ENDOCRINE

PHARMACOLOGY

1
Learning objective
At the end of this chapter the student will be able to:
Describe the effects of insulin on different organ/systems
Differentiate the types of insulin with their therapeutic uses and adverse
reactions
Identify the mechanism of action, uses and side effects of oral hypoglycemic
agents
Recognize drugs used as oxytocic agents
Differentiate types of hormonal contraception with their uses and adverse
effects including preparations
Describe actions, therapeutic uses and adverse effects of glucocorticoids

2
ANTIDIABETIC DRUGS
INTRODUCTION
 Diabetes Mellitus (DM) is a disease that occurs as a result of absolute or
relative deficiency of insulin that results in metabolic and vascular
abnormalities.
 The etiologies include:
 Obesity (because chronic calorie intake and prolonged stimulation of  cell
causes a decrease in insulin receptor and also adipose tissue and muscle are less
sensitive)

3
Hereditary
Damage of pancreatic tissue
Diabetogenic hormones(like growth hormone, thyroid, epinephrine)-are
antagonize the action of insulin
Diabetogenic drugs like thiazide diuretics, epinephrine, phenothiazines ,
Other factors like Pregnancy-eg.placenta & placental hormones create
resistance to insulin

4
 TYPE 1
 Absolute deficiency of insulin secretion.
 Autoimmune destruction of beta cells
 The immune system mistakenly attacks and destroys the insulin-
producing cells.
 The body is unable to produce insulin, leading to high blood sugar
levels.
 Identified by autoimmune pathologic process occurring in pancreatic
islets

 70% of cases dx’d under age 30

5
 TYPE 1

 It develops in childhood or adolescence,

but it can occur at any age.
 People with type 1 diabetes require lifelong
insulin therapy for blood sugar control.

6
Type 2
 It is the most common form of diabetes
 Occurs when the body becomes resistant to the effects of insulin
Fails to produce enough insulin to maintain normal blood sugar
levels.
 Often associated with lifestyle factors such as obesity, sedentary
lifestyle, and poor dietary habits.
Type 2 diabetes can develop at any age, but it is more common in
adults.

12/06/2024 7
Type 2

DX:
 Poly-symptoms (polydipsia, polyphagia, and polyuria) PLUS
 Random plasma glucose test greater than or equal to 200
mg/dl.
 Fasting plasma glucose (FPG) test greater than or equal to
126 mg/dl
 Oral glucose tolerance test (OGTT)(the two-hour plasma
glucose level ) greater than or equal to 200 mg/dl.
 Hemoglobin A1c (HbA1c) test is greater than 6.5%
Gestational diabetes mellitus (GDM)

 GDM occurs during pregnancy when hormonal changes

interfere with insulin action.
 It affects women who did not have diabetes prior to
pregnancy.
 GDM usually resolves after childbirth.
 It is usually diagnosed after 20 weeks of gestation.
 Women who have had GDM are at a higher risk of
developing type 2 diabetes later in life
 Blood sugar control during pregnancy is important to reduce
the risk of complications for both the mother and the baby.
Diabetes has dangerous complications including:
 ketoacidosis (in types I)
 hyperglycemic osmolal non ketotic coma (in type II);-resulted from dehydration
 cardiovascular like atherosclerosis;
 myocardial infarction
 Peripheral arterial insufficiency;
 Anemia
 Hypertension
 stroke; nephropathy; retinopathy; and, neuropathy

10
DM can be classified as:
Type I: IDDM (or Juvenile type)
 This occurs predominantly in children and young adults who have no insulin
secretion
Type II: NIDDM (or maturity onset type)
 Usually occur after the age of 40 years

11
Diabetic ketoacidosis (DKA)
 This is a serious complication of diabetes.
 It is a severe metabolic disturbance due to insulin deficiency
 It results in hyperglycemia, ketonimia and later acidosis

12
This condition is characterized by:
headache
nausea
vomiting
rapid pulse, dry skin
Deep breathing, and change in mentation
Management includes:
Regular (soluble) insulin IV infusion
Treatment of dehydration and precipitating factor

13
Hypoglycemic Coma
 This is a more serious complication which usually occurs due to excess dose of
insulin that produces severe lowering of blood glucose.
 This may leads to coma.

14
The Sign /Symptom are:
 mental confusion
 uncoordination
Paresthesia
Convulsion
coma and Signs of sympathetic over activity
 The aim of treatment is to restore blood glucose to normal by
giving glucose 50% 20 – 100 ml IV, or glucagon 1mg iv,
im, sc

15
Antidiabetogenic drugs
I. INSULIN
 Sources of insulin include:
Pork or beef or a combination of pork and beef, and
Human insulin (Recombinant DNA technique)

16
Actions:
 Insulin lowers the blood glucose level by increasing utilization of glucose by
peripheral tissue and promoting synthesis and storage of glycogen
 The main actions of the hormone are exerted on metabolism of carbohydrate
(CHO), fat and protein in liver, muscle & adipose tissue.

17
Effects of insulin on:
Carbohydrate metabolism
 Liver: it increases glycogen synthesis from glucose and glucose utilization, while
it decreases gluconeogenesis and glycogenolysis
 Muscle: it increases glucose uptake, glucose utilization and glycogen synthesis.
 Adipose tissue: it increases glucose uptake and glycerol synthesis (esterifies
fatty acid)

18
Fat metabolism
 Liver: it increases lipogenesis (fatty acid formation)
 Adipose tissue: it increases synthesis of triglycerides and synthesis of fatty acid
Protein metabolism
 Liver: it increases protein catabolism
 Muscle: it increases aminoacid uptake and protein synthesis

19
Other metabolic effect:
 It increases uptake of K+ and Ca++ into cells and synthesis of nucleic acids
 There are some factors that increase insulin demand:
 Like infection, surgery, pregnancy and
 Drugs (those that antagonize actions of insulin glucocorticoids, thyroid
hormone and/or adrenaline)

20
Types of insulin preparation:
 Rapid-acting insulin:
 Injected form includes-insulin lispro, insulin aspart, insulin glulisine, and
 Inhalation form- human insulin recombinant inhaled
o Replaces endogenous prandial insulin secretion than does regular insulin
o they have the additional benefit of allowing insulin to be taken immediately
before the meal without sacrificing glucose control
 Short acting (rapid onset): Eg. Regular Insulin
 Intermediate acting Eg. Lente insuline,NPH(neutral protamine
hagodern) insulin
 Long acting E.g Protamine Zn insuline, insulin determir, insulin glargine
 insulin glargine-is not mixed with other insulin since its solubility is
affected due change in PH (soluble at PH is 4.0)

21
 Types Route
 Regular insulin IV, SC, IM
 Lente insulin SC, IM
 Protamine Zn insulin SC, IM
N.B. It is only regular insulin that can be given by intravenous route.

22
Therapeutic use
 IDDM
 NIDDM (not controlled by diet and oral hypoglycemic agents)
 Diabetic ketoacidosis
 For control of diabetes in pregnancy
 During surgery and in infections
 They are also used in the treatment of
hyperkalmia due to renal failure

23
Adverse Reaction: can be categorized as
 Local: Atrophy or hypertrophy at site of injection, local hypersensitivity and
secondary infections
 Injection of older animal insulin preparations sometimes led to atrophy of subcutaneous
fatty tissue at the site of injection
 But this never seen since the development of human and analog insulin preparations of
neutral pH
 Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the
same site
 However, this may be corrected by avoidance of that specific injection site or with
liposuction
 Systemic: Hypoglycemic coma and Immunologic reaction like hypersensitive
and insulin resistance

24
ORAL HYPOGLYCEMICS
 These are drugs administered orally to lower blood glucose level used in
mild diabetes
 They are grouped as:
Insulin secretagogues eg. Sulphonylureas, meglitinides, D-phenylalanine
derivatives
Biguinides eg. metformin, phenformin, buformin
Thiazolidinediones eg. Pioglitazone,rosiglitazone
ἀ-glucosidase inhibitors eg. Miglitol, acorbase

25
Sulphonyl ureas
 These compounds are chemically related to sulphonamides
First generation: Tolbutamide, Chlorpropamide,tolazamide,acetohexamide
Second generation: Glibenclamide(glyburide), Glipizide, glimepiride,gliquidone

26
Mechanism of action
 Hypoglycemic action is due to:
the stimulation of insulin released from  cell
depression of glucagon secretion
increased number of insulin receptor
reduce insulin output from liver (Decrease hepatic gluconeogenesis and
glycogenolysis)

27
Pharmacokinetics:
 They are rapidly absorbed from the GIT
 They are also extensively plasma protein bound and are mainly metabolized in
the liver
 Use: Mild diabetes mellitus in old patients
(type II)

28
Adverse reaction:
 The toxicity of these compounds is remarkably low.
 The important toxic effects include:
 hypoglycemia
 allergic skin rash
 bone marrow depression
 cholestatic jaundice (esp. chlorpropamide)

29
 Gastric irritation
 Prolonged hypoglycemia (esp. Chlorpropamide);
 In large doses confusion; vertigo; ataxia; leucopenia; aggranulocytosis
 Thrombocytopenia
 Teratogenecity

30
Drug interaction:
 Hypoglycemia is enhanced by sulphonamides, phenylbutazone
 Alcohol produces “Disulfirum” like action (flushing of the face, severe
headache, vomiting etc.)
 Sulphonyl ureas increase anticoagulant effect of oral anticoagulant
 Thiazides oppose the action of sulphonylureas

31
Biguinides
 They potentiate the hypoglycemic action of insulin and sulphonyl ureas but
they don’t produce clinical hypoglycemia in diabetics.
 Biguanides include drugs like metformin and phenformin

32
Mechanism:
 They do not stimulate the release of insulin
 They increase glucose uptake in skeletal muscle
 have effects on glucose absorption and hepatic glucose production
 They also enhance anaerobic glycolysis-this is why it associated with lactic
acidosis

33
• Pharmacokinetics: Phenformin and metformin are rapidly absorbed
from the GIT
• Metformin is largely excreted unchanged in the urine and has a
longer duration of action.
• Side effects: Nausea, vomiting, anorexia, diarrhea, abdominal cramp,
lactic acidosis (esp. phenformin)

34
Use:
 Obese diabetics (uncontrolled by diet alone, they cause loss of appetite or
anorexia w/c leads to wt loss),
 Supplement to sulphonyl urea
Contraindication:
Diabetes with hepatic, & renal insufficiency
In IDDM,
NIDDM (with infection, fever, surgery) and during pregnancy
 They have no value in diabetes complicated by acidosis or coma

35
Hormone of posterior pituitary
glands
OXYTOCICS
 These are group of drugs that cause contraction of the uterus.
Oxytocin
Actions:
1. Oxytocin stimulates the uterus and cause physiologic type of
contraction
2. It also causes ejection of milk through contraction of the myo-
epithelial cells around the alveoli of the mammary gland

36
Pharmacokinetics:
 It is inactivated orally and absorbed rapidly after intramuscular administration
 It can also be absorbed from the nasal and buccal membranes
Oxytocin is administered intravenously for initiation and augmentation of labor
 It also can be administered intramuscularly for control of postpartum bleeding
Use:
 Induction of labor in women with uterine inertia;
 relief of breast engorgement during lactation (few minutes before breast
feeding) as nasal spray; and,
postpartum hemorrhage

37
Side effect:
 Oxytocin may cause over stimulation and leads to rupture of the uterus in the
presence of cephalo-pelvic disproportion
 Therefore it’s contraindicated in woman with a uterine scar
 When given intravenously may cause water retention - leading to water
intoxication

38
Prostaglandins
 They induce labor at anytime during pregnancy but are most effective at the
third trimester.
 In female reproductive system:
prostaglandin E & F are found in ovaries, endometrium and menstrual fluid
which are responsible for initiating and maintaining the normal birth process.
 PGF, PGF2ά, PGE stimulate both the tone and amplitude of the uterine
contraction.

39
Adverse reaction:
 nausa; vomiting; headache; diarrhea;and, fever etc.
 PGs should be used cautiously in the presence of hypertension, angina, and
diabetes
 They are contraindicated in the presence of cardiac, renal, pulmonary or
hepatic disease

40
Ergometrine
 This is one of the ergot alkaloids which has the ability to cause contraction of
the uterine smooth muscle
 It causes sustained uterine contraction
 It is completely absorbed after subcutaneous and intravenous administration
 It is metabolized in the liver and eliminated in the urine
 Liver damage enhances the toxicity of ergot alkaloid

41
Use:
 After delivery of placenta if bleeding is severe (Prevent postpartum bleeding)
Adverse effect:
 Nausea and vomiting - but serious toxic effects are rare

42
 Adenocortical hormones control the metabolism of carbohydrate (CHO),
protein, fat and water /electrolytes
 Adrenocortical hormones are classified into:
Glucocorticoid - Cortisone
- Hydrocortisone(Cortisol)
Mineralocorticoid - Aldosterone
- Desoxycorticosterone
Sex Hormone – Estrogen
- Androgen

43
Glucocorticoids
 The important glucorticoid secreted in man is hydrocortisone
 It posseses some mineralocorticoid activity as well.
 Cortisone is less potent and is converted to hydrocortisone by the liver.
They are classified as
1. Short acting e.g cortisone ,hydrocortisone
2. Intermediate acting e.g. predinsolone, triamcinolone
3. Long acting e.g dexamethasone, betamethasone

44
  Dexamethasone and betamethasone have got a high glucorticoid activity
 while cortisone and hydrocortisone have high mineralocorticoid action.
 Therapeutic activity in inflammatory disorder is proportional to the
glucocorticoid activity.
Actions on CHO metabolism:
antinsulinic effect
Decreases peripheral utilization of glucose,
Increases gluconeogenesis
Promote glycogen storage

45
Protein metabolism:
Inhibit protein synthesis,
Increases catabolism
Fat metabolism:
Interferes with fat storage causing deposits with characteristic distribution
(neck, supraclavicular area, and face)
Electrolyte and H2O metabolism:
Sodium and water retention
Hypokalmia

46
Suppression of pitutary adrenocortical system:
 CNS: Euphoria and stimulation
 CVS: Restore vascular reactivity
 GIT: Increase gastric acid secretion
 Blood: Increase number of RBC, Hypercoagulability
 Uric acid: Increased excretion
Calcium metabolism:
 increased Ca+excretion, interfere with Ca++ absorption

47
Anti -inflammatory:
 Inhibits exudation, capillary dilatation, migration of phagocyte, fibroblast
Inhibit fibrous tissue formation
Antiallergic:
through inhibition of antibody production suppresses tissue inflammatory
response
 Absorption & fate: It has fair absorption, bound to  -globulin, in the liver,
cortisone is converted into hydrocortisone

48
Therapeutic use
1) Replacement therapy
 In Addisons disease and Addisonian crisis
2) Anti-inflammatory
 In conditions like Collagen disease (rheumatoid carditis, arthritis),
3) Hypersensitivity reactions
 Bronchial Asthma, status asthmatic
 blood disease due to circulating antibodies (autoimmune disease);
 eye disease (allergic inflammation of the eye);
 nephrotic syndrome; and, acute gout
4) Immunosuppression: In tissue / organ transplantation.

49
5) Glucocorticoids such as
 Bethamethasone(12mg IM every 24 hrs for two doses)
 Dexamethasone (6mg IM every 12hrs for four doses) are used in the setting
of premature labor to decrease:
 The incidence of respiratory distress syndrome
 Intraventricular hemorrhage, and
 Death in babies delivered prematurely

50
Precautions
 Check weight for fluid retention;
 Test urine for sugar;
 Follow blood pressure through measurement and check bones by X-ray for
osteoporosis;
 Doses should be tapered slowly (Don’t stop abruptly);
 Increase dose in surgery, infection
 Encourage diet rich in K+, protein and adequate calcium, low Nacl; and,
 Rule- out infection before initiation of treatment

51
Side effects:
Due to prolonged use:
 Weight gain and edema,hypokalmia; hyperglycemia; osteoporosi, psychiatric
disturbance; susceptibility to infection (like TB);
 peptic ulceration; cushing syndrome(excessive production of hydrocortisone);
and, retarded growth
 Complication with rapid withdrawal results in adrenacortical insufficiency due
to depression of adrenocortical activity

52
Contraindication:
 They are contraindicated in patients with:
 peptic ulcer disease
 acute infection like active tuberculosis
 diabetes mellitus
 psychosis
 pregnancy

53
Mineralocorticoid
Aldosterone
 It is the main mineralocorticoid of the adrenal cortex.
 It increases absorption of Na+ at the distal tubule and increases K+ excretion.
 They are not widely used in therapeutics

54
Thyroid hormones
 are responsible for optimal growth, development, function, and maintenance of all
body tissues
• inadequate secretion of thyroid hormone (hypothyroidism) results in bradycardia, poor
resistance to cold, and mental and physical slowing (in children this can cause mental
retardation and dwarfism
• Excess secretion of thyroid hormone (hyperthyroidism), causes tachycardia and cardiac
arrhythmias, body wasting, nervousness, tremor, and excess heat production can occur
 levothyroxine (T4) is the preparation of choice for thyroid replacement and suppression
therapy because of its stability
 Liothyronine (T3) is three to four times more potent than levothyroxine, it is not
recommended for routine replacement therapy
 It is used for short term suppression TSH
 T3 has greater risk of cardiotoxicity, it should be avoided in patients with cardiac
disease

55
Antithyroid drugs
 Antithyroid drugs inhibit the function of the thyroid gland and are used in
hyperthyroidism
 Antithyroid drugs include:
Thiourea compounds, e.g., propylthiouracil, methimazole, carbimazole
Ionic inhibitors, e.g. , potassium percholate, potassium thiocyanate;
Iodide, e.g. , Lugol’s iodine, potassium iodide; and,
Radioactive iodine (131I)

56
Thiourea Compounds
 These agents inhibit the formation of thyroid hormone by inhibiting the
oxidation of iodide to iodine by peroxidase enzyme
 It blocks the coupling of iodothryosines to form iodothyronines
 They are contraindicated in pregnant and lactating women
 Toxicities include: drug fever; skin rashes; increased size and vascularity of the
thyroid gland; and, agranulocytosis.

57
Ionic Inhibitors
• Potassium percholate prevents the synthesis of thyroid hormones
through inhibition of uptake and concentration of iodide by the gland.
• It has the risk of aplastic anemia, therefore is no longer used in the
treatment of hyperthyroidism.

58
Iodides:
 Improve manifestations of hyperthyroidism by decreasing the size and
vascularity of the gland, they are required for preoperative preparation of the
patient and for partial thyroidectomy
 Iodides act through inhibition of the “protease” enzyme which releases T3 and
T4 from thyroglobulin, and organification

59
Radioactive Iodine:
• It is used orally in hyperthyroidism as sodium 131I.
• It is trapped and concentrated as ordinary iodine, which emits beta
rays that act on parenchymal cells of the gland.
• It is contraindicated in pregnancy and lactation as it affects thyroid
gland in the fetus and the infant.
• Its important toxicity is hypothyroidism.

60
Propranolol
 This is an important drug which controls the peripheral manifestations of
hyperthyroidism (tachycardia, tremor).
 In addition, it decreases the peripheral conversion of T4 to T3.

61
Sites of action of various drugs that interfere with thyroid
hormone biosynthesis 62