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📚 Lippincott Pharmacology — Haematology Module

Lippincott Illustrated Reviews: Pharmacology, 8th Ed.

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TOPIC 1: AGENTS USED TO TREAT ANAEMIA — Haematopoietic Growth Factors

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A. IRON

Background

• Iron is stored as ferritin (iron-protein complex) in intestinal mucosal cells, liver, spleen, and bone marrow
• Delivered to marrow for Hb production by transferrin (transport protein)
• Iron deficiency = most common nutritional deficiency worldwide
• Causes: blood loss, menstruation, pregnancy, malabsorption, growth spurts

Clinical Features of Iron Deficiency Anaemia (IDA)

• General anaemia symptoms (fatigue, pallor)
• Pica — craving for ice, dirt, paper
• Koilonychia — spoon-shaped (upward curved) nails
• Soreness/cracking at corners of mouth

Mechanism of Action

• Supplementation with elemental iron corrects the deficiency
• CDC recommends: 60–120 mg/day of oral elemental iron in divided doses 2–3×/day
• In pregnancy: 30 mg/day
• Note: Higher doses (60–120 mg/day) may not be more effective than lower doses (40–80 mg/day) — newer evidence suggests paradoxical ↓ in absorption at higher doses
• Every-other-day dosing is emerging as an equivalent, better-tolerated option

Pharmacokinetics

• Absorption: Oral → acidic gastric environment keeps iron in ferrous (Fe²⁺) form (more soluble) → absorbed in duodenum
• Absorption is inversely related to body iron stores (more absorbed when depleted)
• Relative % absorbed decreases with increasing dose

Oral Formulations (% Elemental Iron)

Parenteral Formulations

• Used when: oral iron fails, intolerance, malabsorption, CKD requiring ESA therapy
• Parenteral treats deficiency faster than oral (oral may take weeks)

Adverse Effects

• Oral: Constipation, nausea, dark stools, GI upset
• Parenteral: Anaphylaxis risk (especially iron dextran) — test dose required; fever, myalgia

Drug Interactions

• Antacids, proton pump inhibitors, calcium → ↓ iron absorption
• Tetracyclines, fluoroquinolones → chelate iron, ↓ their absorption
• Vitamin C → ↑ absorption (maintains ferrous form)

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B. FOLIC ACID (Folate)

Background

• Water-soluble B vitamin, essential for DNA synthesis (thymidylate synthesis) and red cell maturation
• Deficiency → megaloblastic anaemia (large, immature RBCs)

Causes of Deficiency

• Poor diet, alcoholism, malabsorption, pregnancy (increased demand), drugs (methotrexate, trimethoprim, phenytoin)

Mechanism of Action

• Dietary folate → reduced to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR)
• THF is required as a cofactor for one-carbon transfer reactions in purine and pyrimidine (thymidylate) synthesis
• Without folate: DNA synthesis ↓, cell maturation arrest → megaloblasts

Treatment

• Oral folic acid 1 mg/day for most patients
• Pregnancy prophylaxis: 0.4–0.8 mg/day (reduces neural tube defects)
• High-risk (previous NTD, anticonvulsant therapy): 4 mg/day

Important Note

• Folate corrects haematologic manifestations of B12 deficiency but does NOT correct neurological damage
• Always rule out B12 deficiency before giving folate alone

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C. CYANOCOBALAMIN & HYDROXOCOBALAMIN (Vitamin B12)

Background

• Required for: (1) conversion of homocysteine → methionine; (2) conversion of methylmalonyl-CoA → succinyl-CoA
• Deficiency → megaloblastic anaemia + subacute combined degeneration of spinal cord (neurological)

Causes of B12 Deficiency

• Pernicious anaemia — autoimmune destruction of gastric parietal cells → ↓ intrinsic factor (IF) → ↓ B12 absorption in terminal ileum
• Strict vegetarian diet (no animal products)
• Gastrectomy, terminal ileal disease/resection
• Metformin (↓ B12 absorption)

Pharmacokinetics

• Dietary B12 binds intrinsic factor in stomach → absorbed in terminal ileum
• Stored in liver (large stores — deficiency takes years to develop)

Treatment

• Pernicious anaemia: IM cyanocobalamin or hydroxocobalamin (bypasses absent IF)
• Hydroxocobalamin preferred (longer duration, also used in cyanide poisoning)
• High-dose oral B12 (1000–2000 mcg/day) can also work even without IF (passive diffusion)
• Intranasal cyanocobalamin also available for maintenance

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D. ERYTHROPOIETIN (EPO) & DARBEPOETIN

Background

• Erythropoietin = glycoprotein hormone produced by peritubular cells of kidney in response to hypoxia
• Stimulates RBC production in bone marrow
• Recombinant forms: Epoetin alfa (Epogen, Procrit), Darbepoetin alfa (Aranesp)
• Darbepoetin = hyperglycosylated form → longer half-life → less frequent dosing

Indications

• Anaemia of chronic kidney disease (CKD)
• Anaemia due to chemotherapy (cancer patients)
• Anaemia associated with HIV/AIDS (zidovudine therapy)
• Reduction of allogeneic blood transfusions in surgery

Mechanism of Action

• Bind to EPO receptor on erythroid progenitor cells in bone marrow
• → Proliferation, differentiation, and survival of erythroid precursors
• → ↑ RBC production

Adverse Effects

• Hypertension (most common — monitor BP)
• Thrombosis (DVT, PE, MI, stroke) — especially if Hb rises too fast
• Pure red cell aplasia (PRCA) — rare but serious; anti-EPO antibodies
• Headache, flu-like symptoms

Monitoring

• Target Hb: 10–12 g/dL in CKD (do NOT normalize Hb — increased CV risk)
• Iron supplementation often required concurrently (EPO increases iron demand)

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TOPIC 2: COAGULANTS / ANTICOAGULANTS

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Overview of Haemostasis

1. Primary haemostasis — platelet plug formation
2. Secondary haemostasis — coagulation cascade → fibrin clot
3. Fibrinolysis — clot dissolution

• Thrombus = clot adherent to vessel wall
• Embolus = detached, floating thrombus
• Conditions: MI, DVT, PE, ischaemic stroke → treated with anticoagulants/fibrinolytics

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A. PLATELET INHIBITORS (Antiplatelet Agents)

1. Aspirin

• Mechanism: Irreversible inhibition of COX-1 → ↓ thromboxane A2 (TXA2) synthesis → ↓ platelet aggregation
• Low dose (81 mg) used for antiplatelet effect
• Effect lasts for platelet lifetime (~10 days) (platelets have no nucleus, can't regenerate COX)
• Uses: ACS, MI prophylaxis, stroke, PCI after stenting
• ADRs: GI bleeding, peptic ulcer, Reye syndrome in children

2. P2Y12 ADP Receptor Inhibitors

3. GP IIb/IIIa Inhibitors

4. Dipyridamole

• Mechanism: Inhibits phosphodiesterase → ↑ cAMP → ↓ platelet aggregation; also inhibits adenosine uptake
• Used with aspirin (Aggrenox) for stroke prevention

5. Cilostazol

• PDE3 inhibitor → ↑ cAMP in platelets and vascular smooth muscle → antiplatelet + vasodilation
• Used for peripheral artery disease (intermittent claudication)
• Contraindicated in heart failure

6. Vorapaxar

• PAR-1 (protease-activated receptor) antagonist — blocks thrombin-mediated platelet activation
• Add-on therapy for MI/PAD

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B. ANTICOAGULANTS

I. Heparin (Unfractionated Heparin, UFH)

• Binds antithrombin III (AT III) → conformational change → AT III rapidly inhibits thrombin (factor IIa) and factor Xa (and other factors)
• Heparin–AT III complex: 1000× more potent inhibitor than AT III alone
• Acts on both thrombin and factor Xa (requires chain length ≥18 saccharides for anti-IIa activity)

• IV or SC only (not absorbed orally — large, charged molecule)
• Immediate onset (IV); SC onset 1–2 hrs
• Metabolized by liver heparinase; also binds plasma proteins (unpredictable)
• Monitored by aPTT (target: 1.5–2.5× normal)

• Bleeding (most common)
• Heparin-Induced Thrombocytopenia (HIT):
  • Type I — mild, non-immune, transient ↓ platelets (benign)
  • Type II — immune-mediated; IgG antibody against PF4-heparin complex → paradoxical thrombosis (life-threatening); must switch to direct thrombin inhibitor
• Osteoporosis (long-term use)
• Hypoaldosteronism → hyperkalemia

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II. Low Molecular Weight Heparin (LMWH)

• Binds AT III → preferentially inhibits factor Xa (anti-Xa > anti-IIa activity)
• Short chains (< 18 saccharides) inhibit Xa but NOT thrombin

• More predictable pharmacokinetics (less protein binding)
• Longer half-life → once or twice daily SC dosing
• No routine monitoring needed (can measure anti-Xa levels if needed)
• Lower risk of HIT
• Can be given at home

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III. Fondaparinux (Arixtra)

• Synthetic pentasaccharide (synthetic AT III activator)
• Selectively inhibits factor Xa only (too short to bridge AT III to thrombin)
• SC injection, once daily
• No HIT (does not bind platelets/PF4)
• Reversal: No specific antidote (andexanet alfa may be used)

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IV. Warfarin (Coumadin)

• Inhibits vitamin K epoxide reductase (VKOR) → ↓ regeneration of active vitamin K (KH₂)
• Vitamin K is required for carboxylation (activation) of clotting factors II, VII, IX, X and anticoagulant proteins C and S
• Delayed onset (2–5 days) — must wait for existing clotting factors to be cleared
• Factor VII has shortest half-life → PT/INR rises first, but anticoagulation not fully effective until factors II, IX, X also depleted

• Oral administration; excellent bioavailability
• Highly protein-bound (albumin)
• Metabolized by CYP2C9 (and 3A4)
• Genetic polymorphisms: CYP2C9 (metabolism), VKORC1 (target sensitivity) → dose variability

• ↑ anticoagulant effect: Broad-spectrum antibiotics (↓ gut flora → ↓ vit K synthesis), aspirin, NSAIDs, cimetidine, amiodarone, fluconazole (CYP inhibitors)
• ↓ anticoagulant effect: Rifampin, carbamazepine, barbiturates (CYP inducers), vitamin K, cholestyramine (↓ absorption)

• Bleeding (antidote: Vitamin K / fresh frozen plasma / prothrombin complex concentrate)
• Warfarin skin necrosis (early therapy → transient hypercoagulability due to ↓ protein C first; seen in protein C deficiency)
• Teratogenic — crosses placenta → do NOT use in pregnancy (use LMWH instead)

• Non-urgent: oral/IV vitamin K
• Urgent: Fresh Frozen Plasma (FFP) or 4-factor PCC (Kcentra) + IV vitamin K

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V. Direct Oral Anticoagulants (DOACs)

Direct Thrombin Inhibitors (DTIs)

• Oral direct thrombin (IIa) inhibitor
• Prodrug (dabigatran etexilate)
• Renal excretion (dose adjust in CKD)
• Reversal agent: Idarucizumab (Praxbind) — humanized antibody fragment

• Argatroban — hepatic metabolism; used in HIT (liver failure OK for renal pts)
• Bivalirudin — used in PCI/HIT; enzymatic degradation + renal

Direct Factor Xa Inhibitors

• All directly block factor Xa (no AT III needed)
• Reversal agent: Andexanet alfa (Andexxa) — modified factor Xa decoy

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VI. VITAMIN K (Coagulant)

• Phytonadione (Vitamin K1) — used to reverse warfarin overdose, treat neonatal haemorrhagic disease, vitamin K deficiency
• Menaquinone (K2) — synthesized by gut bacteria
• Parenteral vitamin K can take 6–12 hours to take full effect

VII. OTHER COAGULANTS

• Tranexamic acid, Aminocaproic acid — antifibrinolytics (see Topic 3)
• Protamine sulfate — heparin reversal
• Recombinant factor VIII — haemophilia A
• Recombinant factor IX — haemophilia B

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TOPIC 3: THROMBOLYTICS / FIBRINOLYTICS

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Overview

• Used to dissolve existing thrombi (unlike anticoagulants which prevent new clots)
• All act by converting plasminogen → plasmin
• Plasmin: serine protease that degrades fibrin → clot dissolution

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A. Common Characteristics of Thrombolytic Agents

1. All are IV administered
2. All work by activating plasminogen → plasmin
3. Plasmin degrades fibrin clot AND fibrinogen (systemic fibrinolysis → bleeding risk)
4. Contraindications (absolute):
   • Recent (< 3 months) intracranial surgery or head trauma
   • Prior intracranial haemorrhage
   • Ischaemic stroke < 3 months (except acute ischaemic stroke treated within 3–4.5 hrs)
   • Active internal bleeding
   • Aortic dissection

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B. Fibrinolytic Agents

1. Alteplase (tPA — Tissue Plasminogen Activator)

• Recombinant human t-PA
• Mechanism: Preferentially activates fibrin-bound plasminogen (clot-selective) → more specific lysis of existing clot vs systemic fibrinogenolysis
• Short half-life (~5 min) → given as bolus + infusion
• Uses: Acute ischaemic stroke (within 3–4.5 hrs of onset), MI (STEMI), massive PE
• Stroke: Most important indication — "clot-buster"

2. Reteplase (Retavase)

• Deletion mutant of t-PA
• Longer half-life than alteplase → given as two IV boluses 30 min apart
• Used for MI

3. Tenecteplase (TNKase)

• Genetically engineered variant of t-PA with mutations → longest half-life
• Single IV bolus (weight-based)
• Greater fibrin selectivity than alteplase
• Used for STEMI

4. Streptokinase (Historical/developing world)

• Bacterial protein from beta-hemolytic streptococci
• Forms complex with plasminogen → activates other plasminogen molecules (indirect)
• NOT fibrin-selective → systemic fibrinogenolysis
• Antigenic → cannot re-use within 6–12 months (anti-streptokinase antibodies)
• Lowest cost

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C. Adverse Effects of Thrombolytics

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D. Management of Bleeding from Thrombolytics

• Aminocaproic acid (Amicar) — inhibits plasminogen activation; used to reverse fibrinolysis
• Tranexamic acid (Cyklokapron) — similar mechanism; also used for menorrhagia, surgical haemostasis

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TOPIC 4: MODALITIES OF ANTICANCER DRUGS

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I. OVERVIEW

• 25% of the US population will face a cancer diagnosis

• < 25% cured by surgery/radiation alone → most receive systemic chemotherapy
• ~10% of patients achieve cure/prolonged remission with chemotherapy
• Overall 5-year cancer survival: ~68%

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II. PRINCIPLES OF CANCER CHEMOTHERAPY

Cell Cycle & Drug Classification

• S-phase: Antimetabolites (methotrexate, 5-FU, cytarabine)
• M-phase: Vinca alkaloids, taxanes

• Alkylating agents, nitrosoureas, antibiotics (doxorubicin), cisplatin

Log-Kill Hypothesis

• Chemotherapy kills a constant fraction of tumour cells, not a constant number
• Rationale for combination chemotherapy (hits multiple targets/phases)

Resistance

• P-glycoprotein (MDR1) — ATP-dependent drug efflux pump → pumps drugs out of cancer cells → multidrug resistance (MDR)
• Mutations in drug target, enhanced DNA repair, altered drug metabolism

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III. CLASSES OF ANTICANCER DRUGS

A. ALKYLATING AGENTS (Cell-Cycle NON-Specific)

• Act in any phase of cell cycle

• Bone marrow suppression (all)
• Haemorrhagic cystitis (cyclophosphamide, ifosfamide) — caused by acrolein metabolite → prevented by MESNA (sulfhydryl compound that binds acrolein)
• Pulmonary fibrosis (busulfan, BCNU)
• Secondary malignancies (leukaemia) — especially alkylating agents
• Platinum compounds: nephrotoxicity (cisplatin) — prevented by aggressive hydration + amifostine; peripheral neuropathy; ototoxicity
• Cisplatin is highly emetogenic → ondansetron + dexamethasone prophylaxis essential

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B. ANTIMETABOLITES (Cell-Cycle Specific — S Phase)

1. Folate Antagonists

• Inhibits dihydrofolate reductase (DHFR) → ↓ THF → ↓ thymidylate synthesis + purine synthesis → ↓ DNA/RNA synthesis
• Uses: ALL, choriocarcinoma, lymphoma, osteosarcoma, ectopic pregnancy, psoriasis, RA
• Leucovorin (folinic acid) rescue: Given after high-dose MTX to rescue normal cells (tumour cells lack carrier but leucovorin bypasses blocked pathway partially)
• ADRs: Mucositis, myelosuppression, hepatotoxicity, nephrotoxicity, teratogenic

2. Pyrimidine Antagonists

• Converted intracellularly to FdUMP → inhibits thymidylate synthase (TS) → ↓ dTMP synthesis → ↓ DNA synthesis (also incorporates into RNA)
• Uses: Colorectal, breast, head and neck, gastric cancers
• Leucovorin potentiates 5-FU (↑ binding of FdUMP to TS)
• ADRs: Myelosuppression, mucositis, hand-foot syndrome (palmar-plantar erythrodysaesthesia), cerebellar ataxia
• Capecitabine — oral prodrug converted to 5-FU in tumour tissue

• Inhibits DNA polymerase and incorporates into DNA
• Used in AML and ALL; CNS lymphoma (intrathecal)
• ADRs: Myelosuppression, cerebellar toxicity, "Ara-C syndrome" (fever, bone pain)

• Pyrimidine analogue; inhibits ribonucleotide reductase + DNA polymerase
• Pancreatic, lung, ovarian, bladder cancer

3. Purine Antagonists

• Activated by HGPRT → inhibits de novo purine synthesis
• Metabolized by xanthine oxidase → drug interaction: Allopurinol (xanthine oxidase inhibitor) markedly increases 6-MP toxicity — reduce 6-MP dose by 75%
• Used in ALL maintenance

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C. ANTITUMOUR ANTIBIOTICS (Cell-Cycle NON-Specific)

1. Anthracyclines

• Mechanism: (1) Intercalate into DNA → block transcription (2) Inhibit topoisomerase II → DNA strand breaks (3) Generate free radicals → oxidative damage
• Uses: Doxorubicin — breast, lymphoma, sarcoma; Daunorubicin — AML, ALL
• Key ADRs:
  • Cardiotoxicity (dose-dependent, cumulative) — dilated cardiomyopathy (doxorubicin); lifetime cumulative dose limit ~550 mg/m² — prevented by dexrazoxane (iron chelator, protects against free radical damage)
  • Myelosuppression, alopecia, mucositis
  • Red urine (harmless)

• Anthracenedione; similar mechanism to anthracyclines
• Less cardiotoxic; used in AML and prostate cancer

2. Bleomycin

• Mechanism: Binds DNA + Fe²⁺ → generates free radicals → single/double strand DNA breaks (G2/M specific)
• Uses: Testicular cancer (BEP regimen), lymphomas (ABVD)
• Unique ADR: Pulmonary fibrosis (dose-limiting); NO bone marrow suppression (unusual among chemotherapy drugs)
• Also: Skin toxicity, Raynaud phenomenon, fever

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D. MICROTUBULE INHIBITORS

1. Vinca Alkaloids (Cell-Cycle Specific — M Phase)

• Mechanism: Bind β-tubulin → inhibit tubulin polymerisation → prevent microtubule formation → metaphase arrest
• Uses: Vincristine — ALL, lymphoma, Wilms tumour; Vinblastine — testicular, bladder

2. Taxanes (Cell-Cycle Specific — M Phase)

• Mechanism: Bind β-tubulin → stabilise/prevent depolymerisation of microtubules → metaphase arrest (opposite to vinca alkaloids)
• Uses: Breast, ovarian, lung, prostate cancer
• ADRs: Myelosuppression, peripheral neuropathy, hypersensitivity reactions (paclitaxel — premedicate with dexamethasone + diphenhydramine + H2 blocker), alopecia, fluid retention (docetaxel)

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E. TOPOISOMERASE INHIBITORS

Topoisomerase I Inhibitors (Camptothecins)

• Inhibit topoisomerase I → single strand DNA breaks → cell death
• Irinotecan: Colorectal cancer; ADR — severe diarrhoea
• Topotecan: Ovarian, SCLC

Topoisomerase II Inhibitors (Epipodophyllotoxins)

• Inhibit topoisomerase II → double-strand DNA breaks
• Etoposide: Testicular cancer, lung cancer, lymphoma
• Risk of secondary leukaemia (AML)

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F. HORMONAL AGENTS

1. Selective Oestrogen Receptor Modulators (SERMs)

• Competitive partial antagonist of oestrogen receptor (ER)
• Agonist in bone/uterus; antagonist in breast
• Uses: ER+ breast cancer (adjuvant therapy); ductal carcinoma in situ (DCIS)
• ADRs: Hot flushes, endometrial cancer (uterine agonist effect), thromboembolism, cataracts

2. Aromatase Inhibitors

• Non-steroidal (reversible): Anastrozole (Arimidex), Letrozole (Femara)
• Steroidal (irreversible): Exemestane (Aromasin)
• Used in postmenopausal ER+ breast cancer
• ADRs: Hot flushes, osteoporosis (↓ oestrogen → ↓ bone density), arthralgia

3. GnRH Agonists (Hormonal Castration)

• Continuous use → pituitary desensitisation → ↓ LH/FSH → ↓ testosterone/oestrogen
• Initial flare phenomenon: Transient ↑ tumour growth before desensitisation (prevent with short-course antiandrogen)
• Uses: Prostate cancer, premenopausal breast cancer, endometriosis
• ADRs: Hot flushes, sexual dysfunction, decreased bone density, gynecomastia

4. Antiandrogens

• Competitive antagonists at androgen receptor
• Prevent testosterone/DHT action in prostate
• Used in prostate cancer
• ADRs: Gynaecomastia, constipation, hepatotoxicity (flutamide), interstitial pneumonitis (nilutamide)

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G. TARGETED/BIOLOGICAL AGENTS (Brief Overview)

• First-in-class BCR-ABL tyrosine kinase inhibitor
• BCR-ABL = constitutively active kinase in CML (Philadelphia chromosome — t(9;22))
• Also inhibits c-Kit and PDGFR
• ADRs: Nausea, oedema (periorbital/peripheral), hepatotoxicity, myelosuppression

• Anti-CD20 monoclonal antibody
• Binds CD20 on B cells → complement-mediated lysis + ADCC
• Used in B-cell lymphomas (NHL), CLL, RA

• Anti-HER2/neu monoclonal antibody
• Used in HER2-overexpressing breast cancer and gastric cancer
• ADR: Cardiotoxicity (monitor LV function)

• Anti-VEGF monoclonal antibody → blocks tumour angiogenesis
• Colorectal, lung, renal cell, ovarian cancers

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H. ADR SUMMARY TABLE

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🔑 HIGH-YIELD EXAM POINTS

• Ferrous sulfate → duodenal absorption; oral in acidic medium; reticulocytosis in 3–5 days
• Vitamin B12 deficiency → neurological symptoms (subacute combined degeneration) — folate does NOT correct neuro
• Intrinsic factor deficiency → pernicious anaemia → IM B12
• EPO → target Hb 10–12 in CKD (NOT normalise)

• Heparin → monitored by aPTT → reversed by protamine
• Warfarin → monitored by PT/INR → reversed by Vit K / FFP / PCC
• HIT Type II → stop heparin → start argatroban/bivalirudin (direct thrombin inhibitor)
• DOACs: Dabigatran reversed by idarucizumab; Xa inhibitors reversed by andexanet alfa
• Warfarin crosses placenta → teratogenic; use LMWH in pregnancy

• All convert plasminogen → plasmin
• Alteplase → fibrin-selective; used in stroke within 3–4.5 hrs
• Streptokinase → antigenic; not fibrin-selective
• Contraindicated in recent surgery, bleeding, haemorrhagic stroke

• Cyclophosphamide → haemorrhagic cystitis → MESNA
• Doxorubicin → cumulative cardiotoxicity → dexrazoxane
• MTX → DHFR inhibitor → leucovorin rescue
• 5-FU → TS inhibitor → enhanced by leucovorin
• 6-MP + allopurinol → dangerous interaction → reduce dose 75%
• Bleomycin → pulmonary fibrosis; NO myelosuppression
• Vincristine → neuropathy; Vinblastine → myelosuppression
• Tamoxifen → endometrial cancer risk
• Imatinib → CML (BCR-ABL inhibitor)
• P-glycoprotein → multidrug resistance mechanism

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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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