GIS30 Treating Hepatitis And Parasitic Infection Flashcards
Hepatitis B virus
Survive outside the body for at least 7 days
Acute hepatitis B
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
Antiviral therapy
may not help if already have severe liver damage
Liver cancer
- almost always fatal (die within months of diagnosis)
- Surgery, chemotherapy prolong life up to a few years
- Liver transplant varying success
Treatment for chronic hepatitis B
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):
- IFN / pegylated-IFN
- NRTI
- Entecavir
- Tenofovir
- Lamivudine
- Adefovir dipivoxil
- Telbivudine
Interferon
- 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
Pegylated interferon
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
SE of (peg)-interferon
(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
Pros and Cons of (peg)-interferon
Pros:
- Good choice for young ppl without serious liver disease (well-compensated liver disease)
- Good choice for ***genotype A / B infection > type C / D
- ***Short treatment duration (24-48 weeks)
Cons:
- Not available for failing liver (***cirrhosis / decompensated / deteriorating liver disease) —> Hepatitis flare
- Very serious SE
- Expensive
- Pegylated interferon not approved for children
NRTI: Nucleos(t)ide reverse transcriptase inhibitors
- Entecavir —> Deoxy***guanosine analogue
- Tenofovir —> Deoxy***adenosine 5’-monophosphate analogue
- Lamivudine —> Cytidine analogue
- Adefovir dipivoxil
- 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
Pros and Cons of NRTI
Pros:
- Can be used with ***decompensated liver disease
- Low rate of resistance for ***Entecavir and Tenofovir
Cons:
- Require ***long term of treatment
- High rate of resistance for Lamivudine, Adefovir and Telbivudine
- Tenofovir: NOT approved on children
- Tenofovir / Adefovir: cause ***Proximal tubular dysfunction —> renal function monitoring required
Hepatitis C
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
***Ribavirin MOA
***Guanosine analogue
- Inhibition of **inosine monophosphate dehydrogenase (IMPDH) (same as Mycophenolate)
—> IMP -X-> GTP
—> **deplete GTP —> critical building block for HCV RNA replication - Block viral ***DNA and RNA synthesis
- Induce **immune clearance: **Th1 favoured host response
- Increase HCV RNA ***mutation rate
SE and CI of Ribavirin
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
Newer drugs for HCV
- NS3/4A inhibitor (-previr) (***Simeprevir)
- NS5A inhibitor (-asvir)
- 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
NS5B-NI, NS5B-NNI, NS5A, NS3/4A inhibitors
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
Region and predominant HCV genotype
Southeast Asia: 3 Asia: 6 Europe, North America, Japan: 1a,1b (2,3 less common) Egypt, Middle East, Central Africa: 4 South Africa: 5
Treatment options
1, 2, 3, 4: Sofosbuvir; 1b: Simeprevir
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
Intestinal parasites
- Amebiasis (***Protozoan infections)
2. Helminthiasis (***Parasitic worm infections)
Amebiasis
2 forms:
-
**Cystic form
- inactive
- **resistant to drugs, heat, cold, drying
- survive outside of body for long periods
- carried in faeces (re-contaminate other sources) -
**Trophozoites
- active form
- invade body tissues
- penetrate into **blood vessel —> forming abscess in other organs
- cause erosions / ulceration in ***intestinal wall with resultant diarrhoea
Amebicides
- NO prophylaxis drugs for amebiasis
Classified according to site of action:
1. Intestinal amebicide
—> ***Iodoquinol (act within GI lumen)
- Tissue / extraintestinal amebicide
—> ***Chloroquine (act in bowel wall, liver, other tissues) - Both intestinal and extraintestinal amebiasis
—> ***Metronidazole
Iodoquinol
- Act against trophozoites in GI lumen
- unknown mechanism
- SE:
—> GI disturbance
—> mild to moderate skin reaction
—> ophthalmological abnormalities (rare, vision resume after stopping)
Chloroquine
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
Metronidazole
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)
Helminthiasis infections (parasitic worm infections)
- **penetrate body tissues / produce **larvae that ***migrate (to the blood, lymph channels, lungs, liver, other body tissues)
- Hookworm
- Pinworm
- Roundworm
- Tapeworm
- Threadworm
- Trichinella
- Whipworm
Anthelmintics
- Mebendazole
- Pyrantel (praziquantel)
- Ivermectin
Mebendazole
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)
Pyrantel (praziquantel)
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
Ivermectin
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
Summary
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)
