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Flashcards in Pharmacology Deck (49):
1

Anti-fungal (Polyene)
Binds to ergosterol and forms artificial membrane pores causing leakage of intracellular ions and macromolecules from fungal cell
Very broad spectrum of action, fungicidal
Resistance due to efflux pumps

IV; available in salt and lipid formulations
Excreted slowly, can accumulate in tissues causing toxicity
Poor CNS penetration, intrathecal for meningitis

Toxicity is mostly related to binding to cholesterol in host cells
After infusion: chills, fever, muscle spasms, headache, vomiting, hypotension (reduced by slowing infusion, using antipyretics/antihistamines, and sodium loading)
Long term: renal damage is first reversible (decreased perfusion) and then irreversible (tubular injury); limit cumulative dose (not good for long term therapy)

Serious life-threatening systemic mycotic infections (broadest spectrum)
Can be used in pregnancy

Amphotericin B

2

Anti-fungal (Polyene)
Binds to ergosterol and forms artificial membrane pores causing leakage of intracellular ions and macromolecules from fungal cell
Very broad spectrum of action, fungicidal
Resistance due to efflux pumps

Too toxic for parenteral administration; available in creams, ointments, suppositories for application to skin and mucous membranes

Localized candida infections including oropharyngeal thrush and vaginal candida

Nystatin

3

Anti-fungal (azole)
Broad spectrum, resistance is more frequent because of increased clinical use of azoles (mutation of drug target)
Decrease synthesis of ergosterol by inhibiting a fungal cytochrome P450 enzyme (14-alpha-sterol demethylase)

Inhibits human P450s leading to drug interactions
Oral or IV; renal excretion
Best penetration of all the azoles into the CSF; therapeutic index is highest of the azoles
Potent inhibitor of CYP2C9 (increases serum concentration of phenytoin and warfarin)

Relatively safe with few adverse effects
Rash, Stevens-Johnson syndrome (erythema multiforme major)
Nausea, alopecia with longer treatment

Drug of choice for cryptococcal meningitis and prophylaxis in high risk patients with recurrent oral or esophageal candidiasis (resistance is a concern)
Teratogenic – contraindicated in pregnancy

Fluconazole

4

Anti-fungal (azole)
Broad spectrum, resistance is more frequent because of increased clinical use of azoles (mutation of drug target)
Decrease synthesis of ergosterol by inhibiting a fungal cytochrome P450 enzyme (14-alpha-sterol demethylase)

Poor CNS penetration; reduced bioavailability with rifamycins
Potent inhibitor of CYP3A4 (contraindicated with statins)

Can result in congestive heart disease

Drug of choice for dimorphic fungi Histoplasma, blastomyces and sporothrix; also effective against dermatophytes
Avoid in patients with ventricular dysfunction

Itroconazole

5

Anti-fungal (azole)
Broadest spectrum of the azoles, resistance is more frequent because of increased clinical use of azoles (mutation of drug target)
Decrease synthesis of ergosterol by inhibiting a fungal cytochrome P450 enzyme (14-alpha-sterol demethylase)

Oral and IV

Visual disturbances are common (blurring, changes in color vision/brightness) and occur in the first 30 min of dose and are reversible

Drug of choice for treatment of invasive aspergillosis (better outcomes and less toxicity than amphotericin B)

Voriconazole

6

Anti-fungal (echinocandin)
Inhibits synthesis of beta(1-3) glucan; disrupts the fungal cell wall

IV

GI discomfort, flushing, drug interactions
Hepatotoxicity (increased in combination with cyclosporine

Limited to Aspergillus and Candida
Used in invasive asperogillosis in patients not responsive to voriconazole
Contraindicated in pregnancy

Caspofungin

7

Anti-fungal
Derived from penicilium; fungistatic mitotic inhibitor that interferes with microtubule assembly

Administered orally in microcrystalline form
Deposited in newly growing keratin of skin and nails; treatment must persist until old infected tissue is no longer present

CNS effects, allergic syndrome similar to serum sickness, hepatotoxicity, GI disturbance
P450 inducer (increased metabolism of warfarin, phenobarbital, OCPs)

Used for dermatophytosis only

Griseofulvin

8

Anti-fungal
Inhibits fungal squalene epoxidase which results in increased levels of squalene (toxic)

Oral
Keratophilic but also has direct fungicidal properties (potentially shorter treatment)

Generally well tolerated, no P450 drug interactions, some GI disturbance and headache

Treatment of dermatophytoses, especially onychomycosis (fingernail and toenail infections)
Contraindicated in pregnancy

Terbinafine

9

Anti-fungal (antimetabolite)
Taken up in fungal cells by cytosine permease, converted to 5-fluorouracil (5-FU) by cytosine deaminase; 5-FU metabolized to nucleotide that blocks DNA and RNA synthesis
Humans do not convert it to 5-fluorouracil

Oral; excreted unchanged by the liver

Converted to 5-FU in intestine by gut microflora resulting in hematotoxicity especially in renal insufficiency or AIDS

Narrow spectrum of action (only used in combinations, synergistic)
Contraindicated in pregnancy

Flucytosine

10

Anti-helminthic
Used for nematodes and certain cestodes/trematodes

Stage killed: eggs, larvae, adults

Mechanism of action: inhibit microtubule polymerization, inhibit energy production

Adverse effects: GI disturbances, bone marrow suppression

Resistance: switch beta-tubulin isotype, beta-tubulin point mutation

Benzimidazoles

11

Anti-helminthic
Used for nematodes: Onchocerciasis (in combination with steroids), lymph filariasis (in combination with benzimidazoles)
Ineffective against trematodes and cestodes
Contraindicated in loiasis

Stage killed: microfilariae

Mechanism of action: activates glutamate-gated Cl- channels, causing flaccid paralysis

Adverse effects: Mazzotti-like reaction due to dying microfilariae (use steroids)

Resistance: P-glycoprotein, mutation in channel

Ivermectin
(Avermectin)

12

Anti-helminthic
Use for nematodes: loiasis, lymph filariasis (in combination with benzimidazoles)
Contraindicated in Onchoceriasis

Stages killed: microfilariae, adults

Mechanism of action: stimulate host immune response

Adverse effects: Mazzotti-like reaction due to dying microfilariae (use steroids)

Resistance: typically not a problem

Diethylcarbamazine (DEC)

13

Anti-helminthic
Used for nematodes in the GI lumen

Stages killed: larvae, adults

Mechanism of action: stimulate nicotinic receptor, increases ACh release, spastic paralysis

Adverse effects: GI disturbances, headaches

Resistance: typically not a problem

Pyrantel

14

Anti-helminthic
Used for trematodes (schistosomiasis) and cestodes
Ineffective against nematodes
Contraindicated in intraocular cysticercosis

Stages killed: immature stages, adults

Mechanism of action: increase membrane permeability to calcium, spastic paralysis

Adverse effects: GI disturbances, headaches

Resistance: typically not a problem, mutation in VGCC?

Praziquantel

15

Targeted cancer drug
Metastatic colon cancer, metastatic non-small cell lung cancer

Mechanism of action: monoclonal Ab against VEGF-A to inhibit angiogenic VEGF signaling pathway

Adverse effects: hypertensive crisis, arterial thromboembolism
black box warning: GI perforations, wound healing complications, hemorrahge

Resistance/Considerations: resistance due to VEGF gene amplification

Bevacizumab

16

Targeted cancer drug
EGFR/ERBB1 overexpressed in metastatic colon cancer; ERBB1 overexpressed in head and neck cancer

Mechanism of action: monoclonal Ab against ERBB1 extracellular domain to prevent stimulation by EGF

Adverse effects: infusion reaction, renal failure, interstitial lung disease
Black box warning: cardiopulmonary arrest and sudden death in head and neck cancer patients

Resistance/Considerations: patients must have wild-type K-RAS prior to therapy; 50% of patients have primary resistance due to K-RAS mutation (pharmacogenetic testing)

Cetuximab

17

Targeted cancer drug
CML, Philadelphia chromosome positive ALL

Mechansim of action: small molecule inhibitor of intracellular kinase domain of BCR-ABL

Adverse effects:
D: myelosuppression, thrombocytopenia, QT prolongation

Resistance/Considerations:
D: greater efficacy than imitanib, used for imitanib-resistant BCR-ABL mutants with exception of T315I mutation
use P for T315I mutation

Dasatinib
Ponatinib

18

Targeted cancer drug
Non-small cell lung cancer (NSCLC)

Mechanism of action: small molecule inhibitor of intracellular kinase domain of EGFR

Adverse effects: serious, potentially life-threatening; interstitial lung disease, GI perforations

Resistance/Considerations: patients eligible for treatment must have exon 19 deletion mutation or L858R point mutation in ERBB1 tend to be non-responders
Acquired resistance due to T790M mutation in ERBB1 or amplification of MET oncogene leading to alternative activation of RAS-MAPK pathway

Erlotinib
Getfitnib

19

Targeted cancer drug
CML, Philadelphia chromosome positive ALL

Mechanism of action: small molecule inhibitor of intracellular kinase domain of BCR-ABL

Adverse effects: edema, myelosuppression, hepatotoxicity

Resistance/Considerations: acquired resistance due to up-regulation of MDR1, amplification of BCR-ABL oncogene, resistance mutations in kinase domain of BCR-ABL

Imitanib

20

Targeted cancer drug
HER2+ breast cancer

Mechanism of action: small molecule inhibitor of intracellular kinase domain of HER2

Adverse effects: cardiotoxicity, nephrotic syndrome, interstitial lung disease

Resistance/Considerations: may be effective in trastuzumab-resistant cancer

Lapatinib

21

Targeted cancer drug
localized breast cancer with HER2 overexpression, metastatic HER2 breast cancer

Mechanism of action: monoclonal Ab against HER2 extracellular domain to inhibit RAS-MAPK signaling pathway

Adverse effects: hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease
Black box warning: cardiomyopathy, fatal infusion reaction in the form of ARDS

Resistance/Considerations: acquired resistance due to cleavage of extracellular domain of HER2 (decoy receptors); enhances cytotoxic chemo and reduces recurrence

Trastuzumab

22

Anti-malarial
blood stages (asexual and gametocyte)
blood stages of P. falciparum, asexual blood stage of P. vivax
counterfeit drugs

mechanism: endoperoxide is reduced by heme to form a free radical that results in toxic adducts in the food vacuole and cytoplasm of Plasmodium

oral
Rapid absorption and metabolism, modest protein binding, induce their own CYP metabolism, biliary excretion

Not useful in prophylaxis due to short half-life, ineffective as a monotherapy (artemisinin based combination therapies (ACTS) increase efficacy and decrease resistance)

generally well tolerated
not recommended for children

Artemether
Artemisinin

23

Anti-malarial
blood stages (asexual and gametocyte)
blood stages of P. falciparum, asexual blood stage of P. vivax
counterfeit drugs

mechanism: endoperoxide is reduced by heme to form a free radical that results in toxic adducts in the food vacuole and cytoplasm of Plasmodium

IV/rectal
Rapid absorption and metabolism, modest protein binding, induce their own CYP metabolism, biliary excretion

Not useful in prophylaxis due to short half-life, ineffective as a monotherapy (artemisinin based combination therapies (ACTS) increase efficacy and decrease resistance)

generally well tolerated
not recommended for children

Artesunate
Artemisinin

24

Anti-malarial
blood stages (asexual and gametocyte)

artemisinin based combination therapy (ACT)

additional component complexes with heme
longer half-life, large variability in plasma concentrations (absorption increases with high fat meal, take with food or milk)
drug-drug interactions with antriretrovirals/protease inhibitors

adverse effects
adults: headache, anorexia, asthenia, arthralgia, myalgia
children: fever, cough, vomiting, headache, loss of appetite

contraindicated in patients with cardiac arrhythmias, cardiac disease

Artemether with Lumefantrine
Artemisinin

25

Anti-malarial
blood stage

Former mainstay for choloroquine resistant and MDR P. falciparum asexual blood stages; gametocyticidal against P. vivax and P. ovale

Oral or IM (quinidine enantiomer is more potent – IV)
Readily absorbed good distribution

Risk cannot be ruled out in pregnancy, not recommended in first trimester

Protein binding, extensive hepatic metabolism, renal excretion

Resistance in SE Asia and S America – Pfmdr1 gene amplification

Adverse effects: Dose related toxicities are rate and are more common with quinidine
Cinchonism: tinnitus, deafness, visual disturbance, headache, nausea, vomiting, dizziness, postural hypertension (reversible)
Hypoglycemia – drug stimulates insulin release, can be fatal without IV glucose
Hypotension is rare but serious and associated with IV infusions
Hypersensitivity reaction – rash, urticarial, angioedema, bronchospasm
Blackwater fever – severe hemolysis and hemoglobinuria
Milder hemolysis (increased with G6PD deficiency)

Fatal oral dose in adults is 2-8 grams
Overdose: pulmonary edema, immune thrombocytopenic purpura, irreversible deafness, arrhythmias

Contradindications and drug interactions:
Parenteral solutions can be irritating
Caution in patients with hypersensitivity – discontinue with evidence of hemolysis
Contraindicated in patients with tinnitus/optic neuritis
Caution in patients with cardiac dysrhythmias
Potentially safe in pregnancy, monitor glucose

Decrease dose with renal insufficiency
Aluminum containing antacids delay GI absorption
Increase plasma warfarin and digoxin levels

Quinine
Quinolines

26

Anti-malarial
blood stage

Highly effective against all species asexual blood stages and some gametocytocidal activity
Interferes with heme digestion

Oral, IM, SC, IV
Readily absorbed, large volume of distribution, CNS/CSF to lesser extent, moderate protein binding, renal excretion
Complex pharmacokinetics – Cp determined by distribution vs elimination rate – loading dose required
Parenteral routes can result in potentially lethal Cp (slow IV or small divided dosing in IM/SC)

Mechanism of action: a base that is protonated in the acidic food vacuole of Plasmodium (unable to leave the vacuole, accumulates), results in build-up of toxic metabolites

Resistance:
Pfcrt mutations and CRT results in drug efflux

Safe with proper dosing, narrow safety margin
Safe in pregnancy

Acute toxicities primarily involve CV and CNS
Hypotension, vasodilation, arrhythmias, cardiac arrest, confusion, convulsions

Parenteral doses >5g usually fatal
Oral therapy: GI upset, headache, visual disturbance, urticarial, pruritis in persons of African descent, rare hemolysis (increase with G6PD deficiency), potential discoloration of nail beds/mucous membranes

Contraindicated with epilepsy, MS, cardiac dysrhythmias
Caution in patients with advanced renal or liver disease or severe GI/neuro/blood disorder
Avoid Ca/Mg containing antacids – delay GI absorption
CYP inhibitor

Chloroquinine
Quinolines

27

Anti-malarial
blood stage (gametocyte), primary and hypnozoite liver stages

Acts on primary and latent hepatic stages of plasmodia – effective against relapse in P. vivax and P. ovale
Gametocytocidal against P. falciparum
Inactive against asexual blood stages

Induces ROS formation, less GSH available as an anti-oxidant, RBC damage
Potentially converted to electrophilic intermediates that mediate oxidation-reduction
ROS interfere with mitochondrial ETC in the parasite

Oral (parenteral-risk of hypotension), good absorption, large volume of distribution, rapid hepatic CYP metabolism, renal excretion

Hemolysis in G6PD deficiency (screen first) – decrease dose or do not use depending on severity
Few side effects with therapeutic doses
Overdose: granulocytopenia
Hemolytic anemia in G6PD deficiency – 11% of African Americans, more severe in some white ethnic groups (Sardinians, Sephardic Jews, Greeks, Iranians)
Contraindicated in pregnant women, rule out G6PD deficiency in infant before use in breast feeding mother
Contraindicated in active forms of RA and SLE
Do not administer with myelosuppressive drugs

Primaquine
Quinolines

28

Adjunctive with quinolones

slow acting blood schizonticides
ineffective as a monotherapy, useful as adjunct to treat P. falciparum
inhibit protein translation in protozoa, results in the death of progeny

Doxycylines and Clindamycin

29

Anti-malarial
Active against P. falciparum asexual blood stages (not P. vivax)

Inhibits parasite mitochondrial electron transport
Resistance to monotherapy
Cytb mutations inhibit drug binding and confer resistance
High cure rates combined with proguanil (synergy) – used for chemoprophylaxis/uncomplicated P. falciparum

Oral, highly lipophilic, slow erratic absorption increase with fatty meal, protein bound, no significant metabolism, biliary excretion

Generally safe
Stomach pain, nausea, vomiting, diarrhea, headache, rash
Risk cannot be ruled out in pregnancy
May compete for protein binding of other drugs
Rifampin/tetracycline decreases plasma levels

Atovaquone

30

1. Active against asexual blood and primary liver stages of P. falciparum and acute P. vivax

Prodrug
Inhibits dihydrofolate reductase disrupting DNA synthesis
Enhances atovaquone effect

Slow absorption, renal excretion
Safe in conjunction with atovaquone
Risk cannot be ruled out in pregnancy

Proguanil

31

Anti-Herpes, Anti-CMV
Decreasing activity in: HSV1, HSV2, VZV, EBV, CMV

Guanosine (nucleoside) analog that lacks 3’OH required for phosphodiester bond formation
Requires 3 phosphorylation reactions by viral and cellular kinases to become activated
Initial phosphorylation by viral HSV thymidine kinase (important for selectivity)
Triphosphate form competes with cellular dGTP – blocks viral replication by chain termination and direct suicide inhibition of viral DNA polymerase
Drugs that reduce dGTP can be used in combination

Higher plasma levels achieved with IV than PO, topical preps are available but absorption is low
Increased oral bioavailability with oral prodrug administration
Wide distribution including CSF
Crosses the placenta and distributes to breast milk
Renal elimination
Probenecid and cimetidine increase plasma levels by interfering with elimination

In HSV and VZV due to decreased levels of or mutations in viral thymidine kinase
Less common: alteration of viral DNA polymerase (target)
Use foscarnet in resistant infection

Resistance: In HSV and VZV due to decreased levels of or mutations in viral thymidine kinase
Less common- alteration of viral DNA polymerase (target)
Use foscarnet in resistant infection

Toxicity: Well tolerated, associated with nausea, vomiting, diarrhea, rash
Neutropenia in infants is rare, no know teratogenic effect in pregnancy
Nephrotoxicity in some patients (often when given other nephrotoxic agents) – reversible
CNS effects include delirium, tremor, and seizures – reversible

Acyclovir

32

Anti-Herpes, Anti-CMV
All HSVs, 100x more effective against CMV than acyclovir
CMV retinitis in AIDS and CMV prophylaxis post transplantation

Guanosine analog that requires 3 phosphorylations to be converted to active nucleotide
First phosphorylation is catalyzed by viral thymidine kinase (HSV) or viral phosphotransferase UL97 (CMV) during infection; the last 2 phosphorylations are catalyzed by cellular enzymes
inhibits viral DNA synthesis by chain termination and viral DNA polymerase inhibition

Higher plasma levels with IV than PO
Oral bioavailability is increased by oral administration of the prodrug
Higher intracellular concentrations than acyclovir; very high levels in vitreous humor
Slow renal elimination (explains effectiveness against CMV)

Resistance: Mutations in the genes encoding UL97 viral phosphotransferase (most common) or mutations to viral DNA polymerase in CMV – if both mutations are present, multi-drug resistance
Use foscarnet in resistant infections

Myelosuppression is a common dose-limiting toxicity; neutropenia, thrombocytopenia (reversible unless neutropenia has occurred)
CNS toxicity: headache, behavioral alterations, convulsions, coma
Embryotoxic and teratogenic

Ganciclovir

33

Anti-Herpes, Anti-CMV
All HSV and HIV
CMV retinitis in AIDS, ganciclovir-resistant CMV, acyclovir resistant HSV/VZV

Pyrophosphate analog
Non-competitively inhibits viral replication by reversibly blocking the pyrophosphate binding site of viral DNA polymerase and HIV reverse-transcriptase

Poorly absorbed PO, administered IV
Penetrates vitreous humor and CSF
Renal elimination
Penetrates bone and can remain in bone for period of time (long half-life)

Resistance: HSV mutations in the gene encoding the viral DNA polymerase

Toxicity: Nephrotoxicity, hypocalcemia (CNS effects: paresthesia, tetany, seizures, arrhythmias)
Hyperphosphatemia, hypokalemia, hypomagnesemia
Known mutagen

Foscarnet

34

Anti-Influenza
Viral uncoating agent, no longer common due to resistance (M2 mutation in seasonal flu)

spectrum: Influenza A

Target the M2 protein responsible for acidification of virion and dissociation of ribonucleoproteins
Enter the M2 channel, prevent protein movement/interior acidification and dissociation of ribonucleoproteins – prevents viral replication, alters conformation of hemagglutinin which decreases its function

Amantidine

35

Anti-Influenza
Influenza A and B, speeds recovery in adults and children and is prophylactic against seasonal flu

Neuraminidase inhibitor
Carboxylate is an analog of sialic acid, phosphate is a prodrug that is hydrolyzed by hepatic esterases to yield active drug
Bind neuraminidase and inhibits cleavage of sialic acid on host cell preventing release of the virus

Phosphate is well absorbed, rapid first pass conversion to active carboxylate (high bioavailability)
Renal elimination, clearance decreased by probenecid

Mutations in the genes encoding hemagglutinin or neuraminidase; H1N1 seasonal influenza A is resistant but swine flu (nH1N1) is susceptible

Occasional headache and GI disturbances such as nausea, vomiting and general discomfort (minimized by taking the drug with food)

Oseltamivir

36

Anti-influenza
Influenza A and B; strains that are resistant to amantadine and some resistant to oseltamivir

Neuraminidase inhibitor
Binds neuraminidase and inhibits cleavage of sialic acid on the host cell preventing release of the virus

Poor absorption and bioavailability PO; powder is administered by oral inhalation, most of the drug deposits in the oropharynx, this results in a longer half-life than IV
Renal elimination

Resistance: Mutations in genes encoding hemagglutinin or neuraminidase – less virulent in animal models
H mutants, cross-resistance to oseltamivir

Toxicity:
Well tolerated after inhalation with only bronchospasm/wheezing observed
Pre-existing respiratory problems, decreased lung function observed

Zanamivir

37

Anti-Retroviral class
Zidovudine/AZT (still used)

spectrum: HIV1 and HIV2

Resemble nucleosides
Competitive inhibition of reverse transcriptase and incorporation into viral DNA
Activated by cellular phosphorylation to triphosphate

Food increases bioavailability

Resistance: Due to mutations in viral reverse transcriptase

Toxicity: Interact with mitochondrial DNA polymerase gamma
Hyperlipidemia/insulin resistance
Lactic acidosis with hepatic steatosis (may be life threatening), due to inhibition of mitochondrial function causing a build-up of triglycerides

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

38

Anti-Retroviral
Nucleoside RTIs

Guanosine analog, competitive inhibition of reverse transcriptase and incorporation into viral DNA

Administered with lamivudine
Hepatic deactivation

Resistance: Slow, requires 2-3 mutations in the reverse transcriptase

Toxicity: MI, caution in CVD
Hypersensitivity reactions may be fatal, associated with HLA-B5701 (these individuals not given the drug); may also result in skin rash

Abacavir

39

Anti-Retroviral
Nucleoside RTIs

spectrum: HIV1 and HBV

Cytosine analog, competitive inhibition of reverse transcriptase and incorporation into viral DNA; synergistic with other nucleoside analogs

Administration with concurrent emtricitibine is not recommended, administered with tenofovir

Lamivudine

40

Anti-Retroviral
Nucleoside RTIs

spectrum: HIV1 and HBV

Cytosine analog, competitive inhibition of reverse transcriptase and incorporation into viral DNA; synergistic with other nucleoside analogs

Administration with concurrent lamivudine is not recommended, administered with tenofovir
Fluorinated analog of lamivudine; longer half-life allows once daily dosing

Emtricitabine

41

Anti-Retroviral
Nucleotide RTIs

Nucleotide (adenosine) analog, competitively inhibits reverse transcriptase resulting in chain termination after incorporation into DNA
Only requires 2 phosphorylations to become active (both by cell kinase)

Co-administered with emtricitabine as a first line therapy, also used in chronic hepatitis
Renal excretion

Toxicity: Fatigue, muscle weakness flatulence
Tubular necrosis, renal failure Fanconi’s syndrome
Bone loss/osteopenia

Tenofovir

42

Anti-Retroviral
Non-Nucleoside/Nucleotide RTIs

Binds directly to HIV1 reverse transcriptase and inhibits RNA and DNA dependent DNA polymerase
Distinct binding site from NRTIs

No phosphorylation required, not a nucleoside analog
Does not compete with nucleotide triphosphate
Extensive metabolism/induction via CYP3A4 pathway (drug-drug interactions) – limits use of HAART
Long half-life, once daily dosing

Resistance: rapid with one mutation

Toxicity: Nightmares, psychiatric disturbances (at the start of therapy, resolve in 2-3 weeks)
GI intolerance, skin rash, severe hypersensitivity

Efavirenz

43

Anti-Retroviral class

spectrum: HIV1 and HIV2

Peptidomimetics, inhibit proteolytic cleavage of Gag and Gag-pol, do not require intracellular activation

Metabolized by inhibitors of CYP3A4 (drug interactions)

Resistance: Common, use in combo therapy

Toxicity: Redistribution and accumulation of body fat (lipodystrophy)
Increased triglycerides/LDL
MI, hyperglycemia, insulin resistance, bleeding in hemophilia, hepatotoxicity

HIV Protease Inhibitors

44

HIV protease inhibitor

Inhibits CYP3A4, used with other protease inhibitors to increase their serum level (boosting)
Increase tolerability with less frequent dosing

Food increases bioavailability

Increased triglycerides/LDL, elevated serum aminotransferase levels

Ritonavir

45

HIV Protease Inhibitor

Peptidomimetics, inhibit proteolytic cleavage of Gag and Gag-pol, do not require intracellular activation

Treatment of choice for naïve patients in combination with ritonavir

Toxicity: Rash, sulfonamide moiety caution with sulfa allergy

Darunavir

46

HIV Protease Inhibitor

Peptidomimetics, inhibit proteolytic cleavage of Gag and Gag-pol, do not require intracellular activation

Treatment of choice for naïve patients in combination with ritonavir

Toxicity: Hyperbilirubinemia, rash, kidney stones, cholelithiasis

Atazanavir

47

Anti-retroviral
Fusion/entry inhibitor

Only for treatment of experience HIV patients with ongoing HIV replication; not in HIV2

Binds to gp41 subunit of the viral envelop glycoprotein preventing conformational changes required for fusion (no entry pore is formed)

SC injection
resistance may develop, use in combo therapy

Efuvirtide

48

Anti-retroviral
Fusion/entry inhibitor

spectrum: HIV1 strains resistant to other drugs

Binds selectively to CCR5

oral
hepatotoxicity

Maraviroc

49

Anti-retroviral
Integration (Integrase) Inhibitors

Spectrum: HIV1 and HIV2; use in resistance to other drugs

Binds integrase which is essential for viral replication, inhibits viral DNA integration into the host genome

Toxicity: Generally well tolerated, hypersensitivity, elevated liver enzymes with HCV/HBV co-infection

Dolutegravir