Experiment : Case Study 1 Antifungal Agents ١ DL is a 43-year-old recovering drug addict who, until recently, was living on the streets of New York. The indigent clinic affiliated with the shelter where he now lives conducted an entering health exam and found that, although symptom-free, DL is HIV positive. He also has enlarged kidneys and blood in his urine, and a diagnosis of polycystic kidney disease was made. This renal disease is often accompanied by hypertension, and DL’s blood pressure is borderline high. He has recently presented to the free clinic with a persistent cough, shortness of breath, fever, headache, and photophobia. A diagnosis of cryptococcosis is made. Drugs are scarce in the free clinic but, particularly because of the CNS involvement and his immunocompromised condition, DL requires immediate and sustained treatment with an antifungal agent. the clinic physician would like to try monotherapy with one of the following drugs. OH OH O H3C OH O CH3 OH OH OH OH OH O NH2 F O N OH H3C O O CH3 O N H 1 HO 2 OH NH2 N N N N OH N CH3 N N F 3 4 F Terbinafine 1. Identify the therapeutic problem(s) where the pharmacist's intervention may benefit the patient. DL has many therapeutic problems but his most immediate need is for effective antifungal monotherapy to eradicate the yeast infection that has invaded his lungs and brain. his blood pressure regularly monitored, as hypertension causes rapid progression of PKD. His diet should be reviewed for sodium content He could be a candidate for diuretic therapy. DL should be monitored for progression of his immunoinsufficiency (although it is asymptomatic). If and when possible, prophylactic antiretroviral therapy should be initiated. 2. Identify and prioritize the patient specific factors that must be considered to achieve the desired therapeutic outcomes. DL is immunocompromised and is He has fungal infection. He is at greater risk for disease dissemination, morbidity, and mortality (due to HIV infection). DL has an inherited kidney disease & should not be placed on nephrotoxic medications. DL cannot pay for medications nor afford a hospitalization. Oral therapy will be required for the acute and chronic treatment of this infection. 3. Conduct a thorough and mechanistically oriented structure-activity analysis of all therapeutic alternatives provided in the case. Compound 1 OH H3C OH OH O O CH3 OH OH OH OH OH O O OH H3C O O CH3 1 HO OH NH2 is a polyene lipophilic macrolide with seven conjugated double bonds. MOA: binds to ergosterol in fungal membranes ►↑ increased permeability ► cell death? The number of conjugated double bonds is inversely proportional to mammalian toxicity, (it is the safest of the three polyenes available for therapeutic use). Amphotericin B Has enhanced safety margin (the only polyene that can be used by IV) It is highly nephrotoxic, → used with extreme caution in kidney diseases. Sodium loading with hydration can also reduce the risk of nephrotoxicity. The oral dosage form is reserved for fungal infections of the mouth and throat. Compound 2 NH2 F N O N H 2 It is a fluoro pyrimidine derivative. It must be metabolized by fungal cytidine deaminase enzymes to ► 5-fluorouracil, then ► 5-FdUMP (active form). MOA: 5-FdUMP inhibits thymidylate synthase in the fungal cell, leading to aberrations in RNA and protein synthesis. It is relatively nontoxic to humans, (because mammalian cells do not contain the activating deaminase). It is effective for only a limited time as monotherapy rapid development of resistance to its antifungal action. It is used effectively in combination with agents that act by a different mechanism Compound 3 N N N N OH N N F 3 It is a triazole antifungal MOA: inhibits CYP-induced F 14α-demethylation of the lanosterol ►dysfunctional sterols ►↑ membrane permeability Has good oral bioavailability, and very little first pass metabolism. The fact that it is excreted unchanged leads to a long duration of action. It is a noncompetitive inhibitor of CYP3A4 , (not a good substrate). drug-drug interactions with many of these agents is high distributes well to all body tissues, (CNS & brain), and is excreted primarily unchanged via the kidney so dosage adjustment is recommended in renal disease Compound 4 CH3 N 4 Terbinafine It is allyl amine antifungal agents. MOA: squalene epoxidase inhibitors ►↑ squalene fungal cell membrane, to toxic level. It is well-absorbed orally. Clearance: mainly via the kidney, so it is significantly impaired in patients with kidney disease (dosage adjustments are usually recommended). The allyl amines distribute preferentially from the plasma to the nail bed, and do not accumulate in the lungs or the CNS, so its oral use is reserved for fungal infections of the fingernails and toenails. 4. Evaluate the SAR findings against the patient specific factors and desired therapeutic outcomes and make a therapeutic decision. Compound 4 CH3 N 4 Terbinafine DL requires therapy that will distribute in therapeutic concentrations to lungs & brain. This rules out compound 4 (terbinafine), which selectively distributes to the nail bed and is used orally to treat onychomycoses secondary to dermatophytic infection. OH Compound 1: H3C OH OH O OH O CH3 OH OH OH OH O O OH H3C O O CH3 1 HO amphotericin B OH NH2 DL has chronic, renal disease which lower the ability to clear drugs via the kidneys. Unless a lipoidal formulation of compound 1 (amphotericin B) was available, his kidneys would probably not tolerate this nephrotoxic agent. Sodium loading can sometimes be used to minimize amphotericin’s nephrotoxicity, but this would not be appropriate with DL’s borderline hypertensive state. Insufficient bioavailability precludes the use of oral amphotericin B for serious systemic fungal infections. Compound 2: NH2 F N N H O 2 Flucytosine If amphotericin B could be used, compound 3 (flucytosine) could be used in synergistic antifungal combination??. Monotherapy, with flucytosine would not be effective for a long enough period of time (here, should be 2–3 months after the CSF cultures negative). Why?? Because, resistance to this antimetabolite prodrug is reported to develop quickly Compound 3 N N N N OH N N F 3 F Fluconazole would be the drug of choice for DL. (why)???? 1. It is orally active, distributes well to all tissues (lung & brain), 2. used once daily. 3. It has100% oral bioavailability, oral and IV doses are equivalent. The risk of drug-drug interactions between fluconazole and agents metabolized by CYP3A4 is high, but DL is not currently on any other medication. If necessary and possible, flucytosine (compound 3) could be added to the regimen to achieve a negative CSF culture more quickly. 5. Counsel your patient. DL should know that his therapy will be prolonged, as maintenance therapy is generally necessary to prevent relapse. DL should be counseled to report any signs and symptoms of fluconazole toxicity (WHY)? Use of fluconazole in AIDS patients may result in skin disorders. DL’s renal disease will retard fluconazole excretion. WHAT are the signs and symptoms of fluconazole toxicity At low dose: nausea, headache, rash, abdominal pain At very high dose: may cause hallucinations Fluconazole inhibits CYP3A4, that metabolize between 2/3 to and 3/4 of all xenobiotics. • He should be counseled to report any OTC medications. • Dosage adjustments must be considered if anti-AIDS therapy with protease inhibitors is initiated (because many of which are inactivated by CYP3A4) . Learning objectives By the end of this case students should 1. be able to identify the given compounds from their chemical structure 2. Know the chemical classification for these compounds 3. be able to identify their MOA 4. Know the use limiting side effects for these compounds 5. be able to Identify the therapeutic problem(s) 6. be able to determine the patient specific factors that must be considered in the treatment 7. Know the SAR for these compound 8. Evaluate the SAR findings and can make a decision based on the SAR study 9. Able to Counsel this patient