Anti-anginal & Anti-thrombotic Flashcards
Angina pectoris
an imbalance btwn oxygen supply and demand, resulting in inadequate oxygen supply to myocardium
chronic stable angina (CSA)
symptom reversibility (rest/NTG), repetitive attacks, occurs over mo. to yrs
Nitrates, role in therapy
immediate sx relief, prevention of stress induced angina
Nitrates MOA
relaxation of vascular sm. mm. vasodilation d/t the effect these drugs have on cGMP; venous relaxation reduces preload, which in turn reduces oxygen consumption
**venous dilation > arterial dilation
Nitrate s/e
hypotension, HA, flushing, light headedness
Nitroglycerin (NTG) class
nitrate
When is Nitroglycerin (NTG) indicated?
Angina (prophylactic and acute)
Can use before exercise or stress to prevent ischemic episodes
**more fast-acting; quick relief agent of nitrates
Nitroglycerin (NTG) should not be used with
PDE-5 inhibitors (e.g. Sildenafil)
Nitroglycerin (NTG) pharmacokinetics
1) onset is 1-3 min SL (primary use), 30 min patch, 60 min ER
2) duration is 25 min SL, 10-12 hr patch, 4-8 hr ER
3) extensive first pass metabolism and some non-hepaticmetabolism in RBC and vascular walls
What is preferred dosage form of Nitroglycerin (NTG)?
SL
- quick onset of action
- NTG has extensive first-pass metabolism in the liver
Isosorbide Mononitrate class
Nitrate
Isosorbide Mononitrate indications
anginal pectoris
**more of a long-acting, preventative agent
Isosorbide Mononitrate pharmacokinetics
1) onset is 30-45 min via IR and ER
2) duration is > 6 hr IR, 12- >24 hr ER
3) extensive first pass metabolism and some non-hepaticmetabolism in RBC and vascular walls
What natural products do nitrates interact with?
1) coleus (major)
2) hawthorn (major)
3) L-citrulline (major)
4) N-acetyl cysteine (major)
**any with hypotensive properties
What is the interaction between nitrates and coleus?
might cause additive coronary vasodilatory effects
Major
What is the interaction between nitrates and hawthorn?
might cause additive coronary vasodilatory effects
Major
What is the interaction between nitrates and L-citrulline (converted to L-arginine)
might cause additive coronary vasodilatory effects
Major
What is the interaction between nitrates and NAC?
severe hypotension, intolerable HA, anticoagulation
Major
Why should combination of nitrates with sildenafil be avoided?
too much of a build-up of cGMP –> dangerous hypotension
Are nitrates more specific to arterial or venous blood vessels?
venous
Beta-blockers role in therapy
1) prophylactic (first-line prophylactic tx)
2) blunts cardiac stimulation
3) *prevents reflex tachycardia
4) decreases HR, contractility, and BP
What is tachyphylaxis?
when people build up a tolerance to medicine with repetitive dosing
happens with isosorbide mononitrate; pt. needs to take a break to prevent tolerance
Beta-blockers MOA
blocks beta adrenergic receptors (can be selective or non-selective)
Beta-blockers s/e
bradycardia, heart block, HA, fatigue, exercise intolerance, hypotension, erectile dysfn
s/e vary with selectivity, but these tend to have a lot of s/e (“achilles heel” of this med)
Why should you avoid the use of beta-blockers with intrinsic sympathomimetic activity (ISA)?
they simultaneously block beta receptors and stimulates the sympathomimetic pathway; with heart pathology we generally want to avoid sympathomimetic stimulation
Where are Beta-3 receptors found?
adipose tissue and heart
Beta-blocker considerations
1) taper gradually or pt. may get reflex tachycardia
2) selectivity changes effect
3) CNS adverse s/e are common - dizziness, fatigue, depression, etc.
4) caution in elderly (> 65 y/o)
5) sx of hypoglycemia are often blunted
Metoprolol class
Beta blocker
Cardioselective (B1) competitive antagonist
Metoprolol indications
MI, CHF, angina, HTN
Metoprolol cautions
avoid in persons with heart block or severe bradycardia (HR < 60)
Metoprolol ________ is extended release (ER) or tablet and ________ is immediate release (IR)
1) Succinate
2) Tartrate
Metoprolol pharmacokinetics
1) onset: w/in 1 hr
2) duration: 3-6 IR, 24 hr ER
3) metabolism: CYP2C19 (minor) and CYP2D6 (major)
Metoprolol natural products interactions
many moderate (“be cautious”) warnings
Atenolol class
Beta-blocker
Cardioselective (B1) competitive antagonist
Atenolol indications
MI, HTN, angina
Atenolol cautions
avoid in persons with heart block or severe bradycardia (HR < 60)
**concerns about safety b/c in some populations, more ppl are dying on this drug than other beta blockers; although better mortality rates in silent ischemia population
Atenolol pharmacokinetics
1) onset < 1 hr
2) duration 12-24 hr
3) limited hepatic metabolism, 50% feces, 40% urine (unchanged drug)
What is the significance of Atenolol limited hepatic metabolism?
potentially less subject to interactions, as most drug interactions occur via CYP450 pathways in liver
Atenolol natural products interactions
1) many moderate (“be cautious”) warnings
2) major interaction with apple (reduced Atenolol concentrations)
Propranolol class
Beta blocker
Nonselective (B1 and B2)
Propranolol indications
MI (tx and prevention), HTN, angina, migraine prophylaxis, SV arrhythmias
Propranolol cautions
avoid in persons with heart block or severe bradycardia (HR < 60)
Propranolol pharmacokinetics
1) onset 1-2 hr
2) duration: 6-12 hr IR, 24-72 hr ER
3) metabolism: CYP1A2 (major), CYP2C19 (minor), CYP2D6 (major), CYP3A4 (minor), p-glycoprotein
Propranolol natural products interactions
1) many moderate (“be cautious”) warnings
2) major interaction with Rauwolfia (Indian snakeroot) - enhanced beta-blockade
3) major interaction with Hypericum - increased metabolism
Carvedilol class
Beta-blocker
nonselective with alpha-1 adrenergic blockade activity
Carvedilol indications
MI, HTN, CHF, angina (off-label)
Carvedilol cautions
avoid in persons with heart blockage or severe bradycardia (HR < 60)
Carvedilol pharmacokinetics
1) onset: < 1 hr
2) duration: 24 hr
3) metabolism: CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (major), CYP2E1 (minor), CYPE3A4 (minor), P-glycoproteins
Carvedilol natural products interactions
1) many moderate (“be cautious”) warnings
2) major interaction w/ grapefruit juice (increases bioavailability)
Which beta blockers are more likely to interact with beta-agonists used in asthma?
non-selective
Which beta-blocker covers both beta and alpha receptors?
carvedilol
although it turned out to be no more effective than other beta blockers
CCBs role in therapy
- prophylactic tx
- decreases BP
- dilates coronary b.v.
- dilates peripheral b.v.
(second-line angina tx)
CCBs MOA
blocks calcium influx leading to relaxation of cardiac and smooth muscles
CCBs s/e
**Tachycardia, **edema (esp. lower extremity), HA, fatigue, exercise intolerance, hypotension
vary with selectivity
rebound sx w/ abrupt d/c is less of a concern
Avoid IR nifidipine for _______ d/t poor outcomes
stable angina
Avoid non-dihydropyridines in pt with __________ and in pt. also taking __________
1) ejection fraction < 35% (heart failure)
2) beta-blockers
Amlodipine class
DHP CCB
Amlodipine indications
HTN, chronic stable angina, variant angina, heart failure, d/o of CV system (prophylaxis)
Amlodipine pharmacokinetics
1) onset 24 hr (slowest)
2) duration > 24 hr (longest T 1/2)
3) CYP3A4 metabolism
Amlodipine natural products interactions
1) many moderate interactions
2) Cholea - increased vasodilatory effects
3) Grapefruit (CYP3A4 inhibitor)
4) Hypericum (CYP3A4 inducer)
Verapamil class
Non-DHP
phenylalklamine CCB
Verapamil indications
HTN, CSA, variant angina, SVT, Afib/Aflutt
Verapamil pharmacokinetics
1) onset 1-2 hr
2) duration 6-8 hr IR, 24 hr ER
3) metabolism: CYP1A2 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein
Verapamil natural products interactions
1) many moderate interactions
2) Cholea - increased vasodilatory effects
3) Grapefruit (CYP3A4 inhibitor)
4) Hypericum (CYP3A4 inducer)
5) Alcohol (incr. hepatotoxicity)
Diltiazem class
Non-DHP
Benzothiazepine CCB
Diltiazem indications
atrial arrhythmia, HTN, SVT, angina
Diltiazem cautions
avoid w/ hypotension, LVEF < 30%, AV block, sick-sinus syndrome, certain arrhythmias (WPW, accessory tract arrhyth.)
Diltiazem pharmacokinetics
1) onset: 15-60 min
2) duration: 6 hr IR, 24 hr ER
3) metabolism: CYP2C0 (minor), CYP2D6 (minor), CYP3A4 (major), p-glycoprotein
Diltiazem natural product interactions
1) many moderate interactions
2) Cholea - increased vasodilatory effects
3) Grapefruit (CYP3A4 inhibitor)
4) Hypericum (CYP3A4 inducer)
How do the mechanisms differ between DHP and non-DHP CCBs?
DHP primarily work in the periphery and non-DHP primarily work in the heart
*if pt. is not already on a beta-blocker, you would lean more twd non-DHP meds
Why are CCBs more likely to have drug interactions w/ other therapeutic moieties?
first-pass metabolism in liver with so many diff CYP’s
Aspirin class
anti-platelet
Aspirin MOA
non-selective, irreversible COX inhibitor
**this action is what is responsible for aspirin’s cardioprotective effects
How long is the lifespan of a platelet?
7-10 days
Aspirin caution
1) avoid in pt. < 18 y/o d/t association w/ Reye’s Syndrome
2) increased bleeding (GI)
3) Disruption of renal perfusion
Aspirin pharmacokinetics
1) onset w/in 1 hr if chewed
2) hydrolyzed to salicylate (active form) by esterases in GI, RBC, synovial fluid, and blood; quickly broken down (< 3 hr) via hepatic conjugation…so it only has 3 hr to bing to as many platelets as possible, but once bound it binds to life of platelet
Aspirin natural products interactions
1) Cocoa
2) Danshen
3) Dong Quai
4) Evening primrose
5) policosanol
6) willow bark
**incr. bleeding
Do NSAIDs other than aspirin have effects on platelets?
YES
it’s just that they don’t have cardioprotective capabilities because the bind reversibly to COX-1 (they do still cz incr. bleeding)
Clopidogrel (Plavix) class
antiplatelet
Clopidogrel (Plavix) MOA
irreversibly blocks P2Y_12 component of ADP receptors on platelets surface –> reduces platelet aggregation
**just as effective as aspirin but doesn’t affect PG production, so see less GI bleeding
Clopidogrel (Plavix) indications
post NSTEMI, ACS, CVA, PCI, and arterial occlusive dz to prevent clots
Clopidogrel (Plavix) pharmacokinetics
1) onset: detected 2nd day of tx
2) lasts lifespan of platelet
3) primarily metabolism in liver via CYP450-mediated rxn
Clopidogrel (Plavix) natural interactions
1) Cocoa
2) Danshen
3) Dong Quai
4) Evening primrose
5) policosanol
6) willow bark
* *incr. bleeding
7) Grapfruit (CYP34A inhibitor)
8) Hypericum (CYP34A inducer)
Ticagrelor (Brilinta) class
antiplatelet
Ticagrelor (Brilinta) MOA
reversibly blocks P2Y_12 component of ADP receptors on platelets surface –> reduces platelet aggregation
Ticagrelor (Brilinta) indications
prophylaxis post ACS, MI, or PCI
Ticagrelor (Brilinta) cautions
increased risk of bleeding, increased uric acid levels
Ticagrelor (Brilinta) pharmacokinetics
1) onset: ~41% platelet inhibition w/in 30 min
2) duration depends on concentration of drug (not lifespan of platelet) - up to 24 hr
3) Metabolism: CYP34A (major)
Ticagrelor (Brilinta) interactions
1) Cocoa
2) Danshen
3) Dong Quai
4) Evening primrose
5) policosanol
6) willow bark
* *incr. bleeding
7) Grapfruit (CYP34A inhibitor)
8) Hypericum (CYP34A inducer)
Prasugrel (Effient) class
antiplatelet
Prasugrel (Effient) MOA
irreversibly blocks the P2Y_12 component of ADP receptors on platelets surface –> reduces platelet aggregation
Prasugrel (Effient) cautions
- avoid in persons who have had a prior TIA or stroke (higher risk of cerebral hemorrhage)
- incr. risk for bleeding w/ body weight < 60 kg
Prasugrel (Effient) pharmacokinetics
1) onset < 30 min
2) duration lasts lifetime of platelets
3) CYP450-mediated pathway (CYP3A4 and CYP2B6) converts it into its active form
Do drug interactions affecting CYP enzymes tend to increase or decrease the effectiveness of P2Y_12 inhibitors?
depends on the drug and how it’s metabolized
s/t CYP enzymes metabolize drug into active form and s/t they metabolize drug into inactive form
Warfarin (Coumadin) class
anticoagulants
Warfarin (Coumadin) MOA
inhibits vitamin K oxide reductase (enzyme responsible for regenerating vit K so it can activate clotting factors)
Warfarin (Coumadin) cautions
1) genetic polymorphisms affect safety/efficacy
2) antidote is Vit K, but process is slow and cumbersome
3) **must do lifetime INR monitoring
4) many drug interactions
Vitamin K dependent clotting factors
II, VII, IX, X
Warfarin (Coumadin) pharmacokinetics
1) onset: effects INR w/in 2-5 days
2) T 1/2 = 20-60 hr
3) Metabolism: CYP1A1 (minor) CYP2C19 (minor), CYP2C9 (major), CYP34A (minor)
Warfarin (Coumadin) natural products interactions
alfalfa, American ginseng, alcohol, cocoa, danshen, dong quai, EDTA, evening primrose oil, glucosamine HCl and sulfate, grapefruit, licorice, N-acetyl glucosamine, policosanol, Hypericum, Vit K, willow bark, wintergreen
What is the INR?
International Normalized Ratio
INR is the std unit used to report prothrombin time (PT)
We tend to want a target INR of 2-3 (risk of bleeding incr. significantly at INR above 5)
Rivaroxaban (Xarelto) class
novel oral anticoagulant
Xa-inhibitor
Rivaroxaban (Xarelto) MOA
direct, reversible inhibition of factor Xa –> prevents activation of thrombin (factor II) and downstream prevents conversion of fibrinogen to fibrin
Rivaroxaban (Xarelto) cautions
1) Taking w/out food can significantly reduce absorption
2) Must monitor renal fn (but do not need INR)
3) Onset is quick but T1/2 is short so they dose a lot of drug at once time - increases risks
Rivaroxaban (Xarelto) pharmacokinetics
1) onset 2-4 hr
2) T 1/2 5-9 hr
3) Metabolism: hepatic via CYP3A4/5 and CYP2J2
Rivaroxaban (Xarelto) interactions with natural products
cocoa, danshen, dong quia, EPO, grapefruit, policosanol, Hypericum, Willow bark
Apixaban (Eliquis) class
novel oral anticoagulant
Xa-inhibitor
Apixaban (Eliquis) MOA
direct, reversible inhibition of factor Xa –> prevents activation of thrombin (factor II) and downstream prevents conversion of fibrinogen to fibrin
Apixaban (Eliquis) cautions
1) Must monitor renal fn (but do not need INR)
more favorable safety/efficacy than warfarin or rivaroxaban
Apixaban (Eliquis) pharmacokinetics
1) onset 3-4 hr
2) T1/2 = 12 hr
3) Metabolism: hepatic mainly via CYP3A4/5
What is the only novel oral anticoagulant that is not renally adjusted?
Apixaban (Eliquis)
dosage is determined by SCr, weight, and age
Apixaban (Eliquis) natural product interactions
Coca, danshen, dong quai, EPO, grapefruit, policosanol, Hypericum, willow bark
Dabigatron (Pradaxa) class
Novel oral anticoagulants
IIa (thrombin) inhibitor
Dabigatron (Pradaxa) MOA
direct thrombi (activated factor II) inhibitor –> prevents conversion of fibrinogen to fibrin
Dabigatron (Pradaxa) cautions
similar safety and efficacy to warfarin (concern for GI bleed, MI)
Dabigatron (Pradaxa) pharmacokinetics
1) onset 1 hr (delayed 2 hr by food)
2) Metabolism is mostly renal; prodrug hydrolyzed to active form hepatically
Dabigatron (Pradaxa) reversal agent
Praxbind (idarucizumab) - monoclonal antibody that rapidly binds pradaxa
Dabigatron (Pradaxa) natural products interactions
cocoa, danshen, dong quai, EPO, policosanol, Hypericum, willow bark
Does warfarin target more or fewer targets compared to NOACs to elicit its anticoagulant effects?
more
Which of the NOACs is dosed once per day?
Rivaroxaban (Xarelto)
What is Enoxaparin (Lovenox)
low molecular weight “fractioned” heparin (LMWH)
enhances inhibition rate of clotting proteases (more factor Xa inhibition compared to factor IIa)
What is reversal agent for warfarin?
Vitamin K (PO and IV) - slow and cumbersome
leafy greens, cabbage, broccoli
Compared to unfractioned heparins, LMWHs have less activity at which factor?
IIa
