Other Antiviral Agents
Amantadine and its alpha-methyl
derivative rimantadine are mainly used in the prophylaxis and treatment of
influenza A virus infections. Amantadine is also used in the treatment of
Parkinsonism and drug -induced (carbon monoxide, antipsy-chotics)
extrapyramidal effects, as well as herpes zoster. There are indications that it
may also be useful in treating cocaine withdrawal symptoms.
Amantadine is well absorbed orally
(55 to 90%). Peak blood levels are reached in 1 to 4 hours after an oral dose.
Adverse effects include anticholinergic symptoms of dry mouth, tachy-cardia and
difficulty in focusing, while the two most serious areas of toxicity are
cardiac arrhythmias and CNS stimulation. Chronic use of amantadine (especially
in the elderly, and in the renally compromised) can produce delirium,
hallucinations, disorientation, and weakness. These can be greatly aggra-vated
if anticholinergic drugs are given concomitantly. Ocular toxicity may
occasionally occur, characterised by blurred vision, corneal irritation,
oculogyric crises, and mydriasis. There are also reports of peripheral oedema,
congestive heart failure, and urinary retention.
Amantadine, a dopamine agonist, is
considered as a serotonergic drug. Theoretically, any drug or combination of
drugs, that has the ability to increase serotonin activity can produce
serotonin syndrome. At the present time, there are few reports in the
literature of this adverse event with amantadine.
A study of elderly patients
receiving antiviral treatment revealed a lower incidence of adverse effects
related to the CNS in patients receiving rimantadine compared with amantadine.
Acute overdose causes dry mouth,
mydriasis, psychosis, and urinary retention. Psychosis is characterised by
agitation, disorientation, and hallucinations. Convulsions can occur.
Cardiovascular manifestations include ventricular fibrillation, prolonged QT
interval, torsade de pointes, and cardiopulmonary arrest. There are also
reported cases of ARDS and pulmonary oedema. While survival has been reported
with an acute inges-tion of 2.8 grams, doses more than 2 grams are potentially
fatal. Levels over 4 mcg/ml are associated with severe toxicity.
■■ Gastric emptying may
be beneficial upto 4 hours post-ingestion. Activated charcoal is said to be
X-rays should be obtained in significant inges-tions. Death due to pulmonary
oedema, in the absence of preceding signs or symptoms, has been described. If
pulmo-nary oedema is developing, maintain adequate ventilation and oxygenation
with frequent monitoring of arterial blood gases and/or pulse oximetry. If a
high FIO 2 is required to maintain adequate oxygenation, mechanical
ventilation and positive-end-expiratory pressure (PEEP) may be required;
ventilation with small tidal volumes (6 ml/kg) is preferred if ARDS develops.
of the large volume of distribution, amantadine is generally not well removed
by peritoneal dialysis, haemo-dialysis, or forced diuresis.
(0.5 mg IV) is helpful in countering agita-tion, tremors, hallucinations, and
delirium. Caution must be exercised with this drug since it can induce
seizures, bradycardia, and asystole. Physostigmine should not be used in
patients with suspected tricyclic antidepressant overdose, or an ECG suggestive
of tricyclic antidepressant overdose (QRS widening, R wave in aVR). In the
setting of tricyclic antidepressant overdose, use of physostigmine has
precipitated convulsions and intractable cardiac arrest.
can be controlled with benzodiazepines or barbiturates.
■■Continuous ECG monitoring is
essential to watch out for signs of cardiovascular toxicity. Since ventricular
arrhyth-mias and pulmonary changes can have an onset of up to 48 hours post-ingestion,
cardiac and pulmonary monitoring is recommended for at least 48 hours in
patients with significant ingestions. Lignocaine is the drug of choice for
cardiac arrhythmias. Amiodarone, phenytoin, or over-drive transvenous pacing
can also be effective. Sodium bicarbonate may be effective for ventricular
arrhythmias, particularly in association with QRS widening. Administer sodium
bicarbonate 1 to 2 mEq/kg intravenously. Repeat as needed to achieve an
arterial pH of 7.4 to 7.5. Monitor frequent blood gases and ECGs. For torsades
de pointes, emergent treatment with magnesium, isoproterenol, or atrial
overdrive pacing is indicated. Avoid class Ia antiarrhyth-mics (quinidine,
disopyramide, procainamide, aprindine) and most class III antiarrhythmics (N- acetylprocainamide,
sotalol) since they may further prolong the QT interval and have been
associated with torsades de pointes.
Interferons are naturally occurring,
species specific, proteins or glycoproteins that are “biological response mediators”
that are produced by cells in response to an event. They are powerful cytokines
which possess immunomodulating, antiproliferative, and antiviral actions. There
are 3 major classes—alpha, beta, and gamma. The different kinds of interferons
include Human leukocyte interferon, Alpha-A-interferon, Alpha-2-interferon,
Interferon alfa-2c, Human lymphoblastoid interferon, Interferon alfa-n3,
Interferon-beta, T Lymphocyte interferon, and Interferon gamma-1b. Alpha
interferons are approved for use in India for the treatment of condyloma
acuminata, chronic hepatitis B, and AIDS-related Kaposi’s sarcoma. They have
also been recommended for the treatment of certain types of leukaemia (e.g.
hairy cell leukaemia), as well as renal cell carcinoma, malignant melanoma, and
Interferons inhibit viral
transcription, translation, assembly, and release. They do not directly destroy
tumour cells or viruses; they stimulate existing host defenses. They induce
T-cell mediated cytotoxicity, natural killer cell activity, macro-phage
activity, and antibody production.
Interferons are poorly absorbed on
oral administration. Following IM or SC injection, absorption exceeds 80%,
plasma levels generally peaking at 4 to 8 hours and returning to baseline by 18
to 36 hours. Elimination from the blood relates to the tissues, cellular
uptake, and metabolism primarily in the liver and kidney. Insignificant
excretion occurs in the urine.
Adverse effects include an
influenza-like syndrome (usually self-limiting), characterised by fever,
headache, malaise, chills, tachycardia, myalgia, anorexia, vomiting, and
diarrhoea. Dizziness, lightheadedness, nasal congestion, sinus drainage, and
urinary urgency are reported less frequently. A salty or metallic taste has
been described at the start of interferon therapy and at high doses. Excessive
growth of eyelashes has been reported.
More serious effects include bone
marrow suppression, mental confusion, convulsions, neurasthenia, thyroid
dysfunc-tion, pulmonary oedema, respiratory insufficiency, pneumonitis, and
cardiotoxicity (cardiac arrhythmias, cardiomyopathy, myocardial ischaemia and
infarction, and hypo/hypertension). Somnolence, lethargy, confusion, mental
laziness, and extreme fatigue have been reported with doses greater than 100 million
units. Spastic paraplegias have also been reported in paediatric patients.
Hyperkalaemia and hypocalcaemia may occur with high doses. A decrease may be
seen in erythrocytes, leucocytes, granulocytes, lymphocytes and platelets.
Most of these toxic effects induced
by interferons are reversible on discontinuation of therapy. The acute syndrome
of fever, chills, malaise, and myalgias can be managed by paracetamol or
non-steroidal anti-inflammatory drugs.
Ribavirin is a purine nucleoside analogue
which has a broad-spectrum antiviral activity against many RNA and DNA viruses.
It is recommended for use in the treatment of influenza, respiratory syncytial
viral infections, herpes viral infections, and acute viral hepatitis. In India,
ribavirin is available as an oral preparation, while abroad it is available in
an aerosolised form (for respiratory syncytial viral infections). Oral
bioavail-ability is only 40 to 45%.
Adverse effects of oral ribavirin
include anaemia and bone marrow suppression, apart from headache, fatigue,
dizziness, insomnia, irritability, dyspnoea, pharyngitis, skin rashes, and
gastrointestinal disturbances (anorexia, dyspepsia, vomiting). Intravenous
infusion can cause rigors. Aerosolised ribavirin is well tolerated, but may occasionally
cause rash, conjunctival irritation, and transient wheezing. Infrequent reports
of cardiac abnormalities have developed in patients following aerosolised
There are indications that ribavirin
may be teratogenic and oncogenic. Ribavirin was teratogenic in all rodent
species tested. Cleft palate was a common effect. Pregnant women should not
directly care for patients receiving the aerosolised form of the drug.
Treatment is mostly symptomatic and
supportive. Monitor haemoglobin and liver function tests. These changes have
been seen with chronic therapeutic administration, and have been reversible
upon discontinuation. Patients may have decreased haemoglobin and in a few
instances transfusions have been given. Although there may be an increase in
indirect bilirubin, ribavirin does not appear to be hepatotoxic. Haemodialysis