detailed slides on both antifungals and atiiviral drugs. read them and like it

1. ANTIFUNGALS
(Antimycotics)
Medicine II June 2012
Third term

2. SOME PROPERTIES OF FUNGI
1. Yeasts (single cell) or moulds (multicellular)
2. Eukaryotes
3. Cell membrane – has lots of ergosterol
4. 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

3. MYCOSES
1. 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 ‘coz
1. Previously disease burden from fungal infections far fewer
than from bacterial infections; increase is due to
immunosuppression (HIV, organ transplant)
2. Differences/targets between fungi and man that can be
exploited are fewer cf to bacteria
3. Fungi turnover is much slower cf to bacteria

4. ANTIFUNGALS
1. Polyene – Amphotericin, natamycin, nystatin
2. Azoles – ketoconazole etc
3. Allyamines –
4. Flucytosine
5. Griseofulvin
6. Miscellaneous
Tolnaftate
Ciclopirox olamine
Fatty acids e.g. Benzoic acid, Undecylenic acid
Salicylic acid
Potassium iodide
Haloprogin

5. ANTIFUNGALS
ALTERATION OF
CELL MEMBRANE
/ WALL PROPERTIES
BLOCK NUCLEIC
ACID SYNTHESIS
INHIBIT
MICROTUBULE
FUNCTION
Porin-
Formation
Synthesis
inhibitors
Polyene antibiotics
 Amphotericin B
 Nystatin
Flucytosine
Griseofulvin
1.Azoles
2.Allylamines
3.Glucan synthesis inhibitors

6. AMPHOTERICIN B

7. 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 fluids
CSF- adequate if inflamed & (co-adm with Flucytosine)
Protein bound (90%)
Elimination: Largely metabolized, minor renal excretion

8. 1. AMPHOTERICIN B
ADR – is a very toxic drug
1. 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 by
1. Hydrating patient
2. Use of low concentrations & compensate by prolonging
infusion time
3. Give drug on alternate days
4. Alkalinize the urine

9. 1. AMPHOTERICIN B - ADR
2. Hepatic dysfunction
3. Thrombocytopenia
4. Anaphylactic rxns
5. Infusion related effects (universal):
- Fever, chills, nausea & vomiting, headache, muscle &
joint pain, hypotension, rare pulmonary involvement
Pre-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

10. 1. AMPHOTERICIN B
Uses:
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)

11. 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. NATAMYCIN
Spectrum: Aspergillus, candida
Poor oral abs, given locally (inhalation, topical, oral,
vaginal tablets)

12. Precursors
Squalene
Squalene epoxide
ergosterol
14--demethylase
Squalene epoxidase
Allylamines
Azole
antifungals
Fungal cell membrane
Steps at which AZOLES & ALLYLAMINES antifungals work

13. 4. AZOLES (imidazoles and triazoles)
Mxn:
Selectivity: different sensitivities
Spectrum: Broad
E.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, topical
Abs: 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 CSF
Elimination: hepatic metabolism, Fluco -long t1/2

14. B) AZOLES
ADR (dose dependent)
1. GIT irritation
2. 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
index
4. Itraco- impaired cardiac fxn
5. vorico –reversible, transient visual disturbance
D/I
Increased conc. of other drugs (effect varies w/ individual
member) – cyslosporine, cisapride (arrhythmias)
C/I: 1st trimester of pregnancy
Uses: differ

15. USES
Ketoconazole:
1. Mucocutaneous candidiasis
2. Non-meningeal coccidioidomycosis
3. Off label use: cushing dse, prostate cancer (suppresses steroidogenesis)
Itraconazole
1. Aspergillosis (the main drug with significant activity)
2. DOC for Dermatophytoses
Onychomycosis
Histoplasma
Blastomyces
Sporothrix
3. Candidiasis
Fluconazole and Voriconazole
1. Cryptococcal meningitis (Oral)
2. DOC (oral) prophylaxis of cryptococcal meningitis
3. Systemic candidiasis
4. Mucocutaneus candididiasis
5. Coccidioidal infections (esp meningitis, where it is preferred to intrathecal
amphotericin)
Posaconazole
Infections refractory to other antifungals

16. ALLYAMINES
Mxn:
Selectivity:
Adm: oral, topical
Abs: good
Dist: 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

17. FUMP - 5-fluorouracil-ribose mono(P),
5-FdUMP -5-fluorodeoxyuridinemono(P)
METABOLISM OF 5-FC
IN A FUNGAL CELL5-FC
Cytosine
permease
5-FC
5-FU
5-FUMP 5-FUDP 5-FUTP
5-FdUMP
dUMP dTMP
RNA
DNA
Cytosine deaminase
Ribonucleotide reductase
Thymydylate
synthetase
Fungal
cytoplasm

18. FLUCYTOSINE
Mxn: …………………+ active uptake via a permease
Selectivity: fungal cytosine deaminase,
Adm: oral, IV
Abs: well
Distribution: into all body tissues and fluids including CSF, lung
Elimination: Renal, thus caution in renal dysfunction
S/E
1. Bone marrow depression– pancytopenia, alopecia (co-adm w/ uracil
ameliorates this effect w/out affecting its antimycotic effect)
2. liver damage
4. Skin rash
3. Toxic enterocolitis
D/I
Synergistic w/ amphotericin B and azoles
Uses: (always combined with others to prevent resistance)
Cryptococcal meningitis, systemic candidiasis
Some dermatophytic infection

19. GRISEOFULVIN
Mxn: Binds to microtubules inhibits and inhibits their function e.g. in
metaphase (no activity on yeast)
Adm; oral,
Abs: erratic, increases w/ fatty foods
Distribution: to skin (keratophilic)
Elimination: metabolized w/ renal excretion of products
D/I - is an enzyme inducer e.g. oral anticoagulants
- potentiates effects of alcohol
S/E
♦ GIT irritation, headache
♦ Photosensitivity
♦ Hypersensitivity rxns e.g. exacerbation of SLE)
♦ Hepatotoxicity (↑ blood & urine pophyrias; C/I in porphyria)
♦ Hematological disorders
♦ Teratogenic risk
Uses
1. Dermatophyte infections of skin, nails
Therapy must be continued till infected keratin is replaced by new keratin
containing the drug

20. GLUCAN SYNTHESIS INHIBITORS
ECHINOCANDINS: 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 aspergillosis
2. Fungal infections in neutropenia
3. Candidemia
4. Intra-abdominal, pleural, peritoneal, esophageal candidiasis

21. Minor agents with antifungal activity
THIOCARBAMATES
e.g. Tolnaftate
Inhibits squalene epoxidase
Spectrum: dermatophytes
AMOROLFINE
An ergosterol synthesis inhibitor
Uses: Nail infections - topical

22. 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

23. ANTIVIRAL AGENTS

24. 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

25. 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 viruses
A 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)

26. ANTIVIRAL AGENTS
1. Entry inhibitor e.g. CXCR5 inhibitors
2. Uncoating inhibitors - Amatadine, Rimatadine (influenza)
Pleconaril (rhinoviruses)
3. Viral nucleic acid synthesis inhibitors
DNA polymerase inhibitors
Reverse 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)

27. ACTIVITY SITES OF MAJOR ANTIVIRAL AGENTS
1. Attachment
2. 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.Assembly
of virions
Release
-globulins
Amantadine
Formivisen (CMV)
DNA polymerase inhibitors
(Purine, pyrimidine analogues)
Protease inhibitors
Neuraminidase
inhibitors
Reverse transcriptase
inhibitors

28. 1. Inhibitors of uncoating
AMATADINE & RIMATADINE Mxn: inhibit uncoating of
viral mRNA
Spectrum: influenza A (not B)
Adm: oral
Distri: 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 effects
Uses
1. influenza A in patients allergic to the vaccine and in
epidemics
2. Parkinson's diseases (increases availability of dopamine or
has anticholinergic effects)

29. 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 excretion
S/E. - Bronchospasm esp. in patients w/ asthma or COPD
Oseltamivir:
PK: oral, Renal excretion
S/E – GIT (↓if taken w/food)
USES
♦ Acute uncomplicated influenza A and B

30. GAATTGCGCCTTTTG
NUCLEIC ACID SYNTHESIS INHIBITORS

31. 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

32. 3. DNA POLYMERASE INHIBITORS
Acyclic (sugar) Guanosine analogues
1. Acyclovir-
2. Valacyclovir – prodrug of acyclovir
3. 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
manner
Spectrum: HSV, VZV…………………CMV

33. 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

34. Nucleoside analogues - INHIBITORS of DNA
POLYMERASE
Adm: oral, parenteral, topical, intra-vitreal injection, intraocular implant
Abs: acyclovir, gancyclovir - small but adequate
Famcyclovir – good
Penciclovir – 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

35. NUCLEOSIDE ANALOGUES – usually acyclic
Deoxyguanosine

36. VIDARABINE - Analogue of adenosine
Mxn: triphosphorylated, competitively inhibits DNA
polymerase (not v. selective)
Uses; toxicity Limits its use
HSV infections of the eye (topical, alternative)
IDOXURIDINE (iodinated analogue),
SORIVUDINE, TRIFLURIDINE (fluorinated
analogue) of uridine
Uses: HSV, CMV infections of the eye (topical,
alternative)

37. Trifluridine Deoxyuridine

38. 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/I
Infuse slowly and adm fluids to reduce toxicities
Avoid co- adm w/ other neprotoxic drugs (e.g. pentamidine)

39. Deoxyuridine
Deoxyadenosine

40. 4. Inhibitors of IMP dehydrogenase – RIBAVIRIN
(TRIBAVIRIN) (guanosine analogue)
Mxn: deplete GTP nucleotide pool
Adm; oral, IV, aerosol
Distri: 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

41. 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 fxn
ADR: 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: oral
ADR: Hepatic damage, lactic acidosis, renal toxicity
(iii). TENOFOVIR- (ntNRT) HIV as part of HAART
Adm: Oral (in combination with other antiretrovirals )
ADR:
Common: nausea, vomiting, diarrhea, and asthenia, headache
Less common: hepatotoxicity, renal failure

42. ANTISENSE THERAPY
Sense sequence –is a nucleotide sequence that contains
information for a protein synthesis.
Antisense sequence - is the nucleotide chain that is
complementary to the sense sequence.
Antisense molecules recognize and bind to the nucleotide
sense sequence of specific RNA molecules, preventing the
synthesis 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)

43. Schematic representation of the structure of
HIV:

44. ANTIRETROVIRALS
1. Nucleoside reverse transcriptase inhibitors (nRTIs)
2. Nucleotide reverse transcriptase inhibitors (ntRTIs)
3. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
4. Protease inhibitors
5. Entry inhibitors – fusion inhibitors (Enfuvirtide),
coreceptor blockers, adsorption/attachment
inhibitors (polyanionic agents)
6. Integrase inhibitors

45. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
(nRTIS)
Mxn:
Resistance; - develops v. rapidly for many
E.g.
Zidovudine (azidothymidine, AZT) - thymidine
Lamivudine (3TC, 2’-deoxy-3’- thiacytidine) – cytidine
Abacavir
Stavudine (d4T) – thymidine
Didanosine (dideoxyinosine, ddi) – inosine (adenine)
Zalcitabine (weakest) (ddC, dideoxycytidine) – cytidine
Combivir (AZT + 3TC)
Trizivir (AZT + 3TC + abacavir)
Emtricitabine (FTC + emitrava)

47. NRTIs – General PK
Adm: most oral
Abs: adequate
ddC – interfered w/ by food, antacids,
metoclopramide
Distribution: wide – CSF, brain
Elimination; some metabolized, some renal,
– avoid co-adm w/ drugs of similar toxicity; for
majority - adjust dose w/ renal dysfxn

48. General S/E – NRTI’s
1. 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 toxicities
4. Pancreatitis (ddi, ddC, D4T)
5. Neuropathy (ddI, dT4,
6. Myopathy e.g cardiomyopathy (ZDV)
7. Lipodystrophy (ZDV, d4T

49. NRTI- USES
1. HIV
HAART regimen
PMTCT: Monotherapy – ZDV (not DOC)
2. Lamivudine – Hepatitis B
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS (NNRTIS)
Mxn:
Resistance: rapid; There is little cross-resistance amongst
these drugs
There is no cross resistance w/ NRTIs nor w/ protease
inhibitor
E.g. Nevirapine, efavirenz, delavirdine, etravirine

50. NNRTIs - General PK
(NB. Delavirdine – not in current HIV use ‘coz of
efficacy issues)
Adm: oral
Abs: good;
♦ Efavirenz - avoid taking w/ fatty meals
Distribution: 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

51. NNRTIs S/E in general
1. Hypersensitivity rxns e.g. SJS (NVP, DLV, EFV)
Highest w/NVP, corticosteroid use- no help
Discontinue 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)

52. PROTEASE INHIBITORS
Mxn:
Specificity:
Resistance: Some cross –resistance amongst protease
inhibitors may occur
E.g Lopinavir, Ritonavir, saquinavir, Indivavir, Nelfinavir,
Amprenavir, darunavir
General S/E of protease inhibitors
1. GIT irritation (most common) – e.g. diarrhoea
2. 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

53. PROTEASE INHIBITORS – General PK
(Ritonavir – not used ‘coz of toxicities unless as PK
enhancer – lopinavir, kelatra)
Adm: oral
Abs: many affected by food
Distr: 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

54. ANTIRETROVIRALS- most significant A/E for some
Zidovudine: Myelosuppresion
Stavudine: Peripheral neuropathy
Didanosine: Pancreatitis
Lamivudine: Exacerbates HepB on stopping, A/E not common
Zalcitabine: Peripheral neuropathy, oral ulceration,
Abacavir: Systemic hypersensitivity rxn (± fatal)
Tenofovir: Exacerbates HepB on stopping
Nevirapine: Hepatotoxicity, Skin reactions
Efavirenz: Neuropsychiatric symptoms, teratogenicity
Delavirdine: Skin reactions, abnormal liver fxns
Indinavir: Nephrolithiasis, hyperbiliribunemia
Ritonavir: Liver toxicities, drug-drug interactions, vasodilation,
perioral & peripheral paresthesia
Amprenavir: Skin rash, SJS, paresthesias, avoid in pregnancy
Saquinavir: DKA (w/ RTV), rare SJS
Nelfinavir: Rash
Lopinavir: Pancreatitis, dyslipidemia, rash

55. INTERGRASE INHIBITORS
Mxn: 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, Elvitegravir
Adm: oral
Elimination: glucuronidation
ADR:
Common: nausea, dizziness, headache, diarrhea, & pyrexia
Less common: creatinine kinase elevations, myopathy, and
rhabdomyolysis

56. 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®)

57. ENFUVIRTIDE
Adm: Subcutaneous
S/E
♦ Hypersensitivity
♦ Local injection site rxns
♦ Peripheral neuropathy
INTERFERONS
Mxn: 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/E
Flu-like syndrome, fever, fatigue, myalgia, anorexia, diarrhea
CNS effects
IMMUNOGLOBULINS (vaccines)

58. 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 life
4. Reduce morbidity and mortality
Factors to consider before initiating ARV Therpy
. Adherence
Avalability, accessibility and affordability of RX
Supporting services- clinical (e.g. diagnostic),
social, nutrition, counseling,

59. 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

60. 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)

61. 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