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Chapter: Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Anti-Infectives

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Other Antiviral Agents

Amantadine and its alpha-methyl derivative rimantadine are mainly used in the prophylaxis and treatment of influenza A virus infections.

Other Antiviral Agents

1.  Amantadine

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.

Treatment:

■■   Gastric emptying may be beneficial upto 4 hours post-ingestion. Activated charcoal is said to be useful.

■■  Chest 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.

■■  Because of the large volume of distribution, amantadine is generally not well removed by peritoneal dialysis, haemo-dialysis, or forced diuresis.

■■  Physostigmine (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.

■■  Convulsions 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.

2. Interferons

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 bladder cancer.

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.

3.  Ribavirin

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 ribavirin.

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 is ineffective.

 

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