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PHCY220 > GI > Flashcards

GI Flashcards

1
Q

Stomach and Duodenum

  • Read over
  • Few pathogens can survive in the acidic environment (pH2) and proteolytic enzymes, which can survive in it?
A
  • One pathogen that can is HELICOBACTER PYLORI
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2
Q

Helicobacter pylori

  • Pic on L2, pg 4
  • how do they survive?
  • How are they transmitted?
  • What are infection rates linked to?
A
  • Gram -ve, spiral, 1-6 flagella, non-invasive
  • Survives by living in gut mucus layer, urease activity
  • Protected from immune system
  • Transmission - ingestion of food or water contaminated with faeces
  • Infection rates also linked to household crowding density
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3
Q

Diagnosis in NZ

  • Diagram on L2, pg 5
A
  • Stool/faecal antigen test
    • widely available, recommended
  • Breath test
    • gold standard, unfunded
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4
Q

H. pylori - dyspepsia

  • Symptoms?
  • Treatment?
A
  • Can be acute or chronic
  • Abdominal pain, nausea, vomiting, bloating, flatulencce, heartburn
  • Treatment/symptom relief - antacids
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5
Q

H. pylori - ulcers

Production of?

Damages the?

What makes the damage worse?

A
  • Production of exotoxins (vacuolating cytotoxin), inflammatory mediators, proteases etc)
  • Damage the gut wall
  • Stomach acid exacerbates damage
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6
Q

H. pylori - ulcers

Symptoms:

Emergency symptoms:

Treatment:

A

Symptoms: is dull, gnawing ache - often occurs when stomach is empty,
- weight loss, bloating, burping, nausea, vomiting

Emergency symptoms: Sharp, sudden, persistent stomach pain

  • Bloody or black stools
  • Bloody vomit or vomit that looks like coffee grounds

Treatment: eliminate bacteria
- reduce stomach acid

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7
Q

H. pylori - cancer

  • How does H. pylori cause cancer?
  • L2, pg 9
A
  • H.pylori infections causes accumulation of N-nitroso compounds and an elevated production of reactive oxygen species -> DNA damage
  • Cytotoxin-associated antigen A (cagA) gene - dysregulates SHP2 oncoprotein
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8
Q

H. pylori - prevention

A
  • Difficult to make a vaccine

- Best so far… subunit vaccine

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9
Q

Intesine

  • How many microbes in the intestine?
  • What do pathogens compete with?
  • What are the main symptoms
  • How are pathogens transmitted
A
  • Huge number of microbes in the intestine
  • Pathogens must compete with normal microflora
  • Main symptoms - diarrhoea
  • Transmission - contaminated food and water, zoonosis
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10
Q

Bacteria Intestinal diseases

A
  • L2, Pg 12
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11
Q

Food Poisoning

  • What is it?
  • What are the symptoms
  • How long does it last?
  • How is it treated?
  • How is it prevented?
A
  • Intoxification not infection
  • Ingest a large number of bacteria + bacterial toxins
  • Sudden, rapid onset
  • Violent diarrhoea, vomiting, cramps but no fever
  • Short duration (24 hours)
  • Treatment - fluid replacement
  • Prevention - high food handling standards
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12
Q

Staphylococcus aureus

  • What is it?
  • Where is it found?
  • How is it transmitted?
  • What are the complications?
  • How is it treated?
A
  • Gram +ve, toxin producing cocci
  • Ubiquitous
  • Transmission - contaminated food, milk, asymptomatic carriers (food handlers)
  • Complication - toxic shock syndrome - fever, hypotension, oedema, rash, organ failure
  • self limiting - treat dehydration
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13
Q

Clostridium perfringens & C. botulinum

pic on L2, pg 15

  • What is it?
  • Which one is common and which one is rare but can be fatal?
  • What does C.b. produce?
  • When can C.p. occur?
  • What is C.b. commonly associated with
A
  • Gram +ve, anaerobic rod, heat resistant spores
  • C.p. common, C.b. rare but can be fatal
  • Toxin producing - C.b. neurotoxin 10,000 x’s more potent than cyanide, treat with anti-toxin
  • C.p. outbreaks in institutions, C.b. canned foods
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14
Q

Vibrio parahaemolyticus & V. vulnificus

  • What is it?
  • Where is it found?
  • What are the symptoms?
  • What are the complications?
A
  • Gram -ve, marine bacteria
  • In NZ found sporadically in raw shellfish
  • Also common cause of food poisoning in S-E Asia, USA
  • Most stains not pathogenic
  • Diarrhoea, headache, vomiting, nausea, and abdominal pain
  • Complications - infection in immune compromised individuals
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15
Q

GI infections

  • What is the incubation time?
  • What is it?
  • Symptoms?
  • How do you treat?
A
  • Longer incubation - days not hours
  • Longer disease progression
  • Bacterial division and invasion
  • Fever
  • May not be self limiting
  • Main symptom still diarrhoea
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16
Q

Campylobacter jejuni

  • What is it?
  • What does it produce?
  • How is it transmitted
  • What are the symptoms?
  • What is the treatment?
  • How is it prevented?
A
  • Most common cause of bacterial diarrhoea
  • Gram ive, rod, flagella
  • superficial invasion, toxin producing
  • Transmission - zoonosis, contaminated food and water
  • Symptoms - diarrhoea, fever, abdominal pain, nausea, headache and muscle pain
  • self-limiting (7-10 days)
  • treatment - antibiotics - resistance!
  • prevention - improved hygiene
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17
Q

Yersiniosis

  • What is it
  • How is it transmitted?
  • What are the symptoms?
  • What is the treatment?
A
  • Gram negative, motile, coccobacillus
  • Yersinia enterocolitica and Y.pseudotuberculosis
  • Transmission - contaminated food, contact with farm animals, person - person
  • Symptoms - depends on age - diarrhoea, vomiting, fever +/- abdominal pain
  • Treatment - mild disease is self limiting, rehydrate
    • antibiotic therapy for severe disease, some resistance
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18
Q

Listeriosis

  • What is it?
  • How is it transmitted?
  • How is it treated?
A
  • Listeria monocytogenes, gram positive, motile, coccobacillus, grows at low temp
  • Uncommon, but outbreaks possible - contaminated food
  • Vertical transmission - in utero and during delivery
  • self-limiting mild GI disease, no specific therapy required
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19
Q

Shigella Dysentery

  • What is it
  • How is it transmitted?
  • How infectious is it?
  • What are the symptoms?
  • What is the treatment
A
  • Slender, non-motile, rods
  • Outbreaks - overcrowding, poor nutrition and poor hygiene
  • Person to person transmission, food and water
  • Highly infectious
  • Symptoms - depending on shigella sp. can range from fever + mild diarrhoea to bloody diarrhoea and cramping to dysentery
  • Treatment - mild disease is self limiting after 10 days to 2 weeks
  • antibiotic therapy for severe diarrhoea and dysentery
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20
Q

Salmonella

  • What is it?
  • How is it transmitted?
  • What are the symptoms?
  • What is the treatment?
A
  • Gram -ve, motile rod, toxin producing, facultatively intracellular
  • Widespread - animals, water, soil, carriers
  • Transmission - contaminated food and water
  • Wide variety in disease severity
  • S. enteritidis - mild gastroenteritis, minimal invasion & system involvment (self-limiting)
  • S. typhi - typhoid fever - multi-organ involvement (vaccine available)
  • Treatment - fluoroquinolones, some strains MDR
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21
Q

Escherichia coli

  • What is it?
  • How is it transmitted?
  • What is Enterotoxigenic (ETEC)
  • What is Enteropathogenic (EPEC)
A
  • Motile, gram -ve , toxin producing
  • Transmission via water/food contaminated with faeces

5 types of enterovirulent E. coli (EEC)

  1. Enterotoxigenic (ETEC) - travellers diarrhoea
    - Toxins heat-labile (LT) and heat-stable (ST) toxins
    - self-limiting, treat dehydration
  2. Enteropathogenic (EPEC) - infant diarrhoea
    - Bottle feed infants in developing countries
    - Self-limiting, treat dehydration
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22
Q

Escherichia coli

3.

  • What is Enterohaemorrhagic (EHEC)
A
  1. Enterohaemorrhagic (EHEC)
    - Are also known as Shiga toxin-producing E. coli (STEC) or Vero toxin-producing E. coli (VTEC)
    - Produce toxins (shiga/verotoxin) that cause a bloody diarrhoea
    - Complication - haemolytic uremic syndrome (HUS)
    - Raw or undercooked mince
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23
Q

E.coli

4.

5.

  • What is Enteroinvasive (EIEC)
  • What is Enteroaggregative (EAEC)
  • Pic on L2, pg 28
A
  1. Enteroinvasive (EIEC)
    - Bacillary dysentry
    - May be confused with shigella dysentery
    - Outbreaks associated with raw mince
    - Self-limiting, children at risk from HUS
  2. Enteroaggregative (EAEC)
    - Bacteria adhere to mucosa, forming a biofilms
    - Acute and chronic diarrhoea in children & travellers
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24
Q

Antibiotic associated diarrhoea

  • Whaat is it caused by?
A
  • Diarrhoea is most common drug adverse event
  • Usually no damage to GI tract
  • Can be acute or chronic
  • Common after use of antimicrobials, resolves after discontinuation
  • Caused by removal of normal microflora &
  • Proliferation of pathogens
  • Loss of metabolic function of microflora
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25
Q

AAD

A
  • Severe disease usually C. difficile, others C. perfringens, S aureus
  • Normally microflora prevents establishment
  • Can be severe
    • Pseudomem-branous colitis, dehydration, kidney failure, death
  • Risk factors - exposure to antimicrobials, age, hospitalisation
  • Prevention - very important, gloves, hand washing, probiotics?
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26
Q

Probiotics for diarrhoea

A
  • Many studies on use of probiotics to treat/prevent diarrhoea including ADD
  • Some evidence for efficacy
  • Also evidence for adverse effects in risk patients
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27
Q

Norovirus

  • Diagram on L3, pg 4
  • What is it?
  • What is sapovirus?
A
  • Single stranded (+) RNA, non-enveloped virus, high diversity
  • Sapovirus - also a human pathogen, fewer outbreaks than norovirus but similar settings. Can get co-infection with norovirus
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28
Q

Norovirus

  • How is it transmitted?
  • How contagious is it?
  • Where do outbreaks occur?
  • What other cases are there?
  • How is it treated?
A
  • transmission - direct, contaminated food/water
    • Highly contagious
  • Outbreaks in hospitals, cruise ships, elderly care facilities common
  • Also sporadic cases
  • Acute self-limiting gastroenteritis, or can be asymptomatic
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29
Q

Norovirus

  • How long is incubation?
  • How does it infect the dendritic cells, macrophages and B cells?
  • What are the symptoms
A
  • 48 hour incubation period
  • Pathogenesis not well described
  • Cross intestinal epithelial barrier to then infect dendritic cells, macrophages and B cells
  • Sudden D&V, stomach pain +/- fever, malaise
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30
Q

Norovirus - prevention & control

  • How is it prevented
A
  • Prevention & outbreak policies (eg ward closures, isolation of cases on ships etc) and staff training
  • Hand hygiene
  • Disinfection - chlorine products recommended for surfaces
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31
Q

Norovirus - vaccine?

  • What are the obstacles?
A

Obstacles

  • Cant grow it, highly diverse, dont understand pathogenesis or immunology
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32
Q

T+Rotavirus

  • What is it?
A
  • Single most important cause of severe infant gastroenteritis
  • DS non-enveloped RNA Virus
  • Worldwide distribution
  • Incidence similar, more deaths in developing countries
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33
Q

Rotavirus

  • Transmission
  • What are the symptoms?
A

Transmission

  • Faecal-oral route - virus highly contagious, stable in environment
  • Hospital infections a problem in developed countries
  • Water bourne, food bourne outbreaks are rare

Clinical features - acute rotavirus gastroenteritis

  • vomiting 1-2 days
  • Watery diarrhoea lasting ~5 days
  • Fever, malaise, dehydration
  • Little inflammation
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34
Q

Rotavirus Pathogenesis

  • L3, pg 11
A

-

-

-

-

-

-

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35
Q

Rotavirus - pathogenesis but is there more?

A

Have a look on L3, pg 12

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36
Q

Rotavirus treatment

  • how long does it take for the infection to go away without treatment?
  • How are infants treated?
  • What do you need to introduce?
A
  • Infection resolves within 1-2 weeks without treatment
  • Infants dehydrate very quickly so supportive care is vital - iv or oral rehydration
  • reintroduce age appropriate diet as soon as baby/infant wants to eat
  • Hyperimmune bovine colostrum
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37
Q

Rotavirus - Prevention

A

Rotashield vaccine introduced into the US in 1998, live oral vaccine given at 2,4,6 months of age, vaccine withdrawn 9 months later after severaal cases of intussusception (bowel obstruction)

  • Several large safety studies then done
  • Live, oral vaccine
  • Monovalent but has cross protection
  • Live virus will be shed after first vaccine
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38
Q

Rotavirus - prevention

A
  • Avoid contact with cases (48hr exclusion for day care)
  • Strict hygiene
    • hand washing
    • Surface disinfection
  • Breast feeding - protective maternal Ig
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39
Q

Enteroviruses

  • What is it?
  • How is it spread?
  • what does it infect?
A
  • family Picornoviridae, small, non-enveloped, + strand RNA
  • Spread via faecal-oral route or respiratory
  • Infect GI (or respiratory tracts) then spread systemically
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40
Q

Poliovirus - Epidemiology

A
  • Epidemiology changed with advent of improved public hygiene - infections no longer in infants, no later - more likely to cause paralysis
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41
Q

Poliovirus - Pathogenesis

  • What are the pathogenesis steps of poliovirus?
A
  1. GI replication (few/no GI symptoms, virus excreted for 2-8 weeks)
  2. Spread to lymphoid tissue, replication
  3. Invasion into blood - viremia
  4. Penetration of BBB - targets motor neurons
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42
Q

Poliovirus - vaccine

  • L3, pg 23
A
  • Live attenuated oral vaccine and an inactivated polio vaccine
  • IPV initially used, switched to OPV
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43
Q

Poliovirus - vaccine

A
  • NZ switched from OPV to IPV in 2002
  • 3 doses gives 99-100% seroconversion
  • Safe in pregnancy & breast feeding
  • Antibody does decline with time, no evidence of increased disease
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44
Q

Cryptosporidium

  • What is it?
  • What is it carried by?
  • How is it transmitted?
A
  • C.parvum, C. hominis
  • Protozoa - thick oocyst resistant to many disinfectants
  • Carried by animals & humans
  • Faecal-oral transmission, commonly water, also person-person & zoonotic
  • Acute infections in adults but diarrhoea can be prolonged (14 days)

-

-

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45
Q

Cryptospordium

  • How long is the incubation time?
  • What are the symptoms?
  • Who can is persist and spread in?
A
  • 1-12 day incubation
  • Invades gut epithelium, replicates, forming oocysts - excreted in feces
  • Immune response develops - CD4 cells vital (severe disease in HIV/AIDS)

Symptoms - diarrhoea (1-2 weeks), stomach pain, nausea, weight loss

  • Can persist and spread in immune suppressed people
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46
Q

Cryptospordium

  • When is therapy not needed?
  • What treatments are there?
  • What medicine is approved by the FDA and is on the NZ hospital medicines list?
A
  • Therapy not needed if immune-competent
  • No good treatments
  • Nitazoxanide is approved by the FDA & is on the NZ hospital medicines list
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47
Q

Giardia lamblia

  • What is it?
  • How is it transmitted?
  • What are the symptoms?
  • How is it diagnosed?
A
  • Flagellated protozoa
  • Cysts carried by animals & humans
  • Faecal-oral transmission of cysts, commonly water (swimming pools, river, lakes, tank water) person-person & sexual, zoonotic
  • Acute infection in adults but diarrhoea can be prolonged or chronic
  • Non-invasive
  • Stool sample for diagnosis
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48
Q

Giarda

  • How long is incubation?
  • What can cause complications?
  • What develops?
  • What are the symptoms?
A
  • 1-2 week incubation
  • Infection of gut epithelium, villi shortening, malabsorption & diarrhoea, increased permeability can cause complications
  • Immune response develops
  • Symptoms - diarrhoea, abdominal pain, bloating, weight loss, temporary lactase deficiency
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49
Q

Giarda

  • What is the firstline treatment?
  • What is the prevention?
  • What is being developed?
A
  • First line treatment is metronidazole, but resistance is increasing
  • Prevention - cysts resistant to chlorine disinfectants
  • Is a high level of surface antigen variation
  • Animal vaccines being developed
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50
Q

Gastric acid secretion overview

A

L4, pg 3

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51
Q

Gastric acid secretion - Parietal cell

A

L4, pg 4

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52
Q

Modulation of gastric Acid Secretion Phase 1 - Cephalic

L4, pg 5

A
  • Sight, smell, taste or thought of food. These stimuli, processed by the brain, activate enteric neurons via parasympathetic preganglionic neurons travelling in the vagus nerve
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53
Q

Modulation of Gastric Acid secretion Phase 2 Gastric

L4, pg 6

A

Food stretches the walls of the stomach;

  • this is sensed by mechanoreceptors, activating a neural reflex to stimulate acid secretion (purple)
  • Peptides and amino acids in food stimulate G cells to release gastrin (blue)
  • Food also acts as a buffer, the pH and thus stimulus for somatostatin secretion (light blue-green)
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54
Q

Modulation of gastric acid secretion phase 3 - Intestinal

L4, pg 7

A
  • Once chyme enters the duodenum, intestinal phase stimuli activate negative feedback mechanisms to reduce acid secretion and prevent the chyme from becoming too acidic
  • SOmatostatin (SST) released from antral D cells when gastric ph <3 inhibits gastric release in -ve feedback loop
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55
Q

How do these parasympathetic molecule work?

A

L4, pg 8

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56
Q

Gastric Defences Against Acid

  • Theres four of em
A
  1. Primary oesophageal defence is lower oesophageal sphincter
    - prevents reflux of gastric acid contents
  2. Key stomach defence - secretion of mucous layer
    - slows ion diffusion, prevents damage by pepsin
  3. Prostaglandins PGE2 and PGI2 stimulate mucous production and inhibit H+ secretion by parietal cells
  4. Secretion of bicarbonate by superficial gastric epithelial (or goblet) cells -> increases pH and prevents acid-related damage
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57
Q

Gastric defences against acid

A

L4, pg 10 & 11

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58
Q

Gastric Acid Conditions

  1. Gastrointestinal Oesophageal Reflux Disease (GORD)

pic on L4, pg 13

A
  • Chronic acid-related disorder
  • Reflux of gastric acid into the oesophagus
  • Left unresolved can develop erosive oesophagitis (strictures) and adenocarcinomas (bartletts metaplasia)
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59
Q

Gastric Acid Conditions

  1. Peptic Ulcer (gastric and Duodenal)
    - What are the symptoms?
    - What are the red flags?
    - What is the main causative factor?
    - What are some risk factors?
A
  • Caustic effects of acid , pepsin and bile overwhelm the defense factors of gastrointestinal mucosa
  • Burning stomach pain, nausea, full/bloated/belching
  • Red flags (severe signs): vomiting, black or tarry stools, unexpected weight loss
  • Main causative factor is presence of helicobacter pylori
  • Other risk factors include
    • Smoking
    • Excess alcohol
    • Genetic factors
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60
Q

gastric Acid Conditions

  1. Zollinger-Ellison Syndrome
    - Who gets this?
    - What are the symptoms?
A
  • Are rare, usually in 20-50. year olds
  • Symptoms
    • abdominal pain, diarrhoea, burning/aching/gnawing in upper abdomen, heartburn, nausea & vomiting, bleeding in digestive tract, unintended weight loss
  • Pancreatic or duodenal gastrinomas (produce gastrin) that stimulate production of very large amounts of acid
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61
Q
  1. Stress related mucosal injury
    - What is it?
    - How is it treated?
A
  • Ulcers of stomach or duodenum in context of profound illness or trauma requiring intensive care
  • Risk of gastric haemorrhage
  • Etiology involves acid and mucosal ischemia
  • treatment IV H2-blocker or IV PPI
  • Danger of aspiration pnemonia due to gastric colonization by bacteria in alkaline milieu
  • Sucralfate offers protection without risk of pnemonia
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62
Q

Therapeutic Strategies

  • There are 2:
A
  1. Enhance Mucosal Defence
    - Prostaglandin analogs: Misoprostol
    - Antacids
  2. Acid Suppression
    - Proton pump inhibitors (PPI)
    - H2-receptor antagonists (H2RA)
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63
Q

Enhancing Mucosal Defence: Antacids

A

L4, pg 19

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64
Q

Enhancing Mucosal Defence: Prostaglandins

  • L4, pg 21
  • What are the major PG’s synthesised in the gastric mucosa?
  • How is gastric acid secretion reduced?
  • What can stimulate the secretion of mucin and bicarbonate
A
  • Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the major PG’s synthesised in the gastric mucosa
  • PGE2 & PGI2 bind to the parietal EP3 receptor
    • Linked to Gi subunit, therefore inhibits AC and decreases cAMP and gastric acid secretion
  • PGE2 can also stimulate mucin & bicarbonate ssecretion
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65
Q

Acid suppression: H2 receptor Antagonists (H2RA’s)

A
  • L4, pg 22
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66
Q

Specific H2RA’s

A
  • Ranitidine (Zantac, peptisoothe, ranitidine relief, OTC/Rx)
    • More potent H2RA vs cimetidine
    • Also inhibits CYP450, but not clinically relevant at OTC doses (liquid and tablet)
    • Rx is subsidised
  • Famotidine (Pepzan, Rx)
    • Greatest affinity of all H2RAs
    • Does not inhibit CYP450
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67
Q

Acid Suppression: Proton-pump inhibitors (PPIs)

A

L4, pg 24

  • said dont need to know something (cant remember)
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68
Q

Proton-pump inhibitors (PPI’s)

A

L4, Pg 25 & 26 & (27- dont need to know)

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69
Q

Proton-pump inhibitor PK/PD)

A

L4, pg 28

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70
Q

PPI Adverse Effects

A

L4, pg 29 & 30

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71
Q

PPI Drug Interactions

A

L4, pg 31

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72
Q

CTZ

  • L5, pg 3
  • What does the vomiting centre control and integrate?
A
  • Impulses from the CTZ pass to areas of the brainstem referred to as the vomiting centre
  • Vomiting centre controls and integrates the visceral and somatic response involved in vomiting
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73
Q

What makes you vomit?

L5, pg 4

A
  • Emetic stimuli include:
  • Pathway and mediators include:
  • Enkephalins implicated in the mediation of vomiting
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74
Q

The Reflex Mechanism of Vomiting

  • L5, pg 5
  • Read over L5, pg 76
  • What is vomiting regulated by?
  • What is the main site of action for many emetic and antiemetic drugs?
  • The blood-brain-barrier (BBB) around the CTZ is relatively permeable. What does this mean?
  • What else does the CTZ regulate?
A
  • Vomiting is regulated centrally by the vomiting centre and the chemoreceptor trigger zone (CTZ)
  • The CTZ is sensitive to chemical stimuli and is the main site of action of many emetic and antiemetic drugs
  • The blood-brain-barrier (BBB) around the CTZ is relatively permeable, therefore circulating mediators act directly on CTZ
  • The CTZ also regulates motion sickness
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75
Q

Nausea

  • read over card

L5, pg 7

A

kufgd

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76
Q

Emetic factors

A
  1. Drug therapy induced emesis
  2. Others
    - odours
    - Tastes
  3. Motion Sickness
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77
Q

Emesis complications

A
  • dehydration
  • malnutrition
  • patient discomfort
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78
Q

Anti-emetics

  • L5, pg 11 & 12

There are 5 receptor antagonists

A
  • 5-HT3 receptor antagonists
  • Centrally acting dopamine receptor antagonists
  • Histamine H1 receptor antagonists
  • Muscarinic receptor antagonists
  • Neurokinin receptor antagonists
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79
Q

Treatments

A
  • L5, pg 13
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80
Q

H1 Antagonists (Antihistamines)

  • What are some examples?
  • Effective treatment for?
  • Not effective against?
  • What are the adverse effects?
A
  • Examples include promethazine, cyclizine, meclozine (not subsidised)
  • Effective treatment for nausea and vomiting arising from many causes
    • motion sickness
    • irritants in the stomach
  • NOT effective against substances acting on the CTZ
  • Most also have antagonistic activity at mACh receptors (likely to be important part of their mechanism of action)
  • Adverse Effects: Drowsiness and ssedation most common unwanted effect (H1 receptor involved in CNS arousal)
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81
Q

mACh Antagonists

  • L5, pg 15
A

dfrt

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82
Q

5-HT3 Antagonists

  • L5, pg 16
A

efrgthy

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83
Q

D2 Antagonists

  • L5, pg 17
A

ewrgty

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84
Q
  1. constipation
    - What is it?
    - How is it treated?
A
  • Infrequent defecation (usually <3 times /week) with stools that are hard, uncomfortable and difficult to pass (need to strain or feeling of incomplete evacuation)
  • Rationale for treatment is to:
    • relieve symptoms and restore ‘normal’ defecation pattern
    • Avoid straining, eg postoperative, ischaemic heart disease, haemorrhoids
  • Laxatives, cathartics, purgatives, aperients, and evacuants
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85
Q

Purgatives

1.

A
  • Purgatives hasten food transit through the intestine
  • Used to relieve constipation or to clear bowel before surgery or examination
  1. Bulk laxatives
    - Examples are methylcellulose, bran, psyllium
    - Polysaccharide polymers which do not get broken down
    - Attract water and form hydrated mass, promoting peristalsis
    - Generally take several days to work
86
Q

Purgatives

2.

3.

-L5, pg 25

A
  1. Osmotic laxatives
  2. Faecal Softeners
  3. Stimulant laxatives
87
Q
  1. Diarrhoea - types

- L5, pg 28

A

> 3 loose or liquid bowel movements a day

  • Osmotic
  • Secretory
  • Exudative
88
Q

Antidiarrhoeal Agents

1.

  • L5, pg 29
A
  1. Absorbents
89
Q

Antidiarrhoeal Agents

2.

  • L5, pg 30
A
  1. Morphine (& codeine)
90
Q

Antidiarrhoeal Agents

3.

4.

A
  1. Lopeeramide

4. Diphenoxylate (diastop)

91
Q

Genetics refresher

Mutation

Polymorphism

  • Pretty sure polymorphism is a change to the base sequence

L16, pg 18

A

Mutation:

  • Any change in DNA base sequence
  • May change protein function or expression

Polymorphism:

  • A change in DNA base sequence that is common in the population
  • > 1% frequency = polymorphism
92
Q

Genotype vs Phenotype

  • What is a genotype?
  • What is a phenotype?
A

genotype

  • DNA imprint (a set of genes)
  • Forever

Phenotype

  • Observed characteristics
  • May change
93
Q

What factors can predict differences in drug response?

A
  • Adherence to therapy
  • Differences in organ function and maturation (eg kidneys and liver)
  • Differences in body size and composition
  • Drug interaction
  • Genetic differences in drug handling
  • Old age
  • Sex
  • Co-morbidities
94
Q

Azathioprine

many indications:

Know these adverse effects:

A

many indications:

  • Inflammatory bowel disease
  • Severe inflammatory dermatoses
  • Rheumatic diseases
  • Prevention of solid organ transplant rejection

Know these adverse effects:

  • Bone marrow depression (myelosuppression, eg leucopenia)
  • Hepatic toxicity
95
Q

Azathioprine metabolism (for your reference)

  • L16, pg 29
A

lkjhgf

96
Q

Azathioprine toxicity

  • L16, pg 30
A
  • elevated conc. of 6MMP are asscoiated with hepatotoxic
  • 6TGN
    • The primary active metabolite
    • Elevated conc. associated with an increased risk of bone marrow toxicity
97
Q

Azathioprine pharmacogenetics

A
  • L16, pg 31
98
Q

How do we screen patients at risk of toxicity

  • read over
A
  • L16, pg 32 & 33 & 34
99
Q

TMPT-guided azathioprine dosing

A
  • L16, pg 35
100
Q

Omeprazole

A
  • Treatment of peptic ulcers and GORD
101
Q

Proton pump for H+

  • L6, pg 5
  • Shit on L6, pg 6
A
  • Omeprazole is a PPI
  • Interested in the parietal cell
    • we want to reduce the acid secretion
  • Proton pump controls the stuff
  • Omeprazole prevents the hydrogen ions from pumping into the lumen
  • Omeprazole is absorbed (systemically) in the small intestine
  • Binds irreversibly to proton pump
  • Omeprazole is a prodrug (inactive) in blood
  • Acidic conditions of the secretory canaliculi is the trigger for the activation of omeprazole
102
Q

Enteric coating

  • What does it improve?
  • When does it release?
  • What is the primary site?
A
  • To improve bioavailability

Enteric coating:

  • Intact at low pH and release at higher pH
  • Small intestine is the primary site for drug absorption
  • Hydroxyproplycellulose
103
Q

Solubility of enteric coated polymers

A
  • Eudragit

- Solubility stays low at low pH, when pH gets to the higher pH then solubility inc.

104
Q

Nasogastric tube

  • Inserted in the nose -> to the stomach
  • L6, pg 15
A
  • Maintain stability of omeprazole
  • Ensure correct dose
  • Volume of dispersant
105
Q

Colon

  • healthy mucosa
  • inflamed mucosa
A
  • L6, pg 17
106
Q

Degradation mechanisms unique to the colon

A
  • Many and diverse bacteria
  • Anaerobic
  • Fermentation
    • SCFA production
  • Bacterial enzymes
  • Caution with the concomitant use of antibiotics
    • Disrupts colonic microflora
107
Q

Azoreductase activity - targeted delivery

  • L6, pg 19
A
  • two different enzymes

- Inc of enzymatic activity towards end (terminal) of GI tract

108
Q

Aminosalicylate prodrug

  • L6, pg 20
  • What does it require to be released as the active form?
  • Once it reaches the colon, which group is cleaved by colonic bacteria?
A
  • Sulphasalazine - the original IBD drug
  • inactive that requires enzymatic transformation in vivo to release the active moiety
  • Not absorbed from the small intestine
  • Once reached the colon, the nitrogen group is cleaved by colonic bacteria (azoreductase)
109
Q

Mesalazine formulations

  • What does it contain?

PENTASA

  • What is it for?
  • What type of release?
A
  • Contain 5-aminosalicyclic acid (5-ASA)
    0 Anti-inflammatory action
  1. PENTASA (5-ASA)
    - Ulcerative colitis and crohns disease
    - Time-dependent release
    - Prolonged release microgranules
    - Release continuously throughout the GIT
    - Release at all pH conditions
110
Q

Oral formulations

A
  • SR microgranules in a shachet

- SR microgranules in a tablet (500mg)

111
Q

rectal formulations

A
  • Liquid enemas
    • Suspension in purified water
      - Shake well before use
    • Distal colon
  • Suppositories
    • Sustained release base
112
Q

Mesalazine formulations cont

  • What are the 2 types of formulation?
A
  1. Asacol

Oral formulation

  • Delayed release formulation
  • Enteric coated tablets (gastro-resistant)
    • Film coating dissolves at ph >7

Rectal formulation
- Suppository

113
Q

Drug Dosing: three methods

  • What is the population method?
  • What is the covariate-based dosing method?
  • What is the Dose-individualisation method?
A
  1. The population method (same dose given to everyone)
    - Some patients would be under - or over-dosed
    - The clinical significance of this variability is negligible
  2. Covariate-based dosing (same dose for similar group)
    - A dose is adjusted based on covariate (eg weight or creatinine CL)
    - Assumes people of the same value of a covariate handle drug similarly
  3. Dose-individualisation (response-based dosing)
    - When even a small variability in response is detrimental to the patient
    - Therapeutic drug monitoring ‘TDM’
114
Q

response

  • L7, pg 9
A

defrgtyhuj

115
Q

PK response (aka drug conc.)

A
  • We usually measure a drug conc. (usually in plasma)

- But response is usually variable

116
Q

Variability

  • L7, pg 11
A
  • Between-subject
  • Within-subject
  • Random
117
Q

How are drugs with a narrow therapeutic range problematic?

A
  • An ‘average’ dose may be appropriate for one patient, toxic for a second patient, and sub-therapeutic for a third patient
118
Q

Therapeutic range

  • refers to:
  • defined as?
A
  • Refers to the plasma conc. that should lead to effectiveness without toxicity in most patients
  • Defined as the drug concentration range above the minimum effective conc. (MEC) and below the minimum toxic conc. (MTC)
119
Q

Therapeutic window

A

L7, pg 14

120
Q

Bioavailability

L7, pg 16

A

uygftdr

121
Q

The determinants of bioavailability

  • There are three primary determinants of bioavailability:
A

a) Disintegration and dissolution of the drug
b) Absorption across the membranes in the gut wall
c) Pre-systemic metabolism (or ‘first-pass’) and elimination

122
Q

Same drug and dose, different formulations

  • L7, pg 18
A

jkhbvgh

123
Q

Determinants of drug absorption from the gut

  • there are four determinants
  • Pic on L7, pg 20
A
  1. Disintegration and dissolution of the drug
  2. Physiology of gastrointestinal tract
  3. Food or drug interactions in the gut lumen
  4. Passage through the gut wall
124
Q
  1. Disintegration and dissolution
    - What can readily traverse the gut wall
    - What does it depend on?

L7, pg 21

A
  • Only dissolved drug can readily traverse the gut wall

Will depend on:

  • The release characteristics of dosage form
  • Physiochemical properties of the drug
125
Q

The rate limiting step. If has:

L7, pg 22

A

uyut

126
Q
  1. Physiology of Gastrointestinal tract

L7, pg 23, 24, 25

A
  • Gastric emptying - highly variable b/w people
  • Small intestine transit time - much less variability
  • Gastric emptying time may impact absorption rate for drugs that readily dissolve in the stomach (paracetamol) or enteric coated drugs
  • Insoluble drugs may have enhanced absorption if transit time is slow
127
Q
  1. Food or drug interactions in the gut lumen

L7, pg 26, 27, 28

A
  • Altered pH

- Complexation

128
Q
  1. Passage though the gut wall (cellular mechanisms)

- L7, pg 29

A
  • Passive diffusion
  • Carrier-mediated transport
    • Active transport
129
Q

Passive diffusion

  • Drug diffuses from?
  • When will the conc. in the gut be much higher than in the plasma?
A
  • The primary absorption process for most drugs
  • Drug diffuses from high conc. to low conc.
  • After oral drug administration, when drug is reaching the gut lumen, the conc. in the gut will be much higher than in the plasma
130
Q

Active transport

  • What is required?
  • Transporters are?
  • What do they include?
A
  • May be against a conc. gradient
  • Energy is required
  • Transporters are saturable and can be competitively inhibited (drug interactions)
  • Include efflux transporters (eg P-glycoprotein) that limit drug absorption from the gut
131
Q

What are the different types of observational studies

A
  • Cross sectional
  • Case-control studies
  • Cohort studies
132
Q

Cohort study

  • L8, pg 9, 10
A
  • Data obtained from groups who have already been exposed, or not exposed, to the factor of interest. No allocation of exposure is made by the researcher. Best risk factors on an outcome
133
Q

Pros and cons of cohort study

A

Advantages:

  • Ethically safe
  • Participants can be matched
  • Can establish timing and directionality of events
  • Eligibility criteria and outcome assessments can be standardised

Disadvantages

  • Controls may be difficult to identify
  • Exposure may be linked to a hidden confounder
  • Blinding is difficult
  • For rare disease, large sample sizes or follow-up necessary
134
Q

Case-control study

  • L8, pg 12, 13
A
  • Patient with a certain outcome or disease and an appropriate group of controls, without the outcome or disease, are selected (usually with some matching) then information is obtained on whether the subjects have been exposed to the factor under investigation
135
Q

Pros and Cons of case-control study

A

Advantages

  • Quick and cheap as fewer people needed than cross-sectional studies
  • Only feasible method for very rare disorders or those with long lag b/w exposure and outcome

Disadvantages:

  • Reliance on recall or records to determine exposure status
  • Confounders
  • Selection of control groups is difficult
  • Potential bias: recall, selection
136
Q

Cross sectional study

L8, pg 15, 16

A

kjhgf

137
Q

Pros and cons of cross sectional study

A

Advantages:

  • Cheap and simple
  • Ethically safe

Disadvantages:

  • Establishes association at most, not causality
  • Recall bias, social desirability bias
  • Researchers (Neyman) bias
  • Group sizes may be unequal
  • Confounders may be unequally distributed
138
Q

sum shit on L8, pg 18

A

kjhg

139
Q

Error

  • What does random error mean?
  • What is a systematic error?
  • What is a random error?
A
  • Random error = random variation, or ‘noise in the system’, chance
  • Systematic error = is consistent, repeatable error associated with faulty equipment or a flawed experiment design
  • Random error can be reduced by large study sizes: bigger studies give more precise estimates Systematic error can’t
140
Q

Bias (systematic error)

  • L8, pg 20
A

hkujh

141
Q

Selection/Sampling bias

  • L8, pg 22
A
  1. Control selection bias
  2. Loss to follow-up bias
  3. Self-selection bias
  4. “Healthy worker” effect
142
Q

Selection Bias in a case-control study
- L8, pg 23, 24

Selection bias in a retrospective cohort study
- L8, pg 25

A

Information bias
- L8, pg 26, 27

Confirmation Bias
- L8, pg 28

143
Q

Confounding

- L8, pg 29, 30

A

measure of association

-L8, pg 31, 32, 33, 34, 35

144
Q

Pharmacological Therapy: 4 classes of laxatives

A
  1. Bulk-forming laxatives
  2. Stool softeners
  3. Stimulant laxatives
  4. Osmotic laxatives
145
Q

Bulk forming laxatives

Describe:

  • Mode of action
  • Time frame for effect
  • Common side effects
A
  • Exert effect by mimicking increased fibre consumption and increasing feacal mass
  • Patients should inc. fluid intake at the same time
  • Effect seen 12-36 hours but can take as long as 72 hours
  • Side effects: flatulence and abdominal distension
  • Safe in pregnancy
  • Tip: briskly stir in powder and drink immediately
146
Q

Stool softener

Describe:

  • Mode of action
  • Time frame for effect
  • Common side effects
A
  • Effective for mild constipation (especially prevention of haemorroids)
  • Examples docusate sodium
  • Docusate works as a stool softener as well as a stimulant
  • Poloxamer is a non-ionic surfactant with similar properties to docusate
  • X liquid paraffin
147
Q

Stimulant laxatives

Describe:

  • Mode of action
  • Time frame for effect
  • Common side effects
A
  • Increase GI motility & irritate lining of colon to produce contractions
  • Examples: bisacodyl, senna
  • Quicker onset than other laxatives (6-12 hours) hence take at night
  • Most commonly abused laxative
  • Nu-lax (natural alternative) contains senna leaves
148
Q

Osmotic laxatives

Describe:

  • Mode of action
  • Time frame for effect
  • Common side effects
A
  • Act by retaining fluid in the bowel by osmosis
  • Example: Lactulose, macrogols
  • Common side effects: Flatulence, abdominal pain and colic
  • Can take 48 to 72 hours before an effect is seen
149
Q

Haemorrhoids

  • read over
A
  • Haemorrhoids or “piles” are common and affect around 50% of adults at some point in their lives
  • They occur when vascular-rich connective tissue cushions become engorged and swollen
  • They can be categorised into two types based anatomically: internal or external
150
Q

Causes of haemorrhoids

A
  • Anatomical (degeneration of elastic of connective tissue due to ageing)
  • Physiological (increased anal canal pressure from heavy lifting, obesity, chronic diarrhoe, childbirth, standing for long periods of time)
  • Mechanical (straining at stool from constipation and prolonged sitting on toilet interfering with blood flow to and from rectal area)
151
Q

haemorrhoids

symptoms:

red flags:

Treatment:

A

Symptoms

  • bleeding from rectal areas, especially after bowel motion
  • Perianal itching and pain

Red flags

  • Symptoms longer than 3 weeks
  • Large volume of blood
  • Sharp or stabbing pain at time of defecation
  • Over 50 years of age

Treatment:

  • Inc. fibre in diet
  • Avoid becoming constipated
  • Pharmacological
    • anaesthetics
    • Astringents
    • Anti-inflammatories
152
Q

Anusol:

Proctosedyl:

Ultraproct:

A

L9, pg 21

  • more about them in Lt
153
Q

irritable Bowel Syndrome (IBS)

symptoms:

Treatment:

red flags:

A

Characterised by abdominal pain and discomfort; usually associated with at least 2 of the following symptoms

  • Pain and discomfort relieved by defecation or passing wind
  • Bowel motions more or less often usual
  • Change in bowel habit - diarrhoe and/or constipation
  • Symptoms occuring at least 3 time a month

Other symptoms include

  • Feeling of incomplete defacation
  • Passing mucus
  • Bloating

Treatment:

  • Diet and lifestyle changes are first line treatment
  • Smaller, more frequent meals
  • A low FODMAP diet
  • Avoid triggers eg alcohol, caffeine
  • Manage stress
  • Ensure adequate hydration
  • Increasing physical activity
  • Pharmacological options (L9, pg 27)

Red flags

  • Children under 16 years of age
  • Over 45 years of age with recent change to bowel habit
  • Change in nature and severity of pain
  • Pain that is not normal in the left lower quadrant
  • Blood in stool
154
Q

Threadworms

A
  • Also known as pinworm
  • Most common in children but can also affect adults
  • Most children between 5-14 will be infected at some stage
  • Small, thin, white worms between 2mm an 13mm long
  • look like cotton threads
155
Q

Threadworms transmission

migrate nocturnally

A

Transmission via

  • Self-infection - ingestion of eggs
  • Person to person via contaminated cloths and bed linen
156
Q

Threadworms

Clinical maifestations:

Red flags:

Hygiene measures and advice:

Treatment options:

A

Clinical maifestations:

  • Itchy anal region
  • Secondary infection from scratching
  • Teeth grinding and isomnia due to disturbed sleep
  • Loss of appetite
  • Abdominal pain

Red flags:

  • Pregnant women
  • Children under 1 year old
  • Secondary skin infection from scratching
  • Recent travel (exotic worms)

Hygiene measures and advice:

  • Shower in the morning to remove infected eggs
  • Frequently change cloths, bedding etc
  • Avoid scratching
  • Treat the whole family

Treatment options:

  • Mebendazole
  • Pyrantel
157
Q

Protection of the gut

  • Pic on L10, pg 4
  • not assessed
A
  • One side is good for protecting the gi tract from pathogens and the other is for absorbing nutrients
158
Q

Health vs Disease

  • Pic on L10, pg 5
A

in the leaky barrier the antigens are getting in and the T cells respond

  • Inflammation causes more damage
  • Leaky barrier is due to genetics & environment which cause inflammation
159
Q

Coeliac disease

  • Pics on L10, pg 6
A

Inflammatory disease of the small intestine triggered by gluten in susceptible individuals, characterised by damage to villi and nutrient malabsorption - GI symptoms (D&V, weight loss) and/or malnutrition related problems eg fatigue, anemia, bone/joint pain depression

160
Q

Coeliac disease epidemiology

  • L10, pg 8 & 9 & 10
A
  • Female bias (2-3:1)
  • Genetic influence
  • Environmental - Exposure to gluten peptides - gliadins & glutenins (high proline & glutamine content)
    • These are not easily digested in the GI tract
  • Breast feeding - increased duration, reduced risk
161
Q

Coeliac disease

Diagnosis:

Treatments:

L10, pg 12

A

Diagnosis:
- History, biopsy, Ig to TG2 or deamidated gluten peptides (blood test)

Treatments:

  • Gluten free diet
  • Decrease/remove immunogenic epitopes from gluten
  • Sequester gluten
  • Prevent gluten uptake
  • TG2 inhibition
162
Q

Inflammatory Bowel Disease (IBD)

L10, pg 13

A
  • Crohns disease

- Ulcerative colitis

163
Q

Crohn’s Disease

Risk factor:

Location:

Pathology:

Histology:

A

Risk factor:
- Genetics, environment (smoking)

Location:
- Inflammation frequently affects distal ileum and colon

Pathology:
- Discontinuous, patchy gut inflammation with skip lesion

Histology:
- Transmural inflammation (all layers of the bowel wall)

164
Q

Ulcerative Colitis

Risk factors:

Location:

Pathology:

A

Risk factors:
- Genotype and environment

Location:
- Inflammation affects the colon only (distal colitis or proctitis, left-sidedd colitis and pancolitis

Pathology:
- Continuous inflammation from the rectum to proximal parts of the colon

165
Q

Smoking

A
  • its protective for UC

- Nicotine may be a therapeutic for UC

166
Q

CD and UC - diagnosis

A
  • No definitive diagnostic test

- History, presentation, endoscopy, blood tests for inflammation & infection

167
Q

Genetic Factors:

Environment:

L10, pg 22

A

Genetic Factors:

Environment:

  • Diet?
  • Stress?
  • Drugs?
  • Smoking?
  • Microflora/infection?
168
Q

IBD - Microbiota

  • Presence of these bacteria stimulates what?
  • What does it protect against?
  • L10, pg 23
A
  • Presence of these bacteria stimulates the immune system to keep them in check
  • Protects against colonisation by pathogens
169
Q

IBD - Dysbiosis

  • Environment induces changes in what?

L10, pg 24

A
  • Environment induces changes in bacterial composition
    • dec. diversity
    • Inc. pathogen adherence
  • Combined with genetic predisposition = IBD
170
Q

IBD pathogenesis

  • What are the simple steps
  • L10, pg 25
A
  • Alterations in epithelial barrier function
  • Translocation of luminal antigens
  • Aberrant and excessive cytokine responses
  • Failure to resolve acute intestinal inflammation leads to chronic intestinal inflammation & pathology
171
Q

IBD treatments - biologics

  • How many available?
  • What do they target?
  • What are the side effects?
  • What is the issue?
  • L10, pg 28
A
  • Numerous biologics available
  • Lack of head to head studies to address differences in efficacy
  • many target TNF
  • Side effects - increased risk of malignancy or serious infection
  • Data on long term efficacy still coming in
  • As always the issue of cost
172
Q

Faecal Microbiota transplant

  • What does it use?
  • How is it delivered?
  • What is the remission percentage for UC and CD
  • What are some side effects?

L10, pg 29 & 30 & 31

A
  • Use fresh or frozen faeces preps
  • Various delivery - top or bottom
  • UC - 33% remission
  • CD - 52% remission
  • Safe - some transient bloating, flatulence, cramping
173
Q

Ulcerative Colitis

What type of reaction? And where?

  • Pics on L11, pg 6
A
  • Inflammatory reaction restricted to the colon

- From the rectum, inflammation is uniform and continuous

174
Q

Potential targets for Drug therapy

  • L11. pg 9

Potential targets for Drug therapy contd L11, pg 10

A
  • If GI epithelium damaged, bacterial antigens gain access to antigen presenting cells (APC) who present antigens to CD4+ cells
  • APC either secrete IL-12 and IL-18 to induce differentiation of Th1 cells (CD or IL-4 to induce differentiation of Th2 (T helper cells) (UC)
  • Pro-inflammatory and anti-inflammatory balance governed by Th17 (inc. inflam) and Treg cell (dec inflam)
  • Transforming growth factor (TGFb) and IL-6 drive expansion of Th17 and Treg cells
175
Q

Goals of therapy

A
  1. Induce and maintain remission
  2. Ameliorate symptoms
  3. Improve pts quality of life
  4. Adequate nutrition

5, Prevent complication of both the disease and medications

176
Q

Drug classes to treat IBD

A
  1. Anti-inflammatory drugs
    - Aminosalicylates (mesalazine)
    - Glucocorticosteriods (prednisolone)
  2. Antibiotics
    - Metronidazole
    - Ciprofloxacin
  3. Immunosuppressants
    - Azathioprine
    - Methotrexate
    - Ciclosporin
    - Mercaptopurine
  4. Biological response modifiers
    - Infliximab
    - Adalimumab
177
Q
  1. Anti-inflammatory drugs
A
  • 5-aminosalicylate (mesalazine), sulfasalazine

- Administered by oral or rectal formulations

178
Q
  1. Anti-inflammatory drugs (Glucocorticoids)
    - What is the major steroid for UC and CD?
    - What are the routes of administration?

L11, pg 16 & 17 & 18 & 19

A
  • Anti-inflammatory and immunosuppressant drugs
  • Prednisone is the major steroid for UC and CD
  • Routes of administration
    • Oral prednisone, budesonide
    • IV methylprednisolone, hydrocortisone (HC)
    • enema (HC) and rectal foams (HC)
179
Q

Long term risks of glucocorticoids

Adrenal axis suppression:

Effects on carbohydrate, protein and fat metabolism:

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
  • Redistribution of body fat (‘moon face’, ‘buffalo humps’)
  • Elevation of mood
  • Skin thinning
180
Q

Immunosuppressants

  • L11, pg 21
A

jhgvh

181
Q

Immunosuppressants - Methotrexate

Uses:

MoA:

SE:

A

Uses:
- Cytotoxic and immunosuppressive actions, potent anti-rheumatoid action

MoA:
- Folic acid antagonist - competitively inhibits dihydrofolate reductase important for de novo synthesis of thymidine (nucleotide)

SE:
- Blood dyscrasias (sometime fatal, folic acid) and liver cirrhosis

182
Q

Immunosuppressants

Ciclosporin

  • L11, pg 24
A

defy

183
Q

Biologicals - Anti-TNFa therapy

Infliximab

A
  • L11, pg 25
184
Q

Treating viral infections

A
  • Target the virus = DAA (direct acting antivirals)
185
Q

Selective Drug targets for DAA

A
  1. Receptor/co-receptor binding
  2. Fusion to release subvirion
  3. Release viral genome
  4. Translation for viral proteins
  5. Genome multiplication
  6. Assembly, packaging, and release
186
Q

HAV

A
  • Acute, self limiting infection
  • +ve strand -non-enveloped, acid stable, heat resistant
  • Transmission via contaminated food and water person-person transmission, blood transmission
187
Q

HAV replication

A
  • +ve strand RNA virus - direct translation of enzymes and structural proteins
  • Transcription of RNA by viral polymerase occurs in a cytoplasmic vesicle
  • Virus does not enter nucleus
  • Virus is released by lysis
188
Q

HAV

A
  • 2-7 week incubation
  • Symptoms - malaise, nausea, dark urine, jaundice, hepatomegaly

Treatment:

  • No specific therapy
  • Alcohol avoidance
  • Monitor medications

Prevention

  • Passive immunisation
  • Active immunisation
189
Q

Hepatitis B virus (HBV)

  • L14, pg 12 & 13
A
  • Acute and chronic hepatic infection
  • Enveloped virus
  • Partially ds circular DNA virus, -ve strand, incomplete (+) strand
190
Q

HBV

transmission:

A

Transmission:
- Via blood, blood products, sexual contact, perinatal transmission, insects

  • In areas with high HBV prevalence, childhood infections are common
  • In areas of low HBV prevalence, most infections occur in adult
191
Q

Pathophysiology

A
  1. Immune-tolerant phase
    - elevated HBV DNA, normal ALT
  2. HBeAg-positive
    • immune-active phase - elevated ALT & HBV DNA levels, liver injury from immune response
  3. Inactive/chronic phase - HBV DNA and ALT down/normal, anti-HBe is present, liver recovery, ~ 0.5%/year will get disease resolution (clearance of HBsAg with acquisition of antibody to HBsAg)
  4. HBeAg-negative immune reactivation phase - elevated ALT & HBV DNA levels, liver injury
192
Q

Testing

A
  • serology for antigen & antibody

- Provides information on phase of infection

193
Q

Treatment

A
  • Aim to suppress viral replication & stop progression
194
Q

Prevention

A
  • Public Health measures & education.
    • Blood product screening, no needle sharing (IDU, tattoos, piercings), safe sex
  • Passive immunisation
  • Active immunisation
195
Q

Hepatitis C (HCV)

A
  • Acute and chronic hepatic infection
  • +ve strand, RNA virus
  • Huge sequence diversity (high replication rate and poor proof reading)
  • Replication - similar to HAV
  • Transmission - blood, both HCV & HBV more infectious than HIV, high risk of co-infection
196
Q

Risk factors of HCV

A
  • History of drug use
  • Sexual contact
  • Tattoo
197
Q

Before can treat need to screen

screen patients with risk factors for chronic HCV infection

A
  • received a blood transfusion or organ transplant prior to 1992
  • Use of injectable drugs
  • spent time in prison
  • Have a tatoo
198
Q

Treatment

A
  • move away from drugs that only work on afew genotypes to drugs that work on many genotypes
  • eg Maviret
199
Q

HCV prevention

A
  • Blood product screening, no needle sharing, safe sex

- No vaccine is present

200
Q

Summary

A

HAV - self limiting

HBV - control with vaccination (on schedule) and treat

HCV - no vaccine, screen, treat & now cure

201
Q

Aminotransferases (‘transaminases’)

  • Alanine transaminase (ALT)
  • Aspartate transaminase (AST)
A
  • Intracellular enzymes involved in the production of amino acids
  • Ubiquitous throughout the body but conc. vary greatly in different tissues
  • Increased plasma conc. caused by leakage (injury) from enzyme-rich tissue
202
Q

Alanine transaminase (ALT)

A
  • Very high conc. in the liver compared to other organs

- Elevations suggest liver injury

203
Q

Aspartate transaminase (AST)

A
  • High conc. in several organs
    • cardiac muscle>skeletal muscle>Kidneys>Lungs>RBC
  • Elevations may suggest
    • cardiac muscle injury
    • Skeletal muscle injury
    • Haemolysis
    • Hepatocyte injury
  • Not specific for liver injury
204
Q

AST & ALT elevation

A

Mild/moderate elevations (2 - 20x normal)

  • Non-specific (eg a night out at the pub)
    • most chronic viral hepatitis
    • Alcohol hepatitis
    • Various drugs
  • Marked elevations (20 - 1000x normal)
    • Suggest severe liver injury
      • Ischemic liver injury
    • Acute viral hepatitis
    • Fulminant necrosis
    • Some acute drug toxicities
205
Q

AST/ALT ratio elevation

A

AST/ALT ratio > 2

  • Alcohol hepatitis
  • Alcoholics are often malnourished and lacking in vitamin B6 - required for the formation of ALT

Fluctuating AST and ALT
- Hepatitis C (LFTs may be normal)

206
Q

Alkaline phosphatase (ALP)

A
  • Enzymes that cleaves phosphate from proteins (and other molecules)
  • Found on canalicular surface of hepatocytes, bone, kidney, placenta
  • Elevated in plasma when there is damage to biliary tract (but not a specific marker)
  • The clinical value of this test is detection of cholestatic disease
207
Q

Elevated ALP

A

Mild elevation:

  • Hepatic disease
  • Pregnancy
  • Bone growth in children

Marked elevation

  • Cholestatic disease
  • Bone disease (osteomyelitis, bony metastasis)
  • Cancer
208
Q

Gamma glutamyltranspeptidase (GGT)

A
  • Found on canalicular surface of hepatocytes, kidney, pancreas and gut
  • Not a specific marker of liver disease

Clinical value:
1. inc. GGT and inc. ALP is suggestive of cholestasis

  1. Isolated inc. GGT can occur in alcohol abuse
209
Q

Bilirubin

A
  • A metabolic product of heme (RBCs)
  • Hyperbilirubinaemia may be due to:
    1. over production (eg haemolysis)
    2. Impaired metabolism (rare genetic disorders)
    3. Under-excretion
  • Hyperbilirubinaemia involves blockage of the biliary tree due to;
    • Obstruction (eg cholelithiasis)
    • Inflammation (cholangitis)
  • In excess, bilirubin is deposited in skin, sclera, mucus membranes (jaundice)
210
Q

Bilirubin: conjugated vs. unconjugated

L15, pg 20

A
  • “direct bilirubin” = conjugated = glucuronidated in the liver
  • “Indirect bilirubin” = unconjugated = not glucuronidated
211
Q

Bilirubin: conjugated vs. unconjugated

  • L15, pg 21
A
  • Elevated conjugated bilirubin suggest an obstructive cause
212
Q

Test for liver function - Albumin & Prothrombine time (PT) & INR

A

L15, pg 24 & 25

PHCY220 (5 decks)

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