A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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SELECTED ANTI-DYSRHYTHMIC DRUGS 227<br />
effect when treating sinus bradycardia, in the event <strong>of</strong> haemodynamic<br />
compromise, for example following myocardial<br />
infarction.<br />
ADRENALINE<br />
Use<br />
Although not usually classed as an ‘anti-dysrhythmic’ drug (it<br />
is, <strong>of</strong> course, powerfully pro-dysrhythmogenic in healthy<br />
individuals), adrenaline (also called epinephrine) is used in<br />
the emergency treatment <strong>of</strong> patients with cardiac arrest<br />
(whether due to asystole or ventricular fibrillation). For these<br />
indications it is administered intravenously (or sometimes<br />
directly into the heart or down an endotracheal tube, as discussed<br />
in the above section on cardiac arrest). It has important<br />
uses other than in cardiac arrest, being essential for the treatment<br />
<strong>of</strong> anaphylactic shock (see Chapter 50) <strong>and</strong> useful in<br />
combination with local anaesthetics to reduce the rate <strong>of</strong><br />
removal from the injection site (see Chapter 24).<br />
Mechanism <strong>of</strong> action<br />
Adrenaline is a potent <strong>and</strong> non-selective agonist at both<br />
α- <strong>and</strong> β-adrenoceptors. It causes an increased rate <strong>of</strong> depolarization<br />
<strong>of</strong> cardiac pacemaker potential, thereby increasing<br />
heart rate, in addition to increasing the force <strong>of</strong> contraction <strong>of</strong><br />
the heart <strong>and</strong> intense α 1 -mediated peripheral vasoconstriction<br />
(thereby producing a very marked pressor response), which is<br />
partly <strong>of</strong>fset by β 2 -mediated arterial vasodilation.<br />
Adverse effects<br />
Adrenaline is powerfully pro-dysrhythmogenic <strong>and</strong> increases<br />
the work <strong>of</strong> the heart (<strong>and</strong> hence its oxygen requirement). Its<br />
peripheral vasoconstrictor effect can reduce tissue perfusion.<br />
For these reasons, it is only used systemically in emergency<br />
situations.<br />
Pharmacokinetics<br />
Adrenaline is rapidly eliminated from the circulation by a<br />
high-affinity/low-capacity uptake process into sympathetic<br />
nerve terminals (‘uptake 1’) <strong>and</strong> by a lower-affinity/highercapacity<br />
process into a variety <strong>of</strong> tissues (‘uptake 2’). It is<br />
subsequently metabolized by monoamine oxidase <strong>and</strong><br />
catechol-O-methyl transferase, <strong>and</strong> is excreted in the urine as<br />
inactive metabolites, including vanillyl m<strong>and</strong>elic acid (VMA).<br />
Drug interactions<br />
Tricyclic antidepressants block uptake 1 <strong>and</strong> so may potentiate<br />
the action <strong>of</strong> adrenaline. Adrenoceptor antagonists, both α<br />
<strong>and</strong> β, block its actions at these receptors.<br />
CALCIUM CHLORIDE<br />
Use<br />
Calcium chloride is uniquely valuable when given (slowly)<br />
intravenously for treating the broad complex (‘sine-wave’)<br />
ventricular tachycardia that is a preterminal event in patients<br />
with severe hyperkalaemia (<strong>of</strong>ten secondary to renal failure; see<br />
Chapter 36). Its use may ‘buy time’ during which other measures<br />
to lower the plasma potassium concentration (e.g. glucose<br />
with insulin, ion-binding resins, dialysis) can take effect or be<br />
mobilized. In addition, calcium chloride is used in patients<br />
with hypocalcaemia, but these usually present with tetany<br />
rather than with cardiac dysrhythmia. It may be useful for treating<br />
patients who have received an overdose <strong>of</strong> Ca 2 -antagonists<br />
such as verapamil or diltiazem.<br />
Mechanism <strong>of</strong> action<br />
Ca 2 is a divalent cation. Divalent cations are involved in<br />
maintaining the stability <strong>of</strong> the membrane potential in<br />
excitable tissues, including the heart. The outer aspects <strong>of</strong> cell<br />
membranes contain fixed negative charges that influence the<br />
electric field in the membrane, <strong>and</strong> hence the state <strong>of</strong> activation<br />
<strong>of</strong> voltage-dependent ion channels (Na <strong>and</strong> Ca 2 ) in<br />
the membrane. Divalent cations bind to the outer membrane,<br />
neutralizing the negative charges <strong>and</strong> in effect hyperpolarizing<br />
the membrane. Conversely, if the extracellular concentration<br />
<strong>of</strong> Ca 2 falls, Ca 2 dissociates from the membrane,<br />
rendering it more unstable.<br />
Adverse effects <strong>and</strong> contraindications<br />
Calcium phosphate can precipitate in the kidneys <strong>of</strong> patients<br />
with hyperphosphataemia, worsening renal function. However,<br />
this consideration is irrelevant when one is faced with a hyperkalaemic<br />
patient with broad complex tachycardia.<br />
Drug interactions<br />
• Calcium carbonate precipitates if calcium chloride<br />
solution is mixed with sodium bicarbonate. Therefore,<br />
these should not be given through the same line,<br />
or consecutively without an intervening saline<br />
flush.<br />
• Calcium increases digoxin toxicity <strong>and</strong> calcium chloride<br />
must not be administered if this is suspected.<br />
MAGNESIUM<br />
Use<br />
Magnesium sulphate by intravenous infusion is used in broad<br />
complex tachycardia in the peri-arrest situation, in conjuction<br />
with other treatment (DC shock, lidocaine <strong>and</strong> correction <strong>of</strong><br />
hypokalaemia). Intravenous magnesium sulphate is sometimes<br />
effective in treating dysrhythmias caused by digoxin <strong>and</strong><br />
in drug-induced torsades de pointes. It is invaluable in eclampsia<br />
in prevention <strong>of</strong> further convulsions (see Chapter 28).<br />
Magnesium chloride may be particularly useful in settings<br />
where magnesium deficiency is common. These include prior<br />
chronic diuretic treatment, hypocalcaemia, hypokalaemia, alcoholism,<br />
diarrhoea, vomiting, drainage from a fistula, pancreatitis,<br />
hyperaldosteronism or prolonged infusion <strong>of</strong> intravenous<br />
fluid without magnesium supplementation. There is no<br />
simple test currently available to detect total body magnesium