PANCREATIC HORMONES AND ANTIDIABETIC DRUGS

Drugs Pharmacodynamics/Pharmacokinetics Clinical Use Side/ Adverse Effects Contraindications/ Drug

Interactions/ Caution
INSULIN
Insulin  Released from pancreatic beta cells at low basal rate and at a Cough – Inhaled Insulin Stimulatory drugs:
1. Rapid-Acting much higher stimulated rate in response to: glucose, other 1. Sulfonylurea
2. Short-Acting sugars, amino acids, GLP 1, GIP, glucagon, cholecystokinin, Hypoglycemia 2. Meglitinide and
3. Intermediate- high conc of fatty acids and beta adrenergic activity nateglinide
Acting  Insulin Degradation: Liver and kidney Insulin allergy 3. Isoproterenol
4. Long-Acting  Half-life of circulating insulin: 3-5minutes 4. Ach
 Promotes storage of fats as well as glucose within specialized Immune Insulin
target cells and influences cell growth and metabolic Resistance Inhibitory Signals:
functions 1. Insulin itself
 Goal of SQ insulin therapy: replicate normal physiologic Lipodystrophy at 2. Somatostatin
insulin secretion and replace the backround or basal as well Injection sites 3. Leptin
as bolus or prandial insulin
Increased Cancer risk Inhibitory Drugs:
Rapid-acting Insulin  Very fast onset and short duration 1. Diazoxide
1. Insulin Lispro  Permit more physiologic prandial insulin replacement 2. Phenytoin
2. Insulin Aspart  More closely mimic normal endogenous prandial insulin 3. Vinblastine
3. Insulin Glulisine secretion than regular insulin 4. Colchicine
 Preferred insulins for use in continuous SQ insulin infusion
devices
 Insulin Lispro – first monomeric insulin analog; very low
propensity to self-associate in antiparallel fashion and forms
dimers; rapidly absorbed with onset of action with 5-15
minutes and peaks activity as early as 1 hour
Short-acting Insulin  Effect appears within 30minutes, peaks between 2 and 3
1. Regular Insulin hours after SQ injections
 Generally last 5-8 hours
 Should be injected 30-45 minutes or more before the meal
to minimize mismatching
 The only type that should be administered IV
 Useful for IV therapy in management of diabetic ketoacidosis
and when the insulin requirement is changing rapidly
(surgery or acute infections)
Intermediate and Long-  NPH – intermediate-acting insulin; onset 2-5 hours and
acting Insulins duration 4-12 hours; usually mixed with regular, lispro,
1. Neutral aspart, or glulisine insulin and given 2-4x daily for insulin
protamine replacement; action is highly unpredictable

KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12TH EDITION | the LEV guide
 Hagedorn (NPH)  Insulin Glargine – soluble, peakless, long-acting insulin
or isophane analog; provides a reproducible, convenient, background
2. Insulin Glargine insulin replacement; usually given once daily; should not be
3. Insulin detemer mixed with other insulins and separate syringes should be
used to minimize risk of contamination and subsequent loss
of efficacy
 Insulin detemer – most recently developed long-acting
insulin analog; has the most reproducible effect of the
intermediate- and long-acting insulins; less hypoglycemia
than NPH; has dose-dependent onset and duration of action
Mixture of Insulins  because intermediate-acting NPH require several hours to
reach adequate therapeutic levels, they usually require
supplements of rapid- or short-acting u=insulin before meals
 mixed together in same syringe
 Lispro, aspart, and glulisine can be acutely mixed with NPH
 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart
– premixed prep
 Insulin glargine and detemer must be given as separate
injections
ORAL ANTIDIABETIC AGENTS
SULFONYLUREA
Sulfonylureas  Increases insulin release from the pancreas
 Binding of a sulfonylurea inhibits the efflux of potassium ions
 depolarization  opening of voltage-gated calcium
channels  calcium influx  release of preformed insulin
 Metabolized by the liver (except acetohexamide)
First Generation Sulfonylurea
Tolbutamide  Duration of effect is relatively short (6-10 hours) Prolonged hypoglycemia Sulfonamides, phenylbutazones,
 Best administered in divided doses oral azoles – inhibit metab of
 Relatively safe in the elderly and in patients with renal tolbutamide in the liver and
impairment increase its circulating levels
Chlorpropamide  Half-life – 32 hours Prolonged hypoglycemia C/I: elderly
 Given as single dose in the morning in elderly D/I: hyperemic flush after alcohol
Tolazamide  Comparable to chlorpropamide in potency but has shorter
DOA
 More slowly metab than the other sulfonylureas
Acetohexamide  Half-life: 1 hour
Second Generation Sulfonylureas
Glyburide  Very low hypoglycemic activity Hypoglycemia Caution in CV disease and elderly
Flushing C/I: hepatic and renal impairment
Enhances free water
clearance
Glipizide  Shortest half-life (2-4 hours) Caution in CV disease and elderly
 Should be ingested 30minutes before breakfast (absorption C/I: hepatic impairment
delayed by food)

KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12TH EDITION | the LEV guide
  Preferable than glyburide in the elderly
Glimepiride  Once daily use as monotherapy or in combination with Caution in CV disease and elderly
insulin
 Achieves blood glucose lowering with the lowest dosage of
any sulfonylurea
Glicazide  Half-life: 10hours Caution in CV disease and elderly
MEGLITINIDE ANALOGS
Repaglinide  First member of the group Use in controlling Hypoglycemia
 Modulates beta-cell insulin release by regulating potassium postprandial glucose
efflux excursions
 Fast onset of action Monotherapy or in
 Can be used in patients with renal impairment and elderly combination with
biguanides
DM II with
sulfonylurea allergy
Metiglinide  Benzylsuccinic acid derivative that binds to sulfonylurea
receptor
D-PHENYLALANINE DERIVATIIVE
Nateglinide  Stimulates rapid and transient release of insulin from beta Hypoglycemia
cells through closure of ATP-sensitive K channel Mild elevation of HBA1c
BIGUANIDES
Metformin  Activate the enzyme AMP-activated protein kinase (AMPK) First line for DM 2 Lactic acidosis Temporarily halted on the day of
and reduce hepatic glucose production Prevention of DM 2 GI (persisten diarrhea, radiocontrast use
 Euglycemic agent Reduce risk of some etc) – most common
 Impair hepatic metab of lactic acid cancers B12 malabsorption
 Insulin sparing agent and does not increase body weight or
provoke hypoglycemia Reduce CV deaths
 Interfere with calcium dependent absorption of vitamin b12-
intrinsinc factor complex
THIAZOLIDINEDIONES
Thiazolidinedione  Act to decrease insulin resistance Fluid retention C/I: heart failure
 Ligands of peroxisome proliferator-activated receptor- Heart failure
gamma (PPAR-gamma) Macular edema
 Increases glucose transporter expression (GLUT 1 and 4), Loss of bone mineral
decrease fatty acid levels, decrease hepatic glucose output, density
increase adiponectin and decrease release of resistin from Anemia
adipocytes, and increase differentiation of pre-adipocytes to Weight gain
adipocytes
Pioglitazone  PPAR-alpha and gamma activity Monotherapy or in Bladder tumor
 Absorbed within 2hours of ingestion combination with Increased risk of bladder
 Absorption is decreased with concomitant use of bile acid metformin, cancer
sequestrants sulfonylurea, and
 Lowers triglycerides and increases HDL cholesterol without insulin for DM2
affecting total cholesterol and LDL

KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12TH EDITION | the LEV guide
  Reduces neointimal proliferation after coronary stent
placement
Rosiglitazone  Rapidly absorbed and highly protein bound Monotherapy in DM2 Increases risk of angina
 Increases total cholesterol, HDL, and LDL but no significant or MI
effect on triglyceride
 Reduces microalbuminuria
Troglitazone  Fatal
DRUGS THAT AFFECT ABSORPTION OF GLUCOSE (ALPHA-GLUCOSIDASE INHIBITOR)
Acarbose  Competitively inhibit the intestinal alpha-glucosidase Flatulence Not in renal failure
Miglitol enzymes and reduce postmeal glucose excursions by Diarrhea
Voglibose delaying the digestion and absorption of starch and Abdominal pain
disaccharides
GLUCAGON-LIKE PEPTIDE 1 (GLP-1) RECEPTOR AGONIST
Exenatide  Derivative of the exendin-4 peptide in Gila monster venom Nausea – major C/I: medullary thyroid CA or MEN
 Approved as an injectable, adjuvant therapy Weight loss (2-3kg) 2 syndrome
Increase risk of
pancreatitis
Liraglutide  Soluble fatty acid-acylated GLP-1 analog Increase risk of
pancreatitis
AAlbiglutide  Human GLP-1 dimer fused to human albumin Nausea
Injection site erythema
Increase risk of
pancreatitis
Dulaglutide  Consists of two GLP-1 analog molecules covalently linked to Increase risk of
an Fc fragment of human IgG4 pancreatitis
DIPEPTIDYL PEPTIDASE-4 (DDP-4) INHIBITOR
Sitagliptin  Given orally as 100mg once daily Nasopharyngitis, URTI,
headaches
Acute pancreatitis
Hypersensitivity rxn
Saxagliptin  Given orally as 2.5-5mg daily Increase rate of
infections, headaches,
hypersensitivity
Linagliptin  Lowers HBA1c by 0.4-0.6% Nasopharyngitis,,
hypersensitivity
Risk of pancreatitis
Vidagliptin  Lowers HBA1c by 0.5-1% URTI, nasopharyngitis,
dizziness, headache
Hepatitis
SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITOR
Canagliflozin  Reduces the threshold for glycosuria from a plasma glucose Increased incidence of C/I: GFR <45ml/min/1.73m2
threshold of 180mg/dL to 70-90mg/dL genital and urinary tract
Dapagliflozin  Reduces HBA1c by 0.5-0.8% infections
Empagliflozin  Reduces HBA1c by 0.5-0.7% C/I: GFR <45ml/min/1.73m2

KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12TH EDITION | the LEV guide
 OTHER HYPOGLYCEMIC AGENTS
Pramlintide  Islet amyloid polypeptide (IAPP) analog Hypoglycemia
 Physiologically acts as a negative feedback on insulin GI symptoms
secretion
 Reapidly absorbed after SQ administration. Injected
immediately before meals
 Cannot be mixed with insulin
Colesevelam HCL  Bile acid sequestrant and cholesterol-lowering drug Hypertriglyceridemia
 Interrupts enterohepatic circulation and decrease in
farsenoid X receptor activation
Bromocriptine  Dopamine agonist Nausea, fatigue,
dizziness, vomiting,
headache
GLUCAGON
Glucagon  Synthesized in the alpha cells of the pancreatic islets of Severe Hypoglycemia Transient nausea Not in pheochromocytoma
Langerhans Occasional Vomiting
 Extensively degraded in the liver and kidneys Endocrine Diagnosis
 Facilitates catabolism of stored glycogen and increase
gluconeogenesis and ketogenesis Beta-Adrenoceptor
 Raises blood glucose at the expense of stored hepatic Blocker Overdose
glycogen
 Potent inotrophic and chronotropic effect on heart Radiology of Bowel
 Profound relaxation of intestine

KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12TH EDITION | the LEV guide