antifungals and antivirals drugs
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ANTIFUNGALS(Antimycotics)
Medicine II June 2012Third term
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SOME PROPERTIES OF FUNGI1. Yeasts (single cell) or moulds (multicellular)2. Eukaryotes 3. Cell membrane – has lots of ergosterol4. Have a rigid cell wall (inner & out layers)- of
mannopeptides, β-glucan, chitin, lipids etc
5. Importance of cell wall: agent of attachment to host site, stimulate host immune response, poorly degraded by man
6. Produce spores
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MYCOSES1. Most fungal infections are superficial (stratum cornea),
cutaneous (keratinized layers), or subcutaneous; few but serious infections are systemic (I°) and opportunistic mycoses
2. Mycoses w/ highest incidence are candidiasis and dermatophytosis
3. Most mycoses are difficult to treat
Antifungals are few ‘coz4. Previously disease burden from fungal infections far fewer
than from bacterial infections; increase is due to immunosuppression (HIV, organ transplant)
5. Differences/targets between fungi and man that can be exploited are fewer cf to bacteria
6. Fungi turnover is much slower cf to bacteria
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ANTIFUNGALS1. Polyene – Amphotericin, natamycin, nystatin2. Azoles – ketoconazole etc3. Allyamines – 4. Flucytosine5. Griseofulvin6. Miscellaneous
TolnaftateCiclopirox olamineFatty acids e.g. Benzoic acid, Undecylenic acidSalicylic acid Potassium iodideHaloprogin
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ANTIFUNGALS
ALTERATION OF CELL MEMBRANE / WALL PROPERTIES
BLOCK NUCLEICACID SYNTHESIS
INHIBIT MICROTUBULE FUNCTION
Porin-Formation
Synthesis inhibitors
Polyene antibiotics Amphotericin B Nystatin
FlucytosineGriseofulvin
1.Azoles 2.Allylamines3.Glucan synthesis inhibitors
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AMPHOTERICIN B
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A) POLYENE ANTIFUNGALS
1. AMPHOTERICIN B (Polyene macrolides) Mxn: Binds to sterols, forms pores and alters membrane permeability
leading to loss of cellular constituents especially K+
Selectivity: Fungi have ergosterol while mammals have cholesterol
Spectrum: The most broad spectrum antifungal♦ Most fungi and yeast (**Norcadia and aspergillus are resistant)♦ Amoeba – Naegleria fowleri ♦ Protozoa: Leishmania Donovani
Adm: IV or intrathecally for systemic effect (not well abs from GIT or muscle)Local for local effect (e.g. oral for GIT)
Distributn: widely into body tissues and fluidsCSF- adequate if inflamed & (co-adm with Flucytosine)Protein bound (90%)
Elimination: Largely metabolized, minor renal excretion
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1. AMPHOTERICIN B
ADR – is a very toxic drug1. Nephrotoxic: very common
(i) - A reversible component (pre & post infusion N/Saline hydration helps)(ii) -An irreversible component (usually w/ prolonged or high doses)♦ Leads to - - - - tubular acidosis, K+ & Mg2+ loss, anemia
Renal toxicity minimized by1. Hydrating patient2. Use of low concentrations & compensate by prolonging
infusion time 3. Give drug on alternate days4. Alkalinize the urine
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1. AMPHOTERICIN B - ADR
2. Hepatic dysfunction3. Thrombocytopenia4. Anaphylactic rxns5. Infusion related effects (universal):
- Fever, chills, nausea & vomiting, headache, muscle & joint pain, hypotension, rare pulmonary involvementPre-medication w/ sedatives and antihistamines may minimize these
- Neurotoxicity (seizures) w/ intrathecal adm - thrombophlebitis- minimize w/ H/cortisone &
heparin
Liposome packed amphotericin B is less toxic (expensive)D/I – synergistic w/ flucytosine (probably by increasing
permeability)IV prepared w/dextrose not NS as NS will induce precipitation
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1. AMPHOTERICIN BUses:
1. (DOC) for serious, acute systemic mycotic infections e.g. cryptococcal meningitis, fungal pneumonia, sepsis due to fungi 2. Emperic Rx of fungal infections in patients at risk in whom if the fungal infection is left untreated will suffer serious infection e.g. cancer patients w/ neutropenia
• Local adm:3. Mycotic infections of – GIT, eye, fungal arthritis, mycotic infections of the bladder (bladder irrigation)
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A) POLYENE ANTIFUNGALS
2. NYSTATIN Adm; topical or local only (too toxic for systemic use)Abs: very poor (GIT, other mucus membrane or skin)Uses
Candida infections – oropharynx, GIT, vagina, skin
3. NATAMYCINSpectrum: Aspergillus, candidaPoor oral abs, given locally (inhalation, topical, oral,
vaginal tablets)
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Precursors
Squalene
Squalene epoxide
ergosterol
14--demethylase
Squalene epoxidaseAllylamines
Azoleantifungals
Fungal cell membrane
Steps at which AZOLES & ALLYLAMINES antifungals work
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4. AZOLES (imidazoles and triazoles)Mxn: Selectivity: different sensitivitiesSpectrum: BroadE.g.
Imidazoles: Ketoconazole (lipid soluble), Triazoles: Fluconazole, Itraconazole, Voriconazole Topical- miconazole, ecnonazole, clotrimazole, sulconazole etc
Some lipid soluble (keto, itra); water soluble (Fluco, vori)
Adm: oral, parenteral, topicalAbs: variable -ketoconazole and itraconazole but good for
Fluco and vorico; best on acidic medium and w/food, D/I antacids, proton pump inhibitors, H2-histamine blockers
which reduce gastric pH Distribution – only Fluco and voriconazole into CSFElimination: hepatic metabolism, Fluco -long t1/2
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B) AZOLESADR (dose dependent)
1. GIT irritation2. Hepatic damage ( usually minor) 3. Inhibition of microsomal enzymes (Ketoco, posaco)– Endocrine (adrenal, gonads) effects: gynecomastia, menstrual irregularities, infertility
♦ itraconazole - Less inhibition ♦ Fluconazole and voriconazole -Least effect on hepatic
enzyme, Least effect on GIT irritation, Widest therapeutic index4. Itraco- impaired cardiac fxn5. vorico –reversible, transient visual disturbance
D/IIncreased conc. of other drugs (effect varies w/ individual
member) – cyslosporine, cisapride (arrhythmias)C/I: 1st trimester of pregnancy
Uses: differ
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USESKetoconazole:
1. Mucocutaneous candidiasis2. Non-meningeal coccidioidomycosis3. Off label use: cushing dse, prostate cancer (suppresses steroidogenesis)
Itraconazole1. Aspergillosis (the main drug with significant activity)2. DOC for Dermatophytoses
OnychomycosisHistoplasmaBlastomycesSporothrix
3. Candidiasis
Fluconazole and Voriconazole1. Cryptococcal meningitis (Oral)2. DOC (oral) prophylaxis of cryptococcal meningitis3. Systemic candidiasis4. Mucocutaneus candididiasis5. Coccidioidal infections (esp meningitis, where it is preferred to intrathecal amphotericin)
PosaconazoleInfections refractory to other antifungals
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ALLYAMINESMxn: Selectivity:Adm: oral, topicalAbs: goodDist: skin, mucous membranes (is keratophilic)Elimination: metabolized, renal excretion of metabolized
S/E♦ GIT irritation, headache♦ Hypersensitivity rxns♦ Joint & muscle pains♦ Hepatotoxicity – rare, ± fatal,
C/I in active or chronic liver dse (monitor liver)
Uses:Cutaneous fungal infections (esp of nails) – candida &
dermatophytes; 6-12wk treatment
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FUMP - 5-fluorouracil-ribose mono(P),5-FdUMP -5-fluorodeoxyuridinemono(P)
METABOLISM OF 5-FCIN A FUNGAL CELL5-FCCytosine
permease
5-FC
5-FU
5-FUMP 5-FUDP 5-FUTP
5-FdUMP
dUMP dTMP
RNA
DNA
Cytosine deaminase
Ribonucleotide reductase
Thymydylate synthetase
Fungalcytoplasm
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FLUCYTOSINEMxn: …………………+ active uptake via a permease Selectivity: fungal cytosine deaminase, Adm: oral, IVAbs: wellDistribution: into all body tissues and fluids including CSF, lungElimination: Renal, thus caution in renal dysfunctionS/E1. Bone marrow depression– pancytopenia, alopecia (co-adm w/ uracil
ameliorates this effect w/out affecting its antimycotic effect)2. liver damage4. Skin rash3. Toxic enterocolitis
D/ISynergistic w/ amphotericin B and azoles
Uses: (always combined with others to prevent resistance)Cryptococcal meningitis, systemic candidiasisSome dermatophytic infection
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GRISEOFULVINMxn: Binds to microtubules inhibits and inhibits their function e.g. in
metaphase (no activity on yeast)Adm; oral, Abs: erratic, increases w/ fatty foodsDistribution: to skin (keratophilic)Elimination: metabolized w/ renal excretion of productsD/I - is an enzyme inducer e.g. oral anticoagulants
- potentiates effects of alcoholS/E
♦ GIT irritation, headache ♦ Photosensitivity♦ Hypersensitivity rxns e.g. exacerbation of SLE)♦ Hepatotoxicity (↑ blood & urine pophyrias; C/I in porphyria)♦ Hematological disorders♦ Teratogenic risk
Uses1. Dermatophyte infections of skin, nailsTherapy must be continued till infected keratin is replaced by new keratincontaining the drug
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GLUCAN SYNTHESIS INHIBITORSECHINOCANDINS: Caspofungin, Micafungin, Anidulafungin
Mxn: Inhibitors of β-glucan synthase thus defective fungal cell wall resulting in osmotic lysis
Adm: IV
Elim: Hepatic metabolism
S/E – few♦ Infusion related- pruritus, fever, chills♦ GIT effects – nausea etc♦ Mild liver damage♦ Kidney damage (rare)♦ Embryotoxic
USES; (candida and aspergillus including those resistant to Ampho B)1. Invasive aspergillosis2. Fungal infections in neutropenia3. Candidemia4. Intra-abdominal, pleural, peritoneal, esophageal candidiasis
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Minor agents with antifungal activity
THIOCARBAMATESe.g. TolnaftateInhibits squalene epoxidaseSpectrum: dermatophytes
AMOROLFINEAn ergosterol synthesis inhibitorUses: Nail infections - topical
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Minor agents with antifungal activity►various acids e.g. Benzoic acid, undecylenic
acid, propionic acid - disrupt cell membranes ► salicylic acid, Triacetin (Glyceryl triacetate)-
are keratolytic(Benzoic acid + salicylic acid =Whitfield's
ointment)
►Potassium iodide► Ciclopirox is a fungicidal, inhibits Na+/K+
ATPase and thus transport esp of aminoacids► Gentian Violet ► Haloprogin
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ANTIVIRAL AGENTS
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ANTIVIRAL AGENTS
CHARACTERISTICS OF VIRUSES♦ DNA or RNA viruses, ♦ Capsid (protein coat) (nucleic acid + protein coat =
nucleocapsid)♦ Envelop (lipoprotein, may have antigenic glycoprotein) ♦ Enzymes - that initiate replication♦ Obligate intracellular parasites, ♦ No cell wall or cell membrane,♦ No self sustaining metabolic ability - depend on host
metabolic machinery to live & multiply – difficult to get drugs that are selective for the virus and harmless to the host
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ANTIVIRAL AGENTS
1. For all antiviral drugs, the host immune defense is essential for recovery and complete eradication of the virus
2. Most drugs don’t act on non-replicating/latent virusesA few - used for chronic suppression
3. Clinically effective conc. of the active form of the drug must be achieved at the site of infection (intracellular)
4. Unfortunately most clinical manifestations appear after or at the peak of viral replication – ideal mngt is prevention (e.g. w/ vaccines)
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ANTIVIRAL AGENTS1. Entry inhibitor e.g. CXCR5 inhibitors
2. Uncoating inhibitors - Amatadine, Rimatadine (influenza)
Pleconaril (rhinoviruses)3. Viral nucleic acid synthesis inhibitors
DNA polymerase inhibitorsReverse transcription
4. Integrase inhibitors 5. Antisense agents – formivisen (CMV)
6. Protease inhibitors
8. Release phase inhibitors- neuraminidase inhibitors
9. Immune system stimulation –Interferon alpha (HBV, HBC)
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ACTIVITY SITES OF MAJOR ANTIVIRAL AGENTS
1. Attachment2. Entry & Uncoating
3. Transfer of (DNA / RNA) to host nucleus/cytoplasm & early transcription
4. Early viral protein syn
5. (Genome) DNA/RNA syn
6. Late protein syn
7. Late protein processing
8.Assemblyof virions
Release
-globulins
Amantadine
Formivisen (CMV)
DNA polymerase inhibitors(Purine, pyrimidine analogues)
Protease inhibitors
Neuraminidase inhibitors
Reverse transcriptase inhibitors
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1. Inhibitors of uncoating
AMATADINE & RIMATADINE Mxn: inhibit uncoating of viral mRNA
Spectrum: influenza A (not B)Adm: oralDistri: wide (only amantadine into CSF)Elimination: Amantidine – mainly renal - NB. kidney fxn
Rimantidine –part liver metabolism, part renal S/E ♦ GIT disturbances
♦ CNS disturbance (amantadine mainly) ♦ Teratogenic and embryotoxic - avoid in pregnancy
♦ Anticholinergic effectsUses 1. influenza A in patients allergic to the vaccine and in
epidemics 2. Parkinson's diseases (increases availability of dopamine or
has anticholinergic effects)
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2. Inhibitors of release NEURAMINIDASE INHIBITORS (initiate w/in 48hrs of symptoms)
Mxn: Neuraminidase is a viral glycoprotein essential for viral budding
E.g. Zanamivir, oseltamivir
Zanamivir: PK: Inhalation (powder), Renal excretionS/E. - Bronchospasm esp. in patients w/ asthma or COPD
Oseltamivir: PK: oral, Renal excretionS/E – GIT (↓if taken w/food)
USES♦ Acute uncomplicated influenza A and B
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GAATTGCGCCTTTTG
NUCLEIC ACID SYNTHESIS INHIBITORS
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1’2’
3’
1’2’
3’4’
5’
4’5’
2’
3’
2’
3’4’
5’
4’5’
1’
DNA chain growth is driven by PPi release/hydrolysis
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3. DNA POLYMERASE INHIBITORS Acyclic (sugar) Guanosine analogues 1. Acyclovir- 2. Valacyclovir – prodrug of acyclovir3. Penciclovir –4. Famciclovir – prodrug or penciclovir – 5. Ganciclovir –
Mxn: Specificity: - viral kinases phosphorylate them
(e.g.x200) more efficiently than do mammalian enzymes; viral DNA polymerase also more sensitive
Ganciclovir : specifically phosphorylated by a CMV-encoded kinase
Resistance: Cross resistance w/ other drugs activated in a similar
mannerSpectrum: HSV, VZV…………………CMV
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Uses: Acyclic (sugar) Guanosine analogues
Acyclovir & Valacyclovir, Famcylcovir & pencyclovir
1. Herpes simplex infections – mucocutaneous and genital 2. Herpes simplex encephalitis (DOC, IV)3. VZV- higher doses (as it is less effective)
Uses: Ganciclovir (intraocular implant, direct intravetreal injection)
1 CMV infections e.g. retinitis (usually w/ foscarnet), GIT infections (colitis, esophagitis), pneumonitis, ventriculitis (CVS)
2. Before organ transplantation to reduce risk of CMV manifests
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Nucleoside analogues - INHIBITORS of DNA POLYMERASE
Adm: oral, parenteral, topical, intra-vitreal injection, intraocular implant Abs: acyclovir, gancyclovir - small but adequate
Famcyclovir – goodPenciclovir – topical
Distribution: wide including CSF Elimination: that inside cells - degraded rapidly (by cellular
phosphatases) renal excretion NB. kidney fxn
S/E (well tolerated)♦ Myelosuppression ♦ GIT irritation (50%)♦ Headache, vertigo, arthralgia♦ Renal toxicity esp w/ high dose or rapid infusion of acyclovir
(crystallize)–(esp in those dehydrated) ♦ Phlebitis (IV infusion) ♦ ↑Hepatic enzymes♦ CNS effects (confusion, hallucinations) w/ valacyclovir♦ Intraocular adm – retinal detachment, hemorrhage
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NUCLEOSIDE ANALOGUES – usually acyclic
Deoxyguanosine
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VIDARABINE - Analogue of adenosineMxn: triphosphorylated, competitively inhibits DNA
polymerase (not v. selective)
Uses; toxicity Limits its useHSV infections of the eye (topical, alternative)
IDOXURIDINE (iodinated analogue), SORIVUDINE, TRIFLURIDINE (fluorinated analogue) of uridine
Uses: HSV, CMV infections of the eye (topical, alternative)
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FOSCARNET - An non-nucleoside (an inorganic pyrophosphate)Mxn: binds (at the pyrophosphate site) and inhibits polymerases (DNA,
RNA polymerase and reverse transcriptase), and terminates chain
Adm: parenteral (poor GIT abs, GIT S/E)Dist: wide including CSF, deposited in bone (increases t1/2)Elimination: renal (NB. renal fxn)
Uses: CMV retinitis & other CMV infections (alternative to ganciclovir)S/E
♦ Nephrotoxic (major; 1/3 of patients)♦ ↓ conc. of K 2+, Ca 2+ , Mg 2+ and phosphate ♦ Penile ulcerations (from high conc. in urine)♦ CNS disturbance – (headache, hallucinations, seizures)♦ Blood disorders♦ Nausea, Fever
Precautions, C/IInfuse slowly and adm fluids to reduce toxicitiesAvoid co- adm w/ other neprotoxic drugs (e.g. pentamidine)
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Deoxyuridine
Deoxyadenosine
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4. Inhibitors of IMP dehydrogenase – RIBAVIRIN (TRIBAVIRIN) (guanosine analogue)
Mxn: deplete GTP nucleotide poolAdm; oral, IV, aerosolDistri: wide, Elimination: mainly renal excretion (NB renal fxn)S/E
♦ Transient anemia ♦ Elevated bilirubin♦ Psychiatric effects – depression, suicidal tendencies♦ Teratogenic and mutagenic
C/I: End stage renal failure, heart dse, hemoglobinopathies, pregnancy
Uses: ♦ RSV infections (bronchiolitis, pneumonia) in infants & youngsters (controversial)♦ Hepatitis C (w/ interferon)♦ Lassa fever ♦ Congo-Crimean hemorrhagic fever
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5. ACYCLIC NUCLEOSIDE PHOSPHONATES Mxn: Target viral DNA polymerase;
(i). CIDOFOVIR- CMV retinitis, Progressive multifocal leukoencephalopathy
Adm: injectable, Elimination: Renal (active secretion, probenecid) NB. renal fxnADR: Nephrotoxic (dose-dependent, reduce by adm w/ probenecid and
hydration) (monitor renal fxn); Others: nausea (48%), fever, allopecia, myalgia
C/I – other nephrotoxic drugs
(ii). ADEFOVIR – (ntNRT) HBV (hepatitis B)Adm: oralADR: Hepatic damage, lactic acidosis, renal toxicity
(iii). TENOFOVIR- (ntNRT) HIV as part of HAARTAdm: Oral (in combination with other antiretrovirals )ADR: Common: nausea, vomiting, diarrhea, and asthenia, headacheLess common: hepatotoxicity, renal failure
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ANTISENSE THERAPY Sense sequence –is a nucleotide sequence that containsinformation for a protein synthesis. Antisense sequence - is the nucleotide chain that iscomplementary to the sense sequence.Antisense molecules recognize and bind to the nucleotidesense sequence of specific RNA molecules, preventing thesynthesis of specified proteins.
e.g. Formivirsen Sodium –is complementary to a sequence of CMV mRNA.
Adm: direct injection into the vitreous body Uses; CMV retinitis (alternative)
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Schematic representation of the structure of HIV:
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ANTIRETROVIRALS
1. Nucleoside reverse transcriptase inhibitors (nRTIs)2. Nucleotide reverse transcriptase inhibitors (ntRTIs) 3. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)4. Protease inhibitors5. Entry inhibitors – fusion inhibitors (Enfuvirtide),
coreceptor blockers, adsorption/attachment inhibitors (polyanionic agents)
6. Integrase inhibitors
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NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (nRTIS)
Mxn:
Resistance; - develops v. rapidly for manyE.g.Zidovudine (azidothymidine, AZT) - thymidineLamivudine (3TC, 2’-deoxy-3’- thiacytidine) – cytidineAbacavir Stavudine (d4T) – thymidineDidanosine (dideoxyinosine, ddi) – inosine (adenine)Zalcitabine (weakest) (ddC, dideoxycytidine) – cytidine
Combivir (AZT + 3TC)Trizivir (AZT + 3TC + abacavir)Emtricitabine (FTC + emitrava)
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NRTIs – General PKAdm: most oralAbs: adequateddC – interfered w/ by food, antacids,
metoclopramideDistribution: wide – CSF, brainElimination; some metabolized, some renal,– avoid co-adm w/ drugs of similar toxicity; for
majority - adjust dose w/ renal dysfxn
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General S/E – NRTI’s1. Lactic acidosis & hepatic steatosis due to
Mitochondrial toxicities (esp ZDV, d4T, ddI & in pregnancy); ± fatal Risk: obese, female, prolonged NRTI
2. Myelosuppression- (ZDV, D4T) 3. Osteopenia
Other mitochondrial toxicities4. Pancreatitis (ddi, ddC, D4T)5. Neuropathy (ddI, dT4,6. Myopathy e.g cardiomyopathy (ZDV)7. Lipodystrophy (ZDV, d4T
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NRTI- USES1. HIV
HAART regimenPMTCT: Monotherapy – ZDV (not DOC)
2. Lamivudine – Hepatitis B
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)
Mxn: Resistance: rapid; There is little cross-resistance amongst
these drugsThere is no cross resistance w/ NRTIs nor w/ protease
inhibitorE.g. Nevirapine, efavirenz, delavirdine, etravirine
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NNRTIs - General PK(NB. Delavirdine – not in current HIV use ‘coz of
efficacy issues)Adm: oralAbs: good;
♦ Efavirenz - avoid taking w/ fatty mealsDistribution: wide including CSF, Placenta
Elimination: metabolized (CYP 450) (NB. liver fxn) T1/2- long for Efavirenz
♦ Nevirapine – Inducer & Substrate of CYP3A4 enzymes
♦ Efavirenz – Mixed inducer & inhibitor of CYP3A4
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NNRTIs S/E in general1. Hypersensitivity rxns e.g. SJS (NVP, DLV, EFV)
Highest w/NVP, corticosteroid use- no helpDiscontinue use if severe
2. CNS toxicity (EFV) (↓if taken at bedtime)Avoid in- unstable psychiatric disorders, or concomitant use of most CNS drugs
3. Hepatitis (NVP,± fatal, monitor liver)
4. GIT irritation – nausea, vomiting, diarrhea
5. Fetotoxic (EFV- avoid in pregnancy)
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PROTEASE INHIBITORSMxn: Specificity: Resistance: Some cross –resistance amongst protease
inhibitors may occurE.g Lopinavir, Ritonavir, saquinavir, Indivavir, Nelfinavir,
Amprenavir, darunavir
General S/E of protease inhibitors 1. GIT irritation (most common) – e.g. diarrhoea2. Insulin resistance-hyperglycemia, DKA, new or worse
diabetes mellitus 3. Lipodystrophy - altered body fat distribution – (buffalo
hump, truncal obesity, breast enlargment, facial and peripheral atrophy), and
4. Lipid abnormalities 5. Osteopenia
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PROTEASE INHIBITORS – General PK(Ritonavir – not used ‘coz of toxicities unless as PK
enhancer – lopinavir, kelatra)Adm: oralAbs: many affected by foodDistr: saquinavir -wide but not CSF,
●Indinavir – wide and highest (of proteases) CSF conc.
Elimination: all fecal ●Saquinavir – sig. 1st pass metabolism ● All inhibitors of cyp 450 enzymes – increase conc. of drugs e.g. benzodiazepines
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ANTIRETROVIRALS- most significant A/E for someZidovudine: MyelosuppresionStavudine: Peripheral neuropathyDidanosine: PancreatitisLamivudine: Exacerbates HepB on stopping, A/E not commonZalcitabine: Peripheral neuropathy, oral ulceration, Abacavir: Systemic hypersensitivity rxn (± fatal)
Tenofovir: Exacerbates HepB on stopping
Nevirapine: Hepatotoxicity, Skin reactionsEfavirenz: Neuropsychiatric symptoms, teratogenicityDelavirdine: Skin reactions, abnormal liver fxns
Indinavir: Nephrolithiasis, hyperbiliribunemiaRitonavir: Liver toxicities, drug-drug interactions, vasodilation,
perioral & peripheral paresthesiaAmprenavir: Skin rash, SJS, paresthesias, avoid in pregnancySaquinavir: DKA (w/ RTV), rare SJSNelfinavir: RashLopinavir: Pancreatitis, dyslipidemia, rash
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INTERGRASE INHIBITORSMxn: intergrase - integrates HIV genetic material into the
DNA of human thus the drug prevents HIV genome from being intergrated into the host genome
E.g. Raltegravir, ElvitegravirAdm: oralElimination: glucuronidation
ADR: Common: nausea, dizziness, headache, diarrhea, & pyrexia Less common: creatinine kinase elevations, myopathy, and
rhabdomyolysis
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ENTRY and FUSION INHIBITORS
Mxn: HIV binds to CD4 receptors by the protein gp120. Upon
binding GP120 deforms facilitating the viral protein gp41 to embed itself into the host cell's plasma membrane to form a pore.
Entry Inhibitors: bind and inhibit either the surface proteins present on HIV particle that are necessary for attachment to specific host receptors e.g. gp 120
Or bind to the specific receptors present on host cells e.g.CD4, CXCR4 or CCR5 (Selzentry -maraviroc®)
Fusion inhibitors: bind to gp41 thus prevent fusion with cell membrane and the formation of a pore that the capsid needs to enter the cell.
e.g. Enfuvirtide (T-20, Fuzeon®)
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ENFUVIRTIDEAdm: SubcutaneousS/E♦ Hypersensitivity ♦ Local injection site rxns♦ Peripheral neuropathy
INTERFERONSMxn: bind to specific receptors on host cell membrane, act by
inducing the synthesis of enzymes that interfere with translation of mRNA into viral proteins
S/EFlu-like syndrome, fever, fatigue, myalgia, anorexia, diarrheaCNS effects
IMMUNOGLOBULINS (vaccines)
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GOALS OF ARV THERAPY (it is part of a Comprehensive Care)
1. suppression of HIV replication - maximal & durable
2. Restore & preserve immune fxn 3. Improve quality of life4. Reduce morbidity and mortality
Factors to consider before initiating ARV Therpy. AdherenceAvalability, accessibility and affordability of RXSupporting services- clinical (e.g. diagnostic),
social, nutrition, counseling,
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GENERAL CONSIDERATIONS IN THE CLINICAL USE OF ANTIMICROBIAL AGENTS
Emperic (presumptive) Rx -Indications - ● when disease is severe, ● if withholding Rx will
result in life-threatening infection, ● or if early intervention will improve the outcome
- requires knowledge of likely infecting microorganism (history, site of infection) and their sensitivity to particular antimicrobials
-give broad spectrum coverage (either singe drug broad in spectrum or combine)
- Always collect appropriate specimens for identification and sensitivity tests before instituting Rx
- Change to more narrow spectrum and specific after identification of microbe
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GENERAL CONSIDERATIONS IN THE CLINICAL USE OF ANTIMICROBIAL AGENTS
Drug combinations - indications● Emperic Rx when broad coverage is necessary
● Rx of polymicrobial infections e.g. intra-abdominal infections
● To decrease rate of emergence of resistance - antivirals, antimycobacterials
● To minimize dose-related adverse effects (flucytosine + amphotericin B)
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E.g. Indications for prophylactic use of antimicrobial agents
1.Some surgical procedures/conditions - before, during (sterilizing the area) and after
2. Persons at risk of developing serious infections because of underlying conditions – ● Rheumatic heart disease patients or ● Patients w/ prosthetic valves undergoing certain medical procedures e.g. dental procedures, ● Close contacts of TB patients, ● Prevention of mother to child HIV transmission