Anti-Tuberculosis Drugs

India is known as the TB capital of the world. But as doctors, you must already know that. There are always multiple cases of tuberculosis in India. The treatment of TB goes on for a very long period, at least a minimum of 6 months. In this blog post, you will learn everything about anti-tuberculosis drugs. 

This topic is crucial while covering Pharmacology for NEET PG preparation. 

• The treatment of TB takes a long time. This is because the various bacteria involved are in different phase , some are slowly multiplying, and some are fast multiplying. The second problem is resistance. If the patient is not completely cured, the bacteria become resistant to the drugs. Nowadays, multidrug-resistant TB and extensively drug resistant TB can be seen, which are very difficult to treat. The treatment of these complex TB conditions can go on for around 1 to 2 years. 

Anti Tuberculosis Drugs

The drugs used to treat tuberculosis affect almost all organs of the body. Anti-TB drugs can be divided into the following:

• First line drugs
• Second line drugs

First-line drugs are used in the beginning.

Four important drugs are present in this category.

1. H- Isoniazid
2. R- Rifampicin
3. Z- Pyrazinamide
4. E- Ethambutol 
5. S- Streptomycin (considered a first-line supplement drug). 

Second-line drugs are used in resistance cases.

H- Isoniazid

Full Form: Isonicotinic Acid Hydrazide or INH

Mechanism of Action

MOA:

⊖Mycolic acid synthesis

↓

⊖Cell wall synthesis

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Tuberculocidal

INH [Prodrug]

• It inhibits mycolic acid synthesis, which is important for making the cell wall of the tuberculosis bacteria. The cell wall is there for not formed as an effect of this drug and is there for tuberculocidal. 
• INH is a pro-drug. It enters the bacteria. Catalase-peroxidase enzyme in the bacteria makes it transform into its active form. The active form forms a complex with two important molecules, 

• NADP +, which will inhibit the enzyme called DHF reductase, and 
• NAD inhibits two important actions: inhibiting acyl carrier protein reductase and inhibiting beta ketoacyl ACP synthase. 

• When these enzymes are inhibited, that is inhibition of mycolic acid synthesis. 
• This leads to the inhibition of cell wall synthesis.
• This is leading to a cidal effect. 

• Acyl carrier protein reductase is coded by certain genes called INHA genes or INHA proteins. Beta ketoacyl ACP synthase is coded by a gene called Kas A. 
• Kat G gene is responsible for catalase-peroxidase.
• When an INH drug is used, bacteria will mutate its gene. The enzyme catalase-peroxidase will not be produced in such a case. This will cause INH, when it enters inside, to not become active, and therefore the drug will not work. This major mutation is a Kat G gene mutation. 
• Kas A can also undergo minor mutation. This will again lead to a resistance problem.
• INH A will also produce resistance due to overexpression. A high dose of this drug has to be given to overcome this resistance.

Pharmacokinetics of the Drug

Pk = Acetylation

t1/2 3 hrs ← Slow acetylators = 60%

t1/2 1 hr ← Fast acetylators = 40%

• Enz. Inhibitor CYP3A4IS
• Enz. Inducer “CYP2E1”

↓

         Generate

↓

Toxic metabolite

↓

    Hepato toxic

• For drugs undergoing acetylation, acetylation can happen in two ways. 
• Slow acetylators in the body (60% of the Indian population). For slow acetylators the drug is not metabolised fast. The half-life In these cases will be 3 hours.
• Fast acetylators in the body ( 40% of the Indian population). In such cases, the half-life of the drug will be one hour. 
• Drugs undergoing acetylation can produce drug-induced lupus. This is seen majorly in the case of often anti-arrhythmic drugs called procainamide. 
• Isoniazid is mainly an enzyme inhibitor and inhibits the enzyme CYP 3A 4/5. 
• It is an enzyme inducer of CYP2E1. It generates toxic metabolite, which causes hepatotoxicity.

Uses

• It is used mainly in cases of Tuberculosis and prophylaxis of TB. Suppose there are four people living in the room, and one of them has TB. The other three are also at risk of contracting tuberculosis. The drug is also given to the rest of the three people in such a case.
• It is used in infections of M Kanasii. 

Adverse Effects

• It is an inhibitor of enzymes and an MAO inhibitor. 
• It produces peripheral neuropathy. The drug interferes with pyridoxine, which becomes pyridoxine 5 phosphate. This interferes with the drug, and this will lead to the patient having a tingling sensation in the peripheries. 
• To treat peripheral neuropathy, the patient is given pyridoxine at 10 mg/day. 
• The drug produces hepatotoxicity. INH toxicity is caused when this drug is given at a high dose. 

Triad of INH Toxicity

• Metabolic acidosis (not easily treated with Sodium Bicarbonate)

• Seizures (resistant to Barbiturates and Phenytoin and hence treated with benzodiazepines like lorazepam and diazepam)
• Coma

Antidote

• (MCQ) The antidote for INH toxicity is pyridoxine. Normally on use, it becomes pyridoxine 5 phosphates. When INH is given, it becomes INH-pyridoxal. The active form of pyridoxine depletes, leading to a decrease in GABA synthesis. This will lead to glutamate levels going up, and hence CNS excitation. This will again cause the patient to develop seizures. 
• Pyridoxine is given intravenously on a gram-to-gram basis, dependent on how much pyridoxine has been taken. If the patient does not know the dose it can be given at 70 mg per kg.

Rare Adverse Effects

• Since it is an MAO inhibitor, it will increase serotonin levels. This can cause psychosis and hallucinations. 
• It can also increase the activity of noradrenaline due to MAO inhibition. Therefore the patient will have a risk of seizures. 
• The decrease in pyridoxine can also lead to seizures due to a decrease in GABA synthesis. 
• The drug can produce gynecomastia.
• Another side effect of this drug is shoulder hand syndrome, characterized by pain and stiffness in the shoulders and hands. The patient will have similar features as that of rheumatoid arthritis. 
• The patient may also develop Sideroblastic anemia due to pyridoxine deficiencies. This condition is treatable with pyridoxine or B6. 
• In some patients, this has caused memory impairment.

Speciality

• The speciality of the drug is that it can act on intracellular and extracellular bacteria. When the bacteria are outside the cell, it is extracellular bacteria, and when the bacteria are present inside the macrophage, it is intracellular bacteria. For intracellular bacteria, the drug has to go inside the cell and kill it. 

• The second speciality is that it is effective in rapidly multiplying bacilli. 
• This drug has maximum CSF penetration. 
• This drug is effective in acidic and alkaline pH. 

R- Rifampicin

 The Mechanism of Action

• From the DNA, RNA is obtained. It is DNA-dependent RNA synthesis. The Messenger RNA synthesis is the main result of this process. If it is inhibited, mRNA synthesis does not occur, and the bacteria will not be able to multiply. This blockade is done by rifampicin. The mechanism of action of this drug is that it inhibits DNA-dependent RNA polymerase.

• RNA-dependent RNA polymerase is also observed and is mainly seen in viruses. It is mainly inhabited by a drug called remdesivir.  
• Rifampicin belongs to a group of drugs called rifamycin. Rifampicin is an enzyme inducer.

Types of the Drug

• Rifampicin- this is the maximum enzyme inducer.
• Rifapentine- this is a moderate enzyme inducer.
• Rifabutin- this is the minimal enzyme inducer. 
  • This drug is used to treat mycobacterium avium complex. The adverse effects of this drug include uveitis, pseudo-jaundice, and arthralgia. This drug has better utility in MAC infection and is preferred more than Rifampicin. 
  • If a patient is newly diagnosed with HIV and tuberculosis, he is treated first for tuberculosis. After 2 weeks of being treated, HIV treatment is started. 
  • If HIV is treated first, the immunity will boost, which was earlier suppressed. Immune reconstitution inflammatory syndrome (IRIS) will take place in which the immune response will then cause the patient to have a fever, lymph node enlargement, and other symptoms. Therefore after tuberculosis is treated, HIV can be treated to avoid IRIS. 
  • If rifampicin is added to a patient having TB, since it is an enzyme inducer, it will induce the metabolism of the HIV drugs. 
  • Therefore for newly diagnosed patients, instead of this drug, Rifabutin is used. Rifabutin has less enzyme induction, and therefore the drugs used in HIV are not metabolized and will not become short-acting. 
• Rifaximin
  • This drug has very poor oral absorption. It is used to treat irritable bowel syndrome, especially diarrhea-predominant conditions. It is also used in the management of pseudomembranous colitis.

Implications of Rifampicin

• When a woman is on an oral contraceptive pill and has been recently diagnosed with tuberculosis, the treatment for tuberculosis has to be started, and the major drug for treatment is Rifampicin. Since it is an enzyme inducer, the oral contraceptive pills will be metabolized faster, leading to contraceptive failure.
• If the lady becomes pregnant again, the drugs will affect the fetus  . A barrier method of contraception is therefore advised in such a case. 
• Rifampicin
  • It is an enzyme inducer.
  • It undergoes enterohepatic recycling.

Uses

• It is used to treat tuberculosis, leprosy, MRSA, meningococcal prophylaxis, H influenza, Brucellosis (Doxy + Rifampicin), and Legionella. 

Adverse effects

• It causes orange-red discolouration secretions.
• It can cause hepatotoxicity.
• It can cause the cutaneous syndrome, flu syndrome and abdominal syndrome in case of intermittent dosing. 

Special effects

• This drug acts on intra and extracellular bacteria, 
• It treats sperters and persistors. 
• H+R is responsible for producing synergism. 

Z- Pyrazinamide

• When does drug enter the bacteria, it acts on an enzyme called pyrazinamidase which is coded by a gene called pnc A gene. It gives rise to pyrazonic acid. This drug inhibits the fatty acid synthase and cell wall synthesis and disrupts the cell membrane of the bacteria and the transport mechanism.

Special effects

• This drug especially acts very well in acidic PH and intracellular bacteria, and inflammatory areas. H+Z+R+E reduces the duration of treatment from 9 months to 6 months; it has exceptional sterilising properties. 

Adverse effects

• Pain and Arthralgia. Hyperuricemia is also observed. Hepatotoxicity is also observed. It is the most hepatotoxic first-line drug. 

E - Ethambutol (Static)

• This drug inhibits arabinosyl transferase,  causes arabinogalactan synthesis inhibition and inhibits cell wall synthesis. 

Adverse effect

• Eye toxicity is observed. Retrobulbar optic neuritis is seen, which causes red-green blindness and decreases visual acuity. 
• Mild increasing uric acid is also observed. 

Uses

• This drug is used to treat tuberculosis and MAC. 

Streptomycin

• It is AGs “cidal” and contraindicated in cases of pregnancy. 

Special uses

• These drugs are very effective in alkaline pH and extra cellular bacilli. These drugs are given as injections.

A Summary

• Fast multiplying bacilli (Wall of cavitary lesion)
• Slow multiplying bacilli (Inflammatory site/macrophages)
• Slow and intermittently dividing (persister/spurters) bacilli
• Dormant bacilli → Bedaquilline
• Casious material → pH neutral low O₂

(H+R) = Synergistic Effect

L = 9 months → 6 months

    = Good sterilizing properly

E = ↓ Resistance

• Drugs are used in combination because when the bacteria mutates the combination of the drugs can kill the mutation. 

Second Line Drugs

• The second-line drugs are used because the first-line drugs made develop resistance. Types of second-line drugs

1. Fluoroquinolones

• These include two major drugs
• Moxifloxacin (this comes with the risk of QT prolongation) and levofloxacin. Ofloxacin and ciprofloxacin are also used but are less effective for treating tuberculosis.

2. Injectables/Second-Line Injectables

• These are known as ACK drugs.
  • Amikacin
  • Capriomycin
  • K- Kanamycin

3. Thioacetazone

• This was one of the earlier drugs for tuberculosis. It is static, and the major adverse effect is that it is hepatotoxic. It is a low-cost drug and has been shown to decrease the resistance problem.

4. Cycloserine

• It is a static drug. It can cause psychosis and seizures. 
• Terizodone is made up of two molecules of Cycloserine and has fewer neuropsychiatric adverse effects. It is the preferred drug for genitourinary tuberculosis.

5. Ethionamide/Prothionamide

• This has cross-resistance with INH. These inhibit cell wall synthesis.

6. Para Amino Salicylate

• Drug numbers 5 and 6 may develop the adverse effect of hypothyroidism.

7. Linezolid

• This drug is used for the treatment of drug-resistant TB.

8. Unknown Efficacy Drugs

• Imipenim+ Cilastatin, Amoxicilin+ Clavulanic acid, Meropenim.

9. Clofazimine

• New drugs for treating tuberculosis

10. Bedaquiline

• The drug inhibits mycobacterium ATP synthesis. This is even effective in cases of dormant bacilli and is bactericidal. It has a very long half-life of 160 to 165 days due to the high volume of distribution. Fatty food increases the absorption of this drug. It is metabolised by the enzyme CYP3A4/5. 
• Adverse effects of this drug include QT prolongation and hepatotoxicity. It has cross-resistance with clofazimine. 
• This drug is given for 0 to 2 weeks at 400 mg daily. From the third week to 24 weeks, 200 mg is administered thrice weekly. The total dose in a week should be 600 mg. 
• It is used only for drug-resistant pulmonary TB. It is not used for DST TB and extrapulmonary TB. 

Regime Used to Treat Tuberculosis

B- Bedaquiline

Pa- Pretomanid

L- Linezolid

• It is used to treat MDR and DR TB. All of these drugs are already administered, and safety is ensured. Bedaquiline should not be used in cases of pregnancy. 
• Pretomanid belongs to the group bicyclic Nitroimidazole. Examples of drugs from this group include Delamanid as well. These inhibit protein and mycolic acid synthesis and also inhibit cell wall synthesis. The only adverse effect is that they can cause QT prolongation. These are suited for drug-resistant TB.

We hope you found the above blog post helpful and informative. That is everything you need to know about anti-TB drugs for Pharmacology preparation. For more interesting and informative posts like these, keep reading PrepLadder blogs!