Slajd 1

Report
Department of Clinical Pharmacology
Pharmacotherapy
of chronic ischemic heart
disease
Jerzy Jankowski, MD
FORMS OF ANGINA PECTORIS
(AP)
•
ATHEROSCLEROTIC (CLASSIC)
ANGINA
•
VARIANT (VASOSPASTIC ANGINA)
Anginal conditions other than CAD causing chest discomfort
Non-CAD causes of chest discomfort
Syndrome X: Chest pain syndrome with objective evidence of
ischemia and normal coronary arteries on angiography
Prinzmetals angina: Vasospastic angina with normal or nearnormal coronary arteries; can have Prinzmetals angina with
significant CAD
Aortic stenosis: Myocardial ischemia can be caused by an
imbalance between the increased myocardial oxygen demand related
to left ventricular hypertrophy and increased wall stress and the
available coronary blood supply in the absence of coronary
atherosclerosis
Esophageal disease: Esophagitis, reflux, motility disorders
ANTIANGINAL DRUGS
•
ORGANIC NITRATES
•
ΒETA- ADRENORECEPTOR- BLOCKING
DRUGS
•
CALCIUM CHANNEL- BLOCKING DRUGS
•
METABOLIC AGENTS
DRUG ACTION IN ANGINA
• DECREASE MYOCARDIAL O2 REQUIREMENT BY:
decreasing peripheral vascular resitance
decreasing cardiac output
both ways
• INCREASE MYOCARDIAL O2 DELIVERY
nitrates
calcium channel antagonists
ORGANIC NITRATES
PHARMACOKINETICS
CHARACTERISTICS
•
EXTENSIVE FIRST-PASS EFFECT (90%)
•
LOW BIOAVAILABILITY (10%)
•
RAPID ONSET OF ACTION (1-3 min)
•
BRIEF DURATION OF ACTION (up to 30 min)
Adverse effects of nitrates
EFFECT
OCCURRENCE
Headache
Common
Nausea and vomiting
Occasional
Dizziness or overt syncope
Occasional
Palpitations and tachycardia
Uncommon
Tolerance and attenuation
Common
Avoidance of nitrate tolerance
Use smallest effective dose
Administer the fewest possible doses per
day
Avoid continuous or sustained exposure to
nitrates
Provide a nitrate-free interval of ≥10 h
every day
BETA-ADRENORECEPTOR
BLOCKING DRUGS
MAJOR DIFFERENCES AMONG
BBs
•
ISA
•
Beta-receptor selectivity
Cardioselective
Nonselective
•
Local anesthetic action
•
Pharmacokinetic characteristics
Beta-blockers with ISA






Acebutolol
Cartreolol
Celiprolol
Oxprenolol
Penbutolol
pindolol
Cardioselective beta-blokckers






Acebutolol
Atenolol
Betaxolol
Bisoprolol
Celiprolol
Metoprolol
Non-selective beta-blockers







Labetalol
Nadolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Generations of beta-blockers



I generation: non-selective BBs
II generation: cardioselective BBs
III generation: beta-blockers (non-selective or
cardioselectve BBs) with vasodilator activity:
carvedilol, celiprolol, nebivolol
Local anesthetic action






Acebutolol
Betaxolol (slight)
Labetalol
Metoprolol
Pindolol
Propranolol
Pharmacokinetic differences


Lipid solubility: penbutolol, propranolol
labetalol, metoprolol, pindolol,
timolol
low lipid solubility: acebutolol, atenolol,
betaxolol, bisoprolol, esmolol, nadolol, sotalol
Mechanism of action in angina and
cardiovascular effects of -blocking agents
Decreased myocardial oxygen consumption
Decreased heart rate
Decreased blood pressure
Decreased myocardial contractility
Increased coronary blood supply
Preserved coronary blood flow because of
prolonged diastole
A. Solubility characteristics of -blocking agents
Hydrophilicity
Lack of hepatic first-pass effect lowers the chance
of drug interactions and food interference
Often results in longer half-life
Low penetrability into CNS, resulting in fewer side
effects
Lipophilicity
Requires hepatic metabolism
Greater chance of significant first-pass effect
Often results in shorter half-life
Higher penetrability into the CNS
Adverse effects of -blocking agents
Cardiac
Increased ventricular volume resulting in congestive heart failure
Excessive heart rate slowing or heart block
Withdrawal syndrome
Noncardiac
Fatigue
Mental depression
Insomnia
Nightmare
Raynauds phenomenon
Worsened claudication symptoms
Bronchoconstriction
Metabolic
Increased LDL cholesterol and triglycerides; lowered HDL cholesterol
Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms
Increased blood sugar in insulin-resistant diabetics
CALCIUM CHANNELBLOCKING DRUGS
PHARMACOLOGIC EFFECTS OF
CALCIUM CHANNEL BLOCKERS
HR
A-V CONDUCTION
CONTRACTILITY
PERIPHERAL
VASODILATION
CO
CBF
MO2 DEMAND
VER
↓
↓↓↓
↓↓
↑
v
↑
↓
DIL DHPS
↓
↑↔
↓
↔
↓
↓↔
↑
v
↑
↓
↑↑
v
↑
↓
↑INCREASE; ↓ DECREASE; v VARIABLE;
A. Adverse cardiovascular effects of calcium channel
antagonists
SYMPTOM
CAUSE
Dizziness, light-headedness, syncope, Excessive hypotension
palpitation
IMPLICATED CALCIUM
CHANNEL ANTAGONIST
All
Bradycardia
Verapamil, diltiazem
Reflex tachycardia
Dihydropyridines
Exacerbation or precipitation of
congestive heart failure
Negative inotropic
action
Most; amlodipine, felodipine are the
safest to use, even in heart failure
Severe bradycardia or heart block
Negative chronotropic
action, especially sick
sinus node disease
Verapamil, diltiazem
Precipitation of angina
Hypotension, coronary
steal
Nifedipine and possibly other
dihydropyridines
B. Noncardiac Side Effects Associated with Calcium
Channel Blockers
SYMPTOM
VERAPAMIL
DILTIAZEM
NIFEDIPINE
Headache
Rare
Rare
Occasional
Postural dizziness
Rare
Rare
Common
Flushing
Rare
Rare
Common
Peripheral edema
Rare
Rare
Common
Common
Rare
Rare
Other gastrointestinal
disorders
Rare
Rare
Rare
Paresthesias
Rare
Rare
Occasional
Constipation
METABOLIC DRUGS
•
METABOLIC INHIBITORS WITH CARDIOCYTOPROTECTIVE EFFECT
•
RANOLAZINE
•
TRIMETAZIDINE (PREDUCTAL MR 35mg)
•
3-KETOACYLO-CoA THIOLASE INHIBITOR
Combinations of antianginal drugs
COMBINATION
BENEFICIAL
Nitrates + b-blocker
X
Nitrates + diltiazem,
verapamil
X
Nitrates + dihydropyridine
b-blockers + dihydropyridine
b-blockers + diltiazem,
verapamil
SHOULD BE
AVOIDED OR IS
RELATIVELY
CONTRAINDICATED
X
X
X
Thienopyridines




Ticlopidine (2 x 250 mg)
Clopidogrel (1 x 75 mg)
P2Y12 adenosine diphosphate receptor blocker
For 1 year after NSTEMI, PCI + DES
EUROPA TRIAL
EUropean trial on Reduction
Of cardiac evens with
Perindopril in stable coronary
Artery disease
• Randomized, placebo controled, duble blind study
• 4 years follow-up
• 12218 patients at low risk; perindopril 8 mg vs
placebo
EUROPA TRIAL - RESULTS
• The primary end-point ( cardiovascular death +
nonfatal MI + non fatal cardiac arrest ) ↓ 20%
• Risk of MI ( fatal + nonfatal )
↓ 24%
• Hospitalisation for HF
↓ 39%
PERTINENT TRIAL
PERindopril, Thrombosis, INflammation,
Endothelial dysfunction and Neurohormonal
activaTion
•
•
•
•
•
•
•
Rate of apoptosis of EC
Activity and expression of NOS
Proapoptotic protein Bax
Antiapoptotic protein Bcl-2
Von Willebrand factor
Levels of AT II, bradykinin, TNF
Assesment at baseline and after 1 year of treatment
PERTINENT TRIAL - RESULTS
One year of treatment with perindopril
was able significantly reduce the rate of
apoptosis and increase the activity and
expression of NOS
Major purposes of the treatment

To improve short and long term prognosis by
preventing MI and death and thereby increase
the length of life

To improve quality of life by reducing
symptoms of angina and occurrence of
ischemia
Recommendations for
Pharmacotherapy To Prevent MI and
Death and To Reduce Symptoms
The following agents should be used in patients with
symptomatic chronic stable angina to prevent MI or death
and to reduce symptoms:




Aspirin (level of evidence: A) or clopidogrel when aspirin
is absolutely contraindicated (level of evidence: B)
ß-Blockers in patients with previous MI (level of evidence:
A) or without previous MI (level of evidence: B)
Low-density lipoprotein cholesterol–lowering therapy with
a statin (level of evidence: A)
ACE inhibitor (level of evidence: A)
Recommendations for
Pharmacotherapy To Prevent MI and
Death and To Reduce Symptoms
The following agents should be used in patients with
symptomatic chronic stable angina to reduce symptoms
only:



Sublingual nitroglycerin or nitroglycerin spray for the
immediate relief of angina (level of evidence: B)
Calcium antagonists (long-acting) or long-acting nitrates
when ß-blockers are clearly contraindicated (level of
evidence: B)
Calcium antagonists (long-acting) or long-acting nitrates
in combination with ß-blockers when ß-blockers alone are
unsuccessful (level of evidence: B).
TREATMENT OF STABLE ANGINA
ACCORDINGLY TO CCS
CLASSIFICATION
CLASS I correction of risk factors, nitroglycerin
sl
aspirin 75-150mg
CLASS II as above+ chronic therapy with
LA nitrates or
ß1-blockers or
LA Calcium antagonists or
Trimetazidine or
combination of these drugs
TREATMENT OF STABLE ANGINA
ACCORDINGLY TO CCS
CLASSIFICATION
CLASS III and IV
As above and
establish indications for invasive treatment

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