Pharmacology Flashcards
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
- 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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
Anti-retroviral
Fusion/entry inhibitor
spectrum: HIV1 strains resistant to other drugs
Binds selectively to CCR5
oral
hepatotoxicity
Maraviroc
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
