Clinical infections

Question 1

Viruses

• Definition:

Answer 1

“Sub microscopic entity consisting of a single nucleic acid surroundedmby a protein coat and capable of replication only within living cells”
• Obligate Intracellular Parasite
• Can infect Bacteria, fungi, protozoa, plants or animals
• Specific (species/cell-type) or broad spectrum (many cell
types/many species)

Question 2

Viruses consist of:

Answer 2

• DNA or RNA genome
• Protein coat (Capsid) made of protein subunits (capsomers)
• Envelope (not always present) derived from the plasma membrane of the host cell
• Surface proteins/glycoproteins (spikes) that bind to receptors of host cells

Question 3

Capsids & Capsomers

Answer 3

• If 1 protein for 1 capsid:
• Need > 18,000 amino acids
• Need > 54,000 nucleotides
• Small viruses hold max. of 5,000 nucleotides
• Must use many copies of 1 (or a few) protein(s)
• High symmetry
• Minimizes # different subunit interactions involved with assembly
• Simpler protein
• Self assembly
• Self-contained assembly “instructions”.

Question 4

Viral geometry

Answer 4

• Organized around a single axis (the “helix axis”)
• Probably evolved along with other helical structures like DNA, α-helix, etc. Allow flexibility (bending)
• Helical viruses form a closely related spring like helix instead
• The best studied TMV but many animal viruses and phage use this general arrangement
• Note; All helical animal viruses are enveloped, unlike many phage and plant viruses
• Most helixes are formed by a single major protein arranged with a constant relationship to each other

Question 5

Icosahedral symmetry

Answer 5

• 1956, Watson and Crick
• only cubic symmetry leads to isometric particle
• Only three cubic symmetry exist:
• tetrahedral (2:3) – 12 identical subunits
• octahedral (4:3:2) – 24 identical subunits
• icosahedral (5:3:2) – 60 identical subunits
• For viruses of 150-200 Å - ~ 60 of 20 kDa protein subunits

Question 6

Aciclovir, penciclovir, ganciclovir etc

Answer 6

• Most commonly used antiviral medicines
• Used in the treatment of Herpes virus infections
• Most common infections are:
• Herpes Simplex Virus (HSV)
• Cold sores, genital herpes, scrum pox
• Cytomegalovirus
• Usually treated only in immunocompromised patients

Question 7

Acyclovir

Answer 7

• Activated by viral thymidine kinases to become inhibitors of viral
DNA polymerases and block viral DNA synthesis
• Intracellular phosphorylation to monophosphate derivative by sHSV thymidine kinase
• Cellular enzymes convert monophosphate to triphosphate
• 40-100 fold higher in HSV-infected cells than in uninfected cells
• Triphosphate incorporated into viral DNA
• leads to irreversible inactivation of DNA polymerase

Question 8

Acyclovir Pharmacokinetics

Answer 8

• Oral bioavailability - 15-21%
• Prodrug valaciclovir - (L-valine ester of acyclovir)
• 3-5 x greater oral bioavailibility compared to acyclovir
• Protein binding - < 20%
• CSF - 1/2 of plasma levels
• t1/2 - 2.5 - 3 hours
• Renal excretion - 60-91%

Question 9

Acyclovir Adverse Effects

Answer 9

• I.V. (often with decreased renal function - serum conc > 25 mcg/ml)
• CNS - lethargy, confusion, tremor - 1-3%
• Reversible renal dysfunction - 5%
• Oral acyclovir
• nausea, vomiting, rash, headache - infrequent
• Appears to be safe in pregnancy

Question 10

Acyclovir
• Dosing regimens:
Drug interactions

Answer 10

• Dosing regimens:
• Oral - 200 – 4000 mg/day in divided doses
• I.V. - 5-20 mg/kg - every 8 hours
• May be increased in imunocompromised
• Also available as topical cream for Herpes Labialis and Genitalis
• Drug interactions
• Cyclosporin - increased renal toxicity
• Decreases renal clearance of other drugs

Question 11

Variations on a theme

Answer 11

• Penciclovir
• Similar spectrum of antiviral cover
• Topical cream
• Oral treatment with prodrug, famciclovir
• Valaciclovir
• prodrug of aciclovir
• Ganciclovir
• predominantly used to treat cytomegalovirus
• much more toxic than aciclovir so risk:benefit balance shifts
• severe interaction (myelosuppression) with zidovudine – not normally given together

Question 12

Influenza

Answer 12

• Highly infectious
• Family: Orthomyxoviridae
• Enveloped
• Negative (-) strand RNA genome, 8 (7) segments
• Three types; A, B and C
• A and B responsible for seasonal flu
• Unusually for an RNA virus, synthesis of influenza mRNAs and genome replication occurs in the nucleus
• For other RNA viruses, these proceses occur in the cytoplasm
• Influenza A viruses are divided into subtypes based on the presence of hemagglutinin (H) and neuraminidase (N)
• 18 hemagglutinin subtypes,11 neuraminidase subtypes
• e.g. Influenza A H1N1 was responsible for the 2009 spring flu pandemic

Question 13

Influenza Pathogenesis

Answer 13

• Direct cell lysis
• Primary mechanism for influenza virus
• Upper and lower respiratory tracts
• Role of immune response
• Primarily protective rather than pathogenic
• Induces virus- and type-specific immunity
• Virus-mediated suppression (NS1 protein)
• Tamiflu and Rilenza
• Active prophylaxis against influenza-A and –B
• Most effective if taken within 48-hours of first symptoms
• Reduce duration of symptoms by 1-1.5 days
• Reduce risk of complications in the elderly and patients with complications
• Licensed for community-wide prophylactic use to prevent spread of epidemic/pandemic

Question 14

Oseltamivir (Tamiflu)

Answer 14

• Oral dosing: 75mg once daily for 10 days after exposure
• twice daily for treatment rather than prophylaxis
• Pharmacokinetics
• F~100%; converted to active carboxylate
• T1/2 = 5hrs (for carboxylate)
• Renally eliminated
• Adverse effects
• nausea and vomiting
• headache
• cough
• blocked nose

Question 15

Zanamivir (Relenza)

Answer 15

• Dry powder inhaler
• Dose: 10mg once daily for 10/28 days
• twice daily for treatment rather than prophylaxis
• Pharmacokinetics
• F~10-20% by inhalation
• T1/2 = 2-5 hrs
• renally eliminated
• Adverse effects
• rash
• Cautions
• risk of bronchospasm so care should be taken in patients with asthma and chronic pulmonary disease