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ESSAYS

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ESSAY 1: Hormonal Contraceptives - Classification, Oral Contraceptives (Mechanism, Types, Uses, Adverse Effects)

Classification of Hormonal Contraceptives

1. Combined Oral Contraceptive Pills (COCPs)
   • Monophasic (fixed estrogen + progestin dose)
   • Biphasic (varying progestin, fixed estrogen)
   • Triphasic (varying both)
   • Extended-cycle / continuous-cycle pills
2. Transdermal patch (changed weekly)
3. Vaginal ring (replaced monthly or annually)
4. Combined injectable contraceptives

1. Progestin-only pills (Mini-pills) - e.g., norethindrone, desogestrel
2. Depot injection - Medroxyprogesterone acetate (DMPA) 150 mg IM every 3 months
3. Subdermal implants - Etonogestrel implant (Implanon/Nexplanon), lasts 3 years
4. Levonorgestrel-releasing intrauterine system (Mirena, Kyleena)

1. Levonorgestrel (Plan B) - within 72 hours
2. Ulipristal acetate (selective progesterone receptor modulator) - within 120 hours
3. Copper IUD - most effective, within 5 days
4. Combined estrogen-progestin (Yuzpe regimen) - older, less used

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Oral Contraceptive Pills (OCPs) - Detailed Discussion

Mechanism of Action

• Provides negative feedback to the hypothalamus and anterior pituitary, suppressing FSH secretion
• Inhibits follicular development and formation of a dominant follicle
• Stabilizes the endometrium (prevents breakthrough bleeding)
• Contributes to suppression of pituitary responsiveness to GnRH

• Suppresses LH secretion and prevents the LH surge - thus inhibiting ovulation (primary effect)
• Thickens cervical mucus - impedes sperm penetration
• Alters endometrial receptivity - renders endometrium hostile to implantation
• Impairs tubal motility - reduces ovum transport
• May inhibit capacitation and acrosome reaction of sperm

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Types of OCPs

• 1st generation: Norethindrone, norethynodrel
• 2nd generation: Levonorgestrel, norgestrel (androgenic)
• 3rd generation: Desogestrel, gestodene, norgestimate (less androgenic)
• 4th generation: Drospirenone (anti-androgenic, anti-mineralocorticoid), dienogest

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Therapeutic Uses

1. Primary contraception - failure rate 0.1% (perfect use), 8% (typical use) for COCPs
2. Dysmenorrhea - reduced prostaglandin synthesis, lighter periods
3. Menorrhagia - regulates and reduces blood loss
4. Endometriosis - suppresses ectopic endometrial growth
5. Polycystic ovary syndrome (PCOS) - reduces hyperandrogenism, regulates menstrual cycle
6. Premenstrual syndrome / PMDD - especially drospirenone-containing pills
7. Acne vulgaris - reduces androgenic stimulation of sebaceous glands
8. Hirsutism - androgen suppression
9. Ovarian cyst suppression - reduces functional cyst formation
10. Cancer risk reduction - ~50% reduction in endometrial cancer, ~40% reduction in ovarian cancer with long-term use
11. Hormone replacement (off-label) - in perimenopausal women
12. Iron-deficiency anemia - by reducing menstrual blood loss
13. Emergency contraception (Yuzpe regimen)

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Adverse Effects

• Nausea, vomiting, breast tenderness, bloating
• Fluid retention and mild weight gain (edema-related)
• Headache, migraine
• Increased risk of venous thromboembolism (DVT/PE): 3-15 per 10,000 women-years - due to increased clotting factors (II, VII, VIII, X) and decreased antithrombin III
• Hypertension (mild increase in BP in some patients)
• Cholestatic jaundice
• Melasma (chloasma - facial pigmentation)
• Increased risk of hepatic adenoma (rare)
• Increased risk of stroke in women with migraine with aura

• Acne, oily skin (androgenic progestins)
• Weight gain (anabolic effect)
• Mood changes (depression) - though large meta-analyses do not confirm significant effect
• Decreased libido
• Breakthrough bleeding (spotting)

• Increased risk of cervical cancer with long-term use (>5 years)
• Small increased risk of breast cancer (evidence remains debated)
• Drug interactions: rifampicin, anticonvulsants reduce efficacy; OCPs increase theophylline and cyclosporin levels
• Return of fertility may be delayed 1-2 months after stopping

• Smoking age >35 years
• Current DVT/PE or history of thrombophilia
• Migraine with aura
• Breast cancer (current)
• Hypertension >160/100 mmHg
• Ischemic heart disease or stroke
• Postpartum <6 weeks (breastfeeding)
• Active liver disease / viral hepatitis

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ESSAY 2: Glucocorticoids - Classification, Mechanism, Doses, Indications, Contraindications, Adverse Effects

Classification of Glucocorticoids

• Systemic: oral, IV, IM
• Topical: skin (Class I-VII potency), inhaled (beclomethasone, budesonide, fluticasone), intranasal, intraocular, intra-articular

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Mechanism of Action

1. Glucocorticoid diffuses across cell membrane and binds to the intracellular glucocorticoid receptor (GR-alpha), a cytoplasmic nuclear receptor
2. Binding causes dissociation of heat shock proteins (Hsp90, Hsp70, Hsp56) from the receptor complex
3. The hormone-receptor complex undergoes conformational change and translocates to the nucleus
4. In the nucleus, the activated GR binds to Glucocorticoid Response Elements (GREs) on DNA promoter regions
5. Transactivation: upregulation of anti-inflammatory genes - lipocortin-1 (annexin-1), IkB-alpha, IL-10, MKP-1 (MAP kinase phosphatase-1)
6. Transrepression: the GR-ligand complex interacts with transcription factors NF-kB and AP-1 and suppresses pro-inflammatory gene expression (IL-1, IL-2, IL-6, TNF-alpha, COX-2, iNOS, cell adhesion molecules)

• Direct effects on cell membrane receptors or G-protein-coupled membrane receptors
• Rapid feedback suppression of ACTH (too fast for transcription)
• Palmitoylated receptors near plasma membranes interact with membrane-associated proteins

• Stabilizes mast cell membranes - reduces degranulation
• Inhibits phospholipase A2 (via lipocortin-1) - reduces arachidonic acid release, reducing both prostaglandins and leukotrienes
• Inhibits production of inflammatory cytokines (IL-1, IL-2, IL-6, TNF-alpha, IFN-gamma)
• Inhibits neutrophil migration and macrophage activation
• Reduces capillary permeability
• Inhibits lymphocyte proliferation
• Reduces production of IgE (anti-allergic effect)

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Doses

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Indications

• Addison's disease (primary adrenal insufficiency) - hydrocortisone 20 mg/day + fludrocortisone
• Secondary adrenal insufficiency (pituitary disease)
• Congenital adrenal hyperplasia (CAH)
• Adrenal crisis - hydrocortisone 100 mg IV stat

• Asthma (inhaled + systemic for acute exacerbations)
• COPD exacerbations
• Allergic reactions, anaphylaxis
• Rheumatoid arthritis and other connective tissue diseases (SLE, dermatomyositis, vasculitis)
• Inflammatory bowel disease (Crohn's, ulcerative colitis)
• Nephrotic syndrome
• Organ transplantation (immunosuppression)
• Inflammatory skin diseases (pemphigus, dermatitis)
• Multiple sclerosis (acute relapse - high-dose methylprednisolone)

• Cerebral edema (dexamethasone 4-8 mg every 6 hours)
• Bacterial meningitis (dexamethasone reduces deafness)

• Lymphomas, leukemias (part of chemotherapy regimens - CHOP)
• To reduce cerebral edema from brain tumors
• Anti-emetic (dexamethasone)
• Hypercalcemia of malignancy

• Betamethasone/dexamethasone - fetal lung maturation in preterm labor (24-34 weeks)

• Dexamethasone suppression test - for Cushing's syndrome diagnosis

• Thyroid storm (inhibits T4 to T3 conversion)
• Septic shock (controversial, used in vasopressor-dependent patients)

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Contraindications

• Active untreated infections (tuberculosis, fungal infections, sepsis without antibiotics)
• Live viral vaccine administration during high-dose therapy
• Hypersensitivity to specific glucocorticoid

• Uncontrolled diabetes mellitus (will worsen hyperglycemia)
• Peptic ulcer disease (especially combined with NSAIDs)
• Osteoporosis (long-term use accelerates bone loss)
• Hypertension
• Glaucoma and cataracts
• Psychiatric history (may precipitate psychosis or mania)
• Congestive heart failure / fluid retention states
• Pregnancy (category D - risk of cleft palate in 1st trimester)
• Children (growth retardation with prolonged use)

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Adverse Effects

• Hyperglycemia and diabetes mellitus (steroid-induced diabetes)
• Hyperlipidemia
• Negative nitrogen balance, muscle wasting
• Hypokalemia (from mineralocorticoid-like effects at higher doses)

• HPA axis suppression (adrenal atrophy) - with prolonged use >2-3 weeks; risk of adrenal crisis on abrupt withdrawal
• Cushingoid features: moon face, buffalo hump, central obesity, supraclavicular fat pads
• Growth retardation in children
• Menstrual irregularities

• Osteoporosis and avascular necrosis of bone (femoral head)
• Proximal myopathy (steroid myopathy)

• Hypertension (sodium and water retention)
• Atherosclerosis acceleration

• Peptic ulcer (especially with NSAIDs - relative risk; glucocorticoids alone have modest ulcerogenic effect)
• Pancreatitis (rare)

• Posterior subcapsular cataracts
• Glaucoma (raised intraocular pressure)

• Euphoria, mood swings, insomnia (common)
• Psychosis, depression, mania (less common)
• Pseudotumor cerebri (raised ICP on withdrawal)

• Susceptibility to infections (bacterial, fungal, viral, opportunistic)
• Masking of signs of infection
• Impaired wound healing

• Skin atrophy, striae, bruising, purpura
• Acne, hirsutism

• Acute adrenal insufficiency (crisis) if abrupt withdrawal
• Gradual taper required for therapy >3 weeks

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ESSAY 3: Anti-thyroid Drugs - Classification, Mechanisms, Uses, Adverse Effects, PTU vs Carbimazole

Classification of Anti-thyroid Drugs

• Propylthiouracil (PTU)
• Methimazole (MMI)
• Carbimazole (pro-drug of methimazole) - used in UK/India

• Perchlorate (KClO4) - inhibits iodide uptake by competitive inhibition of NIS
• Thiocyanate - rarely used
• Pertechnetate - diagnostic use

• Lugol's iodine (5% iodine + 10% potassium iodide)
• Saturated solution of potassium iodide (SSKI)
• Effect: Wolff-Chaikoff effect - reduces organification; also reduces vascularity of gland preoperatively

• Iodine-131 (¹³¹I) - definitive treatment for Graves' disease

• Propranolol - controls sympathetic symptoms, also inhibits T4 to T3 conversion at high doses
• Atenolol, metoprolol

• Sodium ipodate, iopanoic acid - inhibit T4 to T3 peripheral conversion; block thyroid hormone release

• Lithium carbonate - inhibits thyroid hormone release (second-line)

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Detailed Account of Each Class

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A. Thioamides

1. Inhibition of thyroid peroxidase (TPO): They block the oxidation of iodide to iodine, and consequently inhibit the organification of iodine into tyrosine residues (MIT and DIT formation) on thyroglobulin
2. Inhibit coupling reaction: Prevent coupling of MIT and DIT to form T3 and T4
3. Extrathyroidal effect (PTU only): Propylthiouracil at doses >200-300 mg/day inhibits the peripheral enzyme 5'-deiodinase (5'-DI), which converts T4 to the more active T3. This is particularly valuable in thyroid storm. Methimazole and carbimazole do NOT have this effect.
4. Immunosuppressive effect (Graves' disease): Thioamides reduce thyroid autoantibody levels (TSH receptor antibody - TRAb), contributing to remission in Graves' disease

• Carbimazole is a pro-drug - rapidly converted to methimazole in the body
• PTU is ~80% protein bound; methimazole is not protein bound
• PTU has shorter half-life (~1.5 hours) - requires dosing every 6-8 hours
• Methimazole has longer half-life (~6 hours) - can be given once daily
• Both drugs cross the placenta and enter breast milk (PTU less so - preferred in pregnancy)
• Latency of 3-4 weeks before clinical effect (existing hormone stores must be depleted)

1. Graves' disease (primary indication) - both as definitive treatment and as preparation for surgery or RAI
2. Toxic multinodular goiter - pretreatment before RAI or surgery
3. Toxic adenoma - pretreatment
4. Thyrotoxicosis in pregnancy - PTU preferred in first trimester; methimazole from second trimester onward
5. Thyroid storm - high-dose PTU (preferred because of additional T4-to-T3 conversion inhibition)
6. Neonatal hyperthyroidism - PTU or methimazole
7. Preparation for subtotal thyroidectomy - to render patient euthyroid preoperatively

• PTU: 100-150 mg every 6-8 hours (initial); maintenance 50-100 mg/day
• Carbimazole: 10-40 mg/day (initial); maintenance 5-15 mg/day
• Methimazole: 10-30 mg/day (initial); maintenance 5-10 mg/day

• Skin rashes, urticaria, pruritus
• Mild leukopenia
• Arthralgias, arthritis
• Nausea, GI upset

• Agranulocytosis - most serious, occurs in 0.1-0.5%; presents as sore throat, fever, mouth ulcers; requires immediate drug withdrawal and WBC count; can be fatal from overwhelming infection
• Aplastic anemia (rare)
• Hepatotoxicity - PTU causes potentially fatal hepatic necrosis (rare but more common than with methimazole; FDA issued black box warning for PTU hepatotoxicity in 2010); methimazole causes mainly cholestatic jaundice
• Vasculitis (PTU - ANCA-associated)
• Hypoprothrombinemia (PTU)
• Hypothyroidism (dose-dependent)
• Neonatal hypothyroidism and goiter (with maternal use)

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B. High-dose Iodide (Lugol's Iodine, SSKI)

• The Wolff-Chaikoff effect: Large doses of iodide transiently inhibit organification of iodine within the thyroid, reducing hormone synthesis
• Reduces release of pre-formed thyroid hormones
• Decreases vascularity and firmness of the gland (important preoperatively in Graves' disease)

1. Preoperative preparation for thyroidectomy (given 10-14 days before surgery) - reduces gland vascularity and risk of thyroid storm
2. Thyroid storm (adjunct, given after thioamides)
3. Radioprotection - following radiation exposure (prevents ¹³¹I uptake)
4. Expectorant (potassium iodide)

• Iodism: metallic taste, salivation, rhinitis, burning of mouth/throat
• Hypersensitivity reactions (angioedema, drug fever)
• Thyroid gland enlargement
• Acneiform skin rash

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C. Radioactive Iodine (¹³¹I)

• Taken up by thyroid follicular cells via the sodium-iodide symporter (same as stable iodine)
• ¹³¹I undergoes beta (b-) decay, emitting high-energy beta particles (>99% of tissue damage) and gamma rays
• Beta particles have a tissue penetration of only 0.5-2 mm - localized destruction of thyroid follicular cells while sparing surrounding structures
• Results in radiation thyroiditis, fibrosis, and gradual ablation of functioning thyroid tissue

1. Graves' disease - most common definitive treatment in the USA
2. Toxic multinodular goiter
3. Toxic adenoma
4. Thyroid carcinoma (after total thyroidectomy - ablation of remnant tissue and metastases)

• Pregnancy (absolute - causes fetal hypothyroidism and mental retardation)
• Breastfeeding
• Active Graves' ophthalmopathy (may worsen)

• Hypothyroidism (permanent, in >50-80% within 10 years) - actually the goal in most cases
• Radiation thyroiditis (pain, swelling) in first week
• Transient worsening of hyperthyroidism

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D. Adrenoceptor Blockers (Beta-blockers) - as adjuncts

• Block sympathetic hyperactivity (tachycardia, tremor, anxiety, palpitations, sweating)
• Propranolol (non-selective): doses >160 mg/day inhibit 5'-deiodinase peripherally - reduces conversion of T4 to T3 by ~20%
• Do NOT reduce thyroid hormone levels (except the T3 reduction from propranolol's high-dose effect)

• Rapid symptomatic control in hyperthyroidism (within hours)
• Thyroid storm (IV propranolol + thioamides + iodide)
• Perioperative management

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Comparative Features of Propylthiouracil (PTU) and Carbimazole

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SHORT NOTES

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Short Note 1: Selective Estrogen Receptor Modulators (SERMs)

Mechanism of Action

• Agonistic effects in tissues where coactivators are predominant (bone, cardiovascular, uterus in some agents)
• Antagonistic effects in tissues where corepressors predominate (breast in most SERMs)

Classification and Individual Drugs

• Estrogen antagonist in breast tissue; partial agonist in uterus, bone, liver
• Uses: Treatment and prevention of hormone receptor-positive (ER+) breast cancer; premenopausal and postmenopausal women
• Dosage: 20 mg/day orally for 5-10 years in adjuvant therapy
• Adverse effects: Hot flushes, vaginal discharge/bleeding, endometrial cancer (uterine agonist effect), DVT/PE, cataracts

• Estrogen antagonist in breast AND uterus; agonist in bone and cardiovascular system
• Uses: Prevention and treatment of postmenopausal osteoporosis; prevention of breast cancer in high-risk women
• Advantage over tamoxifen: No endometrial stimulation
• Adverse effects: Hot flushes, DVT/PE, leg cramps

• Similar to tamoxifen; used in metastatic breast cancer
• Slightly less thrombogenic

• Partial agonist/antagonist at hypothalamic ER - blocks estrogen negative feedback on hypothalamus
• Results in increased GnRH pulsatility -> increased FSH/LH -> follicular development and ovulation
• Uses: Anovulatory infertility (PCOS is most common indication); ovulation induction
• Adverse effects: Multiple pregnancies, ovarian hyperstimulation syndrome (OHSS), hot flushes, visual disturbances (anti-estrogen effects on eye)

• Used in combination with conjugated estrogen (Duavee) - for menopausal symptoms without endometrial stimulation

• Agonist in vaginal epithelium; used for dyspareunia due to vulvovaginal atrophy

• Competitive antagonist + downregulator of ER (no agonism in any tissue)
• Used in advanced/metastatic ER+ breast cancer resistant to tamoxifen
• Also called "selective estrogen receptor downregulator" (SERD)

Clinical Applications Summary

• Breast cancer (adjuvant and preventive): tamoxifen, raloxifene, toremifene
• Ovulation induction: clomiphene
• Osteoporosis: raloxifene
• Menopausal symptoms: ospemifene, bazedoxifene

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Short Note 2: Antiandrogens

Classification

• Spironolactone - aldosterone and androgen receptor antagonist; most commonly used antiandrogen in women (hirsutism, PCOS)
• Cyproterone acetate - potent AR blocker + progestin; used in hirsutism, PCOS, male hypersexuality, prostate cancer; also in combined OCP (Diane-35)
• Medroxyprogesterone acetate (MPA) - some AR blocking activity

• Flutamide - pure AR antagonist (no progestin activity); used in prostate cancer; hepatotoxic
• Bicalutamide - more potent, better tolerated than flutamide; prostate cancer
• Nilutamide - prostate cancer; causes visual adaptation problems

• Enzalutamide, Apalutamide, Darolutamide - next-gen AR antagonists for castration-resistant prostate cancer (CRPC)

• GnRH agonists (leuprolide, goserelin, triptorelin) - initial flare then suppression of LH/FSH
• GnRH antagonists (degarelix, relugolix) - immediate suppression

• Ketoconazole - inhibits CYP17, reduces adrenal and testicular androgen synthesis
• Abiraterone acetate - selective irreversible CYP17A1 inhibitor; used in CRPC
• Aminoglutethimide - blocks cholesterol side-chain cleavage
• 5-alpha reductase inhibitors (separate class - see note 3)

Mechanism of AR Antagonists

Uses

1. Prostate cancer (medical or combined androgen blockade)
2. Hirsutism in women (spironolactone, cyproterone acetate)
3. PCOS with hyperandrogenism
4. Acne vulgaris (in women)
5. Female pattern hair loss (alopecia)
6. Precocious puberty
7. Male hypersexuality / paraphilias (cyproterone acetate)
8. Gender-affirming therapy (male-to-female transition)

Adverse Effects

• Spironolactone: gynecomastia (in men), hyperkalemia, menstrual irregularities, hypotension
• Cyproterone acetate: hepatotoxicity, decreased libido, weight gain
• Flutamide: hepatotoxicity (serious), gynecomastia, diarrhea
• Bicalutamide: gynecomastia, hot flushes (better hepatic profile than flutamide)
• GnRH agonists/antagonists: hot flushes, osteoporosis, erectile dysfunction, metabolic syndrome

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Short Note 3: 5-Alpha Reductase Inhibitors

Mechanism of Action

• Type I 5-AR: predominant in skin, liver, scalp
• Type II 5-AR: predominant in prostate, seminal vesicles, hair follicles

Drugs

• Selective inhibitor of Type II 5-alpha reductase
• Reduces DHT by approximately 70%
• Half-life: 6-8 hours
• Doses: 5 mg/day (BPH); 1 mg/day (male-pattern baldness)
• Duration to effect: 3-6 months for baldness; 6-12 months for BPH symptom relief
• Reduces prostate-specific antigen (PSA) by approximately 50% (must double PSA when interpreting on finasteride)

• Inhibits BOTH Type I and Type II 5-alpha reductase (dual inhibitor)
• Reduces DHT by >90%
• Half-life: ~5 weeks (very long)
• Dose: 0.5 mg/day (BPH); 0.5 mg/day (hair loss - off-label)
• More complete DHT suppression than finasteride

Therapeutic Uses

1. Benign prostatic hyperplasia (BPH) - reduce prostate volume, improve urinary flow, reduce risk of acute urinary retention and need for surgery
2. Male-pattern androgenetic alopecia (androgenic alopecia) - finasteride 1 mg/day shown to arrest progression and promote regrowth
3. Hirsutism in women - off-label (teratogenic, so only post-menopausal women or with reliable contraception)
4. Prostate cancer prevention - reduced incidence in PCPT trial (finasteride), though small increase in high-grade cancers noted

Adverse Effects

• Sexual dysfunction: decreased libido, erectile dysfunction, reduced ejaculate volume (occur in ~5-10%, often reversible)
• Gynecomastia (rare, ~1-3%)
• Post-finasteride syndrome: persistent sexual dysfunction, depression, cognitive changes reported by some patients even after stopping drug (controversial, rare)
• Teratogenicity: Category X in pregnancy - must not be handled by pregnant women (DHT essential for male fetal genital development); women of childbearing potential should not touch crushed tablets
• Reduced PSA by ~50% (diagnostic pitfall for prostate cancer screening)
• Possible small increased risk of high-grade prostate cancer (Grade 7+) with finasteride (from PCPT trial)

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Short Note 4: Mineralocorticoid and Glucocorticoid Antagonists

A. Mineralocorticoid Antagonists (Aldosterone Antagonists)

• Mechanism: Competitive antagonist at the mineralocorticoid receptor in distal convoluted tubule and collecting duct; prevents aldosterone-mediated sodium reabsorption and potassium excretion. Also has anti-androgenic properties (binds AR, inhibits 5-alpha reductase, and reduces testosterone synthesis).
• Pharmacokinetics: Prodrug - active metabolite is canrenone and 7-alpha-spirolactone; T1/2 varies
• Uses:
  • Primary hyperaldosteronism (Conn's syndrome) - both diagnosis and treatment
  • Heart failure with reduced ejection fraction (reduces mortality - RALES trial)
  • Hypertension (resistant hypertension)
  • Edema (cirrhotic ascites, nephrotic syndrome, cardiac edema)
  • Hypokalemia prevention/correction
  • Hirsutism and PCOS (anti-androgenic effect)
  • Pre-menstrual syndrome
• Adverse effects: Hyperkalemia (most important - potentially fatal), gynecomastia (dose-related - problematic in men), menstrual irregularities in women, breast tenderness, impotence, metabolic acidosis

• Mechanism: More selective MR antagonist (minimal AR/PR binding - no gynecomastia/endocrine side effects)
• Uses: Heart failure post-MI (EPHESUS trial), hypertension, heart failure with reduced EF (EMPHASIS-HF trial)
• Adverse effects: Hyperkalemia (same risk as spironolactone), no gynecomastia/sexual side effects

• Not an antagonist - a synthetic mineralocorticoid agonist used for replacement in Addison's disease and orthostatic hypotension

B. Glucocorticoid Antagonists

• Mechanism: Competitive antagonist at glucocorticoid receptor (GR) AND progesterone receptor (PR), with high affinity for both. At the GR, it blocks cortisol's genomic actions. Has partial agonist activity.
• Uses:
  • Cushing's syndrome (ectopic ACTH or adrenal causes) - blocks peripheral glucocorticoid effects; does not reduce cortisol levels
  • Medical abortion (as anti-progestagen) in combination with misoprostol - up to 10 weeks gestation
  • Emergency contraception
• Adverse effects: Nausea, vomiting, adrenal insufficiency (blocks GR - cortisol levels actually rise as feedback loop is impaired), hypokalemia, endometrial thickening, vaginal bleeding

• Inhibits CYP11B1 (11-beta-hydroxylase) - reduces cortisol synthesis
• Used in Cushing's syndrome

• Inhibits 11-beta-hydroxylase - reduces cortisol and aldosterone synthesis
• Used diagnostically (metyrapone test) and therapeutically in Cushing's syndrome

• Adrenolytic agent - destroys zona fasciculata and reticularis
• Used in adrenocortical carcinoma

• Inhibits early steps of steroidogenesis (cholesterol side-chain cleavage, CYP11A)
• Reduces cortisol, aldosterone, androgens, estrogens
• Used in Cushing's syndrome, adrenal carcinoma, breast cancer

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Short Note 5: Mechanism of Action of Sildenafil and Its Contraindications

Background - Physiology of Penile Erection

Mechanism of Sildenafil

• Increasing and prolonging cGMP levels in corpus cavernosum smooth muscle
• Enhancing and sustaining smooth muscle relaxation and vasodilation
• Amplifying the erectile response to sexual stimulation

• Pulmonary arterial hypertension (PAH) - PDE5 is expressed in pulmonary vasculature; sildenafil reduces pulmonary vascular resistance
• Female sexual arousal disorder (investigational)

Contraindications of Sildenafil

1. Nitrates (any form) - Most critical contraindication. Nitrates (nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, amyl nitrite) also work via the NO-cGMP pathway. Combining sildenafil with nitrates causes severe, potentially fatal hypotension. Even patients requiring nitrates for angina must not use sildenafil. Must wait ≥24 hours after sildenafil before giving nitrates (>48 hours for tadalafil).
2. Guanylate cyclase stimulators (riociguat, soluble GC stimulators) - additive hypotension
3. Hypersensitivity to sildenafil or any component

1. Severe cardiovascular disease - recent MI (<90 days), unstable angina, severe cardiac failure, uncontrolled hypertension (>170/110), hypotension (BP <90/50), recent stroke (<6 months)
2. Alpha-blockers - significant additive hypotension (especially at high doses of both; tadalafil + tamsulosin can cause severe hypotension) - caution required; allow adequate time between doses
3. Retinitis pigmentosa - hereditary degenerative retinal disease; risk of visual complications (PDE6 inhibition in rods)
4. Anatomical deformation of penis (e.g., Peyronie's disease, severe curvature) - caution only
5. Predisposition to priapism (sickle cell disease, multiple myeloma, leukemia) - erection lasting >4 hours is a urological emergency
6. Severe hepatic impairment (Child-Pugh C) - reduced metabolism; use with caution
7. CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, ritonavir) - increase sildenafil levels significantly; dose reduction required

• Headache (most common), flushing, rhinitis, dyspepsia
• Visual disturbances: blue-green color tinge, blurred vision, photophobia (PDE6 inhibition in retina)
• Sudden hearing loss (rare)
• Priapism (prolonged painful erection)
• Hypotension (especially with nitrates)
• Nasal congestion

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Short Note 6: Hypothyroidism - Features and Pharmacological Management

Definition

Etiology

• Primary (most common): Hashimoto's thyroiditis (autoimmune), post-radioactive iodine therapy, post-thyroidectomy, iodine deficiency (worldwide), drug-induced (amiodarone, lithium, thioamides, interferon-alpha, tyrosine kinase inhibitors)
• Secondary: Pituitary disease (TSH deficiency)
• Tertiary: Hypothalamic disease (TRH deficiency)
• Congenital (cretinism): Thyroid agenesis, dyshormonogenesis, maternal iodine deficiency

Clinical Features

• Fatigue, lethargy, cold intolerance, weight gain
• Bradycardia, hypertension (diastolic)
• Dry skin, hair loss, periorbital puffiness, macroglossia
• Constipation
• Delayed tendon reflexes
• Menstrual irregularities (menorrhagia)
• Myxedema (non-pitting edema), hoarse voice
• Hyperlipidemia, hyponatremia
• Elevated TSH (primary), low free T4

Pharmacological Management

• Oral bioavailability: 70-80% (improved with Tirosint liquid/gel cap formulations)
• Must be taken on an empty stomach (30-60 minutes before breakfast) - food, calcium, iron, proton pump inhibitors, cholestyramine all reduce absorption
• Half-life: 6-7 days (pure T4)
• Steady state achieved in 6-8 weeks

• Average replacement dose: 1.6 mcg/kg/day (approximately 75-150 mcg/day in adults)
• Starting dose in elderly or cardiac patients: low dose (25-50 mcg/day), increase slowly by 12.5-25 mcg every 4-6 weeks
• Young healthy patients: can start at 75-100 mcg/day
• In hypothyroid pregnancy: doses are often increased by 25-30% (estrogen increases TBG, requiring more T4)
• Goal: TSH in normal range (0.5-4.0 mIU/L); suppress TSH to 0.1-0.5 mIU/L after thyroid cancer surgery

• Calcium carbonate, aluminum hydroxide, ferrous sulfate, cholestyramine, soy products, proton pump inhibitors

• Rifampicin, phenytoin, carbamazepine, phenobarbital, HIV protease inhibitors - may require higher T4 dose

• Medical emergency with high mortality
• Treatment: IV liothyronine (T3) 5-20 mcg every 4-12 hours (or IV levothyroxine 200-500 mcg loading dose), hydrocortisone 100 mg IV every 8 hours (covers concurrent adrenal insufficiency), airway support, passive rewarming, IV fluids

• TSH checked 6-8 weeks after dose change (time to reach steady state)
• Symptoms of over-replacement: palpitations, tremor, heat intolerance, weight loss (iatrogenic hyperthyroidism); long-term risk of atrial fibrillation and osteoporosis

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Short Note 7: Role of Beta Blockers in Thyrotoxicosis and Thyroid Storm

Thyrotoxicosis

• Upregulate beta-adrenergic receptors, increasing catecholamine sensitivity
• Potentiate catecholamine effects (increased chronotropy, inotropy)

Role of Beta Blockers in Thyrotoxicosis

1. Beta-1 receptor blockade: Reduces heart rate, palpitations, cardiac output
2. Beta-2 receptor blockade: Reduces tremor, anxiety, sweating
3. Inhibition of peripheral T4-to-T3 conversion (propranolol at >160 mg/day): Propranolol inhibits the enzyme 5'-deiodinase at higher doses, reducing conversion of T4 to the more potent T3 by approximately 20%. This effect is unique to propranolol at high doses and is not shared by selective beta-1 blockers (atenolol, metoprolol).

• Immediate symptom control while awaiting antithyroid drug effect (bridge therapy)
• Perioperative management (alongside thioamides)
• Adjunct to radioactive iodine therapy (controls symptoms during the latent period)
• Thyrotoxic periodic paralysis (propranolol preferred)
• Preparation for surgery in thyrotoxic patients

Thyroid Storm (Thyrotoxic Crisis)

• IV propranolol 0.5-1 mg given slowly; oral 60-80 mg every 4-6 hours
• Controls the dangerous tachycardia and prevents arrhythmia-induced cardiac failure
• At the high doses used in thyroid storm, additionally reduces T3 levels by blocking 5'-deiodinase
• Esmolol (ultra-short-acting IV beta-1 blocker) used in ICU setting for precise rate control
• Beta-blockers are contraindicated if bronchospasm or decompensated heart failure - use diltiazem (CCB) as alternative in that case

• Severe asthma / bronchospasm (relative) - use cardioselective BB (atenolol, metoprolol) with caution
• Decompensated heart failure with very low EF - relative; however, rate control may improve cardiac output
• Second/third degree heart block
• Cardiogenic shock

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References used: Katzung's Basic and Clinical Pharmacology 16th Edition (Chapters 38, 39); Harrison's Principles of Internal Medicine 22nd Edition (2025); Washington Manual of Medical Therapeutics; Goodman & Gilman's Pharmacological Basis of Therapeutics.