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SECTION A: CHELATING AGENTS & RELATED DRUGS

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1. Desferrioxamine (Deferoxamine) - Mechanism of Action & Therapeutic Uses

Chemistry

Mechanism of Action

Fe³⁺ (Free iron) + Desferrioxamine
         ↓
    Ferrioxamine complex
  (stable, water-soluble, non-toxic)
         ↓
  Excreted via urine (red-brown colored)
  and bile/feces

• DFO binds free iron (both Fe³+ from plasma and iron from inside cells and mitochondria)
• It does NOT bind iron already incorporated into hemoglobin, transferrin, ferritin, or cytochromes - this selectivity is pharmacologically important
• The ferrioxamine complex is water-soluble, non-toxic, and renally excreted
• 100 mg DFO binds approximately 8.5 mg of elemental iron

Routes of Administration

• IV infusion (preferred in acute toxicity) - 15 mg/kg/hr; max 6 g/day
• SC infusion (preferred in chronic iron overload) - using infusion pump over 8-12 hours, 5-7 nights/week
• Oral (for gastric binding in acute poisoning) - 8-12 g orally to absorb unabsorbed iron in the gut

Therapeutic Uses

Adverse Effects

• Ocular: Retinal toxicity, visual field defects, night blindness, cataracts (especially with high doses/young patients)
• Auditory: Sensorineural hearing loss (SNHL) - reversible in early stages
• Systemic: Hypotension with rapid IV infusion, allergic reactions, febrile reactions
• Infections: DFO acts as a siderophore for Rhizopus spp., increasing risk of mucormycosis (especially in dialysis patients)
• Long-term SC use: Local injection site reactions, skeletal dysplasia in children
• Monitoring: Regular ophthalmologic and audiometric testing required during chronic therapy

Newer Oral Iron Chelators

• Deferasirox (tridentate) - oral, once daily; hepatotoxic
• Deferiprone - oral; causes agranulocytosis (requires WBC monitoring)

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2. Dimercaprol (BAL - British Anti-Lewisite)

History

Chemistry & Mechanism of Action

Heavy metal (As, Hg, Pb) + SH groups of tissue enzymes
         ↓
Enzyme inhibition → cell death

Dimercaprol (two free -SH groups)
         ↓
Competes with enzyme -SH groups
         ↓
Metal-BAL complex (water-soluble ring chelate)
         ↓
Excreted in urine

Pharmacokinetics

• Given as 10% solution in arachis oil (peanut oil) with benzyl benzoate via deep IM injection (never IV - too toxic)
• Oily preparation because BAL is water-insoluble
• Peak blood levels: 30-60 minutes
• Metabolized in liver; excreted in bile and urine
• Short half-life (~4 hours) necessitates frequent dosing

Therapeutic Uses

Dosing Schedule (Standard)

• Severe poisoning: 3-4 mg/kg IM every 4 hours for 2 days, then twice daily for 10 days (or until recovery)
• Mild poisoning: 2.5 mg/kg IM every 6 hours for 2 days, then every 12 hours for 7 days

Adverse Effects

• Pain at injection site (IM)
• Hypertension and tachycardia (dose-dependent)
• Nausea, vomiting, salivation, headache, lacrimation, rhinorrhea (within 15-20 min)
• Fever in children (common)
• Nephrotoxic at high doses - alkalinize urine to protect kidneys
• Hemolysis in G6PD-deficient patients (CONTRAINDICATED)
• Hepatotoxic - contraindicated in hepatic failure

Contraindications

1. G6PD deficiency (hemolysis risk)
2. Hepatic damage (liver metabolizes complex)
3. Iron, cadmium, or selenium poisoning (BAL-metal complex is MORE toxic than metal alone)
4. Renal impairment (reduces excretion of toxic complex)

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3. Chelating Agents in Clinical Practice - Complete List & Brief Elaboration

Complete List

Clinical Application Guidelines

• Asymptomatic, blood lead 25-45 μg/dL: succimer (oral DMSA)
• Symptomatic or blood lead >45 μg/dL: CaNa₂-EDTA + dimercaprol (BAL) together
• Lead encephalopathy: BAL first (4 mg/kg), then 4 hrs later add CaNa₂-EDTA

• Inorganic: BAL or DMSA
• Organic (methylmercury): DMSA (BAL may worsen brain distribution)

• BAL (IM) or DMSA (oral)

• Penicillamine (first line) or trientine

• Desferrioxamine (IV)

• Desferrioxamine (IV/IM)

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SECTION B: VITAMINS

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1. Antioxidant Vitamins and Their Uses

What Are Antioxidants?

The Three Major Antioxidant Vitamins

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A. Vitamin C (Ascorbic Acid)

• Water-soluble antioxidant, works in aqueous compartments
• Donates electrons to neutralize superoxide (O₂•⁻), hydroxyl radical (•OH), and peroxyl radicals
• Regenerates oxidized Vitamin E back to its active form (ascorbate-vitamin E cycle)
• Inhibits LDL oxidation (prevents foam cell formation in atherosclerosis)

• Cofactor for prolyl and lysyl hydroxylase (collagen synthesis)
• Enhances iron absorption from gut (reduces Fe³⁺ to Fe²⁺)
• Immune function: supports neutrophil and NK cell activity

1. Scurvy treatment and prevention (100-200 mg/day)
2. Wound healing promotion (post-surgery, burns)
3. Common cold - reduces duration, not incidence
4. Iron deficiency anemia - given with iron to enhance absorption
5. Methemoglobinemia (along with methylene blue)

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B. Vitamin E (Tocopherol)

• Fat-soluble antioxidant - resides in cell membranes and lipid bilayers
• Donates a hydrogen atom to lipid peroxyl radicals (LOO•), breaking the chain reaction of lipid peroxidation
• The tocopheroxyl radical formed is less reactive; regenerated by Vitamin C

LOO• (lipid peroxyl radical) + Vitamin E-OH
              ↓
       LOOH + Vitamin E-O•  (tocopheroxyl radical - stable)
              ↓
 Regenerated by Vitamin C → Vitamin E-OH again

1. Premature infant - prevents hemolytic anemia in neonates
2. Antioxidant in atherosclerosis prevention (controversial in trials - WACS, WAVE)
3. Abetalipoproteinemia (fat malabsorption - requires high dose supplementation)
4. Ataxia with vitamin E deficiency (AVED) - genetic disorder
5. Skin photoaging (topical)
6. Intermittent claudication (marginal benefit)

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C. Beta-Carotene (Provitamin A)

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Summary Table: Antioxidant Vitamins

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2. Vitamin A - Daily Requirement and Therapeutic Uses

Chemistry

• Retinol (preformed vitamin A - from animal sources)
• Retinal (retinaldehyde - visual cycle)
• Retinoic acid (gene regulation, differentiation)
• Beta-carotene (provitamin A from plant sources; 12 μg β-carotene = 1 μg retinol = 1 RAE)

Daily Requirement

Functions (Quick Recap)

Retinol → Retinal → Rhodopsin (rod pigment) → VISION
Retinal ← → Retinoic acid → Nuclear RAR/RXR receptors → GENE EXPRESSION
                           → Cell differentiation, growth
                           → Immune function (T-cell, NK cell maturation)
                           → Glycoprotein synthesis (mucus production)

Deficiency - Clinical Features

Therapeutic Uses

Toxicity (Hypervitaminosis A)

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SECTION C: SPECIAL PHARMACOLOGY TOPICS

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1. Why Folic Acid is Started from 1st Trimester but Iron from 2nd Trimester

Folic Acid - Must Start from 1st Trimester (Ideally Periconceptional)

Fertilization → Implantation → Neural plate forms (Day 18)
                              → Neural groove
                              → Neural tube closure (Days 22-28)
                              → This is in the FIRST TRIMESTER (often before woman knows she is pregnant!)

• Folic acid is required for DNA synthesis (purine and thymidylate synthesis)
• Rapidly dividing neural tube cells require folate for normal cell division
• Deficiency leads to: Spina bifida, anencephaly, encephalocele (neural tube defects)
• Neural tube CLOSES by Day 28 - before most women realize they are pregnant
• Therefore, folate supplementation must begin at least 1 month before conception and through the first trimester (ideally taken by all women of childbearing age)
• Dose: 400 μg (0.4 mg)/day (normal risk); 5 mg/day (high risk - previous NTD child, epilepsy patients on AEDs, etc.)

• Prevents megaloblastic anemia of pregnancy
• Reduces risk of congenital heart defects, orofacial clefts, limb defects
• Lowers homocysteine (reduces thrombotic risk)

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Iron - Started from 2nd Trimester (Even if Hb is Normal)

1st Trimester: Iron demand LOW (no menstruation, fetal growth minimal, iron stores are used up slowly)
2nd Trimester: ↑↑ Fetal growth ↑↑ Plasma volume expansion ↑↑ Red cell mass increases
               → Total iron need = 1000 mg extra over pregnancy
               → 300 mg to fetus/placenta
               → 500 mg for maternal RBC mass expansion
               → 200 mg basal loss
3rd Trimester: Maximum iron demand (fetal liver stores iron for post-natal period)

1. Morning sickness - iron worsens nausea and vomiting (common in 1st trimester)
2. Iron demand is low in 1st trimester - maternal stores are sufficient
3. Risk of excess iron - free iron is pro-oxidant and potentially teratogenic in early organogenesis
4. Compliance - adverse GI effects deter compliance; delaying start improves adherence

• Prophylactic iron prevents iron deficiency anemia that develops in 2nd/3rd trimester
• Fetal iron requirement peaks in 2nd-3rd trimester; maternal stores may be insufficient
• Dose: 100-200 mg elemental iron/day (prophylactic; IFA tablets in government programs = 100 mg elemental iron + 0.5 mg folic acid)

Summary Table

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2. Catecholamines vs Non-Catecholamines - Compare and Contrast

Definition

Structure Comparison

Catechol nucleus:
    OH
    |
  3-C
  |   \
  |    benzene ring
  |   /
  4-C
    |
    OH
          + ethylamine side chain (-CH₂-CH₂-NH₂)

Catecholamines = catechol nucleus + ethylamine
Non-catecholamines = Modified ring (absent/different OH groups) + ethylamine

Examples

Detailed Comparison Table

Mechanism of Action - Key Differences

1. Direct-acting: Phenylephrine (α₁), salbutamol (β₂) - act directly on receptors
2. Indirect-acting: Amphetamine, tyramine - enter nerve terminal → displace NE from storage vesicles → NE released → acts on receptors
3. Mixed-acting: Ephedrine - both direct receptor agonism AND NE release

Indirect mechanism (Amphetamine/Ephedrine):
Drug → enters adrenergic nerve terminal
      → displaces NE from vesicles
      → NE floods synapse
      → NE acts on post-synaptic receptors
      → Adrenergic effect

Pharmacological Effects Comparison

Clinical Uses

• Adrenaline (Epinephrine): Anaphylaxis, cardiac arrest, local anesthetic adjuvant
• Noradrenaline: Septic shock (vasopressor)
• Dopamine: Cardiogenic shock (inotrope + renal dose vasodilation)
• Dobutamine: Acute decompensated heart failure (β₁ inotrope)
• Isoprenaline: Complete heart block (temporary), severe bradycardia

• Salbutamol/Terbutaline: Bronchial asthma (β₂ agonist)
• Phenylephrine: Nasal decongestant, hypotension during spinal anesthesia
• Ephedrine: Hypotension during spinal anesthesia, nasal congestion
• Amphetamine: ADHD, narcolepsy
• Pseudoephedrine: Nasal decongestant (oral)

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3. Drug Use in Children - General Principles

Why Children are NOT "Small Adults"

Age-Based Classification

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A. Pharmacokinetic Differences in Children

1. ABSORPTION

2. DISTRIBUTION

3. METABOLISM

• Neonates lack UGT (UDP-glucuronosyltransferase) → chloramphenicol accumulates
• Features: abdominal distension, vomiting, gray cyanosis, cardiovascular collapse, death
• Dose in neonates: 25 mg/kg/day (vs 50-100 mg/kg/day in adults)

4. EXCRETION (RENAL)

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B. Pharmacodynamic Differences

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C. Dose Calculation Methods

• BSA (m²) = √(Height(cm) × Weight(kg) / 3600)
• Child's dose = (Child's BSA / 1.73 m²) × Adult dose

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D. Specific Drug Problems in Children (High-Yield)

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E. General Principles - Summary

1. Use approved pediatric formulations when available; avoid adult tablet splitting
2. Calculate dose per kg body weight for most drugs; use BSA for chemotherapy and some narrow-TI drugs
3. Adjust for organ maturity - reduce doses for renally eliminated drugs in neonates; recognize reduced CYP activity in neonates but higher in toddlers
4. Avoid certain drugs entirely: tetracyclines (<8 yr), fluoroquinolones (unless no alternative), aspirin (<12 yr viral illness), sulfonamides in neonates
5. Monitor more frequently - children's physiology changes rapidly; dose adjustment needed with growth
6. Flavoring and formulations - liquid formulations preferred; adherence may be poor with bitter drugs
7. Transdermal exposure risk - all topical agents carry higher systemic absorption risk
8. Informed consent - from parent/guardian with child's assent where age-appropriate

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Bone Marrow Histology - Normal vs Folate Deficiency

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