Download Angina

Angina and Antianginal Drugs
Drug classes and list:
Amy J Davidoff '09
VASODILATORS (VENODILATORS)
Nitrates:
isosorbide dinitrate
nitroglycerin
Ca2+ channel blockers:
dihydropyridines (DHPs): amlodipine, nifedipine
diltiazem
verapamil
-ADRENERGIC RECEPTOR BLOCKERS:
(without intrinsic sympathomimetic activity (ISA))
non-selective (1, 2): propranolol
selective (1): metoprolol, atenolol
Carvedilol (see HF drug list) - looks promising
OTHERS:
Anti-inflammatory drugs (ACE-I)
Antiplatelet drugs (aspirin, clopidogrel)
Lipid lowering drugs
Late sodium channel blocker (e.g., ranolazine)
If (sodium leak channel) blocker (ivabradine)
Classification and
pathophysiology
of ischemic heart
disease
Brenner Fig 11-1
Angina
myocardial O2 supply <
( coronary blood flow)
O2 demand
( work)
O2 extraction is near maximal
even at rest
O2 supply regulated by vascular
resistance:
Local factors
(e.g., adenosine, bradykinin,
prostaglandins, NO)
Sherwood Fig 9-32
Coronary Blood Flow
Guyton & Hall Fig 21-3
Dependent on:
•Aortic diastolic pressure
•Collateral blood flow
•Arterial diameter (radius)
•Epicardial-endocardial flow
(subendo. arteries constrict more
with ventricular contraction, 
particularly susceptible to ischemia)
Figure 21-4 Phasic flow of blood through the coronary capillaries of left ventricle
Normal
Restricted circulation
Martini Fig 20-10
The Hurst's The Heart, 8th ed
Fill in desired therapeutic effects (and drugs classes)
which would benefit an angina patient
(with stable coronary artery disease (CAD))
Drug classes:
Nitrates (NO)
CCB
BB
Brenner Fig. 11-2
When oxygen supply does not meet demand
ischemia  LV dysfunction, pain, arrhythmias
Strategies to treat angina
Improve coronary blood flow and/or
Decrease myocardial oxygen demand
VASODILATORS
Improve coronary perfusion - directly
Decrease cardiac work – either on arterial side (red
Afterload, or preload by venodilating dec venous return
(reduce preload and/or afterload)
 BLOCKERS
Decrease cardiac work (reduce HR and contractility)
 myocardial O2 supply
coronaries
Dilate arterioles
systemic
 TPR
Ca2+ channel
blockers
(high doses)
 cardiac work
Nitrates
Dilate veins
(low doses)
systemic
 preload
Reflexes affecting heart
 TPR
 BP
sympathetic
activity
 blockers
contractility
HR
work
O2 demand
Ca2+ channel
blockers
Do not combine verapamil and  blockers
(DHPs have little/no effects on heart muscle)
NITRATES
HEMODYNAMIC EFFECTS
Venous vasodilatation
Preload
Pulmonary congestion
Ventricular size
Ventricular wall stress
MVO2
Coronary vasodilatation
Myocardial perfusion
Arterial vasodilatation
Afterload
Shunting from
ischemic area
because already
maximally
dialyzed
AHA website 2003
Nitroglycerin
• Sublingual, oral, transdermal, buccal
(IV preparations : Sodium nitroprusside (SNP), used in
surgeries - potential risk of cyanide toxicity)
• Onset and duration
(dependent on route of administration)
• Effective for treating or preventing effort (stable),
variant and unstable angina
• Side effects:
reflex tachycardia, hypotension
tolerance develops after 24 hours continuous use
(prevented by 8-12h nitrate-free interval)
Isosorbide dinitrate (mononitrate)
•Sublingual, oral
•Onset and duration
(dependent on route of administration)
(slower than nitroglycerin)
•Tx or prevent angina
•Reflex tachycardia, hypotension
•Tolerance develops
All the nitrates preferentially dilate large veins
 preload   cardiac work and O2 demand
Vasodilation via release of NO from endothelial cells
Tolerance may be due to development of mitochondrial
reactive oxygen species (ROS), which can inactivate nitrate
reductase, resulting in inhibition of NO vasodilatory effects
Proposed mechanism for preferential effects on venous side
(compared to arterial side), regarding potency
Preferential venodilation may be
due to:
•Duration of exposure diminishes
response (tolerance)
•Less endogenous NO in the veins
(therefore veins more responsive
than arteries)
Kojda et al. Mol Pharm 53:547-554, 1998
Isosorbide mononitrate is the active metabolite
Brenner Fig 11-4
Avoid using nitrates
and Viagra
Brenner Fig 11-3
Calcium Channel Blockers (Antagonists)
• Inhibit inward calcium flux (through L-type channels)
– Decrease myocardial and vascular smooth muscle
contraction
– Slow AV conduction and SA rate
• Decrease afterload, contractility, heart rate, and
improve myocardial blood flow
• Agents differ in these activities
• No adverse effects on lipid profiles
(whereas B-blockers have adverse effects)
Indications for Calcium Channel Blockers
• Useful in stable and variant/vasospastic angina
(not unstable angina)
• Used to manage (prevent) angina (not treat attack)
• Effort angina refractory to beta-blockers
• Patients intolerant to beta-blockers and nitrates
• Useful for 24 hour protection (vs nitrates)
• “add on”, not monotherapy
Ca2+ channel blockers
Site of action dependent on tissue selectivity
•Verapamil
most cardiac selective (nodal cells and myocytes)
•Diltiazem
intermediate selectivity (SA node and vascular)
•Dihydropyridines (DHPs)
most vascular selective
All have coronary vasodilatory effects (improve blood flow)
DHPs
Predominantly cause vasodilation:
peripherally  reduce TPR (~afterload) and cardiac work
coronary vasodilation  increase blood flow
Amlodipine
Long acting duration (days), T1/2 ~40hrs
No effects on HR, nodal conduction, myocardial contractility
Reflex tachycardia, arrhythmias
Why?
Nifedipine*
Short acting duration (hours), T1/2 ~3hrs
*ultra-short acting nifedipine may precipitate failure
May depress myocardial contractility a little
Reflex tachycardia, arrhythmias
Verapamil and Diltiazem
Duration (hours)
Undergo significant first-pass hepatic metabolism
Used for stable or variant angina
(also used for certain arrhythmias)
Usually contraindicated for ventricular dysfunction
particularly verapamil (e.g., heart failure)
Decreases cardiac work  O2 demand
Verapamil
Slows A-V conduction and decreases myocardial contractility
Diltiazem
More selective for SA nodal cells than AV
Toxicities are extensions of their therapeutic effects
Choice of Tx in Chronic Stable Angina
• ASA, lipid therapy (target LDL = <100mg/dL), ACEI
• Short-acting NTG
• Beta-blockers
– Reduce mortality post-MI and in HTN
• Calcium channel blockers (except rapid release
nifedipine – b/c reflex tachycardia)
– Rapid release forms may increase morbidity
– May be preferred over long-acting nitrates (lack of
tolerance)
• Long-acting Nitrates
– No effect on mortality with MI or CAD
– Tolerance
• Combination therapy before declaration of treatment
failure
Circulation 2003,107:149
Important Drug Interactions with Ca2+ Blockers
• CYP 3A4 inhibitors (e.g., grapefruit juice) and
amlodipine/felodipine
– These DHPs are normally extensively metabolized
• Amlodipine, verapamil, diltiazem and
cyclosporin
– Decreased cyclosporin metabolism with blockers
• Verapamil and digoxin (cardiac glycoside)
– Both slow A-V conduction (don’t combine them)
• Verapamil and -blockers (don’t combine)
– Too much cardiodepression
-BLOCKERS IN ANGINA
• Used to manage typical angina
not effective for variant angina
• Cardiac work (HR and SV)  O2 demand
• May improve O2 delivery by prolonging diastole (HR)
• Long-term BP because of renin release (via 1 blocking)
Other indications:
• Use immediately after acute MI (improves survival)
• Heart failure patients may benefit because of
reduced myocardial ‘remodeling’
• Also used for certain arrhythmias, hypertension
-Adrenergic Receptor Blockers
Non-selective: 1-, 2-blocker
propranolol
pindolol (partial agonist (ISA))
rarely used ever, not indicated for angina
Selective:
1-blocker
metoprolol, atenolol
1-, 2- and 1- blockers: (discussed later)
carvedilol, labetalol
some indications for angina (not yet FDA
approved) and HF
• All -blockers are competitive inhibitors
• Vary in lipophilicity, bioavailability, metabolism
(i.e., pharmokinetics)
• Some have unfavorable effects on lipids
• Clinical problems with abrupt withdrawal because of
receptor up-regulation - make more receptors/low
concentration
• Contraindications/precautions with
Significant AV block, severe unstable LV failure, HR<50,
SBP<90, asthma
Less effective in blacks, use with caution in elderly (may CO too
much), Asians may be more sensitive (may need to lower dose)
more lipophilic
Opie Fig 1-10, 1997
more hydrophilic
Propranolol
• Non-selective
blocks both 1-AR and 2 –AR
• Duration (hours) – same as metoprolol, shorter than atenolol
• Low bioavailability because of 1st pass hepatic metabolism
(highly lipid soluble)
• MSA (membrane stabilizing activity) local anesthetic effects
Side effects include:
Slight TPR (sympathetic reflex), -AR intact
•  Bronchconstriction (via 2 blocking)
•  Renal blood flow (because CO) therefore,
Na+, H2O retention (may need to add a diuretic)
• May prevent response to hypoglycemia (via 2 blocking) and
mask symptoms of hypoglycemia (e.g., tachycardia, sweating)
care with diabetics (especially type 1)
• May alter serum lipid levels ( VLDL and  HDL)
Side effects also include drowsiness. Why?
Metoprolol & Atenolol
•
•
•
•
Both selective 1-AR blockers = “cardioselective”
Avoid bronchospasms
Avoid masking hypoglycemia
Both (-)renin (good effect),
but may also  renal blood flow via CO (like propranolol),
therefore may need to add diuretic
Metoprolol
• Duration (hours) – similar to propranolol
• Higher bioavailability and slightly less lipophilic than propranolol
• Indicated for heart failure (MERIT-HF study)
Atenolol
• Much less lipophilic, therefore
Less CNS effects (e.g., drowsiness)
but may not have cardioprotective effects like metoprolol
• Longer durations of action (longer half-live)
Strategies for Combination Therapy
Nitrates & -blockers
nitrates reduce venous return (preload)
-blockers prevent sympathetic reflex
(decrease HR and cardiac work)
DHPs & -blockers
DHPs reduce TPR
-blockers prevent sympathetic reflex
Nitrates & DHPs (maybe diltiazem)
nitrates reduce preload
Ca2+ channel blockers reduce TPR (afterload)
Nitrates, -blockers & DHPs
nitrates reduce preload
Ca2+ channel blockers reduce TPR
-blockers prevent sympathetic reflex
atherosclerosis diabetes
(STEMI)
(UA/NSTEMI)
antiplatelet drugs
(inhibit platelet aggregation)
Antiplatelet and
thrombolytic drugs
covered in heme.
From Golan et al. Principles of pharmacology: The pathophysiologic basis of drug therapy 2008
Note:
In addition to aspirin:
Clopidogrel or glycoprotein IIb-IIIa antagonists
(antiplatelet agents) is recommended for acute coronary
syndromes and subsequent to percutaneous coronary
intervention
New drug for stable angina:
Ranolazine (ra noe' la zeen)
used in combination with nitrate, BB or CCB
(symptom prevention, not relief)
mechanism in question
(probably a late sodium channel blocker)
Medical Letter June 2006; Circulation 2006; 113:2462-2472
Choice of Tx in Chronic Stable Angina
• ASA, lipid therapy (target LDL = <100mg/dL), ACEI
• Short-acting NTG
• Beta-blockers
– Reduce mortality post-MI and in HTN
• Calcium channel blockers (except rapid release
nifedipine)
– Rapid release forms may increase morbidity
– May be preferred over long-acting nitrates (lack of
tolerance)
• Long-acting Nitrates
– No effect on mortality with MI or CAD
– Tolerance
• Combination therapy before declaration of treatment
failure
Circulation 2003,107:149
AHA/ACC Guidelines for Secondary Prevention
for Patients with Coronary and Other
Atherosclerotic Vascular Disease: 2006 Update
Circulation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139
Components of Secondary Prevention
Cigarette smoking cessation
Blood pressure control
Lipid management to goal
Physical activity
Weight management to goal
Diabetes management to goal
Antiplatelet agents / anticoagulants
Renin angiotensin aldosterone system blockers
Beta blockers
Influenza vaccination
Guidelines are available on the Web sites of the AHA (www.americanheart.org) and the ACC
(www.acc.org)
Lipid-lowering Therapy
(discussed later)
• Goal = LDL <100mg/dL; perhaps as low as 70
• Diet/exercise
• HMG CoA reductase inhibitors (statins):
atorvastatin, lovastatin, pravastatin, simvastatin
– Interfere with hepatic cholesterol production
– Stabilize, lead to regression of coronary atherosclerotic
plaques
– Anti-inflammatory
– Treating osteoporosis
• 20-30% reduction in mortality and coronary events
(Treatment Guidelines – Medical Records February 2008)