Osteoporosis Drugs

• This document contains lecture notes about drugs used in osteoporosis and other conditions.

Osteoporosis Drugs

Estrogen and Androgen

• Reduces osteoclast apoptosis and increases osteoblast apoptosis.
• Increases the release of growth factors and decreases inflammatory cytokines
• Primary prevention and treatment of osteoporosis.
• Side effects include:
  • Vaginal bleeding
  • risk of breast and endometrial cancer, CAD (coronary artery disease)

Selective Estrogen Receptor Modulators (SERM) - Raloxifene

• It exhibits partial agonistic action of anti-estrogens.
• Acts as agonist in bone and antagonist in some female sex organs.
• Prevents and treats osteoporosis
• Does not stimulate endometrial/breast tissue.
• Has a lower risk of thromboembolism when compared with estrogen.
• May increase hot flashes; no effect on HDL.

Denosumab

• A monoclonal antibody that binds to RANKL, thus terminating osteoclast function.
• Very expensive.

Calcitonin

• Binds to osteoclasts and inhibits bone resorption.
• Administered as a nasal spray.

Parathyroid Hormone (PTH (1-34) (Teriparatide)

• Recombinant formulation of endogenous parathyroid hormone (PTH)
• Stimulates osteoblast function.
• Calcium is released from bone.
• Treats osteoporosis in postmenopausal women at high risk for fracture, e.g., those with previous osteoporotic fracture and multiple risk factors.
• Side effects include:
  • Transient hypercalcemia. Signs include: nausea, vomiting, constipation, low energy, or muscle weakness.
  • Osteosarcoma risk in animals.

Strontium

• It is the first drug to possess dual action with both anabolic and anti-resorptive effects.

Supplementation

Calcium

• Calcium Carbonate:
  • Should be taken with food.
  • Highest calcium content.
  • Causes GIT symptoms more.
  • Below age 50: 1000 mg
  • More than age of 50: 1200 mg
• Calcium Citrate:
  • Does not have to be taken with food
  • Causes fewer GIT issues
  • More expensive
• Side effects include:
  • Most common: constipation. Increase water, fiber, and exercise.
  • Kidney stones.
  • Increased cardiovascular events.

Vitamin D

• Cholecalciferol (D3): Animal source, more potent.
• Ergocalciferol (D2): Plant source.
• The absorption of calcium and phosphate from the GIT and kidneys increases with usage.
• Recommended
  • Below age 50: 400-800 units daily
  • More than age of 50: 800-1000 units daily

Bisphosphonates

• Example drugs include: Alendronate, Ibandronate, Risedronate, Zoledronate
• Route of administration: Oral or IV
• Inhibits osteoclast function preventing bone resorption
• Use:
  • Osteoporosis
  • Paget's disease
  • Malignancy associated hypercalcemia
• Side effects:
  • Gastro-esophageal reflux, ulceration, and esophagitis.
  • Osteonecrosis of the jaw
  • Fracture in long bone (femur)
• Should be taken with an empty stomach in an upright position for 30 minutes with a large amount of water (250 ml).

Gonadal Hormones Pharmacology

• Includes:
  • Estrogen
  • Progesterone
  • Androgens

Estrogen

• Example drugs include: Estradiol, Estrone, and Ethinyl-estradiol
• Effects
  • Reproduction and development of female sex organs
  • Growth of secondary sex characteristics (male + female)
  • Role in ovulation and pregnancy
  • Role in bone density modulation (male + female)
  • Role in mineral, carbohydrate, protein, and lipid metabolism
• Use:
  • Primary Hypogonadism
  • Postmenopausal Hormonal Therapy
  • Oral Contraceptives
  • Suppress ovulation in patients with intractable dysmenorrhea or hirsutism
  • Fertility treatments
• Side effects:
  • Thrombolytic complications
  • Endometrial carcinoma; breast carcinoma
  • Hypertension
  • In men: feminization of genitalia & impotence

Selective Estrogen Receptor Modulators (SERMs)

• Tamoxifen
  • Estrogen antagonist on breast and CNS.
  • Most effective in treatment of tumors that are ER-positive
  • Preventative agent for women at high risk for breast cancer
  • Side Effects: Hot flushes, thromboembolism
• Raloxifene
  • Estrogen antagonist on breast, endometrium, and CNS.
  • Estrogen agonist effect on bone.
  • Treats osteoporosis in post-menopausal women
  • Side Effects: Hot flushes, thromboembolism
• Clomiphene
  • Antagonist effect in pituitary, opposes the negative feedback effect of endogenous estrogen.
  • Major use: induction of ovulation in women with an intact hypothalamic-pituitary-ovarian axis
• Estrogen Antagonists - Fulvestrant
  • Estrogen antagonist in all tissue.
  • Treats breast cancer in patients whom tamoxifen therapy is unsuccessful
  • Side Effects: Hot flushes reduced bone mineralization

Progesterone

• Example drugs include: Natural Progesterone, Medroxyprogesterone, Norethindrone and Drospirenone.
• Effects:
  • Maintenance of Pregnancy
  • Inhibition of follicular maturation and ovulation
• Use
  • Oral contraceptives
  • HRT to limit estrogen's effects on the endometrium
  • Premature labor (decrease uterine contractions)
• Side effects:
  • Weight gain
  • Decrease bone mineralization
  • Norethindrone derivatives may cause hirsutism and masculinization

Anti-progesterones

• Mifepristone is antagonist.
• Used in first trimester to terminate pregnancy (along with prostaglandins to increase uterine contractions)
• Acts as a Post-coital contraceptive (prevent implantation)
• Side effects:
  • Vaginal bleeding, abdominal pain and cramping

Progestins

• Inhibit ovulation by suppressing the release of gonadotrophins (FSH & LH).
• Increase viscosity of the cervical mucus so viscous.
• Inhibit implantation by causing abnormal contraction of the fallopian tubes & uterine musculature

Progestin Only

• Oral formulations of norethindrone or levonorgestrel are taken daily
• Subdermal implants of levonorgestrel.
• IM injections of medroxyprogesterone
• IUD that releases low amounts of progesterone

Combined Pills

• Monophasic: A fixed amount of estrogen & progestin
• Biphasic (2 doses): A fixed amount of estrogen, while the amount of progestin increases stepwise in the second half of the cycle.
• Triphasic (3 doses): Amount of estrogen; fixed or variable & amount of progestin increases stepwise in 3 phases.

Emergency Contraceptives

• Used for the prevention of pregnancy following unprotected intercourse.
• To be effective, they must be taken within 72 hours of intercourse.

Androgens

• Example drugs include: Testosterone, Methyltestosterone, Oxandrolone
• Effect:
  • Maturation of male genitals.
  • Development of secondary sex characteristics.
  • Its ability to build muscle mass, which contributes to differences in muscle strength
  • Promotes the synthesis of erythropoietin
• Use:
  • Male hypogonadism
  • Weight gain in patients with wasting syndrome.
  • Certain types of anemia
• Side effects:
  • Reduced spermatogenesis and fertility due to feedback inhibition
  • Acne, particularly in women
  • Virilization (including facial hair and hirsutism)
  • In older men, increased risk of benign prostate hyperplasia and prostate cancer

Androgen Antagonists

• Flutamide blocks the androgen receptor.
  • Used in conjunction with GnRH analogs to treat metastatic advanced prostate cancer
  • Treats Hirsutism in women -Gynecomastia and Hepatotoxicity
• Finasteride blocks the enzyme that converts testosterone to dihydrotesterone.
  • Treats benign prostatic hypertrophy and male patterned baldness.
  • Impotence
  • Gynecomastia

Drugs Acting on the Uterus

• Include:
  • Oxytocics
  • Prostaglandins
  • Ergot Alkaloids

Oxytocic drugs

• Oxytocin (Syntocinon) promotes the influx of calcium from extra-cellular fluid and from ER into the cell, this increase in cytoplasmic calcium stimulates uterine contraction.
• Stimulate both the frequency and force of uterine contractility particularly of the fundus segment of the uterus.
• Contract the fundus only, not the cervix.
• These contractions resemble the normal physiological contractions of uterus.
• Immature uterus is resistant to oxytocin. Contract uterine smooth muscle only at term.
• Clinically oxytocin is given only when uterine cervix is soft and dilated
• Uses:
  • Induction + augmentation of labor
  • Post partum uterine bleeding Side Effects:
  • Uterine rupture the women wouldn't have
  • Fetal death (ischemia)
  • Water intoxication

Ergot alkaloids

• Ergometrine and Methyl-ergometrine
• Induce Tetanic contraction of uterus without relaxation in between (not like normal physiological contractions).
• It causes contractions of uterus as a whole i.e. fundus and cervix (tend to compress rather than to expel the fetus)
• Use:
  • Post-partum hemorrhage

Prostaglandins

• PGE2 examples Misoprostol PGF2α - examples Dinoprost
• Induce Contraction throughout pregnancy.
• Soften the cervix
• Use:
  • Induction of abortion (pathological)
  • Induction of labor(fetal death in utero)
  • Postpartum hemorrhage.

Corticosteroids Pharmacology

Glucocorticoids and Mineralocorticoids

• Glucocorticoids Example Drugs: cortisone, hydrocortisone methylprednisolone, prednisone, betamethasone, dexamethasone
• Glucocorticoid Effects and Side Effects:
  • Metabolic effects
  • Fat deposition in certain areas (e.g., the face (moon facies), shoulder and back (buffalo hump)
  • Muscle protein catabolism
  • Catabolic effects on bone lead to osteoporosis
  • Immunosuppressive effects
  • Anti-inflammatory effect
  • Stimulate gastric acid secretion Side Effects of Glucocorticoids:
  • Adrenal disorders: Addison's disease, acute adrenal insufficiency, congenital adrenal hyperplasia, Cushing's syndrome
  • Diabetes Mellitus
  • Adrenal suppression
  • Peptic ulcer
  • Non-adrenal disorders allergic reactions, organ transplant, Hematologic Cancer leukemia, lymphomaMyopathy. Hypertension., Osteoporosis
• Mineralocorticoids example drugs; Aldosterone and Fludrocortisone
• Action, promotes Na+ reabsorption, K+ excretion (by enhancing Na+K+ ATPase, in the distal convoluted tubule & thus it is very important in the regulation of blood volume & blood pressure
• Mineralocorticoid Antagonists Drugs: Spironolactone, Eplerenone and Mifepristone
• Treatment of primary aldosteronism. Synthesis Inhibitors – Ketoconazole

Drugs Used in Thyroid Hormone disorders

Anti-Hypothyrodism

• Levothyroxine (T4)
  • A synthetic form of the thyroxine (T4), is the drug of choice for replacement therapy
  • Stable and has a long half life (7 days) given once daily.
  • Absorption is increased when hormone is given on erempty stomach
  • Stable with an increased half-life of 7 days
• Liothyronine (T3)
  • More potent & rapid action than levothyroxine. Short T12.
  • Not recommended for routine replacement therapy, thus avoided in cardiac patients Black Box Warning: Use of thyroid hormone in the treatment of obesity or weight loss is contraindicated.)
• Liotrix is a Combination of synthetic T4 & T3 in ration 4:1

Thioamides

• Propylthiouracil and Methimazole
• Inhibit synthesis of thyroid hormones by inhibiting the peroxidase enzyme that catalyzes the iodination of tyrosine residues
• Recommended in pregnancy i.e PTU
• Recommended in breast feeding.
• Side effects WBC reduction

IODINE

• Lugol's solution, potassium iodide
• Inhibit thyroid hormone synthesis and release.
• *Plock the peripheral coersion
• Prior to thyroid surgery to decrease vascularity & size of the gland. Preoperatively within 10-15 days. Following radio-active iodine therapy.
• Side effects Iodism *Symptoms Hypersalivation

Radioactive iodine (RAI)

• ¹³¹
• accumulates in the thyroid gland and destroys parenchymal cel
• Used to treat Hyperthyroidism mainly in old patients (above 40) Patients with toxic nodular goiter. Side effects include: High incidence of delayed hypothyroidism and may cause genetic damage

Drugs Used In Diabetes

• Insulin
• Increase glucose uptake & utilization by peripheral tissues
• Increase Conversion of carbohydrate to fat
• Increase Lipogenesis- Anabolic effect
• Increase Glycogen synthesis
• Decrease Glycogenesis

Types of Insulin

• Ultra-short Rapid: Lispro, aspart, glulisine
• Short: Regular
• Intermediate: NPH Long: Glargine and Determir
• Side Effect include: Hypoglycemia may result from taking too much insulin Signs of hypoglycemia include: tachycardia, confusion, sweating, and drowsiness lipobypertrophy, the accumulation of fat in the area of injection.
• Treatment: Dextrose *10 & 258% - Solution

Anti-Diabetic Drugs – Insulin secretagogues

• Drugs:
  • Sulfonylurea
  • Meglitinide analogues
• Increase insulin secretion

Anti-Diabetic Drugs – Insulin sensitizers

• Drugs:
  • Biguanides
  • Thiazolidinedio nes (glitazone)
• Increases insulin sensitivity.

Anti-Diabetic Drugs – Other

1. Alpha glucosidase inhibitors reduce carbohydrate absorption
2. Incretin mimetics
3. Dipeptidyl peptidase-4 (DPP-4) Inhibitors 2 & 3 are new agents (Gl hormones) Sulfonylureas cause increased insulin release by block in the ATP sensitive K in beta cells Type II diabetes Hypoglycemia due to increase inappetite and Weight gain due to increase in appetite Patients allergic to sulfonylurea are given second generation drugs to control postprandial glucose level. Increase the sensitivity of target organs to insulin no effect on insulin secretion no hypoglycemia effect Metformin glucofay

Thiazolidinediones

• Activates peroxisome proliferator-activated receptor y nuclear receptors in muscles, liver, and adipose tissue -Increased glucose uptake
• Side Effects include hepatotoxicity and Congestive heart failure in addition to Fluid retention withedema

Drug Class and Drug Facts

Biguanides such as Mel formin increase the sensitivity of target organs to insulin with no hypoglycemia effect A GLUCOSIDASE act by inhibiting inverting enzyme thereby inhibiting carbohydrate digestion at the site of the intestinal tract SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLTZ inhibits sodium and glucose resulting in increased increase glucosuria. Lowers plasma glucose levels Incretin mimetics are Gl hormones secreted in response to food thru the circulation. 25 stimulate 28 colls -Type ll with heart disease: increase volume reduce