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Management of Stillbirth and Abortion — Obstetrics & Gynaecology

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PART 1: ABORTION (< 20 weeks)

Classification of Abortion

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Threatened Abortion

• Diagnosis: bleeding < 20 weeks + fetal cardiac activity on US, closed cervix
• No proven effective therapy (bed rest and progesterone are not effective and carry their own risks)
• Associated with later complications: 3× risk of preterm birth 28–31 weeks, increased risk of IUGR, PPROM, abruption
• Reassure patient: majority do not result in pregnancy loss

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Inevitable Abortion

• Cervix open + effaced, no tissue passed
• Blood type, Rh, CBC
• Rho(D) immune globulin (RhoGAM): give if Rh-negative
  • 50 µg up to 12 completed weeks (if available); otherwise standard 300 µg
• Offer medical or surgical management

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Incomplete Abortion

• Partial POC expulsion; cervix dilated; may see tissue at os
• If tissue protrudes from os → remove with ring forceps to reduce bleeding (vasovagal response possible)
• CBC, blood type, Rh; RhoGAM if Rh-negative
• If febrile → broad-spectrum antibiotics
• Proceed to medical or surgical management

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Management of Spontaneous Abortion (all non-viable types)

1. Expectant Management

• Acceptable for stable, counseled patient
• Success rates vary by type:
  • Incomplete: 91%
  • Missed: 76%
  • Anembryonic: 66%
• May take 4–8 weeks for complete passage
• Higher risk of unscheduled surgical evacuations, bleeding, transfusion (no difference in infection rates)

2. Medical Management (Misoprostol)

• Routes: vaginal, oral, sublingual, buccal; dose 400–800 µg

• Mifepristone + misoprostol: Adding mifepristone 200 mg PO 24 hours before misoprostol improves success significantly — 83% vs 67% at first follow-up (no difference in adverse events, bleeding, or pain)

3. Surgical Management — Suction Curettage

• Patient desires surgical management
• Excessive/haemodynamically significant bleeding
• Unstable vital signs
• Reliable follow-up is not possible

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Recurrent Pregnancy Loss (RPL)

• Parental karyotyping (chromosomal analysis of couple)
• Uterine cavity assessment (HSG, sonohysterography, hysteroscopy)
• Antiphospholipid antibody syndrome screen: lupus anticoagulant, anticardiolipin antibodies (IgG/IgM), β2-glycoprotein I antibodies
• Thyroid function
• Glucose screen (maternal DM)
• In selected cases: thrombophilia panel

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PART 2: STILLBIRTH (≥ 20 weeks)

Definition

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Causes (SCRN Data)

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Evaluation After Stillbirth

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Management of Subsequent Pregnancy After Stillbirth

Preconception / Initial Prenatal Visit

• Detailed medical and obstetric history
• Evaluation/workup of previous stillbirth
• Determination of recurrence risk
• Counsel on smoking, alcohol, illicit substance cessation
• Weight loss in obese women (preconception only; target BMI 18.5–24.9)
• Diabetes screen
• APS testing: lupus anticoagulant, anticardiolipin, β2-glycoprotein IgG/IgM

First Trimester

• Dating ultrasound (crown-rump length)
• First trimester screen: PAPP-A, hCG, nuchal translucency or cell-free fetal DNA

Second Trimester

• Fetal anatomic survey at 18–20 weeks
• Genetic screening if not done (or AFP if 1st trimester screen already done)

Third Trimester

• Serial USS from 28 weeks → rule out FGR (every 2–4 weeks if FGR found + Doppler)
• Fetal kick counts starting at 28 weeks
• Antepartum fetal surveillance (NST + AFI or BPP) from 32 weeks (or 1–2 weeks earlier than the gestation of previous stillbirth)

Delivery

• Planned delivery at 39 0/7 weeks (or earlier if dictated by comorbidities)
• In severe patient anxiety, early term delivery (37–38⁶/⁷ weeks) may be considered after counselling on neonatal risks vs. benefit

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Prevention of Stillbirth (Population Level)

• Low-dose aspirin: reduces risk of FGR and preeclampsia (conditions associated with stillbirth); insufficient evidence specifically for stillbirth prevention alone
• Antepartum surveillance: ACOG/SMFM recommend individualised surveillance for AMA and obesity
  • BMI 35–39.9 kg/m²: start at 37 0/7 weeks
  • BMI ≥40 kg/m²: start at 34 0/7 weeks
• Induction of labour at 39 weeks: meta-analysis shows reduction in stillbirth (RR 0.50; 95% CI 0.25–0.99) and no increase in caesarean rate vs expectant management
• Fetal kick counts: no RCT evidence for reducing stillbirth; not routinely mandated

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Key Risk Factors for Stillbirth

• Maternal age <15 or ≥35 years
• Nulliparity
• Black race (US data)
• Obesity (BMI >30) / large interpregnancy weight gain
• Smoking
• Multiple gestation
• Assisted reproductive technologies
• Previous adverse outcomes (preterm birth, SGA, prior stillbirth)

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Summary Algorithm

ABORTION WORKUP
Positive pregnancy test + bleeding/pain < 20 weeks
    ↓
TVS + β-hCG
    ↓
Viable IUP → Threatened abortion → Supportive care
Non-viable IUP / anembryonic →
    ↓
Stable patient → Expectant / Misoprostol 800 µg vaginally
                  (add Mifepristone 200 mg 24h prior for better outcome)
Unstable / excessive bleeding → Suction Curettage
Always → Blood group & Rh, CBC, RhoGAM if Rh-negative

STILLBIRTH (≥20 weeks)
    ↓
Confirm intrauterine fetal death (ultrasound)
    ↓
Counselling + emotional support
    ↓
Evaluation: autopsy, placental histology, genetics, APS screen, Kleihauer-Betke
    ↓
Delivery planning (induction of labour)
    ↓
Subsequent pregnancy: individualised surveillance, planned delivery at 39 weeks

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• Berek & Novak's Gynecology, pp. 1749–1753 (Spontaneous Abortion Management)
• Creasy & Resnik's Maternal-Fetal Medicine, pp. 1012–1013; Box 42.3 (Stillbirth — Evaluation, Prevention, Subsequent Pregnancy Management)

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Vital Statistics in Obstetrics: Birth Rate, Maternal Mortality Ratio, Perinatal & Neonatal Mortality

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1. BIRTH RATES & FERTILITY

Crude Birth Rate (CBR)

• Definition: Number of live births per 1,000 total population per year
• Formula: (Live births / Mid-year total population) × 1,000
• General indicator of reproductive activity of a population; not age-adjusted

General Fertility Rate (GFR)

• Definition: Number of live births per 1,000 women aged 15–49 years per year
• More specific than CBR as it restricts the denominator to women of reproductive age

Total Fertility Rate (TFR)

• Definition: Average number of children a woman would have over her lifetime if current age-specific fertility rates remained constant
• A TFR of 2.1 = replacement-level fertility (to maintain population size)

Age-Specific Fertility Rate (ASFR)

• Live births per 1,000 women in a specific age group per year

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2. MATERNAL MORTALITY

Key WHO Definitions

Maternal Mortality Ratio (MMR) vs. Maternal Mortality Rate

Why is MMR technically a ratio, not a rate? Because the denominator (live births) excludes women who died from ectopic pregnancies, miscarriages, terminations, and stillbirths. The true denominator — total number of pregnant women — is unknowable, so live births are used as an approximation. Hence the correct term is maternal mortality ratio. — Creasy & Resnik's, p. 1108

Global MMR Data

• Worldwide (2015): 216 per 100,000 live births (~303,000 deaths); 43.9% decrease from 385 in 1990
• High-income countries: ~12 per 100,000
• Sub-Saharan Africa: ~546 per 100,000
• US historical trend: ~900/100,000 in 1901 → ~9/100,000 in 1991 (attributed to hospital births, aseptic technique, prenatal care, blood transfusion, antibiotics, anaesthesia)

Direct vs. Indirect Causes of Maternal Death

In resource-rich countries, rising causes include cardiovascular disease, suicide/homicide, and drug overdose. Suicide and homicide account for more pregnancy-associated deaths than haemorrhage or preeclampsia in many US states. — Creasy & Resnik's, p. 1113

Risk Factors for Maternal Mortality

• Advanced maternal age (>35 years): 17% of births but 37% of pregnancy-related deaths (California data)
• Obesity (BMI >30): 27% of maternal deaths in UK were obese women
• Black/minority race (in US, Black women have substantially higher MMR)
• Underlying comorbidities: hypertension, diabetes, cardiac disease

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3. PERINATAL MORTALITY

Definition (Two WHO/ACOG Definitions)

Perinatal Mortality Rate (PMR) = (Stillbirths + Early neonatal deaths) / (Live births + Stillbirths) × 1,000

Key Data Points

• Preterm birth is the leading cause of perinatal and infant mortality for all racial/ethnic groups
• In 2017 (US): 13,443 fetal deaths + 14,329 neonatal deaths
• 80.8% of neonatal deaths occur within the first 7 days of birth
• Gestational age is the strongest predelivery predictor of survival and morbidity
  • IMR at <32 weeks: 185.79 per 1,000 live births
  • IMR at 32–36 weeks: 21.95 per 1,000 live births

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4. NEONATAL MORTALITY

Definitions

Causes of Neonatal Mortality

• Preterm birth / low birth weight
• Birth asphyxia / intrapartum complications
• Neonatal sepsis / infections
• Congenital anomalies
• Respiratory distress syndrome (hyaline membrane disease)

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5. INFANT MORTALITY RATE (IMR)

• Definition: Number of deaths of liveborn infants before the first year of age per 1,000 live births
• Stillbirths are excluded from the denominator (only liveborn infants counted)
• IMR is considered a key index of a country's overall health and socioeconomic status
• US IMR: 5.72/1,000 (2007) → 4.92/1,000 (2013) — a 14% decrease
• Racial disparity (US 2018): Non-Hispanic Black IMR (10.75) = more than double that of non-Hispanic Whites (4.63)

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6. FETAL DEATH / STILLBIRTH RATE

• Fetal Death Rate: Number of fetal deaths (≥20 wks) per 1,000 live births + fetal deaths
• Stillbirth Rate: Fetal deaths ≥20 weeks per 1,000 total births
• Fetal deaths account for >50% of all perinatal deaths

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7. SUMMARY TABLE: All Key Vital Statistics Definitions

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8. SIGNIFICANCE OF THESE METRICS

• MMR = a "summary indicator" of maternity care quality; combined with IMR, measures a country's maternal-child health system
• IMR = best single indicator of a nation's overall socioeconomic development and healthcare quality
• Perinatal mortality = reflects quality of combined prenatal + intrapartum + early neonatal care
• Reducing MMR/IMR requires: access to skilled birth attendants, emergency obstetric care, antenatal care, nutrition, infection control, and addressing social determinants

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• Creasy & Resnik's Maternal-Fetal Medicine — Chapter 47 (Maternal Mortality, pp. 1107–1115) and Chapter 38 (Preterm Birth / Perinatal & Infant Mortality, pp. 875–876)

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1. Birth Rates — Crude Birth Rate, General Fertility Rate, Total Fertility Rate, Age-Specific Fertility Rate (with formulas and denominators)
2. Maternal Mortality — WHO definitions of maternal death, late maternal death, pregnancy-related vs. pregnancy-associated death; difference between MMR (ratio) vs. maternal mortality rate; global MMR data; direct vs. indirect causes; risk factors
3. Perinatal Mortality — Two WHO/ACOG definitions (Definition I vs. II); what each reflects clinically; key data on fetal deaths vs. neonatal deaths
4. Neonatal Mortality — Early NMR (<7 days), Late NMR (7–27 days), overall NMR (<28 days), post-neonatal MR; causes
5. Infant Mortality Rate — Definition, significance, racial disparities
6. Fetal Death / Stillbirth Rate — Definitions and relationship to perinatal mortality
7. Summary comparison table of all indicators with numerators, denominators, and multipliers
8. Clinical significance of each metric as public health indicators

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General Anaesthetics — Classification, Mechanism, Pharmacokinetics & Adverse Effects

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1. CLASSIFICATION OF GENERAL ANAESTHETICS

A. Inhalational Agents

• Nitrous oxide (N₂O)
• Xenon (experimental)
• Cyclopropane (obsolete)

B. Intravenous (Parenteral) Agents

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2. COMPONENTS OF THE ANAESTHETIC STATE

1. Amnesia
2. Analgesia
3. Unconsciousness
4. Immobility in response to noxious stimulation
5. Attenuation of autonomic responses to noxious stimulation

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3. MECHANISM OF ACTION

Historical — Meyer-Overton Theory (Lipid Theory)

• Early 20th century: anesthetic potency correlated with solubility in olive oil (Meyer-Overton rule)
• Hypothesis: anaesthetics perturb the lipid bilayer of cell membranes → disrupting ion channels
• Discarded because clear exceptions exist; modern evidence points to specific protein targets

Current — Molecular / Receptor Targets

a) GABA-A Receptor Enhancement (majority of agents)

• Agents: Halogenated inhalationals, propofol, barbiturates, etomidate, neurosteroids, benzodiazepines
• Mechanism: Bind to specific allosteric sites on the GABA-A receptor (without competing at the GABA binding site) → increase sensitivity of GABA-A receptor to GABA → enhanced Cl⁻ influx → hyperpolarisation → CNS depression
• Propofol + etomidate: act at β subunits of specific GABA-A receptors (β₂/β₃ subunits mediate hypnosis; β₁ mediates sedation)

b) NMDA Receptor Inhibition

• Agents: Ketamine, nitrous oxide, xenon, cyclopropane
• These agents do not significantly affect GABA-A or glycine receptors
• Mechanism: Block NMDA receptors (glutamate-gated cation channels, Ca²⁺-selective) → inhibit excitatory neurotransmission at glutamatergic synapses

c) Glycine Receptor Enhancement

• Inhalational agents also enhance glycine-gated Cl⁻ channels → important for inhibitory transmission in the spinal cord and brainstem → contributes to immobility

d) Two-Pore Domain K⁺ Channel Activation

• Halogenated inhalationals activate two-pore domain (K₂P) K⁺ channels → neuronal hyperpolarisation
• Xenon, N₂O, and cyclopropane activate different members of this family

Cellular Effects

1. Neuronal hyperpolarisation — affects pacemaker activity and pattern-generating circuits
2. Synaptic transmission suppression — both inhibit excitatory synapses and enhance inhibitory synapses
3. Reduced neurotransmitter release (presynaptic) + altered postsynaptic receptor responses

Anatomic Sites of Action

• Thalamus: A consistent site of metabolic suppression — acts as a relay switch between awake and anaesthetised states
• Cerebral cortex: Suppression of mesial parietal cortex, posterior cingulate cortex, precuneus, inferior parietal cortex
• Spinal cord: Site of immobility response (MAC not altered after spinal cord transection → immobility is spinal, not cortical)
• Hippocampus: Depression of hippocampal neurotransmission → amnesia
• VLPO (ventrolateral preoptic nucleus): GABA-A-active agents enhance VLPO inhibitory output → suppress consciousness (mimicking natural sleep pathways)

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4. PHARMACOKINETICS OF INHALATIONAL ANAESTHETICS

Key Concept: Partial Pressure Gradient

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4A. MINIMUM ALVEOLAR CONCENTRATION (MAC)

• Mirrors brain partial pressure (alveolar ≈ arterial ≈ brain at steady state)
• Allows comparison of potency between agents
• Measured continuously by end-tidal monitoring (infrared spectroscopy / mass spectrometry)
• MAC is the EC₅₀ — 1.3 MAC = EC₉₅ (prevents movement in ~95%)
• MAC awake = 0.3–0.4 MAC (concentration at which patients wake up)
• MAC values are additive (0.5 MAC nitrous oxide + 0.5 MAC isoflurane = 1.0 MAC effect)

• Hyperthermia
• Chronic alcohol use
• Hyperthyroidism
• Young age (infants > adults)
• CNS stimulants (cocaine, amphetamines)

MAC is not altered by: species, sex, or duration of anaesthesia. — Morgan & Mikhail's, p. 294

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4B. BLOOD-GAS PARTITION COEFFICIENT (λ b/g)

• λ b/g of sevoflurane = 0.65 → 1 mL blood contains only 0.65 mL-equivalent of sevoflurane per mL of alveolar gas
• λ b/g of halothane = 2.4 → blood takes up ~5× more halothane than sevoflurane for the same partial pressure rise

• More anaesthetic must dissolve in blood before alveolar partial pressure rises → slower equilibration → slower induction
• Low coefficient (desflurane, N₂O, sevoflurane) = rapid induction AND rapid emergence
• High coefficient (halothane) = slow induction and slow emergence

1. Solubility in blood (blood/gas coefficient)
2. Alveolar blood flow (≈ cardiac output): ↑ CO → more uptake → slower rise in alveolar partial pressure → slower induction; ↓ CO → less uptake → faster induction (risk of overdose with soluble agents in low-output states)
3. Alveolar–venous partial pressure difference: depends on tissue uptake

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4C. CONCENTRATION EFFECT & SECOND GAS EFFECT

Concentration Effect

1. Despite 50% uptake, the remaining gas is concentrated in a smaller total volume → disproportionately higher alveolar concentration
2. Augmented inflow effect: The absorbed gas volume must be replaced by fresh inspired gas → further increases alveolar concentration

Example: At 20% inspired, 50% uptake → 11% alveolar. At 80% inspired, 50% uptake → 67–72% alveolar. A 4× increase in inspired concentration yields a 6× increase in alveolar concentration.

Second Gas Effect

• When N₂O is administered in a high concentration alongside a volatile agent, the concentration effect of N₂O augments the alveolar concentration of the volatile agent as well
• Mechanism: Rapid uptake of large volumes of N₂O concentrates the remaining alveolar gas (including the volatile agent), and the augmented inflow replaces absorbed gas — pulling in more volatile agent
• Clinical relevance: Theoretically described and seen in exam questions; probably clinically insignificant in practice
• Conversely on emergence: rapid outpouring of N₂O from blood can dilute alveolar O₂ → diffusion hypoxia (Fink effect) — prevented by giving 100% O₂ for 5–10 minutes at end of anaesthesia

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5. PHARMACOKINETICS OF INTRAVENOUS AGENTS

• All are highly lipophilic → rapid CNS uptake
• Duration after single bolus = redistribution from brain to muscle/fat (not elimination)
• Thiopental accumulates with repeat dosing (long t½β) → prolonged recovery

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6. ADVERSE EFFECTS

A. Inhalational Agents — General

B. Nitrous Oxide — Specific Adverse Effects

• Expansion of air-containing cavities (35× more soluble than N₂ in blood) → contraindicated in pneumothorax, bowel obstruction, pneumocephalus, venous air embolism, intraocular air bubbles, tympanic membrane graft, middle ear surgery
• Vitamin B₁₂ inactivation: Irreversibly oxidises cobalt atom of B₁₂ → inhibits:
  • Methionine synthetase → impaired myelin formation → peripheral neuropathy
  • Thymidylate synthetase → impaired DNA synthesis → megaloblastic anaemia (with prolonged exposure)
• Bone marrow suppression with prolonged use
• Increased PONV (postoperative nausea and vomiting) — via chemoreceptor trigger zone activation
• Teratogenicity risk (avoided in early pregnancy)
• Diffusion hypoxia on emergence (rapid outpouring dilutes alveolar O₂)
• Immune effects: Altered chemotaxis and motility of PMNs
• Elevated homocysteine (methionine synthetase inhibition) → cardiovascular risk with chronic exposure

C. Propofol — Specific Adverse Effects

• Pain on injection (reduced by lidocaine pretreatment)
• Hypotension + myocardial depression (significant in hypovolaemic patients)
• Respiratory depression (apnoea on induction)
• Propofol Infusion Syndrome (PRIS): Rare, life-threatening — metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure with prolonged high-dose infusion in ICU

D. Etomidate — Specific Adverse Effects

• Pain on injection; myoclonic movements (pre-treat with opioid/BZD)
• Adrenocortical suppression: Inhibits 11-β-hydroxylase → ↓ cortisol synthesis (even a single induction dose causes transient suppression → avoid in sepsis, trauma ICU patients)
• Nausea and vomiting; hiccups

E. Ketamine — Specific Adverse Effects

• Emergence reactions: Dysphoria, vivid dreams, hallucinations, delirium (reduced by midazolam pretreatment)
• ↑ Cerebral blood flow + ICP (contraindicated in ↑ ICP)
• ↑ BP, HR, cardiac output (sympathomimetic — useful in haemodynamically unstable patients, but dangerous in ischaemic heart disease)
• Sialorrhoea (excess secretions) — use anticholinergic premedication
• Bronchodilation (advantage in asthma/bronchospasm)
• Maintains airway reflexes better than other agents

F. Emergence Phenomena (all agents)

• Emergence excitement (5–30%): tachycardia, restlessness, crying, thrashing
• Hypertension + tachycardia (sympathetic tone returns)
• Postanaesthesia shivering (core hypothermia) — treat with meperidine 12.5 mg IV
• Neurological signs: delirium, hyperreflexia, Babinski sign
• Airway obstruction, respiratory depression, hypoxaemia

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7. SUMMARY DIAGRAM

GENERAL ANAESTHETICS
        │
        ├── INHALATIONAL
        │       ├── Gases: N₂O, Xenon
        │       └── Volatile: Halothane, Isoflurane, Sevoflurane, Desflurane
        │
        └── INTRAVENOUS
                ├── GABA enhancers: Propofol, Barbiturates, Etomidate
                ├── NMDA blockers: Ketamine
                └── Adjuvants: Benzodiazepines, Dexmedetomidine

MECHANISM
  ↓ Potency correlation: Meyer-Overton (lipid) → DISCARDED
  ↓ Modern: Specific protein targets
     Most IVA + inhalationals → GABA-A ↑ (Cl⁻ influx → hyperpolarisation)
     Ketamine / N₂O / Xenon → NMDA receptor block
     All inhalationals → K₂P channel activation
     All inhalationals → Glycine receptor ↑

PHARMACOKINETICS
  MAC = ED₅₀ for immobility; ↓ with age, hypothermia, opioids; additive
  Blood/Gas Coefficient: Low (N₂O, Desflurane, Sevoflurane) → FAST induction
                         High (Halothane) → SLOW induction
  Second Gas Effect: High [N₂O] concentrates co-administered volatile agent
  Diffusion Hypoxia: N₂O floods alveoli on emergence → give O₂ for 5-10 min

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• Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 491–494 (Actions & Mechanisms)
• Morgan & Mikhail's Clinical Anaesthesiology, 7e, pp. 281–302 (MAC, Blood/Gas coefficient, Concentration Effect, Second Gas Effect)

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GABA Receptors and Drugs Modulating GABA Receptors

GABA and Its Receptors

GABA-A Receptor Structure

• Subunits drawn from 19 isoforms: α(1–6), β(1–4), γ(1–3), δ, ε, θ, ρ
• Commonest isoform: 2α₁ + 2β₂ + 1γ₂
• Binding sites:
  • GABA binds at the α–β subunit interfaces (two sites)
  • Benzodiazepines bind at the α–γ subunit interface (one site)
  • Barbiturates bind at a separate, distinct site from benzodiazepines

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Drugs Modulating GABA-A Receptors

1. Benzodiazepines (e.g., diazepam, midazolam, lorazepam)

• Mechanism: Positive allosteric modulators — bind at the α/γ interface → increase the frequency of Cl⁻ channel opening in the presence of GABA (require GABA to be present; no direct channel activation)
• Do not activate the channel independently
• Selective for isoforms containing α₁, α₂, α₃, α₅ subunits
• Uses: Anxiolytic, sedation, anticonvulsant, muscle relaxant, pre-medication
• Antagonist: Flumazenil — competitively blocks the benzodiazepine site; reverses benzodiazepine-induced sedation

2. Barbiturates (e.g., phenobarbitone, thiopental)

• Mechanism: Bind at a site distinct from benzodiazepines → increase the duration of Cl⁻ channel opening; at high doses, can directly activate the channel even without GABA
• Bind to multiple GABA-A isoforms
• Uses: Epilepsy (phenobarbitone), anaesthetic induction (thiopental), status epilepticus
• Narrow therapeutic index compared to benzodiazepines

3. Z-drugs / Non-benzodiazepine Hypnotics (zolpidem, zaleplon, eszopiclone)

• Mechanism: Bind at the same benzodiazepine site (α/γ interface) but more selectively — only to isoforms containing α₁ subunits → predominantly sedative/hypnotic, with minimal anxiolytic or muscle relaxant effects
• Reversed by flumazenil
• Uses: Insomnia

4. General Anaesthetics (propofol, etomidate, volatile agents)

• Mechanism: Enhance GABA-A function at allosteric sites; at high concentrations can directly activate the channel
• Propofol/etomidate act at β subunits (β₂/β₃ for hypnosis, β₁ for sedation)

5. Neurosteroids (e.g., brexanolone, allopregnanolone)

• Endogenous and synthetic neurosteroids act as positive allosteric modulators of GABA-A
• Brexanolone: IV neurosteroid approved for postpartum depression

6. Alcohol (Ethanol)

• Potentiates GABA-A (requires α, β, γ subunits for ethanol sensitivity) → CNS depression

7. GABA-B Agonist — Baclofen

• Directly activates GABA-B receptors → reduces excitatory neurotransmitter release
• Uses: Spasticity, muscle relaxation, alcohol withdrawal

8. GABA-A Antagonists / Inverse Agonists

• Flumazenil — competitive antagonist at the benzodiazepine site
• Bicuculline, picrotoxin — experimental GABA-A antagonists (cause convulsions)
• β-carbolines — inverse agonists at the benzodiazepine site → anxiogenic + convulsant effects

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Summary Table

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Targets of Antiviral Drugs

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1. Viral Attachment and Entry

• CCR5 antagonists — Maraviroc: Blocks the CCR5 co-receptor on host CD4+ T cells → prevents HIV-1 gp120 binding → blocks viral entry
• Fusion inhibitors — Enfuvirtide: A peptide that binds to HIV gp41 → blocks the conformational change required for membrane fusion → prevents viral entry into the cell
• Amantadine/Rimantadine (Influenza A): Block viral uncoating after entry by inhibiting the M2 ion channel → prevent release of viral RNA into the host cell

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2. Viral Nucleic Acid Synthesis (Polymerase Inhibition)

a) Nucleoside/Nucleotide Analogues (NAs)

• Structurally mimic natural nucleosides; incorporated into growing viral nucleic acid → chain termination
• Require activation by phosphorylation (often by viral or host kinases)

b) Non-Nucleoside Polymerase Inhibitors (NNRTIs)

• Bind allosteric sites on reverse transcriptase (not the active site) → induce conformational change → inhibit RT non-competitively
• Examples: Nevirapine, Efavirenz, Rilpivirine (HIV)

c) Pyrophosphate Analogues

• Foscarnet: Directly inhibits viral DNA/RNA polymerases at the pyrophosphate-binding site without requiring phosphorylation → useful in thymidine kinase-deficient (acyclovir-resistant) herpes strains

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3. Viral Protease Inhibition

• HIV Protease Inhibitors (PIs): Indinavir, Ritonavir, Lopinavir — bind the active site of HIV-1 protease → prevent cleavage of Gag and Gag-Pol polyproteins → immature, non-infectious virions are produced
• HCV NS3/4A Protease Inhibitors: Boceprevir, Telaprevir, Glecaprevir — block HCV serine protease → prevent maturation of NS4A, NS4B, NS5A, NS5B proteins essential for replication
  • Identifiable by "-previr" suffix

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4. Viral Integrase Inhibition (HIV-specific)

• Integrase Strand Transfer Inhibitors (INSTIs): Raltegravir, Dolutegravir, Bictegravir — chelate the Mg²⁺ in the integrase active site → block strand transfer step → HIV DNA cannot integrate → replication cycle arrested
• Identifiable by "-gravir" suffix

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5. Viral Neuraminidase Inhibition (Influenza)

• Neuraminidase Inhibitors: Oseltamivir (oral), Zanamivir (inhaled), Peramivir (IV) — competitively inhibit influenza A and B neuraminidase → virions remain tethered to the host cell surface → impaired viral spread
• Baloxavir: Inhibits influenza cap-dependent endonuclease (PA subunit of RNA polymerase) → blocks viral mRNA synthesis — a distinct new target

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6. HCV NS5A Replication Complex

• NS5A Inhibitors: Ledipasvir, Velpatasvir, Pibrentasvir — inhibit the NS5A protein, essential for formation of the membranous web replication platform and HCV RNA assembly
• Identifiable by "-asvir" suffix
• Used in combination with NS5B and NS3/4A inhibitors for HCV cure rates >99%

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7. Immunomodulation (Host-Directed)

• Interferons (IFN-α, pegylated IFN-α): Bind host cell receptors → upregulate antiviral state (ISGs) → inhibit viral replication, assembly, and release; enhance immune response
• Used in HBV, HCV (now largely replaced by DAAs)

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Summary Table

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Chelating Agents and Management of Heavy Metal Poisoning

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WHAT IS A CHELATING AGENT?

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THE MAJOR CHELATING AGENTS

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1. DIMERCAPROL (BAL — British Anti-Lewisite)

• Arsenic poisoning (drug of choice)
• Mercury poisoning (inorganic/elemental)
• Lead poisoning (used in combination with calcium-EDTA, especially in encephalopathy)
• Gold poisoning
• Lewisite exposure

• Hypertension, tachycardia
• Nausea, vomiting, headache
• Burning sensation in mouth, throat, eyes
• Pain at injection site
• Transient increase in liver enzymes
• Contraindicated in iron, cadmium, selenium poisoning (forms toxic complexes)
• Contraindicated in hepatic insufficiency

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2. EDETATE CALCIUM DISODIUM (CaNa₂-EDTA, Calcium EDTA)

• Lead poisoning — drug of choice for symptomatic lead poisoning and blood lead ≥45 µg/dL
• Combined with BAL for severe lead encephalopathy (BAL given first to prevent redistribution of lead to CNS)

• Nephrotoxicity (dose-dependent tubular damage) — most important
• Zinc deficiency (EDTA enhances zinc excretion)
• Hypocalcaemia if calcium-free EDTA given (disodium EDTA)
• Fever, chills, fatigue

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3. SUCCIMER (DMSA — Dimercaptosuccinic Acid)

• Orally active (major advantage)
• Does NOT redistribute metals to the brain (unlike BAL)
• More selective — lower adverse effect profile
• Also chelates zinc and copper (monitor)

• Lead poisoning — preferred oral chelator; FDA approved for children with blood lead ≥45 µg/dL
• Mercury poisoning (inorganic/elemental)
• Arsenic poisoning
• Has largely replaced penicillamine for these indications due to better efficacy and safety

• GI symptoms (nausea, vomiting, diarrhoea)
• Transient liver enzyme elevation
• Skin rashes
• Zinc/copper depletion with prolonged use

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4. D-PENICILLAMINE

• Wilson's disease (copper overload) — important indication
• Rheumatoid arthritis (disease-modifying)
• Lead poisoning (when parenteral therapy not feasible)
• Mercury poisoning
• Cystinuria (forms soluble cysteine-penicillamine complex)

• Hypersensitivity: rash, pruritus, drug fever
• Penicillin cross-sensitivity (caution in penicillin allergy)
• Nephrotoxicity — proteinuria, membranous nephropathy
• Pancytopenia with prolonged use
• Pyridoxine (Vit B₆) deficiency (less with D-isomer)
• Lupus-like syndrome, myasthenia gravis (rare)

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5. DEFEROXAMINE (Desferrioxamine)

• Acute iron poisoning — parenteral chelator of choice
• Chronic iron overload (thalassaemia — though largely replaced by oral agents)
• Aluminium toxicity in renal failure (with haemodialysis)
• May have benefit in intracerebral haemorrhage (reduces brain iron from Hb breakdown)

• Hypotension with rapid IV infusion
• Flushing, rash, abdominal discomfort
• Pulmonary toxicity (ARDS) with infusions >24 hours
• Neurotoxicity with long-term use
• Increased susceptibility to Yersinia enterocolitica infection (iron-dependent organism)

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6. DEFERASIROX (Oral Iron Chelator)

• Tridentate chelator with high affinity for Fe³⁺, low affinity for zinc/copper
• Orally active, well absorbed — major advantage
• Complex excreted in bile (faecal elimination)
• FDA-approved (2005) for transfusional iron overload (thalassaemia, myelodysplastic syndrome)
• Adverse effects: GI disturbances, skin rash; monitor renal and liver function (rare renal/liver failure in elderly MDS patients)

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7. DEFERIPRONE (Oral Iron Chelator)

• Bidentate iron chelator; cleared predominantly via kidney
• FDA-approved (2011) as second-line oral chelator for thalassaemia with transfusional iron overload
• Adverse effects: Neutropenia in 5–10%, agranulocytosis in ~1% → regular blood count monitoring mandatory
• Similar efficacy to deferasirox in transfusion-dependent haemoglobinopathies

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MANAGEMENT OF SPECIFIC HEAVY METAL POISONINGS

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A. LEAD POISONING

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B. ARSENIC POISONING

• Acute: BAL (dimercaprol) 3–5 mg/kg IM every 4 hours for 2 days, then every 6 hours × 1 day, then twice daily × 10 days
• Oral succimer (DMSA) may be used when patient can tolerate oral therapy
• Supportive: IV fluids, antiarrhythmics, transfusion if needed
• Haemodialysis in renal failure

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C. MERCURY POISONING

• Acute inorganic mercury: BAL (dimercaprol) — preferred
• Elemental/inorganic chronic: Succimer (DMSA) or N-acetylpenicillamine
• Organic (methylmercury): Succimer; BAL not recommended (redistributes organic mercury to brain — worsens outcome)
• Haemodialysis for renal failure

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D. IRON POISONING (Acute)

1. (0–6 h): GI irritation — nausea, vomiting, haematemesis, diarrhoea
2. (6–24 h): Apparent recovery ("quiet phase")
3. (24–48 h): Systemic toxicity — metabolic acidosis, shock, hepatic failure
4. (2–5 weeks): GI strictures

• Gastric lavage/whole bowel irrigation
• Deferoxamine IV — indicated if serum iron >500 µg/dL or symptomatic systemic toxicity
• Supportive: IV fluids, blood transfusion, treatment of acidosis

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E. COPPER POISONING / WILSON'S DISEASE

• Wilson's disease: Autosomal recessive; ATP7B mutation → copper accumulation in liver, brain, cornea (Kayser-Fleischer rings)
• Treatment: D-Penicillamine (first-line oral chelator) or Trientine (for penicillamine-intolerant); zinc (reduces copper absorption)

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SUMMARY TABLE: Chelating Agents and Their Uses

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KEY PHARMACOLOGY PRINCIPLES

1. Chelation is most effective early — the longer after exposure, the less benefit
2. BAL + EDTA combination is used for severe lead encephalopathy; BAL must be given before EDTA to prevent redistribution of lead to CNS
3. BAL is contraindicated in iron and cadmium poisoning (forms toxic complexes)
4. Redistribution risk: BAL redistributes Hg and As to the brain — avoid BAL in methylmercury poisoning
5. EDTA enhances zinc excretion — consider zinc supplementation with prolonged chelation
6. Chelation is least effective when metal is incorporated into bone matrix (lead) or dense tissues with long half-lives

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Management of Heavy Metal Poisoning

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GENERAL PRINCIPLES OF MANAGEMENT

1. Remove from source — stop ongoing exposure immediately
2. Supportive care — ABC, IV fluids, treat seizures, cardiac monitoring
3. Decontamination — gastric lavage or whole bowel irrigation (if recent ingestion)
4. Chelation therapy — the specific pharmacological intervention; most effective when given early after acute exposure
5. Monitor — blood/urine metal levels, renal function, CBC

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LEAD POISONING

• Mannitol for raised intracranial pressure in encephalopathy
• Anticonvulsants (lorazepam/diazepam) for seizures
• Iron supplementation (improves GI absorption reduction)
• X-ray abdomen — if radio-opaque lead particles in GI tract → whole bowel irrigation with polyethylene glycol

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ARSENIC POISONING

• BAL (dimercaprol) 3–5 mg/kg IM every 4 hours × 2 days → every 6 hours × 1 day → every 12 hours × 10 days
• When patient tolerates oral therapy → switch to Succimer (DMSA)
• IV fluids — aggressive hydration for haemorrhagic gastroenteritis
• Blood transfusion if pancytopenia severe
• Haemodialysis if acute renal failure

• Oral succimer (DMSA)
• Removal from contaminated water/source is paramount

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MERCURY POISONING

• Haemodialysis for acute tubular necrosis (inorganic Hg)
• Seizure management for methylmercury (Minamata disease)
• Respiratory support if chemical pneumonitis (elemental Hg vapour)

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IRON POISONING (Acute)

1. 0–6 h: GI haemorrhage, vomiting, diarrhoea
2. 6–24 h: Apparent recovery (deceptive)
3. 24–48 h: Metabolic acidosis, hepatic failure, shock
4. 2–5 weeks: GI strictures (pyloric stenosis)

• Whole bowel irrigation with polyethylene glycol (if significant iron tablets seen on X-ray)
• Deferoxamine IV (100 mg/kg/day, max 6 g/day) — indicated when:
  • Serum iron >500 µg/dL
  • Symptomatic systemic toxicity (metabolic acidosis, encephalopathy, shock)
  • Urine turns orange-red ("vin rosé" urine — confirms iron chelation)
• Do NOT exceed 24 hours of continuous infusion (risk of ARDS)
• Supportive: IV fluids, blood products, sodium bicarbonate for acidosis

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COPPER POISONING / WILSON'S DISEASE

• Gastric lavage
• D-Penicillamine or supportive care

• D-Penicillamine — first-line oral chelator (250 mg 4×/day); promotes urinary copper excretion
• Trientine — used if penicillamine intolerant
• Zinc — blocks intestinal copper absorption (maintenance therapy, or in presymptomatic patients)
• Tetrathiomolybdate — investigational; rapidly reduces copper in symptomatic neurological Wilson's
• Liver transplantation — for fulminant hepatic failure unresponsive to chelation

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SUMMARY — CHELATOR OF CHOICE BY METAL

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IMPORTANT CONTRAINDICATIONS AND CAUTIONS

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Dosage Forms for Anti-Asthma Drugs

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A. INHALATION DEVICES (Primary Delivery Route for Asthma)

• Delivers drug directly to the site of action (airways)
• Allows smaller doses
• Minimises systemic adverse effects
• Produces rapid onset of action

1. Pressurised Metered-Dose Inhaler (pMDI / MDI)

• Small, portable, canister-based device
• Contains drug suspended or dissolved in a propellant (HFA — hydrofluoroalkane, replaced older CFC propellants)
• Delivers a fixed, metered dose per actuation
• Requires "press and breathe" coordination — common source of error (improper timing, insufficient slow/deep inspiration)
• Accessories:
  • Spacer / Valved Holding Chamber (VHC): Attached between MDI and mouth → reduces oropharyngeal drug deposition, reduces need for precise coordination; recommended for children and those with poor technique
  • VHC with face mask: for children <4 years
• Age guideline: ≥5 years (without spacer); younger children require spacer + face mask

2. Dry Powder Inhaler (DPI)

• Drug is in dry powder form; no propellant needed
• Breath-actuated — patient's own inspiratory effort disperses and delivers the drug
• Requires sufficient inspiratory flow rate to disaggregate powder → not suitable for infants or severe obstruction
• Examples: Turbuhaler, Accuhaler/Diskus, Handihaler, Ellipta, Breezhaler
• Age guideline: ≥4 years

3. Soft Mist Inhaler (SMI)

• Produces a slow-moving, fine aerosol mist (Respimat® device)
• Does not require propellant or high inspiratory effort
• Slower aerosol velocity → more lung deposition, less oropharyngeal impaction
• Examples: Tiotropium (Spiriva Respimat), Combivent Respimat

4. Nebulizer (Small-Volume Nebulizer / SVN)

• Converts liquid drug solution or suspension into an aerosol for inhalation via a mouthpiece or face mask
• Uses compressed air (jet nebulizer) or ultrasonic vibration
• Advantages: No coordination required; used in all ages; useful in acute severe asthma
• Disadvantages: More expensive, takes longer (5–15 min), less portable, requires cleaning
• Age guidelines:
  • Infants: SVN with face mask or hood
  • ≤3 years: SVN with face mask
  • ≥3 years: SVN with mouthpiece
  • ≥5 years: Breath-actuated nebulizer

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Device-Drug Availability Summary (Table 144-1)

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B. DOSAGE FORMS BY DRUG CLASS

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1. β₂-ADRENERGIC AGONISTS

Short-Acting (SABA) — e.g., Salbutamol (Albuterol)

Long-Acting (LABA) — e.g., Salmeterol, Formoterol, Arformoterol

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2. ANTICHOLINERGICS (Muscarinic Antagonists)

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3. INHALED CORTICOSTEROIDS (ICS)

• Most approved for twice-daily administration (beclomethasone, budesonide, ciclesonide, fluticasone propionate, mometasone)
• Fluticasone furoate — once daily (Ellipta DPI)
• Budesonide nebulizer — used in young children and infants who cannot use MDI/DPI
• Rinse mouth after use to prevent oral candidiasis and dysphonia

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4. COMBINATION INHALERS (ICS + LABA)

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5. METHYLXANTHINES — Theophylline, Aminophylline

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6. LEUKOTRIENE MODIFIERS

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7. SYSTEMIC CORTICOSTEROIDS

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8. CROMONES (Mast Cell Stabilisers) — Now Rarely Used

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9. BIOLOGICS / MONOCLONAL ANTIBODIES

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C. SUMMARY TABLE — ALL DOSAGE FORMS AT A GLANCE

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D. AGE-BASED DEVICE SELECTION GUIDE

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