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GIS > GIS30 Treating Hepatitis And Parasitic Infection > Flashcards

GIS30 Treating Hepatitis And Parasitic Infection Flashcards

1
Q

Hepatitis B virus

A

Survive outside the body for at least 7 days

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2
Q

Acute hepatitis B

A

Incubation period: 75 days (30-180)

Symptoms:

  • Most people: ***Asymptomatic
  • flu-like symptoms
  • jaundice
  • dark urine
  • extreme fatigue
  • nausea
  • abdominal pain

Recovery:

  • Healthy adults >90% recovery and completely rid of virus within 6 months (<5% become chronic)
  • Children <6 infected more likely become chronic infection
  • Infants infected during 1st year very likely become chronic
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3
Q

Antiviral therapy

A

may not help if already have severe liver damage

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4
Q

Liver cancer

A
  • almost always fatal (die within months of diagnosis)
  • Surgery, chemotherapy prolong life up to a few years
  • Liver transplant varying success
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5
Q

Treatment for chronic hepatitis B

A

Indication:
1. HBV DNA level > 20000 IU/mL
2. Serum ALT elevated
—> both for 3-6 months

—> ***NOT advised when little indication of liver damage (normal ALT / normal biopsy / latent infection)

Monitoring:
- Blood test: Viral activity + Liver enzymes

Drugs (兩隻):

  1. IFN / pegylated-IFN
  2. NRTI
    - Entecavir
    - Tenofovir
    - Lamivudine
    - Adefovir dipivoxil
    - Telbivudine
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6
Q

Interferon

A
  • protein made by body’s immune system to combat virus
MOA:
1. Alert cells of presence of virus
—> ***Direct own immune system to produce Antiviral proteins
—> Block viral reproduction
—> inhibit spread of virus
2. Block viral ***RNA transcription
3. Block ***protein synthesis

Administration:

  • IM / SC injection
  • 2-3 times / week
  • ***6 months to 1 year

CI:
- Cirrhosis (hepatitis flare —> interferon attack liver cells as well) —> use NRTI instead

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7
Q

Pegylated interferon

A

PEG: polyethylene glycol
—> attach to interferon
—> interferon stay in body much longer
—> ↑ t1/2

Pegylated IFN-α-2a vs 2b
- Main difference: dosing
- IFN alfa-2a:
—> ***fixed weekly dose
—> relatively ***constant absorption after injection
—> distributed mostly in blood and organs
- IFN alfa-2b:
—> weekly dose based on ***weight
—> ***rapid absorption
—> wider distribution (e.g. fat)
  • ***ONLY for adults
  • also used to treat Hep C

Administration:

  • SC injection
  • ***once a week
  • ***6 months to 1 year
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8
Q

SE of (peg)-interferon

A

(Act like fighting infection)

  • ***flu-like symptoms
  • insomnia
  • depression
  • skin rashes
  • ***extreme tiredness
  • loss of appetite / weight loss
  • ***arthritis-like pain in back and joints
  • GI disturbance
  • low blood cell count
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9
Q

Pros and Cons of (peg)-interferon

A

Pros:

  1. Good choice for young ppl without serious liver disease (well-compensated liver disease)
  2. Good choice for ***genotype A / B infection > type C / D
  3. ***Short treatment duration (24-48 weeks)

Cons:

  1. Not available for failing liver (***cirrhosis / decompensated / deteriorating liver disease) —> Hepatitis flare
  2. Very serious SE
  3. Expensive
  4. Pegylated interferon not approved for children
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10
Q

NRTI: Nucleos(t)ide reverse transcriptase inhibitors

A
  1. Entecavir —> Deoxy***guanosine analogue
  2. Tenofovir —> Deoxy***adenosine 5’-monophosphate analogue
  3. Lamivudine —> Cytidine analogue
  4. Adefovir dipivoxil
  5. Telbivudine
MOA:
- Competitive inhibitor for ***HBV reverse transcriptase
—> NRTI incorporated into ***DNA
—> chain termination
—> prevent DNA elongation

Administration:

  • 1 once a day
  • 1 year or longer
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11
Q

Pros and Cons of NRTI

A

Pros:

  1. Can be used with ***decompensated liver disease
  2. Low rate of resistance for ***Entecavir and Tenofovir

Cons:

  1. Require ***long term of treatment
  2. High rate of resistance for Lamivudine, Adefovir and Telbivudine
  3. Tenofovir: NOT approved on children
  4. Tenofovir / Adefovir: cause ***Proximal tubular dysfunction —> renal function monitoring required
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12
Q

Hepatitis C

A

Acute infection:

  • asymptomatic
  • some can clear virus spontaneously

Chronic infection:

  • 55-85% infected person will develop chronic HCV infection
  • risk of cirrhosis: 15-30% within 20 years
  • HCV positive M:F = 2:1

Incubation period:
- 2 weeks to 6 months

Historical standard treatment (三隻):
- **Peg-interferon + **Ribavirin (24-48 weeks) + ***新藥: Simeprevir / Sofosbuvir

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13
Q

***Ribavirin MOA

A

***Guanosine analogue

  1. Inhibition of **inosine monophosphate dehydrogenase (IMPDH) (same as Mycophenolate)
    —> IMP -X-> GTP
    —> **    deplete GTP —> critical building block for HCV RNA replication
  2. Block viral ***DNA and RNA synthesis
  3. Induce **immune clearance: **Th1 favoured host response
  4. Increase HCV RNA ***mutation rate
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14
Q

SE and CI of Ribavirin

A

SE:

  • ***flu-like symptoms
  • GI disturbance
  • low blood count (anaemia, neutropenia)
  • depression
  • insomnia
  • joint, muscle pain
  • hair loss

CI:

  • Pregnancy (***birth defects)
  • Breastfeeding
  • advanced kidney, liver disease, unstable heart disease
  • autoimmune hepatitis
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15
Q

Newer drugs for HCV

A
  1. NS3/4A inhibitor (-previr) (***Simeprevir)
  2. NS5A inhibitor (-asvir)
  3. NS5B inhibitor (-buvir)
    - nucleoside inhibitor (NI) (Sofosbuvir)
    - non-nucleoside inhibitor (NNI) (    Dasabuvir)

***Reason for use
—> cure More ppl
—> in Less time
—> Fewer SE

MOA:
- HCV: single stranded RNA virus
—> genome encodes single polyprotein (massive, non-functional)
—> needs to be cleaved by proteases into 3 structural and 7 nonstructural proteins

NS3/4A: Cleaves ***non-structural proteins
NS5A: Regulate replication and Virus assembly
NS5B: RNA-dependent RNA polymerase

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16
Q

NS5B-NI, NS5B-NNI, NS5A, NS3/4A inhibitors

A

NS5B-NI (IPH):

  • intermediate potency
  • ***pan-genotypic coverage
  • high barrier to resistance

NS5B-NNI (ILL):

  • intermediate potency
  • limited genotypic coverage
  • low barrier to resistance

NS5A inhibitor (HMI):

  • high potency
  • multigenotypic coverage
  • intermediate barrier to resistance

NS3/4A inhibitor (HLL):

  • ***high potency
  • limited genotypic coverage
  • low barrier to resistance
17
Q

Region and predominant HCV genotype

A 
Southeast Asia: 3
Asia: 6
Europe, North America, Japan: 1a,1b (2,3 less common)
Egypt, Middle East, Central Africa: 4
South Africa: 5
18
Q

Treatment options

1, 2, 3, 4: Sofosbuvir; 1b: Simeprevir

A

Genotype 1b:
- ***Simeprevir (3/4A) + Peg-interferon + Ribavirin (12 weeks)
—> then Peg-interferon + Ribavirin (for another 12 weeks for treating naive patients / 36 weeks for treating patients previous failed HCV therapy)

Genotype 1, 4:
- ***Sofosbuvir (5B NI) + Peg-interferon + Ribavirin (for 12 weeks)

Genotype 2, 3:
- ***Sofosbuvir (5B NI) + Peg-interferon
—> genotype 2: for 12 weeks
—> genotype 3: for 24 weeks

19
Q

Intestinal parasites

A
  1. Amebiasis (***Protozoan infections)

2. Helminthiasis (***Parasitic worm infections)

20
Q

Amebiasis

A

2 forms:

  1. **Cystic form
    - inactive
    - **    resistant to drugs, heat, cold, drying
    - survive outside of body for long periods
    - carried in faeces (re-contaminate other sources)
  2. **Trophozoites
    - active form
    - invade body tissues
    - penetrate into **    blood vessel —> forming abscess in other organs
    - cause erosions / ulceration in ***intestinal wall with resultant diarrhoea
21
Q

Amebicides

A
  • NO prophylaxis drugs for amebiasis

Classified according to site of action:
1. Intestinal amebicide
—> ***Iodoquinol (act within GI lumen)

  1. Tissue / extraintestinal amebicide
    —> ***Chloroquine (act in bowel wall, liver, other tissues)
  2. Both intestinal and extraintestinal amebiasis
    —> ***Metronidazole
22
Q

Iodoquinol

A
  • Act against trophozoites in GI lumen
  • unknown mechanism
  • SE:
    —> GI disturbance
    —> mild to moderate skin reaction
    —> ophthalmological abnormalities (rare, vision resume after stopping)
23
Q

Chloroquine

A

Parasite digest RBC —> release free heme (toxic to parasite) —> use Heme polymerase to convert Free heme (toxic) to Hemozoin (non-toxic)

MOA:
***Heme polymerase (from amoeba) inhibitor
—> Free heme (toxic to amoeba) —X—> Hemozoin (non-toxic)

SE:

  • blurred vision
  • pruritus
  • GI disturbance
  • neurotoxicity (high dose, rare): vertigo, confusion, headache
24
Q

Metronidazole

A

MOA:
- nitro group of metronidazole chemically reduced by redox enzyme PFOR (pyruvate-ferredoxin oxidoreductase)
—> disrupts DNA helical structure
—> inhibit DNA synthesis

SE:

  • GI disturbance
  • ***metallic taste
  • ***sensory neuropathy (occasionally)
25
Q

Helminthiasis infections (parasitic worm infections)

A
  • **penetrate body tissues / produce **larvae that ***migrate (to the blood, lymph channels, lungs, liver, other body tissues)
  • Hookworm
  • Pinworm
  • Roundworm
  • Tapeworm
  • Threadworm
  • Trichinella
  • Whipworm
26
Q

Anthelmintics

A
  1. Mebendazole
  2. Pyrantel (praziquantel)
  3. Ivermectin
27
Q

Mebendazole

A

MOA:
Inhibit worm’s ability to ***absorb glucose
—> stopping ATP production
—> helminths die slowly, expelled from GI up to 3 days after therapy

SE:

  • GI disturbance
  • elevated liver enzyme
  • low WBC count, low platelet count (rare)
  • hair loss (high dose, rare)
28
Q

Pyrantel (praziquantel)

A

MOA:
Depolarising neuromuscular blocker
—> activation of Nicotinic ACh receptor in worm
—> **persistent depolarisation (Transient fasciculation)
—> continued exposure
—> depolarisation ↓ and membrane repolarised (muscle relaxed)
—> Nicotinic receptors *desensitised / cannot be excited as occupied by drug
—> muscle cannot contract
—> Paralysing the worm (Flaccid paralysis)
—> lose anchor on GI wall and passed out

SE:

  • GI disturbance
  • headache
29
Q

Ivermectin

A

MOA:
- bind to **glutamate-gated ion channels (in muscle and nerve cells of parasitic worm)
—> **↑ permeability of cell membrane to Cl
—> ***hyperpolarisation of cell
—> paralysis and death of parasite

SE:

  • GI disturbance
  • headache
30
Q

Summary

A

HBV:

  • IFN / peg-IFN (direct own immune system to produce Antiviral proteins)
  • NRTI (competitive inhibitor for HBV reverse transcriptase)

HCV
- IFN + Ribavirin (**MOA see notes)
- NS3/4A (Simeprevir, **HLL), NS5A, NS5B (NI/NNI) (NI: Sofosbuvir, ***IPH)
(genotype 1, 2, 3, 4: Sofosbuvir; 1b: Simeprevir)

Amebiasis

  • Iodoquinol
  • Chloroquine (Heme polymerase inhibitor)
  • Metronidazole

Helminthiasis

  • Mebendazole (glucose absorption)
  • Pyrantel (praziquantel) (transient fasciculation —> flaccid paralysis)
  • Ivermectin (glutamate-gated ion channel —> Cl permeability —> hyperpolarisation)

GIS (29 decks)

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