Pharmacogenomics — CIA II Master Pack

How to score 50/50 read first

The paper is fixed in shape — last year's CIA II (Sep 2025) and your syllabus portion match exactly. Prepare to this blueprint:

note Flowchart diagrams below render with an online library (Mermaid). If you are offline, the coloured image diagrams and all text/tables still work — the gallery at the end has every figure.

1 · Endothelial cells, Hydroxyurea & Sickle Cell Disease Part B fav

Core notes

• Endothelial cells form a single layer lining all blood vessels; regulate exchange between blood and tissue and signal growth of surrounding vessel-wall cells. In SCD they become activated & adhesive, promoting vaso-occlusion — so they are a drug target.
• Sickle cell disease (SCD) is caused by HbS: a point mutation β6 Glu → Val (glutamic acid→valine at position 6 of the β-globin chain). Deoxygenated HbS polymerises → RBCs sickle → haemolysis + vaso-occlusion.
• Hydroxyurea (HU) = hydroxylated derivative of urea. Inhibitor of ribonucleotide reductase (rate-limiting enzyme converting ribonucleotides → deoxyribonucleotides) → blocks DNA synthesis → S-phase-specific cytotoxic; inhibition is reversible.
• HU is freely water-soluble, crosses membranes by passive diffusion, near-complete oral bioavailability; biotransformed to urea by a hepatic P450 (CYP) monooxygenase; eliminated renally & non-renally.

Flowchart — Sickle-cell pathophysiology

flowchart TD
  A["β6 Glu → Val point mutation (HBB gene)"] --> B["Abnormal Hemoglobin S (HbS)"]
  B --> C{Deoxygenation / low O2}
  C -->|yes| D["HbS polymerises"]
  D --> E["RBC sickles (rigid, crescent)"]
  E --> F["Endothelial activation & adhesion"]
  E --> G["Haemolysis"]
  F --> H["Vaso-occlusion"]
  H --> I["Pain crises, organ / tissue damage"]
  G --> J["Chronic haemolytic anaemia"]
  

Flowchart — Hydroxyurea mechanism of action

flowchart TD
  HU["Hydroxyurea (S-phase specific)"] --> RR["Inhibits ribonucleotide reductase (reversible)"]
  RR --> DNA["Blocks DNA synthesis"]
  HU --> GAMMA["Reactivates γ-globin genes"]
  GAMMA --> HBF["↑ Fetal Hb (HbF)"]
  HBF --> POLY["↓ HbS polymerisation → ↓ sickling"]
  HU --> RETIC["↓ Reticulocytes, WBC, platelets"]
  HU --> ANTI["Anti-inflammatory: ↓ adhesion molecules"]
  ANTI --> VOC["↓ Vaso-occlusive crises"]
  POLY --> OUT["Improved blood flow & O2 delivery"]
  RETIC --> OUT
  VOC --> OUT
  

Hemoglobin types Part A: "differentiate HbA vs HbF"

2 · Pharmacogenomics of Neurological / Neurodegenerative Diseases

Disease → Gene → Drug map must-know table

Mechanisms of neuronal death gene examples carry marks

Néri et al. split pathogenesis into an "initiation" phase (a trigger disrupts homeostasis) and an "execution" phase (cell-death pathways finish the neuron).

Flowchart — Neurodegeneration & pharmacogenomic targets

flowchart TD
  INIT["INITIATION phase: trigger disrupts homeostasis"] --> EXEC["EXECUTION phase: cell-death pathways"]
  EXEC --> AP["Apoptosis (CASP3/8/9)"]
  EXEC --> EX["Excitotoxicity: glutamate, Ca2+ influx (GRIN2A/B)"]
  EXEC --> OX["Oxidative stress (SOD2, CAT, GPX1)"]
  EXEC --> MI["Mitochondrial dysfunction (mtDNA)"]
  EXEC --> PR["Protein aggregation (APP, Tau)"]
  EXEC --> IN["Neuroinflammation (TNF, IL1B)"]
  EXEC --> AU["Autophagy dysregulation (ATG5/7)"]
  AP --> DEATH["Neuronal death"]
  EX --> DEATH
  OX --> DEATH
  MI --> DEATH
  PR --> DEATH
  IN --> DEATH
  AU --> DEATH
  DEATH --> PGX["Pharmacogenomic target: gene variant → tailored drug & dose"]
  

Perspectives (5-mark bullet points)

• Personalised medicine — tailor drug/dose to genetic profile for max efficacy, min ADRs.
• Early detection & intervention — identify high-risk genotypes, slow progression.
• Drug development / trial design — stratify participants → efficient trials.
• Ethical & privacy — consent, data privacy, stigma.
• Multi-omics integration — genomics + transcriptomics + proteomics + metabolomics.

3 · Psychiatric Pharmacogenetics — Schizophrenia Part B fav

Core notes

• Schizophrenia affects ~1% worldwide; early onset; ~10% suicide. Dopamine hypothesis: overactivity at dopaminergic synapses (esp. mesolimbic) causes positive symptoms. Serotonin also contributes.
• Typical antipsychotics (chlorpromazine 1952, haloperidol): high D2 affinity; binding potency ∝ clinical potency; more EPS.
• Clozapine = prototype atypical: preferential binding to 5-HT2 and D4 over D2; fast dissociation from D2; effective in up to 60% of treatment-refractory patients; fewer EPS.

The four dopamine pathways 2-mark gold

Pharmacogenetics of clozapine — the exam facts

Flowchart — Clozapine pharmacogenetics

flowchart TD
  CLO["Clozapine (atypical)"] --> PD["Pharmacodynamics: prefers 5-HT2 & D4 over D2"]
  CLO --> PK["Pharmacokinetics: metabolised by CYP1A2"]
  PK --> SMOKE["Smoking induces CYP1A2 → ↓ levels"]
  PK --> FLUV["Fluvoxamine/caffeine inhibit → ↑ levels"]
  PD --> RESP{Response?}
  RESP -->|5-HT2A His452Tyr| NR["Predicts non-response"]
  RESP -->|responder| EFF["Up to 60% refractory patients improve"]
  CLO --> AE["Adverse effects"]
  AE --> AG["Agranulocytosis ~0.38% (monitor CBC)"]
  AE --> TD["Tardive dyskinesia → DRD3 Ser9Gly"]
  AE --> WG["Weight gain → 5-HT2C (HTR2C)"]
  

4 · Major Depression & Antidepressant Treatment

Core notes

• Only 60–70% respond to any given antidepressant; response takes weeks; each failed trial cuts odds of response by ~15–20% — motivates pharmacogenomic prediction.
• Genetic factors act on metabolism, receptors, transporters and CNS elements.

Flowchart — Genotype-guided antidepressant selection

flowchart TD
  PT["Patient with major depression"] --> TEST["Pharmacogenomic test"]
  TEST --> MET["CYP2D6 / CYP2C19 metaboliser status"]
  TEST --> TRN["5-HTTLPR (SLC6A4) long/short allele"]
  TEST --> REC["5-HT2A / 5-HT2C receptor variants"]
  MET -->|poor metaboliser| LOW["↓ dose / avoid drug (toxicity risk)"]
  MET -->|ultra-rapid| HIGH["↑ dose / alternative"]
  TRN -->|long allele l/l or l/s| GOOD["Better SSRI response"]
  TRN -->|short allele s/s| POOR["↓ SSRI response → consider alternative"]
  LOW --> PLAN["Individualised antidepressant plan"]
  HIGH --> PLAN
  GOOD --> PLAN
  POOR --> PLAN
  REC --> PLAN
  

5 · Pharmacogenomics of Bipolar Disorder

• Types: Bipolar I (≥1 manic episode), Bipolar II (major depressive + hypomanic, no mania), Cyclothymic. High heritability ~60–80%; polygenic; shares risk with schizophrenia & MDD.
• Treatment: mood stabilisers (lithium, valproate, carbamazepine, lamotrigine), atypical antipsychotics, cautious antidepressants (can trigger mania → give with a stabiliser).

Flowchart — Bipolar pharmacogenomics

flowchart TD
  BP["Bipolar disorder (heritability 60-80%, polygenic)"] --> GENES["Risk genes"]
  GENES --> G1["CACNA1C, ANK3 (ion channel/structure)"]
  GENES --> G2["DAOA, NRG1, DTNBP1 (glutamate/synapse)"]
  GENES --> G3["COMT, BDNF, 5-HTTLPR (neurotransmitter/plasticity)"]
  BP --> RX["Pharmacogenomic-guided therapy"]
  RX --> LI["Predict lithium response & side effects"]
  RX --> AD["Flag antidepressant-induced mania risk"]
  RX --> ADR["Predict adverse drug reactions"]
  LI --> PLAN["Personalised mood-stabiliser plan"]
  AD --> PLAN
  ADR --> PLAN
  

Numericals — every formula + worked example Part B: 5 marks each

Always write: formula → substitution → answer with unit → one-line interpretation. The interpretation line is worth marks.

Decision flowchart — which formula?

flowchart TD
  Q["Read the question"] --> A{What is asked?}
  A -->|safety margin, TD50/ED50| TI["Therapeutic Index"]
  A -->|dose from genotype| DOSE["Metabolizer Score / Adjusted Dose"]
  A -->|will drug work?| EFF["Effectiveness Score"]
  A -->|risk in cohort study| RR["Relative Risk / ARR / NNT"]
  A -->|case-control association| OR["Odds Ratio"]
  A -->|survival over time| HR["Hazard Ratio"]
  A -->|adjusted for confounders| ADJ["Adjusted Risk Ratio"]
  

1. Therapeutic Index (TI)

TD₅₀/LD₅₀ = dose toxic/lethal in 50%; ED₅₀ = dose effective in 50%.

2. Metabolizer Score & Dosing Adjustment

3. Effectiveness Score

4. Relative Risk (RR), ARR & NNT/NNH cohort study

5. Odds Ratio (OR) case-control

6. Hazard Ratio (HR) survival / time-to-event

7. Adjusted Risk Ratio confounding

Part A question bank — 2 marks, answer ALL 40+ Qs

Every likely 2-mark question with a crisp model answer. Tap to reveal.

Part B question bank — 15 marks, answer ANY TWO essay + numerical

Solved past paper — CIA-II, September 2025 closest predictor

The exact previous paper, fully answered. Some Part A items (statins, thiopurines, asthma, BBB) come from the wider unit — learn these one-liners too, they recur.

Part A — answer ALL (2 × 10 = 20)

Part B — answer ANY TWO (15 × 2 = 30)

Image gallery — all diagrams & reference pages

Featured diagrams appear inline above. Below: the remaining topic figures and the full scanned reference chapter (Ch 17, Neurodegenerative Diseases) for reading. Click any image to open full size.

Topic diagrams

Dopamine synthesis Dopamine hypothesis Serotonin / atypicals Endothelial / sickle types Hydroxyurea mechanism Neurodegeneration notes Schizophrenia figure Bipolar figure Ref Ch11 figure

Reference chapter 17 — Neurodegenerative Diseases (scanned, 17 pp)

p1 p2 p3 p4 p5 p6 p7 p8 p9 p10 p11 p12 p13 p14 p15 p16 p17