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Information on Gliclazide, a sulphonylurea medication used to control blood sugar levels in type 2 diabetes. Learn about its mechanism of action, indications, side effects, interactions with St. John's Wort, and more.
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Pr
Gliclazide 80 mg Tablets
Manufacturer’s Standard
Hypoglycemic sulfonylurea Oral Hypoglycemic Agent
SANIS HEALTH INC. Date of Revision: 1 President's Choice Circle April 6, 2017 Brampton, Ontario L6Y 5S
Control #
PrGLICLAZIDE
Gliclazide 80 mg tablets
Manufacturer’s Standard
Oral Hypoglycemic Agent
GLICLAZIDE (gliclazide) is a hypoglycemic agent of the sulfonylurea group.
The hypoglycemic action of gliclazide is related to an improvement in insulin secretion from the functioning beta cells of the pancreas. It potentiates the insulin release,improves the dynamics of insulin.
Hemobiological properties of gliclazide have been observed in pharmacology studies. These are attributed to gliclazide action on the platelet behaviour, prostaglandin equilibrium and fibrinolysis.
Gliclazide is rapidly absorbed from the gastro-intestinal tract and the plasma peak of gliclazide occurs between 4 and 6 hours. In man it is highly bound to plasma proteins, about 94%. The mean elimination half-life in man approximates 10.4 hours.
Following oral administration the unchanged gliclazide in plasma is extensively metabolized with little of the unchanged compound (<1%) appearing in the urine.
Gliclazide metabolites and conjugates are primarily eliminated via kidneys: 60 to 70% and about 10 to 20% via faeces.
Some five principal metabolites have been identified in urine, essentially oxidized and hydroxylated derivatives, some as glucuronic acid conjugates.
The use of GLICLAZIDE (gliclazide) will not prevent the development of complications peculiar to diabetes mellitus.
Use of GLICLAZIDE must be considered as treatment in addition to proper dietary regimen and not as substitute for diet.
The efficacy of gliclazide, in reducing glucose to the desired level decreases over a long period of time in many patients: this may be due to progression in the severity of the diabetes, or to a reduced response to treatment. If a loss of adequate blood glucose- lowering response to GLICLAZIDE is detected, the drug should be discontinued.
Patient Selection and Follow-up:
Careful selection of patients is important. It is imperative that there be rigid attention to diet, careful adjustment of dosage and instruction of the patient on hypoglycemic reactions, their recognition, remedies and control as well as regular, thorough medical follow-up.
Since the effects of oral hypoglycemic agents on the vascular changes and other long-term sequelae of diabetes mellitus are not fully known, patients receiving such drugs must be closely observed for both short- and long-term complications. Periodic assessment of cardiovascular, ophthalmic, renal and hepatic status is advisable.
In patients stabilized on gliclazide therapy, loss of blood sugar control may occur in cases of acute intercurrent disease or in stressful situations such as trauma or surgery or if used concomitantly with herbs such as St. John's Wort (Hypericum perforatum) preparations or any treatment that may interact with gliclazide metabolism (see DRUG INTERACTIONS & Drug-Herb Interactions). Under these conditions, discontinuation of GLICLAZIDE (gliclazide) and administration of insulin should be considered.
Hematologic
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since GLICLAZIDE belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.
Hepatic
The metabolism and excretion of sulfonylureas including GLICLAZIDE, may be slowed in patients with impaired hepatic function. Isolated cases of impairment of liver function with cholestasis and jaundice, and hepatitis which can regress after withdrawal of the drug or may lead to life-threatening liver failure have been observed. Discontinue treatment if cholestatic jaundice appears. Therefore, GLICLAZIDE is contraindicated in patients with severe hepatic impairment (See CONTRAINDICATIONS and PRECAUTIONS, Monitoring and Laboratory Tests).
Renal
The metabolism and excretion of sulfonylureas including GLICLAZIDE may be slowed in patients with impaired renal function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted. Therefore, GLICLAZIDE is contraindicated in patients with severe renal impairment (See CONTRAINDICATIONS and PRECAUTIONS, Monitoring and Laboratory Tests).
Peri-Operative Considerations
In patients stabilized on gliclazide therapy, loss of blood sugar control may occur in cases of acute intercurrent disease or in stressful situations such as trauma or surgery. Under these conditions, discontinuation of GLICLAZIDE and administration of insulin should be considered.
Hypoglycemic Reactions
As with other sulfonylurea drugs, manifestations of hypoglycemia including dizziness, lack of energy, drowsiness, headache and sweating have been observed and weakness, nervousness, shakiness and paresthesia have also been reported. Severe hypoglycemia can be induced by all sulfonylurea drugs. Particularly susceptible are elderly subjects, patients with impaired hepatic or renal function, those who are debilitated or malnourished and patients with primary or secondary adrenal insufficiency. Hypoglycemia is more likely to occur when caloric intake is inadequate or after strenuous or prolonged physical exercise.
Some cases may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days. Hypoglycemia may be difficult to recognize in elderly patients and in patients receiving beta-blockers.
Possible other symptoms of hypoglycaemia are: intense hunger, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, paresis, sensory disorders, feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome. In addition, signs of adrenergic counter-regulation may be observed: clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.
Usually, hypoglycaemic symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect. Experience with other sulphonylureas shows that hypoglycaemia can recur even when measures prove effective initially. If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by
Severe hypoglycemia can be induced by all sulfonylurea drugs, particularly susceptible are elderly subjects.
Monitoring and Laboratory Tests
Measurement of glycated haemoglobin levels (or fasting venous plasma glucose) is recommended in assessing blood glucose control. Blood glucose self-monitoring is also recommended.
Blood glucose control in a patient receiving gliclazide treatment may be affected by fever, infection, surgical intervention or when used concomitantly with St. John's Wort (Hypericum perforatum) preparations. Closed monitoring is required in these patients. In some cases, it may be necessary to administer insulin.
Hepatic function should be assessed before initiating therapy and the liver function should be assessed periodically in patients with mild to moderately impaired hepatic function. In patients with mild to moderately impaired renal function, renal function should be assessed periodically, blood and urine glucose should be regularly monitored. Measurements of glycated hemoglobin levels are recommended. Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require periodic monitoring and special care.
As a result of drug interactions, hypoglycemia may be potentiated when a sulfonylurea is used concurrently with agents such as: long-acting sulfonamides, tuberculostatics, clarithromycin, phenylbutazone, clofibrate, monoamine oxidase inhibitors, coumarin derivatives, salicylates, non-steroidal anti-inflammatory agents, probenecid, beta-blockers, miconazole (see CONTRAINDICATIONS), azole antifungal agents (oral and parenteral preparations), H2-receptor antagonists, disopyramide and angiotensin converting enzyme inhibitors. In addition, while not approved for use with other antidiabetic agents, hypoglycaemia is potentiated when gliclazide is used in combination with other antidiabetic agents.
Certain drugs tend to induce hyperglycemia and may lead to loss of control of blood sugar control. These include diuretics (thiazides, furosemide), corticosteroids and tetracosactrin, danazol, chlorpromazine, ritodrine/ salbutamol/ terbutaline (IV), oral contraceptives (estrogen plus progestogen) and nicotinic acid in pharmacologic doses.
Barbiturates should be used with caution in patients receiving an oral hypoglycemic agent since they may reduce the hypoglycemic effect.
Concomitant use of fluoroquinolones and GLICLAZIDE may cause hypoglycaemia and hyperglycaemia. Elderly patients may be more sensitive to this interaction. In case of concomitant use of GLICLAZIDE and a fluoroquinolone, the patient should be warned of this risk and the importance of blood glucose monitoring should be emphasized.
Combination with anticoagulant therapy (warfarin and other) must be taken into account because sulfonulureas may lead to potentiation of anticoagulation during concomitant treatment. Adjustment of the anticoagulant dosage may be necessary.
Intolerance to alcohol (disulfiram-like reaction: flushing sensation of warmth, giddiness, nausea and occasionally tachycardia) may occur in patients treated with a sulfonylurea. This reaction can be prevented by avoiding the use of alcohol. Alcohol increases the hypoglycaemic reaction (by inhibiting compensatory reactions) that can lead to the onset of hypoglycaemic coma. Avoid alcohol or medicines containing alcohol.
Drug-Herb Interactions St. John’s Wort Pharmacodynamic interactions between gliclazide and the herbal remedy St. John’s Wort may occur and may lead to hyperglycemia or loss of blood glucose control.
In clinical trials involving about 2000 patients treated with gliclazide, the overall incidence of adverse reaction was 10.5%; this necessitated the discontinuation of therapy in 1.2% of patients.
Adverse Drug Reaction Overview
The most frequently reported adverse drug reactions during long-term studies and post- market experience are hypoglycaemia (see WARNINGS AND PRECAUTIONS) and gastrointestinal disturbances (including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation).
Hypoglycemia (see PRECAUTIONS):
Weakness, nervousness, shakiness and paresthesia have also been reported. Severe hypoglycemia which mimics acute CNS disorders may occur. Hepatic and/or renal impairment, malnutrition, debility, advanced age, alcoholism, adrenal or pituitary insufficiency may be predisposing factors.
Gastro-intestinal reactions:
Nausea, vomiting, diarrhea, epigastric fullness and gastric irritation can be observed. These reactions are generally dose-related and may disappear when the dose is reduced.
Hepatobilliary Reactions:
With sulfonylureas cases were also observed of elevated liver enzyme levels (AST, ALT, alkaline phosphatise) and even impairment of liver function with cholestasis and jaundice and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver failure in isolated cases. Rare cases of jaundice have been reported. Discontinue treatment if cholestatic jaundice appears.
Dermatological Reactions:
elevated liver enzyme levels (AST, ALT, alkaline phosphatise); isolated cases of impairment of liver function with cholestasis and jaundice which can regress after withdrawal of the drug or may lead to life-threatening liver failure. Discontinue treatment if cholestatic jaundice appears.
Symptoms:
Overdosage with sulfonylureas may result in hypoglycemia but it should be noted that the dosage which causes such hypoglycemia varies widely and may be within the accepted therapeutic range in sensitive individuals.
The manifestations of hypoglycemia include sweating, flushing or pallor, numbness, chilliness, hunger, trembling, headache, dizziness, increased pulse rate, palpitations, increased blood pressure and apprehensiveness in mild cases. In more severe cases, coma appears.
However, symptoms of hypoglycemia are not necessarily as typical as those described above and sulfonylureas may cause insidious development of symptoms mimicking cerebrovascular insufficiency.
Treatment:
Discontinue medication and treat hypoglycemia by giving dextrose promptly and in sufficient quantity.
Some sulfonylurea-induced hypoglycemias may be refractory to treatment and susceptible to relapse especially in elderly or malnourished patients. Continuous dextrose infusions for hours or days have been necessary.
Strict monitoring should be continued until the doctor is sure that the patient is out of danger. Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalisation. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 mL of concentrated glucose solution (20 to 30 %). This should be followed by continuous infusion of a more dilute glucose solution (10 %) at a rate that will maintain blood glucose levels above 1 g/L. Patients should be monitored closely and, depending on the patient's condition after this time, the doctor will decide if further monitoring is necessary.
Dialysis is of no benefit to patients due to the strong binding of gliclazide to proteins.
For management of a suspected drug overdose contact your regional Poison Control Center.
Determination of the proper dosage for GLICLAZIDE for each patient should be made on the basis of frequent determinations of blood glucose during dose titration and throughout maintenance.
The recommended daily dosage of GLICLAZIDE is 80 to 320 mg (1 to 4 tablets). Dosage of 160 mg and above should be divided into two equal parts for twice a day administration. GLICLAZIDE should be taken preferentially with meals.
The recommended starting dose of GLICLAZIDE is 2 tablets per day (160 mg) taken as one tablet twice a day with meals. The total daily dose should not exceed 320 mg.
Patients with renal or hepatic impairment may require dosage reduction (See PRECAUTIONS, Hypoglycemic reactions).
In patients where on initial trial the maximal recommended dose fails to lower blood glucose adequately, the drug should be discontinued. During the course of therapy a loss of effectiveness may occur.
It is advisable to ascertain the contribution of the drug in control of the blood glucose by discontinuing the medication semi-annually or at least annually with careful monitoring of the patient. If the need for the drug is not evident, the drug should not be resumed. In some diabetic subjects, short-term administration periods of the drug may be sufficient during periods of transient loss of blood sugar controls.
Patients Receiving Insulin:
Maturity onset diabetics with no ketoacidosis or history of metabolic decompensation and whose insulin requirements are less than 40 units per day may be considered for GLICLAZIDE therapy after cessation of insulin. If a change from insulin to GLICLAZIDE is contemplated in such a patient, discontinue insulin for a period of 2 or 3 days to determine whether any therapy other than dietary regulation and exercise is needed. During this insulin- free interval, test the patient's urine at least 3 times daily for glucose and ketone bodies and monitor the results carefully. The appearance of significant ketonuria accompanied by glucosuria within 12 to 24 hours after the withdrawal of insulin, strongly suggests that the patient is ketosis prone, and precludes the change from insulin to sulfonylurea therapy.
GLICLAZIDE (gliclazide) is available as a white to off-white, round, bevel-edged compressed tablet, quadrisect (+) on one side and engraved N on the other side containing 80 mg of gliclazide. Supplied in bottles of 100.
GLICLAZIDE is contraindicated (must not be taken) in the following conditions: Allergy or hypersensitivity to gliclazide, other sulphonylureas, sulphonamides or to any of the excipients of this product. Unstable and/or insulin-dependent diabetes mellitus (type I diabetes), particularly juvenile diabetes, diabetes ketoacidosis, diabetes pre-coma and coma. Stressful conditions such as serious infection, trauma or surgery. Severe liver impairment. Severe kidney impairment. Treatment with miconazole. Pregnancy and/or breast-feeding.
The safety of GLICLAZIDE in adolescents and children has not been established.
GLICLAZIDE is prescribed for your specific medical problem and for your own use only. Do not give to other people.
Keep all medicines out of the reach of children.
Precautions while using this medicine
Your physician should check your progress at regular visits, especially during the first few weeks that you take this medicine. Please keep your appointments.
Test for sugar in your blood or urine as directed by your physician. This is a convenient way to make sure your diabetes is being controlled and provides an early warning when it is not.
Do not take any other medicine, unless prescribed or approved by your doctor. If you require medical assistance, inform the medical practitioner that you are taking GLICLAZIDE.
Drugs that may interact with GLICLAZIDE are: Other antidiabetic agents, long-acting sulfonamides, tuberculostatics, clarithromycin, NSAIDs, fibrates, monoamine oxidase inhibitors, salicylates, probenecid, beta-blockers, azole antifungal agents (oral and parenteral preparations), H2-receptor antagonists and angiotensin converting enzyme inhibitors, anticoagulants barbiturates and fluoroquinolones. Certain drugs tend to induce hyperglycemia and may lead to loss of blood sugar control. These include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (estrogen plus progestogen), chlorpromazine, ritodrine, salbutamol, terbutaline, danazol and nicotinic acid in pharmacologic doses. Low blood sugar and high blood sugar can occur when a medicine belonging to a class of antibiotics called fluoroquinolones is taken at the same time as GLICLAZIDE, especially if you are elderly. If you are taking these medications together, your doctor will remind you of the importance of monitoring your blood glucose.
Herbs that may interact with GLICLAZIDE are: Saint John's Wort preparations tend to cause high blood sugar and may lead to loss of blood sugar control.
Serious Skin Reactions (DRESS, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, hypersensitivity Syndrome): any combination of red itchy rash with blisters and peeling of the skin and /or of the lips, eyes, mouth, nasal passages or genitals have been reported in patients taking GLICLAZIDE. It often goes with fever, chills, headache, cough, body aches or joint
pain. You may have less or dark urine, yellow skin or eyes. If you suspect these, you should stop taking the drug and talk with your doctor or pharmacist.
Avoid drinking alcoholic beverages and taking medicines containing alcohol while you are taking GLICLAZIDE as it can lead to drop in blood sugar (hypoglycemia).
Inform your physician about any illness which may develop during your treatment with GLICLAZIDE and about any new prescribed or non-prescribed medication you may be taking.
Side effects of this medicine
Along with their needed effects, oral antidiabetes medicines may cause some unwanted effects.
The more frequently reported side effects during clinical trials with gliclazide were hypoglycemia (low blood sugar) and indigestion or stomach upsets.
You should know that the usual signs of low blood sugar level (hypoglycemia) are: anxious feeling, drowsiness, chills, cold sweats, confusion, cool pale skin, difficulty in concentration, excessive hunger, fast heartbeat, headache, nausea, nervousness, shakiness, unsteady walk, unusual tiredness or weakness. If you recognize by some of these signs of the drop in blood sugar, immediately eat or drink something containing sugar and notify your doctor without delay. Good sources of sugar are: orange juice, corn syrup, honey, or sugar cubes or table sugar (dissolved in water).
In addition, some uncommon serious side effects/symptoms may happen and you should stop taking the drug and talk with your doctor or pharmacist in all cases: unexplained fever chills or sore throat; yellowing of skin or eyes, dark-coloured urine or light-coloured bowel movements (e.g. jaundice) which in most cases disappeared after withdrawal of the drug, but may lead to life-threatening liver failure in isolated cases; skin rash, redness, itching or hives; oedema, swelling of the legs or unexpected weight gain; chest pain or pressure, and/or shortness of breath.
Very rare cases of the following have been reported: blood abnormalities with symptoms of sore throat, fever, mouth sore, unusual bleeding or bruising, low level of red blood cells (anemia); allergic inflammation of blood vessels (vasculitis); low sodium level in blood combined with symptoms of tiredness, weakness and confusion (hyponatraemia); rapid swelling of tissues such as eyelids, face, lips, mouth, tongue or throat that may result in breathing difficulty (angioedema); widespread blistering or peeling of the skin.
Serious Skin Reactions (DRESS, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, hypersensitivity Syndrome): any combination of red itchy rash with blisters and peeling of the skin and /or of the lips, eyes, mouth, nasal passages or genitals have been reported in patients taking gliclazide It often goes with fever, chills, headache, cough, body aches or joint pain. You may have less or dark urine, yellow skin or eyes. If you suspect these, you should stop taking the drug and talk with your doctor or pharmacist.
Additional information on GLICLAZIDE may be obtained from your physician or pharmacist.
Proper Name: Gliclazide
Chemical Name: 1-(3-Azabicyclo[3.3.0]-oct-3-yl)-3-(p-tolylsulfonyl)urea
Structural Formula:
Molecular Formula: C 15 H 21 N 3 O 3 S Molecular Weight: 323.
Description: Gliclazide is a white, crystalline, virtually odorless powder. It is practically insoluble in water, freely soluble in chloroform, and sparingly soluble in acetone. Gliclazide has a Pka of 5.8. Gliclazide has a melting point of approximately 168 C.
Partition coefficient:
pH % gliclazide in organic phase (water/CHCl 3 )
0 to 7 almost 100%
8.6 80%
9.0 55%
10.0 12%
Composition:
Each 80 mg tablet contains: glyceryl behenate, lactose, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
STABILITY AND STORAGE RECOMMENDATIONS: Store bottles between 15 -30 C. Store blister packs between 15 -25 C.
GLICLAZIDE (gliclazide) is available as a white to off-white, round, bevel-edged compressed tablet, quadrisect (+) on one side and engraved N on the other side containing 80 mg of gliclazide. Supplied in bottles of 100.
see Published Review by HOLMES et al. (Drugs 1984) HUMAN PHARMACOLOGY:
Absorption: Gliclazide is extensively absorbed from the gastrointestinal tract. Following oral administration of 3 mg/kg of gliclazide to four healthy subjects, the peak plasma levels (mean 5.0 μg/mL) were achieved between 4 to 6 hours. The absorption half-life in man is 1. hours.
Distribution: The mean apparent volume of distribution in 4 healthy subjects was 20 to 40% of bodyweight.
Protein binding: Using equilibrium dialysis, it was shown that the majority of the drug is protein bound. At a plasma concentration of about 8 μg/mL, 94.2% of the drug was protein bound and 5.8% was free.
Metabolism: Although more than 90% of unchanged gliclazide is found in plasma following administration, this is intensively metabolized with little of the unchanged compound (<1%) found in urine. Five principal metabolites have been found in urine, essentially oxidised and hydroxylated derivatives, the majority of which undergo glucuroconjugation.
Excretion: Gliclazide is essentially eliminated via the urine: 60 to 70% as against 10 to 20% via faeces.
Half life: The mean elimination half life is 10.4 h.
Gliclazide acts primarily by enhancing the release of endogenous insulin. Residual function of beta-cells is therefore necessary for its action. Clinical studies demonstrate that the sulphonylureas are ineffective in completely pancreatectomized patients and in juvenile onset diabetic subjects. The mechanism of action is not fully understood. Sulphonylureas including gliclazide cause degranulation of the pancreatic beta-cells, a phenomenon associated with increased rate of insulin secretion.
Extrapancreatic effects of sulphonylureas have been reported and certain of these may potentiate the effects of secreted insulin. These effects include reduction in hepatic uptake of endogenous insulin and increased sensitivity of peripheral tissues to insulin. Sulphonylurea agents may stimulate hyperplasia of the beta-cells.
At normal therapeutic doses gliclazide has been shown in man to reduce platelet adhesiveness and aggregation. When these are close to normal at the inclusion time, no significant difference is observed.
Values are approximate % of dose excreted into 0-24 hour urine.
The hypoglycemic action of gliclazide has been observed in the rat, rabbit, guinea-pig, and dog following intravenous or oral administration. The degree and duration of these effects are dose dependent.
Comparison of ED 30 shows that gliclazide is 9 times more active than tolbutamide in the rabbit and 25 times more active in the rat. The duration of action of gliclazide is also greater than that of tolbutamide.
Gliclazide stimulates the insulin secretion and particularly restores the early peak in the isolated perfused pancreas of diabetic rats.
This insulinotropic action is related to the transfer of calcium into the pancreatic cell. Gliclazide is not involved in the biosynthesis of insulin induced by glucose but modifies the distribution of calcium in isolated rat pancreas cells.
At the extrapancreatic level, gliclazide potentialises the action of insulin on the glucose intracellular transfer and influences its oxidation on an isolated adipocyte model when insulin is present in the medium.
Gliclazide delays the development of the mural thrombus formed after electrical lesion of the vascular endothelium in the rat and increases its disaggregation speed.
In dog, gliclazide prevents the formation of capillary ADP-induced platelet aggregates at the retinal level.
These properties can be explained by its action on:
The platelet behaviour: reduction of the platelet adhesiveness in the diabetic rabbit of platelet aggregation induced by ADP or by collagen in the rabbit.
The prostaglandin equilibrium: inhibition of the acid arachidonic release and in vitro thomboxan synthesis and increase of the PGI 2 production.
The parietal fibrinolysis: increase of the release of the parietal plasminogen activator (t.PA). This activator, of an endothelial origin, acts on the plasmin which is the enzyme degrading the fibrin.
Gliclazide has no action on the central nervous system, autonomic nervous system nor respiratory, gastro-intestinal and cardiovascular systems.
