Discuss the mode(s) of action, therapeutic use(s) and adverse effects of:

(a)            tolbutamide.

(b)            heparin.

(c)            morphine.

Suggested Answer:

(a)

Tolbutamide is a sulphonylurea, one of the two classes of oral anti-diabetic agent commonly used in the management of type 2 diabetes.

Its principal mode of action is to enhance the release of stored insulin from pancreatic beta cells in response to a rising blood sugar level. Binding of tolbutamide to a b-islet cell surface receptor leads to decreased conductance of ATP-sensitive potassium channels. This blocks potassium efflux and leads to cell membrane depolarization. This in turn opens voltage-gated calcium channel and result in an influx of calcium ions. The increased binding of calcium to calmodulin activate kinases associated with secretory granules and so cause exocytosis of insulin-containing secretory granules.

Tolbutamide also appears to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the post-receptor complex enzyme reactions mediated by insulin. The principal result is decreased hepatic glucose output and increased glucose uptake in muscle. It is ineffective in totally insulin-deficient patients.

Tolbutamide is readily absorbed from the GI tract following oral administration. It has a half-life of 7h and is 95% bound to plasma proteins. Tolbutamide is rapidly metabolized by oxidation in the liver and it is excreted together with its metabolites in urine and faeces.

Nausea, epigastric fullness, heartburn, and headache have occurred in patients receiving tolbutamide. These adverse effects appear to be dose related and frequently subside following a reduction in dosage to maintenance levels. Allergic skin reactions including pruritus, erythema, and urticarial, morbilliform, or maculopapular eruptions have also been reported. Tolbutamide therapy has rarely been associated with hepatic dysfunction and jaundice; tolbutamide-induced jaundice usually subsides following discontinuance of the drug. Like other sulfonylureas, tolbutamide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia. Hypoglycemia, which may be severe, has occurred in patients receiving tolbutamide and may resemble acute neurologic disorders such as cerebral thrombosis. Therapy with sulfonylureas, including tolbutamide, may be associated with weight gain. Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving tolbutamide. It can also cause hypothyroidism and nephrotic syndrome.

(b)

Heparin is a mixture of sulfated mucopolysacchardie. It binds to endothelial cell surface, activating antithrombin III, which is a naturally occurring inhibitor of thrombin and of activated factor X. In the presence of heparin antithrombin becomes vastly more active. Factor Xa is involved in both the intrinsic and extrinsic coagulation systems and its inhibition put a premature halt to the coagulation pathway, thereby preventing the formation of blood clots.

Heparin is poorly absorbed from the GI tract and is given i.v. or s.c. It binds to several plasma proteins and to sites on endothelial cells. The onset of action is 20 – 60 min and it is metabolized chiefly in the liver. Control of heparin therapy is by the kaolin-cephalin clotting time (KCCT).

Heparin is used in established venous thromboembolism to prevent extension of an existing thrombus, to recanalize veins and to clear vein valves of thrombus. The site and extent of thrombosis can be determined by venous ultrasound or venography. Heparin is used initially because of its rapid onset of effect and continued until the signs of thrombosis have settled. Low-dose heparin is used to prevent deep vein thrombosis and pulmonary embolism in patients after surgery and those immobilized with strokes, cardiac failure or malignant disease. Anticoagulation with heparin is used to reduce the risk of venous thromboembolism, and the risk and size of emboli from mural thrombi following acute myocardial infarction.

Bleeding is the serious acute complication of heparin therapy. It is uncommon, but patients with impaired hepatic or renal function, with carcinoma, and those over 60 years appear to be most at risk. A further serious complication is the syndrome of thrombocytopenia with arterial thromboemboli and haemorrhage which occurs in about 2 – 3% of patients who receive heparin for a week or more. Osteoporosis may occur and is dose-related. Hypersensitivity reactions and skin necrosis occur but are rare.

(c)

Morphine is the most generally useful high-efficacy opioid analgesic; it eliminates pain and also allows the subjects to tolerate pain.

Morphine acts by binding to m receptors which are located both pre- and postsynaptically in the dorsal horn neurons of the spinothalamic tracts and periaqueductal gray matter of the midbrain. These receptors mediate the transmission of pain and response to nociceptive stimuli. They are coupled to G_i proteins which, by inhibiting adenylyl cyclase, regulating ion channels and phospholipases, inhibit synaptic transmission and decrease release of excitatory neurotransmitters. Morphine exerts its effects by hyperpolarizing and inhibiting postsynaptic neurons via increase K⁺ efflux and reducing Ca²⁺ influx into presynaptic nerve endings and thereby reducing transmitter release.

Morphine is readily absorbed from the GI tract with an oral bioavailability of 15% as it is rapidly metabolized in the liver to the glucuronide. Its plasma half-life and duration of analgesia is about 3 – 5 hours. Morphine is usually administered parenterally although it may be formulated to be administered orally or as rectal suppositories.

Morphine is used in the relief of moderate to severe acute pain especially in palliative care to relieve the intractable pain of chronic cancers; relief of dyspnoea in acute left ventricular failure and in terminal cancer and as premedication for surgery.

At high doses, morphine depresses respiration by reducing sensitivity of the respiratory center to rise in blood carbon dioxide. It causes sedation, lethargy and inability to concentrate. It stimulates chemoreceptor trigger zone of the vomiting center causing nausea (10%) and vomiting (15%). Morphine delays gastric emptying and constipation can occur. It stimulates histamine release and this is manifested by urticaria, cutaneous flushing, bronchoconstriction and hypotension. Urinary retention may result from increased tone of the bladder, ureters and the vesicular sphincter.