Pancreatic Hormones & Diabetic Drugs Flashcards
Which diabetes has more of a genetic predisposition
Type II
Which diabetes has insulin deficiency
Type 1
Which diabetes has a loss of beta cells
Type 1
Which diabetes is more prone to ketoacidosis
Type 1
Which diabetes is prone to a non-ketototic hyperosmolar coma
Type II
K+/ATP and Insulin:
Open state of K+/ATP channel
hyperpolarize the cell by causing outflow of K+ and inhibit insulin release
K+/ATP and Insulin:
Closed state of K+/ATP channel
depolarize the cell and insulin released.
Insulin Receptor signaling:
insulin binding to alpha subunit regulates beta subunit activity –>
autophosphorylation of beta subunit –>
increase tyrosine kinase activity –>
phosphorylation of other substrates –>
activation of phosphoinositide 3-kinase
Effects of insulin on the liver
Stimulates:
- glycogen synthesis
- triglyceride synthesis
Inhibits:
- glycogenolysis
- ketogenesis
- gluconeogenesis
Effects of insulin on skeletal muscle
Stimulates:
- glucose uptake
- protein synthesis
- glycogen synthesis
Inhibits:
- Protein degradation
- Glycogenolysis
Effects of insulin on adipose tissue
Stimulates:
- Glucose uptake
- Triglyceride storage
Inhibits:
- lipolysis
Overall, insulin stimulates ____and inhibits ____
Promotes anabolic processes and
Inhibits catabolic processes
advantages to recombinant DNA insulin
- Less insulin resistance
- Less allergy
- Less lipodystrophy
Rapid/ short-acting insulin:
onset and duration
Onset: 5-15 min
Duration: 3-5 h
Rapid insulin
- Insulin lispro, aspart, glulisine given s.c
- Inhaled human insulin - Indicated only in adults,
- Contraindicated- children, asthma, bronchitis, smokers
short-acting insulin
• duration
• what? method given?
• use?
- Duration: 5-8h
- Regular insulin given s.c and i.v.
- Use in diabetic ketoacidosis and other emergency situations
intermediate-acting insulin: • onset • duration • what? •
- onset: 2-5h
- duration: 4-12h
- Lente insulin, NPH insulin (Neutral protamine Hagedorn or isophane) mixture of insulin with protamine (basic substance obtained from fish sperm)
Ultra-long acting insulin
• onset
• duration
• what?
- onset: slow
- duration: 20-24h
- Ultra lente, Insulin glargine, Insulin detemir
- Peakless, given once daily
Hypoglycemia
• S/Sx
• Tx
- Sympathetic signs (tachycardia, sweating, palpitations, tremors) parasympathetic signs (nausea, hunger)
- Treatment : Glucose or glucagon treatment
Allergy and resistance to insulin
- Local cutaneous reactions or systemic
* Human insulin are less antigenic than insulin from animal sources
lipodystrophy
- Atrophy of fatty tissue at the site of injection
* Never seen since the development of highly purified insulin
Treatment of Type II DM includes
• Diet • Exercise • Wt reduction • Step wise approach to drug treatment • Patient education ➢ Oral drugs for reduction of blood glucose • Used only in the Rx of Type II DM • Oral medication is initiated when 2-3 months of diet and exercise alone are unable to achieve or maintain their optimal plasma glucose levels
Insulin secretogogues
- Sulfonyureas
* Meglitinides
Oral Hypoglycemics
1. Insulin secretogogues • Sulfonyureas • Meglitinides 2. Biguanides 3. Thiazolidinediones 4. Alpha glucosidase inhibitors
First Generation Sulfonylurea
- Chlorpropramide
- Tolbutamide
- Tolazamide
2nd Generation Sulfonuylurea
- Glipizide
- Glyburide
- Glimepiride
Mechanism of action of Sulfonylurea
- Block ATP sensitive K+ channels in pancreatic beta cells –> Inhibits the efflux of K+ resulting in depolarization
- Opening of voltage gated Ca influx –> release of preformed insulin –>
- Increase the sensitivity to insulin by increasing number of insulin Receptors
Chloropropamide (Diabinese)
- Long acting for 32 hours
- Can cause prolonged hypoglycemia in elderly patients (contraindicated age)
- Slowly metabolised in liver, so Contraindicated in patients with hepatic disease
Tolbutamide (Orinase)
- Rapidly metabolised in liver
* Short half life - safest SU in elderly
2nd generation SU drugs:
- glipizide (glucotrol)
- glyburide (micronase, glynase prestab)
- glimepiride
➢ Second generation drugs commonly prescribed agents because of fewer side effects and drug interactions
glipizide (glucotrol)
- 2nd generation SU drug.
- commonly prescribed agents because of fewer side effects and drug interactions
- Half-life - 2 to 4 hours
- Potency – High (2.5 to 40 mg/d)
- 90% is oxidized to inactive metabolites in liver
- Contraindicated in patients with hepatic disease - can cause hypoglycemia
Glyburide (Micronase, Glynase PresTab)
- 2nd generation SU drug.
- commonly prescribed agents because of fewer side effects and drug interactions
- Half-life - 6 hours
Glimepiride
- Approved for once-daily use
* Potency – Highest (1 to 8 mg/d)
Clinical uses of Sulfonylureas
- Hypoglycemic agents for treatment of Type 2 DM
- Act by increasing endogenous insulin secretion \ not indicated for Type 1
- Most effective when ß cell function has not been severely compromised
- Increased insulin secretion favors lipogenesis
- Suitable drug in non obese diabetics
A/E in Sulfonylureas
- Severe hypoglycemia
- Most common with glyburide and chlorpropramide in elderly patient
- Weight gain
- Erythema, skin reactions
- Disulfiram like reaction with alcohol (chlorpropramide)
Contraindications for Sulfonylureas
- Pregnancy
- Surgery, Severe infections
- Severe stress or trauma
- Severe hepatic or renal failure
- Insulin therapy should be used in all of these
Meglitinides:
Repaglinide and Nateglinide
Meglitinides • MOA • DOA • use • a/e
➢ Insulin secretogogues….same as sulfonyl ureas
➢ Rapid onset and short duration of action
• Suitable for controlling postprandial hyperglycemia
➢ Approved for used alone or with biguanides
➢ Common adverse effect is Hypoglycemia
Biguanides
Metformin
Biguanides (Metformin) MOA
Antihyperglycemic:
• Increases peripheral insulin sensitivity
• Inhibits hepatic gluconeogenesis & glucose absorption from GI tract
• Reduction of plasma glucagon levels
• “Euglycemic”, no hypoglycemia. *
• Does not alter insulin secretion *
Clinical use of Biguanides (Metformin)
- They are Insulin sparing agents
- Do not produce hypoglycemia
Secondary beneficial effects on lipids: • Reduced triglycerides • Reduced total cholesterol • Reduced LDL • Increased HDL • Does not increase Weight
Use:
• Appropriate for obese Type 2 diabetics
• Other use: Polycystic ovarian syndrome - lowers the serum androgens and restores normal mentrual cycles and ovulation
used to control postprandial hyperglycemia
Meglitinides: Repaglinide and Nateglinide
Metformin A/E and contraindications
Adverse effects:
• *Gastrointestinal – anorexia, nausea, vomiting, diarrhea
• Lactic acidosis (increased risk in alcoholics & in Pts with hepatic impairment)
• Vitamin B 12 defeciency
Contraindications:
• Alchoholism, renal and hepatic disease- risk of lactic acidosis
Thiazolidinediones
Pioglitazone, Rosiglitazone
Thiazolidinediones MOA
➢ Mechanism: Stimulate the nuclear peroxisome proliferator-activating receptors (PPAR’s) involved in transcription of insulin-responsive genes –> Increase the glucose uptake in muscle and adipose tissue & decreases hepatic gluconeogenesis
• They reduce plasma glucose and Triglycerides
Thiazolidinediones A/E
Adverse effects:
• Do not cause hypoglycemic, earlier drugs were hepatotoxic (troglitazone)
➢ Adverse effects
• Troglitazone*:
• Hepatotoxicity- Withdrawn from market
- Rosiglitazone, Pioglitazone*:
- No evidence of drug-induced hepatotoxicity
- Peripheral Edema, anemia
- Are hepatic enzyme inducers
- TZDs- euglycemics
- Are hepatic enzyme inducers
troglitazone
(Thiazolidinedione)
hepatotoxic–withdrawn from office
- Rosiglitazone, Pioglitazone*:
- No evidence of drug-induced hepatotoxicity
- Peripheral Edema, anemia
- Are hepatic enzyme inducers
- TZDs- euglycemics
- Are hepatic enzyme inducers
- No evidence of drug-induced hepatotoxicity
- Peripheral Edema, anemia
- Are hepatic enzyme inducers
- TZDs- euglycemics
Alpha glucosidase inhibitors
Acarbose, Miglitol
Alpha glucosidase inhibitors MOA
- Competitive and reversible inhibitors of a glucosidase in the small intestine
- Delay carbohydrate digestion and absorption
- Reduction in postprandial hyperglycemia
Alpha glucosidase inhibitors clinical use
- Individuals with significant postprandial hyperglycemia
* Monotherapy or in combination with other oral hypoglycemics
Alpha glucosidase inhibitors A/E
- Flatulence, Nausea, Diarrhea
- Due to increased fermentation of unabsorbed carbohydrate by colonic bacteria
- Do not produce hypoglycemia, lactic acidosis, or significant weight gain
Pramlintide
- Administered s.c
- Synthetic analog of amylin, supress glucagon release
- Targets post prandial blood sugar levels
Exenatide
(1st incretin therapy to be approved for DM)
- Administered s.c
- Synthetic glucagon like polypeptide (GLP-1)
- Potentiates insulin secretion
Sitaglyptin
Inhibitor of dipeptidyl peptidase-4-enzyme that degrades GLP-1
Glucagon effects
➢ The primary counter-regulatory hormone
• Effects are generally opposite those of insulin:
• Stimulates glycogenolysis, ketogenesis, and gluconeogenesis
• Inhibits glycogen synthesis and lipogenesis
• Increased hepatic glucose output
• Increased blood glucose level
➢ Other effects
• Inotropic and chronotropic effects on heart
• Relaxation of intestinal muscle
Glucagon clinical uses
- Severe hypoglycemia
- Overshooting in insulin therapy
- Hypoglycemia from long-acting oral agents
- Relaxation of the GI tract for X-ray and magnetic resonance visualization
- Inotropic effect on heart- can be used to reverse effects of ß-blocker overdose
