Antidiabetic drugs Flashcards
What are the two groups of D.M?
type 1: insulin dependent D.M
type 2: non-insulin dependent D.M
describe Type 1 D.M…
deficiency of insulin.
- autoimmune attack of beta cells of the pancreas -> gradual depletion of beta cell population -> sx’s appear when 80-90% destroyed -> pancreas fails to respond to ingestion of glucose
what is expected in glucose-induced insulin release test for normal subjects, type 1 D.M, and type 2 D.M?
normal subjects: see a huge rise of plasma insulin when infused of glucose.
Type 1 D.M: see no rise of plasma insulin.
Type 2 D.M: see a slow rise of plasma insulin but below normal subjects.
what are the characteristics of type 1 D.M?
- elevated blood glucose and ketone bodies.
- virtually no insulin secretion
- rely on exogenous insulin injxn SC to control hyperglycemia and avoid ketoacidosis
what are the characteristics of type 2 D.M?
- most common
- combination of insulin resistance and dysfunction beta cells.
- insulin levels may be high, esp early in the disease. but peripheral insulin resistance and increased liver production of glucose make insulin levels inadequate to normalize plasma glucose levels.
- insulin production then falls -> no longer compensate for insulin resistance, hyperglycemia develops.
- metabolic alterations are milder than type 1 D.M
- insulin secretion is enough to restrain ketogenesis.
- HYPERGLYCEMIA but NO KETOACIDOSIS
describe insulin…
- small protein
- 2 polypeptide chains connected by disulfide bonds.
describe insulin secretion…
- released from beta cells at a low basal rate and much higher rate in response to a variety of stimuli.
- stimulated by: glucose, amino acids and GI hormones (incretins)
what is the incretin effect?
glucose given orally results in higher insulin levels than glucose given IV. This is b/c incretins, released by the gut, enhance insulin secretion.
what is the mechanism of insulin secretion in beta cells?
Glucose enters via GLUT transporter -> increased glycolysis and citric acid cycle -> elevated ATP -> closes Katp channel -> less K leaves cell -> cell depolarizes -> Ca channel opens -> Ca entry triggers exocytosis and insulin is secreted.
describe insulin receptor…
- two covalently linked heterodimers.
- each contains an alpha subunit and a beta subunit.
- alpha = extracellular and recognition site for insulin.
- beta = spans the membrane and contains a tyrosine kinase.
how is insulin receptor activated?
- insulin binds to alpha subunit, the tyrosine kinase is activated in the beta subunit -> phosphorylation of tyrosine residues on beta subunit and the cytoplasmic proteins.
what are the effects of insulin on its targets?
- glucose entry in muscle and adipose tissue via GLUT4.
- glycogen synthesis in liver and muscle.
- F.A synthesis and storage as TAG in adipose tissue
- glycolysis
- A.A uptake by muscle
- inhibit gluconeogenesis.
what are the sources of insulin?
- isolated insulin from beef or pork pancreas.
2. recombinant DNA technology using strains of E.coli or yeast.
what are the different types of insulin preparations?
- rapid-acting: fast onset and short duration
- short-acting: rapid onset of action
- intermediate-acting.
- long-acting: slow onset of action
what are the rapid-acting insulins?
- insulin Lispro
- insulin Aspart
- insulin Glulisine
- insulin Lispro
- insulin Aspart
- insulin Glulisine
chemistry?
- native insulin monomers are associated as hexamers
- problem: slow the absorption of insulin
Insulin Lispro
chemical differences compared to insulin B-chain?
28th position: Pro replaced by Lys
29th position: Lys replaced by Pro
Insulin Aspart
chemical differences compared to insulin B-chain?
28th position: Pro replaced by Asp
Insulin Glulisine
chemical differences compared to insulin B-chain?
3rd position: Asp replaced by Lys
29th position: Lys replaced by Glu
- insulin Lispro
- insulin Aspart
- insulin Glulisine
PD and PK?
- mimic the prandial release of insulin.
- given along c a longer acting insulin to assure proper glucose control.
- SC, IV
- give 15mins before a meal
Short-acting insulins
PD and PK?
- regular insulin
- soluble crystallin zinc insulin
- given 30mins before a meal
- SC, IV in emergencies.
what is the intermediate-acting insulins?
Neutral protamine Hagedorn (NPH) - aka isophane insulin.
Neutral protamine Hagedorn (NPH) - aka isophane insulin
PD and PK?
- suspension of crystalline zince insulin combined c protamine.
- SC
- used for basal control.
- given along c rapid- or short-acting insulin for mealtime control.
what are the long-acting insulins?
- Insulin Glargine
2. Insulin Detemir
Insulin Glargine
Chemical difference compared to insulin A-chain?
21st position: Asn replaced by Gly
Insulin glargine
Chemical difference compared to insulin B-chain?
extra Arg-Arg at the end.
How does Insulin glargine get into the Blood?
injxn of an acidic sln (pH 4) -> precipitate in SC tissue -> slow dissolution of free glargine hexamers -> dimers -> monomers -> dimers and monomers can enter capillary membrane -> blood.
Insulin Detemir
Chemical difference compared to insulin B-chain?
29th position: Lys with additional N-C=O-R chain.
What is the difference between insulin analogs vs human insulin preparations?
regimens based on rapid- and long-acting insulin analogs improve HbA1c levels and reduce hypoglycemia compared c regimens c regular insulin and NPH insulin.
What are some ways of insulin administrations?
- syringe
- insulin pen
- insulin pump
- IV
- inhaled
when is best to use IV insulin?
- pts c ketoacidosis, during perioperative period, during labor and delivery, and in Intensive Care situations.
- use regular human insulin
Inhaled insulin
PD and PK?
- dry powder formulation or regular human insulin
- for adults c type 1 and 2 D.M
- peak levels reached in 12-15mins and decline to baseline in 3 hrs.
Inhaled Insulin
A.E and contraindications?
- cough, throat pain, hypoglycemia
- pulmonary function should be monitored.
- pts c asthma, COPD, and smokers.
what is the insulin secretion pattern in the pancreas?
secretes boluses of insulin in response to meals.
b/w meals and throughout the night, secretes small amounts to suppress lipolysis and liver glucose output.
what are the two methods to achieve a similar insulin secretion pattern?
- Basal-Bolus insulin regimens
2. insulin pump therapy
Basal-Bolus Insulin regimens
uses?
- long-acting insulin can be given at bedtime or in the morning.
- if pt skips a meal, omit a premeal bolus.
- if eat a larger meal than usual, increase the premeal bolus.
- dose adjustments can be made to accommodate snacks, exercise patterns, and acute illnesses.
Insulin pump therapy
uses?
- mimic normal insulin secretion
- battery-operated pump and a computer that programs the pump to deliver predetermined amounts of insulin.
What are the insulins used in insulin pump?
- glulisine
- lispro
- aspart
what are the A.E of using insulin therapy?
- hypoglycemia (when overdose)
higher risk in regular insulin than rapid-acting.
higher risk in NPH insulin than long-acting. - Allergic rxns (often d/t noninsulin protein contaminants)
- Lipodystrophy at injxn sites
How to manage hypoglycemia from insulin overdose?
mild case: orange juice, glucose or any sugar-containing bev or food.
severe case (unconsciousness or stupor): IV glucose infusion.
glucagon SC or IM if IV not avail.
What are some of the drug interactions that cause hypoglycemia?
- Ethanol
- Beta blockers
- salicylates
How does EtOH cause hypoglycemia w/ insulin therpay?
inhibits gluconeogenesis.
How does beta blockers cause hypoglycemia w/ insulin therpay?
blocking the effects of catecholamines on gluconeogenesis and glycogenolysis.
also mask the sympathetically-mediated sx’s of hypoglycemia (i.e tremor and palpitations).
How does salicyclates cause hypoglycemia w/ insulin therpay?
enhancing pancreatic beta cell sensitivity to glucose and potentiating insulin secretion.
weak insulin like action in the periphery.
What are some of the drug interactions that cause hyperglycemia by acting on peripheral tissues that counter the actions of insulin?
- epi
- glucocorticoids
- atypical antipsychotics
- HIV protease inhibitors.
What are some of the drug interactions that cause hyperglycemia by inhibiting insulin secretion directly?
- phenytoin
- clonidine
- Ca- channel blockers.
What are some of the drug interactions that cause hyperglycemia by inhibiting insulin secretion indirectly?
Diuretics via depletion of K.
What is the management of Diabetes in Hospitalized pts?
d/c oral anti-diabetics and replaced c insulin.
oral agents can be restarted on discharge.
what are some of the non-insulin antidiabetic agents?
- Insulin secretagogues: sulfonylureas & Meglitinides
- Biguanides
- Thiazolidinediones (TZDs)
- alpha- glucosidase inhibitors
- incretin analogs
- inhibitors of DPP-IV
- amylin analogs
- bile-acid sequestrants
- SGLT2 inhibitors.
What are two insulin secretagogues?
- Sulfonylureas
2. Meglitinides
sulfonylureas
MOA?
stimulate insulin release from beta cells
binds to SUR1 subunit and block ATP-sensitive K channel in cell membrane
What are the two first generation sulfonylureas?
Tolbutamide
Chlorpropamide
Tolbutamide
PK and A.E?
short duration of action
Prolonged hypoglycemia occurs rarely
Chlorpropamide
PK and A.E?
- long half life
- hypoglycemia = contraindicated in elderly pts.
- hyperemic flush c EtOH d/t inhibition of aldehyde dehydrogenase.
- potentiate action of vasopressin -> elicit SIADH.
What are the three second generation sulfonylureas?
- glyburide (glibenclamide)
- Glipizide
- Glimepiride
- glyburide (glibenclamide)
- Glipizide
- Glimepiride
PK and A.E?
- more potent than first gen.
- lack some a.e and drug interactions of first gen. - hypoglycemia
- weight gain.
Glyburide
A.E?
hypoglycemia 20-30%
Glipizide
PK and A.E?
shortest half life of the more potent agents
Less hypoglycemia
Glimepiride
A.E?
hypoglycemia 2-4%
approved for once-daily use.
what are the two meglitinides?
- repaglinide
2. nateglinide
Meglitinides MOA?
stimulate insulin release by binding to SUR1 and inhibiting ATP-sensitive K channel.
not as effective as sulfonylureas in reducing FPG and HbA1c levels.
- repaglinide
- nateglinide
PK and PD?
- rapid onset and short duration of action
- postprandial glucose regulators
- rapidly absorbed and cleared.
- taken before each meal, if meal is missed the drug must be omitted.
- repaglinide
- nateglinide
A.E?
Hypoglycemia - repaglinide
less hypoglycemia - nateglinide
weight gain - both
no sulfur = good for pts c sulfur or sulfonylurea allergy
what is one biguanides and its features?
Metformin
- cause insulin secretion
- does not cause hypoglycemia, even in large doses
- equivalent to sulfonylureas in reducing FPG and HbA1c levels.
Metformin
MOA?
- inhibiting gluconeogenesis by reducing gene expression of gluconeogenic enzymes
- increases insulin mediated glucose utilization in muscle and liver.
- activation of AMP-activated protein kinase (AMPK)
Metformin
Indications?
- FIRST LINE AGENT in type 2 DM
- use alone or in combo c sulfonylureas, TZDs and/or insulin.
Metformin
A.E?
- GI: anorexia, nausea, vomiting, abd discomfort, diarrhea
- interfere c B12 absorption
- lactic acidosis
Metformin
contraindications?
- renal disease
- hepatic disease
- hypoxia
- alcoholism
What are the two Thiazolidinediones (TZDs)?
- Pioglitazone
2. Rosiglitazone
- Pioglitazone
- Rosiglitazone
MOA?
- decrease insulin resistance.
- agonists of peroxisome proliferator-activated recpetor gamma (PPAR-gamma) - intracellular receptor in muscle, fat, and liver.
- promote glucose uptake and utilization in adipose tissue.
- less effective in decreasing FPG and HbAc1 compared to sulfonylureas and metformin
- mechanism involves gene regulation
- slow onset and offset of activity over weeks or even months.
how is pioglitazone better than rosiglitazone in the effects of lipids?
sig improvement in: HDL TG LDL particle concentration LDL particle size
- Pioglitazone
- Rosiglitazone
A.E?
- fluid retention
- weight gain
- edema
- exacerbation CHF - contra in Class III and IV HF.
- must monitor liver function
what are the two alpha-glucosidase inhibitors?
- acarbose
2. miglitol
- acarbose
- miglitol
MOA?
inhibit intestinal alpha-glucosidases -> reduce postprandial digestion of starch and disaccharides -> decrease hyperglycemia and hyperinsulinemia -> modest drop in HbAc1 and FPG.
- acarbose
- miglitol
A.E?
- flatulence
- diarrhea
- abd pain
- acarbose
- miglitol
contraindications?
- IBS
- intestinal condition worsened by gas and distension
what is acarbose associated with?
reversible hepatic enzyme elevation
required liver funct monitoring.
define diabetes mellitus…
elevation of fasting blood glucose caused by a relative or absolute deficiency in insulin.
what is an encretin analog?
Exenatide
describe Exenatide…
- analog of GLP-1
- derived from salivary gland of the Gila monster
- injectable
- full agonist at human GLP-1 receptor
- resistant to dipeptidyl peptidase IV (DPP-IV)
exenatide
action of beta cells?
glucose in gut lumen stimulates incretin secretion -> enhance glucose-stimulated insulin secretion in beta cells.
exenatide
MOA?
- enhances glucose-dependent insulin secretion.
- suppresses postprandial glucagon release
- slows gastric emptying
- decrease appetite
- may stimulate beta-cell proliferation
exenatide
clinical applications?
type 2 D.M in adults
exenatide
A.E?
- nausea, vomiting, and diarrhea
- acute pancreatitis
exenatide
contraindications?
pts c gastroparesis
Name the inhibitor of DDP-IV?
Sitagliptin
Sitagliptin
MOA?
- selective inhibitor of DPP-IV
- increases circulating GLP-1 and insulin levels.
sitagliptin
clinical applications?
type 2 d.m in adults.
sitagliptin
A.E?
- pancreatitis
- hypersensitivity rxns:
urticaria
angioedema
anaphylaxis
Stevens-Johnson syndrome
name the amylin analog?
pramlintide
pramlintide
MOA?
- inhibits food intake
- gastric emptying
- glucagon secretion
what is amylin?
co-secreted c insulin from pancreatic beta-cells.
pramlintide
clinical uses?
adjunctive to insulin
Name a bile-acid sequestrants?
colesevelam
colesevelam
MOA?
lower LDL cholesterol
mechanism is unclear
colesevelam
clinical applications?
type 2 DM
Name a SGLT2 inhibitor?
Canagliflozin
What action is SGLT2?
reabsorption of glucose in the proximal tubule of the kidney.
Canagliflozin
MOA?
- blocks SGLT2 -> decreased glucose reabsorption, increase execretion -> decrease blood glucose
Canagliflozin
A.E?
- Genital and urinary tract infxns
- osmotic diuresis -> vol depletion, increased serum creatinine levels, hyperkalemia, hypermagnesemia, hyperphosphatemia, hypotension
anagliflozin
contraindications?
pts c GFR
What is the preferred monotherapy for Type 2 D.M?
Metformin
What is best therapy for HbA1c >9%?
combination of two non-insulin agents or c insulin itself.
What happens if monotherapy does not achieve HbA1c goal over 3mos?
add a second agent (Dual combo therapy)
- oral agent, exenatide, or insulin
What is the next step if the two-drug combo fails?
add a third agent (triple combo therapy)
- insulin most likely
describe the transition to insulin therapy?
- begun at a low dose c a single injxn of basal insulin.
- either NPH, glargine, or detemir
- then dose is uptitrated.
What is the step if significant postprandial glucose excursions occur?
add prandial insulin therapy c shorter-acting insulins.
– lispro, aspart, or glulisine.
When is insulin be warranted as initial therapy in type 2 DM?
- sig hyperglycemia sx’s
- ketonuria
- HbA1c >10%
- random glucose >300mg/dL
How to manage HTN in diabetes complications?
ACE inhibitor or an ARB.
How to manage dyslipidemia in diabetes complications?
Statins given regardless of lipid level.
given:
1. c overt CVD
2. s CVD who are >40y.o and c one or more other CVD risk factors.
(fam hx, HTN, smoking, dyslipidemia, or albuminuria)
How to manage coagulation in diabetes complications?
aspirin
How to manage nephropathy in diabetes complications?
ACE inhibitors or ARBs when pts have albuminuria.
How to manage neuropathic pain in diabetes complications?
- amitriptyline
- pregabalin
- gabapentin
- duloxetine
- venlafaxine
- valproate
- opioids
How to manage gastroparesis in diabetes complications?
metoclopramide or erythromycin
How to manage erectile dysfunction in diabetes complications?
phosphodiesterase type 5 inhibitors
How to manage foot infxns in diabetes complications?
common = staph
emperic abs therapy target gram+ cocci.
what is the DOC to tx pregnant females c D.M?
regular insulin
describe glucagon…
peptide hormone synthesized by pancreatic alpha cells.
what are the functions of glucagon?
(+): glycogen degradation gluconeogenesis fatty acid oxidation insulin release cardiac inotropy & chronotropy relaxation of the intestine (in large doses)
(-): glycolysis
glucagon
uses?
- severe hypoglycemia
- radiology of the bowel
- beta blocker poisoning
- glucagon C-peptide test
