Clinical Pharmacology and Therapeutics

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