Drug treatment of diabetes mellitus Flashcards
How is blood glucose regulated?
Insulin Lowers blood glucose. Increased blood glucose stimulates insulin secretion.
'Counter-regulatory' hormones: Glucagon Adrenaline Glucocorticoids Growth hormone
What are the pancreatic cells?
Alpha cell - secretes glucagon beta cells - secretes insulin delta cell - secretes somatostatin Exocrine pancreas - acinar cells and duct cells F-cell - secretes pancreatic polypeptide
What is the structure of insulin?
It consists of two peptide chains (of 21 and 30 amino acid residues) linked by disulfide bonds.
There is a steady basal release of insulin and also a response to an increase in blood glucose.
How is insulin secreted?
Glucose enters B cells via a membrane transporter called Glut-2. Metabolism of glucose increases intracellular ATP. ATP blocks KATP channels, causing membrane depolarisation and opening of voltage-dependent calcium channels, leading to Ca2+ influx. The increase in cytoplasmic Ca2+ triggers insulin secretion.
What are the actions of insulin?
It is an anabolic hormone.
Acutely, it reduces blood glucose.
What are the actions of insulin in the liver?
In the liver:
Inhibits glycogenolysis.
Inhibits gluconeogenesis.
Stimulates glycogen synthesis.
Increases glucose utilisation (glycolysis).
The overall effect is to increase hepatic
glycogen stores.
Decreases protein catabolism and inhibits
oxidation of amino acids.
Increases the synthesis of fatty acid and
triglyceride and inhibits lipolysis.
What are the actions of insulin in muscle?
In muscle:
Increases the facilitated transport of glucose
via a transporter called Glut-4
Stimulates glycogen synthesis.
Stimulates glycolysis.
Stimulates the uptake of amino acids into
muscle and increases protein synthesis.
What are the functions of insulin in adipose tissue?
In adipose tissue: Increases glucose uptake by Glut-4. Enhances glucose metabolism to form glycerol, which is esterified with fatty acids to form triglycerides. Inhibits lipolysis.
What is the mechanism of action of insulin?
Insulin receptor:
• A large transmembrane glycoprotein
complex belonging to the tyrosine kinase linked receptor superfamily and
consisting of two α and two β subunits
• Receptor autophosphorylation-the first
step in signal transduction-is a
a consequence of dimerization, allowing
each receptor to phosphorylate the other.
• Insulin receptor substrate (IRS) proteins
undergo rapid tyrosine phosphorylation.
• Phosphorylated IRS interact with SH2 domain of phosphatidylinositol 3-kinase
and activate it. As a result recruitment of
insulin-sensitive glucose transporters
(Glut-4) from the Golgi apparatus to the
plasma membrane in muscle and fat cells
occurs.
• The longer-term actions of insulin entail
effects on DNA and RNA, mediated partly
at least by the Ras signalling complex
which regulates cell growth.
What are incretins?
Glucagon-like insulinotropic peptide (GIP) • Secreted by enteroendocrine cells in the duodenum and proximal jejunum. Glucagon-like peptide-1 (GLP-1)
• Secreted by enteroendocrine cells
more widely distributed in the
gut, including in the ileum and
colon as well as more proximally.
What is the action of these hormones?
Actions of these hormones: • An early stimulus to insulin secretion after food ingestion • Inhibition of pancreatic glucagon secretion • Slowing the rate of absorption of digested food by reducing gastric emptying Dipeptidyl peptidase-4 (DPP-4) • Terminates rapidly the actions of GIP and GLP-1.
What is diabetes mellitus?
Reduced (or absent)
secretion of insulin
Often coupled with insulin resistance (reduced sensitivity to its action) which is closely related to obesity
What is the difference between type 1 and 2 diabtes?
Type 1 diabetes Previously known as: Insulin-dependent diabetes mellitus-IDDM Juvenile-onset diabetes Pathogenesis: autoimmune process
Type 2 diabetes
Previously known as:
Non-insulin-dependent diabetes mellitus-NIDD
Maturity-onset diabetes
Pathogenesis: insulin resistance (which precedes overt
disease) and impaired insulin secretion
What are insulin preparations?
Insulin for clinical use was once either porcine or bovine
but is now human (made by recombinant DNA
technology).
What are the routes of administration of insulin preparation?
Routes of administration – as insulin is destroyed in the
gastrointestinal tract, it must be given parenterally:
Usually subcutaneously
Intravenously or occasionally intramuscularly in emergencies
What is the PK of insulin preparations?
PK
Plasma half-life of approximately 10 min.
Inactivated enzymatically in the liver and kidney; 10% -
excreted in the urine.
Renal impairment reduces insulin requirement.
How are insulins classified?
1. Insulins and analogs with fast onset and short duration of action • insulins Insulin Actrapid Insulin Actrapid Penfill Humulin R • analogs Insulin lispro Insulin aspart
2. Insulins with intermediate duration of action • monopreparations Humulin N Insulatard • insulin mixtures Insulin + Isophane insulin: Insulin Mixtard 10 (20, 30, 40, 50) Penfill Humulin M1 (M2, M3, M4) • mixtures of analogs Insulin lispro + Insulin lispro protamine: Humalog Mix 25, Humalog Mix 50
- Insulin analogs with long duration of
action
Insulin glargine
Insulin detemir
What do the insulin analogs do?
Insulin analogs:
Insulin lispro Acts more rapidly but for a shorter time than natural insulin
Insulin glargine Provides a constant basal insulin supply
What are the clinical uses of insulin?
Maintenance treatment for patients with type 1 diabetes:
Intermediate-acting preparation (e.g. isophane insulin) or a longacting analogue (e.g. glargine) is often combined with soluble insulin
or a short-acting analogue (e.g. lispro) taken before meals.
Insulin Actrapid (i.v.) in hyperglycemic emergencies (e.g. diabetic
ketoacidosis).
In type 2 diabetes in combination with oral drugs
Short-term treatment of patients with type 2 diabetes during intercurrent events (e.g. operations, infections, myocardial infarction).
During pregnancy, gestational diabetes is not controlled by diet alone.
Emergency treatment of hyperkalemia: insulin is given with glucose to
lower extracellular K+ via redistribution into cells.
What are some adverse reactions to insulin?
Hypoglycemia:
Treatment of severe
hypoglycemia - i.v glucose
and i.m. glucagon.
Allergy to human insulin –
unusual but can occur. It
may take the form of local
or systemic reactions.
Insulin resistance as a
consequence of antibody
formation – rare.
Lipodystrophy at the
injection site
What are the drugs used in type II diabetes mellitus?
- Biguanides
Metformin
2. Sulfonylureas Glibenclamide Gliclazide Glipizide Glimepiride
- Meglitinides
Repaglinide
Nateglinide - Thiazolidinediones
Pioglitazone - Alpha-glucosidase inhibitors
Acarbose
6. Inhibitors of DPP4 Sitagliptin Vildagliptin Linagliptin Saxagliptin
7. Incretin mimetics Exenatide Liraglutide Dulaglutide Lixisenatide
- Glucuretics
Dapagliflozin
Empagliflozin
Canagliflozin
What does metformin do?
Reduces hepatic glucose
production
(gluconeogenesis)
Increases glucose uptake and utilisation in skeletal muscle (i.e. it reduces insulin resistance)
Reduces carbohydrate
absorption
Reduces LDL and VLDL
What are the adverse effects of metformin?
Adverse effects
Gastrointestinal
disturbances (e.g. anorexia,
diarrhoea, nausea)
Lactic acidosis – a rare but potentially fatal toxic effect. Metformin should not be given to patients with: Reduced tissue oxygenation (repiratory and heart failure) Reduced drug elimination (renal or hepatic disease)
It does not cause
hypolgycemia!
What is the clinical use of metformin?
Clinical use:
Type 2 diabetes, especially
in obese patients
What are some examples of sulfonylureas?
Glibenclamide
Gliclazide
Glipizide
Glimepiride
What is the mechanism of action of sulfonylureas?
Mechanism of action:
Receptors for sulfonylureas on the KATP channels
Block by sulfonylurea drugs of KATP channel activation
Depolarisation
Ca2+ entry
Insulin secretion
What is the PK of sulfonylureas?
PK:
Oral absorption High binding to plasma proteins Renal excretion of the drugs or their active metabolites Cross the placental barrier
What are the ADRs and clinical uses of sulfonylureas?
Adverse drug reactions Hypoglycemia, especially in patient with renal imparment Weight gain –stimulate appetite Gastrointestinal upsets Allergic skin rashes can occur Bone marrow toxicity although rare, can be severe.
Clinical use
Type 2 diabetes
What are the drug interactions of sulfonylureas?
Drug interactions:
Drugs augmenting the hypoglycaemic effect (competition for metabolising enzymes, interference with plasma protein binding or with transport mechanisms for excretion): Non-steroidal anti-inflammatory drugs Coumarins Alcohol Some antibacterial drugs (including sulfonamides, trimethoprim and chloramphenicol) Some imidazole antifungal drugs
Agents that decrease the action of
sulfonylureas
Thiazide diuretics
Corticosteroids
What are meglitinides?
Repaglinide
Nateglinide
• Much less potent than most sulfonylureas
• Have rapid onset and offset kinetics
• Short duration of action
• Low risk of hypoglycemia
• Administered shortly before a meal to reduce the
postprandial rise in blood glucose in type 2
diabetic patients
• Less weight gain than sulfonylureas.
What are the effects of thiazolidinediones?
Effects: Reduce hepatic glucose output. Increase glucose uptake into muscle, by enhancing the effectiveness of endogenous insulin. Decrease triglycerides.
What is the mechanism of action of thiazolidinediones?
Mechanism of action:
Thiazolidinediones bind to a nuclear
receptor called the peroxisome
proliferator-activated receptor-γ (PPARγ),
which is mainly in adipose tissue, but also
in muscle and liver. It is complexed with
retinoid X receptor (RXR).
Thiazolidinediones cause the PPARγ-RXR complex to bind to DNA, promoting transcription of several genes with products that are important in insulin signalling. These include Glut-4.
PPARγ causes differentiation of
adipocytes, increases lipogenesis and
enhances uptake of fatty acids and
glucose.
What is the PK, ADRs, and clinical uses of thiazolidionediones?
PK:
Rapidly and nearly
completely absorbed
Metabolized in the liver
Adverse reactions: Weight gain and fluid retention: Contraindicated in heart failure Increased risk of fractures with chronic use.
Clinical use: In combination with metformin or with a sulfonylurea in patients whose blood glucose is inadequately controlled on one of these drugs
What are α-Glucosidase inhibitors
Acarbose
It delays carbohydrate absorption, reducing the
postprandial increase in blood glucose.
Adverse effects:
Flatulence, loose stools or diarrhoea, and abdominal
pain and bloating
Clinical use:
Like metformin, it may be particularly helpful in obese
type 2 patients, and it can be co-administered with
metformin.
What is an example of Incretin mimetics and related drugs?
Exenatide
Other incretin mimetics:
Liraglutide
Dulaglutide
Lixisenatide
What are the effects, ADRs, and clinical use of Exenatide?
A synthetic version of exendin-4, a peptide found in the saliva
of the Gila monster (a lizard disabling its prey by rendering
them hypoglycemic).
Effects – mimics the effects of GLP-1, but is longer acting:
Increases insulin secretion
Suppresses glucagon secretion
Slows gastric emptying
Reduces food intake (by an effect on satiety) and is associated
with modest weight loss.
Subcutaneous administration twice daily before the first and
last meal of the day.
Adverse effects:
Hypoglycemia
Gastrointestinal effects
Pancreatitis (rare but sometimes severe)
Clinical use:
Type 2 diabetes in combination with oral drugs
What are examples of gliptins?
Sitagliptin
Vildagliptin
Linagliptin
Saxagliptin
What do gliptins do?
Synthetic drugs that competitively inhibit dipeptidylpeptidase-4 (DPP-4), thereby potentiating endogenous incretins (GLP-1 and GIP).
Do not cause weight loss or
weight gain.
Well absorbed from the gut.
Used for type 2 diabetes, usually
in addition to other oral
hypoglycemic drugs
What are examples of glucuretics?
Dapagliflozin
Empagliflozin
Canagliflozin
A novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors
What is the mechanism of action of glucuretics?
Mechanism of action:
Inhibition the transporter protein SGLT2 in the kidneys
Reduction of renal glucose reabsorption
Urinary glucose excretion
Reduction if blood glucose levels
The efficacy of glucuretics is independent of insulin
secretion and action.
Used in the treatment of patients with type 2 diabetes.
An important addition to the therapeutic options for the
management of type 2 diabetes, particularly when used as
add-on therapy
Associated with reductions in body weight
What are the ADRs of glucuretics?
ADR:
Genital infections and urinary tract infections affecting
about 8–9% of patients.
In clinical trials patients taking dapagliflozin had
higher rates of breast cancer (nine cases versus none in
comparator arms) and bladder cancer (nine cases
versus one in placebo arm)
