Diabetes Flashcards
MoA of Incretins GLP-1 and GIP
Stimulated by food –> secreted from the GI tract –> increase β-cell proliferation (in the pancreas) -> increases insuline release –> increases cellular glucose uptake (in the liver & adipocytes)
MoA of GLP-1 alone
stimulated by food –> released from the GI tract –> α-cell proliferation (in the pancreas) –> supresses glucagon secretion –> supressse glucose production (in the liver) –> Decreased hepatic glucose output
Actions of incretins are terminated by?
DPP-4 (dipeptidyl peptidase-4)
Diabetes mellitus is characterised by ——–
Hyperglycaemia
Type 1 diabetes vs Type 2
Type 1 Diabetes
* Absolute deficiency of insulin resulting from
autoimmune destruction of pancreatic β cells
* Insulin is essential for its treatment
Type 2 Diabetes (T2D)
* Insulin resistance
* Impaired insulin secretion
* Excess glucagon
1st line tx for DM type 1
Insulin (SC injection)
1st line tx for type 2 DM
Metformin (oral)
CU of Insulin
Type 1 DM treatment
*SAFE IN GESTATIONAL DIABETES
Why is insulin not adm orally?
destroyed in the GI tract
(so we give it SC, IM ,IV)
* IV–> hyperglycemic emergency
What do give pateints during a hyperglycemic emergency?
IV insulin
(used immediatly before the start of a meal)
Short-acting insulin
lispro,
aspart,
glulisine
girls and lads
Adm of Short-acting insulin
Injected before a meal
Long-acting Insulin
- neutral protamine hagedorn (NPH; insulin
isophane); - glargine;
- determir;
- degludec
dani does great Nan
Adm of Long-acting insulin
Dosage regimens may vary
* Multiple daily injections
* Rapid-acting analogues given with meals
* Basal insulin analogues injected once daily (often at night)
Adm of Soluble insulin
IV emergency (diabetic ketoacidosis)–> Used immediately before the start of a meal
AE of insulin
HYPOGLYCAEMIA
* Weight gain
* Lipohypertrophy at injection site (change site of injection)
* Allergy and insulin resistance are rare
MoA of Metformin
Activation of AMP-dependent protein kinase (AMPK) –> Reduces hepatic glucose production (gluconeogenesis)
AE of Metformin
- less likely to cause hypoglycaemia
- weight loss
- Dose-related gastrointestinal disturbances (e.g. anorexia, diarrhoea, nausea)
- Lactic acidosis is rare but potentially fatal
- Long-term use may interfere with absorption of vitamin B12
Contraindications of Metformin
1) severe renal (excreted unchanged in urine) or hepatic disease,
2) hypoxic pulmonary disease,
3) shock or decompensated heart failure
why? causes Lactic acidosis (due to reduced drug elimination) which is fatal
CU of Metformin
-
T2D esp Obese patients
(may promote weight loss and reduce Cardiovascular events and death) - Can be combined w/ other during in dual or triple therapy
others drug calsses used in combo treatment of Diabtes (Esp type 2)
1) Sulfonylureas (1st/ 2nd gen)
2) Thiazolidinediones
3) GLP-1 mimetics
4) DPP-4 inhibitors
5) SGL T-2i
1st generation Sulfonylureas
Tolbutamide
Chlorpropamide (more sever AE, not used anymore)
-amide
Chlorpromaide vs Tolbutamide
Chlorpromaide -> longer-acting , can cause sever Hypoglycaemia
Tolbutamide –> shorter-acting, less sever AE
AE of Chlorpropamide
- Can cause sever hypoglycaemia
- Flushing after alchohol(because of a disulfiram-like effect)
- ADH action: hyponatraemia and water intoxication
2nd generation Sulfonylureas
Glibenclamide (glyburide), glipizide,
glimepiride,
gliclazide
- 4 Gli’s
which is more potent 1st gen or 2nd gen Sulfonylureas
2nd generation
MoA of Sulfonylureas
Inhibit Katp channels on β-cells -> depolarization -> Ca+2 entery -> Insulin release
AE of Sulfonylureas
1) Hypoglycemia
Can be severe and prolonged (Highest risk: chlorpropamide, glibenclamide, Low risk: tolbutamide)
2) Weight gain
3) GI upset less common
4) Allergic skin rashes and bone marrow toxicity
- Sulfonamide moiety
Contraindications fo Sulfonylureas
PREGNANCY + Breastfeeding
- Glyburide (and metformin) can be considered in pregnancy
CU of Sulfonylureas
1) Early treatment of T2D
(Not useful in T1D or late-stage T2D–> Require functional B cells)
2) Can be used as Monotherapy if metformin is
contraindicated or not tolerated
3) Can be combined with other drugs in dual or
triple therapy
Why are sulfonylureas not useful in T1D or late-stage T2D?
They Require functional B cells to work
(drug) is superior in terms of CV disease prevention
Metformin
Thiazolidinediones
aka GLITAZONES
Ciglitazone
troglitazone
Pioglitazone (only drug lisenced in Europe)
- not used anymore due to sever AE
MoA of Glitazones (Thiazolinediones)
- PPARγ-RXR Activation
- Binds to DNA: transcription of several genes
- Effects are slow in onset (1-2 months after start of treatment)
Where are PPARγ found
adipose tissue, muscle and liver
MoA of PPARγ in adipose tissue
- Decreases plasma triglyceride levels
- Increases lipogenesis and enhances uptake of fatty acids and glucose
- Differentiation of adipocytes
MoA of PPARγ in muscles and liver
- Reduced hepatic glucose output
- Increased glucose uptake into muscle
- Enhanced effectiveness of endogenous insulin (insulin sensitizers): lowers exogenous insulin requirements
AE of Thiazolidinediones (Glitazones)
1) Weight gain
2) Fluid retention
-Promotes Na+ reabsorption in collecting ducts
-Contraindicated in heart failure
3) Increased cardiovascular risk
4) Increased risk of fractures with chronic use
(Shunting of mesenchymal cells into adipocyte lineage and away of osteogenesis)
5) Other symptoms: headache, fatigue, GI disturbances
Contraindications of Glitazones
1) HF –> due to fluid retention
2) Pregnancy
3) breastfeeding
4) children
CU of Thiazolidinediones
* clincily not used anymore expect for Pioglitazone in EU
1) monotherapy when metformin is contraindicated
2) In additive with other oral hypoglycaemic drugs
3) may lessen the progression of impaired glucose tolerance in diabetes
4 May reduce the need for exogenous insulin in
T2D
GLP1- Mimetics
Exenatide, liraglutide, duraglutide,
lixisenatide, semaglutide
-tide
MoA of GLP-1 Mimetics (Exenatide, Liraglutadine, lixisenatide)
Mimic effects of GLP-1: longer acting
1) Increase insulin secretion
2) Suppress glucagon secretion
3) Slow gastric emptying
4) Reduce food intake (by an effect on satiety)
-Associated with modest weight loss
Adm of GLP-1 mimetics
SC administration
- Administered before the first and last meal of the day
- Modified Release (MR) formulation: once weekly
injections
AE of GLP-1 mimetics
1) Hypoglycaemia
2) GI effects
3) Pancreatitis is a rare but sometimes severe problem
4) weight loss
CU fo GLP-1 mimetics
1) In T2D, in combination with other drugs when inadequate
2) Recommended in patients with atherosclerotic
cardiovascular disease, high cardiovascular risk,
kidney disease or heart failure (in addition to
metformin)
-Cardiovascular benefits
3) Recommended in obese patients, who have
failed on dual therapy
DPP-4 inhibitors
sitagliptin,
vildagliptin,
saxagliptin,
linagliptin
MoA of DPP-4 inhibitors
Competitively inhibit DPP-4
–> Potentiate endogenous incretins (GLP-1 and GIP)
Adm of DPP-4 inhibitors (-agliptin)
oral
AE of DPP-4 inhibitors (-agliptin)
Generally well-tolerated
* Less propensity for hypoglycaemia
* GI side effects
Less common but potentially serious:
* Occasional liver disease
* Worsening of heart failure (peripheral oedema)
* Pancreatitis
CU fo DPP-4 inhibitors
- Combination therapy with metformin (and/or other antihyperglycaemic agents) if blood glucose is not adequately controlled
- As monotherapy if metformin is contraindicated or not tolerated
Sodium-Glucose Co-Transporter 2 inhibitors (SGLT 2-i)
Canagliflozin,
dapagliflozin,
empagliflozin
MoA of SGLT 2-i
Block SGLT-2 in proximal tubule
* Increased glucose excretion
* Increased osmotic natriuresis
- Decrease in weight and blood pressure
- Reduced preload
- Reduced intra-glomerular pressure
SGLT-2i have benefits in?
Benefits in renal and CV outcomes in CKD, HF
*CKD: chronic kideny disease
AE of SGLT-2i
1) Polyuria
2) UTIs
3) Vaginal yeast infections
4) Hyperkalaemia
5) Volume depletion (orthostatic hypotension)
* uti and infection because glucose in urine
CU of SGLT-2i
1) T2D, usually in combination with other anti-diabetic drugs (e.g. metformin, insulin)
2) Monotherapy if metformin is not tolerated
3) Recommended in patients with atherosclerotic cardiovascular disease, high cardiovascular risk, kidney disease or HF (in addition to metformin)
3) Symptomatic chronic HF with reduced ejection fraction, inadequately controlled with a β-blocker, ACEI/ARB, and an aldosterone antagonist
4) CKD with albuminuria, alongside an ACEI/ARB
Diabetes Management
- Use of metformin as the optimal first-line drug unless contraindicated
- After metformin, the use of 1 or 2 additional oral or injectable agents, with a goal of minimizing adverse effects if possible
- A major focus on comprehensive cardiovascular risk reduction
