Therapeutics 1 Tutoring Sarah Darby shodge7@uthsc.edu August 26, 2016

Lectures Covered Atherosclerosis and Dyslipidemia Ischemic Heart Disease CV pharmacology review Ischemic stroke Hemorrhagic stroke

Atherosclerosis and Dyslipidemia NLA NLA Risk Factors Age Males 45 and older Females 55 and older Family Hx Male first degree relative <55 years Female first degree relative <65 years Smoking HTN BP > 140/90 or on medication Low HDL Males <40mg/dl Females <50mg/dl NLA Categories of Risk Low 0-1 risk factors Moderate 2 risk factors High 3 or more DM + 0-1 factors CKD 3B or 4 LDL above 190 Very High Clinical ASCVD DM + 2 or more, end organ dam.

Atherosclerosis and Dyslipidemia NLA NLA Categories of Risk Low 0-1 risk factors Moderate 2 risk factors High 3 or more DM + 0-1 factors CKD 3B or 4 LDL above 190 Very High Clinical ASCVD DM + 2 or more, end organ dam.

Atherosclerosis and Dyslipidemia NLA JA is a 56 yo male Currently taking Lisinopril 10mg daily for hypertension Well controlled No other medical problems Lipids TC = 205 HDL = 45 LDL = 135 Family history is negative for CVD Smokes 1/2PPD, denies alcohol or illicit drug use Based on NLA guidelines, what risk category is he? Low Moderate High Very high

Atherosclerosis and Dyslipidemia NLA JA is a 56 yo male Currently taking Lisinopril 10mg daily for hypertension Well controlled No other medical problems Lipids TC = 205 HDL = 45 LDL = 135 Family history is negative for CVD Smokes 1/2PPD, denies alcohol or illicit drug use Based on NLA guidelines, what is his treatment goal? Non-HDL <100mg/dl LDL < 130mg/dl Non-HDL < 130mg/dl ApoB < 90mg/dl

Atherosclerosis and Dyslipidemia When do triglycerides become the primary target of lipid lowering therapy? When TG > 200mg/dl When TG > 500mg/dl When HDL-C < 35mg/dl When a patient has a hx of pancreatitis

Atherosclerosis and Dyslipidemia True or False Raising HDL-C using drug therapy is supported by clinical trials and published in the literature.

Atherosclerosis and Dyslipidemia Additional therapies only for: Statin intolerant and need a replacement Inadequate response to statin Be sure to counsel on med adherence and lifestyle changes first Which agents? ACC = ezetimibe, BAS, or PCSK9 inhibitors NLA = ezetimibe, BAS, or niacin

Atherosclerosis and Dyslipidemia Add-on therapy ACC 1st: Ezetimibe 2nd: PCSK9 or BAS depending on Pt NLA 1st: Ezetimibe 2nd: Colesevelam 3rd: Niacin ER PCSK9 inhibitors: Alirocumab (Praluent) Evolocumab (Repatha) - SQ administration, decreased dosing frequency, expensive

Atherosclerosis and Dyslipidemia Add-on therapy Ezetimibe – reduced cholesterol absorption PCSK9 inhibitors – monoclonal antibody that binds to LDL receptor to promote LDL degradation Bile-acid sequestrants – disrupts enterohepatic recirculation of bile acids which increases conversion of cholesterol to bile acids

Atherosclerosis and Dyslipidemia Add-on therapy 63 yo female in clinic for check-up Started Atorvastatin 40mg at last visit. Lipid levels from 4 mos ago: TC=240, LDL=145, HDL=30 Lipid levels today: TC=130, LDL=70, HDL=32 What do you recommend for treatment? Change to Simvastatin 20mg Add Ezetimibe Decrease to Atorvastatin 20mg Maintain current therapy

Atherosclerosis and Dyslipidemia Add-on therapy 68 yo male in clinic for check-up Started Atorvastatin 80mg at last visit. Lipid levels from 4 mos ago: TC=410, LDL=320, HDL=40 Lipid levels today: TC=250, LDL=150, HDL=40 What do you recommend for treatment? Change to Rosuvastatin 20mg Add Ezetimibe Add Colesevelam Maintain current therapy

Atherosclerosis and Dyslipidemia Add-on therapy Which treatment is recommended for homozygous familial hypercholesterolemia? Evolocumab Ezetimibe Alirocumab Colesevelam

Atherosclerosis and Dyslipidemia Add-on therapy What should be your response if a Pt complains of cognitive changes after initiating a statin? Continue therapy; it will resolve on its own “Man, you’re crazy! It’s not the statin!” Rule out other causes Assess risk vs. benefit of therapy Consider switching to a more hydrophilic statin A and B C, D, and E

Atherosclerosis and Dyslipidemia Add-on therapy What side effect are we most concerned about with statin use? Abdominal pain Headache Increased blood pressure Myalgia

Atherosclerosis and Dyslipidemia Add-on therapy Who is more likely to experience statin- induced myopathy? Males or females? Aged 65 or 85? Hyper- or Hypothyroidism? Simvastatin or Rosuvastatin? Apple juice or grapefruit juice?

Atherosclerosis and Dyslipidemia Add-on therapy HT is a 59 yo female who started Atorvastatin 40mg due to MI 3 mos ago. She has returned to the clinic today with complaints of severe muscle pain. What do you recommend? Increase to Atorvastatin 80mg Switch to Simvastatin 40mg Hold the Atorvastatin, and restart at lower dose in 2 weeks C

Atherosclerosis and Dyslipidemia Add-on therapy Other possible actions for myopathy: Consider drug interactions and avoid certain CYP enzymes Choose statins with longer half life to reduce dosing frequency Rosuvastatin and Atorvastatin Combine lipid lowering agents and use lower doses

Atherosclerosis and Dyslipidemia TY is a 58 yo female recently discharged from hospital after suffering MI. During her stay, she developed a mild candida infection and was treated with Fluconazole. She comes to you with complaints of uncomfortable muscle pain. Rx: Metoprolol, Lisinopril, Atorvastatin, Metformin, and Warfarin What is causing her muscle pain and through what mechanism? Azole antifungals inhibit CYP3A4, increasing her Atorvastatin concentration Azole antifungals inhibit CYP2C9, increasing her Atorvastatin concentration Azole antifungals induce CYP3A4, decreasing her Atorvastatin concentration Azole antifungals induce CYP2C9, decreasing her Atorvastatin concentration

Ischemic Heart Disease Ranolazine Indicated for chronic angina Works by inhibiting late inward sodium channel, which leads to decreased calcium influx = reduced ventricular tension and oxygen consumption No hemodynamic changes MARISA Improved time to angina onset and total exercise duration as compared to placebo CARISA Improved angina when used in combination with other therapies TERISA Similar improvements in angina in patients with diabetes MERLIN-TIMI 36 No difference in terms of CV death or MI compared to placebo Decreased rate of ischemia compared to placebo

Ischemic Heart Disease Ranolazine Dose: 500mg BID up to 1000mg BID Concern for prolonged QT interval No torsades de pointes occurred during clinical trials Contraindications Pre-existing QT prolongation Simultaneous QT-prolonging drug use Strong CYP 3A4 inhibitors or inducers Significant hepatic impairment Drug Interactions! Weak inhibitor of 3A4 Moderate inhibitor of 2D6 and Pgp Substrate of 3A4 (also 2D6 and Pgp)

Ischemic Heart Disease Which of the following will increase plasma concentrations of Ranolazine? Rifampin Ketoconazole Phenytoin Metoprolol Which of the following will decrease plasma concentrations of Ranolazine? Ritonavir Diltiazem Lisinopril Carbamazepine

Ischemic Heart Disease Which of the following should not be used in combination with Ranolazine? Amiodarone Simvastatin Verapamil Gentamicin Which of the following does NOT have a contraindication with Ranolazine? SSRIs Methadone Carvedilol Haloperidol

Ischemic Stroke BP: only treat when > 220/120 mmHg or aortic dissection, acute myocardial dysfunction, pulmonary edema, hypertensive encephalopathy Why?

Ischemic Stroke Acute Treatment Alteplase (rt-PA) aids in reperfusion. Gold standard of therapy Risk? Bleeding Should be given within 4.5 hours Increases likelihood of a favorable outcome LONG LIST of exclusion criteria Dose: 0.9mg/kg total over 60 minutes 10% given as a bolus over 1 minute Maximum dose is 90mg

Ischemic Stroke 70 yo female, presents to ER 1h after sx onset Is Alteplase (rt-PA) therapy appropriate? BP = 200/120 Platelets = 120,000/mm3 Received heparin infusion 24 hours prior Stable on warfarin with INR of 2.0 Negative history for intracranial hemorrhage

Ischemic Stroke 70 yo female, presents to ER 4h after sx onset Is Alteplase (rt-PA) therapy appropriate? Hx of DMT2 and ischemic stroke Stable on warfarin with INR of 1.5 NIHSS = 28

Ischemic Stroke 70 yo female, 55.5kg, presents to ER 1h after sx onset The healthcare team deems Alteplase appropriate. What is her dose? 50mg infusion over 60 min. 5mg bolus over 1 min., followed by 45mg over 60 min. 50mg bolus over 1 min., followed by 40mg over 60 min. 5mg bolus over 1 min., followed by 85mg over 60 min.

Ischemic Stroke 65 yo male, 105kg, presents to ER 1h after sx onset The healthcare team deems Alteplase appropriate. What is his dose? 9.5mg bolus over 1 min., followed by 85mg over 60 min. 95mg infusion over 60 min. 9mg bolus over 1 min., followed by 81mg over 60 min. 95mg bolus over 1 min., followed by 5mg over 60 min.

Ischemic Stroke Acute Treatment when not t-PA eligible Give antiplatelet as soon as possible Choose Aspirin or Clopidogrel Don’t pick dipyridamole (bad headaches)

Ischemic Stroke Anticoagulation Unclear cause? Monitor heart rhythm Cardioembolic origin needs anticoagulation Initiate within 14 days

Hemorrhagic Stroke Intracerebral hemorrhage Gradual increase in sx Causes: think anticoag and HTN BP: SBP is 150-220mmHg Decrease to <140 quickly SBP is >220mmHg Use CIVI and monitoring to get to <140 Management Cont. Inf.: Clevidipine and Nicardipine Boluses: Hydralazine and Labetalol

Hemorrhagic Stroke Reversing Bleeds Kcentra and FEIBA are both 4 factor prothrombin complex concentrates Difference: FEIBA has activated factor 7 Warfarin Vit K Kcentra FEIBA FFP Dabigatran Kcentra FEIBA Hemodialysis Rivaroxaban Kcentra FEIBA Apixaban Kcentra FEIBA

Hemorrhagic Stroke DVT Prophylaxis Intracerebral hemorrhage LMWH started 1-4 days after onset in immobile patients Subarachnoid hemorrhage No treatment until aneurysm is protected via surgery LMWH or UFH started 24 hours after surgery When to restart anticoag? No heart valves: wait at least 4 weeks Aspirin monotherapy can be started back sooner Controversy over mechanical valves

Hemorrhagic Stroke Subarachnoid hemorrhage “worse headache” Sudden onset Highest risk of re-bleeding in first 72 hours BP: Get below 160mmHg Use same drugs as ICH, except lower target with ICH Special: Nimodipine Only indicated for reducing vasospasm associated ischemia after SAH

Hemorrhagic Stroke 72 yo female presents to ER with vomiting and severe headache Pt currently taking warfarin 5mg daily for AF Her current BP is 230/135mmHg. What do you recommend for treatment of her blood pressure? Labetalol continuous infusion Clevidipine continuous infusion Amlodipine bolus No therapy; she’s fine with that BP! B

Hemorrhagic Stroke 78 yo male presents to ER with vomiting and severe headache Pt currently taking Rivaroxaban 20mg daily for AF What reversal strategy do you recommend? Hemodialysis to quickly pull of the Rivaroxaban Kcentra Vitamin K LMWH No treatment Kcentra

Hemorrhagic Stroke 78 yo male presents to ER with vomiting and severe headache Pt currently taking Rivaroxaban 20mg daily for AF (no mechanical valve) When can we safely restart his anticoagulation? Immediately 7 days 1 year 4 weeks

Therapeutics 1 Tutoring Questions? Sarah Darby shodge7@uthsc.edu August 26, 2016