A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

224 CARDIAC DYSRHYTHMIAS
• inappropriate sinus tachycardia (e.g. in association with
panic attacks);
• paroxysmal supraventricular tachycardias that are
precipitated by emotion or exercise;
• rapid atrial fibrillation that is inadequately controlled by
digoxin;
• tachydysrhythmias of thyrotoxicosis;
• tachydysrhythmias of phaeochromocytoma, after
adequate α-receptor blockade.
Atenolol is available for intravenous use after myocardial
infarction. Esmolol is a cardioselective β-adrenoceptor antagonist
for intravenous use with a short duration of action (its elimination
half-life is approximately 10 minutes). β-Adrenoceptor
antagonists are given more commonly by mouth when used for
the above indications.
Contraindications and cautions
Contraindications include the following;
• asthma, chronic obstructive pulmonary disease;
• peripheral vascular disease;
• Raynaud’s phenomenon;
• uncompensated heart failure (β-blockers are actually
beneficial in stable patients (see Chapter 31), but have to
be introduced cautiously).
Drug interactions
• Beta-blockers inhibit drug metabolism indirectly by
decreasing hepatic blood flow secondary to decreased
cardiac output. This causes accumulation of drugs such as
lidocaine that have such a high hepatic extraction ratio
that their clearance reflects hepatic blood flow.
• Pharmacodynamic interactions include increased negative
inotropic effects with verapamil (if given intravenously
this can be fatal), lidocaine, disopyramide or other
negative inotropes. Exaggerated and prolonged
hypoglycaemia occurs with insulin and oral
hypoglycaemic drugs.
AMIODARONE
Use
Amiodarone is highly effective, but its use is limited by the
severity of its adverse effects during chronic administration. It
is effective in a wide variety of dysrhythmias, including:
• supraventricular dysrhythmias – resistant atrial fibrillation
or flutter, re-entrant tachycardias (e.g. WPW syndrome);
• ventricular dysrhythmias – recurrent ventricular tachycardia
or fibrillation.
It can be given intravenously, via a central intravenous line, in
emergency situations as discussed above, or orally if rapid
dysrhythmia control is not required.
Mechanism of action
Amiodarone is a class III agent, prolonging the duration of the
action potential but with no effect on its rate of rise.
Adverse effects and contraindications
Adverse effects are many and varied, and are common when
the plasma amiodarone concentration exceeds 2.5 mg/L.
1. Cardiac effects – the ECG may show prolonged QT,
U-waves or deformed T-waves, but these are not in
themselves an indication to discontinue treatment.
Amiodarone can cause ventricular tachycardia of the
variety known as torsades de pointes. Care is needed in
patients with heart failure and the drug is contraindicated
in the presence of sinus bradycardia or AV block.
2. Eye – Amiodarone causes corneal microdeposits in almost
all patients during prolonged use. Patients may report
coloured haloes without a change in visual acuity. The
deposits are only seen on slit-lamp examination and
gradually regress if the drug is stopped.
3. Skin – photosensitivity rashes occur in 10–30% of patients.
Topical application of compounds which reflect both UV-
A and visible light can help (e.g. zinc oxide), whereas
ordinary sunscreen does not; and patients should be
advised to avoid exposure to direct sunlight and to wear a
broad-brimmed hat in sunny weather. Patients sometimes
develop blue-grey pigmentation of exposed areas. This is
a separate phenomenon to phototoxicity.
4. Thyroid – amiodarone contains 37% iodine by weight and
therefore may precipitate hyperthyroidism in susceptible
individuals; or conversely it can cause hypothyroidism,
due to alterations in thyroid hormone metabolism, with a
rise in thyroxine (T 4 ) and reverse tri-iodothyronine (rT 3 ), a
normal or low T 3 and a flat thyroid-stimulating hormone
(TSH) response to thyrotropin-releasing hormone (TRH).
Thyroid function (T 3 , T 4 and TSH) should be assessed
before starting treatment and annually thereafter, or more
often if the clinical picture suggests thyroid dysfunction.
5. Pulmonary fibrosis – may develop with prolonged use. This
potentially serious problem usually but not always
improves on stopping the drug.
6. Hepatitis – transient elevation of hepatic enzymes may
occur and occasionally severe hepatitis develops. It is
idiosyncratic and non-dose-related.
7. Peripheral neuropathy – occurs in the first month of
treatment and reverses on stopping dosing. Proximal
muscle weakness, ataxia, tremor, nightmares, insomnia
and headache are also reported.
Pharmacokinetics
Amiodarone is variably absorbed (20–80%) when administered
orally. However, both the parent drug and its main
metabolite, desethyl amiodarone (the plasma concentration of
which exceeds that of the parent drug), are highly lipid soluble.
This is reflected in a very large volume of distribution
(approximately 5000 L). It is highly plasma protein bound
(over 90%) and accumulates in all tissues, particularly the
heart. It is only slowly eliminated via the liver, with a t 1/2 of
28–45 days. Consequently, anti-dysrhythmic activity may continue
for several months after dosing has been stopped, and a
loading dose is needed if a rapid effect is needed.