The Poynting Effect

Definition

Historical Background

• Named after John Henry Poynting (1852-1914), an English physicist.
• The principle was applied to produce premixed analgesic gas (Entonox) for clinical use.
• Entonox is a 50% N2O + 50% O2 mixture manufactured and used globally for procedural analgesia.

Mechanism of the Poynting Effect

1. The O2 molecules dissolve into the liquid N2O phase.
2. This dissolution reduces the partial pressure of N2O in the liquid, effectively destabilizing the liquid phase.
3. The liquid N2O vaporizes to re-establish equilibrium.
4. The two gases mutually dissolve into each other, forming a single homogeneous gaseous mixture at high pressure.
5. The resulting mixture exhibits physical properties (particularly its critical behavior) that cannot be predicted from either gas alone.

Entonox: The Clinical Application

Pseudocritical Temperature (The Key Clinical Hazard)

Lamination (Separation)

• N2O liquefies and settles to the bottom of the cylinder (liquid phase with some dissolved O2).
• O2 remains as gas above the liquid.

Danger of Lamination

1. Initially: the gaseous O2-rich layer is delivered first - patient receives a high O2, low N2O mixture (inadequate analgesia).
2. As the cylinder empties: the N2O-rich liquid phase vaporizes and is delivered, giving the patient a hypoxic, near-100% N2O mixture - potentially fatal.

Prevention of Lamination

1. Store cylinders above pseudocritical temperature: Always store and use Entonox cylinders in an environment warmer than -6°C (practically, >5°C is advised).
2. Store cylinders horizontally: Horizontal storage increases the surface area between phases, facilitating re-mixing by diffusion.
3. Invert the cylinder repeatedly before use: Mixing by inversion remixes the separated components; cylinders can be used within a few hours of re-mixing if needed urgently (otherwise, allow 24 hours of horizontal storage well above the pseudocritical temperature for complete re-mixing).
4. Dip tube design: Large Entonox cylinders may be fitted with a dip tube (opening at the bottom of the cylinder). This ensures the liquid N2O-rich phase is used first, and prevents delivery of a hypoxic O2-only gas at the start of use.
5. In pipeline systems: At 4 bar, the pseudocritical temperature is -30°C, so lamination is extremely unlikely under normal clinical conditions.

Clinical Uses of Entonox

• Labour analgesia (self-administered via demand valve)
• Dressing changes and wound care
• Short procedural analgesia (fracture manipulation, IV cannulation in children)
• Pre-hospital and emergency analgesia
• Diagnostic procedures (endoscopy, radiological procedures)

Summary

• Medical Gases (UKZN Anaesthetics, 2021) - Entonox production and pseudocritical temperature
• The Anaesthesia Gas Supply System - PMC/NIH - Lamination and management
• Morgan & Mikhail's Clinical Anesthesiology, 7e - Medical gas cylinder properties
• Miller's Anesthesia, 10e - E-cylinder systems and gas supply
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - Workstation gas supply

Pharmacological Management of Ischaemic Heart Disease (IHD)

Introduction

I. Pathophysiological Basis of Drug Therapy

• Heart rate - most important determinant
• Myocardial contractility
• Ventricular wall tension (determined by intracavitary pressure × radius / 2 × wall thickness - Laplace relation)
• Systolic blood pressure (afterload)
• Ventricular volume (preload)

II. Drug Classes

A. ORGANIC NITRATES

• Nitrates are prodrugs that release nitric oxide (NO) in vascular smooth muscle.
• NO activates guanylyl cyclase → ↑ cGMP → dephosphorylation of myosin light chains → smooth muscle relaxation.
• Primary action: venodilation (↓ preload) at low doses; arteriolar dilation at higher doses.
• Net effects on MVO2: ↓ preload → ↓ ventricular volume → ↓ wall tension → ↓ MVO2.
• Also dilate large epicardial coronary arteries (especially at eccentric atheromas and collateral vessels) and relieve coronary spasm.
• Reduce platelet aggregation (additional benefit in ACS).

B. BETA-ADRENOCEPTOR BLOCKERS (Beta-Blockers)

• Competitive antagonists at beta-1 (and beta-2) adrenoceptors.
• Reduce MVO2 by: ↓ heart rate (most important), ↓ contractility, ↓ BP (afterload).
• Prolonged diastole → improved coronary perfusion time.
• Anti-arrhythmic (Class II) - reduce risk of ventricular fibrillation post-MI.
• Proven mortality benefit post-MI and in heart failure with reduced EF.

• Cardioselective (beta-1): Metoprolol succinate (25-200 mg OD), Atenolol (25-100 mg OD), Bisoprolol (2.5-10 mg OD) - preferred.
• Non-selective: Propranolol (10-40 mg TDS/QDS), Carvedilol (alpha+beta blocker, 3.125-25 mg BD) - mortality benefit post-MI.
• With ISA (intrinsic sympathomimetic activity): Pindolol - less bradycardia, less useful in angina.

C. CALCIUM CHANNEL BLOCKERS (CCBs)

• Block L-type voltage-gated calcium channels in vascular and cardiac muscle.
• ↓ intracellular Ca2+ → smooth muscle relaxation → vasodilation; ↓ cardiac contractility and rate (non-DHP agents).

• Reduce afterload (arteriolar dilation → ↓ MVO2).
• Dilate coronary arteries - particularly useful in vasospastic (Prinzmetal) angina.
• Non-DHP agents additionally ↓ heart rate and contractility.

• DHPs: flushing, headache, ankle oedema (vasodilatory), reflex tachycardia (short-acting nifedipine - now avoided).
• Non-DHPs: bradycardia, AV block, constipation (verapamil), negative inotropy.

D. ANTIPLATELET AGENTS

1. Aspirin (Acetylsalicylic acid)

• Irreversibly inhibits COX-1 (and COX-2) → blocks thromboxane A2 synthesis → ↓ platelet aggregation.
• Dose: 75-150 mg daily (low-dose; analgesic/anti-inflammatory doses cause GI toxicity without added benefit).
• Mandatory lifelong in all patients with established IHD (stable angina, post-ACS, post-PCI, post-CABG) unless contraindicated.
• Reduces MI, stroke, and cardiovascular death by ~25% in high-risk patients.

2. P2Y12 Receptor Inhibitors (ADP receptor antagonists)

• Post-ACS: minimum 12 months (aspirin + ticagrelor preferred over clopidogrel - PLATO trial).
• Post-elective PCI with DES: 6-12 months.
• Beyond 1 year may be considered in high-risk patients with low bleeding risk (PEGASUS-TIMI 54 trial - ticagrelor 60 mg BD).

3. Glycoprotein IIb/IIIa Inhibitors

• Abciximab, Tirofiban, Eptifibatide.
• Block the final common pathway of platelet aggregation (fibrinogen receptor).
• Used IV in high-risk NSTEMI/ACS undergoing PCI.
• Largely superseded by newer oral agents.

E. ANTICOAGULANTS (for ACS)

F. HMG-CoA REDUCTASE INHIBITORS (Statins)

• Target LDL-C <55 mg/dL (1.4 mmol/L) for very high cardiovascular risk (ESC 2019 guidelines).
• High-intensity statins: Rosuvastatin 20-40 mg OD or Atorvastatin 40-80 mg OD.

G. ACE INHIBITORS / ARBs

• Post-MI with LV dysfunction (EF <40%) - proven mortality reduction (SAVE trial - captopril; AIRE - ramipril; TRACE - trandolapril).
• All post-MI patients (especially with diabetes, hypertension, heart failure).
• Ramipril 2.5-10 mg OD is the most evidence-based agent (HOPE trial - reduced CV events in high-risk patients without HF).

H. NEWER/ADDITIONAL ANTIANGINAL AGENTS

1. Ranolazine

• Inhibits late sodium current (INa) in cardiac myocytes → ↓ intracellular Ca2+ overload (via Na/Ca exchanger) → ↓ diastolic wall tension → ↓ MVO2.
• Does not significantly affect heart rate or blood pressure.
• Useful as add-on therapy in refractory stable angina when standard agents are inadequate.
• Dose: 375-500 mg BD, titrate to 750-1000 mg BD.
• The CARISA trial showed ranolazine + atenolol/amlodipine/diltiazem improved exercise tolerance.

2. Ivabradine

• Selective inhibitor of the If (funny current, HCN channel) in the sinoatrial node → pure heart rate reduction without affecting contractility or blood pressure.
• Indicated in stable IHD with sinus rhythm, HR ≥70 bpm, when beta-blockers are contraindicated or not tolerated.
• Dose: 5 mg BD, up to 7.5 mg BD.
• SIGNIFY trial: no mortality benefit in stable IHD without HF (may be harmful in angina with HR ≥70 requiring dose >5 mg BD).

3. Nicorandil

• Dual mechanism: NO donor (like nitrates) + potassium channel opener (opens ATP-sensitive K+ channels → membrane hyperpolarization → vasodilation).
• Used in stable angina refractory to standard therapy.
• Dose: 5-10 mg BD, titrate up to 30 mg BD.
• Unique in dilating both arteries and veins - reduces both preload and afterload.

4. Trimetazidine

• Fatty acid oxidation inhibitor (inhibits 3-KAT, the last enzyme of fatty acid beta-oxidation) → shifts cardiac metabolism from fatty acid oxidation to glucose oxidation → same ATP produced with less oxygen consumed (metabolic efficiency).
• Used in stable angina (especially Europe and Asia).
• Dose: 35 mg BD (modified-release).
• Note: may cause/worsen Parkinson-like symptoms (extrapyramidal effects) - avoid in Parkinson's disease.

I. THROMBOLYTICS (for STEMI only)

• Alteplase (tPA): 15 mg IV bolus, 0.75 mg/kg over 30 min, then 0.5 mg/kg over 60 min (max 100 mg).
• Tenecteplase (TNK-tPA): Single weight-based IV bolus (preferred for ease of use).
• Streptokinase: 1.5 million IU over 60 min (no longer preferred - antigenic, no fibrin specificity).

III. Summary by Clinical Scenario

IV. Combination Drug Strategies

• Beta-blocker + nitrate: Synergistic - beta-blocker prevents reflex tachycardia from nitrate; nitrate reduces venous return (preload) which counters beta-blocker-induced increase in EDV.
• Beta-blocker + DHP CCB (amlodipine): Safe and effective combination for stable angina.
• Beta-blocker + non-DHP CCB (verapamil/diltiazem): Avoid - risk of severe bradycardia and AV block.
• Nitrate + CCB: Useful for refractory angina; additive vasodilation.

References

• Katzung BG. Basic and Clinical Pharmacology, 16th Edition, Chapter 12 - Vasodilators & Treatment of Angina Pectoris & Coronary Syndromes
• Fuster & Hurst's The Heart, 15th Edition - Chronic Phase management post-ACS
• Braunwald's Heart Disease, 10th Edition - CAD and MCS
• ACC/AHA Guidelines for Management of Patients with Unstable Angina/NSTEMI (2012, updated 2014)
• PEGASUS-TIMI 54 trial (ticagrelor beyond 1 year post-MI)
• HOPE trial (ramipril in high-risk cardiovascular patients)
• ATLAS-ACS 2 trial (low-dose rivaroxaban post-ACS)

Antianginal Drugs - Quick Reference Comparison Table

CLASS 1: ORGANIC NITRATES

CLASS 2: BETA-BLOCKERS

CLASS 3: CALCIUM CHANNEL BLOCKERS

CLASS 4: NEWER ANTIANGINAL AGENTS

CLASS 5: ANTIPLATELET AGENTS

COMBINATION EFFECTS AT A GLANCE

DRUG CHOICE BY ANGINA TYPE