TCA Toxicity: Emergency Management and Antidote Strategies

ECG paper has specific measurements: (1) Large squares (10mm x 10mm) equal 200 milliseconds, (2) Small squares (5mm x 5mm) equal 40 milliseconds, (3) 25 small squares equal 1 second, (4) 100 small squares equal 1 minute, (5) 300 large squares equal 1 minute. Standard calibration is 1mV = 10mm (1cm) in voltage and 25mm = 1 second in time. Basic ECG waveforms include: (1) P wave - atrial depolarization, (2) QRS complex - ventricular depolarization, (3) T wave - ventricular repolarization, (4) U wave - repolarization of papillary muscles. Key intervals: (1) PR interval (120-200ms) represents AV conduction time, (2) QT interval must be corrected for heart rate (QTc) using Bazett's or Fridericia's formulas. QRS nomenclature includes Q (first negative deflection), R (first positive deflection), S (first negative deflection after R), R' (second positive deflection), and S' (second negative deflection).

This comprehensive lesson covers all essential aspects of ECG interval measurement. The standard ECG grid uses small boxes (1mm, 0.1mV, 40ms) and large boxes (200ms), with five large boxes equaling one second. Key wave components include P wave (atrial depolarization), QRS complex (ventricular depolarization), and T wave (ventricular repolarization), with segments PR (P to QRS) and ST (S to T) and the J point marking their junction. Three critical intervals must be measured: PR interval (AV conduction, ~150ms normal), QRS duration (ventricular conduction, <120ms normal), and QT interval (depolarization-repolarization cycle). The QT interval shortens at faster rates, requiring correction using QTc = QT × (1/√R-R interval in seconds). Normal QTc values are ≤420ms in males and ≤440ms in females. Abnormal waves like delta waves (WPW syndrome) and epsilon waves (certain cardiac conditions) are also identified. Precise caliper use and alignment with grid lines ensure accurate measurements within acceptable error margins.

An electrocardiogram (ECG) is recorded on millimeter paper where each small square represents 0.04 seconds horizontally and 0.1 millivolts vertically, while each large square (5 small squares) represents 0.20 seconds and 0.5 millivolts. The three main waves are: P wave (atrial depolarization, normal width <0.10s, height <0.25mV), QRS complex (ventricular depolarization, normal duration 0.06-0.12s), and T wave (ventricular repolarization, normal amplitude <5mm in frontal leads, <15mm in precordial leads). Key segments include PR segment (AV node delay, 0.09s), ST segment (ventricular depolarization-repolarization period), and intervals like PR (0.12-0.20s), QT (ventricular depolarization-repolarization), and RR (heart rate). Normal QRS morphology varies by lead, with capital letters for waves >5mm and lowercase for <5mm.

The electrocardiogram represents 3D cardiac conduction in 2D format, requiring multiple derivations for comprehensive assessment. Six precordial leads (V1-V6) span from right to left across the chest, with V1 showing predominantly negative QRS (wave moving away) and V6 showing predominantly positive QRS (wave approaching). Limb leads II, III, and AVF view the inferior wall, while AVR and AVL view the right and left arms respectively. The ECG consists of P wave (atrial depolarization), QRS complex (ventricular depolarization with Q, R, S components), and T wave (ventricular repolarization). Each small square equals 0.04 seconds, enabling heart rate calculation by counting QRS complexes in five large squares and multiplying by 60. Understanding these fundamentals provides the foundation for all subsequent ECG interpretation.

Normal ECG intervals: PR interval = 0.08-0.10 seconds, QRS complex = 0.08-0.10 seconds, QT interval = 0.40-0.43 seconds. PR prolongation indicates first-degree AV block. PR shortening occurs in Wolff-Parkinson-White syndrome. QT prolongation is critical as it can lead to torsades de pointes. The QRS complex represents ventricular depolarization and may consist of one to four waves. R waves are positive (R1, R2...), Q waves are negative before R, and S waves are negative after R. Large amplitude waves use uppercase letters, small amplitude use lowercase. QRS widening indicates ventricular tachycardia or supraventricular tachycardia.

The cardiac action potential has four phases: Phase 0 (rapid depolarization via fast sodium channels), Phase 1 (initial repolarization), Phase 2 (plateau via slow calcium channels), and Phase 3 (repolarization via potassium efflux). Fast sodium channels allow only sodium entry and operate during depolarization, while slow sodium channels allow sodium and calcium entry together during the plateau. Fast sodium channels are blocked by tetrodotoxin, while slow sodium channels are blocked by calcium channel blockers like verapamil.

Phase 0 (rapid depolarization) involves voltage-gated sodium channel opening and sodium influx, causing membrane potential to rise from resting to approximately +20 mV. In ventricular muscle, this phase is very rapid due to high sodium channel density. In nodal cells, phase 0 is slower because it involves calcium influx through L-type calcium channels rather than sodium influx. Phase 1 (early repolarization) begins when sodium channels inactivate and transient outward potassium channels open, causing brief repolarization. This phase is more prominent in ventricular muscle than in nodal cells.

Cardiac depolarization and repolarization involve four main electrolytes (sodium, potassium, calcium, chloride) and a series of phases: (1) Resting membrane potential (-70 to -90 mV) maintained by sodium-potassium pump (3 Na+ out, 2 K+ in); (2) Phase 4 - slow diastolic depolarization due to sodium leakage, fastest in SA node myocytes; (3) Phase 0 - rapid depolarization when fast sodium channels open at threshold; (4) Phase 1 - initial repolarization with sodium influx slowing and chloride entering; (5) Phase 2 - plateau phase with slow sodium and calcium channels open, maintaining flat polarity; (6) Phase 3 - rapid repolarization as potassium channels open and positive ions exit. Calcium availability directly affects contraction strength and duration.

Phase 0 of the fast-response action potential is the rapid upstroke caused by inward sodium current through voltage-gated sodium channels. When the membrane reaches threshold potential from an adjacent action potential, the sodium channel's activation gate opens rapidly, allowing sodium influx. Even after the membrane becomes positive (overshoot), the large sodium concentration gradient continues driving sodium into the cell despite it being against the electrical gradient. This continues briefly until the sodium channel's inactivation gate closes, abruptly stopping the inward current.

An action potential is a rapid sequence of voltage changes across a cell membrane, determined by ion proportions inside and outside the cell. Cells have two compartments: intracellular and extracellular. The extracellular compartment has high sodium and chloride concentrations (like salt), while the intracellular compartment has high potassium. The resting membrane potential is approximately -70 mV. Depolarization is the upward movement of voltage (becoming more positive), while repolarization is the downward movement (becoming more negative). The cardiac conduction system consists of ultra-specialized cardiac muscle cells that transmit action potentials, including the SA node, AV node, Bundle of His, and Purkinje fibers. The SA node serves as the heart's natural pacemaker with automaticity (self-generating impulses) and excitability, firing at 60-100 beats per minute. Cardiac action potentials are classified into slow (nodal) and fast (non-nodal) types. Slow action potentials (SA and AV nodes) have phases 0, 3, and 4: Phase 0 is calcium-dependent depolarization, Phase 3 is potassium-dependent repolarization, and Phase 4 is the 'funny current' (If) involving sodium influx through HCN channels. Fast action potentials (atrial muscle, ventricular muscle, Purkinje fibers, Bundle of His) have five phases: Phase 4 (resting potential maintained by potassium leak channels and Na+/K+ ATPase pump), Phase 0 (sodium and calcium-dependent depolarization), Phase 1 (early repolarization by potassium efflux), Phase 2 (plateau maintained by balanced calcium influx and potassium efflux), and Phase 3 (final repolarization by potassium efflux).

Acids are proton donors, bases are proton acceptors. Weak acids (lactic, carbonic) dominate biology. pH = -log[H+], tightly regulated in blood (7.35-7.45). Physiological pH ranges: gastric lumen (1.5-3.5), cytoplasm (7.5), mitochondria (7.8). Three buffer systems maintain pH: bicarbonate (pKa 6.1, extracellular, most important as open system), phosphates (intracellular/urine), and proteins (histidine in hemoglobin). The bicarbonate-carbonic acid ratio is 20:1 at pH 7.4. pH affects enzyme charge, substrate binding, and protein structure. Ion trapping explains drug absorption: weak acids (aspirin, pKa 3.5) absorb in stomach (pH 2) but are trapped in blood (pH 7.4).

The human body maintains acid-base balance through three primary buffer systems: the carbonic acid-bicarbonate buffer system (the most important), which works with respiration to regulate pH by converting CO2 and water into carbonic acid that dissociates into bicarbonate and hydrogen ions; the phosphate buffer system, which involves dihydrogen phosphate and hydrogen phosphate ions that absorb or release hydrogen ions to counteract pH changes; and the protein buffer system, where amino acid groups in body proteins and plasma act as buffers by accepting or donating hydrogen ions to maintain pH stability. These systems work together to keep blood pH within the narrow range of 7.35-7.45, which is essential for proper biochemical reactions.

Acids donate hydrogen ions (H+) in solution, while bases accept hydrogen ions. Strong acids undergo complete dissociation (100%), while weak acids dissociate partially. pH is defined as the negative logarithm of hydrogen ion concentration: pH = -log[H+]. The normal body pH is 7.4, with a critical range of 6.9-7.8. pH balance is critical because hydrogen ions can bind to proteins, changing their shape and function, affecting enzyme activity, oxygen absorption, and drug absorption. The body has three categories of acids: volatile acids (CO2, eliminated through lungs), fixed acids (sulfuric and phosphoric acids, excreted by kidneys), and organic acids (ketone bodies, produced during carbohydrate depletion). CO2 alone produces approximately 10,000 millimoles of hydrogen ions daily. Buffer systems are the body's fastest defense mechanism, functioning within fractions of a second. The bicarbonate buffer system (H2CO3 and NaHCO3) is most important, with carbonic acid eliminated through lungs and sodium bicarbonate regulated by kidneys. The phosphate buffer system (H2PO4- and HPO42-) is most important in intracellular fluid and urine. The Henderson-Hasselbalch equation (pH = pKa + log([A-]/[HA])) describes the relationship between pH and the base-to-acid ratio.

Drug ionization depends on pH and pKa. In plasma (pH 7.4), weak acids exist primarily in ionized form while weak bases exist primarily in non-ionized form. Drug-protein binding affinity depends on drug acidity: weak acids bind strongly to albumin with fewer binding sites (<4), while weak bases bind weakly to albumin but may bind to alpha-1-acid glycoprotein with more sites (>30). This explains why acidic drugs typically show higher protein binding percentages.

pH is the negative logarithm of hydrogen ion concentration (pH = -log[H+]), ranging from 0-14 with 7 being neutral. Acids donate H+ ions and have low pH, while bases accept H+ ions and have high pH. The body produces metabolic acids (carbonic, lactic, phosphoric) requiring constant buffering. Buffers resist pH changes by containing weak acids and conjugate bases. The pKa value indicates the pH at which half the acid dissociates and determines the buffer's effective range. The Henderson-Hasselbalch equation (pH = pKa + log([A-]/[HA])) calculates pH from buffer components. Maximum buffering occurs when pH equals pKa. The body has three major buffer systems: bicarbonate (extracellular fluid and blood plasma), phosphate (intracellular fluid and kidneys), and protein (blood plasma and cells). The bicarbonate system involves CO2 combining with water to form carbonic acid, which dissociates into bicarbonate and H+. The chloride shift exchanges bicarbonate for chloride across red blood cell membranes, with H+ binding to hemoglobin. The phosphate system helps excrete H+ as phosphoric acid in urine. The protein system uses amino and carboxyl groups to accept or release H+. Hemoglobin is particularly important in blood, binding H+ in tissues and releasing it in the lungs.