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Haematinics, Coagulants, Anticoagulants, and Hypolipidaemic Drugs

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PART 1: HAEMATINICS

Definition

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A. Iron Preparations

• Dietary iron (Fe³⁺) is reduced to ferrous form (Fe²⁺) in the stomach by gastric acid and vitamin C
• Absorbed in the duodenum and proximal jejunum via DMT-1 (divalent metal transporter-1)
• Inside cells, iron is stored as ferritin or transferred to plasma by ferroportin, bound to transferrin
• Iron is incorporated into protoporphyrin IX by ferrochelatase to form haem, which combines with globin chains to produce haemoglobin
• Restoring iron stores corrects microcytic, hypochromic anaemia and restores erythropoietic function

• Ferrous sulphate - cheapest, most widely used; 200 mg tablet contains ~60 mg elemental iron. Taken on an empty stomach for best absorption. Side effects: constipation, black stools, epigastric discomfort.
• Ferric carboxymaltose (Ferinject) - preferred parenteral form; given IV when oral is not tolerated or absorption is impaired (inflammatory bowel disease, post-gastrectomy)
• Iron dextran - IV or IM; risk of anaphylaxis requires a test dose

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B. Vitamin B12 (Cyanocobalamin / Hydroxocobalamin)

• Vitamin B12 acts as a coenzyme in two key reactions:
  1. Methionine synthase reaction - converts homocysteine to methionine using methyltetrahydrofolate; this regenerates tetrahydrofolate (active folate) needed for DNA synthesis
  2. Methylmalonyl-CoA mutase reaction - converts methylmalonyl-CoA to succinyl-CoA (important for myelin synthesis and fatty acid metabolism)
• Deficiency leads to megaloblastic anaemia (impaired DNA synthesis, large immature RBCs) and subacute combined degeneration of the spinal cord (due to myelin damage)

• Cyanocobalamin - synthetic form, given IM or orally in high doses
• Hydroxocobalamin - preferred parenteral form in the UK; longer half-life, given IM. Also used as antidote for cyanide poisoning
• Methylcobalamin - active form used in neurological conditions

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C. Folic Acid (Folate)

• Folic acid is reduced to dihydrofolate (DHF) and then tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR)
• THF is the active coenzyme that carries one-carbon units needed for:
  • Purine synthesis (adenine, guanine)
  • Thymidylate synthesis (thymine) via thymidylate synthase
• These reactions are necessary for DNA synthesis and cell division
• Deficiency leads to megaloblastic anaemia (similar to B12 deficiency but without neurological features)
• Important in pregnancy to prevent neural tube defects (spina bifida)

• Folic acid 5 mg daily - for treatment of folate-deficiency anaemia
• Folic acid 400 mcg daily - prophylaxis in pregnancy (started 3 months pre-conception)
• Folinic acid (leucovorin) - "rescue" after methotrexate therapy (bypasses DHFR blockade)

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D. Erythropoiesis-Stimulating Agents (ESAs)

• Erythropoietin (EPO) is produced by peritubular cells of the kidney in response to hypoxia
• Binds EPO receptors on erythroid progenitor cells in bone marrow, activating JAK2/STAT5 signaling
• This promotes proliferation, differentiation, and survival of red blood cell precursors

• Epoetin alfa/beta - recombinant human EPO; used in anaemia of chronic kidney disease, cancer chemotherapy-induced anaemia
• Darbepoetin alfa - longer-acting glycosylated analogue; less frequent dosing (weekly or every 3 weeks)

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PART 2: COAGULANTS (Haemostatics)

Definition

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Types of Coagulants

A. Vitamin K (Phytomenadione / Vitamin K1)

• Factors II (prothrombin), VII, IX, and X require vitamin K as a cofactor for their synthesis in the liver
• These clotting factors undergo vitamin K-dependent post-translational carboxylation: glutamic acid residues are carboxylated to gamma-carboxyglutamic acid (Gla) residues
• Gla residues bind Ca²⁺ ions, which are essential for interaction between coagulation factors and platelet phospholipid membranes
• During carboxylation, vitamin K hydroquinone is oxidised to vitamin K epoxide; it is regenerated by vitamin K epoxide reductase (VKOR)
• Vitamin K 1 administration restores VKOR substrate and allows new synthesis of active clotting factors
• Response takes ~24 hours (time to synthesise new factors); fresh frozen plasma (FFP) is given for immediate effect

• Phytomenadione (Vitamin K1) - oral, SC, or slow IV infusion; reverses warfarin-induced bleeding, treats neonatal haemorrhagic disease
• Menadione (Vitamin K3) - synthetic, water-soluble; limited clinical use due to toxicity

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B. Antifibrinolytics

• Inhibit plasminogen activation, thereby preventing conversion of plasminogen to plasmin
• Plasmin normally degrades fibrin clots; blocking this pathway preserves the clot

• Tranexamic acid - 10 times more potent than aminocaproic acid; used in trauma, surgical haemorrhage, heavy menstrual bleeding, and hereditary angioedema. Orally active. Excreted unchanged in urine.
• Aminocaproic acid - synthetic analogue; inhibits plasminogen activation; used in fibrinolytic states post-surgery
• Aprotinin - serine protease inhibitor; inhibits plasmin, kallikrein, and trypsin; used in cardiac surgery (withdrawn in many countries due to renal toxicity)

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C. Protamine Sulphate

• A basic protein derived from fish sperm/testes, rich in arginine
• The positively charged protamine binds and neutralises the negatively charged heparin, forming a stable, inactive complex - reversing heparin anticoagulation
• Used to reverse heparin overdose or post-cardiopulmonary bypass
• Adverse effects: flushing, bradycardia, hypotension, anaphylaxis (especially in patients allergic to fish or protamine-containing insulin)

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D. Coagulation Factor Concentrates

• Fresh Frozen Plasma (FFP) - contains all coagulation factors; used for multiple factor deficiencies
• Cryoprecipitate - rich in fibrinogen, factor VIII, vWF, factor XIII; used in haemophilia A, von Willebrand disease, hypofibrinogenaemia
• Recombinant Factor VIII / Factor IX - for haemophilia A and B respectively
• Prothrombin Complex Concentrate (PCC) - contains factors II, VII, IX, X; for urgent warfarin reversal

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PART 3: ANTICOAGULANTS

Definition

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Types of Anticoagulants

A. Unfractionated Heparin (UFH)

• Heparin is a heterogeneous mixture of sulfated glycosaminoglycans (MW 5,000-30,000 Da)
• Binds to antithrombin III (AT-III) via a specific pentasaccharide sequence, inducing a conformational change that dramatically accelerates (1000-fold) antithrombin's natural ability to inactivate coagulation factors
• UFH inactivates both thrombin (factor IIa) and factor Xa (requires heparin chains of ≥18 saccharide units to bridge AT-III to thrombin)
• Result: interruption of the coagulation cascade, preventing fibrin clot formation
• Monitored by aPTT (target 1.5-2.5 × normal)
• Route: IV or SC only (does not cross membranes); does not cross the placenta - safe in pregnancy
• Reversal: Protamine sulphate (1 mg per 100 units heparin)
• Adverse effects: Bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis with long-term use

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B. Low Molecular Weight Heparins (LMWHs)

• Derived by depolymerisation of UFH; MW 2,000-8,000 Da
• Short chains selectively inhibit factor Xa (cannot bridge AT-III to thrombin due to short chain length)
• More predictable pharmacokinetics; once/twice daily SC dosing
• Usually no monitoring needed (except in pregnancy, obesity, renal impairment - monitor anti-Xa levels)
• Half-life: ~4 hours (vs 1.5 hours for UFH); renally excreted

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C. Fondaparinux

• Synthetic pentasaccharide; selectively binds AT-III and potentiates (300-1000 fold) neutralisation of factor Xa only
• No direct effect on thrombin
• Predictable pharmacokinetics; SC administration once daily
• No HIT (does not bind PF4); eliminated renally (t½ = 18 hours)
• Contraindicated in severe renal impairment; no reversal agent available

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D. Vitamin K Antagonists (VKAs)

• Inhibits vitamin K epoxide reductase (VKOR), preventing recycling of vitamin K epoxide back to active vitamin K hydroquinone
• This depletes active vitamin K, impairing gamma-carboxylation of clotting factors II, VII, IX, and X (and proteins C and S)
• Produces clotting factors with only 10-40% normal activity
• Onset of anticoagulation is delayed 72-96 hours (time to deplete circulating active factors); bridging with heparin is required for urgent anticoagulation
• Monitored by INR (target 2.0-3.0 for most indications; 2.5-3.5 for metallic heart valves)
• Reversal: Vitamin K1 (24 h delay), FFP or PCC (immediate)
• Narrow therapeutic index - numerous drug and food interactions (especially vitamin K-rich foods)

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E. Direct Oral Anticoagulants (DOACs)

• Dabigatran (Pradaxa) - directly and reversibly inhibits thrombin (factor IIa) at its active site without requiring AT-III. Prodrug (dabigatran etexilate) converted by esterases. Renally excreted. Reversal: Idarucizumab (specific antidote). Monitored by thrombin time (TT).
• Argatroban - parenteral; targets active site of thrombin; hepatically metabolised; used in HIT. Monitored by aPTT.
• Bivalirudin - divalent synthetic hirudin analogue; binds both active site and exosite 1 of thrombin; t½ = 25 min; used in PCI.

• Rivaroxaban (Xarelto) - directly inhibits free and clot-bound factor Xa; once/twice daily oral; no routine monitoring. Used in AF, DVT/PE, post-orthopaedic surgery.
• Apixaban (Eliquis) - twice daily; partially renally excreted; lower bleeding risk than warfarin.
• Edoxaban (Savaysa) - once daily after initial parenteral anticoagulation.
• Reversal for Xa inhibitors: Andexanet alfa (recombinant modified factor Xa decoy that sequesters Xa inhibitors)

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PART 4: HYPOLIPIDAEMIC (LIPID-LOWERING) DRUGS

Definition

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Types of Hypolipidaemic Drugs

A. Statins (HMG-CoA Reductase Inhibitors) - First-Line

• The rate-limiting enzyme in endogenous cholesterol synthesis is HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase)
• Statins are competitive inhibitors of this enzyme, decreasing cellular cholesterol synthesis by up to 80%
• Hepatic cells respond by upregulating LDL receptors on their surface, enhancing clearance of LDL particles from the bloodstream
• Additional pleotropic effects: improve endothelial function, increase plaque stability, anti-inflammatory, antithrombotic effects

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B. Bile Acid Sequestrants (Resins)

• Anion-exchange resins that bind bile acids in the intestinal lumen, preventing their enterohepatic reabsorption
• The liver compensates by converting more cholesterol to bile acids (via cholesterol 7α-hydroxylase), depleting hepatic cholesterol
• This upregulates hepatic LDL receptors, increasing LDL clearance
• Do not affect triglycerides (may even increase them)

• Cholestyramine - classic resin; 4 g sachets; reduces LDL by ~15-25%
• Colestipol - granules or tablets
• Colesevelam - newer resin; better tolerated; also approved for type 2 diabetes (reduces HbA1c)

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C. Fibrates (Fibric Acid Derivatives)

• Activate peroxisome proliferator-activated receptor alpha (PPAR-α) in the liver
• This increases transcription of lipoprotein lipase (LPL), reduces apoC-III (LPL inhibitor), and upregulates apoA-I/II synthesis
• Net effect: marked reduction in triglycerides (30-50%), modest increase in HDL (10-15%), variable LDL effect
• Main indication: hypertriglyceridaemia (Types IV and V dyslipidaemia) and mixed dyslipidaemia

• Fenofibrate - most widely used; safer combination with statins
• Gemfibrozil - older; higher risk of myopathy when combined with statins (inhibits statin glucuronidation)
• Bezafibrate, Ciprofibrate

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D. Nicotinic Acid (Niacin / Vitamin B3)

• Inhibits lipolysis in adipose tissue by activating Gi-coupled GPR109A receptor, reducing free fatty acid (FFA) delivery to the liver
• Reduces hepatic VLDL secretion (less FFA substrate)
• Decreases LDL and increases HDL (most potent agent for raising HDL)
• Also reduces Lp(a)

• Nicotinic acid (immediate release) - 1-3 g/day; significant flushing (mediated by prostaglandins - reduced by aspirin pre-treatment)
• Extended-release niacin (Niaspan) - less flushing; hepatotoxicity with very high doses
• Note: Niacin fell out of favour after trials (AIM-HIGH, HPS2-THRIVE) showed no added CV benefit on top of statins

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E. Cholesterol Absorption Inhibitors

• Ezetimibe selectively inhibits the NPC1L1 transporter (Niemann-Pick C1-Like 1 protein) at the brush border of small intestinal enterocytes, blocking dietary and biliary cholesterol absorption
• The liver responds by upregulating LDL receptors
• Reduces LDL by ~15-20%; synergistic with statins (additive ~20% further reduction)
• Well tolerated; minimal drug interactions

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F. PCSK9 Inhibitors

• PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is an enzyme that binds hepatic LDL receptors and directs them to lysosomal degradation
• PCSK9 inhibitors are monoclonal antibodies that bind and neutralise PCSK9, preventing LDL receptor degradation
• This markedly increases LDL receptor density on hepatic cells, dramatically lowering plasma LDL
• Reduce LDL by 50-70%, even on top of maximum statin therapy

• Evolocumab (Repatha) - SC injection every 2 weeks or monthly; approved for familial hypercholesterolaemia and high CV risk
• Alirocumab (Praluent) - SC injection every 2-4 weeks

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G. Omega-3 Fatty Acids

• High-dose (prescription) omega-3 fatty acids (EPA and DHA) reduce hepatic VLDL-triglyceride secretion and increase triglyceride clearance via LPL
• Primarily used for severe hypertriglyceridaemia (>500 mg/dL) to reduce pancreatitis risk

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Summary Table

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