Write short notes on:

(a)            halothane.

(b)            fludrocortisone.

(c)            erythromycin.

Suggested Answer:

(a)

Halothane is an inhalation anaesthetic. It was the first halogenated agent to be widely used although it is being replaced by analogues.

Halothane is a colorless, volatile liquid with a sweet smell. In anaesthetic dosage it depresses both cerebral function and sympathetic autonomic activity and produces little, if any, preliminary excitement.

Halothane has high therapeutic efficacy, is non-irritant and non-inflammable. As its blood / gas partition coefficient is low, induction is smooth and rapid and surgical anaesthesia can be produced in 2-5 min. It does not augment salivary or bronchial secretions. The recovery time is rapid and the incidence of post-operative nausea and vomiting is low. Because of its cardiodepressant effect halothane is usually combined with another inhalational agent, such as nitrous oxide. Muscle relaxants are usually required to prepare the patient for abdominal surgery.

About 20% of halothane is metabolized and it induces hepatic enzymes, including those of anaesthetists and operating theatre staff. Contraindications include a history of unexplained jaundice, a family history of malignant hyperthermia and raised cerebrospinal fluid.

The incidence of halothane is approximately 1 in 10,000 most often after repeated administrations over a short period of time. Typically fever develops 2 or 3 days after anaesthesia accompanied by anorexia, nausea and vomiting. In more severe cases this is followed by transient jaundice or, very rarely, fatal hepatic necrosis. Halothane causes a dose-dependent decrease in blood pressure, bradycardia and arrhythmias. Halothane potentiates the response to anti-hypertensive agents. Premedication with atropine reduces the risk of hypotension and bradycardia.

(b)

Fludrocortisone acetate is a synthetic glucocorticoid with very potent mineralocorticoid properties. Fludrocortisone acetate is used for oral mineralocorticoid replacement therapy in patients with adrenocortical insufficiency or salt-losing forms of congenital adrenogenital syndrome after electrolyte balance has been restored.

Like most corticosteroids, fludrocortisone is rapidly absorbed orally and is widely distributed to the tissues. It is metabolized in most tissues, but primarily in the liver to biologically inactive metabolites which are excreted in the urine.

Fludrocortisone has a very great sodium-retaining effect in relation to its anti-inflammatory action, and only at high doses need the non-electrolyte effects be considered. It is used to replace aldosterone where the adrenal cortex is destroyed (Addison’s disease). Fludrocortisone is also the drug of choice in most patients with autonomic neuropathy.

The main adverse effects of fludrocortisone at therapeutic levels is due to its sodium-retaining properties which causes expansion of the extracellular volume leading to hypertension, fluid retention and generalized edema. The other metabolic side effects of steroids are usually only evident at high doses above the recommended dosage.

(c)

Erythromycin is a macrolide antibiotic produced by Streptomyces erythreus. Macrolides are a group of antimicrobial drugs which has a large lactone ring to which are attached one or more sugar residues. Erythromycin is a weak base that readily forms salts and esters with organic acids. Erythromycin is usually bacteriostatic, but it may be bactericidal in high concentrations or against highly susceptible organisms.

Erythromycin inhibits protein synthesis in susceptible organisms by binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. Erythromycin exerts its effect only against multiplying organisms. Erythromycin generally penetrates the cell wall of gram-positive bacteria more readily than that of gram-negative bacteria, and gram-positive organisms may accumulate 100 times more erythromycin than do gram-negative organisms.

Erythromycin is active in vitro against gram-positive cocci (staphylococci and streptococci) and gram-positive bacilli including Bacillus anthracis, Corynebacterium, Clostridium, Erysipelothrix, and Listeria monocytogenes. Erythromycin also is active in vitro against some gram-negative cocci (Neisseria) and some gram-negative bacilli, including some strains of Haemophilus influenzae, Legionella pneumophila, Pasteurella, and Brucella. Some strains of Chlamydia, Actinomyces, Mycoplasma pneumoniae, Ureaplasma urealyticum, Rickettsia, Treponema, and Entamoeba histolytica are inhibited by erythromycin. Enterobacteriaceae (e.g.,Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella, Shigella) and Pseudomonas usually are resistant to erythromycin, as are viruses and fungi. Resistant strains of Haemophilus influenzae, Corynebacterium diphtheriae, and staphylococci, particularly S. aureus, have developed during therapy with erythromycin. Erythromycin-resistant strains of streptococci, including Streptococcus pyogenes (group A beta-hemolytic streptococci), group B streptococci, S. pneumoniae, and viridans streptococci have been reported.

Absorption of orally administered erythromycins occurs mainly in the duodenum. The bioavailability of the drugs is variable and depends on several factors including the particular erythromycin derivative, the formulation of the dosage form administered, acid stability of the derivative, presence of food in the GI tract, and gastric emptying time. Gastric acidity causes partial inactivation of some of these drugs, with the degree of inactivation depending on the acid stability of the particular derivative and dosage form. Erythromycin base is highly susceptible to gastric acid inactivation, and commercially available tablets are coated with acid-resistant (enteric) coatings or are buffered to protect the drug from gastric acidity. Absorption of oral erythromycin is incomplete but adequate for the treatment of non-serious infections. For enteric coated erythromycin base the oral bioavailability is about 35%. The drug is widely distributed in most tissues except the CSF and the brain where penetration is poor. The half-life is approximately 2 hours. Excretion is via bile and urine. Only 2 – 5% of an oral dose and 12 – 15% of an intravenous dose are excreted in the active form in the urine. Erythromycin is mainly concentrated in the liver and excreted in the bile in the active form. There is some reabsorption of the drug from the intestine, forming the enterohepatic circulation.

Erythromycin is used for the treatment of mild to moderately severe infections of the upper and lower respiratory tract, skin, and soft tissue caused by Streptococcus pyogenes (group A beta-hemolytic streptococci). Erythromycin also is used to treat mild to moderately severe infections of the upper and lower respiratory tract caused by Streptococcus pneumoniae. Erythromycin is used orally for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A beta-hemolytic streptococci). Oral erythromycin is used as an alternative to IM penicillin G benzathine, oral penicillin V potassium, and oral sulfadiazine or sulfisoxazole for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis) in patients hypersensitive topenicillins and sulfonamides. Parenteral erythromycin is recommended for use as an alternative to parenteral penicillin G or ampicillin when intrapartum chemoprophylaxis for the prevention of perinatal group B streptococcal (GBS) disease is indicated in a woman who is hypersensitive to penicillin.

Erythromycin in conjunction with an adequate dose of a sulfonamide has been used in the treatment of mild to moderate upper and lower respiratory infections caused by Haemophilus influenzae. However, not all strains of this organism are susceptible to erythromycin concentrations ordinarily achieved, and many clinicians prefer other anti-infectives (e.g., cephalosporins, co-trimoxazole, aminopenicillins) for the treatment of H. influenzae respiratory tract infections. Oral erythromycin is used for the treatment of genital ulcers caused by H. ducreyi (chancroid). Although penicillin G is the drug of choice for the treatment of all stages of syphilis, the CDC states that, when compliance and post-treatment serologic testing can be ensured, oral erythromycin may be used for the treatment of primary or secondary syphilis in nonpregnant adults and adolescents who are hypersensitive to penicillin. Erythromycin has been used as an alternative to the preferred regimens (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline) for the treatment of coexisting chlamydial infections in adults and adolescents receiving treatment for gonorrhea. Oral erythromycin or oral azithromycin is used for the treatment of nongonococcal urethritis. Erythromycin, azithromycin, or clarithromycin is used for the treatment of primary atypical pneumonia caused by Mycoplasma pneumonia. Erythromycin is considered the drug of choice for the treatment of Bordetella pertussis infection (pertussis, whooping cough) and for prophylaxis in contacts of patients with pertussis. Erythromycin is used as an adjunct to diphtheria antitoxin in the treatment of respiratory tract infection caused by Corynebacterium diphtheria (diphtheria). Erythromycin also is used for prophylaxis in close contacts of patients with diphtheria and to eliminate the diphtheria carrier state. Erythromycin (with or without rifampin) is used for the treatment of infections caused by Legionella (Legionnaires’ disease), Campylobacter and Borrelia burgdoferi (Lyme disease).

The most common adverse effects of oral erythromycins are GI and are dose related. Erythromycin stimulates smooth muscle and GI motility. Abdominal pain and cramping occur frequently. Nausea, vomiting, and diarrhea have also occurred, especially after large doses. Occasionally, stomatitis, heartburn, anorexia, melena, pruritus ani, and reversible mild acute pancreatitis have occurred. Hepatic dysfunction, with or without jaundice, has occurred in patients receiving oral or parenteral erythromycin. Venous irritation and thrombophlebitis have occurred following IV administration of erythromycin.  Mild allergic reactions including urticaria, skin eruptions, and rash have occurred with erythromycin therapy. Serious allergic reactions including anaphylaxis have also been reported.

Erythromycin, apparently through inhibition of cytochrome P-450 microsomal enzyme systems, can reduce the hepatic metabolism of some drugs including carbamazepine, cyclosporine, hexobarbital, phenytoin, alfentanil, disopyramide, lovastatin, warfarin, theophylline, midazolam and bromocriptine, thereby decreasing elimination and increasing serum concentrations of these drugs.