Managing Multiple Oral Medications Chris Archer-Chicko, MSN, CRNP PENN Presbyterian Medical Center Arlene Schiro,, CRNP Massachusetts General Hospital Mary Bartlett, CRNP Winthrop University Hospital PH Resource Network Symposium October 12, 2007
Oral Medications available today Calcium Channel Blocker Therapy Endothelin Receptor Antagonist Therapy Bosentan (Tracleer) Letairis (Ambrisentan) Phosphodiesterase (PDE5) Inhibitor Therapy Sildenafil (Revatio) Combination therapy
Calcium Channel Blocker Therapy Used to promote vasodilation in pulmonary vessels to relieve heart failure Indications: Positive vasoreactive response PAH patients (WHO Group 1) primarily IPAH PAH diagnosed by cath (PVR > 3 wood units) Most commonly used: Nifedipine (Procardia) Diltiazem (Cardizem) Amlodipine (Norvasc)
Calcium Channel Blocker Therapy Positive vasoreactive response (ACCP 2004) Drop in MPAP by > 10mmHg, and achieving a MPAP < 40mmHg An increase or no decrease in cardiac output Decrease in PVR by > 20% and achieving a PVR < 8 wood units No or clinically acceptable fall in systemic BP Only 6.8% of all PH patients are long-term responders (Sitbon)
Calcium Channel Blocker Therapy Contraindicated in patients with: Low cardiac output (CI < 2.0) Severe right heart failure Hypotension (BP < 90mmHg) History of adverse reaction or intolerance to CCB
Calcium Channel Blocker Therapy Dosing: Inpatient (rapid escalation) Nifedipine 10-20mg or Diltiazem 60mg Assess hemodynamics every hour until threshold response is achieved Total daily dose = total of drug given during testing (divided in three doses) Outpatient (slow escalation) Nifedipine 10-20mg TID or Diltiazem 60mg TID Goal: Nifedipine 240mg or Diltiazem 720mg over 6-6 12weeks
Calcium Channel Blocker Therapy Side effects: Hypotension Hypoxemia GI upset (nausea, vomiting) Worsening edema Tachycardia Bradycardia Heart block (with Diltiazem)
Calcium Channel Blocker Therapy Long-term considerations: Approximately ½ of patients who are responders and placed on CCB therapy require additional therapy in 1 year. Patients should be monitored closely (every 3-63 months) and should be started on additional therapy if clinical worsening occurs.
Endothelin Receptor Antagonist Therapy Blocks the vasoconstrictive (and possibly other) effects of endothelin ( ET-1) at specific receptor sites in the endothelium and smooth muscle. Indications: PAH patients (WHO Group 1) WHO Functional Class II or III Two FDA approved agents: Bosentan (Tracleer) Ambrisentan (Letairis)
Endothelin Receptor Antagonist Therapy Contraindications: Pregnancy Category X (severe fetal harm) Negative pregnancy test before starting therapy Cyclosporine Glyburide Hypersensitivity (check antifungals)
Endothelin Receptor Antagonist Therapy Dosing: Bosentan 62.5mg or 125mg q12h Letairis 5mg or 10mg daily Side effects: Edema, Headache, Nasopharyngitis,, Flushing, Hypotension, Fatigue, Palpitations, Pruritus Interactions: (Bosentan) Warfarin may need to be adjusted (increased)
Endothelin Receptor Antagonist Therapy Warning: Potential for Liver Injury o Follow LFTs (ALT, AST) before start of therapy & monthly FDA requirement o Elevations of liver enzymes are dose dependent & reversible with reduction or cessation of therapy Modest decrease in Hgb & Hct Patients must not become pregnant on therapy
Endothelin Receptor Antagonist Therapy Long term considerations: Patients may not feel an improvement in symptoms for 8-10 weeks. Patients need to comply with monthly LFTs monitoring. Patients demonstrated an improvement in six minute walk distance and a delay in clinical worsening.
Phosphodiesterase Inhibitor Therapy Sildenafil (Revatio) cgmp metabolism may contribute to increased pulmonary vascular tone & proliferation of pulmonary vascular smooth muscle cells; inhibitors of cgmp metabolism may reduce PA pressures & improve pulmonary vascular resistance
Phosphodiesterase Inhibitor Therapy Indications: PAH patients (WHO Class I) WHO Functional Class II, III (check) Dosing: 20mg every 8 hours Current dosing strategy is to start at 20mg three times a day and increase if the patient is not improving or is worsening Contraindications: No use of nitrates
Phosphodiesterase Inhibitor Therapy Side effects: Epistaxis,, Headache, Dyspepsia, Flushing, Insomnia, Nasal congestion
Phosphodiesterase Inhibitor Therapy Long term Not known if Revatio 20mg q8h will be effective on a long-term basis Two other PDE5 inhibitors (Tadalafil( and Vardenafil) ) may also be beneficial Longer half-life life
Combination Therapy Rationale for combination therapy: Targeting multiple pathogenic pathways Synergistic effect b/t different therapeutic agents Overcome treatment limiting toxicity of monotherapy Potential cost advantage by dose reduction of selected therapies Delay worsening of symptoms; disease progression Combination therapy is used in other diseases (O Callaghan & Gaine)
Combination Therapy When to initiate? Cancer chemotherapy type model At diagnosis in patients with severe disease, severe limitations, rapidly progressive course CHF or Systemic HTN model In patients who do hit treatment targets after a period of monotherapy and show clinical deterioration
Combination Therapy Few prospective trials done thus far to evaluate benefits of combining drugs with differing modes of action Many studies are now underway
Questions
References Alam, Shoaib & Palevsky, Harold, Standard Therapies for Pulmonary Arterial Hypertension, Clinics in Chest Medicine, Vol. 28, 1 (2007) 91-115. 115. Klinger, James, The Nitric Oxide/cGMP Signaling Pathway in Pulmonary Hypertension, Clinics in Chest Medicine, Vol. 28, 1 (2007) 143-167. 167. O Callaghan, Dermot & Gaine, Sean, Combination Therapy and New Types of Agents for Pulmonary Arterial Hypertension, Clinics in Chest Medicine, Vol. 28, 1 (2007) 169-185. 185.
References Package inserts: Bosentan, Letairis, Sildenafil Sitbon,, O. Humbert,, M., Jais,, X., et al. Long-term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension, Circulation 2005, Vol. 111(23) pg 3105-3111. 3111.