Anti-diabetic drugs classification:
1. Insulin preparation
2. Insulin secretagogues
3. Insulin sensitizer
4. Peptide analogues
I. Insulin preparation
A. Short-acting Insulin (Natural Insulin)
· Soluble or Regular Insulin
(Humulin R) (Actrapid)
· Onset, 30-60 min.
· Peak; 2-4 hrs.
· Duration, 4-8 hrs.
· Used to control
Postprandial Hyperglycemia (Bolus ONLY).
B. Rapid-acting Insulin (Human Analogue)
· Insulin Aspart
(NovoRapid") Insulin Lispro (Humalog) Insulin Glulisine (Apidra)
· They are preferred to
Regular Insulin because of faster onset and shorter duration, better mimicking
physiological need during postprandial period.
· Onset; 5-15 min.
· Peak; 1-2 hrs.
· Duration, 3-5 hrs
· Used to control
Postprandial Hyperglycemia (Bolus ONLY).
· Regular Insulin &
Aspart can be used as IV in emergency.
C. Intermediate-acting Insulin (NPH) (Isophane)
· Insulin NPH (Insulatard)
(Humulin® N)
· Neutral Protamine Hagedorn
(NPH) is a suspension (Cloudy/milky) of crystalline Zinc Insulin combined with
the positively charged polypeptide Protamine; less soluble, thus delayed
absorption and a longer duration of action.
· Onset, 1-2 hrs.
· Peak; 5-10 hrs.
· Duration; 10-16 hrs
· Uses; used for basal
coverage.
· NPH and Protamine are
usually mixed with Regular, Lispro, Aspart, or Glulisine Insulin.
D. Long-acting Insulin
· Insulin Glargine (Lantus)
Insulin Detemir (Levemir) Insulin Degludec (Tresiba)
· They are a Peakless (plasma
concentration is plateau = Basal). Long-acting Insulin analogue.
· Onset; 1-2 hrs.
· Peak; Peakless
· Duration; 24 hours.
· Duration of action of
Insulin Degludec is more than 42 hours (ultra-long-acting).
· Should not be diluted or mixed with other Insulin or solution in the same syringe.
I. Insulin Secretagoques
1. Sulfonylureas
a. First Generation
· Tolbutamide, Tolazamide,
Acetohexamide & Chlorpropamide
b. Second Generation
· Glyburide or Glibenclamide,
Glimepiride, Glipizide & Gliclazide
· Dose (Second-generation);
usuall once daily with breakfast or first main meal of the day.
· Second-generations are
usualy combined with Metformin.
· Mechanism of Action;
Sulfonylureas block ATP-sensitive K+ channels, resulting in depolarization;
Depolarization opens a voltage-gated calcium channel and results in Ca+2 influx
and the release of preformed Insulin by exocytosis.
· Side Effects; Weight gain,
hyperinsulilnemia and hypoglycemia.
· Used with caution in
hepatic or renal insufficiency (accumulation of sulfonylureas may cause
hypoglycemia).
· Drug Interactions:
i. decrease Sulfonylureas
effects
1) Atypical antipsychotics
2) Corticosteroids
3) Diuretics - Niacin
4) Phenothiazines
5) Sympathomimetic
ii. Increase Sulfonylureas
effects (hypoglycemia)
1) Azole antifungals
2) B-blockers - Chloramphenicol
3) Clarithromycin - MAOIS
4) Probenecid - Salicylates
5) Sulfonamides - Warfarin
2. Meglitinides
"Glinides"
· Repaglinide, Nateglinide
& Mitiglinide
· Meglitinides act on the
same B-cell receptor as Sulfonylureas (same mechanism) but have a different
chemical structure with rapid onset and a short duration of action; there is no
sulfur in its structure, so they may use in type 2 diabetics with sulfur or
sulfonylurea allergy.
· CYP450 (CYP3A4) metabolizes
them to inactive products.
· Side Effects: Weight gain
& hypoglycemia (less than sulfonylureas). Drug Interactions; Drugs that
inhibit/induce CYP3A4.
II. Insulin Sensitizers
1. Biguanides
· Metformin
· Main Mechanisms of Action:
1) Suppressing liver Glucose
production (hepatic gluconeogenesis).
2) Decreasing intestinal
absorption of Glucose.
3) Improving Insulin
sensitivity by increasing peripheral Glucose uptake and utilization.
· Uses; Type 2 Diabetes (first
line therapy; all patients).
· Off-Label Uses (Decrease
Insulin Resistance); Prediabetes, Gestational Diabetes, Polycystic Ovary
Syndrome (PCOS) and Female Infertility.
· Side Effects;
Gastrointestinal Upset (diarrhea, cramps, nausea, vomiting & flatulence);
dose titration recommended.
· Black Box Warning; Lactic
Acidosis (rare, but potentially severe) risk very increase in patients with
severe renal impairment.
2) Thiazolidinediones (TZDS) "Glitazones"
· Pioglitazone &
Rosiglitazone
· TZDS are ligand of peroxisome
proliferator-activated receptor- gamma (PPARY), a group of nuclear receptors
found in muscles, adipose tissues and liver.
· Black Box Warning; Risk of
Congestive Heart Failure (CHF).
III. Peptide Analogues
1. Injectable Incretin Mimetics (Glucagon-like Peptide-1 Agonists)
· Exenatide, Liraglutide,
Lixisenatide, Albiglutide, Dulaglutide & Semaglutide
· Glucagon-like Peptide-1
(GLP-1) & Gastric Inhibitory Peptide (GIP) are Incretins and released after
eating increase Insulin & decrease Glucagon secretion, slow gastric
emptying time, reduce food intake by enhancing satiety (a feeling of fullness)
and promote B-cell proliferation. Incretins is rapidly degraded by Dipeptidyl
Peptidase 4 (DPP-4) enzyme.
· Block Box Warning; increase
risk of Medullary Thyroid Carcinoma.
2. Dipeptidyl Peptidase-4 (DPP-4) inhibitors "Gliptins"
· Sitagliptin, Vildagliptin,
Saxagliptin, Linagliptin & Alogliptin
· Risk of acute pancreatitis
and severe allergic reactions.
· Risk of severe and
disabling joint pain (Arthralgia).
3. Injectable Amylin Analogues
· Pramlintide
· used as an adjunct to
Insulin therapy (NOT alone)
· Insulin dose should be
decreased by 50% (avoid hypoglycemia)
IV. Glycosurics
· Sodium/Glucose
Co-transporter-2 (SGLT2) Inhibitors "Gliflozins"
· Dapagliflozin,
Canagliflozin, Empagliflozin & Ertugliflozin
· They are inhibits SGLT2,
which is responsible for at least 90% of the glucose reabsorption in the kidney
thus eliminate glucose through the urine Thus Glycosuria.
· Side Effects; Renal
Impairment, Urinary Tract Infection and Increased Urination & Genital
Mycotic (Fungal) Infections.
V. Alpha-glucosidase Inhibitors
· Acarbose & Miglitol
· They are inhibit the intestinal a-glucosidase enzymes, delaying the digestion and absorption of starch and disaccharides, resulting in lower postprandial glucose.
References
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