Endocrine Drugs Flashcards
Indication of sulphonylureas
Type 2 diabetes mellitus is with diet and exercise
Example of sulphonylureas
Gliclazide
Glimepiride
Tolbutamide
Mechanism of action of sulphonylureas
- stimulates B cells of the pancreas to produce more insulin
- increases cellular glucose uptake and glycogenesis; reduces gluconeogenesis
- Binds to the high-affinity receptors on the ATP-sesnitve potassium (KATP) channells on B-islet cell plasma membranes, blocks resulting in Ca2+ entry and insulin release.
- gliclazide is short acting (12hrs approx)
Patient information of sulphonylureas
Compliance important
Maintain consistent diet
Avoid alcohol
Side effects sulphonylureas
Hypoglycaemia Rashes Vomiting Stomach pain Indigestion Weight gain (not recommended as first choice in obese patients)
Example of biguanide
Metformin
Indication of biguanides
Type 2 DM along with diet and exercise
- metabolic and reproductive abnormalities with PCOS
Mechanism of action of biguanides
- increases the activity of AMP dependent protein kinase (AMPK)
- this inhibits hepatic gluconeogenesis
- Increases glucose uptake and utilisation in skeletal muscle thereby reduces insulin resistance
- does not increase insulin production therefore will not cause hypoglycaemia
Pharmacokinetics/ pharmacodynamics of biguanides
- not recommended in pregnancy and renal failure (EGFR
Side effects of biguanides
- diarrhoea
- nausea and vomiting
- taste disturbances (metallic taste)
- lack of appetite
- risk of lactic acidosis in patients with renal failure
Patient information for biguanides
- take them at the same time everyday
- avoid alcohol
Example of thiazlidinediones
Pioglitazone
Mechanism of action of thiazolidinediones
- Bind to a nuclear receptor (peroxisome proliferator-activated receptor gamma PPARy)
- receptor complexed with retinoid X receptor
- receptor found mainly in adipose tissue (may be found in muscle and liver) - increases peripheral insulin resistance
- mediates differentiation of adipocytes, increases lipogenesis and enhances uptake of fatty acids + glucose (hyperinsulinaemia, hyperglycaemia, hypertriglycaeridaemia and HBA1c levels improved)
- drug changes PPARy-RXR complex so that it binds DNA and promotes transcription of several genes important in insulin signalling
Indication of Thiazolidinediones
Type 2 Diabetes (single, dual or triple therapy)
Side effects of TZDs
GI distrubance
headaches
weight gain
Hepatotoxicity
Patient information of TZDs
- Take with metformin or sulphonylureas
- Monitoring of LFTS recommended due to hepatotoxicity
The incretin effect
the increased stimulation of insulin secretion elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels.
Incretin hormones
- glucagon-like peptide 1 (GLP-1)
Gastric inhibitor peptide (GIP)
these hormones are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4)
Type of Incretin effect Drugs
- Mimic hormone secretion (incretin mimics)
2. Inihbit inactivation hormone ( DPP-4 inhibitors
DPP-4 inhibitors
- blocks the action of Didpeptidylpeptidase-4 enzyme that degrades incretin hormones, including glucago-like peptidde-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP)
- incretin hormones increase they synthesis and release of insulin from pancreatic B islet cells when blood glucose concentrations are normal or elevated
- Thus DDP-4 inhibitors increase the level of incretins and subsequently the level of insulin
Example of DPP-4 inhibitor
Sitagliptin, vildagliptin
Indication of DPP-4 inhibitor
Type 2 Diabetes mellitus
Side effects of DPP-4 inhibitors
GI distrubance
Upper respiratory tract infections
peripheral oedema
Pharmacokinetics/PD of DPP4 inhibitors
- avoud in pregnancy and breastfeeding
- may cause increase in plasma digoxin concentrations
Example of incretin mimic
GLP-1 agonists - exenatide
Mechanism of action of incretin mimic
- binds to and activates glucago-like peptide -1 (GLP-1) receptors,
- results in increased synthesis and secretion of insulin from pancreatic B islet cells
- action of exenatide is glucose-dependent therefore as plasma glucose fall, insulin secretion also reduces.
- Exenatide also suppresses the inappropriate secretion of glucagon
Indications for incretin mimics
Type 2 DM
Side effects of incretin mimics
GI disturbance
weight loss (potential benefit)
hypoglycaemia
injecion site reactions
PK/PD of incretin mimics
Exenatide may enhance the anticoagulant effect of warfarin
Actions of GLP-1 and GIP
GLP-1 and GIP act on the beta cells to increase insulin production to increase glucose uptake by peripheral tisues and decrease hepatic glucose production
GLP-1 also acts via the alpha cells to decrease glucagon release therefore decreasing hepatic glucose produciton
Example of SGLUT-2 inhibitor
Gliflozin
Mechanism of action of Gluflozin
-SGLUTs are responsible for mediating glucose reabsorption
SGLUT-2 is primary expressed in the kidney in the epithelial cells of the PCT
- dapaglifizon is a SGLUT-2 competitive inhibitor that acts to decrease renal absorption of glucose, promoting glycosuria and decreased blood glucose concentration
Synthesis of insulin
- Transcription of the insulin gene product and subsequent processing result in production of the full-length mRNA that encodes preproinsulin
- Together the leader sequence + the B, C and A domains constitute preproinsulin
- During translation of mRNA, leader sequence is cleaved in the lumen of the RER (rough endoplasmic reticulum)
- What remains is pro-insulin, which consists of B, C, A domains
- Beginning in the trans-golgi, proteases cleaves the pro-insulin at two sites
- Releasing the C peptide, + mature insulin molecule (contains A and B domains connected by disulphide bonds)
- The secretory granule contains equimolar amounts of insulin and the C peptide as well as smaller amounts of proinsulin
- Components are all released into the extracellular space
Biphasic release of insulin
Insulin release is a biphasic process.
- The initial amount of insulin released upon glucose absorption is dependent on the amounts available in storage.
- Once depleted, a second phase of insulin release is initiated. This latter release is prolonged since insulin has to be synthesized, processed, and secreted for the duration of the increase of blood glucose. Furthermore, beta cells also have to regenerate the stores of insulin initially depleted in the fast response phase.
Glucose triggering insulin release
- Glucose enters B cell through GLUT-2 receptor by facilitated diffusion. Amino acids enter through a different route
- In the presence of glucokinase, entering glucose undergoes glycolysis and raises ATP by phosphorylating ADP. Some amino acids also enter the citric acid cycle and produces similar changes in ATP and ADP. In both, ration of NADH/NAD+ ratio increases
- Increased ATP, Increased ADP/ATP ratio, Increased NADH/NAD+ ratio causes KATP channels to close
- Closure of K+ channel causes Vm to become more positive (depolarisation)
- Depolarisation activates voltage-gated Ca2+ channels to open
- Increased Ca2+ permeability leads to increased Ca2+ influx and increased intracellular free calcium , also evokes a calcium-induced-calcium release
- Elevated calcium leads to exocytosis and release into the blood of insulin contained within the secretory granules
Short acting insulin
insulin aspart - novorapid
Soluble insulin- Actrapid
Intermediate insulin
Isophane insulin (insulatard)
Long acting insulin
- Insulin glargine, inulin detemir
Mechanism of action of exogenous insulin
- exogenous insulin mimics the effects of endogenous insulin
- increases glycogenesis in the liver, adipose tissue and skeletal muscle
- reduces hepatic gluconeogenesis and glycoggenolysis
Indications for insulin
- DM
- Emergency management of hyperkaelamia
Side effects of insulin
- hypoglycaemia
- lipohypertrophy at sites of inject
Type of insulin regimens
Basal bolus regimen - (short acting insulin with each meal and long acting insulin overnight)
Twice daily regimen - Short and intermediate acting insulin given twice a day)
Ways insulin can be administered
pens
- more convenient and easier to transport that traditional sringe
- repeatedly more accurate dosages
- easier to use for those with impairments in visial and fine motor skills
- Less injection pain (as polished and coated needles are not dulled by insertion into a vial of insulin before a second insertion into the skin)
- Can be used without being noticed
Continuous subcutaneous Insulin infusion
- CSII or ‘pump therapy’ can potentially provide significant improvement in glycaemic control and quality of life for some people with Type 1 diabetes.
- Pumps make it easier to achieve glucose control with less danger of severe and incapacitating hypoglycaemia. However, the efficacy of this compared to SMBG is still debatable.
- Specific but infrequent complications of CSII therapy include reactions and occasionally infections at the cannula site, tube blockage and pump malfunction.
- CSII therapy is expensive, incurring costs for batteries, reservoirs, infusion sets, insulin, lancets, test strips and glucometers.
Examples of thionamides
- Carbimazole
- Propylthiouracil
Mechanism of action of carbimazole
- Prodrug that ndergoes metabolism to the active metabolite, thiamazole
- the latter inhibits the iodination of tyrosyl residues in thyroglobulin
- this is mediated through the enzyme thyroperoxidase and it also inhibits the coupling of iodotyrosones
- both actions inhibit thyyroid hormone production
Propylthiouracil mechanism of action
- inhibits the conversion of iodide to iodine which thereby interferes with the degradation of thyroglobulin and thereby reduces T3 and T4 production
Indication of thionamides
- hyperthyroidism
- thyrotoxoxis
- preparing patients for thyroid surgery
Side effects of thionamides
Rash
agranulocytosis
sore throat
Important PD/PK for thionamides
- Carbimazole is rapidly metabolised to thiamazole. The mean peak plasma concentration occurs one hour
- It crosses the placenta and can be found in breast milk
- The effect of anti-thyroid drugs can take several weeks to occur so are usually prescribed alongside a beta-blocker to reduce symptoms of hyperthyroidism
Patient information for thionamides
- Compliance is important
- Regular blood checks will be needed to monitor treatment response and renal, hepatic function and full blood counts
Levythyroxine mechanism of action
- Thyroxine increases the metabolic rate of all tissues in the body
- Synthetically prepared levo-isomer of thyroxine
- Acts like T4 and gets converted to T3 in the liver and kidney
- Maintain brain function, food metabolism, and body temperature, among other effects
Indication of synthetic thyroid hromone
- hypothyrodisim
- chronic lymphocytic thyroiditis
Side effects of synthetic thyroid hormone
- Chest pain
- Coma
- Diarrhoea
- Tachycardia
- Itching
- Muscle cramps
Important PK/PD of synthetic thyroid hormones
- Primarily eliminated by the kidneys
- Intravenous formulations are available
- The half-life is long (6 to 7 days) so thyroid function should be rechecked 6 weeks after a dose adjustment
Patient information on synthetic thyroid hormones
Take 30-60 minutes before breakfast
