Antidiabetic Drugs

Question 1

Sulfonylureas

Answer 1

SULFONYLUREAS

Sulfonylureas have been available for the treatment of diabetes mellitus type 2 since the 1950s. They are effective at reducing fasting plasma glucose (FPG) and HbA1C.

MECHANISM OF ACTION

Stimulation of insulin release from β cells
Sulfonylureas bind to the SUR1 subunit and thus block the ATP-sensitive K+ channel in the β cell membrane and inhibit efflux of K+ resulting in depolarization. Depolarization opens voltage-gated calcium channels resulting in Ca2+ influx and release of preformed insulin.

Reduction of serum glucagon levels
Mechanism unclear, but could involve indirect inhibition due to increased release of insulin and somatostatin, which inhibit α cell secretion.

Question 2

Insulin Lispro

Answer 2

RAPID-ACTING INSULINS

Question 3

Insulin Degradation

Answer 3

INSULIN DEGRADATION

Insulin is inactivated by the enzyme insulinase, which is found mainly in the liver and kidney. The liver normally clears the blood of approx 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow. The kidney removes 35-40%. However, in insulin-treated diabetics receiving SC injections, the ratio is reversed: 60% of exogenous insulin is cleared by the kidney and 30-40% by liver. The half-life of circulating insulin is 3-5 minutes.

Question 4

Mechanism of Insulin Secretion

Answer 4

MECHANISM OF INSULIN SECRETION

Hyperglycemia results in increased ATP levels which close ATP-dependent K+ channels, leading to membrane depolarization and opening of voltage-gated calcium channels. Influx of Ca2+ causes pulsatile insulin exocytosis.

Question 5

Insulin Glulisine

Answer 5

RAPID-ACTING INSULINS

Question 6

Colesevelam

Answer 6

BILE-ACID SEQUESTRANTS: COLESEVELAM

Bile-acid sequestrant used to lower LDL cholesterol. Approved by the FDA as an adjunct to diet and exercise in the treatment of type 2 DM. Given orally. The mechanism of action is unclear.

ADVERSE EFFECTS

Colesevelam can cause constipation, nausea and dyspepsia, increase serum TG levels, and interfere with absorption of other oral drugs.

Question 7

Metformin

Answer 7

BIGUANIDES: Metformin

Metformin is the only currently available biguanide.

Metformin does not cause insulin release from the pancreas, and generally does not cause hypoglycemia, even in large doses.

Metformin is equivalent in its efficacy to sulfonylureas in reducing FPG and HbA1C levels.

Mechanism of Action: Metformin reduces glucose levels primarily by inhibiting gluconeogenesis. Metformin inhibits gluconeogenesis by reducing gene expression of gluconeogenic enzymes. Additionally, metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals.

As a result of the improvement in glycemic control, serum insulin concentrations decline slightly.

At the molecular level, these actions are believed to be mediated at least in part by activation of AMP-activated protein kinase (AMPK).

Metformin reduces plasma triglycerides by 15-20%.

Unlike insulin and insulin secretagogues, metformin is associated with a decrease in weight.

Metformin is indicated as an adjunct to diet and exercise to improve glycemic control

in patients with type 2 DM. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that metformin should be the first-line pharmacological therapy in type 2 DM.

Metformin can be used alone or in combination with sulfonylureas, thiazolidinediones and/or insulin.

Given orally. Well absorbed. Not bound to serum proteins. Not metabolized. Excreted in urine.

ADVERSE EFFECTS

Largely gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, diarrhea). Occur in up to 20% of patients.

Contraindicated in patients with renal or hepatic disease, because of an increased risk of lactic acidosis in the presence of such diseases.

Cardiovascular collapse, acute congestive heart failure, acute MI, and other conditions characterized by hypoxemia have been associated with lactic acidosis. When such events occur in patients on metformin, the drug should be promptly discontinued.

Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should avoid excessive alcohol intake, while on metformin.

Long term use may interfere with B12 absorption.

Monitoring: Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis

OTHER USES

Metformin’s ability to lower insulin resistance can result in ovulation and possibly pregnancy in women with polycystic ovary syndrome (PCOS). Metformin has become the leading treatment PCOS, despite the fact that it has not been approved for this purpose. Studies show that clomiphene is the best treatment for PCOS-related infertility (and is FDA-approved for this indication).

Question 8

LONG-ACTING INSULINS

Answer 8

LONG-ACTING INSULINS: Insulin Detemir and

Insulin Glargine

INSULIN GLARGINE

Long-acting analog of human insulin. Its production involves two alterations in the structure of human insulin: two arginine residues are added to the C terminus of the B chain and an asparagine residue in position A21 of the A chain is replaced by glycine. These modifications produce an analog that is soluble in acidic solution but precipitates in neutral pH after SC injection. Insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin.

Due to insulin glargine’s acidic pH (pH 4) it cannot be mixed with currently available short-acting insulin preparations (regular insulin, lispro or aspart) that are formulated at neutral pH.

Usually given once a day. Insulin glargine has a sustained peakless absorption profile.

It provides a better once-daily 24-h insulin coverage and has a lower risk of hypoglycemia than NPH insulin.

INSULIN DETEMIR

The terminal threonine is removed from the B30 position and myristate is attached to the terminal B29 lysine. These modifications increase self-aggregation in subcutaneous tissue and also result in reversible albumin binding (through the fatty acid chain).

It has lower risk of hypoglycemia than NPH insulin.

The absorption profiles of glargine and detemir are similar, but detemir often requires twice-daily administration.

Question 9

Glimepride

Answer 9

SECOND GENERATION SULFONYLUREAS

Question 10

Sitagliptin

Answer 10

INHIBITORS OF DPP-IV: SITAGLIPTIN

Selective inhibitor of DPP-IV (dipeptidyl peptidase IV). Sitagliptin increases circulating GLP-1 and insulin levels, and decreases glucagon levels.

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Given orally.

ADVERSE EFFECTS

Adverse effects include pancreatitis, hypersensitivity reactions including urticaria, angioedema, anaphylaxis, and skin reactions such as Stevens-Johnson syndrome.

Question 11

Therapeutic Regimens

Answer 11

THERAPEUTIC REGIMENS

The goal of SC insulin therapy is to replace the normal basal (overnight, fasting, and between meals) as well as bolus or prandial (mealtime) insulin.

In the nondiabetic individual, the pancreas secretes boluses of insulin in response to snacks and meals. Between meals and throughout the night, the pancreas secretes small amounts of insulin that are sufficient to suppress lipolysis and hepatic glucose output (basal insulin).

Two methods are used to achieve a similar pattern of insulin release:

Basal-Bolus Insulin Regimens consisting of once to twice daily doses of basal insulin coupled with pre-meal doses of rapid or short-acting insulin.

Insulin Pump Therapy (previously referred to as “continuous subcutaneous infusion of insulin”)

BASAL-BOLUS INSULIN REGIMENS (MULTIPLE DAILY INJECTIONS)

The regimen that most closely mimics physiological insulin release, besides the use of an insulin pump, is the use of a once-daily basal insulin such as insulin glargine or insulin detemir to provide basal insulin levels throughout the day, along with doses of regular insulin, insulin lispro, insulin aspart, or insulin glulisine before meals

The long-acting insulin can be given at bedtime, or, alternatively, in the morning.

If patients skip a meal, they omit a premeal bolus; if they choose to eat a larger meal than usual, they increase the premeal bolus. Similar dose adjustments can be made to accommodate snacks, exercise patterns, and acute illnesses.

INSULIN PUMP THERAPY

The use of an insulin pump is the most precise way to mimic normal insulin secretion. It consists of a battery-operated pump and a computer that can program the pump to deliver predetermined amounts of insulin from a reservoir to a subcutaneously inserted catheter or needle.

These systems are portable and designed to deliver various basal amounts of insulin over 24 hours as well as meal-related boluses.

Most patients using an insulin pump prefer to use the rapid-acting insulin analogs in their pump. For meal coverage, the rapid-acting insulin can be given 0 to 15 minutes before eating.

Question 12

Neuropathy Treatment

Answer 12

NEUROPATHY

Dystal symmetric polyneuropathy (DPN)

Drugs used for neuropathic pain include amitriptyline, gabapentin, pregabalin, duloxetine, venlafaxine, valproate, and opioids.

Gastroparesis

Gastroparesis symptoms may improve with dietary changes and prokinetic agents such as erythromycin and metoclopramide.

Erectile Dysfunction

Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, prostaglandins, vacuum devices, or penile prostheses.

FOOT CARE

Most diabetic foot infections are polymicrobial. The most common causative organisms are aerobic gram positive cocci, especially staphylococci. Empiric antibiotic therapy can be narrowly targeted at gram positive cocci in many acutely infected patients

Question 13

RAPID-ACTING INSULINS

Answer 13

Native insulin monomers are associated as hexamers in currently available insulin preparations. These hexamers slow the absorption and reduce postprandial peaks of SC injected insulin. These pharmacokinetics led to the development of rapid-acting insulin analogs that retain a monomeric configuration.

Insulin Lispro

Insulin analog, produced by recombinant technology. Differs from regular insulin in that lysine and proline at positions 28 and 29 in the B chain are reversed. This analog has very low propensity to form hexamers. When injected SC, insulin lispro quickly dissociates into monomers and is absorbed very rapidly.

Insulin Aspart

Created by substitution of the B28 proline by an aspartate. Absorption and activity profile are similar to lispro.

Insulin Glulisine

Formulated replacing asparagine by lysine at B3 and lysine by glutamate at B29. Similar characteristics to lispro and aspart.

Rapid-acting insulins are administered to mimic the prandial release of insulin, and they are usually not given alone, but along with a longer acting insulin to assure proper glucose control.

Rapid-acting insulins should be injected 15 minutes before a meal. Peak serum levels are seen at 30-90 minutes after injection, as compared to 50-120 minutes for regular insulin. Their duration of action is about 3-4 hours.

The rapid-acting analogues provide greater control of postprandial plasma glucose (PPG), and are associated with less risk of hypoglycemic episodes.

Rapid-acting insulins are given SC. However, they are also suitable for IV. Rapid-acting insulins are preferred over regular insulin for use in insulin pumps because they do not form hexamers.

Question 14

Neutral Protamine Hagedorn (NPH)

Answer 14

INTERMEDIATE-ACTING INSULINS

Neutral Protamine Hagedorn (NPH)

Also called isophane insulin. Suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide: protamine.

Duration of action is intermediate because of delayed absorption of insulin due to conjugation of insulin with protamine to form a less soluble complex. Should only be given SC.

Used for basal control; usually given along with rapid- or short-acting insulin for mealtime control.
The action of NPH is highly unpredictable, and its variability of absorption is over 50%. The clinical use of NPH insulin is waning because of its adverse pharmacokinetics combined with the availability of long-acting insulin analogs that have a more predictable and physiologic action.

Question 15

Canagliflozin

Answer 15

SGLT2 INHIBITORS: CANAGLIFLOZIN

Glucose is filtered by the glomerulus and reabsorbed in the proximal tubule by the action of sodium-glucose transporters (SGLTs). Sodium-glucose transporter 2 (SGLT2) is responsible for most of glucose reabsorption. Canagliflozin inhibits SGLT2 leading to decreased glucose reabsorption, increased glucose excretion, and decreased blood glucose levels.

Given orally.

Canagliflozin reduces HbA1c by 0.6–1% when used alone or in combination with other oral agents or insulin. It also results in modest weight loss of 2–5 kg.

Adverse effects include increased incidence of genital and urinary tract infections. The osmotic diuresis can cause volume depletion, increased serum creatinine levels, hyperkalemia, hypermagnesemia, hyperphosphatemia and hypotension.

Contraindicated in patients with GFR < 45 ml/min/1.73 m2.

Question 16

SECOND GENERATION SULFONYLUREAS

Answer 16

SECOND GENERATION SULFONYLUREAS

Approximately 100 times more potent that the first-generation agents. Lack some of the adverse effects and drug interactions of the first-generation agents. They have largely replaced first-generation agents.

• Glyburide (Glibenclamide)*
• Glipizide*
• Glimepride*

GLYBURIDE

Results in hypoglycemia in up to 20-30% of users.

GLIPIZIDE

Shortest half-life (2-4 hours) of the more potent agents. Because of its shorter half-life it is much less likely than glyburide to produce serious hypoglycemia.

GLIMEPIRIDE

Causes hypoglycemia in only 2-4% of patients. Approved for once-daily use as monotherapy or in combination with metformin or insulin.

PHARMACOKINETICS

Given orally. Metabolized by the liver.

USES

Sulfonylureas are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 DM.

ADVERSE EFFECTS

Sulfonylureas can cause hypoglycemic reactions, including coma. This is a problem particularly in elderly patients with impaired renal or hepatic function.

Renal impairment or hepatic disease can cause elevations in sulfonylurea blood concentrations, and hepatic disease can impair gluconeogenic capacity; both problems increase the risk of hypoglycemia: sulfonylureas should be administered carefully in these patients.

Sulfonylureas cause weight gain.

TACHYPHYLAXIS

About 5-10% of patients per year who respond initially to sulfonylureas become secondary failures, ie, they fail to maintain a good response to sulfonylurea therapy. This may be due to a change in drug metabolism, progression of β cell failure, change in dietary compliance or misdiagnosis of a patient with slow-onset type 1 DM. Most of these patients will eventually require insulin.

Question 17

Glipizide

Answer 17

SECOND GENERATION SULFONYLUREAS

Question 18

Chlorpropamide

Answer 18

FIRST-GENERATION SULFONYLUREAS

Chlorpropamide and Tolbutamide

Half-life 32 hours. Slowly metabolized in liver. Interacts with the drugs mentioned above that depend on hepatic oxidative metabolism. Contraindicated in patients with hepatic or renal insufficiency.

Dosages in excess of 500 mg daily increase risk of jaundice.

Prolonged hypoglycemic reactions are more common than with tolbutamide, particularly in elderly patients; the drug is contraindicated in this group.

Hyperemic Flush. Some patients taking chlorpropamide may experience a hyperemic flush when alcohol is ingested. Facial flushing after alcohol occurs much more frequently in patients taking chlorpropamide than in those receiving other sulfonylureas. The flush reaction is accompanied by increased blood acetaldehyde concentrations; flushers eliminate acetaldehyde more slowly, suggesting a difference in aldehyde dehydrogenase activity. It has been suggested that chlorpropamide is a noncompetitive inhibitor of aldehyde dehydrogenase. It is not clear, however, whether the flush can be explained solely by a rise in acetaldehyde levels; prostaglandin inhibitors, such as aspirin, attenuate the flush in some patients.

SIADH. Sulfonylureas, especially chlorpropamide, potentiate the action of vasopressin and can elicit an apparent syndrome of inappropriate secretion of ADH (SIADH). The features of this syndrome result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This effect has been used therapeutically in patients with mild forms of central diabetes insipidus.

Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients.

Question 19

Exenatide

Answer 19

INCRETIN ANALOGS: EXENATIDE

Analog of the incretin glucagon-like-polypeptide 1 (GLP-1) derived from the salivary gland of the Gila monster. Injectable. It has 53% homology with human GLP-1. Full agonist at human GLP-1 receptors. Resistant to dipeptidyl peptidase IV (DPP-IV), the enzyme that degrades incretins.

Exenatide enhances glucose-dependent insulin secretion, suppresses postprandial glucagon release, slows gastric emptying (and thereby slows the rate of nutrient entry into the circulation), decreases appetite, and may stimulate β-cell proliferation.

Exenatide is approved along with diet and exercise to improve glycemic control in adults with type 2 diabetes.

ADVERSE EFFECTS

Adverse effects include nausea, vomiting and diarrhea, and acute pancreatitis. Exenatide should not be used in patients with gastroparesis.

Question 20

Drugs that Cause Hypoglycemia

Answer 20

DRUGS THAT CAUSE HYPOGLYCEMIA

The most common drugs causing hypoglycemia are ethanol, β-blockers and the salicylates.

• Ethanol inhibits gluconeogenesis.

• β-blockers can cause hypoglycemia in diabetic patients by blocking the effects of catecholamines on gluconeogenesis and glycogenolysis. β-blockers also mask the sympathetically-mediated symptoms of hypoglycemia (eg tremor and palpitations).

• Salicylates cause hypoglycemia by enhancing pancreatic β-cell sensitivity to glucose and potentiating insulin secretion. They also have a weak insulin-like action in the periphery.

Question 21

Acarbose

Answer 21

α-GLUCOSIDASE INHIBITORS

Acarbose

Only monosaccharides, such as glucose and fructose, can be transported out of the intestinal lumen and into the bloodstream. Complex starches, oligosaccharides and disaccharides must be broken down into individual monosaccharide molecules before being absorbed in the duodenum and upper jejenum. This digestion is facilitated by enteric enzymes, including pancreatic α-amylase and α-glucosidases, that are attached to the brush border of the intestinal cells.

Acarbose is a competitive inhibitor of the intestinal α-glucosidases and reduces the postprandial digestion and absorption of starch and disaccharides.

The consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion (and thus absorption) of the ingested starch and disaccharides to the distal small intestine, thereby decreasing both postprandial hyperglycemia and hyperinsulinemia.

Acarbose evokes a modest drop in HbA1C and FPG levels.

Acarbose is approved for use in individuals with type 2 diabetes as monotherapy or in combination with sulfonylureas, metformin or insulin, where the glycemic effect is additive. .

Given orally. Taken just prior to ingesting a meal.

ADVERSE EFFECTS

Adverse effects include flatulence, diarrhea and abdominal pain. These side effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of α-glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing passage of carbohydrate into the colon.

Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment. Hypoglycemia shuld be treated with glucose and not sucrose, whose breakdown may be blocked.

Contraindicated in patients with chronic or inflammatory bowel disease or any intestinal condition that could be worsened by gas and distension.

Acarbose is excreted by the kidneys, therefore it should not be prescribed in individuals with renal impairment.

Acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease. Periodical liver function monitoring is required with acarbose therapy.

Question 22

Meglitinides (Glinides)

Answer 22

MEGLITINIDES (Glinides)

Repaglinide, Nateglinide

Mechanism of Action: Like sulfonylureas, meglitinides stimulate insulin release by binding to SUR1 and thus inhibiting the β cell ATP-sensitive K+ channel. Meglitinides and sulfonylureas bind to different regions on the SUR1 molecule.

Meglitinides are not as effective as sulfonylureas or metformin in reducing fasting plasma glucose (FPG) and HbA1C levels.

In contrast with sulfonylureas, the meglinitides have a rapid onset and short duration of action. They are postprandial glucose regulators.

Repaglinide and nateglinide are rapidly absorbed and rapidly cleared, causing plasma levels of insulin to peak within 30-60 minutes. They must be taken before each meal; if the meal is missed the drug must be omitted.

Nateglinide is less effective than repaglinide.

Nateglinide is a D-phenylalanine derivative.

Meglitinides are given orally. They are partially metabolized in the liver by CYP3A4 and excreted in bile. Both drugs should be used cautiously in individuals with hepatic impairment.

Meglitinides contain no sulfur, so they may be indicated for type 2 diabetic individuals with sulfur or sulfonylurea allergy.

USES

Both drugs are approved as monotherapy or in combination with metformin or a thiazolidinedione to improve glycemic control in adults with type 2 diabetes mellitus.

ADVERSE EFFECTS

The major adverse effect of repaglinide is hypoglycemia.

Nateglinide may produce fewer episodes of hypoglycemia than most other insulin secretagogues.

As with the sulfonylureas, there is a risk of weight gain with the meglitinides.

Question 23

SHORT-ACTING INSULINS

Answer 23

SHORT-ACTING INSULINS

Regular insulin

Short-acting soluble crystalline zinc insulin.
Should be given 30 minutes before a meal. Usually given SC (or IV in emergencies). Safely used in pregnancy. The use of lispro, aspart and glulisine in pregnancy is advised only if clearly needed.

Question 24

Glyburide (Glibenclamide)

Answer 24

SECOND GENERATION SULFONYLUREAS

Question 25

Pioglitazone and Rosiglitazone

Answer 25

THIAZOLIDINEDIONES (Tzds, Glitazones)

Pioglitazone Rosiglitazone

Mechanism of Action: Tzds decrease insulin resistance. They are agonists of peroxisome proliferator-activated receptor-γ. These receptors are members of the steroid and thyroid superfamily of nuclear receptors. PPAR-γ receptors are found in muscle, fat and liver. PPAR-γ receptors modulate the expression of genes involved in lipid and glucose metabolism, insulin signal transduction and adipocyte differentiation.

In diabetic patients Tzds promote glucose uptake and utilization in adipose tissue, and modulate synthesis of lipid hormones and cytokines.

Two Tzds are currently available: pioglitazone and rosiglitazone. They differ in therapeutic action, metabolism, metabolite profile and adverse effects.

Tzds are less effective as monotherapy than sulfonylureas and metformin in decreasing FPG and HbA1C levels.

Their mechanism of action involves gene regulation, therefore Tzds have a slow onset and offset of activity over weeks or even months.

Given orally. Metabolized in liver.

The effects on lipids of pioglitazone are more favourable than those of rosiglitazone.

Compared with rosiglitazone, pioglitazone is associated with significant improvements in HDL, TG, LDL particle concentration, and LDL particle size.

ADVERSE EFFECTS

Tzds cause fluid retention, weight gain and edema.

Tzds cause or exacerbate congestive heart failure in some patients. Tzds are not recommended in patients with symptomatic heart failure and are contraindicated in patients with established Class III or IV heart failure.

In 2010 the FDA restricted the use of rosiglitazone over concerns about increased cardiovascular risk. In 2014, after revaluation of the data, the FDA removed the restrictions placed on rosiglitazone.

Troglitazone was the first Tzd to be approved. It was found to be associated with severe hepatic toxicity, and as a consequence it was withdrawn from the market. Because of the hepatotoxicity observed with troglitazone, the FDA requires periodical monitoring of liver function with Tzd therapy.

To date, pioglitazone or rosiglitazone have not been associated with hepatotoxicity.

OTHER USES

Like with metformin, the relief of insulin resistance evoked by Tzds can cause ovulation to resume in premenopausal women with PCOS. Neither pioglitazone nor rosiglitazone are FDA-approved for this indication.

Question 26

Insulin Aspart

Answer 26

RAPID-ACTING INSULINS

Question 27

Glucagon

Answer 27

GLUCAGON

Synthesized by pancreatic α cells. Peptide -identical in all mammals- consisting of single chain of 29 amino acids, with a MW of 3485.

PHARMACOLOGIC EFFECTS OF GLUCAGON

Metabolic Effects

Glucagon binds to specific receptors on liver cells. This leads to a Gs protein-coupled increase in adenylyl cyclase activity and the production of cAMP, which leads to catabolism of stored glycogen and increases gluconeogenesis and ketogenesis. The immediate pharmacologic result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. There is no effect on skeletal muscle glycogen, presumably because of the lack of glucagon receptors on skeletal muscle. Pharmacologic amounts of glucagon cause release of insulin from normal pancreatic β cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells.

Cardiac Effects

Glucagon has potent inotropic and chronotropic effects on the heart, mediated by cAMP. It produces an effect very similar to that of β-adrenoceptor agonists without requiring functioning β receptors.

Effects On Smooth Muscle

Large doses of glucagon produce profound relaxation of the intestine. This action may be due to mechanisms other than adenylyl cyclase activation.

USES

Severe Hypoglycemia

Glucagon is used to treat severe hypoglycemic reactions in patients with diabetes treated with insulin.

Radiology Of The Bowel

Used in radiology as aid to X-ray visualization of bowel because of its ability to relax intestine.

β-Blocker Poisoning

Glucagon is useful for reversing the cardiac effects of an overdose of β-blockers because of its ability to increase cAMP in the heart.

Glucagon C-peptide Test

The C-peptide response to IV glucagon administration is a test for residual β-cell function in diabetes mellitus.

ADVERSE REACTIONS

Transient nausea and occasional vomiting. Generally mild. Glucagon is relatively free of severe adverse reactions.

Question 28

Drugs that Cause Hyperglycemia

Answer 28

DRUGS THAT CAUSE HYPERGLYCEMIA

Many of these agents have direct effects on peripheral tissues that counter the actions of insulin; examples include epinephrine, glucocorticoids, atypical antipsychotic drugs such as clozapine and olanzapine, and HIV protease inhibitors. Other drugs cause hyperglycemia by inhibiting insulin secretion directly (e.g., phenytoin, clonidine, and Ca2+-channel blockers) or indirectly via depletion of K+ (diuretics).

Question 29

Metabolic Effects of Insulin

Answer 29

EFFECTS OF INSULIN ON ITS TARGETS

Insulin promotes the storage of fat as well as glucose within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues.

METABOLIC EFFECTS OF INSULIN

Effects On Carbohydrate Metabolism

In the liver insulin inhibits gluconeogenesis and glycogenolysis; accelerates glycolysis and glycogen synthesis.

In muscle insulin stimulates glycogen synthesis.

In muscle and adipose tissue insulin increases glucose uptake by increasing the number of GLUT 4 glucose transporters in the cell membrane. There is a cytoplasmic pool of GLUT 4 molecules in vesicles; when insulin activates insulin receptors on these cells, the vesicles fuse with the plasma membrane, inserting the transporters into it. This leads to a rapid increase of the number of functional GLUT 4 transporters. In this way, insulin promotes uptake of glucose by muscle and fat. When insulin action ceases, the patches of membrane that contain the transporters are endocytosed.

NOTE: Insulin also increases the entry of glucose into liver cells, but it does not exert this effect by increasing the number of GLUT 4 transporters in the plasma membrane. Instead, insulin induces the biosynthesis of glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell.

Effects on lipid metabolism

Insulin inhibits hormone-sensitive lipase in adipose tissue. This leads to a decrease of level of circulating fatty acids.

Insulin increases synthesis of fatty acids and TAGs and their storage in the adipose tissue. Insulin increases transport and metabolism of glucose into adipocytes, thus providing glycerol 3-phosphate for TAG synthesis.

Insulin increases levels of lipoprotein lipase of adipose tissue, providing fatty acids for esterification.

Effects on protein synthesis

Insulin stimulates entry of amino acids into cells and protein synthesis in most tissues.

Insulin promotes uptake of branched amino acids (val, leu, ile) by muscle, consequently it leads to build up of muscle protein.

Question 30

Inhaled Insulin

Answer 30

INHALED INSULIN

A dry powder formulation of regular human insulin is now approved for treatment of adults with type 1 or type 2 diabetes. After inhalation peak levels are reached in 12-15 minutes and decline to baseline in 3 hours. The most common adverse effects are cough, throat pain or irritation and hypoglycemia. Pulmonary function should be monitored. The drug is contraindicated in patients with asthma, COPD, and smokers.

Question 31

Pramlintide

Answer 31

ANALOGS OF AMYLIN: PRAMLINTIDE

Synthetic analog of amylin. Injectable. Amylin is a peptide that is co-secreted with insulin from pancreatic β-cells in response to nutrient stimuli. As a partner hormone to insulin, amylin controls nutrient intake as well as nutrient influx to the blood by inhibiting food intake, gastric emptying, and glucagon secretion.

Pramlintide is approved as adjunctive therapy with insulin.

ADVERSE EFFECTS

Adverse effects include nausea, vomiting, anorexia and headache.
Used in combination with insulin, pramlintide has been associated with severe hypoglycemia. Pramlintide should not be used in patients with gastroparesis.