biodistribution

Disadvantages:

  • Bacteria develop resistance (therefore mixtures of phages are used)
  • Immune response to phages
  • Being used in a limited no. of clinics & in agriculture
  • Now also looking at lysis deficient phages & phage vaccines

PHCY220 (5 decks)

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