Antidiabetic drugs Flashcards
Rapid-acting insulins
- Insulin Lispro
- Insulin Aspart
- Insulin Glulisine
- Natural hexamers slow the absorption of insulin.
- Short-acting insulin analogs that don’t form hexamers.
- Rapid-acting insulins are given to mimic the prandial release of insulin.
- They are usually given along with a longer acting insulin to assure proper glucose control.
- Given SC.
- Given 15 minutes before a meal.
- Also suitable for IV.
Short-acting insulin
Regular insulin
• Short-acting soluble crystalline zinc insulin.
• Should be given 30 minutes before a meal.
• Given SC
• Given IV in emergencies.
Intermediate-acting insulin
Neutral protamine Hagedorn (NPH) • Also called Isophane Insulin. • Suspension of crystalline zinc insulin combined with protamine. • Should only be given SC. • Used for basal control. • Usually given along with rapid- or short- acting insulin for mealtime control.
Long-acting insulin
- Insulin Glargine - acidic solution, precipitates at pH 7.4 in SC tissue -> slow dissolution of free glargine hexamers -> protracted action
- Insulin Detemir - added long insoluble FA chain
Basal bolus insulin regimens
- One daily shot of glargine or detemir to provide basal coverage
- Doses of lispro, aspart or glulisine to provide coverage for each meal.
- Long-acting insulin Q HS or Q AM
- If patients skip a meal, they omit a premeal bolus.
- If they 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 best way to mimic normal insulin secretion.
- It consists of a battery-operated pump and a computer that programs the pump to deliver predetermined amounts of insulin.
• Glulisine, lispro, or insulin aspart is used in the insulin pump
Adverse rxns of insulin
Hypoglycemia
• Most serious and common adverse reaction to overdose.
• Risk of hypoglycemia with the rapid-acting insulin analogs is less than with regular insulin.
Hypoglycemia: Management
• Mild hypoglycemia in a conscious patient: orange juice, glucose or any sugar-containing beverage or food.
• Severe hypoglycemia with unconsciousness or stupor: IV glucose infusion.
• If IV therapy is not available: glucagon SC or IM.
Allergic reactions
• Immediate type hypersensitivity. Rare.
• Often due to noninsulin protein contaminants.
• Human and analog insulins have markedly reduced incidence of insulin allergy.
Lipodystrophy at injection sites
• Very rare since the introduction of human and analog insulin preparations of neutral pH.
- The most common drugs causing hypoglycemia are:
- Ethanol - inhibits GNG
- B-blockers - blocks effects of catecholamines on GNG and glycogenolysis. Also mask the sympathetically-mediated sx’s of hypoglycemia (tremor, palpitations, etc)
- Salicylates - enhance pancreatic B-cell sensitivity to glucose and potentiate insulin secretion. Also have weak insulin-like action at periphery
Drugs that cause hyperglycemia
- Many of these agents have direct effects on peripheral tissues that counter the actions of insulin:
- Epinephrine
- Glucocorticoids
- Atypical antipsychotics
- HIV protease inhibitors
- Some drugs cause hyperglycemia by inhibiting insulin secretion directly:
- Phenytoin
- Clonidine
- Ca2+-channel blockers
• Some drugs, like the diuretics, cause hyperglycemia by inhibiting insulin secretion indirectly, via depletion of K+.
Sulfonylureas
- Effective at reducing fasting plasma glucose (FPG) and HbA1C.
- Stimulate insulin release from B cells: bind to the SUR1 subunit and block the ATP-sensitive K+ channel in the B cell membrane.
SE’s
• Hypoglycemia. This is a problem particularly in elderly patients with impaired renal or hepatic function.
• Weight gain.
• Beware sulfa allergies!
First generation sulfonylureas
Tolbutamide
• Short duration of action.
• Prolonged hypoglycemia occurs rarely.
Chlorpropamide
• Long half-life.
• Hypoglycemia is common, particularly in elderly patients. Contraindicated in elderly patients.
• Hyperemic flush when alcohol is ingested. Mainly due to inhibition of aldehyde dehydrogenase.
• Sulfonylureas, especially chlorpropamide, potentiate action of vasopressin and can elicit an apparent syndrome of inappropriate secretion of ADH (SIADH).
Second generation sulfonylureas
- Much more potent that first-generation agents.
- Lack some of the adverse effects and drug interactions of first-generation agents.
- Have largely replaced first-generation agents.
Glyburide
• Causes hypoglycemia in 20-30% of users.
Glipizide
• Shortest half-life of the more potent agents. Less likely to cause hypoglycemia.
Glimepiride
• Causes hypoglycemia in only 2-4% of patients. Approved for once-daily use.
Meglitinides
- Repaglinide
- Nateglinide
- Stimulate insulin release by binding to SUR1 and inhibiting ATP-sensitive K+ channel.
- Not as effective as sulfonylureas in reducing FPG and HbA1C levels.
- In contrast with sulfonylureas, the meglinitides have a rapid onset and short duration of action.
- They are postprandial glucose regulators.
- Rapidly absorbed and rapidly cleared.
- They must be taken before each meal; if the meal is missed the drug must be omitted.
- Meglitinides contain no sulfur. They may be indicated for patients with sulfur or sulfonylurea allergy.
SE’s
• Repaglinide: hypoglycemia.
• Nateglinide: less risk of hypoglycemia.
• Both: Weight gain.
Metformin
- Generally does not cause hypoglycemia, even in large doses.
- Equivalent to sulfonylureas in reducing FPG and HbA1C levels.
- Metformin reduces glucose levels primarily by inhibiting gluconeogenesis. This is done by reducing gene expression of gluconeogenic enzymes.
- Additionally, metformin increases insulin- mediated glucose utilization in muscle and liver.
- As a result of the improvement in glycemic control, serum insulin concentrations decline slightly.
- At the molecular level, these actions are mediated at least in part by activation of AMP- activated protein kinase (AMPK).
- Reduces plasma TGs by 15-20%.
- Decreases body weight.
- Only hypoglycemic agent shown to reduce macrovascular events in type 2 DM.
- The American Diabetes Association (ADA) recommends that metformin should be the first-line agent in type 2 DM.
- Can be used alone or in combination with sulfonylureas, Tzds and/or insulin.
SE’s
• Largely GI: anorexia, nausea, vomiting, abdominal discomfort, diarrhea.
• Long term use may interfere with B12 absorption.
• Small risk of potentially fatal lactic acidosis.
• Contraindicated in patients with renal disease, hepatic disease, or alcoholism.
Thiazolidinediones
• Pioglitazone, Rosiglitazone
• Decrease insulin resistance.
• Agonists of peroxisome proliferator-activated
receptor-y (PPAR-y).
• Intracellular receptors found in muscle, fat and liver.
- In diabetic patients glitazones promote glucose uptake and utilization in adipose tissue.
- Less effective than sulfonylureas and metformin in decreasing FPG and HbA1C levels.
- Their mechanism of action involves gene regulation.
- Glitazones have a slow onset and offset of activity over weeks or even months.
- Pioglitazone increases HDL and decreases TAGs.
- Rosiglitazone increases HDL, but has no effect on TAGs and increases LDL.
SE’s
• Cause fluid retention, weight gain and edema.
• Cause or exacerbate CHF in some patients.
• Contraindicated in patients with Class III or IV heart failure.
• In September 2010 the FDA restricted the use of rosiglitazone.
• The European Medicines Agency recommended suspending use of the drug entirely due to concerns about increased CV risk.
- Troglitazone was the first thiazolidinedione to be approved.
- It caused severe hepatic toxicity and was withdrawn.
- As a consequence, the FDA requires monitoring of liver function with Tzd therapy.
- So far pioglitazone or rosiglitazone have not been associated with hepatotoxicity.
a-glucosidase inhibitors
- Acarbose
- Miglitol
- Competitive inhibitors of intestinal a-glucosidases.
- Reduce postprandial digestion of starch and disaccharides.
- Decrease postprandial hyperglycemia and hyperinsulinemia.
- Evoke a modest drop in HbA1C and FPG levels.
- Acarbose is associated with reversible hepatic enzyme elevation.
- It should be used with caution in the presence of hepatic disease.
- Periodical liver function monitoring is required with acarbose therapy.
