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OCULAR SIDE EFFECTS OF SYSTEMIC DRUGS CARDIAC DRUGS Part Two

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                  OCULAR SIDE EFFECTS OF SYSTEMIC DRUGS


                                  CARDIAC DRUGS

                                       Part Two

Antiarrhythmic Agents


Under normal circumstances in a healthy human being, the heart beats in a regular
fashion at a rate of 60-90 beats per minute, and the only irregularity is the slight but
noticeable speeding up during inspiration, which is termed sinus arrhythmia. A
cardiac arrhythmia is an abnormality of the rate and/or rhythm of the heartbeat. The
heartbeat may be unduly fast or irregular or there may be ectopic beats originating in
a part of the myocardium other than the sinoatrial node interspersed between normal
beats. Arrhythmias may be atrial, ventricular or junctional in origin and are named
accordingly eg. ventricular ectopic beats or paroxysmal supraventricular tachycardia.


The diagnosis and treatment of cardiac arrhythmias is the sphere of the cardiologist
since it requires knowledge of the mechanism and consequences of the particular
arrhythmia to be treated and a clear understanding of the pharmacodynamics and
pharmacokinetics of the drugs used. The latter includes knowledge of drug action on
the mechanical and electrochemical properties of the heart and vasculature and of
their interaction with the autonomic nervous system and with other drugs.




The precise diagnosis of a cardiac arrhythmia is initiated by the history and
examination and accurately established by interpretation of the electrocardiogram
(examples are shown in Figures 1 and 2). It is treated with drugs or by electric shock
treatment, the exact mode of therapy used, including the particular drug
administered, depending on the type of arrhythmia. Antiarrhythmic drugs have been
                                                   2

 grouped together according to the pattern of




1Figure         1:   ECG   showing    atrial         2Figure      2:      Ventricular
tachycardia with atrial rate of about                extrasystole showing bizarre
150/min; the degree of A:V block can be              QRS complex followed by a
variable.                                            compensatory      pause   before
                                                     the next normal complex.




 electrophysiological effects that they produce and/or their presumed mechanisms of
 action. A recent classification is presented in Table 1. This is intended to make the
 optometrist familiar with the names and basic actions of this group of drugs.




       CLASS                     ACTION                            DRUGS

            I               Sodium Channel         Quinidine, Procainamide, Disopyramide,
                            Blockade               Lignocaine, Mexiletine, Tocainide,
                                                   Flecainide, Phenytoin.

            II              ß-adrenergic           Propranolol, Acebutolol, Carvedilol,
                            blockade               Esmolol, etc.

            III             Prolong                Amiodarone, Bretylium, Sotalol,
                            Repolarisation         Difetilide, Azimilide.

            IV              Ca2+ antagonism        Verapamil, Diltiazem, Semotiadil


 Table 1: Classification of antiarrhythmic drugs according to their mechanism of action.
                                             3


                                       Class I Agents


Quinidine (KINIDIN) and procainamide (PRONESTYL), having an intrinsic
membrane stabilizing effect (which confers them their efficacy), may interfere with
neuromuscular transmission. Both procainamide and quinidine have been reported
to aggravate or unmask myasthenia gravis (Drachman & Skom, 1965; Kornfeld et al,
1976). Godley et al (1990) recently reported a case of an elderly patient who
developed respiratory failure secondary to intravenous procainamide (paralysis of
the muscles involved in respiration was induced by the myasthenic crisis precipitated
by the drug). This patient rapidly improved 12 hours after the offending dose. The
myasthenia gravis thus induced may present with ocular symptoms and signs such
as diplopia due to weakness of the extraocular muscles and ptosis due to weakness
of the levator palpebrae superioris.


It is relevant here to note that it is not necessarily plasma levels of quinidine or
procainamide that correlate with induction of a myasthenic crisis, but that threshold
levels of tissue penetration are important. Multiple doses or a single large dose of
drug may be required to achieve the threshold tissue levels eg. ocular levels.


Two patients, both of whom received quinidine for cardiac arrhythmias, developed
red eyes and on examination were found to have conjunctival hyperaemia and
Koeppe nodules on the pupillary border of the iris (Spitzberg, 1979). These cases of
acute anterior uveitis appeared to be secondary to quinidine sensitivity. Uveitis
secondary to systemic medication is uncommon; however, this topic, including
uveitis due to quinidine, has been summarized more recently in a review by
Fraunfelder & Rosenbaum (1997). If the patient is also taking other drugs known to
cause uveitis (e.g. rifabutin, streptokinase or sulphonamides) a cumulative effect
may be occurring


Monninger & Platt (1957) described toxic amblyopia due to quinidine in a 60-year-old
negro man. The patient was admitted with suspected myocardial infarction. There
                                            4

were no abnormal findings on fundus examination and the patient had no visual
complaints on presentation. Electrocardiography showed changes compatible with
atrial fibrillation and myocardial infarction of recent origin. He was given quinidine
3g/day initially, the dosage being adjusted thereafter depending on clinical findings.


Over two weeks after commencement of quinidine the patient complained of blurred
vision and best corrected VA was 6/15 in each eye. Clinical examination was normal
except for an A:V ratio of 1:3 on ophthalmoscopy. On perimetry with a 3mm white
target at 1m the visual fields were constricted; the blue and red fields were reversed.
A diagnosis of toxic amblyopia due to quinidine was made.


The quinidine was discontinued and the patient treated for toxic amblyopia. After six
weeks of therapy, the VA improved to RE: 6/4.5 -2, LE: 6/4.5 -3. Visual fields at this
time were normal.


Quinidine is an isomer of quinine (an antimalarial drug also used to treat night
cramps) and the findings outlined above are the same as those found in quinine
poisoning. Quinine has been known to cause disturbances of vision for more than
100 years. In mild cases, symptoms consist of slight clouding or flickering of vision.
In more severe cases, there is a sudden complete blindness accompanied by
dizziness and tinnitus. Generally, central vision recovers more than peripheral vision.
The findings during the acute phase are dilated pupils unresponsive to light. The
above report of amblyopia due to quinidine probably has a similar mechanism to the
effects of quinine poisoning, considering the very similar chemical structures of the
two compounds. These effects of quinine and quinidine toxicity are collectively
known as “cinchonism”.


Quinidine has also been reported to lead to corneal deposits similar to those
occurring with the use of amiodarone (Zaidman, 1984). Although the use of
quinidine has declined in recent years with the advent of newer antiarrhythmic
agents with greater efficacy and less toxicity, optometrists should be aware of the
possibility of the above adverse effects on the eye and screen patients on quinidine
                                              5

routinely. Conversely, quinidine should be considered in the differential diagnoses of
amblyopia and uveitis.


Systemic lupus erythematosus (SLE) is a disorder affecting several bodily systems
which is well known to have associated ocular involvement, including serious retinal
vaso-occlusive disease. Procainamide is one of a number of drugs implicated in
causing a lupus-like syndrome, which exhibits similar multi-system involvement and
the presence of antinuclear and anti-DNA antibodies in the serum. Drug-induced
SLE can be differentiated from idiopathic SLE by the fact that in the former
pulmonary involvement (including pleurisy) is more common and renal involvement
extremely rare. Ocular involvement in drug-induced lupus is rare, but Nichols &
Mieler (1989) reported a case of severe retinal vaso-occlusive disease as part of a
procainamide-induced lupus syndrome.


Ocular findings in idiopathic SLE include scleritis, episcleritis, conjunctivitis, keratitis,
uveitis and retinopathy (Gold et al, 1972). Very few of these have been reported in
drug-induced lupus. For example, Turgeon et al (1989) described a case of scleritis
as a presenting feature of procainamide-induced lupus. Lupus associated with
procainamide use occurs in approximately 20% of cases and the pathogenesis is
related to the induction of antinuclear antibody (ANA), particularly antihistone
antibody. One hypothesis states that the autoantibodies form circulating immune
complexes which are then deposited in the sclera or scleral vessels. Through the
activation of complement, polymorphonuclear leucocytes migrate and fibrocytes are
activated, leading to scleral inflammation and tissue destruction.


Patients on procainamide (and other drugs implicated in drug-induced lupus eg.
hydralazine, isoniazid and penicillamine) should be carefully monitored by the
optometrist for ocular side effects, particularly if history or general observation
suggest the presence of drug-induced lupus.


       Disopyramide (RYTHMODAN)
This drug is useful in ventricular and supraventricular arrhythmias. Since the drug is
                                           6

widely used, several adverse effects have been described (Koch-Weser, 1979). Most
side effects were caused by its anticholinergic action and included dry mouth and
acute angle-closure glaucoma (see below). Disopyramide has been reported to
cause blurred vision (Wayne et al, 1980) probably due to paralysis of
accommodation resulting from its parasympatholytic action.


Frucht et al (1984) described a patient who suffered from accommodation and
pupillary paralysis as a result of therapy with a high dose of disopyramide for
ventricular arrhythmia. This patient, a 16-year-old girl, was referred to a department
of Cardiology in Israel because of recurrent ventricular tachycardia refractory to
treatment with the usual antiarrhythmic drugs. The patient had no ocular symptoms.
On her second day in hospital the cardiologist decided to treat her with high doses of
disopyramide. A dose of 200mg of disopyramide was injected intravenously and
150mg six times a day was given orally. On the next day the oral dose was
increased to 300mg six times a day. This dose finally prevented the attacks of
ventricular tachycardia.


On the day following the new treatment, the girl complained that she was unable to
read due to poor near vision, had blurred vision and a dry mouth. The pupils were
dilated to 8mm and the pupil reflex was sluggish. The anterior and posterior
segments were normal. In each eye the amplitude of accommodation was 2.50-3.00
dioptres. The patient was orthophoric. She continued to complain that she could not
read and had photophobia.


Twenty hours after the disopyramide was replaced with quinidine 1.8g/day, the
patient had recovered from all ocular symptoms and signs.


A decrease in amplitude of accommodation sufficient to cause inability to read
following systemic administration of drugs even with known anticholinergic side
effects in a young patient is very unusual. It had never been reported after
therapeutic doses of atropine. The very high dose of disopyramide used in this
patient was probably the reason for the effects seen.
                                            7


When an arrhythmia is not controlled by other drugs, these complications of
disopyramide can be overcome by using an additional plus prescription for close
work.


It has been suggested that disopyramide should not be used in patients susceptible
to glaucoma. However, several ophthalmologists have pointed out that these
warnings refer almost universally to the minority of glaucoma patients - namely,
those with anatomical predisposition to acute narrow-angle glaucoma. In contrast,
they state, anticholinergic drugs are not contraindicated in the majority of glaucoma
patients, who have chronic simple open-angle glaucoma.


As far as the optometrist's role is concerned , a drug history should be taken from
every patient, and remembering that the anticholinergic action of disopyramide may
produce glaucoma in a susceptible patient, all patients on disopyramide should have
their IOPs checked regularly. In addition, on ophthalmoscopy, the size, shape,
position and depth of any cups should be noted, together with which part of the
neuro-retinal rim is widest (normally the inferotemporal one). Potentially susceptible
patients may describe a history of recurrent headaches with blurred vision and
rainbow-coloured haloes; they may present with red eyes; or they may have a family
history of glaucoma.




                                   Phenytoin (EPANUTIN)
This drug is also (more often) used as an antiepileptic. Diplopia, colour vision
defects and blurred vision are accepted side effects. In a study by Lopez et al
(1999), the main effect of phenytoin on colour vision (assessed with the Farnsworth-
Munsell [FM] 100-hue test) was in the blue-yellow axis. There were no subjective
complaints of colour vision problems. The effect seen is most likely due to changes
at the retinal processing level.
                                           8

                                Mexiletine (MEXITIL)
Mexiletine, a drug chemically related to lignocaine, has a capacity to reduce
automaticity of Purkinje fibres and can abolish ventricular reentrant arrhythmias.


Two elderly patients, a man and a woman, developed visual hallucinations during
treatment with mexiletine for ventricular tachycardia and multifocal ventricular ectopic
beats, respectively (Holt,
1988). The man, receiving mexiletine 200mg six hourly, complained of seeing pink
elephants walking along the walls of the room; the woman saw dogs, spiders and
people which were reported to be pink in colour. Both patients were fully aware that
these were hallucinations, and both were well orientated.


In both patients hallucinations began 48-72 hours after commencement of therapy
and resolved within 8-12 hours after discontinuation of mexiletine. The temporal
relationship to treatment and its withdrawal, the fact that both patients were non-
drinkers, and received no other psychoactive drugs, makes it very likely that
mexiletine was responsible for the hallucinations. It is interesting that both patients
saw pink animals, especially as altered colour perception has not been reported with
mexiletine, and neither patient suffered any abnormality of colour vision apart from
the hallucinations.


Using isolated rabbit retinas, Maynard et al (1998) showed that mexiletine plus Mg 2+
together significantly reduced retinal glucose utilization and lactate production
(production of lactate is a sign of anaerobic respiration taking place). When added
during two hours of ischaemia, these two agents also protected neurons from
irreversible functional damage under ischaemic conditions. Although this can be
construed as a “beneficial side effect”, it may in
future be exploited in the therapy of ocular
conditions where ischaemia plays a major role.


Flecainide has been shown to exert minimal
ocular effects, namely transient blurred vision
and benign corneal deposits, both completely
insignificant (Ikaheimo et al, 2001).


                                   Class II Agents
These are the ß-adrenoceptor blocking agents
                                                      3Figure 3: Stage 3 amiodarone
and are discussed separately in the next article.
                                                      keratopathy:   verticillate,   whorl-like
                                                      pattern.
                                     Class III Agents
Bretylium tosylate (BRETYLATE) has very specific indications ie it is used only for
certain arrhythmias which are refractory to treatment with conventional agents. No
serious side effects have been reported associated with the use of bretylium
tosylate.


       Amiodarone (CORDARONE X)
This is a drug which has been available in Europe much longer than in the USA.
Amiodarone bears a striking structural resemblance to thyroxine, its benzene ring
containing two iodine molecules (thyroxine is an iodine-containing hormone). Owing
to this similarity, thyroid disorders, both hyperthyroidism and hypothyroidism have
been reported associated with its use (Hyatt et al, 1988). Where severe
hyperthyroidism is induced by amiodarone, the drug is likely to be withdrawn and
hyperthyroidism severe enough to result in exophthalmos has not been reported.


Almost all patients on 400-1000mg/day of amiodarone develop cornea verticillata,
consisting of greyish golden-brown corneal epithelial deposits. This is rarely
associated with symptoms - one of 61 patients (Hyatt et al, 1988) and none of 8
patients (D'Amico et al, 1981). Exceptionally, blurred vision, haloes around lights and
coloured vision have been reported.


Amiodarone keratopathy has been classified into three stages (Kaplan & Cappaert,
1982): Stage 1 is characterised by the coalescence of fine, punctate, greyish golden-
brown opacities into a horizontal linear pattern in the inferior cornea; stage 2 consists
of additional arborizing and horizontal lines; stage 3 is characterised by a verticillate,
whorl-like pattern, and the branching lines may extend into the visual axis. Advanced
cornea verticillata due to amiodarone is shown diagrammatically in Figure 3.
Pathological studies have shown the deposits to be located in the epithelial basal cell
layer. The corneal deposits are bilateral, dose- and duration-related and reversible.
The early deposits of amiodarone keratopathy morphologically resemble the
Hudson-Stahli line (epithelial iron deposits in aged subjects), but the fully-developed
condition strikingly resembles the keratopathy associated with Fabry's disease
(Wilson et al,1980). Histologically, under the light microscope, intracellular inclusions
are seen within basal epithelial cells of the corneal and conjunctival epithelium.
Electron microscopy shows that the inclusions have characteristic lysosome-like
features: single limiting membranes, diameters of 0.2 to 0.5 :m and concentric
membranous lamellae of 6nm thickness.


Continued surveillance of patients receiving amiodarone is essential. The optometrist
is optimally placed to execute this role, and although referral of every patient with
symptomless corneal deposits is not recommended, careful slit-lamp examination of
the cornea is certainly advisable in all patients taking amiodarone.


Other ocular effects of amiodarone consist of lens opacities, optic nerve and retinal
deposits, and optic neuropathy. Retinopathy has also been rarely reported in
association with amiodarone treatment. (Mantyjarvi et al, 1998). Optic neuropathy
has in addition been reported in three elderly patients on 100-400 mg/day of
amiodarone, two with bilateral involvement and one with unilateral involvement
(Sreih et al, 1999). Another side effect which has been reported with amiodarone is
a sicca syndrome (Dickinson & Wolman, 1986). This occurred in a 65-year-old man
who was prescribed amiodarone for ventricular tachycardia unresponsive to other
therapy. Two weeks later his mouth had become so dry he had difficulty eating, and
four months after starting amiodarone he had diminished tear production (Shirmer
test: RE-1mm; LE-1mm).


Novel Class III agents are azimilide, dofetilide and propafenone, whose
antiarrhythmic efficacy is still being investigated. In a relatively rare condition called
Wolff-Parkinson-White (WPW) syndrome, there is an aberrant bundle of electrical
tissue in the myocardium which conducts the electrical impulse in a retrograde
fashion so that a cyclical current occurs, resulting in a repetitive contraction known
as reentrant tachycardia (see Figure 4). Propafenone has been shown to be
efficacious in terminating reentrant tachycardia in children (Hessling et al, 2001).
Similarly, other very recent studies have demonstrated the efficacy of azimilide in
atrial fibrillation and/or atrial flutter (Pritchett et al, 2000), and of dofetilide in
arrhythmias (including atrial fibrillation) associated with WPW syndrome (Krahn et
al, 2001).


These novel antiarrhythmic drugs appear to be free of ocular side effects in as much
as no reports of such effects were found in the literature and also at least one
review by authorities on the subject state this fact.




Class IV Agents
These are the calcium antagonists and two main ones, verapamil (CORDILOX) and
diltiazem (TILDIEM) are used to treat cardiac arrhythmias. Verapamil is the drug of
first choice in paroxysmal supraventricular tachycardia.


No serious ocular side effects have been reported associated with the use of these
drugs, although verapamil can precipitate myasthenia gravis, which could present
with ocular signs and symptoms. Whether verapamil causes a rise in IOP is a matter
of some debate (Beatty et al, 1984). In fact, topical administration of verapamil to the
eye causes a fall in IOP (Abelson et al, 1988).


IOP is maintained as a steady state between aqueous humour production and
aqueous humour outflow. Two components of aqueous humour function are
potentially affected by calcium inhibition: a hydrostatic component from arterial blood
pressure and an osmotic pressure induced by the active secretion of sodium,
calcium and other ions by the ciliary epithelium (Abelson et al, 1988). Effects on
these may be the mechanisms by which verapamil lowers IOP.


A newer calcium antagonist, nicardipine, used more often as an antianginal agent,
has been shown to increase ophthalmic blood flow (Yatsuka et al, 1998). This effect
is not expected to cause any adverse effects; in fact, it may be advantageous in
patients with retinal ischaemia, where an increase in ocular blood flow would be
beneficial. An even newer drug of this class, namely semotiadil, when administered
intravenously, was shown by Tomita et al (2000) to increase the tissue blood velocity
in the retina, but not in the optic nerve head. This selectivity between different ocular
neural tissues is in contrast to other calcium antagonists, such as nicardipine.




Figure 44: Schematic representation of a section of the left side of the heart showing the basic
  mechanism of reentrant tachycardia: the passage of the electrical impulse in a retrograde
   fashion (red arrows) up the aberrant pathway results in a self-perpetuating cycle which
                          manifests itself as the typical tachycardia.
                                    CONCLUSION
The prescription of antiarrhythmic agents is usually initiated in hospital owing to the
tremendous expertise required in their use, and the facilities and personnel required
when things are different from the expected. To say the least, even under expert
management with the most experienced cardiologists, the treatment of cardiac
arrhythmias is not always as successful as can be hoped, simply because of the
immense complexity of the electrophysiology of the heart as well as the high degree
of variability between individual patients. Nevertheless, patients sometimes continue
on maintenance therapy under the supervision of their GPs and for this reason,
optometrists may be faced with their ocular effects. Since the possibility of this
occurring is rather small, optometrists need to approach patients on such therapy
with an index of suspicion for ocular effects.


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