Cloramphenicol, lincosamide and anti-mycobacterial drugs

Question 1

Explain the function of chloramphenicol?

Answer 1

Binds “reversibly” to the 50s ribosomal subunit, to inhibit the action of the “peptidyl transferase” (catalyses the addition of an amino acids in order to elongate the polypeptide chain in protein synthesis.)

Question 2

Resistance of the chloramphenicols?

Answer 2

1. Enzymes that inactivate chloramphenicol
2. Reduced bacterial cell permeability to the drug
3. Ribosomal binding site alterations

Question 3

Pharmacokinetics of chloramphenicols?

Answer 3

IV administration, hepatic metabolism into inactive glucuronide. Renal excretion into the urine. Dosage adjustments in people with hepatic insufficiency.

Adverse effects = 2 types

1. Anaemias: The mitochondrial ribosomes (in host) are similar to that of the bacterial enzymes, can be targeted, leading to lower ATP levels and bone marrow suppression. There are 3 types of anaemia that can be produced, namely: Aplastic, haemolytic and dose-related anaemia.
2. Grey baby syndrome: Foetal kidneys are lesser developed for the excretion of the inactive glucuronide metabolites, leads to a reduced urinary excretion. This elevated concentration of the un-excreted metabolite leads to symptoms if occurring in babies: Depressed CV function, difficulty breathing, cyanosis and poor feeding.

Question 4

MOA of anti-mycobacterial drugs? (Treatment of TB)

Answer 4

There are 4 main types of drugs: Isoniazid, rifamycins, ethambutol and pyrazinamides.

There are 2 types of drugs, namely first line and second line drugs, second line are lesser effective and more toxic compared to first line and are used in cases of resistant TB infections.

The drugs have different bacteriostatic functions, aimed to weaken the bacteria.

Question 5

Explain the pharmacology of isoniazid?

Answer 5

Functions to inhibit 2 bacterial enzymes “acyl carrier protein reductase” and “Beta ketoacyl synthase”, which inhibits the production of mycolic acid, thus halting bacterial cell wall synthesis. Isoniazid is activated by “KatG - mycobacterial catalase peroxidase”. Resistance is aimed at mutations of the KatG, reducing activation and mutations of the acyl carrier protein reductase (target).

Phk: Oral absorption, reduced with food intake. CSF concentration is similar to that of the serum. N-acetylation and hydrolysis in the liver into inactive products, urinary excretion.

Adverse effects:

1. Hepatits
2. Pyridoxine (B6) deficiency
3. Peripheral neuropathy (parasthesia of the hands and feet)
4. Hypersensitivity reaction (rashes and fever)

Question 6

Explain the pharmacology of the rifamycins?

Answer 6

Rifampin, rifabutin and rifapentine are structurally similar macrocyclic antibiotics, which are oral preparations for treating TB. They block bacterial RNA transcription by interacting with the “Beta subunit of DNA dependent RNA polymerase”. Resistance towards rifampin is caused by mutations in the affinity of the DNA dependent RNA polymerase.

Phk: Oral absorption, accumulates in the liver, enters enterohepatic recycling. Unlike the Isoniazid there is a higher concentration in the CSF compared to the plasma (10-20%). Rifampin undergoes “auto-induction” (stimulates enzymes to increase its own metabolism), which shortens its duration of activity. Rifampin induces cytochrome p450 thus stimulating drug interactions. Elimination of rifampin occurs mainly in the bile/feces, small amounts via urine.

Adverse effects:

1. Co administration with isoniazid increases the risk for liver dysfunction.
2. Nausea, vomiting and rash development.
3. Intermittent administration of rifampin leads to the development of a flu-like syndrome.

Rifabutine: Used for the treatment of TB patients co infected with HIV. Adverse effects are similar to rifampin, but additionally include uveitis, neutropenia, and skin hyper-pigmentation.

Rifapentine: When co administrated with isoniazid rifapentine can be used for the treatment of patients with LTBI.

Question 7

Explain the pharmacology of the pyrazinamide?

Answer 7

Oral administration, mechanism of action is unclear. Converted by pyrazinamidase into “pyrazinoic acid” (active drug form). Common adverse effect is uric acid (rarely develops gouty attack) retention, it may also cause liver toxicity.

Question 8

Explain the pharmacology of the Ethambutol?

Answer 8

Functions to inhibit “Arabinosyl transferase”, important for formation of the bacterial cell wall. The drug has a high distribution and is primarily excreted in the urine. The main adverse effect of Ethambutol is “optic neuritis” which can lead to a decreased visual acuity and reduced ability to distinguish the differences between the appearance of red and green colour. Therefore it is important to test the patients vision before initiating therapy with this drug.

In patients with renal impairment taking Ethambutol, uric acid excretion is reduce which can precipitate and cause a gouty attack. The risk of developing optic neuritis increases with higher doses of Ethambutol and in patients with renal failure.

Question 9

Explain the second line anti-microbial agents?

Answer 9

2nd line of treatment – tuberculostatic or tuberculocidal; less effective and more toxic compared to 1st line drugs; combined therapeutic regimens for alternative treatment of multidrug resistant (MDR) or extremely drug resistant (EDR) mycobacterial strains
Streptomycin, Fluoroquinolones, Para-aminosalycilic acid, Amikacin, Capreomycin.

Question 10

Explain the pharmacology of “Lincosamides”?

Answer 10

Lincosamides are a class of antibiotics that are derived from the compound “lincomycin” and that inhibit the growth of bacteria by blocking bacterial protein synthesis.

Narrow spectrum – Gr + (suitable for staphylococcal osteomyelitis, parodontosis) MOA – bind to 50S ribosomal subunit and inhibit protein synthesis

ADRs – GIT disturbances (may cause pseudomembranous colitis, caused by overgrowth of C. difficile), hepatotoxicity, rarely allergies, prolonged treatment – leucopenia, thrombocytopenia

Drug interactions – shouldn’t be combined with other drugs, affecting the 50S subunit; in vitro incompatibility with Erithromycin; cross resistance between Clindamycin.

PhK – oral and parenteral administration; good oral absorption (should be taken with enough water), good intracellular distribution (clindamycin), penetrate into bones, teeth and soft tissues; penetrate feto-placental barrier; excreted with bile and breast milk; metabolised in the liver. (Research online the PhK)