Write short notes on:

(a)            salbutamol.

(b)            lovastatin.

(c)            metronidazole.

Suggested Answer:

(a)

Salbutamol is a synthetic sympathomimetic amine which occurs as a 50:50 mixture of the R- and S- enantiomers. It can be administered by inhalation or orally as salbutamol sulfate.

Salbutamol stimulates beta₂-adrenergic receptors and has little or no effect on alpha-adrenergic receptors. It is believed that beta-adrenergic agonists stimulate the production of cyclic adenosine-3,5-monophosphate (AMP) by activation of the enzyme adenyl cyclase. Cyclic AMP appears to mediate numerous cellular responses. Increased intracellular cyclic AMP enhances the activity of cAMP-dependent protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular calcium concentrations, resulting in smooth muscle relaxation. Increased intracellular cyclic AMP concentrations also are associated with inhibition of the release of mediators from mast cells in the airways. It also decrease microvascular leakiness, increase mucociliary clearance and decrease acetylcholine release from the vagus nerve. The main effect following oral inhalation or oral administration of salbutamol is bronchodilation resulting from relaxation of smooth muscles from the trachea to the terminal bronchial tree; the drug also has some vasodilating effect on peripheral vasculature and may decrease diastolic blood pressure to a small extent.

Bronchodilation begins within 5—15 minutes after oral inhalation of salbutamol or salbutamol sulfate via the metered-dose aerosol or via the special oral inhaler (Rotahaler^®) that delivers powdered drug from capsules, with peak effect in 0.5—3 hours, and generally persists 2—5 hours. Following oral inhalation of salbutamol sulfate via the metered-dose inhaler, the onset of appreciable bronchodilation occurs within 6 minutes; mean time-to-peak bronchodilation occurs within 50—55 minutes. Bronchodilation persists for 3—6 hours.

Salbutamol is well and rapidly absorbed following oral administration with an oral bioavailability of 80%. It has a half-life of 2 – 5 hours, is extensively metabolized by the liver into an inactive metabolite and excreted in the urine and faeces.

The most common adverse effects of salbutamol are tremor, nervousness, dizziness, insomnia, nausea, muscle ache, hyperglycaemia, hypokalaemia and increased appetite. Salbutamol sulfate inhalation powder or aerosol may be associated with clinically important cardiovascular effects, including tachycardia, increased or decreased blood pressure, and related symptoms. Paradoxial bronchospasm and wheezing occurs in a small number of patients.

Being a sympathomimetic, salbutamol should be used with caution in those on TCAs. Its effect may be enhanced due to tricyclic blockage of norepinephrine reuptake.

(b)

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.

(c)

Metronidazole is a nitroimidazole drug which is widely used in parasitic infection, but it also has antibacterial activity. Its antibacterial activity that is useful clinically is confined to the anaerobic microorganisms. The exact mechanism is not known. It is thought that in susceptible cells, the nitro group of metronidazole is reduced. It is the reduced form that produces the biochemical lesions that leads to cell death.

It is generally well absorbed orally with a half-life of 8 hours. Parenteral preparations are available for i.v. use. It diffuses well into all tissues and fluids including the CNS. It is metabolized in the liver and both metabolites and a small percentage of the unchaged drug are excreted in the urine.

Metronidazole is active against a wide range of anaerobic bacteria and also protozoa. Its clinical indications are:

·        Treatment of sepsis to which anaerobic organisms, e.g. Bacteroides spp. and anaerobic cocci, are contributing, notably post-surgical infection, intra-abdominal infection and septicaemia, but also wound and pelvic infections, osteomyelitis and abscesses of brain or lung.

·        Pseudomembraneous colitis.

·        Trichomoniasis of the urogenital tract in both sexes.

·        Amoebiasis, whether symptomless carriers of cysts or intestinal and extra-intestinal infection.

·        Giardiasis.

·        Acute ulcerative gingivitis and dental infections.

·        Anaerobic vaginosis.

Adverse effects include nausea, vomiting, diarrhoea, furred tongue and an unpleasant metallic taste in the mouth; also headache, dizziness and ataxia. Rashes, urticaria and angioedema occur. Peripheral neuropathy occurs if treatment is prolonged and seizures if the dose is high. A disulfiram-like effect occurs with alcohol because metronidazole inhibits alcohol and aldehyde dehydrogenase.