Drugs To Treat Tb And Influenza

Front 1

Describe transmission and progression of TB (from latent infection to reactivated disease) (6)

Back 1

1. Transmission: infectious aerosol (0.5-5 µm)
2. Primary TB:
• skin-test conversion (6-8 weeks)
• spontaneous healing in 6 months
3. Latent TB: TB is capsulized
4. Reactivation TB: (brought about by stress, aging)
• 5% healthy population
• 10% immunocompromised/weak px

Front 2

how does TB change the appearance of the lungs (3)

Back 2

1. healed cavitation
2. fibrosis
3. distorted achitecture (fluid in cavities)

Front 3

what is the TB skin test (tuberculin test or PPD test) (2) and describe the response (4)

Back 3

• PPD extracts (tuberculin Ag) injected into dermis
• bleb develops: 48-72 hrs after see the size
Response:
• negative: bleb < 2 mm
• Category 1 +ve: 5-9 mm
• Category 2 +ve: 10-14 mm
• Category 3 +ve: >15 mm

Front 4

what is category 1, 2, 3 in the tuberculin/PPD/TB skin test?
1.
2. (4)
3.

Back 4

1: immunocompromised px

2: kidney disease, DM, healthcare workers, someone who contacted TB

3. normal immune system px

Front 5

how to diagnose TB (3)

Back 5

1. positive skin test
2. abnormal chest radiograph
3. positive sputum smear or culture

Front 6

describe the epi of drug-resistant TB worldwide (2)

Back 6

• mostly China & India
• 1.3 million new cases every year

Front 7

How are antitubercular drugs divided?
When do we use which one?
what is the main difference between them?

Back 7

1. Primary agents, Secondary agents
• Primary [isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin]
• Secondary

2. use secondary if can't tolerant primary drugs, or infection is resistant
3. secondary equally as effective, but more toxic

Front 8

describe administration (1) and metabolism (3) isoniazid (INH, isonicotinylhydrazine)

Back 8

1. oral or IV
2. acetylated in liver to acetyl-isoniazid
3. acetylation rate (amount of N-acetyltransferase) determines response:
• slow acetylators: more likely to accumulate to toxic conc.
• rapid acetylators: need unusually high doses of INH

Front 9

MoA of isonizaid

Back 9

• INH is a prodrug, converted to active form by catalase peroxidase
• activated INH inhibits action of InhA (enoyl-acyl carrier protein reductase,
• InhA is an enzyme component of FAS-II (fatty acid synthase II) complex
• FAS-II involved in synthesis of long-chain mycolic acids

Front 10

clinical (2) and adverse (2) effects of isoniazid.
how to treat INH's adverse effects?

Back 10

• kills actively growing intracellular & extracellular organisms
• inhibits growth of dormant organisms in macrophages and TB lesions

• liver injury (hepatitis, elevated liver enzymes)
• peripheral neuropathy
• treat with pyridoxine (vitamin B6)

Front 11

describe the MoA of rifampicin (4)

Back 11

• inhibit synthesis of RNA → cause defective, non-functional bacteria proteins production

• interferes with RNA transcription
• directly binds to B-subunit of RNA polymerase
• inhibits mRNA transcription (mRNA transcripts) needed for protein synthesis

Front 12

clinical effects (1) and adverse (3) effects of rifampicin,
and how can you take it (2)?

Back 12

clinical: kills intracellular & extracellular TB

adverse:
• harmless red-orange discoloration of body secretions
• GI upset, skin rash, hepatitis
• strong inducer of drug metabolizing enzymes (P450)

admin: oral, IV

Front 13

describe Rifabutin:
1) metabolism (3)
2) MoA
3) adverse effects

Back 13

1.
• derived from rifampicin.
• long serum half-life (~45 hrs)
• reduced hepatic drug metabolizing enzymes

2. same as rifampicin (inhibit RNA synthesis)
3. same as rifampicin; but induces drug-metabolizing enzymes in liver to lesser extent

Front 14

ethambutol
0. when do we use
1. clinical effects
2. MoA (2)
3. adverse effects

Back 14

0. px unresponsive to INH, rifampicin, rifabutin
1. interefere w. cell wall biosynthesis.

2.
• ethambutol inhibits action of EmbB (arabinose transferase), membrane of cell wall
• EmbB: membrane-associated enzyme involved in synthesis of arabinogalactan, an essential structural component of mycobacterial cell wall

3. optic neuritis
• (inflamm. demyelinating disorder of optic nerve. ↓ visual acuity & ability to differentiate red from green)

Front 15

pyrazinamide
1. clinical effects (3)
2. MoA (3)
3. adverse effects (2)

Back 15

1.
• potent intracellular bactericidal activity
• weakly bactericidal vs extracellular MTB
• inhibits cell wall biosynthesis

2.
• pyrazinamide is pro-drug converted to active form, 'pyrazinoic acid' by pyrazinamidase
• pyrazinoic acid inhibits FAT-1 (fatty acid synthase I)
• FAT-1 involved in synthesis of short chain mycolic acids

3. GI upset, hepatotoxicity

Front 16

streptomycin:
1. clinical effects
2. admin
3. MoA
4. adverse effects

Back 16

1.
• act against extracellular organism
• don't penetrate macrophages or TB lesions

2. regular intramuscular injections

3.
• interfere w. translation of mRNA transcripts
• streptomycin binds to ribosomal protein that is component of 30S subunit of ribosomal complex
• facilitate codon misreading, inhibit synthesis of mycobacterial proteins

4. affects hearing

Front 17

1. what are some combination of primary drugs?
2. describe their dosage
3. most common tx regime?

Back 17

$$$$$$$$$$$$
1. Rifamate; 2 tablets daily for 6 months
• INH 50 mg
• rifampicin 300 mg

2. Rifater; 2 months of 6 month treatment
• INH 50 mg
• rifampicin 120 mg
• pyrazinamide 300 mg

Dosage depends on weight:
• 4 tablets daily if 44kg or less
• 5 tablets daily if 45-54 kg
• 6 tablets daily for >55 kg

3.
• *3-drug (INH, rifampin, pyrazinamide) daily for 2 months, then INH & rifampin for 4 months
• 2 drug: INH, rifampin for 9 months

Front 18

secondary agents
• examples (5)
• main action
• adverse effects (3)

Back 18

• cycloserine, amikacin, kanamycin, levofloxacin, ofloxacin
• inhibit either RNA or cell wall synthesis
• kidney damage, severe skin damage, arrhythmia

Front 19

how to treat active TB (2)

Back 19

• collect coughed sputum sample and bring to lab
• sputum culture & susceptibility reports require 6-8 weeks because Mycobacteria multiples slowly in culture

Front 20

tx regime for MDR-TB (5)

Back 20

• 5 or 6 drug regime (susceptible to 起碼 4 drugs)
• individualized according to susceptibility reports
• given 1-2 yrs after cultures become -ve
• daily admin, strict compliance
• very expensive

Front 21

what is the trend in TB prevention

Back 21

• use drugs in combination: avoid resistant strains developing
• increasing use of short course regime

Front 22

describe influenza (3) & what it causes (2)

Back 22

• enveloped RNA virus
• segmented genome made of 8 single stranded RNA segment, 890-2341 nucleotides long
• 3 types: A, B, C

• causes serious resp. illness, hospitalization, death
• 3-5 million cases of severe illness

Front 23

Influenza A (3)
• types
• effects

Back 23

• divided into 16 H and 9 N subtypes
• H1N1, H1N2, H3N2, H5N1, H7N3, H7N7, H9N2
• causes pandemics

Front 24

why are there so many subtypes of influenza A? (5)

Back 24

• natural reservoir: large variety of species (chickens, birds, ducks, pigs, humans)
• animal to human transmission
• reassortment of segmented genome of 2 parent viruses
• mutations at high rate (esp. surface glycoproteins)
• new variant able to escape host defense, vaccinated or not vaccinated

Front 25

influenza B (5)

Back 25

• found only in humans and seals
• limited hosts limits generation of new strains by re-assortment
• mutates at rate 2-3 x lower than A viruses
• influenza B mutates enough so lasting immunity isn't possible
• doesn't cause pandemics

Front 26

influenza C (2)

Back 26

• found in humans
• people generaly not ill from influenza type C viruses

Front 27

describe survival of influenza (3) and how it's killed (2)

Back 27

• up to 4 days, 22 degrees in water
• >30 days at 0 degrees
• survives indefinitely in frozen material

• heat (56 degrees for 3 hours, 60 degrees for 30 mins)
• common disinfectant (formalin, iodine compounds)

Front 28

describe transmission of influenza (4) and symptoms (2) and treatment (1)

Back 28

Transmission
• nasal secretions
• aerosol containing virus
• direct contact w. bird droppings
• contact w. contaminated surfaces

Symptoms
• high fever with sudden onset
• extreme fatigue

Treatment
• antiviral drugs effective if given early

Front 29

describe H5N1 (2) and H1N1 (swine flu) (3)

Back 29

H5N1
• infection of birds (major host)
• species barrier still significant

H1N1: (Mexico)
• combined genes from human, pig, bird flu
• transmitted by inhaling viral particles from pig to human, or human to human
• symptoms: high fever, cough/sneeze, breathing difficulty, loss of appetite

Front 30

describe the influenza replication cycle

Back 30

1. dispersal of virus particle
2. attachment & internalisation to epithelial cell surface (haemagglutinin, sialic acid sugar)
3. fusion (haemagglutinin protein fuses viral envelope with vacuole's membrane: releasing vRNA) & uncoating
4. Translation
5. Assembly and packaging
6. Budding (4hr)

Front 31

describe the function of hemagglutinin and neuraminidase

Back 31

HA: binding & entry. binding virus to host cell receptors

NA: budding & release. release of progeny virions form cell surface

Front 32

what drugs are there for influenza virus: (3)

Back 32

1. Amantadine/rimantadine:
2. Oseltamivir/Zanamivir
3. peramivir (neuraminidase inhibitor) vs. A & B

Front 33

Describe amantadine/rimantadine (rimantadine is a methyl derivative of amantadine)
1. spectrum,
2. most effective time
3. MoA (4)
4. toxic effects (4)

Back 33

1. prevent/tx influenza A (although there are resistant influenza A mutants)
2. within 48 hours after contact

3.
• inhibit un-coating of influenza A virus
• block pore formation by M2 proteins
• prevents H+ ions from entering virus
• prevent acidification of virus core: needed to active viral RNA transcriptase

4.
• GI irritation
• dizziness
• ataxia (lack voluntary coordination of muscles)
• slurred speech

Front 34

oseltamivir/zanamivir
1. spectrum,
2. most effective time
3. MoA (3)
4. toxic effects (2)

Back 34

1. influenza A or B (resistance increasing though)
2. more effective if used within 24 hours
3.
• binds to influenza neuraminidase
• prevents cleavage of sialic acid residues
• inability to release progeny virions
4.
• GI symptoms
• cough, discomfort

Front 35

describe peramivir's
1. spectrum
2. administrated

Back 35

1. influenza A and B virus
2. IV

• temporary emergency used by FNA in Nov 09 (H1N1 pandemic)
• now marketed in south korea