Pharmacology and pharmacokinetics of antitublar agents

1. Dreamz College of Pharmacy
Pharmacokinetics and Pharmacology
of Anti-Tuberculosis Drugs
Mrinal
Assistant Professor
Pharmacology

2. Introduction
• Robert Koch discovered Mycobacterium tuberculosis in 1885.
• In 2016 worldwide 10.6 million people became sick with TB and 1.7 million
TB-related deaths.
• India has a large load of HIV infected subjects Moreover, they are especially
vulnerable to severe forms of tubercular/Mycobact. avium complex (MAC)
infection.
• Emergence or ' multidrug resistant' (MOR) TB which now accounts for ~ 20%
of previously treated, and 3.3% of new TB cases worldwide is a major
challenge in antitubercular chemotherapy.
• Without treatment, approximately 5-10% of patients with latent TB will
progress to active TB disease at some point in their lifetime.
• Isoniazid (lsonicotinic acid hydrazide, H) can reduce the incidence of active TB
about 90% .
• The Revised National Tuberculosis Control Programme (R TCP) was launched
in 1997, and its treatment guidelines have been successively revised, the last
time in 20 16*
(* RNTCP: Technical and operational guidelines for tubcrculosis control in India,
2016; www.tbcindia.gov.in.)

3. Tuberculosis Drug Discovery/Development
and Its Impact on Treatment
• 1944 – Para-aminosalicylic acid (PAS)
• 1947 – Streptomycin (SM)
• 1952 – Isoniazid (INH, H)
Replaces sanatorium as major treatment
Patients can be treated as out-patient
• 1954 – Pyrazinamide (PZA, Z)
Combination therapy of INH and PZA cures TB
• 1955 - Cycloserine (CS)
• 1957 - Kanamycin/amikacin (AK)
• 1961 - Ethambutol (EMB)
• 1962 – Rifampin (RIF, R)
Combination of rifampin and INH adopted as international regimen for treatment of TB
• 1966 – Ethionamide (ETA)
• 1967 – Capreomycin (CM)
• Fluoroquinolones (FQs) and some rifampin congeners are the later additions to the
antimycobacterial drugs. Two novel drugs, bedaquiline and delamanid have been recently
approved, and bedaquiline is being used as reserve drug.

4. Classification
* An alternative grouping of
antitubercular drugs reflecting
hierarchy in efficacy/priority
in use has also been done.
First line: These drugs have high
antitubercular efficacy as well as low
toxicity; are used routinely.
Second line: These drugs have either
low antitubercular efficacy or higher
toxicity or both; and are used when
first line drugs cannot be used, or to
supplement them.

5. lsoniazid (lsonicotinic acid hydrazide,
H)
• It is the most active drug for the treatment of tuberculosis
and it is primarily tuberculocidal.
• Fast multiplying organisms are rapidly killed, but quiescent
ones are only inhibited .
• A prodrug, which means it requires activation by enzyme
Catalase-peroxidase (Mycobacterium tuberculosis KatG) is
a heme enzyme.
• Resistance mechanisms :-
 By mutation of the catalase-peroxidase (KatG) gene, This
type of resistance cannot be overcome.
 By mutation in the InhA gene. Low level INH resistance or
that by inhA mutation resulting in overproduction of the
carrier 'InhA’: can be overcome by using ' high dose INH' .

6. Isoniazid Mechanism of action
The primary mechanism of action of INH is inhibition of synthesis of mycolic acids which
are unique fatty acid components of mycobacterial cell wall. This may explain the high
selectivity of INH for mycobacteria (it is not active against any other microorganism). The
lipid content of mycobacteria exposed to INH is reduced. Two gene products labelled
‘InhA’ and ‘KasA’, which function in mycolic acid synthesis are the targets of INH action.
INH enters sensitive mycobacterium, (Catalase-peroxidase enzyme) KatG catalyzes the
formation of the isonicotinic acyl radical, which spontaneously couples with NAD(H) to
form the isonicotinoyl-NAD adduct. This complex binds tightly to the enoyl-acyl carrier
protein reductase (enoyl-AcpM ) InhA, thereby blocking the natural enoyl-AcpM substrate
and the action of fatty acid synthase.

7. Isoniazid Pharmacokinetics
• After orally administered: well absorbed, widely distributed
in body and good CNS and macrophages penetration.
• Absorption decreased by food.
• Metabolized by liver : most important pathway being
acetylation by N- acetylation by NAT2. The acetylated
metabolite is excreted in urine. The rate of INH acetylation
shows genetic variation. There are either: Fast acetylators
(30-40% of Indians) t½ of INH is hr. Slow acetylators (60-
70% of Indians) t½ of INH 1s 3 hr.
• A hepatotoxic minor metabolite is produced by CYP2E1
from acetylhydrazine.

8. Interactions
1. Aluminium hydroxide inhibits
INH absorption.
2. INH retards phenytoin,
carbamazepine, diazepam,
theophylline and warfarin
metabolism by inhibiting
CYP2Cl9 and CYP3A4, and
may raise their blood levels.
Dose
Isoniazid 5-10 mg/kg Daily dose
or 15 mg/kg dose twice weekly.
Adult Dose 300 mg oral dose
OD.
ISONEX 100, 300 mg tabs,
ISOKIN 100 mg tab, I00 mg per
5 ml liq.
Adverse drug effects
• Peripheral neuropathy (10-20%)
Tingling and numbness
Concurrent pyridoxine 100 mg/kg
administration with INH prevents most
of these complications
• Predisposing conditions: diabetes,
uremia, malnutrition, HIV infection.
• Other side effects ̶ Hemolytic anemia ̶
Seizures ̶ Psychosis ̶ Lupus-like
syndrome.
• Hepatitis = 2.1% over all incidence is
rare in children, but more common in
older people and in alcoholics (chronic
alcoholism induces CYP2E1 which
generates the hepatotoxic metabolite),
must be stopped at the first sign of
hepatotoxicity, which is due to dose
related damage to liver cells, and is
reversible on stopping the drug.

9. Rifampin (Rifampicin, R)
• It is a semi synthetic derivative of rifamycin B
obtained from Streptomyces mediterranei.
• Rifampin is bactericidal to M tuberculosis.
• Against TB bacilli, it is as efficacious as INH and
better than all other drugs.
• Rifampin resistance is nearly always due to
mutation in the rpoB gene reducing its affinity for
the drug.
• No cross resistance with any other antitubercular
drug, except rifampin congeners, has been noted.

10. Rifamin mechanism of action
Rifampin interrupts RNA synthesis by binding to subunit of mycobacterial DNA-
dependent RNA polymerase (encoded by rpoB gene) and blocking its polymerizing
function. The basis of selective toxicity is that mammalian RNA polymerase does not
avidly bind rifampin.

11. Rifamin Pharmacokinetics
• Oral administration, well absorbed, widely
distributed in body; excellent tissue penetration
• CNS concentration is adequate only if meninges
inflamed, it is largely pumped out from CNS by
P-glycoprotein.
• Metabolized by liver to an active deacetylated
metabolite
• Excreted into bile and some in urine
• t½ = 2-5 hours

12. Interactions
• Rifampin is a microsomal enzyme inducer-
increases several CYP450 isoenzymes,
including CYP3A4 , CYP2D6, CYP1A2
and CYP2C sub family. It thus enhances its
own metabolism as well as that of many
drugs including warfarin, oral
contraceptives, corticosteroids,
sulfonylureas, etc.
• Contraceptive failures have occurred. It is
advisable to switch over to an oral
contraceptive containing higher dose (50
μg) of estrogen or use alternative method of
contraception.
Dose
Rifampin 8-12 mg/kg (Max: 600 mg/dose)
given PO or IV once daily
RCIN 150,300,450.600 mg cap, 100 mg15 ml
susp. RIMACTAN,. RIMPIN 150, 30, 450
mg caps. 1OO mg/5 ml syr.; RIFAMYClN
450 mg cap, ZUCOX 300,450,600 mg tab,;
to be taken I hour before or 2 hour after
meals.
Adverse drug effects
• GI – anorexia, diarrhea, dysphagia
(most common)
• Skin – rash pruritis (6%)
• Arthralgias, myalgias (fairly
common)
• Urine, sweat, tears and contact
lenses may take on an orange color
(harmless)
• Hepatic Hyperbilirubinemia (0.6%)
Hepatitis (0%- alone, 2.7% with
INH) It is infrequent with 600
mg/day dose
• Thrombocytopenia (<0.1%)
• Decreased thyroid, adrenal ,
vitamin D, etc
• Other serious but rare reactions
are: Purpura, haemolysis, shock and
renal failure.

13. Pyrazinamide (Z)
• Bactericidal
• At neutral pH, it is inactive, but at pH 5.5, it inhibits tubercle bacilli and
some other mycobacteria
• Quickly absorbed after oral administration
• Widely distributed in body tissues, including inflamed meninges
• It is used in combination with INH for short-term therapy to exert its
activity against residual intracellular organisms that may cause relapse
• Metabolized by liver
• Excreted in urine
• t½= 6-10 hours (increased in hepatic/renal failure)
• Resistance to Z develops rapidly if it is used alone and is mostly due to
mutation in the pncA gene.
• The mechanism of action of Z is not well established, but like INH it is also
converted inside the mycobacterial cell into an active metabolite pyrazinoic
acid by an enzyme (pyrazinamidase) encoded by the pncA gene.

14. Adverse Reaction
• Hepatotoxicity: (~1%), liver function should be
performed before and during therapy
• Nongouty polyarthralgia: (up to 40%) rarely
requires dosage adjustment or discontinuation of
the drug
• Asymptomatic hyperuricemia: but rarely causes
acute gout, serum uric acid may therefore be used
as marker for patient compliance
• Acute gouty arthritis: very rare, stop the drug
• Skin: rash, photosensitive dermatitis
• Renal Dosage: reduce dose in renal insufficiency

15. Ethambutol (EMB, E)
• Bacteriostatic (bactericidal at highest dose)
• The mechanism of action of E is not fully understood, but it has been found
to inhibit arabinosyl transferases (encoded by embAB genes) involved in
arabinogalactan synthes is thereby interfering with mycolic acid
incorporation in mycobacterial cell wall.
• Well absorbed from the gut and widely distributed in all body tissues and
fluids
• CNS concentration only if meninges are inflamed
• Excreted in urine (50%) and feces (20%)
• Renal dosing is needed to avoid ocular toxicity
• Pregnancy category C (safe in pregnancy according to CDC)
• Not used in children < 5 years old
• Resistance to E develops slowly and is most commonly associated with
mutation in embB gene, reducing the affinity of the target enzyme for E.
• t½= 4 hours

16. Adverse Reactions
• Optic neuritis: most common and serious (dose
related, 18% if dose >50mg/kg/day), blurred
vision, central scotoma, red-green color blindness
(This toxicity occurs in less than 1% of the
patients given 15mg/kg/day but increases with
total daily dose, and it also seems worse with
daily use as opposed to three times/week). Patient
should be instructed to report any changes in
vision
• Hyperuricemia: rare
• Peripheral neuritis: rare

17. Streptomycin (S, SM)
• First antimicrobial drug used to treat TB
• Aminoglycoside antibiotic effective against most tubercular
bacilli, but its activity is weaker than that of INH and RFP
• MOA: inhibition of protein synthesis (bactericidal)
Penetrates into cells poorly and drug-resistance is common
• At present, streptomycin is used when an injectable drug is
desired, principally in individuals with severe, possibly life-
threatening forms of tuberculosis, and in treatment of
infections resistant to other drugs
• It is always given together with other drugs to prevent
emergence of resistance
• Resistance developed rapidly when streptomycin was used
alone in tuberculosis- most patients had a relapse.

18. Adverse Effects
• Ototoxicity: (vestibular, hearing disturbances), risk
increases with age
• Neurotoxicity
• Nephrotoxicity: not as common as with amikacin or
capreomycin
• Contraindicated in pregnancy (risk of fetal hearing loss)
• Poor CNS penetration
• Requires renal dosing and close monitoring