2. Pancreatic hormones
• Insulin & glucagons are produced by the pancreas cells of
Islets of Langerhans:
• β- cells secret insulin
• α- cells secrete glucagons.
• These hormones play an important role in homeostasis of
blood glucose.
• Insuline reduces blood glucose level by:
– ↑ Glucose uptake by fat & muscle cells.
– ↑glycogenesis (glycogen synthesis).
– ↓ Glycogenolysis (glycogen breakdawn).
– ↓ Gluconeogenesis (glucose synthesis)
5. Drugs for Diabetes Mellitus
Diabetes Mellitus (DM)
• DM comprises a group of common metabolic disorders
that share the phenotype of hyperglycemia.
– Caused by a complex interaction of genetics,
environmental factors, and lifestyle choices
• Symptoms result from
– A relative or absolute deficiency of insulin
– Or resistance to insulin’s action
6. Types of DM
A. Insulin dependent diabetes mellitus (IDDM or type I)
β – Cells are destroyed which results in absolute deficiency of
insulin.
B. Non – insulin dependent diabetes mellitus ( NIDDM or type II)
Inabilities of the β-cells to produce appropriate quantities of
insulin, and reduced sensitivity to its action (insulin resistance).
C. Other less common (e.g. gestational)
7.
8. Insulin
MOA
Produce its effect by binding
on insulin receptor
Binding of an insulin
molecule to the subunits at the
outside surface of the cell
activates the receptor
10. Types of insulin: time course of action after Sc injection
Class Generic name Time course
Onset
(min)
Peak
(hr)
Duration
(hr)
Short duration:
Rapid acting
Insulin lispro
Insulin aspart
15-30
10-20
0.5-2.5
1-3
3-6.5
3-5
Short duration:
Slower acting
Regular insulin 30-60 1-5 6-10
Intermediate
duration
NPH insulin
Lente insulin
60-120 6-14 16-24
Long duration Insulin glargine 70 None 24
11. Route of administration
• Orally inactivated by digestive enzymes
• All are given scly
• Only regular insulin can be given IV or Im
• Inhalation- Exubera
Adverse Effects
1. Hypoglycemia (<50mg/dl) when ever insulin levels exceed
insulin needs
2. Lipodystrophies
• lipoatrophy – loss of subcutaneous fat (due to immunologic)
• lipohypertrophy- fat accumulates
3. Weight gain- during intensive insulin therapy
12. Oral Hypoglycemic Agents
• Can be used to treat pts with NIDDM
• Fall into five groups:
a) The sulphonylureas
b) Meglitinides
c) Biguanides
d) Thiazolidinediones
e) Alpha glucosidase inhibitors
13. Oral hypoglycemics for type 2 diabeties
Class & specific
agents
Actions Major adverse effects
Sulfonylureas
Tolbutamide
Glipizide
Glibenclamide
Promote insulin secretion by the
pancreas; may also increase tissue
response to insulin.
Hypoglycemia, nausea
and vomiting, cholestatic
jaundice, agranulocytosis
Meglitinides
Repaglinide
Natiglinide
Promote insulin secretion by the
pancreas.
Hypoglycemia
Biguanides
Metformin
Decreases glucose production by liver
and increases glucose uptake by muscle.
GI symptoms:↓appetite,
nausea, diarrhea
Lactic acidiosis (rarely).
Thiazolidindiones
Rosiglitazone
Pioglitazone
Decrease insulin resistance, and
thereby increase glucose uptake by
muscle and ↓ glucose production by the
liver.
Hypoglycemia but only in
the presence of
excessive insulin.
hepatotoxicity
Apha- glucosidase
inhibitors
Acarbose
Miglitol
Inhibit carbohydrate digestion and
absorption, thereby decreasing the
postprandial rise in blood glucose level.
GI symptoms: flatulence,
cramps, abdominal
distention, borborygmus.
15. Glucagon
• Acts on the liver to cause breakdown of
glycogen (glycogenolysis), releasing glucose
into the bloodstream.
• Increases production of glucose from amino
acids (gluconeogenesis).
• Also increases lipolysis, to free fatty acids for
metabolism.
17. Thyroid Hormones
• The thyroid gland secrets three types of hormones:
– Thyroxine (T4),
– Triiodothyronine (T3) and Calcitonine.
• TRH TSH - controls thyroid hormone synthesis
Synthesis, storage and release of thyroid hormones
1. Iodine trapping
2. Oxidation of iodide
3. Iodination of thyroglobuline
4. Secretion of thyroid hormone
18. Thyroid hormone (T3, T4) actions
• Have three principal actions:
1. Stimulation of energy use Elevates BMR
– 02 consumption &
– Heat production
2. Stimulation of the heart
– Heart rate
– force of contraction & Co
3. Promotion of growth & development
– Brain & other components of the NS
– Maturation of skeletal muscle
19. Thyroid pathophysiology
• Hypothyroidism
Exposure of body tissues to a subnormal amount of thyroid
Primary hypothyroidism (defective thyroid gland )
Secondary hypothyroidism, or pituitary hypothyroidism
(impaired TSH secretion )
Tertiary hypothyroidism, or hypothalamic hypothyroidism
(impaired TRH )
• Hyperthyroidism
There is excessive activity of the thyroid hormones,
resulting in a high metabolic rate, an increase in skin
temperature and sweating and a marked sensitivity to heat.
Graves’ disease (autoimmune disease)
Toxic nodular goiter (benign neoplasm)
20.
21.
22. Thyroid
MOA
Thyroid hormone
mediated it effect by
nuclear receptors
On binding with
thyroid hormone, the
receptors become
activated and initiate
the transcription
process.
23. Thyroid Hormones
• Levothyroxine (T4)
– Is a synthetic preparation of thyroxin (T4)
– Drug of choice for thyroid hormone replacement
Pharmacokinetics
• Absorption of oral T4 is variable
• Much of T4 is converted to T3 for most pts no need to
give T3 along with T4
• T1/2 of T4 7 days
– About 1 month is required to reach plateau (onset
delayed)
– Hormone levels remain steady b/n doses
24. Therapeutic uses
1) For the Rx of hypothyroidism
a) Cretinism
b) Myxedema coma
c) Ordinary hypothyroidism
d) Simple goiter
2) Consequences of cretinism can be prevented if begun
early
3) Hypothyroidism resulting from insufficient TSH or TRH
Adverse Effects
• If dosage is excessive: Thyrotoxicosis
– Tachycardia, angina, tremor, nervousness, hypethermia
25. Liothyronine (T3)
• Qualitatively similar to those of T4 (thyroxine)
• Contrasts with T4
– Has shorter t 1/2 & shorter duration of action
– T3 has a more rapid onset of action, &
– T3 is more expensive
• B/C of its high price & relatively short duration of
action, T3 is less desirable than T4 for long-term use
• Superior than T4 in a situation that requires speedy
results (e.g., myxedema coma)
26. Drugs used to treat hyperthyroidism
• Three major categories:
1) Thioamides
– Propylthiouracil
– Methimazole
– Carbimazole
2) Iodides
– Lugol’s solution
– KI tablets
– Sodium iodide inj.
3) Radioactive iodine
4) Adrenoreceptor blocking agents
27.
28. Propylthiouracil (PTU)
• MOA
– By inhibiting the thyroid hormone synthesis
• Inhibiting the thyroid peroxidase-catalyzed reaction.
Pharmacokinetics
• Propylthiouracil is rapidly absorbed, reaching peak serum
levels after 1 hour.
• Short plasma half-life
• It is more strongly protein-bound and, therefore, crosses the
placenta less readily.
29. Therapeutic uses
1. For therapy of Graves’s disease
2. As adjunct to radiation therapy (to control hyperthyroidism
until radiation effects manifest)
3. To suppress hormone synthesis in preparation for subtotal
thyroidectomy
4. For patients experiencing thyrotoxic crisis
Adverse effects
• Hypothyroidism (excessive dosing)
• Agranulocytosis (rarely)
30. Iodide products
• MOA – when present in high concentration:
a) Iodide uptake
b) Inhibits thyroid hormone synthesis
c) Inhibits release of thyroid hormone into the blood
stream
circulating levels of T3 &T4
With long-term iodide administration suppressant effects
become weaker rarely used alone
31. Therapeutic uses
• Preoperatively to control hyperthyroidism in Graves
disease size of gland & makes the gland firmer.
Preparation
1. Lugols solution
2. Potassium iodide – Tablet
– To protect the thyroid gland in the event of radiation
emergency
3. Sodium iodide (IV) - for acute mgt of thyrotoxicosis
32. Adverse Effects
• Chronic administration iodism
• Brassy test
• Soreness of teeth & gums
• Frontal headache
• Salivation & Skin lesions
Radioactive Iodine (131I)
• 131I, a radioactive isotope of stable iodine, emits a
combination of beta- particles & gamma rays
• Is concentrated in the thyroid gland. Destruction of the
thyroid tissue is produced primarily by emission of gama-rays
33. Therapeutic uses
1. Rx of hyperthyroidism
2. In the Rx of thyroid cancer
3. Diagnostic use- to diagnose a variety of thyroid disorders
(hypothyroidism & Hyper thyriodism)
– The amt & location of 131I uptake reveals the extent of
thyroid activity
Adverse effects
• Delayed hypothyroidism
• Contraindicated in pregnancy & nursing mothers
OTHERS
• β- blockers are used to decrease many of the sign and
sympthoms of hyperthyroidism like tachycardia, tremor,
dysrhthmia and agitation. e.g propranolol
34. Corticosteroids
• The adrenal cortex produces three classes of steroid
hormones:
– Glucocorticoids
– Mineralocorticoids, &
– Androgens
35. • Hormones of adrenal cortex affect multiple processes
– Glucose levels , protein synthesis is suppressed & fat
deposits are mobilized (catabolic effect)
– Sodium and water retention; hypokalemia
– Increased Ca excretion, interfer with Ca absorption
– Development of sexual characteristics
– life-preserving responses to stress
– Anti-inflammatory & immunosuppressant effects
• Mediator synthesis (PGs, Leu.)
• Inhibit the infiltration of phagocytes
• Suppress proliferation of lymphocytes
• Inhibition of growth & cell division
36. MOA of Glucocorticoid
Corticosteroids interact with specific receptor proteins in target
tissues to regulate the expression of corticosteroid-responsive
genes
Inhibition of phospholipase A2
Biological effects
37. Therapeutic uses
1) Addison’s disease (low dose required)
• For acute adrenal insufficiency hydrocortisone in given Iv
• For chronic cortisone acetate orally
2) Rheumatoid arthritis
• Pain & inflammation but don’t alter the course of the
disease (acute Rx)
3) Systemic Lupus Erythematous (SLE)
• Prompt & aggressive glucocorticoid therapy,
manifestation of SLE can be controlled
38. 4) Inflammatory bowel disease
• Used to treat severe cases of ulcerative colitis
5) Allergic conditions
• Bee stings , Hay fever , Drug –induced
6) Dermatological disorders
• Wide variety of skin diseases, psoriasis, dermatitis etc.
7) Neoplasm
• Acute lymphatic leukemia
• Hodgkin’s & non Hodkin’s lymphoma Cause direct toxicity
to malignant lymphocytes
8) Other uses:
• Asthma
• Suppression of rejection of organ transplant
• Ocular disorders
• Cerebral edema
39. Adverse Effects
1. Adrenal insufficiency
• Suppression of glucocorticoid production by adrenals
adrenal insufficiency
2. susceptibility to infection
• By host defenses (Immune response + phagocytosis)
susceptibility to infection
– Risk of
a) new infection
b) reactivating latent infection
– By host defense & inflammation
fulminating infection may develop without detection
40. 3. Peptic ulcer disease
• By PG synthesis
– secretion of acid & pepsin
– Production cytoprotective mucus
– Gastric mucosal blood flow
– Gastric pain masking ulcer development
Perforation & hemorrhage can occur with out warning
4. Fluid & Electrolyte disturbance
– B/c of mineralcorticoid activity H2O & Na+ retention &
K+ Loss (hypokalemia)
– Hypertension & edema
41. Preparations
• Include endogenous cortisol (hydrocortisone), cortisone, &
corticosterone
• The synthetic are derivatives of hydrocortisone
• Individual glucorticoids differ from one another with respect to:
– Biologic t ½
– Mineralocorticoid potency &
– Antiinflammatory potency
43. Routes of administration
• All can be administered orally
• Parentrally
– IM- Cortisone, Triamcenolone
– IM, IV- Dexamethasone, Hydrocortisone,
Methylprednisolone, Prednisolone
– Inhalation – Beclomethasone, Triamcinolone, Flunisolide
– Topical - Beclomethasone , Dexamethasone,
Hydrocortisone, Clobethasole (potent)
Since local therapy (Inhalation, Topical & Local injection)
minimizes systemic toxicity preferred to systemic therapy
(oral or parenteral).
44. Inhibitors of corticosteroid synthesis
Aminoglutethimide
Inhibiting the conversion of cholesterol to pregnenolone
(inhibits CYP11A1,)
Therapeutic use- in pts with
– Adrenal adenoma & adrenal carcinoma
– ACTH-secreting tumors
Doesn’t affect the underlying disease, RX for pts awaiting
more definitive Rx (e.g. surgery)
Ketoconazole
An antifungal agent, strongly inhibits all gonadal and adrenal
steroid hormone synthesis by inhibition of the activity of CYP17
It is used in the treatment of patients with Cushing's syndrome.
45. The gonadal hormones and
contraceptives
• Sex hormones produced by the gonads are necessary:-
- Conception,
- Embryonic maturation
- Development of 1° & 2nd ry sexual characteristics at puberty
• The gonadal hormones are used therapeutically used:-
- In replacement therapy
- For contraception
- In management of menopausal symptoms
- Several antagonists are effective in cancer chemotherapy.
46. Estrogens
• Synthesized by the ovary and placenta.
• The testis and adrenal cortex produce small amount of
estrogens.
• There are 3 main types of estrogens: Estradiol, Estrone & Estriol.
MOA
• By binding to estrogen receptors (ERs) affects transcription of
target genes
Physiological & Pharmacological effects
• Pubertal changes in girls and secondary sexual characteristics
• Neuroendocrine Control of the Menstrual Cycle
Therapeutic uses of estrogens
• Postmenopausal hormone therapy
• Primary hypogonadism
• Contraception
47. Antiestrogens
• Competes with natural estrogens for receptors in target
organs.
Tamoxifen
• Tamoxiphen has anti estrogenic activity in breast tissue and is
used to treat estrogen sensitive breast cancer.
Clomiphen
• Inhibits estrogen binding in the anterior pituitary → inhibit
the negative feed back effect of estrogen in the pituitary →
increase secretion of FSH → enlargement of ovaries and
increase estrogen secretion.
• Main effect in the pituitary is that it induces ovulation and
used to treat infertility caused by lack of ovulation.
• A/E- headache, constipation, allergy, reversible hair loss.
48. Progesterone
• Secreted by the corpus luteum & placenta (and also by testes &
adrenal cortex).
MOA
• By binding to progesterone receptor (PR) affect gene
transcription.
Physiological and Pharmacological Actions
• Neuroendocrine Actions (decreasing the frequency of GnRH
pulses)
• Reproductive Tract (Progesterone decreases estrogen-driven
endometrial proliferation)
• Development of the mammary gland requires both estrogen
and progesterone
Therapeutic uses
• Contraception, In menstrual disorders, In endometrial cancer
49. Contraceptive agents
Birth control can be accomplished by interfering with the
reproductive process at any step.
Conception can be prevented by:
Hormonal methods of contraception
• Oral contraceptives-there are two types
–Combined oral contraceptive pills containing both
estrogen and progestogens
–Progestine only pills (mini pills) contains only
progestogen.
• Injectable preparations-
• Implants
Surgery (Tubal ligation, Vasectomy….)
50. Mechanical devices
• Condom
• Diaphragm
• Cervical cap
• Intrauterine device (IUD)
Others
• Spermicides
• Avoiding intercourse during periods of fertility
51. Oral contraceptives
Non contraceptive Benefits of combined OCs
The risk of several diseases:
• Endometrial & ovarian cancer
• Ovarian cyst
• Pelvic inflammatory disease
• Premenstrual syndrome (PMS)
• Anemia
52. Combination OCs (estrogen + progestin)
a) Monophasic
– The daily estrogen & progestin dosage remains
constant throughout the monthly cycle of use
b) Biphasic
– The estrogen dosage remains constant, but the
progestin dosage is during the 2nd half of the cycle
c) Triphasic
The monthly cycle is divided into three segments
In all triphasic segments, the progestin dosage changes
for each segment of the cycle
• In two regimens, the estrogen dosage varies also
53. Combination OCs
• Most efficacious forms of birth control, very safe, although
minor side effects are common.
• Consist of an estrogen + progestin, only two estrogens are
employed:
– Ethinyl estradiol and mestranol.
– In contrast, several progestins are used, norethindrone
being employed most often.
MOA
• fertility in several ways:
– Estrogen inhibits the release of FSH from the anterior
pituitary by a negative fee back effect → suppresses
development of ovarian follicles.
– Progestrone inhibits secretion of LH → prevents ovulation
– Can modify the endometrium, making it less favorable for
implantation.
54. Adverse effects
1. Thrombotic Disorders
• Caused by estrogen component
• circulating levels of clotting factors
• Incontrast to orlder OCs, currently available OCs carry low
risk of thrombosis
2. Hypertension
• blood levels of angiotensin & aldosterone (Bp)
• Risk with age & duration of OCs use
3. Teratogenic effect
• Progestin during early pregnancy variety of teratogenic
effects (e.g. limb reductions, heart abnormalities etc.)
55. 4. Effects related to estrogen or progestin imbalance .
• Excess estrogen nausea ,breast tenderness and
edema.
• Progestin excess appetite, fatigue & depression
• A deficiency of either cause menstrual irregularities.
5. Multiple birth
• The incidence of twin birth is in women who become
pregnant shortly after discontinuing OCs.
6. Benign hepatic adenoma
• Rare complication of OCs use.
56. Progestin –only OCs (“minipills”)
• Contain a progestin (norethindrone or norgestrel)
MOA
• Makes cervical mucus inconvenient for sperm migration.
• It also hinders implantation through its effect on the
endometrium and on the motility and secretion of the
fallopian tube.
Therapeutic use
• It is prefered in lactating women and in whom estrogen is
contraindicated.
• Relatively ineffective as inhibitors of ovulation (less popular )
• Don’t cause thromboembolic disorders but less effective &
cause more menstrual irregularity
57. Emergency contraception ( Post coital contraception)
• Is a method of contraception used with in 72 hours of
unprotected sexual intercourse.
• Should not be used in place of the normal family planning
methods.
Preparations
• PLAN-B is two doses of the "minipill" (0.75 mg levonorgestrel
per pill) separated by 12 hours.
• Preven method Ethinyl estradiol / Norgestrel (0.05 mg + 0.5mg)
– 2 tabs taken with in 72 hrs & 2 tabs 12 hrs later
• Mifepristone
– Synthetic steroid, blocks receptors for progesterone
– Use – “morning after” pill contraception & termination of
early pregnancy (abortion).
58. Long- acting contraceptives
• Subdermal progestin Implants (Norplant)
– Norplant system, consists of 6 tiny silastic rubber capsules
each containing 36 mg of levonorgestrel, a synthetic
progestin.
– The capsules are surgically implanted on the side of upper
arm through a small incision.
59. MOA
• Cervical mucus is made thick a sticky (barrier to sperm)
• Endometrial growth is suppressed
• In some women Ovulation is suppressed
Pharmacokinetics
• Diffuses slowly & continuously from the capsule providing
blood levels sufficient for contraception for up to 5 years
• Slowly metabolized by the liver
• Following removal, blood levels become undetectable with
in 10-14 days
60. Adverse Effects
• Menstrual irregularities are common:
– Prolonged bleeding or (28%)
– Many bleeding days (17%)
– Amenorrhea (9.4%)
Depot Medroxy Progesterone Acetate (Depo-provera)
• Im, provides effective contraception for 3 or more months
• Prevents pregnancy in three ways:
• Thickening of the cervical mucus
• Alteration of the Endometrium
• Suppression of ovulation
61. Uterine Stimulants and Relaxants
• Drugs used to stimulate uterine contraction are known as
oxytocics; drugs that suppress are known as tocolytics.
I. Uterine Relaxants (Tocolytics) - Use to suppress preterm labor
• Magnesium sulfate (IV)—Control of seizures and
suppression of preterm labor; better for patients with
hyperthyroidism or diabetes.
• Nifedipine—Calcium channel blocker that has been used to
suppress preterm labor.
• Indomethacin—Third-line drug for suppressing preterm labor.
62. Beta2-Adrenergic Agonists
Ritodrine
• Relaxes uterine smooth muscle, so decreases frequency and
intensity.
Therapeutic use
• Only use is suppression of preterm labor for fetal development
or short-term while glucocorticoids promote maturation of
fetal lungs; begin with IV and then oral.
Adverse effects
• Oral effects rare
– Precautions and contraindications—Not for eclampsia,
severe preeclampsia, hemorrhage, maternal heart disease,
and less than 20 weeks’ gestation.
Terbutaline
• Much like ritodrine, was not approved for delay of preterm
labor; 1998 FDA said dangerous and proof of efficacy lacking.
63. II. Uterine Stimulants (Oxytocics)
• Three applications:
1. Induction or augmentation of labor,
2. Control of postpartum bleeding, and
3. Induction of abortion
Oxytocin
• Oxytocin is synthesized in the paraventricular and supraoptic
nuclei of the hypothalamus
• Stimuli for oxytocin release include sensory stimuli from
Cervix and vagina as well as
Suckling from the breast.
64. MOA
• Oxytocin acts through G protein-coupled receptors and the
phosphoinositide-calcium second-messenger system to
contract uterine smooth muscle.
• Activation of the oxytocin receptor also stimulates
prostaglandin synthesis.
Physiologic and pharmacologic effects
• Uterine stimulation—Increased force, frequency, and
duration of uterine contractions
• Milk ejection—Milk produced by glandular tissue of breast is
transferred into large sinuses, and this transfer of milk is
brought about a by milk-ejection reflex
• Water retention—Similar to ADH, so promotes renal
retention
65. Therapeutic uses
a) Induction of labor
b) Augmentation of labor,
c) Postpartum use to control bleeding,
d) Milk ejection,
e) Abortion
Adverse effects— Water intoxication
Precautions and contraindications—Improper use can be
hazardous (uterine rupture)
