Antidiabetic Flashcards
Adrenergic α2
receptor activation decreases insulin release (predominant) by inhibiting β-cell adenylyl cyclase
Adrenergic β2
stimulation increases insulin release (less dominant) by activating β-cell adenylyl cyclase
Vagal stimulation
causes insulin secretion through IP3/DAG- increased intracellular Ca2+ in the β-cell
Insulin receptor
Two α-subunits and two β-subunits. Insulin binds to α-subunit
Activates Tyrosine Kinase → Phosphorylation of tyrosine in β-subunit
Activates insulin receptor substrate (IRS)
Translocation of glucose transporters to cell membrane – increases Glucose uptake into the cells,
Increases glycogen synthesis,
Alters protein and fat metabolism
Actions of Insulin on the liver
Inhibits gluconeogenesis (glucose production from protein, pyruvate, FFA and glycerol) and increases glycolysis
Inhibits glycogenolysis and stimulates glycogen synthesis (glycogenesis)
Increases the synthesis of triglycerides
Increases protein synthesis
Overall effects of insulin
Overall effects of insulin: to favor storage of fuel
Insulin promotes cellular K+ uptake**
Synthesis of proteins and fats (anabolic)
In the absence of insulin, most body cells cannot take up glucose.
Proteins and fats are broken down to provide energy
Actions of Insulin on the muscle
Increases glucose transport and glycolysis
Increases glycogen deposition
Increases protein synthesis
Actions of insulin on adipose tissue
Increases glucose transport
Increases triglyceride synthesis (lipogenesis)
Decreases intracellular lipolysis
Rapid, intermediate & major long term effects
Most of the metabolic actions of insulin are exerted within seconds or minutes (rapid actions)
Others involving DNA mediated protein synthesis have a latency of few hours (intermediate actions)
In addition, insulin exerts major long term effects on multiplication and differentiation of cells
Is insulin orally active
Insulin is orally not active as degraded in the GIT
Insulin is inactivated by insulinase found mainly in kidneys
Sources of insulin
Beef pancreas (bovine insulin): different from human insulin by 3 Amino acids: allergy concerns Associated with a risk of“mad-cow”disease
Pork pancreas (porcine insulin)- differs from human insulin by 1 Amino acids: allergy concerns less than bovine insulin
Human insulin: recombinant DNA technology: Now commonly used
Human insulin differs from bovine insulin by 3 AA and from porcine insulin by 1 AA
How is human insulin produced
Produced by recombinant DNA technology in bacteria (E. coli) and in yeast, or by enzymatic modification of porcine insulin.
Advantages of Human insulin
Diminished antibody (less chance of insulin resistance)
Less allergic reactions
Less lipodystrophy (insulin is lipogenic – could get swelling of subcutaneous fat at the sites of injection)
During surgery or infection
Regular Insulin
(Crystalline Zinc Insulin/Soluble Insulin)
Onset is ≥30 mins, duration of action 6-8 hours;
Regular insulin can be given SC, or IV
intravenous (IV) route (for DKA, during surgery or acute infections)
Need to wait for 30 min to have meals.
Short acting insulin analogues
Insulin Lispro, Insulin Aspart and Insulin Glulisine: Rapid acting
Characteristics of short acting insulin analogues
more rapidly absorbed from subcutaneous sites than regular insulin
Rapid onset within 15 min & duration <3-4 hours;
Meals can be taken within 15 min following injection
more closely mimic normal endogenous prandial insulin secretion than does regular insulin
have the lowest variability of absorption (from s.c. sites) (approx- 5%) of all available commercial insulin
preferred insulin for use in continuous subcutaneous insulin infusion devices
Intermediate acting insulin
NPH (Neutral Protamine Hagedorn, Isophane) and Lente insulin
Duration of action~ 12-24 hours
Long acting insulin
only s.c.
Ultralente, Insulin glargine, Insulin detemir, Protamine-zinc insulin, Insulin degludec
Duration of action ~ 30 hours, Insulin degludec -40 h
Split-mixed regimen
Calculated daily dose of insulin is split in 2 or 3 doses; and insulin preparations used are of mixed types (short-acting+ intermediate acting (30:70, 50:50 etc) or short-acting+ longer-acting, etc)
Frequently used
Insulin dosing for standard treatment
injection of both short and intermediate acting insulin twice a day
Insulin dosing - Intensive treatment
Intensive treatment methods are employed which involve multiple injections:
Multiple regular + intermediate acting insulin injections (in response to monitoring blood glucose levels)
Intensive therapy is not recommended in pts with advanced age and those with hypoglycemic unawareness
Theraputic uses of insulin
Diabetes mellitus (Type 1)**** Diabetes mellitus: Type 2: Sometimes, if not well-controlled. Most type 2 diabetics are treated with dietary changes, reduction in body weight, appropriate exercises and oral antidiabetic agents Diabetic Ketoacidosis (Diabetic coma)**** Hyperosmolar (nonketotic hyperglycemic) coma***
Gestational diabetes**
DKA clinical features
- Nausea and vomiting,
- Abdominal pain
- Dehydration
- Tachycardia
- Hyperventilation – from acidosis
- Hypotension
6 steps to DKA management
- Insulin: Regular insulin IV (bolus + infusion)
After patient becomes fully conscious, maintenance with s.c. inj - IV fluids***: to correct dehydration- Normal saline (0.9% NaCl)
After blood glucose has reached 300 mg/dl, 5% glucose in ½ N saline is the most appropriate solution
glucose is needed to restore the depleted hepatic glycogen
- KCl
Acidosis causes loss of K+ in urine
Additionally, when insulin therapy is instituted K+ is driven intracellularly- leading to severe hypokalemia - NaHCO3
Not routinely needed, because acidosis subsides as ketosis is controlled - Phosphate: (routine use controversial)
- Antibiotics: if required; respiratory infections reported in patients developing ketoacidosis
Hyperosmolae nonketoic hyperglycemic coma
- Usually occurs in elderly type 2 diabetes
- General principle of treatment are same as for DKA, except that faster fluid replacement is to be instituted and NaHCO3 is usually not required.
- Patients are prone to thrombosis (due to hyperviscosity and sluggish circulation), prophylactic heparin therapy is recommended (along with insulin)
ADR of Isulin
Hypoglycemia**
symptoms: sweating, anxiety, palpitation, tremor, dizziness, headache, behavioral changes, visual disturbances, fatigue, weakness, muscular in-coordination, etc → ultimately coma
Most frequent and the most serious reaction
Can occur in any diabetic pt.
Following inadvertent large doses of insulin injection, or by missing a meal or by performing a vigorous exercise
generally, the reflex sympathetic symptoms occur before the neuroglucopenic symptoms
diabetic neuropathy can abolish the autonomic symptoms***
when blood glucose falls further (< 40 mg/dl) mental confusion, seizures and coma occur
S/S of hypoglycemia are related to
counter regulatory sympathetic stimulation- sweating, anxiety, palpitation, tremors neuroglucopenic symptoms (due to deprivation of brain of its essential nutrient- glucose)- dizziness, headache, behavioral changes, visual disturbances, fatigue, weakness, muscular incoordination, etc → convulsion and ultimately coma
Hypoglycemia treatment
Glucose (sugar candy, sugar syrup etc) must be given orally or IV (10% dextrose for severe cases); reverse the symptoms rapidly
Somogyi effect
Blood glucose level drops too low in the midnight hours (Very early morning) due to usage of too much long acting or medium acting insulin at the night before or not eating a snack before bed time.
Released hormones (growth hormone, cortisol, and catecholamines) help to reverse the low blood glucose level but higher than normal in the morning.
Other insulin ADR
sensation: Lipodystrophy (lipoatrophy or lipohypertrophy) of subcutaneous fat at the injection site (less seen with new preparations)
Allergic reactions (Anaphylactoid reactions): due to contaminating proteins added to insulin in its formulation (protamine, etc) (very rare with human/highly purified insulins)
Weight gain (insulin is anabolic)
Hypokalemia (uptake of K+ into cells)
How do beta blockers prolong hypoglycemia
hypoglycemia by inhibiting compensatory mechanisms operating through β2 receptors (β1 selective are less liable).
Additionally, warning signs of hypoglycemia like palpitation, sweating, tremors and anxiety are masked
How does alcohol affect hypoglycemia
can precipitate hypoglycemia by inhibiting gluconeogenesis
Thiazides, Furosemide, corticosteroids, OCPs, Albuterol, effect on insulin
tend to raise blood glucose and reduce effectiveness of insulin
Acute insulin resistance
develops rapidly and is usually a short term problem.
Causes:
infection, trauma, surgery, stress;
corticosteroids and other hyperglycemic hormones (e.g., Epinephrine) produced in excess during stress—–oppose insulin action
Chronic insulin resistance
conventional preparations of bovine or porcine insulin
- Antibodies are formed against insulin
- Treatment is to switch over to human insulin
What are some conditions that are associated with insulin resistance
Pregnancy, metabolic syndrome, acromegaly, Cushing’s syndrome, pheocromocytoma, use of oral contraceptives, corticosteroids are associated with insulin resistance
Administration of insulin by pump
delivers continuous subcutaneous insulin infusion (CSII)
does not need multiple injections during the day
The pump is programmed to deliver basal rate of daily injection of insulin and also allows the patient to control the delivery of a bolus dose of insulin to compensate for high glucose level or in anticipation of postprandial, stress or exercise needs
The type of insulin that is used in the pump is only rapid acting
Insulin secretagogues
Sulfonylureas: Glyburide, Glipizide, Glimepiride, Gliclazide, Meglitinides (Glinides): Repaglinide, Nateglinide
Insulin sensitizers
Biguanides
Thiazolidinediones (glitazones)
alpha glucosidase inhibitors
inhibits glucose absoption
incretin based agents
GLP-1 analogs
Dipeptidyl peptidase-4 (DPP-4) inhibitors
First generation sulfonylureas
Chlorpropamide
Tolazamide
Tolbutamide
Second generation sulfonylureas
Glimepiride
Gliclazide
Glipizide
Glyburide (Glibenclamide)
Second generations are more potent, more efficacious and cause fewer adverse effects.
MOA of sulfonylureas
These drugs promote insulin release from β-cells of pancreas
Sulfonylureas bind to the SUR-1 subunit of sulfonylurea receptor on the intracellular portion of ATP sensitive K+ channels in β- cells and inhibit K+ efflux
The depolarization resulting from the closed K+ channels facilitates entry of Ca2+ into the cell.
Increase in intracellular Ca2+ level leads to Exocytosis and release of insulin from stored insulin vesicles inside the β- cells of pancreas
Sulfonylureas theraputic uses
To control hyperglycemia in patients with type 2 DM (not in type 1 DM) who cannot achieve appropriate control with changes in diet/exercise.
Sulfonylureas require some islet function to produce effect, hence not effective in type 1 DM.
Should not be used in patients with renal or liver diseases
Sulfonylureas ADR
More with first generation, less with second generation
Hypoglycemia*****
more common, can be severe, particularly in elderly with impaired hepatic or renal functions who are taking longer acting sulfonylureas (chlorpropamide, glimepiride)
less with Tolbutamide due to low potency and short duration of action
Secondary failure
Nausea, vomiting Weight gain (moderate)**** Cholestatic jaundice Hypersensitivity Aplastic and hemolytic anemias Intolerance to alcohol & disulfiram like reaction, (esp first-generation OHAs, particularly with chlorpropamide)
Cross placenta → fetal hypoglycemia: can deplete insulin from the fetal pancreas; therefore pregnant women with diabetes should be treated with insulin***)
Sulfonylureas pharmacokinetics
all are well absorbed after oral administration
should be given 30 mins before meal
largely bound (90-99%) to plasma protein
hypoglycemic effects of all sulfonylureas are evident for 12-24 hours
metabolized by the liver, and excreted in urine
Selection of sulfonylureas
depends upon duration of action, patients age, renal function and adverse effects
Long-acting sulfonylureas, e.g., Glyburide (Glibenclamide), are associated with a greater risk of hypoglycemia- hence should be avoided in the elderly
For elderly, shorter acting sulfonylureas, e.g., tolbutamide should be used
In patients with impaired renal function, glipizide or tolbutamide are preferred since they are not excreted by kidneys
Hypoglycemic effects of sulfonylureas
Decreased hepatic metabolism or renal excretion: Androgens, Anticoagulants, Azole antifungals, Allopurinol, MAOIs, Chloramphenicol, Clarithromycin, Tricyclic antidepressants, probenecid
Displacement of sulfonylureas from binding proteins:
Sulfonamides, Salicylates, Clofibrate
Hypoglycemic effects of Sulfonylureas are reduced by increased hepatic metabolism or renal excretion of sulfonylureas or by decreased insulin secretion:
Atypical antipsychotics, corticosteroids, β-blockers, Thiazide Diuretics, Niacin, Diazoxide, Rifampin, cholestyramine, phenytoin, sympathomimetics and urinary alkalinizers
Meglitinide analog (Repaglinide, Nateglinide)
Like sulfonylureas, act by blocking ATP-sensitive K+ channels and increase the release of insulin from pancreatic β-cells
have a fast onset of action, with a peak concentration and peak effect within 1 hour after ingestion.
Metabolized by the liver and should not be used in patients with hepatic insufficiency
Lack sulfur in their structures and may be used in type 2 diabetics with sulfur or sulfonylurea allergies
Meglitinide analog (Repaglinide, Nateglinide)
Like sulfonylureas, act by blocking ATP-sensitive K+ channels and increase the release of insulin from pancreatic β-cells
have a fast onset of action, with a peak concentration and peak effect within 1 hour after ingestion.
Metabolized by the liver and should not be used in patients with hepatic insufficiency
Lack sulfur in their structures and may be used in type 2 diabetics with sulfur or sulfonylurea allergies
Meglitinides are used in combo with?
Should not be used with?
Categorized as what kind of regulator?
They are used in combination with metformin or glitazones, (combination therapy has been shown to be more effective than monotherapy of these agents alone)
They should NOT be used along with sulfonylureas due to overlapping mechanism of action
Particularly effective in early release of insulin that occurs after a meal and thus are categorized as postprandial glucose regulators
Meglitinides ADR
Hypoglycemia (major), Weight gain
Secondary failure
Biguanides: Metformin mechanism
Activation of AMP-activated protein kinase (AMPK)
↓ hepatic glucose production
↑ glucose uptake and glycolysis
↓ glucose absorption from intestine
↑ peripheral (liver, muscle and fat) insulin sensitivity
Biguanides Metformin - Uses
given alone or in combination with other antidiabetic drugs in type 2 DM (in obese patient)***
also found useful in the t/t of Polycystic Ovary Syndrome (PCOS) (lowers insulin resistance and can restore normal menstrual cycles and ovulation)
Advantages of Metformin to Sulfonylureas
causes modest weight loss (due to anorexia).
does not cause hypoglycemia*** (also termed as ‘euglycemic’ agent).
has prominent favorable effect on lipids, producing a significant reduction in serum TG and LDL cholesterol, and an elevation in HDL cholesterol
has potential to prevent macrovascular as well as microvascular complications **of diabetes
Metformin ADR
GI disturbances: metallic taste, anorexia, nausea, vomiting, diarrhea and abdominal pain.
Risk of lactic acidosis***: Serious and potentially fatal condition; especially in patients with kidney or liver impairment.
Alcohol ingestion can precipitate severe lactic acidosis
Vit. B12 deficiency (rare)
Metformin Contraindications
Renal and/or hepatic disease
History of lactic acidosis due to any reason
Uncompensated cardiac failure (CHF)
Chronic hypoxic lung disease
Thiazolidinediones class
Insulin sensitizer
Pioglitazone, Rosiglitazone
Thiazolidinediones Mechanism
Bind to and activate nuclear receptor (Peroxisome Proliferator Activated Receptor- Gamma ( PPAR-γ)***-
↓ Hepatic glucose production
↑ hepatic glucose uptake
↑ GLUT4 glucose transporters
↑insulin sensitivity in adipose tissue, liver and skeletal muscle
Pioglitazone, Rosiglitazone
Thiazolidinediones ADR
Hepatotoxicity (Troglitazone- no longer used)
Cardiovascular toxicities: fluid retention-increased risk of MI and CHF.
Heart failure on long term use: Contraindicated in NYHA class III and IV cardiac status
Edema
Weight gain**
Increased risk of bladder cancer with high doses and long-term use of pioglitazone (removed from Europe).
Thiazolidinediones used to treat? Cause reduction in? Requires the presence of? Can be given alone or with? Beneficial effects on serum?
Used to treat type-2 diabetes
Cause reduction in HbA1c of 0.5-1.4%
require the presence of insulin
Can be given alone or with metformin or a sulfonylurea
Combination of a Glitazone and metformin - no hypoglycemia
Beneficial effects on serum lipid levels – decrease TG
Inhibitors of glucose absorption
Acarbose and miglitol
Usually combined with another antidiabetic drug(s) in type 2 DM
Do not stimulate insulin release, hence do not result in hypoglycemia
Acarbose and miglitol inhibit?
The net result is?
inhibit the gastrointestinal enzymes α-glucosidase found on intestinal brush border, that converts dietary starch and other complex carbohydrates (disaccharides) into simple sugars (monosaccharides) which can be absorbed.
The net result is- they delay the absorption of glucose after meals (decrease postprandial hyperglycemia)
Alpha glucosidase inhibitors ADR
GI effects (most common ***) Release of gas (flatulence- most embarrassing), abdominal bloating, abdominal cramps and diarrhea
Alpha glucosidase inhibitors contraindications
patients with chronic intestinal diseases, inflammatory bowel disease, colonic ulceration or intestinal obstruction
Endogenous human incretins, such as______ and ______, are released from the _____ and enhance ______ secretion
Endogenous human incretins, such as glucagon-like-peptide-1 (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP), are released from the gut and enhance insulin secretion
Exenatide *
Liraglutide *
Albiglutide
Dulaglutide
GLP-1 analog
All of the GLP-1 receptor agonists may increase the risk of pancreatitis.***
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Dipeptidyl peptidase-4 (DPP-4) inhibitors: Oral)
Exenatide -
ADR
Dose
Causes
Causes glucose dependent insulin release- Less hypoglycemia
given s.c. WEEKLY before meals.
marketed as pen which delivers 5 and10 μg.
Adverse effects: GI disturbances: Nausea, vomiting, diarrhea
Weight loss
Liraglutide
Causes?
Given?
Causes glucose dependent insulin release- Less hypoglycemia
Is given as s.c. injection once DAILY.
marketed as pen that delivers 0.6, 1.2 and 1.8 mg of drug.
started with low dose for the initiation of therapy and dose escalated based on clinical response
Decreases appetite, causes nausea and vomiting and can also decrease body weight.
Dipeptidyl Peptidase-4 (DPP-4) inhibitors prevent the breakdown of?
incretins like glucagon-like-peptide-1 (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP), and lead to an increase in insulin secretion and decrease in glucagon level
DPP-4 inhibitors are used alone or in combo with?
combination with other oral antidiabetic agents (such as metformin or thiazolidinedione or Insulin) for treatment of type-2 DM.
Lower HbA1c level by 0.4-1% points
The benefit is their lower adverse-effects (No hypoglycemia, do not cause weight gain),
DPP-4 inhibitors ADR
Nasopharyngitis, upper respiratory infections, and headaches.
Acute pancreatitis (fatal and nonfatal)
Severe allergic and hypersensitivity reactions.
Amylin
also called ‘islet amyloid polypeptide’ (IAPP)
Produced by pancreatic β-cells and acts in the brain to reduce glucagon secretion from α cells, delays gastric emptying, promotes satiety and retards glucose absorption.
Pramlintide
synthetic amylin analog
exerts a centrally mediated anorectic effect.
used as adjuvant to meal time insulin injection (s.c.) to
suppress the glycemic peak in both type 1 and type 2 diabetics.
Reduction in body weight is an additional benefit
Pramlintide:
S.C. injection administered?
With pramlintide, the dose of rapid-or short-acting insulin should be ?
Pramlintide must not be mixed in the same syringe with?
S.C. injection administered prior to meals.
With pramlintide, the dose of rapid-or short-acting insulin should be decreased by 50 %
Pramlintide must not be mixed in the same syringe with any insulin preparation.
Pramlintide ADR
mainly gastrointestinal: nausea, anorexia, and vomiting.
Hypoglycemia
Should not be given to patients with diabetic gastroparesis (delayed stomach emptying), cresol hypersensitivity, or a history of hypoglycemic unawareness.
SGLT-2 inhibitors
Practically all the glucose filtered at the glomerulus is reabsorbed (90%) in the proximal tubules. The major transporter which accomplishes this is SGLT-2
SGLT-2 inhibition induces glycosuria and lowers blood glucose in type 2 DM
Urinary loss of 50 to 80 grams of blood glucose per day
Loss of water and Na+ leads to a decrease in blood pressure, as well as weight loss.**
Canagliflozin, Dapagliflozin, Empagliflozin, ertugliflozin
Used alone or in combination with other oral agents or insulin
In monotherapy, reduce HbA1c by 0.5%-1.0%
Do not cause hypoglycemia
Decrease in blood pressure, as well as body weight (2–5 kg)
Increased dehydration, UTI, vaginal mycotic infections
Increased frequency of DKA (in type-1 patients- off label use)
Increased LDL cholesterol levels.
Lower incidence of cardiovascular events (deaths, MI, strokes)
Higher rates of breast cancer (dapagliflozin)
Contraindicated in patients with renal failure
Effect on BW and risk of hypoglycaemia in the following Sulfonylureas Meglitinides Metformin Thiazolidinediones DPP-4 Inhibitors SGLT-2 inhibitors
Sulfonylureas
BW↑↑
Hypogly↑↑
Meglitinides
BW↑
hypogly↑
Metformin
BW↓
hypogly ─
Thiazolidinediones
bw↑
hypogly↑
DPP-4 Inhibitors
BW─
hypo gly─
SGLT-2 inhibitors
BW↓
hypo gly─
