Haematology Pharmacology and Analgesics: Anaemias, Opioids, and NSAIDs

Clinical Pharmacology, Lecture 6. This final lecture covers the pharmacology of drugs used in haematological conditions (anaemia management, myelosuppression, disease-modifying agents in haematological malignancy) and analgesic pharmacology (the WHO analgesic ladder, opioids, NSAIDs, and adjuvant agents).

DRUGS USED IN ANAEMIA

Iron deficiency anaemia (IDA): the most common nutritional deficiency globally; absolute iron deficiency reflects depleted stores. Oral iron (ferrous sulphate, ferrous fumarate, ferrous gluconate): absorbed in the duodenum and proximal jejunum as Fe2+; ascorbic acid enhances absorption (reduces Fe3+ → Fe2+); taken on an empty stomach maximises absorption but worsens GI side effects (nausea, constipation, black stools). GI intolerance limits adherence in ~20-30%; lower doses (e.g., alternate-day dosing) may be as effective as daily with fewer side effects by reducing hepcidin upregulation between doses. Full response (haemoglobin correction) typically takes 2-4 weeks; continue for 3 months after Hb normalises to replenish stores. Intravenous iron (ferric carboxymaltose, iron sucrose, low-molecular-weight iron dextran): indicated when oral iron not tolerated, not absorbed (coeliac, IBD), or when rapid replenishment is needed (preoperative, late pregnancy, CKD). Risk of hypersensitivity reactions (anaphylaxis rare but possible with iron dextran — test dose required); post-infusion hypophosphataemia especially with ferric carboxymaltose (monitor phosphate).

Megaloblastic anaemia: macrocytic anaemia due to impaired DNA synthesis in rapidly dividing cells (erythroblasts). Two main causes require different treatments: Vitamin B12 (cobalamin) deficiency: pernicious anaemia (autoimmune destruction of intrinsic factor-secreting gastric parietal cells — most common cause of B12 deficiency in adults); malabsorption (gastrectomy, ileal disease, metformin use). Treated with intramuscular hydroxocobalamin (1 mg IM 3 times per week for 2 weeks, then maintenance monthly for life in pernicious anaemia). NB: high-dose oral B12 can also correct deficiency via passive absorption — used in some guidelines. Neurological: subacute combined degeneration of the spinal cord (posterior and lateral columns — peripheral neuropathy, ataxia, cognitive change) — irreversible if untreated. Folate deficiency: poor dietary intake, pregnancy requirement, drugs (methotrexate, trimethoprim, phenytoin — all inhibit dihydrofolate reductase), alcohol. Treated with oral folic acid 5 mg daily. Critical: ALWAYS exclude B12 deficiency before starting folic acid alone — folic acid corrects haematological manifestations but allows neurological damage from B12 deficiency to progress (mask and harm). Periconceptional folic acid 400 µg daily (5 mg in high-risk: prior NTD, antiepileptics, obesity) reduces neural tube defect risk by ~70%.

Erythropoiesis-stimulating agents (ESAs): epoetin alfa/beta, darbepoetin. Recombinant EPO analogues. Stimulate erythroid progenitor proliferation and differentiation. Indicated in anaemia of CKD (reduces transfusion dependence), cancer-related anaemia with concurrent chemotherapy. Risks: hypertension (dose-related), thromboembolism (requires adequate iron stores — monitor ferritin; co-administer iron); pure red cell aplasia (rare — anti-EPO antibody formation); concern re tumour progression at high Hb targets — target Hb 100-120 g/L in CKD.

ANTICOAGULATION IN HAEMATOLOGICAL MALIGNANCY: Patients with malignancy have Trousseau's syndrome — hypercoagulable state from tumour-derived procoagulant factors (tissue factor, mucin). Low molecular weight heparin (LMWH — e.g., dalteparin) is preferred over warfarin for cancer-associated VTE (superior in CLOT trial); DOACs (apixaban, rivaroxaban) are now also recommended for most cancer-associated VTE except GI and genitourinary cancers (higher bleeding risk — use LMWH). Thrombocytopaenia from chemotherapy complicates anticoagulation — balance VTE risk against bleeding risk; consider reducing dose or bridging with compression stockings when platelets <50 ×10⁹/L.

ANALGESIC PHARMACOLOGY — WHO ANALGESIC LADDER

The WHO three-step analgesic ladder (designed for cancer pain, widely applied to all persistent pain): Step 1 — mild pain: non-opioid ± adjuvant; Step 2 — moderate pain: weak opioid ± non-opioid ± adjuvant; Step 3 — severe pain: strong opioid ± non-opioid ± adjuvant.

NON-OPIOID ANALGESICS

Paracetamol (acetaminophen): mechanism incompletely understood — probable central COX-3 inhibition, central serotonergic effects; peripherally inactive at normal doses (no meaningful anti-inflammatory effect). Safe and effective for mild to moderate pain; no GI or antiplatelet effects. Dose: 0.5-1 g every 4-6 hours (max 4 g/day in healthy adults; 2 g/day in hepatic impairment, malnutrition, alcohol excess). Overdose: N-acetyl-p-benzoquinone imine (NAPQI) is a toxic reactive metabolite of CYP2E1/1A2 metabolism, normally conjugated by glutathione; in overdose, glutathione depleted → NAPQI accumulates → centrilobular hepatic necrosis (zone 3 — highest CYP expression). Treatment: N-acetylcysteine (NAC) IV — replenishes glutathione precursor; highly effective if given within 8 hours of overdose; Rumack-Matthew nomogram determines treatment threshold based on plasma paracetamol level and time post-ingestion.

NSAIDs (non-steroidal anti-inflammatory drugs): ibuprofen, naproxen, diclofenac, indomethacin, ketorolac. Mechanism: inhibit COX-1 and COX-2. COX-1 (constitutive): synthesises cytoprotective prostaglandins (PGE2, PGI2 in gastric mucosa — increase mucus and bicarbonate secretion, reduce acid secretion, maintain mucosal blood flow); produces TXA2 in platelets (platelet aggregation). COX-2 (inducible at inflammation sites): mediates prostaglandins of inflammation (PGE2, PGI2) — pain sensitisation (peripheral sensitisation), fever (IL-1 stimulates hypothalamic COX-2). Non-selective NSAIDs block both → analgesic, anti-inflammatory, antipyretic AND adverse effects. Adverse effects: GI — gastric erosions, peptic ulceration, GI haemorrhage (COX-1 inhibition removes gastric mucosal prostaglandin protection); co-prescribe proton pump inhibitor (PPI) with prolonged NSAID use in at-risk patients (age >65, prior peptic ulcer, corticosteroid use, anticoagulation). Renal — NSAIDs constrict afferent arterioles by removing vasodilatory prostaglandins (PGE2, PGI2); in patients dependent on renal prostaglandins to maintain GFR (volume-depleted, CCF, CKD, elderly, on ACEi/ARBs) → acute kidney injury; avoid in CKD, decompensated CCF. Cardiovascular — COX-2 inhibition reduces endothelial PGI2 (vasodilatory, anti-platelet) without affecting platelet TXA2 → pro-thrombotic state; naproxen has most favourable CV profile; avoid selective COX-2 inhibitors (celecoxib, etoricoxib) post-MI. Platelet — reduced TXA2; relevant perioperatively. Bronchospasm — aspirin/NSAID-exacerbated respiratory disease (NSAID-AERD or Samter's triad: aspirin-sensitive asthma + nasal polyps + chronic rhinosinusitis) — arachidonic acid redirected from COX to lipoxygenase (LOX) → excessive leukotriene production → bronchoconstriction.

OPIOID ANALGESICS

Mechanism: agonism at mu-opioid receptors (MOR, encoded by OPRM1) — Gi-coupled; (1) hyperpolarise neurons (↑ K+ conductance); (2) inhibit voltage-gated Ca2+ channels; net effect: reduced neurotransmitter release. Analgesia via: periaqueductal grey matter, rostral ventromedial medulla (descending inhibition), spinal dorsal horn (pre- and postsynaptic), and peripheral receptors (inflamed tissue). MOR also mediates euphoria (mesolimbic), respiratory depression (pre-Bötzinger complex), reduced GI motility (enteric opioid receptors), and miosis.

Opioid tolerance: repeated activation → MOR internalisation, Gi uncoupling, reduced receptor density — increasing doses needed for the same effect. Cross-tolerance exists between opioids. Physical dependence develops alongside tolerance — abrupt withdrawal causes characteristic withdrawal syndrome (anxiety, restlessness, piloerection, diaphoresis, diarrhoea, abdominal cramps, mydriasis, insomnia, yawning) — life-threatening in neonates of opioid-dependent mothers (neonatal abstinence syndrome); managed with morphine NAS protocol or methadone.

Strong opioids: morphine (gold standard for severe cancer pain; active metabolite morphine-6-glucuronide — M6G — more potent than morphine; accumulates in renal failure → prolonged respiratory depression; sustained-release formulations for background pain, immediate-release for breakthrough), oxycodone (semi-synthetic; more predictable pharmacokinetics than morphine; metabolised to oxymorphone), hydromorphone (5-10× more potent than morphine; preferred in renal failure — fewer active metabolites), fentanyl (transdermal patches for stable opioid requirements; 72-hour patch; IV/IM/IN for procedural pain and breakthrough; 100× more potent than morphine; high lipophilicity — rapid CNS penetration), methadone (unique: long half-life 24-60 hours with variable distribution, complex dosing, NMDA antagonism — useful for neuropathic pain component; used in opioid substitution therapy; significant QTc prolongation and drug interactions — specialist use). Pethidine (meperidine): avoid in chronic pain — active metabolite norpethidine accumulates → seizures; not recommended.

Opioid toxicity: respiratory depression (rate-limiting adverse effect; opioids suppress the chemoreceptor response to CO2 — hypercapnoea fails to stimulate breathing; pupils constrict = miosis); reversal with naloxone (competitive MOR antagonist — IV/IM/IN; short half-life 30-90 min compared to opioids; repeated doses or infusion needed for long-acting opioids; titrate to restore respiratory rate, NOT full reversal as this precipitates acute pain and withdrawal).

Weak opioids: tramadol (weak MOR agonist + SNRI — dual mechanism; serotonin syndrome risk with SSRIs; seized in epilepsy; metabolised to active O-desmethyltramadol by CYP2D6 — poor metabolisers have reduced effect, ultra-rapid metabolisers have toxicity); codeine (pro-drug, CYP2D6 → morphine — ultra-rapid metabolisers at risk of toxicity; contra-indicated as analgesia in children post-tonsillectomy after FDA black box warning — post-surgical deaths in CYP2D6 ultrarapid metabolisers).