Write short notes on:

(a)            paracetamol toxicity.

(b)            fluoxetine.

(c)            glibenclamide.

Suggested Answer:

(a)

Paracetamol toxicity is a result of a toxic metabolite, NABQI which accumulates in the liver in the event of an overdose.

Paracetamol is inactivated in the liver principally by conjugation as glucuronide and sulphate. Minor metabolites are formed such as NABQI, which is highly reactive chemically. This substance is normally rendered harmless by conjugation with glutathione. But the supply of hepatic glutathione is limited and if the amount of NABQI formed is greater than the glutathione avaailable, then the metabolite oxidizes –SH groups of key hepatic enzymes, causing cell necrosis.

Severe hepatic and renal damage can result from taking 150 mg/kg (about 10g or 20 tablets) in one dose, which is only 2.5 times the recommended maximum daily clinical dose. Patients especially at risk are those whose enzymes are induced as a result of taking drugs or alcohol and those who are malnourished. The INR and plasma creatinine are used as monitors for liver and renal status respectively. The clinical signs of paracetamol toxicity are jaundice, abdominal pain and hepatic tenderness. These do not become apparent for 24 – 48h and liver failure, when it occurs, does so between 2 and 7 days after the overdose.

Activated charcoal by mouth is effective in adsorbing the ingested paracetamol and preventing further absorption. N-acetylcysteine and methionine are used as oral antidotes in replenishing the store of glutathione and so diminishes the amount of toxic metabolite available to do harm.

(b)

Fluoxetine is the first SSRI to be used clinically. It is an antidepressant which selectively blocks the reuptake of serotonin. Increased serotonin neurotransmision is associated with its mood-elevating property. Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The onset of antidepressant activity following oral administration of fluoxetine hydrochloride usually occurs within the first 1—3 weeks of therapy, but optimum therapeutic effect usually requires 4 weeks or more of therapy with the drug. Fluoxetine and norfluoxetine, the principal metabolite, are eliminated slowly. Following a single oral dose of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 2—3 days (range: 1—9 days) and that of norfluoxetine averages about 7—9 days.

Fluoxetine is used in the clinical management of major depressive disorder, obsessive-compulsive disorder, panic disorder, social phobia, bulimia nervosa, premature ejaculation, alcohol dependence and depression associated with bipolar disorder.

Headache, nervousness, anxiety, insomnia, drowsiness and fatigue are the most common side effects of fluoxetine. The common GI effects are nausea, vomiting and diarrhea. Maculopapular rashes, urticaria and purpura have been reported. Weight loss frequently occurs during therapy with fluoxetine and is reversible after discontinuation of the drug. Sexual dysfunction occurs in a small percentage of patients on fluoxetine, the most common of which is ejaculatory delay.

The concurrent administration of tramadol and fluoxetine may result in an additive blockage of serotonin reuptake, resulting in central serotonergic hyperstimulation and serotonin syndrome. The SSRIs may inhibit the metabolism of tramadol at the cytochrome P450-2D6 isoenzyme and may lower the seizure threshold.  Symptoms of serotonin syndrome may include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death. The concurrent administration of tramadol with fluoxetine may also increase the risk of seizures. Fluoxetine may displace warfarin from its plasma protein binding sites or inhibit its hepatic metabolism leading to an increase in the clinical effects and toxicities of warfarin. It also inhibit the metabolism of benzodiazepines, TCAs and clozapine resulting in an increase in their clinical effects.

(c)

Glibenclamide alone or in fixed combination with metformin hydrochloride is used as an adjunct to diet for the management of noninsulin-dependent diabetes mellitus (type 2) in patients whose hyperglycemia cannot be controlled by diet alone.

Glibenclamide is a sulfonylurea antidiabetic agent. Like other sulfonylurea antidiabetic agents, glibenclamide lowers blood glucose concentration in diabetic and nondiabetic individuals. On a weight basis, glibenclamide is one of the most potent of the sulfonylurea antidiabetic agents.

The principal mode of action of glibenclamide is to enhance the release of insulin from pancreatic beta cells in response to a rising blood sugar level. Thus, they can only be effective in relatively mild maturity onset diabetics who still have substantial insulin secretory capacity. Binding of glibenclamide to beta-islet cell surface receptors leads to reduced conductance of the ATP-sensitive K⁺ channels. This blocks K⁺ efflux and leads to cell membrane depolarization. This in turn opens voltage-gated Ca²⁺ channels and result in influx of Ca²⁺ and so cause exocytosis of insulin-containing secretory granules. Glibenclamide produces a mild diuresis by enhancing renal free water clearance.

Currently available tablet formulations of glibenclamide appear to be reliably and almost completely absorbed following oral administration. Following single oral doses of glibenclamide in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 15—60 minutes. Glibenclamide has a half-life of 10 hours. It is a potent drug which is usually taken once a day, before or with a meal. It is concentrated in islet beta cells to produce a prolonged insulin release, especially after meals. It is effective for 24 hours, a feature that also explains why it can cause prolonged hypoglycaemia. It appears to cross the placenta, since prolonged hypoglycemia has occurred in neonates born to women who received the drug up to the time of delivery. Glibenclamide appears to be completely metabolized, probably in the liver. Its metabolites have a week blood sugar lowering effect which is not clinically important. Unlike other currently available sulfonylurea antidiabetic agents which are excreted principally in urine, glibenclamide is excreted as metabolites in urine and feces in approximately equal proportions. Fecal excretion appears to occur almost completely via biliary elimination.

Hypoglycemia, which may be severe and has occasionally been fatal, may occur in patients receiving glibenclamide. Like other sulfonylurea antidiabetic agents, glibenclamide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia. It can also cause headache, anorexia, constipation, diarrhoea, drowsiness, heartburn, nausea and vomiting.

Glibenclamide should be used with caution in patients on beta-blockers as they reduce the response to it. Frequency and severity of hypoglycaemic episodes may be increased while warning symptoms of low blood sugar may be masked. Azole antifungals inhibit the metabolism of glibenclamide thereby increasing its clinical effectiveness and hypoglycaemia may result. Salicylates may cause displacement of glibenclamide from binding proteins and they may have intrinsic glucose lowering properties which can potentiate the hypoglycaemia. Gluconeogenesis, glycogenolysis and lipolysis are increased by epinephrine resulting in decreased effectiveness of glibenclamide.