DEPARTMENT OF PHARMACOLOGY

CALCIUM METABOLISM
Introduction
Calcium metabolism involves the regulation of calcium levels in the blood and
bones, crucial for bone health, nerve transmission, muscle contraction, and
blood clotting. The body maintains calcium balance through the coordinated
action of hormones like parathyroid hormone, calcitonin, and vitamin D, which
influence calcium absorption, excretion, and storage.

Classification of drugs affecting calcium metabolism

Mechanism of Action of Drugs Affecting Calcium Metabolism

1. Bisphosphonates

(e.g. Alendronate, Zoledronate, Risedronate)

Bind to bone surfaces and are taken up by osteoclasts.

Inhibit osteoclast activity by:

● Disrupting the ruffled border of osteoclasts.

● Promoting osteoclast apoptosis
● Blocking the mevalonate pathway needed for osteoclast function
(important for alendronate, risedronate)

2. Vitamin D (Calcitriol and Analogues)

● Increase plasma calcium and phosphate by:

○ Enhancing intestinal absorption of calcium and phosphate.
○ Increasing renal tubular reabsorption.
● Promoting bone resorption to release calcium and phosphate

3. Parathyroid Hormone (PTH, Teriparatide)

● Acts on PTH receptors (G-protein coupled) → activates

adenylyl cyclase → ↑ cAMP → cellular effects:
○ ↑ Bone resorption (in continuous doses).
○ ↑ Renal reabsorption of calcium.
○ ↓ Renal reabsorption of phosphate.
○ Stimulates calcitriol synthesis, enhancing GI calcium absorption
4. Calcitonin

● Synthesized by thyroid C-cells; opposed PTH.

● Lowers plasma calcium and phosphate by:
○ Inhibiting osteoclasts → ↓ bone resorption.
○ Reducing renal tubular reabsorption of calcium and phosphate

5. Cinacalcet (Calcimimetic Agent)

● Binds to calcium-sensing receptors on parathyroid gland.

● Suppresses PTH secretion → ↓ serum calcium level

6. Glucocorticoids
● Decrease calcium absorption from the gut.
● Increase renal excretion of calcium
Promote osteoblast inhibition and osteoclast activation, leading to bone
loss/osteoporosis
Therapeutic Indications of Calcium Metabolism Drugs

Drug/Class Therapeutic Indications

Calcium Salts - Calcium deficiency (growth, pregnancy,

osteoporosis, rickets) - Tetany - Antacid
- Urticaria/dermatoses

Vitamin D & Analogues - Nutritional rickets/osteomalacia - Renal

rickets - Hypoparathyroidism - Vitamin
D–dependent/resistant rickets -
Osteoporosis - Psoriasis (Calcipotriol)

Bisphosphonates - Paget’s disease - Postmenopausal and

corticosteroid-induced osteoporosis -
Hypercalcaemia of malignancy -
Hyperparathyroidism-associated
hypercalcaemia - Painful lytic bone
lesions

Calcitonin - Hypercalcaemia (e.g., in malignancy) -

Paget’s disease - Osteoporosis
(postmenopausal, corticosteroid-induced)

Teriparatide (PTH analogue) - Severe osteoporosis (especially in

postmenopausal women)

Cinacalcet (Calcimimetic) - Hypercalcaemia due to parathyroid

tumour - Secondary hyperparathyroidism
due to chronic kidney disease

Glucocorticoids - Used in vitamin D toxicity to reduce

serum calcium - Long-term use may
cause
Adverse Effects of Calcium Metabolism Drugs

Drug/Class Adverse Effects

Calcium Salts - Constipation - Hypercalcaemia with

high doses - IV calcium chloride may
cause tissue necrosis

Vitamin D - Hypercalcaemia (nausea, fatigue,

weakness, polyuria) - Renal stones -
Renal failure with prolonged overdose

Bisphosphonates - Esophagitis (oral forms) -

Abdominal pain, nausea -
Osteonecrosis of jaw (rare, serious) -
Hypocalcaemia

Teriparatide (PTH analogue) - Hypercalcaemia - Expensive

therapy

Calcitonin - Nausea, vomiting - Flushing - Pain

at injection site - Antibody formation
with porcine source

Cinacalcet (Calcimimetic)
- Hypocalcemia
BISPHOSPHONATES
Introduction
Bisphosphonates are a class of drugs that prevent bone resorption by inhibiting
osteoclast activity. They are primarily used in the management of osteoporosis,
Paget’s disease, and hypercalcemia of malignancy. Their mechanism of action
varies depending on the chemical structure—nitrogenous and non-nitrogenous
subtypes.

Classification of Bisphosphonates

Mechanism of Action of Bisphosphonates

Non-nitrogen bisphosphonates:
Incorporated into ATP analogs, causing osteoclast apoptosis.
Nitrogen bisphosphonates:
Inhibit farnesyl pyrophosphate synthase in the mevalonate
pathway → inhibits osteoclast function and promotes
apoptosis
Therapeutic Indications of Bisphosphonates

Condition Drug Example

Postmenopausal osteoporosis Alendronate, Risedronate

Paget’s disease of bone Etidronate, Zoledronate

Hypercalcemia of malignancy Zoledronate

Osteolytic bone metastases Clodronate, Zoledronate

Glucocorticoid-induced osteoporosis Alendronate

Adverse Effects of Bisphosphonates

● GI effects: Esophagitis, gastritis (oral forms)

● Musculoskeletal pain
● Hypocalcemia
● Osteonecrosis of the jaw (rare, more common with IV forms)
● Atypical femur fractures (with long-term use)

ANTIDIURETICS
Introduction
Antidiuretics, also known as antidiuretic hormones or ADH analogues, regulate
the body’s water balance by controlling the amount of water reabsorbed in the
kidneys. These agents are used in conditions such as diabetes insipidus and
nocturnal enuresis and work by acting on specific receptors in the renal tubules.

Classification of Antidiuretics

Class Drugs

Natural hormone Vasopressin (ADH)

Synthetic analogues Desmopressin (DDAVP)

Vasopressin receptor agonists Terlipressin, Lypressin

ADH secretion stimulants Chlorpropamide, Carbamazepine

ADH degradation inhibitors Clofibrate

Mechanism of Action of Antidiuretics

● Vasopressin (ADH) acts on V2 receptors in renal collecting

ducts
→ ↑ insertion of aquaporin-2 water channels
→ ↑ water reabsorption → ↓ urine output

● Desmopressin: Selective V2 agonist (longer acting, minimal V1 effect)

● Terlipressin: Acts on V1 receptors → vasoconstriction

(used in bleeding esophageal varices

Therapeutic Indications of Antidiuretics

 Drug/Class Therapeutic Indications

Desmopressin Central diabetes insipidus, nocturnal

enuresis, von Willebrand disease

Vasopressin Vasodilatory shock (e.g., septic

shock), GI bleeding

Terlipressin Bleeding esophageal varices,

hepatorenal syndrome

Chlorpropamide Mild diabetes insipidus (rare use)

Adverse Effects of Antidiuretics

● Water intoxication → hyponatremia

● Headache, nausea, abdominal cramps
● Vasopressin: Vasoconstriction → hypertension, angina,
arrhythmia
● Desmopressin: Seizures (due to hyponatremia in children)
● Terlipressin: Ischemia due to vasoconstriction

SUPERINFECTIONS
Introduction
Superinfections occur when normal microbial flora is disrupted, often due to
prolonged or broad-spectrum antibiotic use, leading to the overgrowth of
opportunistic pathogens. These infections are challenging to treat and often
require additional or alternative antimicrobial therapy.
Example:
Pseudomembranous colitis
Candidiasis
Enterococcal infection

Mechanism of Action of Superinfections

● Disruption of normal microbial flora (especially in the gut and mucosa).
● Overgrowth of resistant or opportunistic pathogens.
● Reduced immune defense (especially with immunosuppressants).

Therapeutic Indications of Superinfections

Drug/Class Therapeutic Indications

Vancomycin (oral) Clostridioides difficile infection (first-

line in severe cases)

Fidaxomicin Recurrent or severe C. difficile

infections

Metronidazole Mild to moderate C. difficile colitis

Fluconazole, Nystatin Oral/vaginal candidiasis

Amphotericin B, Caspofungin Systemic fungal infections

Linezolid, Daptomycin MRSA or VRE infections

Adverse Effects of Superinfections

● Vancomycin: Nephrotoxicity, ototoxicity (rare with oral form)
● Metronidazole: Metallic taste, GI upset, disulfiram-like reaction
● Fluconazole: Liver enzyme elevation, QT prolongation
● Amphotericin B: Nephrotoxicity, electrolyte imbalance
● Linezolid: Myelosuppression, neuropathy with long-term use
ANDROGENS AND RELATED DRUGS
Introduction
Androgens are male sex hormones responsible for the development and
maintenance of male characteristics. Drugs affecting androgen pathways
include anabolic steroids, anti-androgens, and hormone analogues, used in a
variety of conditions ranging from hypogonadism to prostate cancer and
androgenic alopecia.

Classification of Androgens and related drugs

0
Mechanism of Action of Androgens and Related drugs
● Testosterone binds to androgen receptors → regulates
gene expression → promotes male sexual development,
muscle growth.
● Anabolic steroids enhance protein synthesis → increased
muscle mass
● Anti-androgens block androgen receptors → inhibit
androgen action (e.g., in prostate cancer)
● 5α-reductase inhibitors prevent conversion of testosterone
to dihydrotestosterone (DHT) → useful in BPH, androgenic
alopecia
 ● GnRH analogues/antagonists suppress LH and FSH
secretion → ↓ testosterone production
Therapeutic Indications of Androgens and related drugs

Drug/Class Therapeutic Indications

Testosterone

Hypogonadism, delayed puberty, male

hormone replacement

Nandrolone Anemia, wasting syndromes,

osteoporosis

Finasteride Benign prostatic hyperplasia, male

pattern baldness

Flutamide, Bicalutamide Prostate cancer

Leuprolide Prostate cancer, precocious puberty,

endometriosis

Adverse Effects of Androgens and related drugs

● Androgens: Acne, virilization in females, premature epiphyseal closure

in children, hepatotoxicity
● Anabolic steroids: Aggression, gynecomastia, testicular atrophy,
infertility
● Anti-androgens: Gynecomastia, liver dysfunction
● 5α-reductase inhibitors: Impotence, ↓ libido
 ● GnRH analogues: Hot flashes, decreased bone density (with long-term
use)
FIXED DOSE COMBINATIONS (FDCs)
Introduction
Fixed Dose Combinations (FDCs) are pharmaceutical products that contain two
or more active drugs in a single dosage form. FDCs are commonly used to
improve patient compliance, reduce pill burden, and enhance therapeutic
outcomes in conditions like hypertension, diabetes, tuberculosis, and HIV.

FIXED-DOSE COMBINATIONS EXAMPLES

Trimethoprim + Sulfamethoxazole
Amoxicillin + Clavulanic Acid
Glimepiride + Metformin
Amlodipine + Atenolol
Fluticasone + Salmeterol
Artemether + Lumefantrine
Lopinavir + Ritonavir

Mechanism of Action of Fixed Dose Combinations (FDCs)

FDCs act through multiple mechanisms depending on the combination, e.g.:

● Amoxicillin + Clavulanic acid
o Amoxicillin: inhibits bacterial cell wall synthesis
o Clavulanic acid: inhibits β-lactamase enzyme →
prevents degradation of amoxicillin
● Glimepiride + Metformin
o Glimepiride: increases insulin release
 o Metformin: decreases hepatic glucose production and increases
insulin sensitivity

Adverse Effects of Fixed Dose Combinations (FDCs)

● Dose inflexibility: Cannot titrate individual components

● Increased risk of adverse effects due to drug interactions

● Inappropriate combinations (e.g., irrational FDCs found in market)

● Overuse can lead to resistance, especially in antimicrobials