Department of Clinical Pharmacology

Pharmacotherapy
of chronic ischemic heart
disease

Jerzy Jankowski, MD
www.zfk.ump.edu.pl

www.ump.edu.pl/eng
 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 near-
normal 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

• HEART – RATE LIMITING 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
 ORGANIC NITRATES
 NTG, ISDN, IS-5-MN
 Donors of NO in vascular smooth muscle cells
 Induce cross-tolerance when given in large doses
 All are highly lipophylic
 The lipophility (depending on the stereochemical
configuration and the number of ONO2-groups) affects
the degree of activation of guanylate cyclase, of the NO-
release and of a rapid onset of efficacy (NTG > ISDN >
IS-5-MN)
 Due to a slow denitration IS-5-MN maintaines the effects
for hours
 ORGANIC NITRATES

 The higher the lipophylity of a nitrate, the

higher the velocity of its uptake in different
tissues
( NTG > ISDN > IS-5-MN ), particularly in the
smooth muscle cells of blood vessels

 Nitrates are acting via the release of NO – they

need intracellular SH-groups to form NO
 PHARMACOKINETICS
CHARACTERISTICS

• AFTER ORAL ADMINISTRATION

• EXTENSIVE FIRST-PASS EFFECT (90%)
• LOW BIOAVAILABILITY (10%)

• AFTER SUBLINGUAL ADMINISTRATION

• RAPID ONSET OF ACTION (1-3 min)
• BRIEF DURATION OF ACTION (up to 30 min)
 MECHANISM OF ANTIANGINAL
ACTION OF NITRATES
 DECREASED MYOCARDIAL O2 CONSUMPTION
- decreased LV dimension
- decreased LV filling pressure
- decreased LV systolic pressure
- decreased vascular impedence

 INCREASED CORONARY BLOOD SUPPLAY

- epicardial coronary artery dilation
- coronary stenosis enlargement
- dilation of coronary collaterals

 ANTIPLATELET ANTITHROMBOTIC ACTION

 UNDESIRABLE EFFECTS OF
NITRATES

 INCREASED MYOCARDIAL O2 DEMAND

- reflex tachycardia
- reflex increase in contractility

 DECREASED MYOCARDIAL PERFUSION

- decreased diastolic perfusion time
due to tachycardia
 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

 MECHANISMS OF NITRATE
TOLERANCE

 BIOCHEMICAL TOLERANCE = CELLULAR

- exhaustion of the cysteine (SH) store
- decreased sensivity of guanylate cyclase

 PSEUDO-TOLERANCE = ACTIVATION OF
NEUROHUMORAL MECHANISMS
- increased sympathetic activity
- increased ACE activity
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
 EXCRETION OF NITRATES

 Primarily in the form of glucuronide derivatives

of the denitrated metabolites

 Largely by way of the kidney

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
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
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
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 CHANNEL-
BLOCKING DRUGS
 PHARMACOLOGIC EFFECTS OF
CALCIUM CHANNEL BLOCKERS
VER DIL DHPS
HR ↓ ↓ ↑↔
A-V CONDUCTION ↓↓↓ ↓ ↔
CONTRACTILITY ↓↓ ↓ ↓↔
PERIPHERAL
VASODILATION ↑ ↑ ↑↑
CO v v v
CBF ↑ ↑ ↑
MO2 DEMAND ↓ ↓ ↓

↑INCREASE; ↓ DECREASE; v VARIABLE;

A. Adverse cardiovascular effects of calcium channel
antagonists
SYMPTOM CAUSE IMPLICATED CALCIUM
CHANNEL ANTAGONIST
Dizziness, light-headedness, syncope, Excessive hypotension All
palpitation
Bradycardia Verapamil, diltiazem

Reflex tachycardia Dihydropyridines

Exacerbation or precipitation of Negative inotropic Most; amlodipine, felodipine are the

congestive heart failure
Severe bradycardia or heart block
Precipitation of angina
action safest to use, even in heart failure
Negative chronotropic Verapamil, diltiazem
action, especially sick
sinus node disease
Hypotension, coronary Nifedipine and possibly other
steal 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

Constipation Common Rare Rare

Other gastrointestinal Rare Rare Rare

disorders
Paresthesias Rare Rare Occasional
 METABOLIC DRUGS

METABOLIC INHIBITORS WITH CARDIO-

CYTOPROTECTIVE EFFECT

RANOLAZINE (RANEXA 375mg, 500mg, 750mg)

TRIMETAZIDINE (PREDUCTAL MR 35mg)

 TRIMETAZIDINE

• 3 - ketoacylo – CoA thiolase inhibitor

• In cells exposed to ischaemia, the drug:

- prevents a decrease in intracellular ATP levels
- reduces intracellular acidosis
- alterations in transmembrane ion flow
- decreases the migration and infiltration of PNN
 TRIMETAZIDINE

 In man the drug:

- increases coronary flow reserve
- limits rapid swings in blood pressure
- decreases the frequency of angina attacks
- decreases the use of NTG
 PK OF TRIMETAZIDINE

 Well absorbed with Cmax, on average, 5 hours

after taking the tablet

 Protein binding is low

 Eliminated primarily in the urine, mainly in the

unchanged form; T1/2 7 hours
 TRIMETAZIDINE

 Side effects:
- gastrointestinal (dyspepsia, diarrhoea, nausea,
vomiting, constipation)
- nervous system (headaches, vertigo, sleep disorders)
aggravation of Parkinsonian symptoms
- cardiovascular (orthostatic hypotension)
- skin disorders
 Special warnings: pregnancy and breastfeedindg
 RANOLAZINE ( R )

 Inhibitor of the late Na+ current (late INa)

 Inhibitor of the fast rectifying K+ current (IKr)
 Reduces Ca++ overload in the ischemic myocyte
 Does not affect Na+- H+ and Na+- Ca++exchangers
 Antianginal effect related to decreased LV diastolic
tension and improved myocardial perfusion
 PHARMACOKINETICS OF R
 Sustained – release form
 Prolonged absorption with Cmax 4 – 6 h after oral
administration
 Bioavailability 30% - 55%
 Plasma protein binding ~ 62%
 T1/2 ~ 7h
 Steady state within 3 days
RANOLAZINE METABOLISM
 CYP 3A4 – the major pathway
 Additional pathways include:
- CYP 2D6 (10% - 15%)
- glucuronidation (< 5%)
 ~ 5% excreted unchanged
 Weak inhibitor of CYP 3A4 and CYP 2D6
 Inhibitors of CYPs 3A4 and 2D6 increase plasma R
concentration 2 – 4 fold
 Clearance of R is reduced by renal insufficiency and
moderate hepatic impairment
 DRUG – DRUG INTERACTION
 Inhibitors of CYP 3A4 (itraconazole, ketokonazole,
voriconazole, HIV protease inhibitors, clarithromycin,
verapamil, diltiazem, erythromycin, fluconazole grapefruit
juice
 Inhibitors of CYP 2D6 (paroxetine)
 Inhibitors of P-gp (cyclosporin, verapamil)

INCREASED EXPOSURE TO RANOZALINE

DRUG-DRUG INTERACTION

 CYP 2D6 inducers (rifampicin, phenytoin,

phenobarbital, carbamazepine, St. John’s Wort)

DECREASED EXPOSURE TO RANOZALINE

ADVERSE DRUG REACTIONS

 Mild to moderate in severity

 Common ADRs: dizziness, headache,
constipatin, vomiting, nausea,
 ECG effects: ↑QTc, ↓T wave amplitude, T wave
notching
 CONTRAINDICATIONS
 Hypersensitivity to the drug
 Severe renal impairment (CrC < 30ml/min)
 Moderate or severe hepatic impairment
 Co-administration of potent CYP 3A4
inhibitors
 LQTS
 Co-administration QT-prolonging drugs
(quinidine, dofetilide, sotalol)
 HEART-RATE LOWERING
DRUGS

 Ivabradin (Procoralan 5 mg, 7,5 mg tablets)

 Selective and specific inhibitor of If current that

controls the spontaneous diastolic depolarisation
in the sinus node

 Dose-dependent reduction in heart rate and MO2

 INDICATIONS
 Symptomatic treatment of chronic stable angina
pectoris with normal sinus rhythm:
- in adults unable to tolerate or with a contra-
indication to the use of beta-blockers
- or in combination with beta-blockers in pts
inadequately controlled with an optimal beta-
blocker dose and whose rate is > 60 bpm
 Treatment of chronic heart failure
 PHARMACOKINETICS

 S-enantiomer, highly water-soluble

 Rapidly and completely absorbed from the gut
 C max after 1 hour under fasting condition
 Food delays absorption by 1 h and increases
plasma contrentation by 20 to 30%
 Plasma protein bounding 70%
 Half-life 11 hours
 BIOTRANSFORMATION
 Metabolised by CYP 3A4 only
 Active metabolite – N-desmethlated derivative
 Very low affinity for CYP 3A4
 CYP 3A4 inhibitors and inducers influence its
metabolism and pharmacokinetics
 Treatment including potent CYP 3A4 inhibitors
as azole antifungals, macrolide antibiotics, HIV
protease inhibitors, nefazodone is contraindicated
 BIOTRANSFORMATION

 the combination of ivabradine with moderate CYP

3A4 inhibitors (diltiazem, verapamil) is not
recommended

 CYP 3A4 inducers (rifampicin, barbiturates,

phenytoin, St John,s Wort) may decrease ivabradine
exposure and activity
 CONTRAINDICATIONS
 Hypersensitivity to the active substance
 Resting heart rate below 60 bpm prior to treatment
 Acs, cardiogenic shock, severe hypotension
 Severe hepatic insufficiency
 Sick sinus syndrom, sino-atrial block
 A-V block of 3rd degree
 Combination with strong CYP 3A4 inhibitors
 Pregnancy, lactation
 UNDESIRABLE EFFECTS

 Headache
 Dizziness
 Bradycardia – 3,3%
 Luminous phenomena (phosphenes) – 14,5%
 Uncontrolled blood pressure
Combinations of antianginal drugs
COMBINATION BENEFICIAL SHOULD BE
AVOIDED OR IS
RELATIVELY
CONTRAINDICATED
Nitrates + b-blocker X
Nitrates + diltiazem, X
verapamil
Nitrates + dihydropyridine X
b-blockers + dihydropyridine X
b-blockers + diltiazem, X
verapamil
 Thienopyridines
 Ticlopidine (2 x 250 mg)
 Clopidogrel (1 x 75 mg)
 P2Y12 adenosine diphosphate receptor blocker
 For 1 year after NSTEMI, STEMI, PCI + DES
 GASTROINTESTINAL RISKS OF
ANTIPLATELET THERAPY

 ASA causes topical injury to the mucosa and

systemic effects induced by prostaglandin depletion
 Tissue PGs are produced via 2 pathways: COX-1
and COX-2 pathway
 Clopidogrel – impairs the healing of gastric ulcers
by inhibiting platelet release of pro-angiogenic
growth factors ( VEGF ) which promotes
endothelial proliferation and accelerates the healing
of ulcers
 GASTROINTESTINAL RISKS OF
ANTIPLATELET THERAPY

 Recommendation: the use of low-dose ASA for

cardioprophylaxis is associated with a 2-4 – fold
increase in UGIE. Enteric-coated preparations do
not reduce the risk of bleeding. For patients at risk
of adverse events, gastroprotection should be
prescribed. The risk of UGIE increases with dose
of ASA; thus, doses greater than 81mg should not
be prescribed
 GASTROINTESTINAL RISKS OF
ANTIPLATELET THERAPY
 Recommendation: substitution of clopidogrel for
ASA is not recommended strategy to reduce the risk
of recurrent ulcer bleeding in high-risk patients and is
inferior to the combination of ASA plus PPI

 Recommendation: when warfarin is added to ASA

plus clopidogrel an INR of 2,0 to 2,5 is recommended

 Recommendation: PPIs are the preferred agents for

the therapy and prophylaxis of ASA-associated UGIE
 GASTROINTESTINAL RISKS OF
ANTIPLATELET THERAPY
 Esomeprazol and pantoprazol are preferred PPIs
in patients treated with clopidogrel
 Omeprazol is not recommended due to a risk of
significant interaction with clopidogrel
 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
LIPID-LOWERING THERAPY
 Statins – HMG-CoA reductase inhibitors

Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin

 Significant LDL reduction, relatively small reduction in TG,

minor increas in HDL

 Lower is better ( LDL < 70 mg%)

 Fibrates – fenofibrate (↑ HDL)

 Ezetimib (Ezetrol 10mg)

 STATINS
 Natural (fungal fermentation): lovastatin,
simvastatin, pravastatin
 Synthetic: fluvastatin, atorvastatin, rosuvastatin
 Metabolized by CYP 3A4: lovastatin, simvastatin,
atorvastatin
 CYP 2C9 for fluvastatin
 Pravastatin does not use CYP P450
 Hydrophilic statins: pravastatin, fluvastatin
 ADVERSE EFFECTS OF STATINS
 All statins are well tolerated
 Most common ADRs are mild, transient, reversible –
dyspepsia, abdominal pain, flatulence
 The most important ADRs are liver toxicity (↑ ATs) and
myopathy ( pain, weakness, ↑CK ≥ 10 X)
 Rhabdomyolysis and acute renal failure – very rare
 Risk of muscle toxicity increases during therapy with
cyclosporine, erythromycin, clarithromycin, azole
antifungals, protease inhibitors – CYP 3A4 inhibitors
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 mg

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