Medication Therapy for Bacterial Infections – Part 2 (Anti-parasitic, Antifungal & Antiviral Drugs)

Overview: Parasites & Antiparasitic Pharmacology

• Parasites = organisms that live in a host’s blood cells, organs, or body structures (e.g., intestines, vagina) and derive nutrients at the host’s expense.

• Common human parasites & their preferred sites:

  • Malaria – protozoan enters bloodstream ➔ travels to liver for maturation.

  • Helminths – intestinal worms (roundworms, tapeworms, hookworms).

  • Trichomonas vaginalis – colonises reproductive tract of women and men.

• Antiparasitic drug families (antiprotozoals highlighted in this lecture):

  • Nitroimidazoles → Metronidazole.

  • Antimalarials → Chloroquine.

Metronidazole (Flagyl)

• Classification: Anti-infective, Antiprotozoal (Nitroimidazole).

• Expected action: Produces free-radical metabolites that damage DNA of anaerobic organisms ➔ cell death.

• Key indications:

  • Trichomoniasis.

  • Giardiasis.

  • Amebiasis (intestinal & extra-intestinal).

• Dosage forms & administration pearls:

  • PO: tablets, capsules, sustained-release (SR).

  • Regular tablets may be crushed if dysphagia present.

  • SR must be swallowed whole (do not crush/chew).

  • Give 1 h before or 2 h after meals for optimal absorption.

  • IV: reconstitute powder, dilute, infuse slowly to avoid phlebitis.

  • Topical cream & vaginal gel for local infections.

• Precautions:

  • Heart, liver, or renal failure; seizure disorders; h/o blood dyscrasias.

• Contra-indicated in: active CNS disease & pregnancy (teratogenic).

• Important interactions:

  • Alcohol (disulfiram-like reaction) – teach total abstinence.

  • SSRIs (e.g., Celexa), IV nitroglycerin, sulfamethoxazole – ↑ toxicity risk.

  • Phenobarbital ↓ serum Flagyl.

  • Lithium levels ↑.

  • Disulfiram (Antabuse) – psychosis risk.

• Adverse effects & nursing care:

  • GI: N/V, diarrhea, metallic taste, anorexia, dry mouth.

  • Urine may darken (benign).

  • CNS: headache, vertigo, ataxia → severe = seizures, peripheral neuropathy.

  • Nursing: monitor GI/CNS; d/c if seizures/neuropathy; warn about urine color; stress no alcohol.

Chloroquine (Aralen)

• Classification: Antimalarial (4-aminoquinoline).

• Exact mechanism unknown; concentrates in parasite food vacuoles, interfering with heme detoxification.

• Uses: prophylaxis & treatment of malaria (effective vs. sensitive Plasmodium spp.).

• Routes: PO (routine), IM (rare, painful; reserve for when PO impossible).

• Precautions:

  • Pre-existing optic neuritis/psoriasis.

  • Hepatic impairment.

  • Pregnancy & lactation (generally considered safe in pregnancy, but use clinical judgment).

• Absolute contraindications: allergy or previous chloroquine-induced visual changes.

• Adverse reactions:

  • Visual: blurred vision, photophobia, retinopathy with long-term use.

  • GI: N/V, diarrhea.

• Nursing/teaching:

  • Baseline & periodic eye exams; advise dark sunglasses.

  • Take with food or just after meals if GI upset.

  • Report any vision changes promptly.

Overview: Fungal Biology & Drug Classes

• Fungi = plant-like organisms not requiring light, thriving in damp, dark areas; saprophytic (feed on dead tissue).

• Opportunistic entry via breaks in skin or mucous membranes.

• Common superficial infections:

  • Tinea pedis (athlete’s foot).

  • Tinea corporis (ringworm).

• Two major systemic antifungal classes:
  1. Polyene antibiotics → Amphotericin B.
  2. Azoles → Ketoconazole (others: fluconazole, itraconazole, etc.).

Amphotericin B

• Prototype polyene antifungal.

• Mechanism: binds to ergosterol → forms pores → ↑ membrane permeability → fungal cell death.

• Indications:

  • Life-threatening systemic mycoses (Histoplasma, Cryptococcus, Aspergillus).

  • Severe or refractory candidiasis.

• Formulations & administration notes:

  • IV only for systemic use; daily or alternate-day dosing.

  • Strictly follow recommended dilution & infusion rate.

  • Assess IV site q30min for phlebitis.

  • Oral suspension: “swish & swallow” for oropharyngeal candidiasis.

  • Topical cream for cutaneous/vaginal Candida.

• Precautions: bone-marrow suppression, anemia, renal insufficiency.

• Contraindications: known allergy, breastfeeding.

• Major drug interactions: corticosteroids (↑ K⁺ loss), digoxin (↑ toxicity with hypokalemia), nephrotoxic agents (aminoglycosides, cyclosporine, furosemide, vancomycin).

• Infusion-related adverse effects (“shake & bake”): chills, fever, nausea, tachycardia, hypotension, HA.

• Other toxicities: nephrotoxicity, anemia (↓ EPO), thrombophlebitis.

• Nursing strategies:

  • Pre-medicate with diphenhydramine + acetaminophen 30 min prior.

  • Vital signs q15min initially; halt infusion if severe reaction or respiratory distress.

  • Daily weights; monitor I&O, BUN, creatinine, electrolytes (K⁺, Mg²⁺), CBC.

  • Encourage fluid intake if not contra-indicated.

  • Teach patients to expect infusion reactions & to report increasing fatigue.

Ketoconazole

• Family: Imidazole (azole) antifungal.

• Mechanism: inhibits fungal lanosterol → ergosterol conversion, disrupting cell membrane integrity.

• Uses:

  • Topical: superficial tinea & cutaneous Candida.

  • PO (reserve for refractory cases due to hepatotoxicity): systemic mycoses.

  • Shampoo form for seborrheic dermatitis/dandruff.

• Precautions: pregnancy, lactation, onychomycosis (nail infection) due to long therapy course.

• Contra-indication: hypersensitivity to azoles.

• Interactions: antacids ↓ absorption (requires acidic pH); ↑ warfarin levels (CYP-450 inhibition).

• Adverse effects:

  • Topical: burning, itching, redness, contact dermatitis.

  • Systemic: hepatotoxicity, GI upset (N/V/constipation/diarrhea), drowsiness, dizziness.

• Nursing/teaching:

  • Baseline & periodic LFTs; discontinue if jaundice, ↑ ALT/AST.

  • Take tablets with food to ↓ GI symptoms; avoid antacids 2 h pre/post.

  • Safety: caution with driving until CNS effects known.

Viruses & Antiviral Therapy Principles

• Viruses = obligate intracellular parasites; hijack host machinery for replication.

• Challenge: drugs targeting viral processes may also harm host cells.

• Antibiotics are ineffective; require virus-specific antivirals or host immune support.

• Examples discussed: Herpes Simplex Virus (HSV 1/2), Varicella-Zoster Virus (VZV).

Acyclovir

• Classification: Purine nucleoside analog.

• Mechanism: phosphorylated by viral thymidine kinase ➔ acyclovir triphosphate competitively inhibits viral DNA polymerase and terminates chain growth.

• Spectrum/uses:

  • IV: severe HSV/VZV infections in immuno-compromised patients (encephalitis, disseminated disease).

  • PO: genital herpes suppression, acute shingles, chickenpox.

  • Topical: herpes labialis (cold sores), mild genital lesions.

• Dosage forms: capsules, tablets, oral suspension, topical cream/ointment, IV solution.

• Precautions: renal insufficiency, neurologic disorders, dehydration (↑ nephrotoxicity risk).

• Contra-indicated with known hypersensitivity.

• Interactions:

  • Probenecid ↑ acyclovir half-life (competitively blocks renal tubular secretion).

  • Zidovudine ↑ CNS side-effects.

  • Concomitant nephrotoxic drugs ↑ renal injury.

• Adverse effects:

  • Topical: transient burning/itching.

  • PO: GI upset, headache, vertigo.

  • IV: crystal nephropathy, neurotoxicity (tremors, delirium), thrombophlebitis.

• Nursing care:

  • Ensure adequate hydration before, during, after IV infusion; infuse slowly (>1 h) to prevent nephropathy.

  • Monitor BUN/creatinine; adjust dose in renal impairment.

  • Assess IV site; interrupt infusion if pain/inflammation.

  • Observe for early CNS symptoms; institute seizure precautions PRN.

• Patient education:

  • Do not scratch lesions; keep area clean/dry.

  • Avoid getting topical preparation into eyes.

  • Take oral dose with food if GI distress.

  • Report burning at IV site, persistent skin issues, or CNS changes.

  • Acyclovir is not a cure; virus remains latent – safe sex & hand hygiene remain critical.

Integrative Clinical & Ethical Notes

• Opportunistic infections often arise in immuno-compromised hosts (e.g., AIDS, transplant, chemotherapy) – emphasize infection-control practices & prophylactic therapy.

• Teratogenic potential (Metronidazole) mandates pregnancy screening & counselling.

• Nephrotoxicity (Amphotericin B, Acyclovir) highlights ethical obligation to monitor organ function and advocate fluid management.

• Patient adherence key: improper schedules or premature discontinuation fosters resistance (Chloroquine, Acyclovir).

Study Tips & Mnemonics

• “FLAGyl → think FLAGellated parasites (Giardia, Trichomonas).”

• “Shake & Bake for Ampho-terrible” = infusion chills/fever.

• “Queen Chloro-quine rules malaria.”

• Associate -azole with inhibiting CYP enzymes (↑ drug interactions).

• Memorise nephrotoxic trio: \text{Amphotericin B} + \text{Acyclovir IV} + \text{Aminoglycosides}.

Motivational Closer

• Keep calm & study hard – consistent review of mechanisms, indications, and nursing considerations enhances exam success & clinical competence.

Overview: Parasites & Antiparasitic Pharmacology

• Parasites = organisms that live in a host’s blood cells, organs, or body structures (e.g., intestines, vagina) and derive nutrients at the host’s expense. They often have complex life cycles involving different hosts or stages.

• Common human parasites & their preferred sites:

  • Malaria – caused by Plasmodium protozoan, transmitted by Anopheles mosquitos. Enters bloodstream ➔ travels to liver for maturation (exo-erythrocytic stage) ➔ infects red blood cells (erythrocytic stage).

  • Helminths – parasitic worms including:

  • Nematodes (roundworms) e.g., Ascaris, hookworms, pinworms – primarily intestinal.

  • Cestodes (tapeworms) e.g., Taenia solium – intestinal, can cause cysticercosis if larvae migrate to tissues.

  • Trematodes (flukes) e.g., Schistosoma – found in blood vessels, liver, lungs, bladder.

  • Trichomonas vaginalis – a flagellated protozoan that colonises the reproductive tract of women and men, primarily via sexual transmission.

  • Giardia lamblia – a flagellated protozoan causing giardiasis, primarily infecting the small intestine through contaminated water/food.

  • Entamoeba histolytica – an amoeba causing amebiasis, infecting the colon and potentially other organs (liver).

• Antiparasitic drug families (antiprotozoals highlighted in this lecture):

  • Nitroimidazoles → Metronidazole.

  • Antimalarials → Chloroquine.

  • Benzimidazoles (e.g., Albendazole) → for helminths.

  • Praziquantel → for flukes and tapeworms.

Metronidazole (Flagyl)

• Classification: Anti-infective, Antiprotozoal (Nitroimidazole). Also has significant antibacterial activity against obligate anaerobes.

• Expected action: Metronidazole is a prodrug that is reductively activated by anaerobic metabolism within susceptible organisms (protozoa and anaerobic bacteria). This activation produces short-lived, highly reactive free-radical metabolites that damage the DNA structure, leading to strand breaks and inhibition of nucleic acid synthesis ➔ irreversible cell death.

• Key indications:

  • Trichomoniasis (first-line treatment).

  • Giardiasis (first-line treatment).

  • Amebiasis (intestinal & extra-intestinal forms, including hepatic abscesses).

  • Anaerobic bacterial infections (e.g., Clostridium difficile colitis, bacterial vaginosis, intra-abdominal infections, bone and joint infections, CNS infections).

  • Prophylaxis for colorectal surgery.

• Dosage forms & administration pearls:

  • PO: tablets, capsules, sustained-release (SR). Typically rapid and complete oral absorption.

  • Regular tablets may be crushed if dysphagia present. Administer with a full glass of water.

  • SR must be swallowed whole (do not crush/chew) to maintain its slow-release kinetics.

  • Give 1 h before or 2 h after meals for optimal absorption and to reduce GI upset (though often given with food to minimize nausea).

  • IV: reconstitute powder, dilute in NS or D5W, infuse slowly over 30-60 minutes to avoid phlebitis, especially at higher concentrations. Avoid rapid infusion as it can increase CNS toxicity.

  • Topical cream & vaginal gel for local infections (e.g., rosacea, bacterial vaginosis).

• Precautions:

  • Heart, liver (hepatic metabolism impairment reduces clearance), or renal failure (dose adjustment may be needed for severe renal impairment);

  • Seizure disorders or other underlying CNS conditions; h/o blood dyscrasias (can cause transient neutropenia/leukopenia).

• Contra-indicated in: active CNS disease (due to potential neurotoxicity) & first trimester of pregnancy (teratogenic, especially in early development – use only if clearly needed in later trimesters). Breastfeeding mothers should consider a temporary interruption or alternative.

• Important interactions:

  • Alcohol (Ethanol): Severe disulfiram-like reaction (acetaldehyde syndrome) characterized by flushing, headache, nausea, vomiting, abdominal cramps, and palpitations due to inhibition of alcohol dehydrogenase. Teach total abstinence from alcohol (including alcohol-containing cough syrups, mouthwashes, and topical preparations) during therapy and for at least 3 days after the last dose.

  • SSRIs (e.g., Celexa), IV nitroglycerin, sulfamethoxazole – ↑ toxicity risk (mechanism often related to CYP450 inhibition or additive effects).

  • Phenobarbital (a strong CYP inducer) ↓ serum Flagyl levels, potentially reducing efficacy.

  • Lithium levels ↑ due to decreased renal excretion, increasing risk of lithium toxicity (monitor lithium levels closely).

  • Disulfiram (Antabuse) – concomitant use can lead to acute psychosis and confusion; avoid concurrent administration.

  • Warfarin: Metronidazole inhibits the metabolism of warfarin (via CYP2C9 inhibition), significantly potentiating its anticoagulant effect; monitor INR frequently and adjust warfarin dose as needed.

• Adverse effects & nursing care:

  • GI: Nausea, vomiting, diarrhea, unpleasant metallic taste (very common and distinctive), anorexia, dry mouth. To mitigate, take with food if tolerated.

  • Urine may darken to a reddish-brown color (benign, due to metabolites). Advise patients this is expected.

  • CNS: Headache, vertigo, dizziness, ataxia (impaired coordination) are common. Severe adverse effects include seizures, peripheral neuropathy (numbness, tingling, pain in extremities), and encephalopathy. These are more likely with high doses or prolonged therapy.

  • Nursing: Monitor GI distress and provide symptomatic relief; closely monitor for neurological symptoms (headache, dizziness, confusion, paresthesias, seizures); d/c if seizures or peripheral neuropathy occur (neuropathy can be irreversible); warn patients about urine color changes; stress total abstinence from alcohol for the duration of treatment and for 3 days after. Ensure adequate hydration.

Chloroquine (Aralen)

• Classification: Antimalarial (4-aminoquinoline).

• Exact mechanism largely unknown but involves interference with the parasite's detoxification of heme. Plasmodium parasites digest host hemoglobin within their food vacuoles. This process releases toxic heme, which the parasite normally detoxifies by polymerizing it into an insoluble, non-toxic pigment called hemozoin. Chloroquine concentrates in the parasite food vacuoles, prevents the polymerization of heme into hemozoin, leading to an accumulation of toxic free heme within the parasite, ultimately causing its death. It targets the erythrocytic (blood) stage of the parasite lifecycle.

• Uses: prophylaxis & treatment of malaria (effective vs. sensitive Plasmodium spp., particularly P. vivax and P. ovale, but widespread resistance in P. falciparum limits its use). Also used as an anti-inflammatory in certain autoimmune conditions (e.g., rheumatoid arthritis, lupus).

• Routes: PO (routine for treatment and prophylaxis), IM (rare, painful, and associated with higher risk of severe adverse effects; reserve for when PO impossible or in severe malaria).

• Precautions:

  • Pre-existing optic neuritis/psoriasis (can exacerbate these conditions).

  • Hepatic impairment (metabolized in the liver).

  • Pregnancy & lactation (generally considered safe in pregnancy for malaria prophylaxis/treatment, but use clinical judgment and weigh risks/benefits. It crosses the placenta and is excreted in breast milk).

  • G6PD deficiency (can cause hemolytic anemia, though less common than primaquine).

• Absolute contraindications: known allergy or previous chloroquine-induced irreversible visual changes (especially retinopathy).

• Adverse reactions:

  • Ocular/Visual: Blurred vision, difficulty focusing (accommodation paresis), photophobia. Retinopathy (macular degeneration) is the most serious long-term adverse effect, especially with high doses or prolonged use, and can lead to irreversible blindness. It typically affects central vision.

  • GI: Nausea, vomiting, diarrhea, abdominal cramps (common; can be minimized by taking with food).

  • CNS: Headache, dizziness, fatigue (less common).

  • Cardiac: ECG changes, cardiomyopathy (rare, with high cumulative doses).

  • Dermatologic: Pruritus (itching), skin rash, hair bleaching/loss.

• Nursing/teaching:

  • Baseline & periodic ophthalmologic examinations (including visual acuity, visual fields, fundoscopy, and sometimes specific tests like Amsler grid or OCT) are crucial, especially for long-term use, to detect early retinopathy.

  • Advise dark sunglasses to manage photophobia.

  • Take with food or just after meals if GI upset occurs to minimize nausea and stomach discomfort.

  • Report any vision changes promptly, including blurred vision, difficulty reading, light flashes, or spots in vision. Emphasize that early detection of retinopathy is key to preventing irreversible damage.

  • For malaria prophylaxis, emphasize strict adherence to dosing regimen (e.g., weekly) starting before travel, during travel, and for several weeks after returning to endemic areas.

Overview: Fungal Biology & Drug Classes

• Fungi = eukaryotic, plant-like organisms (but lack chlorophyll, so no photosynthesis) not requiring light, thriving in damp, dark areas; saprophytic (feed on dead organic tissue) or parasitic. They have rigid cell walls containing chitin and cell membranes containing ergosterol (unique to fungi, analogous to cholesterol in human cells).

• Opportunistic entry via breaks in skin or mucous membranes (e.g., candidiasis) or inhalation of spores (e.g., histoplasmosis, cryptococcosis).

• Types of fungal infections:

  • Cutaneous/Superficial Mycoses: Affect skin, hair, nails (dermatophytes) or mucous membranes (Candida).

  • Tinea pedis (athlete’s foot) – common dermatophyte infection of the feet.

  • Tinea corporis (ringworm) – dermatophyte infection of the body skin.

  • Onychomycosis – fungal infection of the nails.

  • Oral candidiasis (thrush) or Vaginal candidiasis (yeast infection).

  • Systemic Mycoses (Deep Fungal Infections): Affect internal organs, often life-threatening, particularly in immunocompromised individuals. Can be endemic (geographic specific) or opportunistic.

• Two major systemic antifungal classes (targeting ergosterol):
  1. Polyene antibiotics → Amphotericin B.
  2. Azoles → Ketoconazole (and newer agents like fluconazole, itraconazole, voriconazole, posaconazole).

  • Other classes: Echinocandins (e.g., Caspofungin – target cell wall synthesis), Flucytosine (targets DNA/RNA synthesis).

Amphotericin B

• Prototype polyene antifungal, often referred to as “Ampho-terrible” due to its severe side effects.

• Mechanism: Directly binds to ergosterol (a sterol component unique to fungal cell membranes) in the fungal cell membrane. This binding disrupts the membrane's integrity, leading to the formation of channels or pores, which causes an increase in membrane permeability. This results in leakage of intracellular ions (especially K⁺) and macromolecules, ultimately leading to fungal cell death.

• Indications:

  • Life-threatening systemic mycoses, particularly in immunocompromised patients (Histoplasma capsulatum, Cryptococcus neoformans, Aspergillus species, Coccidioides immitis, Blastomyces dermatitidis).

  • Severe or refractory candidiasis (e.g., candidemia, disseminated candidiasis, severe mucocutaneous infections).

  • Leishmaniasis (a parasitic disease, though less common use).

• Formulations & administration notes:

  • IV only for systemic use; daily or alternate-day dosing regimen. Requires slow infusion.

  • Conventional Amphotericin B deoxycholate is the parent compound.

  • Lipid formulations (e.g., Amphotericin B liposomal, Amphotericin B lipid complex): These formulations encapsulate the drug in a lipid vehicle, reducing renal toxicity and infusion-related reactions while maintaining efficacy. They are preferred for patients with renal impairment or those who cannot tolerate conventional Amphotericin B, but are significantly more expensive.

  • Strictly follow recommended dilution & infusion rate (typically over 2-6 hours) to minimize infusion-related reactions and phlebitis. A central venous catheter is often preferred for long-term IV administration to prevent thrombophlebitis.

  • Assess IV site q30min for phlebitis (redness, pain, swelling, tenderness along the vein). Rotate IV sites if using peripheral lines.

  • Oral suspension: “swish & swallow” for oropharyngeal candidiasis (acts locally, minimal systemic absorption).

  • Topical cream for cutaneous/vaginal Candida infections.

• Precautions:

  • Bone-marrow suppression (can worsen existing myelosuppression);

  • Anemia (can worsen);

  • Renal insufficiency (major toxicity; requires careful monitoring and often necessitates lipid formulations);

  • Electrolyte imbalances (can exacerbate hypokalemia, hypomagnesemia).

• Contraindications: known allergy, breastfeeding (consider risk vs. benefit).

• Major drug interactions:

  • Corticosteroids (↑ K⁺ loss): Concurrent use exacerbates hypokalemia (due to amphotericin B's effect on renal tubules).

  • Digoxin (↑ toxicity with hypokalemia): Hypokalemia induced by Amphotericin B increases the risk of digoxin toxicity.

  • Nephrotoxic agents: Concurrent use with other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, NSAIDs, vancomycin, furosemide, cisplatin) significantly ↑ risk of severe renal injury. Avoid concurrent use if possible, or monitor renal function extremely closely.

  • Antineoplastics: Increased risk of bone marrow suppression.

  • Flucytosine: Synergistic antifungal effect, but also increased risk of bone marrow suppression.

• Infusion-related adverse effects (“shake & bake” syndrome): Common (occur in 50-90 ext{%} of patients), typically within 1-3 hours of starting infusion. Due to pro-inflammatory cytokine release (e.g., TNF-α, IL-1, IL-6). Symptoms include chills, fever, nausea, vomiting, tachycardia, hypotension, headache, myalgia, arthralgia.

• Other toxicities:

  • Nephrotoxicity: Major dose-limiting toxicity. Occurs in nearly all patients receiving conventional Amphotericin B. Manifests as decreased GFR, renal tubular acidosis, hypokalemia, hypomagnesemia. Can be dose-dependent and cumulative.

  • Anemia (normochromic, normocytic) due to suppressed erythropoietin (↓ EPO) production by damaged kidneys.

  • Thrombophlebitis at the IV site.

  • Electrolyte imbalances: Hypokalemia and hypomagnesemia are common due to renal tubular damage and leakage.

• Nursing strategies:

  • Pre-medicate with diphenhydramine (antihistamine) + acetaminophen (antipyretic) 30 min prior to infusion to reduce infusion-related reactions. In some cases, hydrocortisone or meperidine may also be used.

  • Administer a 1 mg test dose prior to the first full dose to assess tolerance and potential for severe reaction.

  • Vital signs q15min initially; halt infusion if severe reaction or respiratory distress occurs.

  • Daily weights; closely monitor I&O, BUN, creatinine, GFR, and electrolytes (K⁺, Mg²⁺ especially) daily or several times a week. Report abnormal values promptly.

  • Encourage liberal fluid intake (e.g., 1 L of NS before and 1 L after infusion if not contra-indicated) to promote renal perfusion and help mitigate nephrotoxicity. Check for fluid overload in patients with cardiac/renal compromise.

  • Monitor CBC for anemia and white blood cell changes.

  • Teach patients to expect infusion reactions and to report increasing fatigue, muscle weakness (hypokalemia), or changes in urination. Reassure them that pre-medication helps.

Ketoconazole

• Family: Imidazole (azole) antifungal. First oral azole approved in the US.

• Mechanism: Inhibits fungal CYP450 enzyme lanosterol ext{14} ext{-demethylase}, which is crucial for the conversion of lanosterol to ergosterol in the fungal cell membrane synthesis pathway. This disruption leads to impaired ergosterol synthesis and accumulation of toxic ext{14} ext{-alpha} ext{-methylsterols} within the fungal cell membrane, thereby disrupting membrane integrity and permeability, ultimately inhibiting fungal growth.

• Uses:

  • Topical: Broadly used for superficial tinea infections (e.g., tinea pedis, tinea corporis, tinea cruris, tinea versicolor) & cutaneous Candida infections.

  • PO (oral tablets): Historically used for systemic mycoses, but limited use now due to significant hepatotoxicity and drug interactions. Reserved for refractory cases where other systemic antifungals are not tolerated or effective. Can be used for chronic mucocutaneous candidiasis.

  • Shampoo form for seborrheic dermatitis/dandruff (topical mechanism).

  • Off-label: Used in Cushing's syndrome to inhibit adrenal steroidogenesis (due to its effect on mammalian CYP450 enzymes).

• Precautions:

  • Pregnancy (Category C): Use only if potential benefit justifies potential risk to fetus. Avoid during lactation (excreted in breast milk).

  • Onychomycosis (nail infection): Due to the long therapy course required (6-12 months) and associated risk of hepatotoxicity, other agents (e.g., oral terbinafine, itraconazole) are generally preferred.

  • Achlorydia or hypochlorhydria (reduced stomach acid): Requires an acidic pH for dissolution and absorption.

• Contra-indication: Hypersensitivity to azoles.

• Interactions:

  • Antacids, H2 blockers, PPIs (e.g., omeprazole) ↓ absorption: Ketoconazole requires an acidic pH for optimal dissolution and absorption. Avoid taking these agents together or separate by at least 2 hours (some recommend 4 hours).

  • CYP-450 inhibition: Ketoconazole is a potent inhibitor of various human CYP450 enzymes (especially CYP3A4, CYP2C9), leading to increased plasma concentrations and potential toxicity of co-administered drugs. Examples:

  • ↑ warfarin levels (enhances anticoagulant effect, monitor INR).

  • Oral hypoglycemics (sulfonamides) → ↑ risk of hypoglycemia.

  • Cyclosporine, tacrolimus, sirolimus (immunosuppressants) → ↑ levels, risk of toxicity.

  • Statins (e.g., simvastatin) → ↑ risk of rhabdomyolysis.

  • Benzodiazepines (e.g., midazolam, triazolam) → ↑ sedation.

  • Non-sedating antihistamines (e.g., terfenadine, astemizole, cisapride – contraindicated due to risk of serious QT prolongation and arrhythmias, though some of these drugs are no longer marketed).

• Adverse effects:

  • Topical: Local burning, itching, redness, irritation, contact dermatitis (generally mild).

  • Systemic (oral):

  • Hepatotoxicity: Most significant adverse effect. Can range from asymptomatic transaminase elevation to severe, life-threatening hepatic necrosis. Can occur at any time during therapy.

  • GI upset (Nausea, Vomiting, Constipation, Diarrhea) – common, can be minimized by taking with food.

  • Endocrine effects: Gynecomastia, decreased libido, impotence in men (due to inhibition of steroid synthesis).

  • CNS: Drowsiness, dizziness, headache.

  • Dermatologic: Rash, pruritus.

• Nursing/teaching:

  • For systemic use: Baseline & periodic Liver Function Tests (LFTs) – ALT, AST, bilirubin, alkaline phosphatase – are essential throughout therapy to monitor for hepatotoxicity. Discontinue immediately if signs of hepatic injury (jaundice, dark urine, persistent elevated liver enzymes, severe nausea/vomiting) appear.

  • Take oral tablets with food to ↓ GI symptoms, and with an acidic beverage (e.g., cola) if achlorhydria is present. Avoid antacids 2 h pre/post dose.

  • Safety: Advise caution with driving or operating machinery until CNS effects (drowsiness, dizziness) are known.

  • Instruct patients to report signs of liver problems (unusual fatigue, anorexia, nausea, vomiting, dark urine, pale stools, yellow skin or eyes) immediately.

Viruses & Antiviral Therapy Principles

• Viruses = obligate intracellular parasites; they lack cellular machinery for replication and metabolism and must hijack host cell machinery (ribosomes, enzymes, nucleotides) to reproduce.

• Challenge: Since viruses use host cell processes, drugs targeting viral processes may also harm host cells, leading to significant host toxicity. Achieving selective toxicity is difficult.

• Antibiotics are ineffective against viruses because viruses lack bacterial cellular structures (e.g., cell walls) and metabolic pathways that antibiotics target. Antiviral therapy requires virus-specific agents that target unique viral enzymes or replication steps, or host immune support.

• Antivirals do not cure viral infections but can suppress viral replication, reduce symptoms, shorten the duration of illness, and prevent complications.

• Examples discussed: Herpes Simplex Virus (HSV 1/2), Varicella-Zoster Virus (VZV). Other important viruses include HIV, Hepatitis B/C, Influenza, CMV, RSV.

Acyclovir

• Classification: Purine nucleoside analog (specifically, a guanosine analog). It is a prodrug.

• Mechanism: Acyclovir is transformed into its active form (acyclovir triphosphate) predominantly within virus-infected cells. This activation is initiated by viral thymidine kinase (TK), which phosphorylates acyclovir to acyclovir monophosphate. Host cellular enzymes then further phosphorylate it to acyclovir triphosphate. This selective activation by viral TK is key to its safety profile as it is minimally activated in uninfected cells.

  • Acyclovir triphosphate then competitively inhibits viral DNA polymerase (competing with natural deoxyguanosine triphosphate) and is