DRUGS FOR THE TREATMENT OF VIRAL DISEASES
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Acyclovir and valacyclovir
1. Acts against herpes simplex viruses type 1 and 2 (HSV-1, HSV-2); is also some activity against herpes zoster virus (HSV-3).
2. Valacyclovir is a prodrug that yields acyclovir.
3. Mode of action – inhibition of viral DNA synthesis
4. Can be administered orally, intravenously or as topical ointment; oral bioavailability is under 30%. Crosses the placenta and can be found concentrated in breast milk.
5. Uses
b. Decreases intensity, duration and frequency of herpes simplex attacks
c. Topical preparation less effective
d. Given intravenously as prophylaxis in carriers who receive immunosuppression, for HSV encephalitis and for varicella pneumonia and encephalitis
e. Valacyclovir has been found useful for the pain of herpes zoster (Chicken Pox), but not post-herpetic neuralgia
6. Side effects
One. Acyclovir – minimal side effects – nausea, diarrhea, rash, headache
Two. Valacyclovir – headache, nausea, diarrhea
7. Toxic effects
One. Acyclovir – renal failure, tremor, altered sensorium, delirium, seizures, extrapyramidal signs
Two. Valacyclovir – kidney damage, thrombocytopenia (in immunocompromised patients)
8. Interactions
One. Acyclovir with zidovudine may cause deep lethargy and sleepiness.
Two. Acyclovir with cyclosporine (or other nephrotoxic drug) has increased risk of nephrotoxicity
Three. Probenecid causes increased activity of acyclovir.
Four. Acyclovir increases activity of methotrexate.
Famciclovir and penciclovir
1. Famciclovir is a pro-drug of penciclovir.
2. Same mode of action as acyclovir
3. Penciclovir has very low oral bioavailability; famciclovir can be given orally with better results
4. Uses – herpes zoster in immunocompromised adults
5. Side effects – headache, diarrhea, nausea
6. Toxic effects – may increase risk of tumor and cause mutations
7. Interactions – famciclovir increases concentrations of digoxin
Foscarnet
1. Acts by inhibiting synthesis of viral nucleic acids – works on DNA polymerase (of the herpes viruses) or reverse transcriptase (of the HIV virus)
2. Oral bioavailability is low; also given intravenously
3. Uses
One. cyto-megalo virus (CMV) retinitis and other CMV infections
Two. CMV resistant to ganciclovir
Three. HSV resistant to acyclovir
4. Side effects – headache, tremor, seizures, hallucinations, irritability, fever, nausea, vomiting, leukopenia, genital ulcers and changes in liver function tests.
5. Toxic effects – clinical hypocalcemia, acute tubular necrosis, interstitial nephritis
6. Interactions – when given with pentamidine, risk of hypocalcemia is increased
Ganciclovir
1. Inhibits synthesis of viral DNA
2. Especially effective against CMV
3. Low oral bioavailability; given orally or intravenously
4. Uses
One. Treatment of CMV retinitis
Two. Prophylaxis of CMV infection in immunocompromised patients
5. Side effects – headache, phlebitis, rash, anemia, fever, nausea, vomiting, changes in liver function tests
6. Toxic effects – bone marrow suppression, convulsions, coma
7. Interactions
One. Risk of bone marrow suppression increased with concurrent use of zidovudine, nephrotoxic drugs and cytotoxic drugs
Two. Probenecid decreases clearance of ganciclovir.
Zidovudine
1. Inhibits reverse transcriptase by competing with thymidine; inhibits retroviruses
2. Good oral absorption and bioavailability
3. Uses
One. in HIV positive patients with CD4 counts of under 500/mm3
Two. in pregnant women with AIDS and their neonates to prevent vertical transmission
4. Major problem with zidovudine is that there is tolerance after about a year
5. Side effects – bad headache, nausea, vomiting, difficulties in sleeping, muscle aches
6. Safety in pregnancy not completely clear – neonates show anemia and growth retardation, but no excess malformations found
7. Toxic effects – granulocytopenia and anemia
8. Interactions
One. Increased risk of bone marrow suppression with fluconazole, ganciclovir or probenecid
Two. Reduced consciousness may occur with acyclovir.
Three. Clarithromycin decreases absorption of zidovudine.
Four. Rifampin may decrease concentration of zidovudine.
Didanosine
1. Acts via competitive inhibition of reverse transcriptase
2. Given orally, regular or buffered tablet, or intravenously
3. Uses – advanced HIV infection after at least 4 months of zidovudine
4. Side effects – diarrhea, rash, headache, seizures, difficulty sleeping, optic neuritis, loss of retinal pigmentation in children, hyperuricemia
5. Toxic effects – peripheral neuropathy, pancreatitis
6. Interactions – buffered tablet can decrease absorption of ketoconazole, dapsone, tetracycline, quinolones
Stavudine
1. Competitive inhibition of reverse transcriptase
2. Well-absorbed orally
3. Uses – in AIDS where other agents have not helped
4. Side effects – anemia, arthralgia, rash, fever
5. Toxic effects – peripheral sensory neuropathy, elevated liver enzymes
6. Interactions - avoid giving with didanosine or zalcitabine because of increased risk of neuropathy.
Zalcitabine
1. Competitive inhibition of reverse transcriptase
2. High oral bioavailability; also given intravenously
3. Uses
One. Together with zidovudine for AIDS patients with CD4 under 300/mm3
Two. For AIDS patients intolerant to zidovudine
4. Side effects – fever, nausea, rash, headache, mouth ulcers, granulocytopenia
5. Toxic effects – peripheral neuropathy
6. Interactions – avoid use of didanosine and stavudine.
Amantadine and rimantadine
1. Inhibit replication of influenza A viruses
2. Good oral absorption
3. Uses – treatment and prophylaxis of influenza A; amantadine is also used in Parkinson’s disease
4. Side effects – nausea, anorexia, nervousness, lack of concentration, difficulty sleeping
5. Toxic effects of amantadine - delirium, hallucinations, seizures, coma, arrhythmias, worsening of psychiatric problems and epilepsy
6. Interactions – toxic effects on the CNS worsened by use with antihistamines, neuroleptic drugs or anticholinergic drugs
Interferons
1. Interferons are cytokines and are divided into a, b, and g interferons. One of their functions is in increasing resistance to viruses, either directly or via modulation of the immune response.
2. Oral bioavailability is nil; intramuscular or subcutaneous administration is effective.
3. Uses
One. Human papilloma virus – genital warts
Two. Chronic hepatitis B and C
Three. Multiple sclerosis
Four. Kaposi’s sarcoma
4. Side effects – flu-like syndrome, elevated liver enzymes, interstitial nephritis, proteinuria, hair loss
5. Toxic effects – myelosuppression, sleepiness, confusion, fatigue, weight loss, thyroid problems and cardiac damage
6. Interactions – increases myelotoxicity of zidovudine
Ribavirin
1. Inhibits synthesis of viral m-RNA
2. Fair oral absorption; also given intravenously, but mostly as aerosol
3. Uses
a. Respiratory infections due to RSV (respiratory syncytial virus)
b. Severe influenza
c. Parainfluenza and measles in immunocompromised patients
4. Side effects
One. Aerosol preparation can cause irritation to the eyes, rash and wheezing.
Two. Systemic side effects include anemia, elevated bilirubin, iron and uric acid.
5. Toxic effects – rigors
6. Ribavirin appears to be teratogenic, embryotoxic, oncogenic and gonadotoxic.
DRUGS FOR THE TREATMENT OF FUNGAL INFECTIONS
Amphotericin B
1. Can only be given parenterally; new preparations based on liposomes are in use in other countries
2. Effective against Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidioides, Aspergillus and mucormycosis
3. Side effects
a. Fever and chills are most common. Also seen are nausea, vomiting, headache, weight loss and phlebitis (inflammation of a vein).
b. Respiratory distress and a slight fall in blood pressure may occur – this may be serious in patients with cardiac or respiratory disease; best to pretreat such patients with paracetamol/acetaminophen or intravenous hydrocortisone hemisuccinate.
4. Toxic effects – azotemia is very common and is dose-dependent; renal tubular acidosis and loss of magnesium and potassium in urine also occur
Flucytosine
1. Effective against Cryptococcus, Candida and chromomycosis.
2. Given orally
3. Resistance develops quickly and so should not be used as single agent.
4. Side effects – rash, nausea, vomiting, diarrhea, enterocolitis, transient elevation of liver enzymes
5. Toxic effects - myelosuppression
Ketoconazole
1. Other similar antifungals are clotrimazole, miconazole, econazole, butoconazole and sulconazole.
2. Effective against Blastomyces, Histoplasma, Coccidioides, ringworm, tinea versicolor, Candida vulvovaginitis, oral and esophageal Candida and chronic mucocutaneous candidiasis
3. Given orally; metabolized by cytochrome P450 and cleared by hepatic microsomal enzymes. Can also be given intrathecally for brain mycoses.
4. Used also to decrease androgen production in women with polycystic ovary disease and cortisol production in Cushing’s disease
5. Side effects
a. Vomiting and loss of appetite are most common. Also seen are rash and pruritus.
b. Transient elevations in liver enzymes are common; full-blown hepatitis is rare but may be fatal
6. Toxic effects
a. ketoconazole inhibits synthesis of steroids and so can cause menstrual irregularities, gynecomastia, lowered libido
b. because of the risk of Addison’s disease due to inhibited steroidogenesis, best not to use ketoconazole in patients with burns, trauma or before surgery
7. Interactions
a. Bioavailability is decreased when given with H2 blockers or antacids – due to less acidic environment.
b. Rifampin and phenytoin decrease concentration of ketoconazole.
c. Ketoconazole increases concentrations of cyclosporine (via cytochrome P450); it also increases concentrations of terfenadine and astemizole and can cause torsades de pointes
8. Not recommended during pregnancy or lactation
Itraconazole
1. Other similar antifungals are terconazole and fluconazole.
2. Very similar to ketoconazole with a wider range of effectiveness and fewer side effects
3. Uses – drug of choice for histoplasmosis (other than meningeal); also used in candidiasis, onychomycosis, ringworm and tinea versicolor
4. Given orally
5. Side effects – nausea, vomiting, increased blood lipids, hypokalemia, rash,
6. Toxic effects – adrenal insufficiency, edema of legs, hypertension
7. Interactions
a. like ketoconazole, with rifampin, phenytoin and carbamazepine; with antacids, proton pump inhibitors and H2 blockers, and with digoxin and cyclosporine
b. Don’t give with didanosine since it also reduces gastric acid.
Fluconazole
1. Effective against Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, sporotrichosis, ringworm
2. Excellent oral absorption; also given parenterally
3. Uses
a. candidiasis
b. cryptococcal meningitis in AIDS patients
c. coccidioidal meningitis
4. Side effects – nausea, vomiting, headache, rash, abdominal pain, diarrhea, hair loss
5. Interactions
a. Fluconazole increases concentration of phenytoin, zidovudine, rifabutin, cyclosporine, warfarin and sulfonylureas.
b. Rifampin decreases fluconazole concentration, but not significantly.
Griseofulvin
1. Effective against Microsporum, Epidermophyton and Trichopyton (dermatophytes)
2. Given orally; since very poor aqueous solubility given as powder
3. Uses – ringworm, athlete’s foot – if topical preparations have not helped
4. Side effects
a. minimal – most common is headache
b. less common are peripheral neuritis, fatigue, syncope, vertigo, blurry vision, confusion, nausea, vomiting, diarrhea, flatulence, leukopenia, neutropenia
5. Interactions – induces hepatic microsomal enzymes
Topical antifungals
1. Used for superficial fungal infections – candidiasis, ringworm, tinea versicolor, fungal keratitis, athlete’s foot
2. Not usually effective in fungal infections of the nails (onychomycosis) or hair
3. Examples are clotrimazole, econazole, miconazole, ciclopirox olamine, haloprogin, terbinafine and Nystatin
4. Applied to skin or inserted into the vagina; oral formulations are available for oropharyngeal candidiasis
5. Side effects
a. local reactions on skin and vagina
b. Systemic effects are almost non-existent.
6. These antifungals can be used in pregnancy.
DRUGS FOR THE TREATMENT OF HELMINTHIASIS (PARASITIC WORMS)
Benzimidazoles
1. Examples are mebendazole, albendazole and thiabendazole.
2. Act by inhibiting microtubule polymerization
3. Thiabendazole has rapid oral absorption; mebendazole and albendazole are poorly absorbed.
4. Uses – nematodes of the GIT; albendazole is not available in the USA but in other countries is the drug of choice for cysticercosis and cystic hydatid disease.
5. Side effects of thiabendazole
One. Most common are loss of appetite, nausea, vomiting and dizziness.
Two. Also seen are diarrhea, fatigue, sleepiness and headache.
6. Mebendazole has minimal side effects.
7. Avoid use in patients with liver disease, potentially hepatotoxic.
8. Safety not established in pregnant women or children in the first two years.
Praziquantel
1. Acts on the neuromuscular system and activates host defenses against the worms
2. Oral absorption is good
3. Effective against cestodes and trematodes (not effective against nematodes).
4. Uses in the USA – schistosomiasis and liver flukes
5. Side effects
One. Abdominal pain, nausea, headache, dizziness, sleepiness
Two. May be fever, urticaria, pruritus joint and muscle pains and eisonophilia
Three. In CNS infections – inflammatory reactions may cause meningismus, seizures, cells in the CSF and changes in mental status
6. Interactions - bioavailability is reduced by carbamazepine and phenobarbital; it is increased by cimetidine and dexamethasone.
7. Contraindications – do not give in cases of ocular cysticercosis – may be irreversible damage.
DRUGS USED IN MALARIA
The malarial parasite's life cycle. Images from Purves et al., Life: The Science of Biology, 4th Edition,
Chloroquine and hydroxychloroquine
1. Effective against all four types of malaria when in red blood cells, but not against gametocytes of Plasmodium falciparum and not against latent forms of P. ovale or P. vivax; many strains of P. falciparum are resistant to chloroquine.
2. Good oral absorption; also given parenterally
3. Uses
One. Malaria – chloroquine is the main drug for use in treatment and in prophylaxis
Two. Hydroxychloroquine is used also for mild rheumatoid arthritis, amoebic infections of the liver and systemic lupus erythematosus.
4. Side effects
One. Headache, nausea and vomiting, urticaria, blurred vision, diplopia, wide QRS
Two. Pruritus is common in persons with dark skin
5. Toxic effects
One. Hypotension, changes in ECG, myocardial depression and even cardiac arrest
Two. Ototoxicity
Three. Retinopathy – at doses above 250 mg/day
Four. Myopathy, peripheral neuropathy, cardiopathy
6. Contraindications
One. Patients with hepatic, gastrointestinal, neurological or hematological disorders
Two. Patients with G6PD deficiency
Three. Patients with porphyria cutanea tarda or psoriasis
7. Interactions – increased risk of dermatitis if given with gold or phenylbutazone
Quinine
1. Acts on forms in the red blood cells and gametes of P. vivax and P. malariae
2. Given orally, intravenously or intramuscularly
3. Uses
One. Treatment of malaria due to chloroquine-resistant P. falciparum
Two. Blocks the action of physostigmine on muscles and is used for symptomatic treatment in myotonia congenita and in nocturnal muscle cramps.
4. Side effects
One. High levels of insulin cause hypoglycemia.
Two. Hypersensitivity reactions are common.
5. Toxic effects are called cinchonism.
One. Tinnitus, vertigo, headache, nausea and disturbances of vision (diplopia, photophobia, night blindness, scotomas, dilated pupils) are the first signs.
Two. Later, GIT disturbances (nausea, vomiting, diarrhea), sweating, flushed face and rashes appear.
Three. Arrhythmias are also common.
Four. “Blackwater fever”, characterized by massive hemolysis with hemoglobinuria and hemoglobinemia, occurs in pregnant women treated with quinine or quinidine, causes anuria, renal failure and can be fatal. It is rare.
6. Contraindications
One. Patients with myasthenia gravis (can cause dysphagia and difficulties in breathing)
Two. Patients with G6PD deficiency
Three. Patients with tinnitus or optic neuritis
7. Interactions
One. Compounds containing aluminum decrease oral absorption of quinine..
Two. Quinine increases concentrations of digoxin and warfarin and enhances effects of neuromuscular blocking agents. It antagonizes acetylcholinesterase inhibitors.
Three. Cimetidine decreases renal clearance of quinine and acid urine increases it.
Primaquine
1. Effective against hepatic and latent tissue forms of P. vivax and P. ovale
2. Given orally because parenteral administration decreases blood pressure; oral absorption is good
3. Uses – recurrent attacks of malaria, best given together with chloroquine
4. Side effects – epigastric and abdominal discomfort,
5. Toxic effects – methemoglobinemia, leukopenia
6. Contraindications
One. Patients with G6PD deficiency
Two. Patients with acute illness and risk of granulocytopenia (i.e. active rheumatoid arthritis or active systemic lupus erythematosus)
Three. Use together with other drugs which affect hematopoiesis or hemolysis
Pyrimethamine
1. Effective against acute attacks of falciparum malaria
2. Slow oral absorption
3. Uses
One. Malaria – usually in a preparation also containing a sulfonamide for synergism – mostly for chloroquine-resistant strains
Two. Together with sulfadiazine is used to treat toxoplasmosis
4. Toxic effects – megaloblastic anemia (due to folate deficiency)
Halofantrine
1. Acts against P. falciparum in the red blood cells, but no effect on latent forms or gametocytes; most effective against mature forms
2. Slow oral absorption; minimally soluble in water so can’t be used parenterally
3. Uses
One. Acute attack of resistant falciparum malaria
Two. Should not be used for prophylaxis since its slow elimination allows development of resistant strains
4. Side effects – nausea, vomiting, diarrhea, abdominal pain; pruritus and rash may occur in persons with dark skin
5. Toxic effects may occur even at low doses due to unpredictable absorption and bioavailability. They include arrhythmias and prolonged QT interval.
Mefloquine
1. Effective against P. falciparum
2. Good oral absorption; parenteral use causes serious local reactions
3. Uses – treatment and prophylaxis of chloroquine-resistant P. falciparum
4. Side effects
One. Vomiting is very common.
Two. Also see nausea, diarrhea, abdominal pain and mild dizziness
5. Toxic effects
One. Headache, ataxia, severe dizziness, hearing and visual disturbances are mild and self-limited.
Two. Seizures, encephalopathy, psychotic behavior and disorientation are more serious, but usually reversible upon stopping the drug.
6. Contraindications
One. Pregnant (especially first trimester) and nursing women
Two. Children less than 2 years old (or less than 15 kg body weight)
Three. Patients with neurological or psychiatric disorders
7. Interactions
One. Increased risk of convulsions and arrhythmias if given with quinine, quinidine or chloroquine
Two. Increase risk of convulsions in patients treated with valproic acid
Other drugs used in the treatment of malaria include sulfonamides and the tetracyclines, which are used together with the above drugs.
DRUGS USED IN OTHER PROTOZOAL DISEASES
Structure of Paramecium, a typical ciliate. Image from Purves et al., Life: The Science of Biology,
Metronidazole
1. Effective against protozoans such as Trichomonas vaginalis and Entamoeba histolytica but also against anaerobic bacteria.
2. Given orally, intravenously and topically to the vagina and skin
3. Uses
One. Anaerobic bacteria including Bacteroides, Clostridium and Helicobacter
Two. Used in the treatment of pseudomembranous colitis
Three. Used in Trichomonas infections in both men and women
Four. Used also in amebiasis and giardiasis
4. Side effects
One. Most common are headache, nausea, metallic taste in the mouth and dryness of the mouth.
Two. Vomiting and diarrhea may also occur.
Three. Neutropenia may be seen and it is reversible.
5. Toxic effects
One. Dizziness, vertigo, encephalopathy, convulsions, ataxia
Two. Numbness or paresthesias are rare, but may not be completely reversible.
6. Interactions
One. Metronidazole’s metabolism in the liver is decreased by cimetidine and increased by phenobarbital, rifampin and prednisone.
Two. Avoid alcohol since metronidazole has a disulfiram effect. Avoid disulfiram since psychosis or confusion may occur.
7. Use in the first trimester of pregnancy is not advised.
Pentamidine
1. Effective against trypanosomes and Pneumocystis carinii
2. Given intramuscularly or intravenously for treatment; as aerosol for prophylaxis (less systemic toxicity)
3. Uses
One. Main use is for AIDS patients with Pneumocystis carinii – treatment and prophylaxis.
Two. Together with suramin is used in treatment of West African trypanosomiasis.
Three. Also used in visceral leishmaniasis
4. Side effects – rash, thrombophlebitis and sterile abscesses at site of injection, thrombocytopenia, anemia, neutropenia, renal insufficiency
5. Toxic effects
One. Can be immediate and serious – breathlessness, increased heart rate, headache, vomiting, dizziness, syncope
Two. Pancreatitis, hypoglycemia or hyperglycemia and even insulin-dependent diabetes may occur
6. Interactions – risk of hypocalcemia if given with foscarnet
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Acyclovir and valacyclovir
1. Acts against herpes simplex viruses type 1 and 2 (HSV-1, HSV-2); is also some activity against herpes zoster virus (HSV-3).
2. Valacyclovir is a prodrug that yields acyclovir.
3. Mode of action – inhibition of viral DNA synthesis
4. Can be administered orally, intravenously or as topical ointment; oral bioavailability is under 30%. Crosses the placenta and can be found concentrated in breast milk.
5. Uses
b. Decreases intensity, duration and frequency of herpes simplex attacks
c. Topical preparation less effective
d. Given intravenously as prophylaxis in carriers who receive immunosuppression, for HSV encephalitis and for varicella pneumonia and encephalitis
e. Valacyclovir has been found useful for the pain of herpes zoster (Chicken Pox), but not post-herpetic neuralgia
6. Side effects
One. Acyclovir – minimal side effects – nausea, diarrhea, rash, headache
Two. Valacyclovir – headache, nausea, diarrhea
7. Toxic effects
One. Acyclovir – renal failure, tremor, altered sensorium, delirium, seizures, extrapyramidal signs
Two. Valacyclovir – kidney damage, thrombocytopenia (in immunocompromised patients)
8. Interactions
One. Acyclovir with zidovudine may cause deep lethargy and sleepiness.
Two. Acyclovir with cyclosporine (or other nephrotoxic drug) has increased risk of nephrotoxicity
Three. Probenecid causes increased activity of acyclovir.
Four. Acyclovir increases activity of methotrexate.
Famciclovir and penciclovir
1. Famciclovir is a pro-drug of penciclovir.
2. Same mode of action as acyclovir
3. Penciclovir has very low oral bioavailability; famciclovir can be given orally with better results
4. Uses – herpes zoster in immunocompromised adults
5. Side effects – headache, diarrhea, nausea
6. Toxic effects – may increase risk of tumor and cause mutations
7. Interactions – famciclovir increases concentrations of digoxin
Foscarnet
1. Acts by inhibiting synthesis of viral nucleic acids – works on DNA polymerase (of the herpes viruses) or reverse transcriptase (of the HIV virus)
2. Oral bioavailability is low; also given intravenously
3. Uses
One. cyto-megalo virus (CMV) retinitis and other CMV infections
Two. CMV resistant to ganciclovir
Three. HSV resistant to acyclovir
4. Side effects – headache, tremor, seizures, hallucinations, irritability, fever, nausea, vomiting, leukopenia, genital ulcers and changes in liver function tests.
5. Toxic effects – clinical hypocalcemia, acute tubular necrosis, interstitial nephritis
6. Interactions – when given with pentamidine, risk of hypocalcemia is increased
Ganciclovir
1. Inhibits synthesis of viral DNA
2. Especially effective against CMV
3. Low oral bioavailability; given orally or intravenously
4. Uses
One. Treatment of CMV retinitis
Two. Prophylaxis of CMV infection in immunocompromised patients
5. Side effects – headache, phlebitis, rash, anemia, fever, nausea, vomiting, changes in liver function tests
6. Toxic effects – bone marrow suppression, convulsions, coma
7. Interactions
One. Risk of bone marrow suppression increased with concurrent use of zidovudine, nephrotoxic drugs and cytotoxic drugs
Two. Probenecid decreases clearance of ganciclovir.
Zidovudine
1. Inhibits reverse transcriptase by competing with thymidine; inhibits retroviruses
2. Good oral absorption and bioavailability
3. Uses
One. in HIV positive patients with CD4 counts of under 500/mm3
Two. in pregnant women with AIDS and their neonates to prevent vertical transmission
4. Major problem with zidovudine is that there is tolerance after about a year
5. Side effects – bad headache, nausea, vomiting, difficulties in sleeping, muscle aches
6. Safety in pregnancy not completely clear – neonates show anemia and growth retardation, but no excess malformations found
7. Toxic effects – granulocytopenia and anemia
8. Interactions
One. Increased risk of bone marrow suppression with fluconazole, ganciclovir or probenecid
Two. Reduced consciousness may occur with acyclovir.
Three. Clarithromycin decreases absorption of zidovudine.
Four. Rifampin may decrease concentration of zidovudine.
Didanosine
1. Acts via competitive inhibition of reverse transcriptase
2. Given orally, regular or buffered tablet, or intravenously
3. Uses – advanced HIV infection after at least 4 months of zidovudine
4. Side effects – diarrhea, rash, headache, seizures, difficulty sleeping, optic neuritis, loss of retinal pigmentation in children, hyperuricemia
5. Toxic effects – peripheral neuropathy, pancreatitis
6. Interactions – buffered tablet can decrease absorption of ketoconazole, dapsone, tetracycline, quinolones
Stavudine
1. Competitive inhibition of reverse transcriptase
2. Well-absorbed orally
3. Uses – in AIDS where other agents have not helped
4. Side effects – anemia, arthralgia, rash, fever
5. Toxic effects – peripheral sensory neuropathy, elevated liver enzymes
6. Interactions - avoid giving with didanosine or zalcitabine because of increased risk of neuropathy.
Zalcitabine
1. Competitive inhibition of reverse transcriptase
2. High oral bioavailability; also given intravenously
3. Uses
One. Together with zidovudine for AIDS patients with CD4 under 300/mm3
Two. For AIDS patients intolerant to zidovudine
4. Side effects – fever, nausea, rash, headache, mouth ulcers, granulocytopenia
5. Toxic effects – peripheral neuropathy
6. Interactions – avoid use of didanosine and stavudine.
Amantadine and rimantadine
1. Inhibit replication of influenza A viruses
2. Good oral absorption
3. Uses – treatment and prophylaxis of influenza A; amantadine is also used in Parkinson’s disease
4. Side effects – nausea, anorexia, nervousness, lack of concentration, difficulty sleeping
5. Toxic effects of amantadine - delirium, hallucinations, seizures, coma, arrhythmias, worsening of psychiatric problems and epilepsy
6. Interactions – toxic effects on the CNS worsened by use with antihistamines, neuroleptic drugs or anticholinergic drugs
Interferons
1. Interferons are cytokines and are divided into a, b, and g interferons. One of their functions is in increasing resistance to viruses, either directly or via modulation of the immune response.
2. Oral bioavailability is nil; intramuscular or subcutaneous administration is effective.
3. Uses
One. Human papilloma virus – genital warts
Two. Chronic hepatitis B and C
Three. Multiple sclerosis
Four. Kaposi’s sarcoma
4. Side effects – flu-like syndrome, elevated liver enzymes, interstitial nephritis, proteinuria, hair loss
5. Toxic effects – myelosuppression, sleepiness, confusion, fatigue, weight loss, thyroid problems and cardiac damage
6. Interactions – increases myelotoxicity of zidovudine
Ribavirin
1. Inhibits synthesis of viral m-RNA
2. Fair oral absorption; also given intravenously, but mostly as aerosol
3. Uses
a. Respiratory infections due to RSV (respiratory syncytial virus)
b. Severe influenza
c. Parainfluenza and measles in immunocompromised patients
4. Side effects
One. Aerosol preparation can cause irritation to the eyes, rash and wheezing.
Two. Systemic side effects include anemia, elevated bilirubin, iron and uric acid.
5. Toxic effects – rigors
6. Ribavirin appears to be teratogenic, embryotoxic, oncogenic and gonadotoxic.
DRUGS FOR THE TREATMENT OF FUNGAL INFECTIONS
Amphotericin B
1. Can only be given parenterally; new preparations based on liposomes are in use in other countries
2. Effective against Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidioides, Aspergillus and mucormycosis
3. Side effects
a. Fever and chills are most common. Also seen are nausea, vomiting, headache, weight loss and phlebitis (inflammation of a vein).
b. Respiratory distress and a slight fall in blood pressure may occur – this may be serious in patients with cardiac or respiratory disease; best to pretreat such patients with paracetamol/acetaminophen or intravenous hydrocortisone hemisuccinate.
4. Toxic effects – azotemia is very common and is dose-dependent; renal tubular acidosis and loss of magnesium and potassium in urine also occur
Flucytosine
1. Effective against Cryptococcus, Candida and chromomycosis.
2. Given orally
3. Resistance develops quickly and so should not be used as single agent.
4. Side effects – rash, nausea, vomiting, diarrhea, enterocolitis, transient elevation of liver enzymes
5. Toxic effects - myelosuppression
Ketoconazole
1. Other similar antifungals are clotrimazole, miconazole, econazole, butoconazole and sulconazole.
2. Effective against Blastomyces, Histoplasma, Coccidioides, ringworm, tinea versicolor, Candida vulvovaginitis, oral and esophageal Candida and chronic mucocutaneous candidiasis
3. Given orally; metabolized by cytochrome P450 and cleared by hepatic microsomal enzymes. Can also be given intrathecally for brain mycoses.
4. Used also to decrease androgen production in women with polycystic ovary disease and cortisol production in Cushing’s disease
5. Side effects
a. Vomiting and loss of appetite are most common. Also seen are rash and pruritus.
b. Transient elevations in liver enzymes are common; full-blown hepatitis is rare but may be fatal
6. Toxic effects
a. ketoconazole inhibits synthesis of steroids and so can cause menstrual irregularities, gynecomastia, lowered libido
b. because of the risk of Addison’s disease due to inhibited steroidogenesis, best not to use ketoconazole in patients with burns, trauma or before surgery
7. Interactions
a. Bioavailability is decreased when given with H2 blockers or antacids – due to less acidic environment.
b. Rifampin and phenytoin decrease concentration of ketoconazole.
c. Ketoconazole increases concentrations of cyclosporine (via cytochrome P450); it also increases concentrations of terfenadine and astemizole and can cause torsades de pointes
8. Not recommended during pregnancy or lactation
Itraconazole
1. Other similar antifungals are terconazole and fluconazole.
2. Very similar to ketoconazole with a wider range of effectiveness and fewer side effects
3. Uses – drug of choice for histoplasmosis (other than meningeal); also used in candidiasis, onychomycosis, ringworm and tinea versicolor
4. Given orally
5. Side effects – nausea, vomiting, increased blood lipids, hypokalemia, rash,
6. Toxic effects – adrenal insufficiency, edema of legs, hypertension
7. Interactions
a. like ketoconazole, with rifampin, phenytoin and carbamazepine; with antacids, proton pump inhibitors and H2 blockers, and with digoxin and cyclosporine
b. Don’t give with didanosine since it also reduces gastric acid.
Fluconazole
1. Effective against Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, sporotrichosis, ringworm
2. Excellent oral absorption; also given parenterally
3. Uses
a. candidiasis
b. cryptococcal meningitis in AIDS patients
c. coccidioidal meningitis
4. Side effects – nausea, vomiting, headache, rash, abdominal pain, diarrhea, hair loss
5. Interactions
a. Fluconazole increases concentration of phenytoin, zidovudine, rifabutin, cyclosporine, warfarin and sulfonylureas.
b. Rifampin decreases fluconazole concentration, but not significantly.
Griseofulvin
1. Effective against Microsporum, Epidermophyton and Trichopyton (dermatophytes)
2. Given orally; since very poor aqueous solubility given as powder
3. Uses – ringworm, athlete’s foot – if topical preparations have not helped
4. Side effects
a. minimal – most common is headache
b. less common are peripheral neuritis, fatigue, syncope, vertigo, blurry vision, confusion, nausea, vomiting, diarrhea, flatulence, leukopenia, neutropenia
5. Interactions – induces hepatic microsomal enzymes
Topical antifungals
1. Used for superficial fungal infections – candidiasis, ringworm, tinea versicolor, fungal keratitis, athlete’s foot
2. Not usually effective in fungal infections of the nails (onychomycosis) or hair
3. Examples are clotrimazole, econazole, miconazole, ciclopirox olamine, haloprogin, terbinafine and Nystatin
4. Applied to skin or inserted into the vagina; oral formulations are available for oropharyngeal candidiasis
5. Side effects
a. local reactions on skin and vagina
b. Systemic effects are almost non-existent.
6. These antifungals can be used in pregnancy.
DRUGS FOR THE TREATMENT OF HELMINTHIASIS (PARASITIC WORMS)
Benzimidazoles
1. Examples are mebendazole, albendazole and thiabendazole.
2. Act by inhibiting microtubule polymerization
3. Thiabendazole has rapid oral absorption; mebendazole and albendazole are poorly absorbed.
4. Uses – nematodes of the GIT; albendazole is not available in the USA but in other countries is the drug of choice for cysticercosis and cystic hydatid disease.
5. Side effects of thiabendazole
One. Most common are loss of appetite, nausea, vomiting and dizziness.
Two. Also seen are diarrhea, fatigue, sleepiness and headache.
6. Mebendazole has minimal side effects.
7. Avoid use in patients with liver disease, potentially hepatotoxic.
8. Safety not established in pregnant women or children in the first two years.
Praziquantel
1. Acts on the neuromuscular system and activates host defenses against the worms
2. Oral absorption is good
3. Effective against cestodes and trematodes (not effective against nematodes).
4. Uses in the USA – schistosomiasis and liver flukes
5. Side effects
One. Abdominal pain, nausea, headache, dizziness, sleepiness
Two. May be fever, urticaria, pruritus joint and muscle pains and eisonophilia
Three. In CNS infections – inflammatory reactions may cause meningismus, seizures, cells in the CSF and changes in mental status
6. Interactions - bioavailability is reduced by carbamazepine and phenobarbital; it is increased by cimetidine and dexamethasone.
7. Contraindications – do not give in cases of ocular cysticercosis – may be irreversible damage.
DRUGS USED IN MALARIA
The malarial parasite's life cycle. Images from Purves et al., Life: The Science of Biology, 4th Edition,
Chloroquine and hydroxychloroquine
1. Effective against all four types of malaria when in red blood cells, but not against gametocytes of Plasmodium falciparum and not against latent forms of P. ovale or P. vivax; many strains of P. falciparum are resistant to chloroquine.
2. Good oral absorption; also given parenterally
3. Uses
One. Malaria – chloroquine is the main drug for use in treatment and in prophylaxis
Two. Hydroxychloroquine is used also for mild rheumatoid arthritis, amoebic infections of the liver and systemic lupus erythematosus.
4. Side effects
One. Headache, nausea and vomiting, urticaria, blurred vision, diplopia, wide QRS
Two. Pruritus is common in persons with dark skin
5. Toxic effects
One. Hypotension, changes in ECG, myocardial depression and even cardiac arrest
Two. Ototoxicity
Three. Retinopathy – at doses above 250 mg/day
Four. Myopathy, peripheral neuropathy, cardiopathy
6. Contraindications
One. Patients with hepatic, gastrointestinal, neurological or hematological disorders
Two. Patients with G6PD deficiency
Three. Patients with porphyria cutanea tarda or psoriasis
7. Interactions – increased risk of dermatitis if given with gold or phenylbutazone
Quinine
1. Acts on forms in the red blood cells and gametes of P. vivax and P. malariae
2. Given orally, intravenously or intramuscularly
3. Uses
One. Treatment of malaria due to chloroquine-resistant P. falciparum
Two. Blocks the action of physostigmine on muscles and is used for symptomatic treatment in myotonia congenita and in nocturnal muscle cramps.
4. Side effects
One. High levels of insulin cause hypoglycemia.
Two. Hypersensitivity reactions are common.
5. Toxic effects are called cinchonism.
One. Tinnitus, vertigo, headache, nausea and disturbances of vision (diplopia, photophobia, night blindness, scotomas, dilated pupils) are the first signs.
Two. Later, GIT disturbances (nausea, vomiting, diarrhea), sweating, flushed face and rashes appear.
Three. Arrhythmias are also common.
Four. “Blackwater fever”, characterized by massive hemolysis with hemoglobinuria and hemoglobinemia, occurs in pregnant women treated with quinine or quinidine, causes anuria, renal failure and can be fatal. It is rare.
6. Contraindications
One. Patients with myasthenia gravis (can cause dysphagia and difficulties in breathing)
Two. Patients with G6PD deficiency
Three. Patients with tinnitus or optic neuritis
7. Interactions
One. Compounds containing aluminum decrease oral absorption of quinine..
Two. Quinine increases concentrations of digoxin and warfarin and enhances effects of neuromuscular blocking agents. It antagonizes acetylcholinesterase inhibitors.
Three. Cimetidine decreases renal clearance of quinine and acid urine increases it.
Primaquine
1. Effective against hepatic and latent tissue forms of P. vivax and P. ovale
2. Given orally because parenteral administration decreases blood pressure; oral absorption is good
3. Uses – recurrent attacks of malaria, best given together with chloroquine
4. Side effects – epigastric and abdominal discomfort,
5. Toxic effects – methemoglobinemia, leukopenia
6. Contraindications
One. Patients with G6PD deficiency
Two. Patients with acute illness and risk of granulocytopenia (i.e. active rheumatoid arthritis or active systemic lupus erythematosus)
Three. Use together with other drugs which affect hematopoiesis or hemolysis
Pyrimethamine
1. Effective against acute attacks of falciparum malaria
2. Slow oral absorption
3. Uses
One. Malaria – usually in a preparation also containing a sulfonamide for synergism – mostly for chloroquine-resistant strains
Two. Together with sulfadiazine is used to treat toxoplasmosis
4. Toxic effects – megaloblastic anemia (due to folate deficiency)
Halofantrine
1. Acts against P. falciparum in the red blood cells, but no effect on latent forms or gametocytes; most effective against mature forms
2. Slow oral absorption; minimally soluble in water so can’t be used parenterally
3. Uses
One. Acute attack of resistant falciparum malaria
Two. Should not be used for prophylaxis since its slow elimination allows development of resistant strains
4. Side effects – nausea, vomiting, diarrhea, abdominal pain; pruritus and rash may occur in persons with dark skin
5. Toxic effects may occur even at low doses due to unpredictable absorption and bioavailability. They include arrhythmias and prolonged QT interval.
Mefloquine
1. Effective against P. falciparum
2. Good oral absorption; parenteral use causes serious local reactions
3. Uses – treatment and prophylaxis of chloroquine-resistant P. falciparum
4. Side effects
One. Vomiting is very common.
Two. Also see nausea, diarrhea, abdominal pain and mild dizziness
5. Toxic effects
One. Headache, ataxia, severe dizziness, hearing and visual disturbances are mild and self-limited.
Two. Seizures, encephalopathy, psychotic behavior and disorientation are more serious, but usually reversible upon stopping the drug.
6. Contraindications
One. Pregnant (especially first trimester) and nursing women
Two. Children less than 2 years old (or less than 15 kg body weight)
Three. Patients with neurological or psychiatric disorders
7. Interactions
One. Increased risk of convulsions and arrhythmias if given with quinine, quinidine or chloroquine
Two. Increase risk of convulsions in patients treated with valproic acid
Other drugs used in the treatment of malaria include sulfonamides and the tetracyclines, which are used together with the above drugs.
DRUGS USED IN OTHER PROTOZOAL DISEASES
Structure of Paramecium, a typical ciliate. Image from Purves et al., Life: The Science of Biology,
Metronidazole
1. Effective against protozoans such as Trichomonas vaginalis and Entamoeba histolytica but also against anaerobic bacteria.
2. Given orally, intravenously and topically to the vagina and skin
3. Uses
One. Anaerobic bacteria including Bacteroides, Clostridium and Helicobacter
Two. Used in the treatment of pseudomembranous colitis
Three. Used in Trichomonas infections in both men and women
Four. Used also in amebiasis and giardiasis
4. Side effects
One. Most common are headache, nausea, metallic taste in the mouth and dryness of the mouth.
Two. Vomiting and diarrhea may also occur.
Three. Neutropenia may be seen and it is reversible.
5. Toxic effects
One. Dizziness, vertigo, encephalopathy, convulsions, ataxia
Two. Numbness or paresthesias are rare, but may not be completely reversible.
6. Interactions
One. Metronidazole’s metabolism in the liver is decreased by cimetidine and increased by phenobarbital, rifampin and prednisone.
Two. Avoid alcohol since metronidazole has a disulfiram effect. Avoid disulfiram since psychosis or confusion may occur.
7. Use in the first trimester of pregnancy is not advised.
Pentamidine
1. Effective against trypanosomes and Pneumocystis carinii
2. Given intramuscularly or intravenously for treatment; as aerosol for prophylaxis (less systemic toxicity)
3. Uses
One. Main use is for AIDS patients with Pneumocystis carinii – treatment and prophylaxis.
Two. Together with suramin is used in treatment of West African trypanosomiasis.
Three. Also used in visceral leishmaniasis
4. Side effects – rash, thrombophlebitis and sterile abscesses at site of injection, thrombocytopenia, anemia, neutropenia, renal insufficiency
5. Toxic effects
One. Can be immediate and serious – breathlessness, increased heart rate, headache, vomiting, dizziness, syncope
Two. Pancreatitis, hypoglycemia or hyperglycemia and even insulin-dependent diabetes may occur
6. Interactions – risk of hypocalcemia if given with foscarnet
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