Transcript Second-line anti

Classes of antituberculosis drugs
GROUPING
DRUGS (ABBREVIATION)
Group 1 – First-line oral
antituberculosis agents
Isoniazid (H); Rifampicin (R); Ethambutol (E);
Pyrazinamide (Z)
Group 2 – Injectable
antituberculosis agents
Streptomycin (S); Kanamycin (Km); Amikacin
(Am); Capreomycin (Cm); Viomycin (Vi)
Group 3
Fluoroquinolones
Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin
(Lfx); Moxifloxacin (Mfx);a Gatifloxacin (Gfx)a
Group 4 – Oral bacteriostatic
second-line antituberculosis
agents
Ethionamide (Eto); Protionamide (Pto);
Cycloserine (Cs); Terizidone (Trd)a; Paminosalicylic
acid (PAS); Thioacetazone (Th)b
Group 5 – Antituberculosis
agents
with unclear efficacy (not recommended by WHO for routine use
in MDR-TB patients)
Clofazimine (Cfz); Amoxicillin/Clavulanate (Amx/
Clv); Clarithromycin (Clr); Linezolid (Lzd)
CYCLOSERINE (Cs)
G CLASS: ANALOG OF D-ALANINE
Bacteriostatic,
60-70 % excreted unchanged in urine via glomerular filtration;
small amount excreted in faeces;
small amount metabolized.
No cross resistance with other anti-TB drugs
Capsules (250
mg).
10–15 mg/kg
daily (max. 1000
mg),
Usually 500–750
mg per day given
in two divided
doses.
Storage:
Storage; at room temperature (15–25 °C) in
air-tight containers.
Oral absorption
Oral absorption: Modestly decreased by
food (best to take on an empty stomach).
Distribution and CSF penetration:
•Ethionamide: additive nervous system sideeffects.
•Isoniazid: additive nervous system side-effects.
•Phenytoin: may increase phenytoin levels.
•Toxic effect if combined with alcohol, increases
risk of seizures.
•Vitamin B6 decreases CNS effect.
Hypersensitivity to cycloserine.
Epilepsy.
Depression, severe anxiety or psychosis.
Severe renal insufficiency.
Excessive concurrent use of alcohol.
Seizures
Shakiness or trouble talking
Depression or thoughts of intentional self-harm
Anxiety, confusion or loss of memory
Personality changes, such as aggressive behaviour
Rash
Headache
ETHIONAMIDE (Eto), PROTIONAMIDE (Pto)
DRUG CLASS: CARBOTHIONAMIDES GROUP, DERIVATIVES OF
ISONICOTINIC ACID
 Bacteriostatic.
 complete
cross-resistance between
ethionamide and protionamide.
 Partial cross resistance with thiacetazone.
 Extensively metabolized, probably, in the
liver.
 Less than 1% of the dosage excreted in
urine unchanged.
Preparation and dosage:
Tablets containing 125 mg or 250 mg of
active drug.
The maximum optimum daily dose is 15–
20 mg/kg/day (max. 1 g/day), usually
500–750 mg.
Storage:
At room temperature (15–25 °C),
in airtight containers.
Oral absorption:
100% absorbed but
sometimes erratic absorption
caused by gastrointestinal
disturbances associated with
the medication.
Distribution and CSF penetration:
 Rapidly
and widely distributed into body
tissues and fluids with significant
concentrations also are present in CSF.
Frequent: severe gastrointestinal intolerance
(nausea, vomiting, diarrhoea, abdominal pain, excessive
salivation, metallic taste, stomatitis, anorexia and weight
loss).
Adverse gastrointestinal effects appear to be doserelated, with approximately 50% of patients unable to
tolerate 1 g as a single dose.
Gastrointestinal effects may be minimized by decreasing
dosage, by changing the
time of drug administration, or by the concurrent
administration of an antiemetic agent.
Adverse effects, cont.:
Occasional: allergic reactions; psychotic
disturbances (including depression), drowsiness,
dizziness, restlessness, headache, and postural
hypotension. Neurotoxicity (administration of pyridoxine
has been recommended to prevent or relieve neurotoxic
effects); transient increases in serum bilirubin; reversible
hepatitis (2%) with jaundice (1–3%); gynaecomastia;
menstrual irregularity, arthralgias, leukopenia,
hypothyroidism especially when combined with PAS.
Rare: reports of peripheral neuritis, optic neuritis,
diplopia, blurred vision, and a pellagra-like syndrome,
reactions including rash, photosensitivity,
thrombocytopenia and purpura.
Drug inter-actions:
Cycloserine: potential increase incidence of neurotoxicity.
Ethionamide temporarily raises serum concentrations of isoniazid.
Thionamides may potentiate the adverse effects of other antituberculosis drugs
administered concomitantly.
In particular, convulsions have been reported when ethionamide is administered
with cycloserine.
Excessive ethanol ingestion should be avoided because of possible psychotic
reaction.
PAS: possible increase in liver toxicity, monitor liver enzymes;
Hypothyroidism in case of combined administration.
 Hypersensitivity
 Epilepsy.
 Depression,
to cycloserine.
severe anxiety or psychosis.
 Severe renal insufficiency.
 Excessive concurrent use of alcohol.
Distribution & CSF penetration:
 In
extr-acellular fluid, abscesses, ascitic fluid,
pericardial fluid, pleural fluid, synovial fluid,
lymphatic fluid and peritoneal fluid.
 Not
well distributed into bile, aqueous
humour, bronchial secretions, sputum and
CSF.
 Penetrates inflamed meninges only.

Kanamycin sulfate, sterile powder for intramuscular
injection in sealed vials.

The optimal dose is 15 mg/kg body weight, usually 750 mg
to 1 g given daily or 5–6 days per week, by deep
intramuscular injection.

Rotation of injection sites avoids local discomfort. When
necessary.

It is possible to give the drug at the same total dose 2 or 3
times weekly during the continuation phase, under close
monitoring for adverse effects.
 Powder
stable at room temperature (15–25 °C),
diluted solution should be used the same
day.
There is no significant oral absorption.
Frequent:
- Pain at injection site, renal failure (usually
reversible).
 Occasional:
-
vestibular and auditory damage – usually
irreversible; genetic predisposition possible (check
family for aminoglycoside ototoxicity),
nephrotoxicity (dose-related to cumulative and peak
concentrations, increased risk with renal
insufficiency, often irreversible),
peripheral neuropathy,
rash.
Drug interactions:
Co-administration of aminoglycosides with loop diuretics
may have an additive or synergistic ototoxicity.
possible enhanced action of non-depolarizing muscle
relaxant resulting in possible respiratory depression.
Nephrotoxic agents (amphotericin B, foscarnet, cidofovir):
additive nephrotoxicity.
Penicillins: in vitro inactivation (possible). Do not mix
together before administration.
Contraindications
Pregnancy (congenital deafness seen with
streptomycin and kanamycin use in pregnancy).
Hypersensitivity to aminoglycosides.
Caution with renal, hepatic, vestibular or
auditory impairment.
Alerting symptoms
— Problems with hearing; dizziness
— Rash
— Trouble breathing
— Decreased urination
— Swelling, pain or redness at injection site
— Muscle twitching or weakness
OFLOXACIN (Ofx)
DRUG CLASS: FLUOROQUINOLONES
Bactericidal: acts by inhibiting reproduction of bacterial DNA.
There is no cross-resistance with other anti-tuberculosis agents, but
complete cross-resistance between Ofloxacin and Ciprofloxacin.
Ofloxacin is eliminated mainly by the kidneys.
65–80% of a dose is excreted unchanged in the urine over 24–48
hours, resulting in high urinary concentrations.
At room temperature (15–25 °C), in
airtight containers protected from light.
90–98% oral absorption
 About
25% is bound to plasma proteins.
Ofloxacin is widely distributed in body fluids,
including the CSF, and tissue penetration is
good. It crosses the placenta and is distributed
into breast milk.
 It
also appears in the bile.
 Generally
well tolerated.
Occasional: gastrointestinal intolerance;
CNS-headache, malaise, insomnia,
restlessness, and dizziness.
Rare: allergic reactions; diarrhea;
photosensitivity; increased LFTs; tendon
rupture; peripheral neuropathy.
Contraindications
Pregnancy & intolerance of fluoroquinolones.
Alerting symptoms
 Pain,
swelling or tearing of a tendon or
muscle or joint pain.
 Rashes, hives, bruising or blistering,
trouble breathing.
 Diarrhea
 Yellow skin or eyes.
 Anxiety, confusion or dizziness.
 Bacteriostatic,
disrupts folic acid
metabolism.
 Excreted via glomerular filtration and
tubular secretion.
Distributed in peritoneal fluid, pleural
fluid, synovial fluid. Not well distributed
in CSF (10–15%) and bile.
Frequent: gastrointestinal intolerance
(anorexia and diarrhoea); hypo-thyroidism
(increased risk with concomitant use of
ethionamide).
Occasional: hepatitis (0.3–0.5%); allergic
reactions; thyroid enlargement; malabsorption
syndrome; increased prothrombin time; fever.
Careful use in patients with glucose-6phosphate dehydrogenase (G6PD) deficiency.
 Digoxin:
possible decrease in digoxin absorption;
monitor digoxin level – may need to be
increased.
 Ethionamide: possible increase in liver toxicity,
monitor liver enzymes; hypothyroidism in case
of combined administration.
 Isoniazid: decreased acetylation of isoniazid
resulting in increased isoniazid level. Dose may
need to be decreased.
 Allergy
to aspirin;
 severe renal disease;
 hypersensitivity to the drug.
Alerting symptoms
 Skin
rash, severe itching, or hives
 Severe
abdominal pain, nausea or vomiting
 Unusual
 Black
tiredness or loss of appetite
stools as a result of intestinal bleeding