Tuberculosis & TT technique

· Bacillary sub-populations in pulmonary TB:

	A	B (persisters)	C	D
Site of bacilli	Extra-cellular in cavity	Intra-cellular in MQs	Extra-cellular in caseum	Dormant fatty
Responds to	S, H, R	Z, H, R	R only	Nothing
Resistant to	Z	S	H, Z, S, E	All
PH needed	Neutral or Alk.	Acidic	Neutral	_
O2 tension	Needs high	_	Needs low	_
Responsible for	Ttt failure	Relapse (must >2Ms ttt)	_	_

· Drugs used in TB:

a) 1^st Line Drugs:

	INH	R	P.T.B	E.T.B	S
Dose (adult-child)	5-10mg/kg/d (max 300-600mg)	10-20mg/kg (max 600mg for >50kg, 450mg for <50kg)	25-40mg/kg (max 2gm for >50kg, 1.5gm for <50kg)	15-25mg/kg (0.8-1.2gm)	15mg/kg/d (max 1gm)
Prep.	.Isocid 100 .I.forte 200 .Inhibex (50H+5Z) .TBzide 50 .Rimactazide .Riozid (300R+150H)	.Rifadin (v:600)(c:150/300) .Rimactan (cap/syrup) .Rifampin300 .Rifampicin	.P.T.B 500 .Pyrazide 500 .Pyraldina 500 .Rifater 2 (H,R,Z = 50,120,300)	.E.T.B 500, 100, 400	.Strept IM (ineffective more than 2Ms and toxic as well)
Mech. Of Action	-Bactericidal -IC/EC -Inh. synth. of DNA, cell wall Mycolic acid. -Acts on replicating bacilli (even in persisters they are slowly replicating not completely dormant. -Competes pyridoxine (structure analogue). -On empty stomach as R.	-Bactericidal -IC/EC (kills intermittently, rapidly dividing org.) -Dec.RNA synthesis through Dec. DNA depend. RNA polymerase. -Also on: G+ve/-ve, pox virus, Chlamydia, Mycoplasma.	-Bactericidal -IC only (acidic media) -Change by pyrazinamidase of bacillus to pyrazinoic acid (wall). -Must do pre-ttt sensitivity test. -Main ttt in relapse and short course ttt (sterilizing) -No effect in continuation phase.	-Bacteriostatic -IC/EC -Dec. RNA synthesis to inhibit MB cell wall synthesis.	-Bactericidal -EC only (alk. media) -Binds to 30S ribosomal subunità prevents protein synthesis. -Break polysomes to monosomes. -Misreading in genetic code à abn. Protein. -Inactivates initial complex of synthesis.
Absorpt. Peak conc Metabol. Half life Excretion Penetrat.	-Easy -2 hrs -Acetylators (rapid/slow) -1.5-3 hrs -Urine - Crosses BBB	-In ½ hr -3 hrs -75% bound, partial deacetylation in liveràbile -5 hrs -Bile, less Urine (EHC). -Inflamed meninges. only, well to other tissues.	----------------- -1-2 hrs -50% bound, hepatic deaminase changes it to active pyridazinoic acid then with xanthine oxidase to inactive metabolite. ------------------Urine -CSF=plasma conc. -Dose decreased in renal failure.	-Inh. 'e ethanol , alumOH -2-4 hrs -Not altered with liver disease. -must suspend at once. -------------------Urine unchanged. -No cross BBB even inflamed. -Dose decreased in renal failure (drug level not>5ug/ml) (not used in clearance <50)	---------------- -1 hr -Cross-resistance with vio/ kanamycin -----------------Urine completely. -Inflamed meninges. -Crosses placenta (1/2 mother's level).
S.Es.CNS .Eye .Ear .Allergy .BM dep. .Blood .GIT .Liver .Pancreas .Kidney .Adrenal .Bone .Resistanc .Drug interact. .Others Follow up	-PN (slow A), insomnia, restlessness, Ms twitches, Convulsions in epileptic pt. -Atropine like (dry mouth, tinnitus, GIT) -Rash, Fever, Pellagra (nicotinamide) -Inhibit Histaminases (inc. histamin) +ve -Hemolytic anemia -GIT upset -Hepatitis (rapid A) -D.M.(x B-cells) -Lupus like ----------------- ----------------- +ve -Hydralazine, Procainamide, PAS inc. its toxicity. -Carcinogenic in mice -/4wks CBC, liver function, -/3Ms urine test for compliance. -Caution in epilepsy, alcoholics, pregnant	----------------Conjunctivitis -Flushing, Acne form, Conjunctiv. -Flu symp., asthma, purpra, ATN ('eintermittent ttt) -----------------A.hemolytic anemia, thrombocytopenic purpra. -Pseudo-memb.colitis. -Transient insig. inc. transaminases, Cholestatic jaundice. -----------------Light chain protinuriaàRF, ATN -Pseud crisis -Osteomalacia +ve -PAS inh. Its absorption. -R is enzyme inducer. -Turns fluids red. -Teratogenic -as INH -as INH -caution in pregnancy	-----------------Photosensitivity (Erythema with sunlt.) -as eye ------------------Sideroblastic anemia. -GIT upset -Hepatitis (most hepatotoxic drug) ---------------------------------- ----------------- -Arthralgia, Gout (comp.'e uric A. excretion àPAS dec. it +ve -PAS decreases hyperuricemia ----------------- -as INH -as INH -uric acid	-PN, -Retro-bulbar neuritis (optic atrophy rev. dose depend., central>periph) (given to >13yr pt only to detect abnormality) -as others ------------------Thrombocytopenia. -GIT upset -Jaundice ------------------------------------ ------------------ - Hyperuricemia +ve ------------------ ------------------ -examine each eye separately /4wks with CBC and urine and uric acid. -caution in children, renal patients.	-----------------Vestibulo-cochlear damage (rev.) (V1st then C) -fetal Ototox. -as others -----------------Blood discariasis (an., tcp, agranulocyt.) -low Ca, Mg, K -GIT upset ---------------- -----------------Renal tubular damage (irrev.) ------- ---------------- +ve, cross R -Curare like action (when used with D-tubocurarine topically) -Teratogenic -/4wks renal function -as INH -caution in renal, prev. hearing problem,preg.

b) 2^nd Line Drugs: (reserve drugs)

	Thioacetazone (not in WHO)	PAS acid	Cycloserine	Ethionamide/ pro-ethiona.	Fluorinated Quinolones
Dose	2-4 mg/kg (150mg/d)	150-300 mg/kg	15 mg/kg (1gm max)	15 mg/kg (max 0.75-1)	800mg (tarivid 600)
Prep.	+H = 150-300 + 50-100mg	500mg tab., IV in mening.	500mg tab.	.Trecator 250 .Isoprodian (proeth.+ H + Dapsone)	.Moxifloxacin (best, safe, tolerable) .Ofloxacin .Ciprofloxacin .Norfloxacin .Sparfloxacin (less eff.on atypical MB)
Action	-Bacteriostatic -IC/EC -Thiosemi carbazone gp. -Used 1st line instead S or E -Tolerated by africans.	Bacteriostatic -IC/EC caseum -Delay Resist -Like sulphonamides -Competes with PABA for di-hydro-petroate synthetase in folic acid synth. Pathway.	Bacteriostatic -Effect. in non human TB -Competes with D-alanine 4 synth. of cell wall peptidoglycans	-Bactericidal -Effect. In bovine type -Structural similarity to INH and same way of action.	-Bactericidal -Used with MDR -Inhibits DNA gyrase.
Kinetics	---	.Good absorb. .Acetylation .Inactive in urine. .Cross BBB if inflamed. .No adjust. in RF /LCF.	-No cross R -Cross BBB -Excreted in kidney.	-Acetylation -Eth. à Eth. Sulphoxide (potent) -Excreted in urine. (Pro-eth. is less toxic)	-Excreted unchanged in urine. -Safe in LCF. -Adjusted in RF.
S.Es	-Cerebral edema. -Ototoxicity ofS -GIT upset -Liver toxicity -D.M. -Bl. discariasis -Exfoliative dermatitis with HIV -Chinese rash with cheese meals, fish. -Cross R with Ethionamide/pro	-Goitrogenic -Glandulat like fever -GIT upset,PU -Liver damage -Dec. glucose -Bl. discariasis -Allergy (rash/fever) -dec.K, inc.Ca -Crystalluria in kid.(not 'e S) (phenstix strips in urine) -Drug interactions: .R/H/Z (CB4) .Probencid (inc. toxicity) .'e Aspirin (salicylism).	-Psychosis, dep, tremors, convulsions, slurred speech, confusion (add B6 50mg) -GIT upset -D.M. -Adjust in renal failure	-Psychosis, PN -Dec. T4 -GIT upset (metallic taste, sulpher eructation). -Dec. glucose. -Allergy -Liver damage -Teratogenic -Gynecomastia, impotence, menstrual irregularities, acne. -Cross R with thioacetazone	-Headache, insomnia, tremors. -GIT upset. -Liver enzymes high -Leucopenia -Damage articular cartilage (<16yrs) -Drug interactions: (except oflo.) .NSAIDs .Cimetidine. .Cyclosporine. .Theophylline. .Warfarin.
FU	Caution for S.Es and urine test/ 3Ms for compliance

*If sensitivity occurred à desensitization is done either:

Slow:à 1/10 dose à double every 12hrs à full dose.

Rapid: à ¼ dose à increase every day (1/2, ¾, full) then taper. + Steroids 20mg/d

c) New Drugs: (not in WHO except aminoglycosides)

- Clofazimine (Iminopherazine derivative):

.Action: anti-leprosy & antiTB in vitro

.Peak conc.: in 1M

.S.Es: à Crystalline deposits in organs (sp. In fat content)

à Brownish-black pigmentation of skin

à Severe life threatening abdominal pain

- B-lactam/ B-anti-lactamase: in vitro > in vivo so it has a limited use as it

poorly penetrates mammalian cells.

- Macrolides: Concentrated in MQs à antiTB effect (IC) so prevents

multiplication. (Azithro., Roxithro., Clarithromycins)

- Rifamycins: in vitro

	Rifapentin	Rifalazil	Rifabutin
Derived from	Cyclopentyl	----	Spiropiperidyl
Activity on TB	>20 times than R	Intermediate between both	Used in R resistance Used in M. avian complex > R
Half life	20 hrs	Longest	16 hrs, rapid abs.
Dose	600mg once/wk	----	5mg/kg/d 150mg/d in new case 300mg/d in MDR 600mg/d in avian
Resistance	Cross with R	----	Used in R resistance

- O xazolidinones (Linezolid):

.Used in: MDR and drug resistant G +ve coccal infections.

.S.Es: hematological, PN, expensive.

- Nitroimidazopyranes (Metronidazole derivative):

Bactericidal against Dormant TB & bacilli in anaerobic environment.

- Aminoglycosides:

.Action: Bactericidal

.Preparations: Amikin, Capreomycin, Kanamycin, Viomycin

.Dose: 15mg/kg/d or max. 0.75-1gm (all IM only except amikin can

be given IV too)

.S.Es: 1^st 2 drugs à auditory = vestibular effects

2^nd 2 drugs à auditory > vestibular effects

- Others: à Analogues of Z (but more active, no cross resistance)

à Drugs target iso-citrate lyase (enzyme that establishes latent TB)

à Immuno-modulation (improve effect of ttt):

.M. Vaccae (for protective cytokine release)

.Post-infection vaccine with LIBI

.Protective cytokines (INFg, IL12, GMCSF)

.Levamisole

.Transfer factors

à Alternative drug delivery system:

.Implanted SC slow release Z, H

.Inhalation micro particles (dec. dose/toxicity)

(stimulates alveolar MQs)

.Liposomal encapsulation of antiTB (on MQs)

d) Steroids in TB:

.Indications: -Absolute: à Addison's disease

à Collagen disorders

à Sarcoidosis

à Transplanted organ

-Relative: à Severely ill (TB pneumonia, miliary)

à TB meningitis, pericarditis, peritonitis

(decrease adhesions)

à TB urethritis (dec. stricture)

à TB salpingitis and in vas

à Desensitization in drug sensitivity

à Suppress LN enlargement during

chemotherapy when symptomatizing

.Response: gives rapid improvement to fever, weight loss, ESR level,

exaudative lesion.

.Dose: 20mg/d (60 in pericarditis) à 4-6wks orally

then taper 5mg/d every wk (given under cover of anti-TB)

*N.B.

Thalidomide is used instead of steroids in TB meningitis when no response.

*For Full Text --> download from: Tuberculosis.pdf

Diagnosis of Tuberculosis Emerging trend

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