Download Therapeutics I - 8-26

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Therapeutics 1 Tutoring
Sarah Darby
[email protected]
August 26, 2016
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Lectures Covered
 Atherosclerosis
 Ischemic
 CV
and Dyslipidemia
Heart Disease
pharmacology review
 Ischemic
stroke
 Hemorrhagic
stroke
+ Atherosclerosis and Dyslipidemia
NLA
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NLA Risk Factors
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
Age

Males 45 and older
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Females 55 and older
Family Hx

Male first degree relative <55 years

Female first degree relative <65 years
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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?
A. Low
B. Moderate
C. High
D. 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?
A. Non-HDL <100mg/dl
B. LDL < 130mg/dl
C. Non-HDL < 130mg/dl
D. ApoB < 90mg/dl
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Atherosclerosis and Dyslipidemia
 When
do triglycerides become the
primary target of lipid lowering therapy?
A.
B.
C.
D.
When TG > 200mg/dl
When TG > 500mg/dl
When HDL-C < 35mg/dl
When a patient has a hx of pancreatitis
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Atherosclerosis and Dyslipidemia
 True
or False
 Raising
HDL-C using drug therapy is
supported by clinical trials and published
in the literature.
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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
 ACC
agents?
= ezetimibe, BAS, or PCSK9 inhibitors
 NLA = ezetimibe, BAS, or niacin
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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
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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
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Atherosclerosis and Dyslipidemia
Add-on therapy

63 yo female in clinic for check-up

Started Atorvastatin 40mg at last visit.
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Lipid levels from 4 mos ago:
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
Lipid levels today:
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
TC=240, LDL=145, HDL=30
TC=130, LDL=70, HDL=32
What do you recommend for treatment?
A.
B.
C.
D.
Change to Simvastatin 20mg
Add Ezetimibe
Decrease to Atorvastatin 20mg
Maintain current therapy
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Atherosclerosis and Dyslipidemia
Add-on therapy
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68 yo male in clinic for check-up
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Started Atorvastatin 80mg at last visit.
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Lipid levels from 4 mos ago:
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
Lipid levels today:
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
TC=410, LDL=320, HDL=40
TC=250, LDL=150, HDL=40
What do you recommend for treatment?
A.
B.
C.
D.
Change to Rosuvastatin 20mg
Add Ezetimibe
Add Colesevelam
Maintain current therapy
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Atherosclerosis and Dyslipidemia
Add-on therapy
 Which
treatment is recommended for
homozygous familial hypercholesterolemia?
A.
Evolocumab
B.
Ezetimibe
C.
Alirocumab
D.
Colesevelam
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Atherosclerosis and Dyslipidemia
Add-on therapy
 What
should be your response if a Pt complains
of cognitive changes after initiating a statin?
A.
Continue therapy; it will resolve on its own
B.
“Man, you’re crazy! It’s not the statin!”
C.
Rule out other causes
D.
Assess risk vs. benefit of therapy
E.
Consider switching to a more hydrophilic statin
F.
A and B
G.
C, D, and E
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Atherosclerosis and Dyslipidemia
Add-on therapy
 What
side effect are we most concerned
about with statin use?
 Abdominal pain
 Headache
 Increased blood pressure
 Myalgia
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Atherosclerosis and Dyslipidemia
Add-on therapy
 Who
is more likely to experience statininduced myopathy?
 Males or females?
 Aged 65 or 85?
 Hyper- or Hypothyroidism?
 Simvastatin or Rosuvastatin?
 Apple juice or grapefruit juice?
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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?
A. Increase to Atorvastatin 80mg
B. Switch to Simvastatin 40mg
C. Hold the Atorvastatin, and restart at lower
dose in 2 weeks
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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
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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?

A.
B.
C.
D.
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
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Ischemic Heart Disease
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Ranolazine
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MARISA
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Improved angina when used in combination with other therapies
TERISA
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Improved time to angina onset and total exercise duration as
compared to placebo
CARISA
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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
Similar improvements in angina in patients with diabetes
MERLIN-TIMI 36
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No difference in terms of CV death or MI compared to placebo
Decreased rate of ischemia compared to placebo
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Ischemic Heart Disease
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Ranolazine
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Dose: 500mg BID up to 1000mg BID
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Concern for prolonged QT interval
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No torsades de pointes occurred during clinical trials
Contraindications
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Pre-existing QT prolongation
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Simultaneous QT-prolonging drug use
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Strong CYP 3A4 inhibitors or inducers
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Significant hepatic impairment
Drug Interactions!
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Weak inhibitor of 3A4
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Moderate inhibitor of 2D6 and Pgp
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Substrate of 3A4 (also 2D6 and Pgp)
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Ischemic Heart Disease
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Which of the following will increase plasma
concentrations of Ranolazine?
A.
Rifampin
B.
Ketoconazole
C.
Phenytoin
D.
Metoprolol
Which of the following will decrease plasma
concentrations of Ranolazine?
A.
Ritonavir
B.
Diltiazem
C.
Lisinopril
D.
Carbamazepine
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Ischemic Heart Disease
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Which of the following should not be used in combination
with Ranolazine?
A.
Amiodarone
B.
Simvastatin
C.
Verapamil
D.
Gentamicin
Which of the following does NOT have a contraindication
with Ranolazine?
A.
SSRIs
B.
Methadone
C.
Carvedilol
D.
Haloperidol
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Ischemic Stroke
 BP:
only treat when > 220/120 mmHg or
aortic dissection, acute myocardial
dysfunction, pulmonary edema,
hypertensive encephalopathy
 Why?
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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
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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
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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
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Ischemic Stroke
 70
yo female, 55.5kg, presents to ER 1h after sx
onset
 The healthcare team deems Alteplase
appropriate. What is her dose?
A.
50mg infusion over 60 min.
B.
5mg bolus over 1 min., followed by 45mg over 60 min.
C.
50mg bolus over 1 min., followed by 40mg over 60 min.
D.
5mg bolus over 1 min., followed by 85mg over 60 min.
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Ischemic Stroke
 65
yo male, 105kg, presents to ER 1h after sx
onset
 The healthcare team deems Alteplase
appropriate. What is his dose?
A.
9.5mg bolus over 1 min., followed by 85mg over 60 min.
B.
95mg infusion over 60 min.
C.
9mg bolus over 1 min., followed by 81mg over 60 min.
D.
95mg bolus over 1 min., followed by 5mg over 60 min.
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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)
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Ischemic Stroke
 Anticoagulation
 Unclear
cause? Monitor heart rhythm
 Cardioembolic origin needs anticoagulation
 Initiate within 14 days
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Hemorrhagic Stroke
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

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
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Hemorrhagic Stroke
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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
Rivaroxaban
• Kcentra
• Kcentra
• FEIBA
• FEIBA
• Hemodialysis
Apixaban
• Kcentra
• FEIBA
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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
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Hemorrhagic Stroke
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

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
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Hemorrhagic Stroke
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
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
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?
A. Labetalol continuous infusion
B.
Clevidipine continuous infusion
C. Amlodipine bolus
D. No therapy; she’s fine with that BP!
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Hemorrhagic Stroke
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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?
A. Hemodialysis to quickly pull of the Rivaroxaban
B.
Kcentra
C. Vitamin K
D. LMWH
E.
No treatment
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Hemorrhagic Stroke
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

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
[email protected]
August 26, 2016