Antidiabetics 2 Flashcards
list the Non-insulin Antidiabetic Agents
- Insulin Secretagogues
- Biguanides
- Thiazolidinediones (TZDs)
- alpha-Glucosidase Inhibitors
- Incretin Analogs
- Inhibitors of DPP-IV
- Amylin Analogs
- Bile-Acid Sequestrants
- SGLT2 Inhibitors
Sulfonylureas overview and moa?
• Effective at reducing fasting plasma glucose
(FPG) and HbA1C.
MOA
• Stimulate insulin release from beta cells: bind to the
SUR1 subunit and block the ATP-sensitive K+
channel in the beta cell membrane
First-generation Sulfonylureas example and overview, ae, and contraindication?
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.
• Chlorpropamide may potentiate action of
vasopressin and elicit an apparent syndrome of
inappropriate secretion of ADH (SIADH).
list three Second Generation Sulfonylureas, Differences between first and second generation?
• Glyburide (Glibenclamide)
• Glipizide
• Glimepiride
• 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.
How often do 2nd generation sulfonylureas cause hypoglycemia?
Glyburide
• Causes hypoglycemia in 20-30% of users.
Glipizide
• Short half-life. Less likely to cause hypoglycemia.
Causes hypoglycemia in 10-15% of users.
Glimepiride
• Causes hypoglycemia in only 9-14% of users.
Approved for once-daily use.
Sulfonylureas: Adverse Effects?
- Hypoglycemia
* Weight gain
name 2 Meglitinides and their moa?
• 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.
Meglitinides pk and dosing?
• In contrast with sulfonylureas, the meglinitides have a rapid onset and short duration of
action.
• They are postprandial glucose regulators.
• They must be taken before each meal; if the
meal is missed the drug must be omitted.
Meglitinides: Adverse Effects?
• Repaglinide: hypoglycemia.
• Nateglinide: less risk of hypoglycemia.
• Both: Weight gain.
• Meglitinides contain no sulfur. They may be
indicated for patients with sulfur or sulfonylurea
allergy.
What biguanide is currently available and overivew?
• Only currently available biguanide.
• Does not cause insulin secretion.
• Generally does not cause hypoglycemia, even in
large doses.
• Equivalent to sulfonylureas in reducing FPG and
HbA1C levels.
Metformin MOA?
• 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 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).
Metformin: Other Effects?
- Reduces plasma TG by 15-20%.
* Decreases body weight.
Metformin: Indications?
• The American Diabetes Association (ADA)
recommends that metformin should be the
first-line agent in type 2 DM
Metformin: Adverse Effects?
• 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, hypoxia, or alcoholism.
Thiazolidinediones (TZDs) examples and overview?
• Pioglitazone
• Rosiglitazone
• Decrease insulin resistance.
• Agonists of peroxisome proliferator-activated
receptor-gamma (PPAR-gamma).
• Intracellular receptors found in muscle, fat and
liver.
Thiazolidinediones (TZDs) moa, pk, and efficacy?
• 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.
Thiazolidinediones (TZDs) effect on lipids
• 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
• LDL particle size
TZDs AE?
• 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 2010 the FDA restricted use of rosiglitazone.
• In 2014, after revaluation of the data, the FDA
removed the restrictions placed on rosiglitazone.
Troglitazone AE?
• 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.
acarbose belong to what class and moa?
alpha-glucosidase inhibitors
Competitive inhibitor of
intestinal alpha-glucosidases.
• Reduces postprandial digestion of starch and
disaccharides.
• Minimizes upper intestinal carbohydrate
absorption and defers absorption to the distal
small intestine.
• This decreases postprandial hyperglycemia and
hyperinsulinemia.
• Evokes modest drop in HbA1C and FPG levels.
Acarbose: Adverse Effects?
• Flatulence, diarrhea, abdominal pain.
• Contraindicated in IBS or any intestinal condition
worsened by gas and distension.
• Acarbose is associated with reversible hepatic
enzyme elevation.
• Periodical liver function monitoring is
required with acarbose therapy.
Overview of Incretin Analogs:
Exenatide • Analog of glucagon like-polypeptide 1 (GLP-1). • Derived from the salivary gland of the Gila monster. • Injectable. • Full agonist at human GLP-1 receptors. • Resistant to dipeptidyl peptidase IV (DPP-IV)
Describe the Incretin Effect?
• Incretins, released
by the gut, enhance
insulin secretion.
Glucose in gut lumen stimulates incretin secretion
Incretins enhance glucose-stimulated insulin secretion
Effects of Exenatide?
- Enhances glucose-dependent insulin secretion.
- Suppresses postprandial glucagon release.
- Slows gastric emptying.
- Decreases appetite.
- May stimulate β-cell proliferation.
Exenatide: Adverse Effects?
• Nausea, vomiting and diarrhea.
• Acute pancreatitis.
• Should not be used in patients with
gastroparesis.
Inhibitors of DPP-IV overview
Sitagliptin
• Selective inhibitor of DPP-IV.
• Increases circulating GLP-1 and insulin levels.
• Given orally.
Sitagliptin: Adverse Effects?
• Pancreatitis.
• Hypersensitivity reactions including urticaria,
angioedema, anaphylaxis, and skin reactions
such as Stevens-Johnson syndrome.
Amylin Analogs: Pramlintide overview?
• Synthetic analog of amylin.
• Peptide co-secreted with insulin from pancreatic
β-cells.
• Inhibits food intake, gastric emptying, and
glucagon secretion.
• Injectable
Bile-acid Sequestrants: Colesevelam?
• Bile-acid sequestrant used to lower LDL cholesterol. • Approved for treatment of type 2 DM. • Mechanism unclear. • Given orally.
SGLT2 Inhibitors overview
Canagliflozin
• Glucose is filtered by the glomerulus and
reabsorbed in the proximal tubule by sodium glucose
transporters (SGLTs).
• SGLT2 is responsible for most of glucose
reabsorption.
• Canagliflozin blocks SGLT2.
• This leads to decreased glucose reabsorption,
increased glucose excretion, and decreased
blood glucose levels.
• Given orally.
Canagliflozin: Adverse Effects?
• 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.
INITIAL DRUG THERAPY for type 2 diabetes according to american diabetes association guidelines?
• Metformin is the preferred first agent.
• Started if lifestyle intervention did not achieve
HbA1c goals.
• Monotherapy with most non-insulin antidiabetic
agents can reduce HbA1c ~ 1%.
• Patients with HbA1c ≥9.0% are unlikely to
achieve HbA1c goals with monotherapy.
• Therefore, therapy may be started with a
combination of two noninsulin agents or with
insulin itself.
ADVANCING TO DUAL COMBINATION THERAPY for type 2 diabetes according to american diabetes association guidelines?
• If monotherapy does not achieve HbA1c goal over
∼3 months, the next step is to add a second agent.
• The choice could be: oral agent, exenatide, or
insulin.
• The higher the HbA1c, the more likely insulin will be
required.
• If the two-drug combination fails to achieve the
glycemic target a third agent can be added.
• Diabetes is associated with progressive β-cell loss:
many patients will eventually need to be transitioned
to insulin.
• The decision to transition to insulin should be
favored when the HbA1c ≥ 8.5%.
TRANSITION TO INSULIN THERAPY for type 2 diabetes according to american diabetes association guidelines?
• Insulin is typically begun at a low dose, with a
single injection of basal insulin.
• The dose is then uptitrated.
• If there is postprandial hyperglycemia the patient
will require addition of prandial insulin therapy.
• Typically, rapid-acting insulins are used: lispro,
aspart or glulisine.
Describe insulin’s efficacy?
• Insulin is the most effective of diabetes
medications in lowering glycemia.
• It can decrease any level of elevated HbA1C to,
or close to, the therapeutic goal.
• There is no maximum dose of insulin beyond
which a therapeutic effect will not occur.
• Large doses of insulin may be necessary to
overcome the insulin resistance of type 2
diabetes.
Patients with Severe Hyperglycemia criteria?
Insulin may be warranted as initial therapy for patients with type 2 diabetes with: • Significant hyperglycemic symptoms • Ketonuria • HbA1c > 10% • Random glucose > 300 mg/dL
Management of Diabetes in Pregnancy?
• Gestational Diabetes Mellitus • Preexisting Type 1 Diabetes & Type 2 Diabetes •Insulin is the preferred agent. •It does not cross the placenta to a measurable extent.
Choice of Insulin in Pregnancy?
• All insulins are category B except glargine,
glulisine, and degludec, which are C.
• Use of insulin preparations of low antigenicity
minimizes transplacental transport of insulin
antibodies.
• Human insulin is the least immunogenic
• Lispro, aspart, and glulisine are comparable in
immunogenicity to human insulin.
• Only lispro and aspart have been shown to be
safe in pregnancy.
• A typical regimen may start with a single dose of
bedtime NPH insulin.
• If postprandial glucose control is required
injections of lispro or aspart can be added.
Complications of diabetes?
CARDIOVASCULAR DISEASE • Hypertension • Dyslipidemia • Antiplatelet Therapy • NEPHROPATHY • NEUROPATHY • Neuropathic Pain • Gastroparesis • Erectile Dysfunction
CVD considerations in diabetics?
• CVD is the major cause of morbidity and mortality for individuals with diabetes.
Hypertension
• Patients with diabetes and hypertension should
be given either an ACE inhibitor or an ARB.
Dyslipidemia
• Statins should be given, regardless of lipid
levels, to diabetic patients:
• With overt CVD
• Aged < 40 yr with CVD risk factors
• Aged > 40 yr with or without CVD risk
Antiplatelet Agents
• Aspirin therapy should be considered as a
primary prevention strategy in patients with type
1 or type 2 diabetes at increased CV risk.
Glucagon uses?
Severe Hypoglycemia
• Used to treat severe hypoglycemia in patients
with diabetes treated with insulin.
Radiology Of The Bowel
• Used because of its ability to relax intestine.
beta-Blocker Poisoning
• Antidote for beta-blocker overdose.
Glucagon C-peptide Test
• Test for residual β-cell function in diabetes.
Nephropathy and Neuropathy considerations in diabetes?
NEPHROPATHY
• ACE inhibitors or ARBs are recommended for
patients with albuminuria.
Neuropathic Pain • Drugs used for neuropathic pain include: • Amitriptyline • Pregabalin • Gabapentin • Duloxetine • Venlafaxine • Valproate • Opioids Gastroparesis • Gastroparesis symptoms may improve with dietary changes and prokinetic agents such as metoclopramide or erythromycin. Erectile Dysfunction • Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors.
