Lecture 3 - Antianginals Flashcards
List the drugs in this section
- nitroglycerin, isosorbide dinitrate
- sildenafil
- nifedipine, amlodipine, felodipine
- verapamil, diltazem
- propranolol
- metoprolol
What is nitroglycerin and isosorbide dinitrate metabolized to?
nitric oxide (NO)
What is sildenafil?
type 5 phosphodiesterase inhibitor
What are nifedipine, amlodipine, felodipine?
all calcium channel blockers (CCBs); dihydropyridines
What are verapamil and diltazem?
all CCBs (calcium channel blockers); non-dihydropyridines
What is propranolol?
B-blocker
What is metoprolol?
B1-blocker
List the 3 types of angina
- Stable (angina of effort)
- Unstable
- Vasospastic (Variant; Prinzmetal’s)
What is angina defined as?
O2 demand > O2 supply
Describe a stable angina (angina of effort)
- most common (atherosclerosis with cap)
- a fixed narrowing of the coronary artery
- onset associated with a given level of activity
- PREDICTABLE
Describe an unstable angina
- onset at rest or increased physical activity
- NOT PREDICTABLE
- related to coronary atherosclerotic plaque rupture (emboli)
- dislodged clots lodge in coronary blood vessels
Describe vasospastic angina
occurs at anytime, spasms of the coronary artery
Angina pectoris treatment does one of two things - what are they?
increases oxygen supply
and/or
decreases oxygen demand
What can increase oxygen supply to treat angina pectoris?
- pO2, Hgb concentration
- coronary blood flow*
- micro-circulation*
- oxygen extraction
*sites for pharmacological intervention
What can decrease oxygen demand to treat angina pectoris?
- heart rate*
- ventricular wall stress*
- intraventricular pressure
- ventricular wall radius
- wall thickness
- contractile state*
*sites for pharmacological intervention
List the 3 types of treatment for angina pectoris
1) modify/treat risk factors
2) pharmacological treatment
3) surgical intervention
Describing modify/treat risk factors for angina pectoris
- smoking, dyslipidemias, diabetes, hypertension, sedentary, obesity, stress
- family history is important but unable to modify
Describe pharmacological treatment for angina pectoris
- nitrates/nitrites
- B-blockers
- calcium channel blockers
- Acetylsalicylic acid (ASA)
Describe surgical intervention
- angioplasty
- revascularization
List the 2 nitrates
- nitroglycerin
- isosorbide dinitrate
Describe nitroglycerin
- acute and prophylactic use
- acute (pain)
- sublingual (popular)
- lingual spray (less popular)
- rapid onset 2-5 mins
- duration 15-30 mins
- prophylactically (prevent pain with exercise)
- patch - onset 30 mins; duration 8-14 hours
- oral - long acting; duration 6-8hrs
Describe isosorbide dinitrate
- prophylactically (prevent pain with exercise)
- sublingual - onset 2-5 mins; duration 1.5 to 2 hr
- oral - onset 15 - 30 mins; duration 3 - 6 hrs
Mechanism of nitrates?
- metabolized to nitric oxide (mainly in veins)
- nitric oxide increases cGMP which mediates dilation
- avoid giving with drugs that block cGMP breakdown (ex. sildenafil - a type 5 phosphodiesterase inhibitor)
- relaxes veins at lower doses
- relaxes larger arteries at higher doses
- decrease preload (venous return)
- decrease heart size (Law of LaPlace - decrease wall stress)
- may redistribute blood to ischemic areas
- decreases pulmonary artery resistance
- useful in pulmonary hypertension seen in COPD
Describe how the veins are relaxed to decrease preload
- vasodilation
- decreases preload
- decreases venous return
- decreases filling pressure
- decreases stretch
- decreases myocardial oxygen demand
- and less decrease in endocardial flow (inner wall) during systole
When does the endocardium get blood flow?
only during diastole
When does the pericardium get blood flow?
during diastole and systole
What do nitrates prevent?
coronary steal is prevented
Describe how nitrates prevent coronary steal?
- smaller arterioles and pre capillary sphincters less affected by nitrates (good!)
- prevents blood flow to only “healthy regions”
- arterial vessels effected tend to be larger
- increases blood flow to healthy and ischemic regions
Some vasodilators may worsen angina (ex. ________)
hydralazine
What is coronary steal?
- part after the occlusion is maximally dilated due to metabolites (cannot be dilated further)
- reflex dialtion on healthy tissue actually steals blood from ischemic area
- do not want to dilate this area further - no need and would steal more flow
Nitrates: Tolerance develops (need \_\_\_\_ hr treatment intervals)
12
Adverse effects of nitrates?
- orthostasis
- throbbing headache
- reflex activation of SNS
- salt and water retention
- high doses may decrease BP and increase sympathetic nerve activity - resultant increased oxygen demand and decreased perfusion pressure may be problematic
What is the formula for oxygen demand?
oxygen demand = HR * SBP
What does double product allow?
allows you to exercise longer before pain and hypoxia occur
What do nitrates do?
decrease oxygen demand, but do not increase delivery
With treatment for angina - may have a ______ in blood pressure
decrease
- reflex response to a decrease in BP may be a problem
- RAAS - slide 15
Nitrates:
If _____, a slight tingling sensation should be felt under the tongue
potent
Nitrates:
crumbly tablets = ____
bad
Nitrates:
_____ and _____ sensitive
heat
light
Nitrates:
Better absorption if sublingual mucosa ____
MOIST
List some general points about the use of nitrates
- contact physician if pain persists or worsens 5 mins after one tablet (some say wait til after 3 tablets - may be wasting valuable time?)
- use for acute episodes
- under used for when increased activity is anticipated (mowing lawn, walking, etc.)
Nitrates:
30-50% of ____ may be poor responders
Asians
Nitrates:
Why are a proportion of Asians poor responders?
- due to decreased mitochondrial aldehyde dehydrogenase (ALDH2)
- which is needed to convert nitrate to nitric oxide
- therefore they will make less nitric oxide and have a lower therapeutic effect
What is ALDH2 also needed for?
- to breakdown aldehyde associated with alcohol metabolism
- a flush response to alcohol suggests lack of ALDH2
Propranolol and metoprolol are _______
B-blockers
Propranolol and metoprolol are ____ line treatment in chronic stable angina, but not for acute angina attacks
first
What type of B-blockers do you want to avoid?
want to avoid beta-blockers with ISA (intrinsic sympathetic activity)
Mechanism of action of B-blockers in treating angina
- decreased oxygen demand (decreased heart rate, blood pressure and contractility)
- reverse steal? Increase flow to ischemic region
Is coronary steal prevented by beta blockers?
Yes
Benefit of beta-blockers?
- improved survival (important)
- following an MI, only abtianginal proven to decrease incidence of reinfarction and improve patient survival
- if a patient has no previous MI, B-blockers are as good as CCBs and nitrates as antianginal
- prophylactic use of antianginals to prevent the first MI appears to be ineffective
- benefit in systolic heart failure
Adverse effects of beta-blockers?
slowing of the heart increases EDV and increases oxygen demand
*may use with nitrates to decrease preload and EDV
What type of angina is B-blockers not intended for?
vasospastic angina
**may worsen if B2 is blocked?
List the 2 classes of calcium channel blockers (CCB’s)
Dihydropyridines
Non-dihydropyridines
List 2 points about the classes of CCB’s
- both block calcium channels (arteries, heart)
- both effective in treating stable angina pectoris
List 2 Dihydropyridines (CCB’s)
amlodipine
felodipine
How do Dihydropyridines (CCB’s) work?
- arterial vessels more sensitive than veins
- decrease after load (peripheral resistance)
- DECREASE AFTERLOAD NOT PRELOAD
- may also decrease coronary vascular tone
- little cardiac suppression
- may cause reflex increase (SNS) in cardiac B-receptor activity
- decreases coronary artery spasm - good for Prinzmetal angina (vasospastic angina)
- do not change “double product” value where angina is felt
- WORK BY DECREASING OXYGEN DEMAND
List 2 Non-Dihydropyridines (CCB’s)
verapamil
diltiazem
What kind of effects does verapamil produce?
mainly cardiac effects
What kind of effects does diltiazem produce?
cardiac and vascular effects
How does verapamil work?
- decreases oxygen demand
- negative inotrope, chronotrope, lowers blood pressure
- *poor vascular dilator
- *that’s why it has mainly only cardiac effects
How does diltiazem work?
- decreases oxygen demand
- negative inotrope, chronotrope, lowers blood pressure
- effective coronary arterial dilator (less peripheral)
Benefits of CCB’s?
- decrease symptoms, increase exercise tolerance/time
- if beta-blocker alone is ineffective or CI
- substitue with a CCB or combine with a CCB
- effective for vasospastic angina - dihydropyridines (preferred)
Adverse effects of CCB’s?
- serious cardiac suppression
- verapamil and B-blocker - possible heart block
- constipation, ankle edema
- sympathetic reflexes (nifedipine vs. verapamil)
- dizziness, hypotension, headache, flushing
Where does amlodipine work?
vasodilates really well
Where does verapamil work?
- decreases AV and SA node activity
- decreases contractility
- vasodilates
Where does nicardipine work?
selective for coronary arteries?
Where does amlodipine work?
- peripheral and coronary vasodilation
- less tachycardia
List 2 combination treatments that make sense
B blocker + amlodipine
B blocker + nitrate
*slide 25
How do we want to treat angina of effort?
- ASA or clopidogrel if ASA CI (to block platelet aggregation)
- nitrates or B-blockers as initial treatment
- CCB if there’s a problem with the first 2
- increase time of onset of angina and ST depression during exercise treadmill test
- get angina at same level of oxygen demand - decreases oxygen demand for a given level of exercise
Long-term:
- start with B-adrenergic receptor blocker
- improve survival and prevention of re-infarction
How do you treat angina of effort for hypertensives?
B blockers or long acting CCB (dihydropyridine)
How do you treat angina of effort for normotensive?
long acting nitrate
What drugs are available to be combined to treat angina of effort?
- nitrate
- calcium channel blocker
- B blocker
Angina of effort:
is combination of products better than single therapy?
yes
-added drug blocks compensatory effect of the other
Angina of effort:
Which drug combinations work?
B-blocker with amlodipine or nitrate
verapamil with amlodipine or nitrate
Angina of effort:
combination effects are ______
additive
*amlodipine (decreases after load) + nitrate (decreases preload)
How do you treat unstable angina?
- antiplatelet therapy
- ASA (ASAP) or clopidogrel
- IV heparin (anticoagulant) added to ASA
- oxygen
- nitroglycerin (sublingual), give IV if pain persists after three tablets
- morphine, IV for pain and anxiety
- oral B-blockers (IV if hemodynamic stability)
- statins
-B blockers decrease ischemic episodes but not mortality
How do you treat vasospastic angina?
-calcium channel blockers (vascular) and/or nitrate
Avoid:
- b-blockers may worsen condition (B1 selective ok?)
- ASA - decreases prostacyclin which is a vasodilator
- sumatriptan - used in migraine, may constrict coronary arteries
*revascularization and angioplasty not indicated
Preferred and least preferred drugs in:
Asthma
Preferred:
- CCB’s
- nitrate
Least Preferred:
-B-blocker
Preferred and least preferred drugs in:
Diabetes mellitus
Preferred:
- CCB’s
- nitrate
Least Preferred:
-B-blocker
Preferred and least preferred drugs in:
Heart failure
Preferred:
- nitrate
- B -blocker
Least Preferred:
CCB’s non-dihydropyridines
Preferred and least preferred drugs in:
Hypertension
Preferred:
- B-blocker
- CCB’s
Least Preferred:
-nitrate
Preferred and least preferred drugs in:
Peptic ulcer
Preferred:
- B-blocker
- nitrate
Least Preferred:
-CCB’s
