The mosteffective management of diabetes
mellitus demands an interprofessional approach
involving both lifestyle modifications with diet
and exercise and pharmacologic therapies as
necessary to meet individualized glycemic goals.
Lifestyle modifications must be combined with
oral pharmacologic agents for optimal glycemic
control, particularly as type 2 diabetes mellitus
progresses with continued loss of pancreatic
beta-cell function and insulin production.
Oral hypoglaecimics drugs include
Introduction
Oral hypoglycaemicagents can further be classifiied
broadly as;
1. Insulin secretagogues –These are drugs which increase the
amount of insulin secreted by the pancreas. Includes:
Sulfonylurea drugs,
Meglitinide analogues
2. Insulin sensitizers- they lower blood sugar by increasing the
muscle, fat and liver's sensitivity to insulin. They include:
Biguanides
Thiazolidinediones
Others -Alpha glucosidase inhibitors, Dipeptidyl peptidase-
4(DPP-4) inhibitors
Mechanism of actionof sulfonylureas:
Stimulate insulin release from functioning B
cells by blocking of ATP-sensitive K channels
resulting in depolarization and calcium
influx(Hence, not effective in totally insulin-
deficient pts (type-1).
They potentiate insulin action on target tissues.
They cause reduction of serum glucagon
concentration.
8.
Pharmacokinetics of sulfonylureas:
Orally, well absorbed.
Reach peak concentration after 2-4 hr.
All are highly bound to plasma proteins. Duration
of action is variable.
Second generation has longer duration than first
generation.
Metabolized in liver and excreted in urine
Cross placenta, stimulate fetal B cells to release
insulin hypoglycemia at birth
→
First generation sulfonylureas
Tolbutamide: safe for old diabetic patients or pts
with renal impairment.
Availability
Chlorpropamide (dibonis) 250mg
Currently rarely available
Availabilty
Glipizide isa 2.5 mg to 10 mg tablet, taken as a single dose or in two
divided doses, 30 minutes before breakfast.
Glimepiride is available as 1 mg, 2 mg, or 4 mg tablets, taken once a
day with breakfast or twice a day with meals.
For patients at increased risk for hypoglycemia, such as older
patients or those with chronic kidney disease, the initial dose could
be as low as 0.5 mg daily.( Glypin/ amaryl)
Glyburide is available as 1.25 mg, 2.5 mg, or 5 mg tablets, taken as
a single dose or two divided doses.
Glibenclamide5mg tabs-(nogluc)-2.5mg daily before the first meal
increased by 2.5mg till blood sugar is under control
Gliclazide-30/60mg(controlled release) -30mg to 120mg daily after
breakfast (diamicron MR-30/60MG)
Non controlled release- gliclazide 80mg
Gliclaz m-gliclazide +metformin
13.
Uses of sulfonylureas
Type II diabetes: monotherapy or in combination
with other antidiabetic drugs.
Unwanted/adverse effects:
Hyperinsulinemia & Hypoglycemia:
Weight gain due to increase in appetite
CNS- Syncope , dizziness , nervousness , anxiety ,
depression, hypoesthesia , insomnia paresthesia ,
drowsiness headache, diaphoresis
GIT-diarrhea , flatulence , dyspepsia , and vomiting
pruritus , increased lactate dehydrogenase,
e.g. Repaglinide
Rapidly acting insulin secretagogues
Mechanism of Action:
They are Insulin secretagogue as sulfonylureas
Pharmacokinetics of Meglitinides
Orally, well absorbed.
Very fast onset of action, peak 1 h.
short duration of action (4 h).
Metabolized in the liver & excreted in bile
- Meglitinide analogues
16.
Uses of Meglitinides
Type II diabetes: monotherapy or combined with other
antidiabetic drugs.
Patients allergic to sulfonylurea
Administration/availability
Repaglinide is available as 0.5 mg, 1 mg, or 2 mg tablets,
taken orally in two to three divided doses per day.
Adverse effects of Meglitinides e.g Repaglinide:
Hypoglycemia
weight gain
Headache
upper respiratory tract infection
Cardiovascular- ischemia .
17.
1. Biguanides, e.g.Metformin
2. Thiazolidinediones, e.g. pioglitazone
- Biguanides E.g. Metformin
Mechanism of action of metformin
Does not stimulate insulin release.
Increases liver,muscle &adipose tissues sensitivity to
insulin & increase peripheral glucose utilization.
Inhibits gluconeogenesis.
Impairs glucose absorption from GIT.
2. Insulin sensitizers
18.
Pharmacokinetics of metformin
orally.
Not bound to serum protein.
Not metabolized.
t ½ 3 hours.
Excreted unchanged in urine
Uses of metformin
Obese patients with type II diabetes Monotherapy or
in combination.
Advantages:
No risk of hyperinsulinemia or hypoglycemia or
weight gain.
19.
Adverse effects ofmetformin
Metallic taste in the mouth
GIT disturbances: nausea, vomiting, diarrhea flatulence
Long term use interferes with vitamin B 12
absorption-- vitamin B12 deficiency.
chest discomfort, flushing, palpitation, headache,
chills, dizziness, diaphoresis,
nail disease, skin rash, Also, in less than 1% of
patients,
It causes lactic acidosis, which can be life-threatening,
and it is precipitated by conditions predisposing to
hypoperfusion and hypoxemia, such as severe renal
failure
20.
Contraindications of metformi
Hypersensitivity to the drug.
Any type of acute metabolic acidosis(such as lactic
acidosis and diabetic ketoacidosis)
Diabetic pre-coma.
Severe renal failure(GFR<30 ml/min)
Acute conditions with potential to alter renal function
such as:dehydration,severe infection,shock.
Liver disease.
Alcoholism.
Heart failure
21.
Availability
Metformin isthe initial drug of choice in
patients with type 2 diabetes mellitus.
It is given orally in 500 to 1000 mg tablets twice
a day.
Common brands Glucophage 500mg/1g
tabs,Glucomet 500mg/1g tabs
22.
- Thiazolidinediones (glitazones)
E.g. Pioglitazone
Mechanism of action
They increase sensitivity of target tissues to insulin.
Increase glucose uptake and utilization in muscle and adipose
tissue.
Pharmacokinetics of pioglitazone
Orally (once daily dose).
Highly bound to plasma albumins (99%)
Slow onset of activity
Half life 3-4 h
Metabolized in the liver
Excreted in urine 64% & bile
23.
Uses of pioglitazone
Type II diabetes with insulin resistance.
Used either alone or combined with sulfonylurea, biguanides or
insulin.
No risk of hypoglycemia when used alone
Adverse effects of pioglitazone
Hepatotoxicity ?? (liver function tests for 1st year of therapy).
Fluid retention (Edema).
Precipitate congestive heart failure
Mild weight gain.
hypoglycemia
headache,
bone fracture (decreased osteoblast activity) , myalgia
sinusitis and pharyngitis
24.
Availability
Pioglitazone isgiven as 15 mg, 30 mg, or 45 mg tablets
daily.
Common brand-Piogluc 15mg/30mg tabs
Rosiglitazone, while rarely used, is given as 2 mg, 4
mg, or 8 mg daily.
Contraindications
Hypersensitivity to the drug
New York Heart Association Class III or IV heart failure
serious hepatic impairment
bladder cancer, history of macroscopic hematuria
pregnancy.
25.
E.g. Acarbose,Meglitol
mechanism of action
Reversible inhibitors of intestinal Alpha - glucosidases in
intestinal brush border responsible for degradation of
oligosaccharides(complex non absorbable carbohydrates) to
monosaccharides (simple absorbable carrbohydrates)
They therefore decrease carbohydrate digestion and absorption
in small intestine.
There is also delay in digestion and absorption of starch and
sucrose
Decrease postprandial hyperglycemia thus taken just before
meals.
No hypoglycemia if used alone.
3. Alpha-glucosidase inhibitors
26.
Pharmacokinetics Alpha-glucosidase inhibitors
Acarbose
Given orally, poorly absorbed.
Metabolized by intestinal bacteria.
Excreted in stool and urine.
Adverse effects
GIT: Flatulence, diarrhea, abdominal pain,
abdominal distension.
No hypoglycemia if used alone.
increased serum transaminases- hepatitis and
jaundice
27.
Availability
Acarbose isavailable as 25 mg, 50 mg, or 100 mg
tablets, given three times (tds) a day just before
meals.
contraindications
Hypersensitivity to acarbose,
diabetic ketoacidosis
Cirrhosis
inflammatory bowel disease
ulcers of the intestine
partial intestinal obstruction
digestive and absorptive issues
28.
e.g. Exenatide(GLP-1)
Incretinsare GI hormones secreted in response to
food, carried through circulation to the beta cells to
stimulate insulin secretion & decrease glucagon
secretion.
There are two main Incretin hormones:
– GLP-1 (glucagon-like peptide-1)
– GIP (gastric inhibitory peptide or glucose-
dependent insulinotropic peptide)
Both are inactivated by dipeptidyl peptidase-4 (DPP-
4) enzyme.
4. Incretin mimetics
29.
Exenatide
is glucagon-likepeptide-1 (GLP-1) agonist.
given s.c. once or twice daily
Therapy of patients with type 2 diabetes who
are not controlled with oral medicine.
Adverse effects
Nausea & vomiting(most common)
30.
Dipeptidyl peptidase-4 (DPP-4 ) inhibitors e.g.
Sitagliptin
Mechanism of action of sitagliptin
Inhibit DPP-4 enzyme leading to an increase in incretin
hormones level.
This results in an increase in insulin secretion & decrease
in glucagon secretion.
pharmacokinetics
Orally
Given once daily
half life 8-14 h
Dose is reduced in pts with renal impairment
31.
Clinical uses
Type2 DM as an adjunct to diet & exercise as a monotherapy or in
combination with other antidiabetic drugs.
Adverse effects
Sitagliptin: Hypoglycemia, nasopharyngitis, increased serum
creatinine, acute pancreatitis (including hemorrhagic or
necrotizing forms) Nausea, abdominal pain, diarrhea and acute
renal failure.
Saxagliptin: Peripheral edema , headache , hypoglycemia , urinary
tract infection , lymphocytopenia , and acute pancreatitis.
Linagliptin: Hypoglycemia , increased uric acid , increased serum
lipase , nasopharyngitis , and acute pancreatitis.
32.
Availability
linagliptin isavailable as 5 mg daily.
Vildagliptin is given as 50 mg once or twice weekly
Sitagliptin as 25 mg, 50 mg, or 100 mg once daily
Saxagliptin as 2.5 mg or 5 mg once daily.
Common brands-
Treviamet 50/1g or50/500mg- sitagliptin and
metformin
glucowell 50- Vildagliptin 50mg
Galvus MET- Vildagliptin and metformin 50/500mg
33.
MOA
They inhibitsodium-glucose co-transporter 2 (SGLT-2) in proximal
tubules of renal glomeruli, causing inhibition of 90% glucose
reabsorption and resulting in glycosuria in people with diabetes
which in turn lowers the plasma glucose levels.
SGLT2 inhibitors are a safe and efficacious treatment option for
T2DM.
(SGLT2) inhibitors, have shown to significantly reduce CV mortality
and heart failure (HF) hospitalizations.
The mechanism behind these surprising cardiac benefits remains
unclear.
Given their cardiac benefits (reduction in HF and death) and the low
incidence of adverse events, SGLT2 inhibitors are being currently
studied as a treatment for HF also in non diabetic individuals.
5. SGLT2 inhibitors
34.
Pharmacokinetics
rapid oralabsorption, a long elimination half-life allowing once-
daily administration
They have an extensive hepatic metabolism mainly via
glucuronidation to inactive metabolites
Have a low renal elimination as a parent drug.
Adverse effects
Dyslipidemia (3%)
hyperphosphatemia , hypovolemia
nausea,
fungal vaginosis , urinary tract infection , increased urine
output , dysuria ,
influenza
bone fracture
renal impairment
35.
Availability
canagliflozin isinitially given as 100 mg daily,
which is gradually increased to 300 mg daily
dapagliflozin as 5 mg or 10 mg daily
empagliflozin as 10 mg or 25 mg daily.
Contraindications
History of serious hypersensitivity to the drug
end-stage renal disease (ESRD)
patients on dialysis.
36.
Bromocriptine (Cycloset)
Itis a sympatholytic dopamine D2 receptor agonist
It resets the hypothalamic circadian rhythm, which might
have been altered by obesity.
This action results in the reversal of insulin resistance and a
decrease in glucose production.
It is used with diet and exercise to lower blood sugar levels
in adults with type 2 diabetes.
Adverse effects
Dizziness, fatigue, headache and/or lightheadedness.
Constipation
Nausea, vomiting,
others
37.
Availability
As 0.8mgtabs
initial dose is 0.8 mg once daily, which is gradually
increased to the usual dose of 1.6 mg to 4.8 mg once
daily.
contraindications
Allergy to the drug
breastfeeding
syncopal migraine
people with type 1 diabetes
diabetic ketoacidosis.
