Write short notes on:

(a)        the newer macrolides like clarithromycin and azithromycin.

(b)            fluoroquinolones interacting with other drugs.

(c)            midazolam.

Suggested Answer:

(a)

Macrolides are a group of antimicrobials which has a large lactone ring to which are attached one or more sugar residues. The macrolides inhibit protein synthesis by binding to 50S ribosomal subunits of bacteria. Erythromycin is the prototype of the macrolides used clinically since 1952. The newer macrolides like clarithromycin and azithromycin are slightly different from erythromycin in terms of potency and spectrum of action.

Clarithromycin acts like erythromycin and has a similar spectrum of antibacterial activity, i.e. mainly against Gram-positive organisms. It is rapidly and completely absorbed from the gastrointestinal tract, 60% of a dose is inactivated by metabolism which is saturable and the remainder is eliminated in the urine. Clarithromycin is used for respiratory tract infections including atypical pneumonias and soft tissue infections. It causes fewer gastrointestinal adverse effects than erythromycin.

Clarithromycin is used orally for the treatment of upper and lower respiratory tract infections, skin and skin structure infections, and otitis media caused by susceptible organisms. Clarithromycin also is used orally in the treatment of disseminated infections caused by Mycobacterium avium complex (MAC) and also for prevention of disseminated MAC infections in patients with advanced human immunodeficiency virus (HIV) infection. Clarithromycin is used in combination with amoxicillin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease. Clarithromycin is used for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A beta-hemolytic streptococci) in adults and children. Clarithromycin is used for the treatment of adults and children with acute bacterial sinusitis caused by Haemophilus influenzae, Branhamella (Moraxella, formerly Neisseria) catarrhalis, or S. pneumoniae.

Azithromycin interferes with bacterial ribosomal function and inhibits protein formation. It is active against a number of important Gram-negative organisms including Haemophilus influenzae and Neisseria gonorrhoeae, and also against Chlamydiae, but less effective against Gram-positive organisms than erythromycin.

Azithromycin is used orally in adults for the treatment of mild to moderate upper and lower respiratory tract infections and uncomplicated skin and skin structure infections caused by susceptible organisms. Oral azithromycin also is used for the treatment of urethritis or cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, and for the treatment of chancroid caused by Haemophilus ducreyi. Azithromycin is used orally alone or in conjunction with rifabutin for the prevention of disseminated infections caused by Mycobacterium avium complex in patients with advanced human immunodeficiency virus (HIV) infection. Azithromycin is used orally in children for the treatment of acute otitis media, community-acquired pneumonia, and pharyngitis or tonsillitis caused by susceptible organisms.

Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. It has a long half-life of 50h. Azithromycin achieves high concentrations in tissues relative to those in plasma. It remains largely unmetabolized and is excreted in the bile and faeces. In addition to direct tissue uptake, it has been suggested that uptake and release of azithromycin by phagocytic cells contribute to distribution of the drug into inflamed and infected tissues. Gastrointestinal effects are less than erythromycin but diarrhoea, nausea and abdominal pain occur. In view of its high hepatic excretion use in patients with liver disease should be avoided.

(b)

The fluoroquinolones such as ciprofloxacin, norfloxacin and ofloxacin, have a broad antibacterial spectrum and their use is extended to the treatment of various systemic infections. The mechanism of action of the fluoroquinolones is due to the inhibition of the enzyme DNA gyrase which prevents DNA supercoiling.

Aluminium and magnesium containing antacids may form chelation compounds with fluoroquinolones resulting in their decreased absorption and clinical effectiveness. Oral iron and sucralfate decreases the bioavailability of fluoroquinolones probably by the same mechanism.

Ciprofloxacin, pefloxacin and enoxacin have been found to decrease theophylline clearance significantly due to inhibition of hepatic enzymes as theophylline is eliminated primarily by metabolism in the liver involving cytochrome P450.

Ciprofloxacin is an inducer of the cytochrome P-450 oxidative enzyme system and may decrease the serum concentration of phenytoin by inducing phenytoin metabolism.

The clearance of some fluoroquinolones such as pefloxacin is reduced when administered concurrently with cimetidine. Cimetidine inhibits hepatic oxidative enzyme activity therefore increasing the plasma concentration and effectiveness of fluoroquinolones.

When a fluoroquinolone is administered together with warfarin, the hypoprothrombinemic effects of warfarin may be increased leading to a possible increase in bleeding.

Use of fluoroquinolones and NSAIDs together may increase the risk of convulsions.

(c)

Midazolam is a short-acting benzodiazepine and possess similar properties like others in the group such as anxiolytic, sedative, hypnotic, muscle relaxant and anticonvulsant actions. Clinical experience with the drug suggests that it may be 3 – 4 times the potency of diazepam.

Absorption of midazolam from IM injection sites is rapid and nearly complete. Midazolam has a half-life of 3 hours. Being highly lipid soluble, it is distributed widely to body tissues including the CSF and across the placenta into the amniotic fluid. Midazolam is metabolized extensively in the liver and intestine by cytochrome P-450 CYP3A4 into metabolites which are inactive. Midazolam is excreted in urine almost entirely as conjugated metabolites.

Midazolam can depress respiration. Relatively small doses, such as those used for preoperative sedation, usually do not substantially impair respiratory function; however, relatively large doses may substantially depress the ventilatory response to carbon dioxide (CO₂) stimulation. Excessive sedation, headache, and drowsiness occur in 1—2% of patients following parenteral administration of midazolam. Adverse reactions manifested as agitation, involuntary movements (e.g., tonic/clonic movements, muscle tremor), hyperactivity, and combativeness have occurred in less than 1% of patients receiving parenteral midazolam. Nausea and/or vomiting occur in 2—3% of adult patients receiving midazolam.

Midazolam is used mainly as an adjunct in anaesthesia for endoscopies, dentistry, etc.

Nausea and/or vomiting occur in 2—3% of adult patients receiving midazolam. Midazolam is used as a continuous IV infusion for sedation of intubated and mechanically ventilated adults, pediatric patients, and neonates during treatment in a critical-care setting (e.g., an ICU) or as a component of anesthesia. Midazolam has been administered orally as a hypnotic for the short-term management of insomnia. The drug also has been used orally for the prevention of night terrors in a limited number of children.