Write short notes on:

(a)            acyclovir.

(b)            gentamicin.

(c)            lovastatin.

Suggested Answers:

(a)

Acyclovir is a synthetic purine nucleoside analog derived from guanine. Acyclovir is commercially available for parenteral use as the sodium salt and for oral use as the base. Acyclovir capsules and tablets should be stored in tight, light-resistant containers at 15—25°C.

Acyclovir inhibits viral DNA synthesis after phosphorylation by virus-specific thymidine kinase, which accounts for its high therapeutic index; phosphorylated acyclovir inhibits DNA polymerase and so prevents viral DNA being formed.

Taken orally about 20% is absorbed from the gut, but this is sufficient for the systemic treatment of some infections. It has a half-life of 3 hours. Acyclovir is widely distributed into body tissues and fluids including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, CSF, and herpetic vesicular fluid. It is excreted in the urine.

Acyclovir is used parenterally and currently is considered the drug of choice for the treatment of initial and recurrent mucosal or cutaneous herpes simplex (HSV-1 and HSV-2) infections in immunocompromised adults and children; for the treatment of severe first episodes of genital herpes infections in immunocompetent patients; for the treatment of herpes simplex encephalitis; for the treatment of neonatal herpes infections; and for the treatment of varicella-zoster infections in immunocompromisedadults and children.

Acyclovir is used orally and currently is considered the drug of choice for the management of first and recurrent episodes of genital herpes in selected patients; for the acute treatment of herpes zoster (shingles); and for the treatment of varicella (chickenpox) in immunocompetent adults and children 2 years of age and older. It is used as prophylaxis and treatment in the immunocompromised and in ocular keratitis as an ointment.

The most frequent adverse effects of parenteral acyclovir are local reactions at the injection site. Local reactions, including cutaneous irritation and erythema or inflammation, pain, and phlebitis, may occur at the site of injection.

Transient increases in BUN and/or serum creatinine concentrations and decreases in creatinine clearance occur in about 5—10% of patients receiving parenteral acyclovir, especially when the drug is administered by rapid IV injection or by rapid (over less than 10 minutes) IV infusion. Increased serum creatinine concentrations also have been reported in patients receiving oral acyclovir. Renal failure, resulting in death in some patients, has occurred in patients receiving acyclovir.

Headache is one of the most common nervous system adverse effects of oral acyclovir, occurring in about 2% of patients receiving the drug as chronic suppressive therapy; headache occurs less frequently during short-term therapy. Paresthesia and asthenia also occur in patients receiving acyclovir as chronic suppressive therapy. Vertigo, dizziness, fatigue, insomnia, irritability, confusion, hallucinations, somnolence, and mental depression have occurred rarely in patients receiving oral acyclovir. Confusion, dizziness, hallucinations, paresthesia, and somnolence during oral acyclovir therapy may be marked, particularly in older adults. Malaise and headache occur in about 12 and 6% of patients receiving high-dose therapy for herpes zoster, respectively. Encephalopathic effects including lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, and coma have occurred in approximately 1% of patients receiving parenteral acyclovir therapy, however.

Nausea and/or vomiting and diarrhea are among the most common adverse effects of oral acyclovir. Nausea occurs in about 5% and diarrhea in about 2% of patients receiving the drug as chronic suppressive therapy; these adverse GI effects occur less frequently during short-term therapy.

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, sometimes resulting in death, has occurred in immunocompromised patients with high exposure to acyclovir.

Rash, pruritus, or urticaria occasionally occurs during acyclovir therapy.

Acyclovir has been used concomitantly with zidovudine in some patients with human immunodeficiency virus (HIV) infections without evidence of increased toxicity; however, neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one patient with acquired immunodeficiency syndrome (AIDS) during concomitant therapy with the drugs.

Concomitant administration of probenecid and acyclovir has reportedly increased the mean plasma half-life and area under the plasma concentration-time curve (AUC) and decreased urinary excretion and renal clearance of acyclovir.

Amphotericin B has been shown to potentiate the antiviral effect of acyclovir against pseudorabies virus in vitro when both drugs are added to the culture medium. Ketoconazole and acyclovir have shown dose-dependent, synergistic, antiviral activity against herpes simplex virus types 1 and 2 (HSV-1 and -2) in in-vitro replication studies.

(b)

Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora purpurea. Gentamicin sulfate injection should generally be stored at a temperature less than 40°C, preferably between 15—30°C, unless otherwise specified by the manufacturer; freezing should be avoided. The manufacturer (Baxter) of the commercially available gentamicin sulfate injections in 0.9% sodium chloride in Viaflex^® The manufacturers state that gentamicin sulfate injection for IM or IV administration should not be mixed with other drugs.

Gentamicin is bactericidal. IT acts inside the cell by binding to the ribosomes in such a way that incorrect amino acid sequences are entered into peptide chains. The abnormal proteins which result are fatal to the microbe.

Gentamicin is poorly absorbed from the GI tract. It is well absorbed following iv. or i.m administration for systemic use. Following absorption, gentamicin is widely distributed into body fluids including ascitic, pericardial, peritoneal, pleural, synovial, and abscess fluids. Gentamicin readily crosses the placenta. The half-life of gentamicin is 2-5 h and it is eliminated unchanged mainly by glomerular filtration and attain high concentrations in the urine.

Gentamicin is the drug of choice in Gram-negative bacillary infection, particularly septicaemia, pelvic and abdominal sepsis. Amikacin has the widest antibacterial spectrum of the aminoglycosides and is best reserved for infection caused by gentamicin-resistant organisms. Gentamicin is usually used as part of the antimicrobial combination for enterococcal, streptococcal or staphylococcal infection of the heart valves, and for the therapy of clinical endocarditis which fails to yield a positive blood culture. It is also used in other infections such as tuberculosis, tularaemia, plague, brucellosis, meningitis, bacterial pneumonia and biliary tract, urinary tract, soft tissue, bone, burn wound and joint infections.

Dose is 2-5 mg/kg body weight per day either in 3 equally divided doses or as a single dose. The rationale behind single dose administration is to achieve higher peak plasma concentrations which correlate with therapeutic efficacy.

Gentamicin toxicity is a risk when the dose administered is high or of long duration, renal clearance is inefficient, or the patient is dehydrated. Both vestibular and auditory damage may occur, causing hearing loss, vertigo and tinnitus which may be permanent. Early signs of vestibular toxicity include motion-related headache, dizziness or nausea. Serious ototoxicity can occur with topical application, including ear-drops. Gentamicin accumulates in renal tubular cells where it may cause renal impairment at high doses. It may impair neuromuscular transmission and aggravate myasthenia gravis, or cause a transient myasthenic syndrome in patients whose neuro-transmission is normal. Other reactions include rashes, and haematological abnormalities, including marrow depression, haemolytic anaemia and bleeding due to antagonism of factor V.

Gentamicin has drug interactions which potentiate its toxic effects. Use of cephalosporins, loop diuretics concurrently with gentamicin increases nephrotoxicity. Concurrent administration of anaesthetics may lead to increased neuromuscular blockade activity and respiratory depression. Circulatory collapse may also occur secondary to the neuromuscular blockade. Penicillin inactivates gentamicin and this decreases the antimicrobial effects of gentamicin if it is used together with a penicillin.

(c)

Lovastatin is the delta-lactone of mevinolinic acid and is produced by fermentation of Aspergillus terreus. Lovastatin is a prodrug and has little, if any, antilipemic activity until hydrolyzed in vivo to mevinolinic acid. Lovastatin tablets should be stored in well-closed, light-resistant containers at 5—30°C. When stored under these conditions, the tablets are stable for 24 months after the date of manufacture.

Lovastatin is a HMG-CoA reductase inhibitor. It inhibits HMG-CoA reductase, the rate-limiting enzyme in endogenous cholesterol synthesis. This results in increased synthesis of LDL receptors in the liver and clearing of LDL from the circulation.

Lovastatin is rapidly absorbed following oral administration and undergo extensive first-pass metabolism in the liver. Lovastatin is distributed mainly to the liver, spleen, kidneys and the adrenal glands. It is extensively metabolised in the liver by the cytochrome P-450 system. It has a half-life of 2-4 hours and is excreted mainly in the urine and faeces.

Lovastatin is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol concentrations in the treatment of primary types IIa and IIb hyperlipoproteinemia (primary hypercholesterolemia), including heterozygous familial hypercholesterolemia and other primary causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia).

Lovastatin is well tolerated orally, the commonest adverse effect being transient, and usually minor, abnormality of liver function tests. Other side effects are allergic reaction, constipation, diarrhea, dizziness, heartburn, nausea, skin rash, stomach pain, myalgia, myositis, rhabdomyolysis, insomnia and impotence.

The following drugs are not to be used in combination with lovastatin as they inhibit its metabolism and may result in elevated levels of lovastatin, leading to rhabdomyolysis. They are gemfibrozil, macrolides, anti-fungal azoles, protease inhibitors, cyclosporine, verapamil and diltiazem. Lovastatin displaces warfarin from its protein binding sites and may inhibit its metabolism leading to increased bleeding tendency.