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📋 What's Covered (Your Syllabus Checklist)

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Key Tips for Studying These Notes

1. Anaemia — Focus on mechanisms of iron absorption (ferrous/duodenum), B12 vs folate (neurological vs haematological), and EPO indications + ADRs
2. Anticoagulants — The most-tested topic: heparin (aPTT/protamine/HIT), warfarin (INR/Vit K/interactions/teratogenicity), LMWH vs UFH differences, and DOACs with their specific reversal agents
3. Thrombolytics — Remember plasminogen → plasmin, alteplase for stroke (fibrin-selective), streptokinase is antigenic, absolute contraindications are heavily tested
4. Anticancer — Learn by drug class + one unique ADR per drug (cyclophosphamide → cystitis + MESNA; doxorubicin → cardiotoxicity + dexrazoxane; bleomycin → pulmonary fibrosis, no myelosuppression; vincristine → neuropathy; 6-MP + allopurinol = dangerous)

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🩸 PHARMACOLOGY — HAEMATOLOGY MODULE

FOER | 1st Year MBBS | KMU | Dr. Tayyaba Qaiser

Conceptual Notes — Learn the "WHY" before the "WHAT"

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🧠 THE BIG PICTURE FIRST

INJURY → Platelets activated → Platelet plug (Primary Hemostasis)
                              ↓
              Coagulation Cascade → Fibrin clot (Secondary Hemostasis)
                              ↓
                    Fibrinolysis → Clot dissolved (Fibrinolytics)

• ❌ Stop clot formation → Antiplatelets, Anticoagulants
• ✅ Dissolve existing clots → Thrombolytics/Fibrinolytics
• ✅ Promote clotting → Coagulants (Vit K, tranexamic acid)

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TOPIC 1: AGENTS USED TO TREAT ANAEMIA + HAEMATOPOIETIC GROWTH FACTORS

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🔑 Concept First: Why does anaemia happen?

Anaemia = Not enough functional RBCs
Cause 1 → Not enough raw material (Iron, B12, Folate)
Cause 2 → Bone marrow not stimulated enough (→ EPO)
Cause 3 → Destruction > Production

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A. IRON — For Iron Deficiency Anaemia (IDA)

The Story of Iron in Your Body:

Food → Stomach (acid keeps iron as Fe²⁺, soluble form)
     → Absorbed in DUODENUM
     → Stored as FERRITIN (liver, spleen, marrow)
     → Transported by TRANSFERRIN to bone marrow
     → Haemoglobin made ✅

Who gets IDA?

• Menstruating women (blood loss monthly)
• Pregnant women (increased demand)
• Children in rapid growth
• GI bleeding (men + postmenopausal women → always do colonoscopy to rule out malignancy)

Clinical Features to Remember:

Treatment — Iron Supplementation:

• Oral: Ferrous sulfate (most common) — 60–120 mg elemental iron/day in divided doses
• Take on empty stomach (better absorption); Vitamin C enhances absorption
• Takes weeks to correct deficiency

💡 Memory trick: Fumarate has the most, Gluconate has the least. F > S > G

• Examples: Iron dextran, iron sucrose, ferric carboxymaltose
• Acts faster than oral
• Risk: Anaphylaxis (especially iron dextran — always give test dose)

⚠️ Adverse Effects:

• Oral: Constipation, dark stools, nausea, GI upset
• Parenteral: Anaphylaxis, fever, myalgia

💊 Important Drug Interactions:

• Antacids/calcium → ↓ iron absorption (don't take together)
• Tetracyclines/fluoroquinolones → chelate iron (take 2 hrs apart)
• Vitamin C → ↑ absorption (keeps Fe²⁺ form)

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B. FOLIC ACID — For Megaloblastic Anaemia

The Concept:

• Folate is needed to make DNA (specifically thymidine) → without folate, cells can't divide → they just grow big without dividing → Megaloblasts (giant immature RBCs)
• Results in Megaloblastic Anaemia

Causes of Folate Deficiency:

• Poor diet (alcoholics, elderly)
• Pregnancy (increased demand — neural tube defects if deficient)
• Drugs: Methotrexate, Trimethoprim, Phenytoin (all block folate)

Treatment:

• Folic acid 1 mg/day orally
• Pregnancy prophylaxis: 0.4–0.8 mg/day → prevents neural tube defects (spina bifida)
• High-risk pregnancy: 4 mg/day

⚠️ Critical Point: Folate corrects the blood count but does NOT fix neurological damage caused by B12 deficiency. Never give folate alone without ruling out B12 deficiency!

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C. VITAMIN B12 — For Pernicious Anaemia

The Concept:

B12 needed for → DNA synthesis + Myelin formation
B12 deficiency → Megaloblastic anaemia PLUS neurological damage
                 (Subacute Combined Degeneration of spinal cord)

How B12 is absorbed (important for MCQs):

Food B12 → Stomach: binds INTRINSIC FACTOR (made by gastric parietal cells)
         → B12-IF complex absorbed in TERMINAL ILEUM

Most Important Cause: Pernicious Anaemia

• Autoimmune destruction of gastric parietal cells → no intrinsic factor → no B12 absorption
• Treatment: IM Cyanocobalamin or Hydroxocobalamin (bypasses the GI route entirely)

Other Causes:

• Strict vegetarian (B12 only in animal products)
• Gastrectomy (removed parietal cells)
• Terminal ileal resection/disease (Crohn's)
• Metformin (reduces B12 absorption — important drug interaction)

Treatment:

• IM B12 for pernicious anaemia (lifelong)
• Hydroxocobalamin preferred (longer duration; also antidote for cyanide poisoning)
• High-dose oral B12 (1000–2000 mcg) can also work even without IF (passive diffusion)

⭐ Neuro Manifestation — Subacute Combined Degeneration:

• Dorsal columns + lateral corticospinal tracts affected
• Features: Loss of vibration/position sense, ataxia, spasticity
• Irreversible if not treated early — folate will NOT fix this

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D. ERYTHROPOIETIN (EPO) & DARBEPOETIN — For Anaemia of CKD

The Concept:

Kidney senses hypoxia → makes EPO → EPO stimulates bone marrow → more RBCs
In CKD → kidneys fail → EPO production falls → anaemia
Solution: Give synthetic EPO

Drugs:

💡 Darbepoetin = hyper-glycosylated = longer half-life = less frequent dosing

Indications:

1. Anaemia of Chronic Kidney Disease (CKD) ← Most important
2. Anaemia from chemotherapy
3. Anaemia from HIV/AIDS (zidovudine)
4. Pre-surgery (reduce transfusion need)

Mechanism:

• Binds EPO receptor on bone marrow erythroid progenitors → proliferation and differentiation → more RBCs

⚠️ ADRs:

• Hypertension (most common — monitor BP)
• Thrombosis (if Hb rises too fast)
• Pure Red Cell Aplasia (PRCA) — rare; anti-EPO antibodies develop

Important Rule:

Target Hb = 10–12 g/dL in CKD. Do NOT try to normalize Hb to 13–14 — this increases cardiovascular risk (MI, stroke, death)!

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TOPIC 2: COAGULANTS & ANTICOAGULANTS

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🔑 Concept First: Normal Haemostasis in 5 Steps (Dr. Tayyaba's Summary)

Step 1 — INJURY: Blood vessel wall breaks → collagen + vWF exposed
Step 2 — ADHESION: Platelets stick to vWF via GpIb receptor
Step 3 — ACTIVATION: Platelets release ADP + TXA₂
Step 4 — AGGREGATION: GpIIb/IIIa receptors bind fibrinogen → platelet plug forms
Step 5 — STABILIZATION: Coagulation cascade → FIBRIN stabilizes the plug

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ANTIPLATELET DRUGS — Block Platelet Plug Formation

1. ASPIRIN ⭐ (Most Important Drug)

Membrane phospholipids
    ↓ (phospholipase A₂)
Arachidonic acid
    ↓ COX-1 (in platelets)
PGH₂
    ↓
TXA₂ (Thromboxane A₂) → ↑ platelet aggregation + ↑ vasoconstriction

💡 Effect lasts entire platelet lifespan (7–10 days) because platelets have no nucleus — they can't regenerate COX-1!

• Low dose (75–150 mg): Antiplatelet (selectively inhibits platelet COX-1)
• High dose: Anti-inflammatory, antipyretic, analgesic

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2. P2Y12 ADP RECEPTOR INHIBITORS

🎯 MCQ Alert: Ticagrelor reversibly inhibits P2Y12 — others are irreversible!

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3. GP IIb/IIIa INHIBITORS

🎯 MCQ: "Final step of aggregation" = GpIIb/IIIa + Fibrinogen

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ANTICOAGULANTS — Block the Coagulation Cascade

Understanding the Coagulation Cascade (Simplified):

Intrinsic pathway (XII→XI→IX→VIII) ─┐
                                     ├─→ X → Prothrombin (II) → Thrombin → Fibrinogen → FIBRIN
Extrinsic pathway (VII + TF) ────────┘

Monitoring:
• Intrinsic pathway → aPTT (test for heparin)
• Extrinsic pathway → PT/INR (test for warfarin)

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HEPARIN (UFH — Unfractionated Heparin) ⭐

Heparin + Antithrombin III → AT III becomes 1000× more active
→ Rapidly inhibits Thrombin (IIa) + Factor Xa
→ Clotting cascade stops

⚠️ Most Important ADR — HIT (Heparin-Induced Thrombocytopenia):

🎯 Key concept: HIT Type II causes thrombosis despite low platelets. You'd expect bleeding, but these patients clot more — this is the "paradox"!

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LOW MOLECULAR WEIGHT HEPARIN (LMWH) ⭐

LMWH → mainly inhibits Factor Xa (some anti-IIa)
UFH → inhibits both Thrombin + Factor Xa equally

Why is LMWH better than UFH?

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WARFARIN (Vitamin K Antagonist) ⭐

Vitamin K (active, KH₂) needed to activate clotting factors II, VII, IX, X + Proteins C and S
Warfarin → blocks VKOR enzyme → vitamin K can't be regenerated → can't activate factors
Result: ↓ Factors II, VII, IX, X → ↓ clotting

💡 Why the delay? Existing clotting factors still work! You need to wait for them to naturally degrade. Onset: 2–5 days. Factor VII has shortest half-life → INR rises first.

Important Drug Interactions (Very Heavy in Exams):

🎯 Mnemonic for Vit K-dependent factors: "1972" → Factors 1 (fibrinogen), 2, 7, 9, 10, Protein C & S. Warfarin blocks II, VII, IX, X, C, S.

⚠️ Critical ADRs:

1. Bleeding — most common
2. Warfarin Skin Necrosis — early therapy; Protein C falls first (short half-life) → transient hypercoagulability → skin necrosis. Seen especially in Protein C deficiency
3. Teratogenic (Category X) — crosses placenta → fetal warfarin syndrome (nasal hypoplasia, stippled epiphyses)

Warfarin Reversal:

⚠️ Warfarin in Pregnancy:

NEVER use warfarin in pregnancy — use LMWH (enoxaparin) throughout!

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DIRECT ORAL ANTICOAGULANTS (DOACs) — The New Generation

Direct Thrombin Inhibitor (anti-IIa):

Direct Factor Xa Inhibitors:

💡 Memory: "-xaban" = Factor Xa inhibitor. Dabigatran ends in -gatran = works against thrombin.

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COAGULANTS (Drugs that promote clotting)

Vitamin K (Phytonadione)

• Used for: Warfarin reversal, newborn haemorrhagic disease, Vitamin K deficiency
• Newborns get Vit K injection at birth (immature gut flora = low Vit K)

Tranexamic Acid (TXA) & Aminocaproic Acid

• Mechanism: Inhibit plasminogen activation → plasmin can't form → fibrin clot is preserved → antifibrinolytic
• Uses: Surgical bleeding, menorrhagia, trauma (TXA given within 3 hrs of trauma for survival benefit), haemophilia bleeds

🎯 MCQ: "Trauma patient gets a drug that stops fibrinolysis" → Tranexamic Acid

Protamine Sulfate

• Heparin antidote: Positively charged protein + negatively charged heparin → neutralization
• 1 mg protamine per 100 units heparin
• Can itself cause allergic reactions/hypotension

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TOPIC 3: THROMBOLYTICS / FIBRINOLYTICS

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🔑 The Core Concept:

Anticoagulants = PREVENT new clots forming
Thrombolytics = DISSOLVE existing clots that have already formed

Mechanism: All activate PLASMINOGEN → PLASMIN
Plasmin = "Pac-Man" for fibrin → chews up the clot

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How the Fibrinolytic System Works:

Tissue Plasminogen Activator (t-PA) → Plasminogen → PLASMIN
                                                          ↓
                                               Degrades Fibrin → Clot dissolved

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THE THROMBOLYTIC DRUGS ⭐

1. ALTEPLASE (t-PA) — The Gold Standard

🎯 MCQ: 65-year-old, sudden weakness, CT no bleed, within 4.5 hrs → Alteplase!

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2. RETEPLASE

• Deletion mutant of t-PA (longer half-life than alteplase)
• Given as two IV boluses 30 min apart
• Used in STEMI

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3. TENECTEPLASE (TNKase)

• Engineered variant of t-PA
• Single IV bolus (weight-based) — easiest to administer
• Most fibrin-selective
• Used in STEMI

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4. STREPTOKINASE (Historical/Low-resource settings)

• NOT fibrin-selective → digests all fibrinogen (systemic lysis)
• Antigenic → causes allergic reactions; anti-streptokinase antibodies develop
• Cannot re-dose within 6–12 months (antibodies neutralize it)
• Cheapest — still used in resource-limited settings

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Absolute Contraindications to Thrombolytics:

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⚠️ ADRs of Thrombolytics:

🎯 MCQ: "Patient on thrombolytics develops severe headache + vomiting" → Intracranial Haemorrhage (most feared complication)

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Comparison Table: Anticoagulants vs Thrombolytics

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TOPIC 4: MODALITIES OF ANTICANCER DRUGS

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🔑 Concept First: Why is cancer hard to treat?

Normal cells: Controlled division → multiply when needed, stop when told
Cancer cells: Uncontrolled division → ignore "stop" signals → keep multiplying

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The Cell Cycle (Critical Foundation):

G1 (growth, preparation) → S phase (DNA synthesis/replication) → G2 (more growth) → M phase (Mitosis/cell division)
↑_________________________G0 (resting phase)_____________________________________________|

• S-phase: Antimetabolites (MTX, 5-FU, Cytarabine)
• M-phase: Vinca alkaloids, Taxanes

• Alkylating agents, Antibiotics (doxorubicin), Cisplatin

💡 CCNS drugs are more useful when tumour cells are slowly dividing (like CLL). CCS drugs are better for rapidly dividing tumours (like leukaemia).

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CLASS 1: ALKYLATING AGENTS ⭐

"Alkyl" = Carbon chain
These drugs ATTACH carbon chains to DNA → Create cross-links → DNA can't open → Can't replicate → Cell dies

Important Drugs:

🔥 MUST KNOW: Cyclophosphamide & Ifosfamide → form Acrolein metabolite → damages bladder → Haemorrhagic Cystitis Prevention: MESNA (2-mercaptoethane sulfonate) — reacts with acrolein in urine to detoxify it

• Carmustine (BCNU), Lomustine (CCNU)
• Used for brain tumours (glioblastoma)
• ADR: Pulmonary fibrosis

Cisplatin protection: Aggressive IV hydration + Amifostine (renal protectant) Cisplatin = most emetogenic chemo drug → always pre-treat with ondansetron + dexamethasone

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CLASS 2: ANTIMETABOLITES ⭐ (S-Phase Specific)

Normal cell: Uses real nucleotides to build DNA
Antimetabolite: Inserts fake version → DNA synthesis stalls → cell dies

A. Folate Antagonists

MTX → inhibits DHFR (Dihydrofolate Reductase)
↓
Can't make THF (Tetrahydrofolate)
↓
Can't make Thymidine or Purines
↓
DNA synthesis stops → Cell death

• Why it works: Leucovorin bypasses the blocked DHFR step → feeds normal cells
• Cancer cells lack the transport to take up leucovorin efficiently

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B. Pyrimidine Antagonists

5-FU → converted to FdUMP inside cell
FdUMP → inhibits THYMIDYLATE SYNTHASE (TS)
↓
Can't make dTMP (thymidine) → DNA synthesis stops
Also: incorporates into RNA → disrupts RNA function

💡 Leucovorin potentiates 5-FU (enhances FdUMP binding to TS) — used together in colorectal cancer protocols

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• Inhibits DNA polymerase; also incorporates into DNA
• Main drug for AML
• ADRs: Myelosuppression, cerebellar toxicity

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C. Purine Antagonists

• Fake purine → inhibits de novo purine synthesis
• Used in ALL maintenance therapy
• CRITICAL DRUG INTERACTION: Metabolized by Xanthine oxidase
  • Allopurinol (used in gout) inhibits xanthine oxidase → 6-MP accumulates → FATAL toxicity
  • Must reduce 6-MP dose by 75% if given with allopurinol

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CLASS 3: ANTITUMOUR ANTIBIOTICS ⭐

Anthracyclines — The "Red" Drugs

1. Intercalate into DNA → blocks transcription
2. Inhibit Topoisomerase II → DNA strand breaks
3. Generate FREE RADICALS → oxidative damage

⚠️ THE Key ADR: CARDIOTOXICITY (Dose-Dependent)

Free radicals → damage cardiac myocytes → Dilated Cardiomyopathy
Cumulative lifetime dose of doxorubicin: do NOT exceed ~550 mg/m²

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Bleomycin — The "Unique" One

⭐ Why Bleomycin is unique — REMEMBER THESE TWO FACTS:

1. Causes Pulmonary Fibrosis (most feared, dose-limiting toxicity)
2. Does NOT cause bone marrow suppression (unlike almost every other chemo!)

🎯 MCQ: "Chemo drug with no myelosuppression but causes lung fibrosis" = Bleomycin

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CLASS 4: MICROTUBULE INHIBITORS ⭐ (M-Phase Specific)

Vinca Alkaloids (from periwinkle plant 🌸)

Taxanes (from yew tree 🌲)

• Vinca: Prevent formation of microtubules
• Taxanes: Prevent disassembly of microtubules → cell stuck in metaphase → dies

💡 Think of it like: Vinca = won't LET microtubules form. Taxanes = won't LET microtubules fall apart. Both = cell can't divide.

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CLASS 5: TOPOISOMERASE INHIBITORS

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CLASS 6: HORMONAL AGENTS

A. TAMOXIFEN — For Breast Cancer

Tamoxifen = Selective Oestrogen Receptor Modulator (SERM)
In BREAST → ER ANTAGONIST → blocks cancer growth ✅
In UTERUS → ER AGONIST → stimulates uterine lining ⚠️
In BONE → ER AGONIST → protects bone ✅

🎯 "Risk of endometrial cancer" with which drug? → Tamoxifen

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B. AROMATASE INHIBITORS — For Postmenopausal Breast Cancer

⚠️ Only work in postmenopausal women (ovarian oestrogen is too dominant in premenopausal)

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C. GnRH AGONISTS — Medical Castration

GnRH normally → pulsatile release → stimulates LH/FSH
Continuous GnRH agonist → pituitary DESENSITIZED → stops making LH/FSH
→ No testosterone (prostate cancer) / No oestrogen (breast cancer)

⚠️ Initial Tumour Flare: First 1–2 weeks, before desensitization → oestrogen/testosterone briefly rises → cancer worsens temporarily → give antiandrogen to cover this period

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D. ANTIANDROGENS — For Prostate Cancer

• Block androgen receptor in prostate → testosterone can't act → cancer starved
• ADRs: Gynaecomastia, liver toxicity (flutamide)

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CLASS 7: TARGETED/BIOLOGICAL AGENTS (Key Ones)

💡 Imatinib = "magic bullet" concept — first targeted cancer therapy. Philadelphia chromosome (t9;22) → BCR-ABL → constitutively active tyrosine kinase → uncontrolled cell division → CML

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🏆 MASTER SUMMARY TABLE — UNIQUE TOXICITIES (Exam Favourites)

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🎯 EXAM-STYLE MCQ PRACTICE (From Your Dr. Tayyaba's Slides)

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🔑 RAPID-FIRE HIGH-YIELD POINTS

• Aspirin → irreversible COX-1 inhibitor → effect lasts 7–10 days (platelet lifespan)
• Ticagrelor → only reversible P2Y12 inhibitor among the -grel drugs
• Heparin → aPTT; reversed by protamine; HIT Type II = paradoxical thrombosis
• Warfarin → PT/INR; reversed by Vitamin K + PCC; teratogenic; do NOT use in pregnancy
• Alteplase → plasminogen → plasmin; used in stroke within 3–4.5 hrs; fibrin-selective
• Streptokinase → antigenic; not fibrin-selective; cannot re-dose within 6–12 months
• Cyclophosphamide → haemorrhagic cystitis → MESNA prevents
• Doxorubicin → cumulative cardiotoxicity → dexrazoxane protects
• Bleomycin → pulmonary fibrosis + NO myelosuppression (unique!)
• MTX → DHFR inhibitor → Leucovorin rescue
• 5-FU → Thymidylate Synthase inhibitor; Leucovorin potentiates it
• 6-MP + Allopurinol = dangerous! Reduce 6-MP dose by 75%
• Vincristine → neuropathy; Vinblastine → myelosuppression
• Tamoxifen → endometrial cancer risk (uterine agonism)
• Imatinib → CML; BCR-ABL tyrosine kinase inhibitor; Philadelphia chromosome t(9;22)

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